stability study

Paper910101 chap4,8 Basic concepts

1

Stability:-

basic concepts and

objectives

DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY

L.M.COLLEGE OF PHARMACY AHMEDABAD-09

GUIDED BY:

Dr. R.K.PARIKH PRESENTED BY:

KALPESH G. VYAS

M.PHARM -1

YEAR-2009-10

ROLL NO-10

Paper 910101 stability basic concepts & objectives

M.Pharm-І-2009-10 KALPESH


L.M.COLLEGE OF PHARMACY, AHMEDABAD-09

ESSENTIAL DEFINITIONS ACCORDING TO ICH

STABILITY

STABILITY is officially defined as the time lapse(period) during which drug

substance (API) or drug product (FPP) to retains the same properties and

characteristics(i.e. Physical, Chemical, Microbiological, Therapeutic and

Toxicological specifications to maintain its identity, strength, quality, and purity

) that it possessed at the time of manufacture.

ACCELERATED STABILITY TESTING

These are the studies designed to increase the rate of chemical degradation and

physical change of a drug by using exaggerated storage conditions as part of the

formal stability testing programme. The data thus obtained, in addition to those

derived from real – time stability studies, may be used to assess longer – term

chemical effects under non-accelerated conditions and to evaluate the impact of

short-term excursions outside the label storage conditions, as might occur

during shipping. The results of accelerated testing studies are not always

predictive of physical changes.

LONG-TERM STABILITY STUDIES

Experiments on the physical, chemical, biological, biopharmaceutical and

microbiological characteristics of an API or FPP, during and beyond the

expected shelf-life and storage periods of samples under the storage conditions

expected in the intended market. The results are used to establish the re-test

period or the shelf-life, to confirm the projected re-test period and shelf-life, and

to recommend storage conditions.

ONGOING STABILITY STUDY

The study carried out by the manufacturer on production batches according to a

predetermined schedule in order to monitor, confirm and extend the projected

re-test period (or shelf-life) of the API, or confirm or extend the shelf-life of the

FPP.

STRESS TESTING–FORCED DEGRADATION (API)

Studies undertaken to elucidate the intrinsic stability of the API. Such testing is

part of the development strategy and is normally carried out under more severe

conditions than those used for accelerated testing.

To identify potential degradants (degradation pathways) of the API and assess

if they can be formed during mfg. or storage of the FPP (Finished

Pharmaceutical Product )





STRESS TESTING–FORCED DEGRADATION (FPP)

Studies undertaken to assess the effect of severe conditions on the FPP. Such

studies include photostability testing (see ICH Q1B) and compatibility testing

on APIs with each other in FDCs and API(s) with excipients during formulation

development.

MEAN KINETIC TEMPERATURE (MKT):

MKT, as defined by the USP, is a “single calculated temperature at which the

total amount of degradation over a particular period is equal to the sum of the

individual degradations that would occur at various temperatures”

RE-TEST PERIOD

The period of time during which the API should be examined to ensure that the

material is still in compliance with the specification and, thus suitable for use in

the manufacture of a given FPP,when stored under the defined conditions.

SHELF LIFE ( Expiration dating period, conformance period):

The time period during which an API or a FPP is expected to remain within the

approved shelf-life specification, if stored under recommended conditions.

SPECIFICATION - RELEASE

The combination of physical, chemical, biological, and microbiological tests

and acceptance criteria that determine the suitability of a drug product at the

time of its release.

SPECIFICATION - SHELF LIFE

The combination of physical, chemical, biological, and microbiological tests

and acceptance criteria that determine the suitability of an API throughout its re-

test period, or that an FPP should meet throughout its shelf life.

PRIMARY BATCH (called also exhibit batch)

A batch of an API or FPP used in a formal stability study, from which stability

data are submitted in a registration application for the purpose of establishing a

re-test period or shelf life, respectively. A primary batch of an API should be at

least a pilot scale batch. For a FPP, two of the three batches should be at least

pilot scale batch, and the third batch a production batch.

PRODUCTION (SCALE) BATCH

A batch of an API or FPP manufactured at production scale by using production

equipment in a production facility as specified in the application.





SUPPORTING DATA

Data, other than those from formal stability studies, that support the analytical

procedures, the proposed re-test period or shelf life, and the label storage

statements. Such data include (1) stability data on early synthetic route batches

of API, small-scale batches of materials, investigational formulations not

proposed for marketing, related formulations, and product presented in

containers and closures other than those proposed for marketing; (2)

information regarding test results on containers; and (3) other scientific

rationales.

TYPES OF STABILITY

Mainly Five types of Stability are generally recognized

Type of

Stability

Condition Maintained throughout the shelf life of drug

product

Chemical Each active ingredient retains its chemical integrity and

labeled potency within the specified limit

Physical The original Physical properties including appearance

palatability, uniformity, dissolution and suspendability are

retained.

Microbiological Sterility or resistance to microbial growth is retained

according to specified requirement.

Therapeutic Therapeutic effect remains unchanged

Toxicological No significant increase in toxicity occurs

What happens due to Instability ?

1) Increse in the concentration of API :-

For some products, loss of vehicle, can result in an increase in the concentration

of active drug.

For example, Some lidocaine gels exhibit this behaviour, perfusion bags

sometimes allow solvent to escape and evaporate so that the product within the

bags show an increase in the concentration.

2) Loss of content uniformity :-





Suspensions are the drug delivery system most likely to show a loss of content

uniformity as a function of time. For such systems, determination of ease of

redispersion or sedimentation volume may be included in a stability protocol.

3) Decline of microbiological status :-

The microbiological status of a pharmaceutical product can change significantly

with time . First, micro – organisms present in the product at the time of

manufacture may reproduce and thus increase the number of viable micro-

organisms.

Drug assayed for the bioburden at the time of manufacture , is within limits ,ay

when tested after say 6 months storage, exceed the maximum permitted limits.

4) Formation of toxic degradation products :-

If a drug degrades to a molecular species that is toxic, there must be a special

attention given to the quantity of such products. E.g. Conversion of p-amino

salicylic acid to p-amino phenol (Toxic).

OBJECTIVES OF STABILITY TESTING:-

(1) Our concerns for patients’ welfare :-

Obviously , our primary reason for stability testing should be our concern for

the well-being of the patients who will use our products. Sometimes in the

mad rush to comply with other requirements, this important fundamental may

be discounted or forgotten .Indeed , sometimes one gains the impression that

is some quarters stability is regarded as having clinical revelance. Certainly ,

if a product that does not degrade to toxic decomposition products and that is

characterized by a narrow therapeutic ratio is present on the market at only

85% of label claim , one would not expect patients to be dropping dead in

the streets because of this deficiency instability . However , this is not to say

that stability problems can never have serious clinical consequences. For

example , in the early 1980s a packaging stability problem with nitroglycerine

tablets unfortunately resulted in some tablets have 10% of label claim. Since

nitroglycerine is used for the emergency treatment of a most serious cardiac

conditions, angina, there is unfortunately strong cause for concern that some

patients may have died as a result of this stability problem.

(2) To protect the reputation of the producer.

We should be jealous for the reputation that the stability of our

pharmaceutical products – compounded or manufactured – enjoys. Thus a

most important reason for conducting a stability testing program is to assure

ourselves the our products will indeed retain fitness for the use with respect to

all functionally relevant attributes for as long as they are on the market.





(3) Requirements of regulatory agencies

In many parts of the world, there are legal requirements that certain types of

stability tests, as required by regulatory agencies, must be perfomed.

Obviously, the law must be obeyed. However, it is wrong to abdicate from all

scientific judgement and only conduct those stability tests that a regulatory

agency is perceived as requiring. Indeed, there are occasions when any

manufacturer with a true dedication to quality will perform stability tests that

are over and above those required by regulation.

(4) To provide a database that may be of value in the formulation of other

products.

Data obtained in the stability evaluation of product X in 1999 may prove to

be of value when, in 2003, we start developing product Y. There may be

occasions, although they are probably rare, when it will worthwhile to

continue stability testing on an R&D formulation that we know will never be

marketed just because we are interested in the stability of a new excipient

that we have included in the formulation.

(5) Shelf-life & storage condition and labeling specification :-

By carrying out stability testing we can find out the shelf –life and expiry

date can be calculated . We ca have information about best storage condition

at which drug will contain its characteristic for long time. And if there is any

specification that we can write it on the label.

(6) Adequate formulation & container closer systems.

We can have idea about the formulation which will be more stable. And if

during stability testing we find any specification of container. e.g. menadione

injection is packed in amber colour ampoule to protect from photo

degradation.

(7) How quality of drug substance or product varies with the time under the

influence of various factors.

(8) Degradation product & possible degradation pathway

(9) Development & validation of stability indicating methodology

(10) Prevent great loss by recalling the batch due to stability.

If any difficulty is found during storage and in marketed product , than

industry has to recall all the drugs of that batch which is not economical . But

if stability studies are carried out than we may over come those problems.





(11) To verify that no changes have been introduced in the formulatn or

manufacturing process that can adversely affect the stability of the

product

(12) Providing evidence on how quality of drug substance or product varies

with the time under the influence of various factors like temp, humidity

and light.

(13) Loss/increase in concentration of API

(14) Modification of any attribute of functional relevance, e.g., alteration of

dissolution time/profile or bioavailability

(15) Loss of pharmaceutical elegance and patient acceptability

Stability study requirement and guidance regarding this is covered in

1. International Conference on Harmonization(ICH) of technical

requirements or registration of pharmaceutical for humane use.

2. ASEAN(Association of South-East Asian Nations) guideline for stability

of drug products.

3. WHO guideline for stability of pharmaceutical products.

4. USFDA guideline

5. SUPAC guideline

TYPE OF STABILITY STUDIES:-

1. Accelerated stability testing

2. intermediate testing

3. Long term testing

4. Stress testing

5. forced degradation testing

6. Photo stability testing

7. Thermal analytical techniques for stability testing

(DSC,microcalorimetry)





Overview of ICH guideline for stability testing

Stability

Q1A (R2) Stability Testing in New Drugs and Products

(Revised guideline)

Q1B Photo-Stability Testing

Q1C Stability testing: New Dosage Forms

Q1D Bracketing and Matrixing Designs for

Stability Testing of Drug Substances and

Drug Products

Q1E Evaluation of Stability Data

Q1F Stability Data Package for Registration in

Climatic Zones III and IV

STRESS TESTING

Stress testing of the drug substance can help identify the likely degradation

products, which can in turn help to establish the degradation pathways and the

intrinsic stability of the molecule and validate the stability indicating power of

the analytical procedures used. The nature of the stress testing will depend on the

individual drug substance and the type of drug product involved.

Stress testing is likely to be carried out on a single batch of the drug

substance. It should include the effect of temperatures (in 10°C increments (e.g.,

50°C, 60°C, etc.) above that for accelerated testing), humidity (e.g., 75% RH or

greater) where appropriate, oxidation, and photolysis on the drug substance. The

testing should also evaluate the susceptibility of the drug substance to hydrolysis

across a wide range of pH values when in solution or suspension. Photostability

testing should be an integral part of stress testing.

Perform essentially during Preformulation study.

Done on single batch same composition & quality as marketing batch including

packaging. Conducted for period of 6 months .

Stress testing of FPPs in solid state





Stress testing of API in solution

STABILITY PROGRAMME

If a manufacturer wants to apply for the registration of a new drug, i.e. if he is

applying for a

(1) Investigative New Drug Application (IND) or

(2) New Drug Application (NDA) or(ANDA) then he has to assure the

FDA regarding the drug’s/drug product’s safety, quality and efficacy.

For this he has to carry out stability tests and submit stability data specified by

Q1A (R2).

An API is considered as stable if it is within the defined/regulatory

specifications when stored at 30±2oC and 65±5% RH for 2 years and at

40±2oC and 75±5%RH for 6 months.





These guidelines divide the world into four zones and specify the temperature

and relative humidity conditions to be maintained by each zone for stability

studies.

CLIMATIC ZONE

The zones into which the world is divided based on the prevailing annual

climatic conditions

International Climatic Zones and Climatic Conditions

Climatic

Condition

Zone I

Temperate

Zone II

Mediterranean

(sub-tropical)

Zone III

Hot/dry or

Hot/moderate

RH

Zone IV

Very

hot/humid

Mean Annual

Temperature

< 20°C 20.5-24°C >24°C >24°C

Kinetic Mean

Temperature

(Virtual

temperature)

21°C 26°C 31°C 31°C

Mean Annual

Relative

Humidity

45% 60% 40% 70%

Few countries of various zones

Zone I : Britain, North Europe, Russia, Canada

Zone II : U.S.A, Japan , South Europe

Zone III : Iran, Iraq, Sudan

Zone IV :Brazil, Ghana, Indonesia, Phillipines

INDIA COMES IN III AND IV ZONE





DESIGNING STEPS

1) SELECTION OF BATCHES

2) TEST PROCEDURES AND TEST CRITERIA

3) SPECIFICATIONS

4) STORAGE TEST CONDITIONS

5) TESTING FREQUENCY

6) PACKAGING MATERIAL

7) EVALUATION

8) STATEMENTS AND LABELLING.

Selection of batches

Stability information from accelerated & long term testing should be provided

on batches of same formulation & dosage form in the container & closure

proposed for marketing.

Stability data on three primary batches are to be provided.

The composition, batch size, batch number and manufacturing date of each of

the stability batches should be documented and the certificate of analysis at

batch release should be attached.

Expected that atleast 1st two batches manufactured should be tested for long

term stability studies.

Testing frequency According to ICH

STABILITY TESTING TESTING INTERVALS

Real time testing (Q1 &

CPMP-QWP/556/96)

0,3,6,9,12,15,24 months

Accelerated testing (Q1A(R)

0, 3 & 6 months

Intermediate (Q1A ( R )) 0,6,9 & 12 months

For accelerated testing , FDA guidelines suggest 0,2,4 & 6 months

WHO guidelines 0,1,2,3, & 6 months

FDA,CPMP & WHO guidelines don’t suggest for intermediate testing





Storage test conditions

ACCORDING WITH ICH Q1A AND Q1F

Zone I AND II TEMPERATURE RELATIVE HUMIDITY

Long term study 250C ± 2 60% ± 5 RH

Intermediate study 300C ± 2 65% ± 5 RH

Accelerated study 400C ± 2 75% ± 5 RH

Zone III AND IV TEMPERATURE RELATIVE HUMIDITY

Long term study 300C ± 2 65% ± 5 RH

Accelerated study 400C ± 2 75% ± 5 RH

Acceptance Criteria :

Significant change for a drug substance is defined as failure to meet its

specification

1. A 5% potency loss from the initial assay value of a batch.

2. Any specified degradants exceeding its specified limit.

3. The product exceeding its pH limits.

4. Dissolution exceeding the specified limits for 12 capsules or tablets.

5. Failure to meet specifications for appearance and physical properties

(e.g., color, phase separation, resuspendability, delivery per actuation,

caking, hardness).

6. 5% loss in water from its initial value ,from packaged in a semi-

permeable container

Specification - Release The combination of physical, chemical, biological, and microbiological tests

and acceptance criteria that determine the suitability of a drug product at the

time of its release

It may be appropriate to have justifiable differences between the shelf life

and release acceptance criteria based on the stability evaluation and the

changes observed on storage.

Shelf-life acceptance criteria should be derived from consideration of all

available stability information.

E.g :Release and shelf-life dissolution acceptance criteria (Q and t) must be

the same





Stability Commitment

For confirmation of provisional (tentative) shelf-life, real-time data are

required

When available long term stability data on the primary batches donot cover

the proposed shelf life granted at the time of approval, a commitment should

be made to continue the stability studies post approval in order to firmly

establish shelf life

First 3 production batches on stability

Follow up stability testing (FUST) – one batch per year

Evaluation

1. Tabulate and plot stability data on all attributes at all storage conditions

and evaluate each attribute separately.

2. No significant change at accelerated conditions within six (6) months.

3. Long-term data show little or no variability and little or no change over

time.

labeling

The use of terms such as “ambient temperature “ or “room temperature “ is

unacceptable.

Where applicable ,specific requirement should be stated eg “protect from

light “,”protect from freezing “. The use of precautionary statements should

not be a substituted

After the stability of the product has been evaluated,

- store under normal storage conditions;

- store between 2 and 8oC (under refrigeration, no freezing);

- store below 8 oC (under refrigeration);

- store between -5 and -20oC(in a freezer);

- store below -18oC(in a deep freezer).

Normal storage conditions have been defined by WHO as: “storage in dry,

well-ventilated premises at temperatures of 15-25 oC or, depending on

climatic conditions, upto 30oC. Extraneous odours, contamination, and

intense light have to be excluded.

STABILITY PROTOCOL AND REPORT

1. Batches tested

2. General information

3. Container/closure system

4. Literature and supporting data





5. Stability-indicating analytical methods

6. Testing plan

7. Test parameters

8. Test results

9. Other requirements (post-approval commitments)

10. Conclusions

Result sheets must bear date and responsible person signature / QA

approval

REQUIREMENT OF TEMPERATURE DEPEND ON TYPE OF

TESTING

TYPE OF

STUDY

TEMPERATURE

RELATIVE

HUMIDITY

TIME

DURATION

Long term 25°C ± 2°C /60% RH ± 5%

RH

12 months

Intermediate 30°C± 2°C /65% RH ± 5%

RH

6 months

Accelerated 40°C± 2°C/ 75% RH ± 5%

RH

6 months

DIFFERENT TEMPERATURE REQUIREMENT DEPEND UPON TYPE

OF DOSAGE FORMS

FOR DISTINCT

PRODUCTS

TYPE OF STUDY

AST IST LST

Solid oral DF, solids for

reconstitution, dry

&lyophilized powders

in glass vials

40°C ± 2°C

75 % ± 5%RH

40°C±2°C

75 % ± 5%

RH

40°C±2°C

75 % ± 5% RH

Liquids in glass bottles

,vials, sealed glass

ampoules which

provide an

impermeable barrier to

water loss

40°C ± 2°C

Ambient

Humidity

30°C±2°C

Ambient

humidity

25°C±2°C

Ambient

Humidity





Drug products in

semipermeable

containers

40°C ± 2°C

NMT 25 %

RH

30°C±2°C

65 % ± 5%

RH

25°C±2°C

40 % ± 5% RH

Or 30°C±2°C

35 % ± 5% RH

Stages where stability studies carried out

Stability testing is done in five different occasion when an NDA is being

contemplated.

1. Preformulation and compatibility

2. Preclinical formulation

3. Clinical and NDA formulation

4. Commitment and product monitoring

5. Post NDA change of formulation

Preformulation and compatibility

In the early stage of drug designing, studies are done to find out what sort of

decomposition is possible, what is the mechanism, sensitivity to moisture and

oxygen interaction probabilities (compatibilities) optimum pH and polymorphic

information. Drug excipient interactions physical as well as chemical are

extensively studied.

Preclinical formulation

Keeping the data from the preformulation studies in mind formulations are

designed and manufactured for use in Phase-I trails. More than the one or two

formulations being used in Phase-I studies are manufactured and started on

stability studies. This is because even a supposedly stable formulation may

while in Phase-I use fail with respect to some stability issue, then you must have

something to fall back upon.

Clinical and NDA formulation

When a product has passed Phase-I, its dosage level, interactions and stability

profile are known to some degree and armed with this knowledge the “Clinical

manufacturing group” of the company manufactures several batches of the

product and keeps some products from every batch for stability. The required

stability aspects of clinical are simply to ascertain that each batch is within

specifications during the length of the trail.

Late Clinical and First Pilot Batch





The ICH stability guidelines require that three substantial batches, made in the

same type production equipment intended for the final product, be made and

that at least 12 months stability be in place at the time of NDA submittal.

Marketed product stability

At the time the NDA is filed, the large clinical and scate-up batches are only

about a year old, and the stability data on them is not yet complete. So at this

time, the company asks for an expiry date based on extrapolation of the existing

stability data. The FDI will take all facts into consideration and grant an expiry

date based on a commitment form the company that the company will continue

to do stability studies on different batches.

The storage requirements and the sampling times are very clearly specified by

the ICH guidelines.

RECENT ADVANCES IN STABILITY TESTING

1) Stability Testing of Herbal Products

Abstract:-

Since last one decade India has seen tremendous growth in herbal

drug market, which has resulted in development of numerous proprietary herbal

drug formulations by various manufacturers, majority of them comprising of

polyherbal formulations. With the advancement of knowledge in the field of

phytochemistry it has now been observed that many of these constituents

present in the drug may react with each other raising the serious concern about

the stability of such formulations. This is the area, which needs to be addressed

in order to determine the efficacy of the formulation. This article is aimed to

give some guidelines for undertaking stability studies for herbal products.

Stability testing of herbal products is a challenging task, because

the entire herb or herbal product is regarded as the active substance, regardless

of whether constituents with defined therapeutic activity are known. The

objective of a stability testing is to provide evidence on how the quality of the

herbal products varies with the time under the influence of environmental

factors such as temperature, light, oxygen, moisture, other ingredient or

excipient in the dosage form, particle size of drug, microbial contamination,

trace metal contamination, leaching from the container, etc. and to establish a

recommended storage condition, retest period and shelf-life. Therefore

evaluation of the parameters based upon chemical, physical, microbiological,

therapeutic and toxicological studies can serve as an important tool in stability

studies .





2) Recent Developments on Long-Term Stability Test Conditions

Abstract:

Stability testing is the only way to demonstrate that the

pharmaceutical product would meet the laid-down specifications within

acceptance criteria throughout its lifetime. It is also required to gain the

regulatory approval. The birth of International Conference on Harmonization

(ICH) in 1991 and finalization of the guideline Q1A in 1993 led to

harmonization of the stability test requirements for new drug applications, and

was instrumental in development of a series of ICH and other National and

regional stability guidelines, both for the new and existing drugs. There have

been some recent developments, especially with respect to defining of storage

condition for long-term stability testing. This note traces the new developments.

REFERENCES:-

1) Drug Stability: Principles and Practices, 3rd Edition, edited by Jens T.

Carstensen and C. T. Rhodes (Marcel Dekker, Inc., New York, 2000)

2) Modern Pharmaceutics.- Drugs and the Pharmaceutical Science by G S.

Banker and C T. Rhodes.

3) I.C.H. guidelines.

4) THE PHARMA REVIEW (APRIL - MAY, 2008)

5) THE PHARMA REVIEW (DECEMBER, 2006)

6)JPS ,VOL 51,1962-”solid state stability”,100

7)JPS,VOL 51,1962,”prediction of stability of drugs &pharmaceutical

preparation “,811

8)www.pharmainfotech.com

http://www.kppub.com/pharmareview-publisher.html

http://www.kppub.com/pharmareview-publisher.html

Paper-910101 Chapter-4 Stability Studies By: Sanjay C. Modi

18

Seminar

on

Order of reaction

And their applications in

predicting shelf life of

pharmaceutical formulations

(Under stability study)

GUIDED BY:

Dr. R. K. PARIKH

PREPARED BY:-

SANJAY C. MODI M.PHARM PART- I (2009-10)

ROLL NO –07.

DEPT. OF PHARMACEUTICS AND TECHNOLOGY

L.M.COLLEGE OF PHARMACY

AHMEDABAD-09.


19

LIST OF CONTENTS:- No. CONTENT

1 KINETIC OF REACTION

2 ZERO ORDER OF REACTION

3 FIRST ORDER OF REACTION

4 SECOND ORDER OF REACTION

5 COMPLEX REACTIONS

6 COMPARISON OF REACTION

7 DETERMINATION OF ORDER OF REACTION

8 PREDICTION OF SHELF LIFE & OVERAGES

9 QUESTION BANK

10 REFERENCES

KINETICS

Kinetics is the study of the rate at which processes occur. It is useful in providing information that: Gives an insight into the mechanisms of changes involved,and Allows a prediction of the degree of the change that will occur after

a given time has elapsed. ORDER OF REACTION This is the number of concentration terms that determine the rate. Consider the reaction:

A + B C + D The rate of the reaction is proportional to the concentration of A to

the power of x, [A]x and also the rate may be proportional to the

concentration of B to the power of y, [B]y.


20

The overall equation is, Rate = k [A]x [B]y The overall order of reaction is x+y

RATE CONSTANT

A rate constant is a proportionality constant that appears in a rate

law. For example, k is the rate constant in the rate law d[A]/dt = k[A]. Rate constants are independent of concentration but depend on other factors, most notably temperature.

ZERO ORDER REACTION

When the reaction rate is independent of concentration of the reacting substance, it depends on the zero power of the reactant and therefore is zero order reaction. In this type of reaction, the limiting factor is something other than concentration, for example, solubility or absorption of light in certain photochemical reactions. The rate of decomposition can be described mathematically as: Rate of concentration decrease = -dCx = K……………………………………….(1) dt Integrating the equation yields X= Kt + constant………………………………(2) A plot of X vs time results in straight line with slope equal to K. The value of K indicate the amount of drug that is degraded per unit time, and intercept of line at time zero is equal to constant in equation (2).

The unit of K is conc time-1, with typical units of mole L-1 s-1. Half-life is given by equation t1/2 = Co/2k. Examples: -Vitamin A acetate to anhydrous vitamin A. Photolysis of cefotaxime. Loss in color of multi sulfa product.

Intravenous infusion, Drug released from TDDS.

time

concen

tration

SLOPE=K


21

FIRST ORDER REACTION

When the reaction rate depends on the first power of concentration of a single reactant, it is considered to be first order. Example are

Absorption,distribution,elimination rates. Microbial death kinetics.

Thus the rate of reaction is directly proportional to the concentration of reacting substance and can be expressed as follows: Rate of concentration decrease = -dCX = KCx…………………………….(3) dt If concentration of reactant X is ‘a’ at beginning of reaction when t = 0, & if amount that has reacted after time t is denoted by x then amount of X remaining at time t will be (a-x). Therefore equation (3) can be rewritten as: -dCX = K (a-x) dt dCX = -K dt---------------------------(4) (a-x) Integrating equation (4) between time limit 0 to t

a ∫a-x dCX = -K 0∫

t dt

dt

ln (a-x) –ln a = -Kt log (a-x) – log a = -kt/2.303 log (a-x) = log a – Kt/2.303 -----------(5) Equation (5) is like y = mx + c (linear relationship) If first order law is obeyed then a graph of log (a-x) v/s time t will give straight line with slope of –K/2.303 and an intercept of log a at t = 0.


22

Log (a-x) Time Rearranging equation (5) we have K = 2.303 log (a/a-x) -----------------------------(6) t Unit of K for first order is time-1 i.e. SI unit is (sec)-1 because K is inversely proportional to t. The half-life, t1/2, of a drug is the time required for 50% of drug to degrade and can be calculated as follows: t1/2 = 2.303 log C0 = 2.303 log 100 k C k 50 =2.303 log 2 = 0.693 k k therefore, t1/2 = 0.693………………………………..(7) k In pharmaceutical field , the time required for 10% of the drug to degrade is an important value to know, since it represents a reasonable limit of degradation of active ingredients. The t10% value can be calculated as t10% = 2.303 log 100 = 0.104 k 90 k t10% = 0.104 ……………………………………(8) k or t10% = 0.152 t1/2

SECOND ORDER REACTION

Rate of change in conc. of product and reactant is dependent on second power of conc. of single reactant or to first powers of the conc. of two reactants.

SLOPE = -K

2.303


23

i.e. -dCX = K [X] [Y]-------------------------------------(9) dt or -dCX = K [X]2-----------------------------------------(10) dt Let us discuss - dCX = K [X] [Y] in detail dt Here decrease in conc. of Y is similar to X. If conc. of X and Y at time t = 0 are a and b respectively, and conc. of each substance that has reacted after time t is equal to x then conc. of X and Y remaining will be (a-x) & (b-x) respectively. In case when (a ≠ b) -dx = K (a-x) (b-x)----------------------------------------(11) dt Where -dx = rate of decrease in conc. of X or Y dt Integrating equation (11) we get Kt = 2.303 log b(a-x)---------------------------------(12) (a-b) a(b-x) Rearranging equation (12) we get log (a-x) = (a-b) Kt + log a----------------------------(13) (b-x) 2.303 b So, if second order reaction is observed then graph of log (a-x) vs t (b-x) gives straight line with slope (a-b) K and 2.303 intercept log a/b at t =0.

Log (a-x) (b-x)

Time

SLOPE = (a-b) K

2.303


24

In case when (a=b) -dCX = K [X] 2 dt Integration gives, Kt = x ------------------------------------(14) a(a-x) Rearrangement of equation (14) gives us Kt = 1 - 1 -----------------------------(15) a-x a So if second order reaction is observed then graph of 1/a-x vs t gives straight line with slope K and intercept 1/a at t = 0. Unit of second order reaction is conc.-1 time-1 and SI unit is mol-1 sec-

1.

Half-life in this case is t1/2 = 1/ak. THIRD ORDER REACTION & HIGHER

Rate of change in conc. is proportional to three concentration terms. However such reactions are rare and their analysis is complex. Reaction of even higher order is unlikely to occur. Rate eqn third order reaction is as follows:

K = 1/2t [1/(a-x) 2 -1/a2]

PSEUDO-ZERO ORDER REACTION

In solid state, may drug decomposes by pseudo zero order i.e. reaction between drug and moisture in solid dosage form. The system behaves like suspensions and because of the presence of excess solid drug; the first order rate actually becomes pseudo zero order. Equation for it is similar to zero order except K is replaced by K’. How suspension degradation follows pseudo zero order reaction? Suspension is the case of zero order kinetics in which the

concentration in solution depends on the drug’s solubility. As the drug decomposes in solution, more drug is released from the suspended particles so that the concentration remains constant.

This concentration is of course the drug’s equilibrium solubility in a particular solvent at a particular temperature. The important point is that the amount of the drug in the solution remains constant despite its decomposition with time.


25

The reservoir of solid drug in suspension is responsible for this constancy. It follows zero order kinetics because the suspended drug reservoir that ensures constant concentration.

Once all the suspended particles have been converted into drug in solution the system changes to a first – order reaction.

PSEUDO-FIRST ORDER REACTION

Here a second order or bimolecular reaction is made to behave like first order. This is found in the case in which one reacting material is present in great excess or is maintained at constant concentration as compared with other substance. Here reaction rate is determined by one reactant even though two are present. EXAMPLES: Decomposition of ascorbic acid tablet. Aspirin hydrolysis.

COMPLEX REACTION

Although most degradative reactions in pharmaceutical systems can be treated by simple zero order, first order and pseudo-first order kinetics, there are certain pharmaceutical formulations that exhibit more complicated reactions. These have opposing, consecutive and side reactions alongwith main reaction. They are as follows:

1. OPPOSING REACTION (REVERSIBLE)

The simplest case is in which both reactions are of first order

A B

A somewhat more complicated reaction is when forward is first order type and reverse reaction is second order type.

A B+C

Example: Epimerization of tetracycline. 1. CONSECUTIVE REACTIONS k1 k2

A B C

Simplest is one where both the reaction is of first order.

K K

K’

K’

K


26

If K2 > K1 then B can be considered as unstable intermediate and rate determining step for overall reaction would be conversion of A to B. Examples: - Radioactive series \ Isotopic decay that follows first order, but

it is a consecutive reaction. Degradation of chlorbenzodiazepine by hydrolysis to lactum

form and further to benzophenone.

2. SIDE REACTIONS (PARALLEL)

Here the reacting substance can be removed by two or more reactions occurring simultaneously, as depicted

B

A

C

EXAMPLES: Purified insulin degrades by two mechanisms- deamidation and

polymerization. The relative rates of deamidation and polymerization are pH and temperature dependent.

KNOWN FACTS: - There is no detectable difference between first order and zero

order at less than 15% decomposition. Many companies take the attitude of plotting by first order in

situation where the order is unknown. Establishing the true order of reaction can often be difficult, due

to the fact that strength chances at 25ºc are small and that unit–to –unit and assay variation make such a distinction difficult.

SUMMARY OF PARAMETERS:- Order Integrate rate

equation

t1/2 Linear Graph

Ordinate Abscissa Slope Intercept

0 X = Kt = a/2K X t K 0

1 log (a/a-x) = Kt/2.303 = 0.693/K log(a-x) t -K/2.303 log a

2 (a = b) X/a(a-x) = Kt = 1/aK 1/a-x t K 1/a

K1

K2


27

COMPARISON OF FIRST, SECOND & ZERO ORDER REACTION

A tablet decomposes after one year to 75% of its initial concentration.In the following table the data of rate constant and half-life is given for particular order.

Initially speed of reaction: 2nd order >1st order > Zero order

• Because in 2nd order reaction, two molecules of reactants collide faster than one. Ideally if every collision between molecules led to product, a second order reaction would be twice as fast as first order. But in our case this is not true as half-life of first order is not twice as that of second order. This indicates that not every collision between molecules lead to reaction. After two years,

Order of reaction Zero First Second

Drug remaining -50% 6.76% 20%

This shows that in 2nd year the speed of reaction reverses and 2nd order reaction becomes slowest as it is dependent upon the concentration of reactants and the concentration of reactants gets depleted as the reaction progresses so the % of drug remaining is more in case of 2nd order reaction while in zero order all the drug got decomposed before two years.

Order of reaction Unit of K

Zero M L-1Sec-1

First Sec-1

Second M-1Sec-1

PARAMETERS 1ST 2ND ZERO

K (Per Year) 1.38 0.03 75%

HALF LIFE 0.50 0.33 0.66


28

METHODS TO DETERMINE ORDER OF REACTION

1. SUBSTITUTION METHOD 2. INITIAL RATE METHOD 3. DATA PLOTTING METHOD 4. HALF-LIFE DETERMINATION METHOD

SUBSTITUTION METHOD:

The data accumulated in a kinetic study may be substituted in the integrated form of the equations which describes the various orders. When the equation is found in which the calculated k values remain constant the reaction is considered to be of that order.

INITIAL RATE METHOD:

Graphs are plotted of rate of reaction against concentration and the

initial rate determined from the gradient at time = 0. If it is a straight line the reaction is first order. If a curve is obtained then we can say it is 2nd order reaction. A reaction which is independent on concentration is zero order.

Fig. Curves for different types of order

DATA PLOTTING METHOD:

Plot of conc. against time is if linear then it is zero order reaction.

Plot of 1/c against time is linear then second order.

Plot of ln c against time is linear then first order reaction. HALF-LIFE DETERMINATION METHOD:

The relationship in general between half-life of a reaction in which the concentrations of all reactants are identical, is

t1/2 ∞ 1/an-1 where n is the order of reaction.


29

• Thus if two reactions are run at different initial concentrations, a1 & a2 with their respective half-lives and putting them in above equation in logarithmic form we finally get

n = log (t1/2(1)/t1/2(2)) + 1 log (a2/a1)

Determination of t10% by Arrhenius equation

o Temperature influences rate and order of reaction. So shelf life

of product can be obtained under exaggerated condition. o It is said that for every 10 0C rise, rate of reaction increases by

2-3 times. o For this Arrhenius equation is used i.e. K = Ae-εa/RT

Where A= frequency factor, R= gas constant, K = rate constant, εa = energy of activation

Therefore, Log K = log A – εa 2.303RT

o Graph of log K v/s 1/T gives straight line with slope εa & intercept at t = 0.

2.303R o εa represents energy required by molecule to react and undergo

reaction. Higher is value of εa higher is dependency on temperature.

o εa = 2-3 k-cal/mole ------Photolysis o εa = 10-30 k-cal/mole ---Hydrolysis-Solvolysis o εa = very high abt 50-70 k-cal/mole-----Pyrolysis o Rate constant at different temperature can be obtained by

log (K2/K1) = εa (T2-T1) R (T2*T1)

o With help of K at different temperature we can predict T10% t 10% = 0.105 / k (For first order only) t 10% = C0/ 10*k (for zero order only)


30

Disadvantages of Arrhenius equation: 1. At higher temperature evaporation of solvent takes place and thus

changes in concentration. 2. At higher temperature change in solubility and humidity

(decreases) which cannot be correlated with room temperature. 3. For disperse systems at higher temperature viscosity decreases

which can change physical characteristics resulting in potentially large errors in prediction of stability.

4. Different degradation mechanisms may predominate at different temperatures thus making stability prediction difficult.

METHOD TO DETERMINE OVERAGES

STEP I: - Perform the experiment and find out concentration of drug remaining at different time intervals at different temperature including room temperature. Plot the graph of concentration vs time for different temp.

As shown in the figure measure the slope and from that get rate

Constant K.

STEP II: - After measuring the K at different temperature find value of K25

from the graph as shown in the figure.

25° C

K25

Log K

TEMP


31

STEP III: - The value of K25 is substituted into eq.

K = 2.303/t * log (a / a-x) And get the value of t10 %, t20%… t 90%. STEP IV: - Calculation for overages

Plot the graph of time (Days) Vs conc. remaining.

Extrapolate line from Y- axis, at 90% to the X- axis. The intersect point will give shelf life.

To maintain or increase the shelf life as per need (from a to b as shown in fig.) draw a parallel line from Y to that of X, the intersect point at Y- axis will give the value of overages per 100 unit.

As shown in the figure, The value of overages is 20%. So need to add 20 unit drugs to preexisting formulation. As per European guidelines the maximum amount of overages is

30%.

STEP V: - Expiration period Prime goal of stability testing is to establish an exp. Date. The terms defined in lines 82-90 of guidelines as

“The date placed on the immediate container label of a drug product that designates the date through which the product is expected to remain within specification.”

If the expiration date includes only a month and year, it is expected that the product meet specification through the last day of the month.


32

Estimation of the Shelf Life (Expiration Period) of

Drug Products :-

Shelf life is best defined as the time span over which the quality of a product remains within specifications. That is, it is the time period over which the efficacy, safety, and esthetics of the product can be assured. When the degradation of the essential components cannot be adequately described by a rate expression, shelf life cannot be easily estimated or projected. When a quality-indicating parameter changes with time via complex kinetics that cannot be adequately explained or predicted, one must determine stability solely from experimental observations. Many physical degradation processes exhibit this kind of behavior. In contrast, estimation of shelf life is often possible when the shelf life is governed by a degradation process that can be adequately described by a rate expression (like many chemical degradation processes). Estimation of product shelf life is done by two methods—estimation from data obtained under the same conditions as those that the final product is expected to withstand and estimation from tests conducted under accelerated conditions. This section describes these two methods for estimating the shelf life of pharmaceuticals when chemical degradation is the major contributor to the degradation process and the degradation can be adequately described by a rate expression.

DIFFERENT METHODS:

A} Extrapolation from Real-Time Data B} Shelf-Life Estimation from Temperature-Accelerated Studies C} Estimation of Shelf Life under Temperature-Fluctuating Conditions


33

FREQUENTLY ASKED QUESTIONS :-

1. Compare the zero ,first,second order of reaction with suitable numerical data(LM-05)

2. How chemical kinetics is useful in studying order of reaction ? (LM-06) 3. Explain different type of order of reaction & enlist the method to

determined it .Explain one of them with suitable example(LM-05;06) 4. Define pharmacokinetics & bio pharmaceutics (2006;LM-06;07) 5. Short note on order of reaction and its utility in stability

studies…………(2006)

STUDY QUESTIONS

1. What is kinetics? 2. What is order of reaction? Describe different methods to determine order

of reaction. 3. Discuss first order drug degradation in detail. 4. How one can predict shelf life of suspension and ascorbic acid tablet? 5. Compare first, zero, second order of degradation. 6. Discuss complex reactions.

REFERENCES

1. Biopharmaceutics and Pharmacokinetics A treatise by D. M. Brahmankar Sunil B. Jaiswal. Page no. 215-220.

2. Stability of drugs and dosage forms by Yoshioka and Stella (2002) 3. Remington’s pharmaceutical Science, Mack Publishing Company,

15th edition 1975, 275-283. 4. Physical; pharmacy by Alfred martin, second edition , 355-377. 5. The theory and practice of industrial pharmacy by Lachman, 760.

Paper code-910101/ Chapter 4/ Importance of Accelerated stability study

Department Of Pharmaceutics and Pharmaceutical Technology L.M.C.P. Ahmedabad 9

34

Importance Of

Accelerated Stability Study

Guided by Dr. R. K. Parikh

Prepared by Himaxi Rajput M.Pharm I (2009-2010) Roll no.9

Department Of Pharmaceutics and

Pharmaceutical Technology

L.M.College of Pharmacy Ahmedabad 9.



35

Accelerated stability testing All medicinal products decompose with time. Paradoxically, when this

decomposition is being assessed the skilled formulator becomes a victim of his own expertise, as a good formulation will take a long time to decompose.

Instability in modern formulations is often detectable only after considerable storage periods under normal conditions.

To assess the stability of a formulated product it is usual to expose it to “high stress”, i.e. condition of temperature, humidity and light intensity that cause break down.

High stress conditions enhance the deterioration of the product and so reduce the time required for testing.

Thus these are the studies designed to increase the rate of chemical degradation and physical change of a drug by using exaggerated storage conditions as part of the formal stability testing programme.

This enables more data to be gathered in shorter time, which in turn will allow unsatisfactory formulation to be eliminated early in a study and will also reduce the time for a successful product to reach a market.

It must be emphasized that extrapolation to normal storage condition must be made with care, the formulator must be sure that such extrapolation are valid.

The results of accelerated testing studies are not always predictive of physical changes.

Significant change occurs due to accelerated testing Significant change at the accelerated conditions is defined as: A 5% potency loss from the initial assay value of a batch. Any specified degradants exceeding its specified limit. The product exceeding its pH limits. Dissolution exceeding the specified limits for 12 capsules or tablets. Physical Changes under Accelerated conditions of Temperature & Humidity

1. Under Light, both Primary and Secondary packaging affected, and fading of container color, and the print is fading.

2. Effervescent Tablet : Gain of moisture, loss of integrity 3. Capsule: Color fading in Blister and Sticking in a Glass bottle. 4. Powder : Spread within strip pockets 5. Suppositories : Softening 6. Change in Viscosity of a Gel, Jelly, Cream & Ointment 7. Lozenges : melting 8. Emulsions : Phase separation



36

Objective

1. Main aim of accelerated stability study to predict the stability profile of a drug product that prediction of self life of the product before launching into market.

2. The rapid detection of deterioration different initial formulations of the same product. This is of use in selecting the best formulation from a series of possible choices

3. Prediction of shelf life, which is the time a product will remain satisfactory when stored under expected or directed storage condition.

4. The provision of rapid mean of quality control, which ensures that no unexpected change has occurred in the stored product.

Good formulation will invariably break down more slowly than poor ones. When

the perceived optimal formulation is decided, attempts can be made to predict its likely stability at proposed storage conditions. These may be at 250C for ambient room temperature (or 3000C for use in hot climates), or 0-400C for a refrigerator.

The amount of decomposition that is acceptable in fixing an expiry date depends on the particular drug. This will be small if therapeutic index is low or if the decomposition products are toxic.

Stability Profiles: Accelerated stability study

Storage Condition Testing Condition

Controlled room temperature 20-250C

400C and 75% RH for 6 months

Refrigerated condition 2-80C

250C and 60% RH for 6 months

Freezer condition -20 to -100C

50C for 6 months

Prediction of shelf life from accelerated stability data Based on the principle of chemical kinetics demonstrated by

Garret and Carper method Free and Blythe method

Shelf Life Determination Based on Arrhenius Plot (Garret and Carper method) The mathematical prediction of shelf life is based on the application of the

arrhenious equation, which indicates the effect of temperature on the rate constant, k, of a chemical reaction of thermodynamic temperature, 1/T, is a straight line.

If the slope of this line is determined from the results of temperature by extrapolation, the k value obtained. And this k value is substituted in appropriate



37

order of reaction allows the amount of decomposition after a given time. Preliminary experiments are there for necessary to determine this order.

K=Ae-Ea/RT Log K=Log A - Ea/2.303*RT Where, K= rate constant R= gas constant =1.987 cal/mole T = absolute temperature A = frequency factor Ea = energy of activation T10% = (2.303/K)*(log100/90) T90% = (2.303/K)*(log100/10)

Garret and Carper method)

1. Keep several samples of the drug product at atleast three temperatures, such as 40oC, 50 oC and 60 oC.

2. Determine the drug content at all three storage points by taking a number of samples and take the mean drug content. We do this for a few weeks.

3. At each temperature we plot a graph between time and log percent drug remaining. If the decomposition is first order this gives a straight line. If it is zero order, percent drug remaining versus time will give a straight line.

4. Next we take the log K or log of reaction constant on Y axis and 1/T x 10-3 on X axis and draw a best fit line. This line is the Arrhenius Plot, extrapolate this line to get k at 25 oC and from this we calculate the shelf-life.

Arrhenius plot for predicting drug stability at room temp.



38

If the reaction is following zero-order

Expiration date at 25 oC = Initial potency – minimum potency / reaction rate at 25 °C

tx =Yo - Yx/ Ko

If the reaction is following first order

Expiration date at 25 oC (tx) = Log initial potency – log minimum potency/reaction rate at 25

tx =log Yo – log Yx / K1

Where Yo = initial potency

Yx = final potency

Ko = zero order constant K1 = first order constant

Limitation of arrhenious relationship for stability prediction: There are varieties of situation in which arrhenious equation can be erroneous or

invalid. Higher temperature may evaporate solvents thus producing unequal moisture

concentration at different temperature. At higher temperature stability for drugs sensitive to the presence of moisture

and oxygen. For dispersive systems viscosity decrease as a temperature increases and

physical characteristic may alter and resulting in potentially large errors in predicting of stability.

In spite of these difficulties the application of accelerated testing to pharmaceutical product is often useful, and predicted shelf lives are sufficiently accurate.



39

SHELF LIFE DETERMINATION Based on t90 values (Free and Blythe /method) In this method the fraction life period is plotted against a reciprocal temp. and the time in days required for drug to decompose to some fraction of its original potency at room temp. this approach clearly illustrate in below fig.

the log% of drug remaining is plotted against time and days and the time for the loss line at several temp. to reach 90% of the theoretical potency is noted by the doted line. Shelf life and expiration date are estimated in this way. The log time to 90% is then plotted against 1/T and the time for 10% loss of potency at room temp. can be obtain from the resulting straight line by extrapolation to 250C



40

Limitation of accelerated stability studies Accelerated stability studies are valid only when the breakdown depends on

temperature. Accelerated stability studies are valid only the energy of activation is about 10 to

30 kcal / mol. In solution phase most reaction has heat of activation in the range of 10 to 30 k.cal / mole. if energy of activation is less than 10 kcal / mol its rate would be fast at room temperature .in such cases elevated temperature has little influence on the decomposition .if energy of activation is higher than 30 kcal / mol very high temperature are required to enhance the degradation . Reaction at such high temperature may not have any relevance, because they do not reflect ambient storage condition.

The result obtained for one set of condition for a preparation cannot be applied to other preparation of same drug.

Stability prediction at elevated temperature is of little use when degradation is due to diffusion, microbial contamination, and photo-chemical reaction.

Stability studies are meaningless when the product looses its physical integrity at higher temperature like coagulation of suspending agent, denaturation of proteins.

Prediction will become erroneous when the order changes at elevated temperatures, as in case of suspension (zero order) which at higher temperature get converted to solution which follow 1st order.

SHELF LIFE DETERMINATION BASED ON REAL TIME TESTING

Another method which involves real time testing and statistical analysis, followed for determinng shelf life.

1. Keep three batches for stability study at least for 1 year at one fixed temperature.

2. Test them at 0, 1, 3, 6, 9, and 12 months for drug content. At each testing time test a number of samples, so that you have a mean and a standard deviation value of the result.

3. Now plot the graph of % drug content on Y axis and time on X axis along with confidence intervals. Where the lower 95% confidence curve intersects minimum potency, there you fix the shelf life.

As an example we can see the data and figure given in Tablets, Volume 3, by Hebet A Lieberman and Leon Lachman.

Vitamin Tablets Stability Confidence Intervals at 40oC



41

Fig: Plot of In potency against time showing 95% confidence limit line

Table: Vitamin Tablets Stability Confidence Intervals at 40oC

Time (Months)

Results

(mg/tablet)

Lower

limit

Upper

Limit

0

1

3

6

9

12

100.0

91.2

83.1

75.8

69.1

63.0

95.2

88.7

79.3

69.8

61.2

53.6

104.9

93.8

87.3

82.5

78.2

74.0

Where estimate of the standard error of regression(s)

y1 = predicted value at t1

n = sample size

Sy = standard error of the line

α = 0.1 two-sided

0.05 One-sided

This method also helps formulation scientists in fixing the amount of overages to be added to vitamin products.



42

Q10 method for Shelf life estimation. Q10 approach taken by Simonelli & Dresback Q10 is the factor by which the rate constant increases for a 100C temp. increase. It is the ratio of two different reaction rate constants. Commonly used Q values OF 2, 3 & 4 relate to the energy of activation of reaction for temperature for room temperature (25°C)

For an Arbitrary temp. change T

As is evident from this relationship, an increase in T will decrease the shelf life and a

decrease in T will increase shelf life.

Scientists has found out that Activation energy (Ea) of all chemical decomposition reaction usually fall in the range 12 to 24 Kcal/mol. With a typical value of 19 to 20 Kcal/mol.



43

Ea ( K cal/mol. ) Q10 ( 300 to 200C)

12.2 2.0

19.4 3.0

24.5 4.0

Q10 = 4 provides the higher estimate for the increase in rate with increasing temp., where as Q10 = 2 provides the lower estimate for the decrease in rate with decreasing temp. Q10 = 4 will estimate the maximum likely decrease in shelf life with increasing temp. and Q10 = 2 will provide the most conservative estimate of the increase in shelf life with decreasing temp. The value Q10 = 3 gives our most likely estimate.

T= T2-T1,

T2= T1+ T

Where,

t90 (T2) is the estimated shelf life, t90 (T1) is the given shelf life at given temp., and

T is the difference in the temp. T1 and T2 Note : the estimate of t90(T2) is independent of the reaction order.



44

Example:

An antibiotic solution has a shelf life of 48 hrs. in the refrigerator (50C). What is its estimated shelf life at room temp.(250C)?using a Q10 value of 3.

Importance of Q10 method in shelf life estimation It solves many problems like one t90 (T1) is the given shelf life at given temp., to determine the shelf life at another temp. t90 (T2). Some specific examples are. The expiration date is given for room temp. What is the expected extension of the

shelf life in a refrigerator? The expiration date is given for refrigeration condition. How long the product may

be left at room temp.? The expiration date is given for room temp. And it is desired to heat the product,

what percent decomposition can be expected at higher temp.? The expiration date is given for refrigeration condition; the product is stored for a

period of time at room temp. And is then returned to the refrigerator. What will be the corrected expiration date?

Overages The excess quantity of drug that must be added to the preparation to maintain at least 100% of labeled amount during the expected self life of drug can be easily calculated and added to the preparation at the time of manufacture.

The international pharmaceutical federation has recommended that overage be

limited to a maximum of 30% over the labeled potency of an ingredient. While adding over-age safety and toxicity should also be considered. By convention overage to the of 10 % of excess dose of drug is added to the product at the time of manufacture. This is to ensure that the product contain 100 % labeled amount during the shelf life period. In other word at the end of one shelf period the concentration of drug of about 100 %. The same product will now take one more shelf life period in order to decrease the drug content to 90 % of labeled amount. Thus product will now take twice the shelf life as an expiry date.



45

Stress testing Stress testing to elucidate the intrinsic stability of the drug substance is part of

the development strategy and is normally carried out under more severe conditions than those used for accelerated testing.

The testing typically includes the effects of temperature (in 10oC increments (e.g. 50oC to 60oC) above that accelerated testing), humidity (e.g. 75%relative humidity or greater) where appropriate oxidation and photolysis on the drug substance.

Stress testing of the drug product is undertaken to assess the effect of severe condition of the products. Such studies include photo stability testing and specific testing of the certain products.

Common high stresses or challenges

Temperature challenge An increase in temperature causes an increase in the rate of chemical reactions. The products are therefore stored at temperature higher than room temperature. Sample is removed at various time intervals and the extent of decomposition is determined by analysis. Sensitive analytical methods are used in all stability tests of this nature, as small change can be detected after very short storage periods. The effects caused by high temperature should not confuse with those that arise from the effect of low humidity. Such confusion is possible because the relative humidity inside the high temperature in storage cabinet is lower than that of room temperature. This low humidity causes loss of moisture, which leads to apparent increase in the concentration of ingredients. If these concentration changes are not allowed for in subsequent analyses decomposition may be unsuspected.

LIMITATION: Ø The arrhenious equation involve only one rate constant and therefore applies to a simple(single step) decomposition mechanism. It cannot be used for complex reactions (consecutive, parallel etc.) or heterogeneous process involving the phase boundaries. Ø The higher temperature may reduce the moisture content of the product, thus slowing the hydrolysis, gelatin may soften or melt, and tablet coating may split. Ø The effects of temperature on photochemical and microbiological destruction are not predictable.

Humidity challenge Storage of the product in atmosphere in high humidity will accelerate decomposition that result from hydrolysis. Marked acceleration will be obtained if the „naked product‟ (i.e. not enclosed in a container) is subjected to these tests, which usually indicate the minimum humidity tolerated by the product without undue decomposition, and therefore useful in determining the degree of protection that should be afforded by a container.

Light challenge The source of artificial light used to accelerate the effect of sunlight or skylight. Day light fluorescent lamp provides a satisfactory source, and banks of such lamps may be used



46

to accelerate the effect of light. To reduce the heating effect of this lamp, glass plates used. Otherwise it is difficult to separate the accelerated decomposition cause by light from that caused by increase temperature.

Objective Use

To select adequate (from the view of stability) formulation and container closure system.

Development of product

To determine shelf life and storage condition

Development of the product and of the registration dossier

To verify no changes have been introduce in the formulation or manufacturing that can adversely affect the stability of the product

Quality assurance in general, including quality control

References

1. Aulton M. E, “Pharmaceutics the science of dosage form design”, “Kinetics and stability testing”.

2. Carstensen, J.T., “Stability and Dating of Solid Dosage Forms” Pharmaceutics of Solids and Solid Dosage Forms, Wiley-Interscience, 182-185, 1977

3. ICH Q1E Evaluation of stability data 4. Haynes, J.D., “Worldwide Virtual Temperatures for Product Stability Testing,” J.

Pharm. Sci., Vol. 60, No. 6, 927 (June 1971). 5. the theory and practice of industrial pharmacy leon lachman, Herbert liberman

joseph kanig third edition.

QUESTIONS:

1. How is accelerated storage stability carried out? (University 2006) 2. outline of accelerated stability study as per ICH guidelines.(lm 04,07) 3. How is accelerated stability carried out? What are current perspectives in

stability testing from view point of regulatory agencies (university 2004, 2007?)

4. Elaborate on the stability testing frequency of pharmaceuticals 5. Explain “shelf life determination based on arrehenius equation” 6. what is Q10 method & its importance in shelf life estimation( LM 06) 7. Define stress testing .why stress testing should be carried out? 8. How accelerated stability test differ from stress testing? (lm 05) 9. explain method of predicting shelf life & overages ?(LM 05)

PAPER-910101 CHAPTER-4 STABILITY STUDIES

NITU

47

EFFECT OF VARIOUS ENVIRONMENTAL / PROCESSING FACTORS ON STABILITY OF THE FORMULATION AND TECHNIQUES FOR STABILIZATION OF PRODUCTS AGAINST THE SAME. PREPARED BY, GUIDED BY,

Nitu Changoiwala Dr. R.K Parikh

Roll No:- 04

M-Pharm Sem-I

DEPARTMENT OF PHARMACEUTICS

&

PHARMACEUTICAL TECHNOLOGY.

L.M.COLLEGE OF PHARMACY

AHMEDABAD -09


NITU

48

PROCESSING FACTORS:-

BLENDING:- It is most important step for manufacturing of solution dosage form.

High speed of mixing may introduce air into the product and slow mixing

may not form a satisfactory product.

For mixing step, both mixing time and speed should be evaluated for

API and Excipients.

Mixing might produce particle size reduction or polymorphic conversion

During mixing some other factors like type of agitator, temperature or

vaccum etc. can affect the stability.

Say for example, if during mixing, vacuum is not applied than air bubble

will present into the product that might produce oxidation of product.

WAYS FOR STABILIZATION:-

Use of optimum time and rate of mixing.

Use of optimum and controlled temperature.

Application of vacuum.

Use of closed system.

FOR SOLID DOSAGE FORM:- During pharmaceutical powder blending process in case of solid dosage

form, electrostatic charges generate due to particle-particle & particle

wall collision.

The effect of electrostatic charging on pharmaceutical powder

homogeneity was investigated on 2 binary blending system:-

LACTOSE as an excipient with CAFFEINE as an API

&

MCC as an excipient with CAFFEINE as an API

3 different blending procedures were conducted

1. Conventional without charge control.

2. Blending with simultaneous charge neutralization.

3. Blending combined with corona(apparatus) charging process

It was found that presence of uncontrolled electrostatic charges has an

adverse effect on powder blend uniformity. Elimination of charges also

appears to have negative impact on blend uniformity. In contrast blending

of negatively charged excipient & positively charged API leads to better

blend uniformity.

(JPS,VOL-98,NO-7,JULY,2009)


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49

FREEZE-DRYING PROCESS:- Freeze-drying process also affects the stability of product & there are

various substances used for the process of freeze-drying which also leads

to either increase or decrease in the stability.

o A method to produce physically stable formulation.

o Applicable for multivitamin preparation, antibiotics, hormones and

Proteins formulation.

o Cryoprotectant is added in formulation when product is

lyophilized.

o To act successfully as a protectant, it should have,

-- A high glass transition temperature (Tg),

-- A poor hygroscopicity,

-- A low crystallization rate,

-- Contain no reducing groups.

Eg:-

Freeze drying was found to have destructive effect on the ordered

structure of starch & this effect varied with respect to preparation

condition.

(JPS,VOL-98, NO-10,OCT 2009, pg no-3387)

Surfactants & sugars possess synergistic effects on the lipoplex stability

during freeze drying.

(JPS,VOL-98,NO-9,SEPT.2009,Pg no-3319)

Impact of bulking agents was studied on the stability of monoclonal

antibody.it was found that sucrose acts as a primary stabilizer but when

glycine was added, glycine leads to increase in the stability & when

mannitol was added instead of glcine again there was increase in the

stability though to a lesser extent as compared to glycine.

(CA,VOL-151, NO-14, NOV 2009,321346z,Pg no-1954)

POLYMERIC FILM COATING PROCESS:- The key to a successful application of an aqueous film coat to solid

dosage forms is a full understanding of the important processing factors

influencing the application process. Here we will enlist processing factors

that contribute to product performance, since slight variation in

processing conditions will impact the properties and therapeutic response

of a film-coated drug delivery system.


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50

List of processing factors influencing the properties of polymeric film

coatings:-

WAYS FOR STABILIZATION:

Use of optimum processing condition for film coating.

Identification and use of excipients which increased stability of film

coated product.

Interactions during Aqueous film coating of Ibuprofen with Aquacoat ECD.

During the development of a coated ibuprofen formulation a sticking

tendency occurred when applying Aquacoat ECD.

The compatibility of the components of Aquacoat ECD with ibuprofen was

investigated by differential scanning calorimetry.

Cetyl alcohol, a stabilizing excipient in Aquacoat, was found to form a

eutectic system with ibuprofen. It was characterized by the construction of a

phase diagram with 33 mol% ibuprofen and an onset temperature of 40.5 °

C.

MILLING The milling process results in a reduction in the particle size of a given

material and can be conducted using the mildest conditions possible to

render a sample homogeneous, or can use more rigorous milling to reduce

the primary particle size.

The formation of a high energy amorphous material is usually undesirable

and given the opportunity, will spontaneously transfer either to a

crystalline hydrate or anhydrate.


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51

These physical changes in the state of the drug substance can alter the

stability, dissolution characteristics and possibly even the bioavailability

of the drug.


Use of moderate condition of milling.

Optimum time of milling.

Eg:-

1. The phase transformation of chloramphenicol palmitate associated

with grinding and the effect of seed crystals

Thus, as we know that with increase in the concentration of form A of

chloramphenicol palmitate the blood level are found to decrease and there is a

detection test for presence of form A in Pharmacopoeias, so while grinding no

impurity of form A should be present and grinding time should not exceed

150 minutes (to prevent conversion of form B to form A).

2) Formation of physically stable amorphous drug by milling.

DRUGS (KETOPROFEN, INDOMETHACIN, NAPROXAN, PROGESTERON)

NEUSILIN (AMOR. MAGNESIUM ALUMINUM SILLICATE)

AMORPHIZATION OF DRUG

NO CONVERSION

Ball Milling

Storage

Form A Form B Form C 16 min. 150 min.

30 min. (1% Form A)

40 min. (1%Form B)


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52

CONCLUSION: - The amorphous form formed was studied for stability and

found that this form is much more stable than normal amorphous form.

AND Similar studies were done on Salbutamol Sulphate & PVP.Experiment

was done to improve the stability of SS as SS gets easily coverted from

amorphous form to agglomerated particles.stability was induced by the method

of co-milling.co-milling of SS with excipients like pvp was done..

EFFECT OF COMPRESSION:- It is generally assumed that overall amount of energy input into a

formulation during compression is not sufficient to induce a phase

transformation and for many substances this situation is certainly

true.There are numerous examples, for which changes in phase

composition do accompany a compression step.

Carbamazepine is a drug which shows differences in the dissolution

rates that are associated with production of different polymorphs by tablet

mfg process.

It has 3 different crystalline form – α, β and Dihydrate form.

Manufacturing process is

Grinding (ball mill for 15 and 60 min)

Compression (single punch machine)

It was found that

Dihydrate - good compressibility but not stable

α - best stability but sticking

β - best stability .

The effects of milling and compression on the solid-state Maillard

reaction between metoclopramide hydrochloride and lactose were

investigated. Anhydrous metoclopramide hydrochloride was milled

for various times, and then mixed with amorphous lactose. The

mixtures were stored at 105°C and 0% RH. The reactivity of

metoclopramide hydrochloride towards the Maillard reaction

increased with milling time, as the result of increased surface area,

formation of amorphous content, and creation of defects.

Metoclopramide hydrochloride anhydrate and lactose were mixed and

the mixtures were compressed into tablets under pressure varied from

70 to 350 MPa. Both tablets and mixtures were stored at 105°C and

0% RH for 9 days. For all three types of lactose used, spray-dried

anhydrous lactose, spray-dried lactose monohydrate, and amorphous

lactose, tablets exhibited higher reaction rate toward the Maillard


NITU

53

reaction than the powder mixtures. Tablets containing metoclopramide

hydrochloride and amorphous lactose prepared at higher pressure

showed higher reaction rates than those prepared at lower pressure.

(JPS, , VOL. 94 , sept 2005)

EFFECT OF LOCAL MOBILITY:- Local mobility in amorphous forms of pharmaceuticals can lead to

changes in their glass transition temperature effect of which is such that

amorphous form converts to crystalline form.

(JPS,VOL-98,NO-9,SEPT 2009,Pg no-2935)

WET GRANULATION:- Wet granulation process, the both wetting phase solvent and drying phase

conditions can cause a suitable environment for the transformation to

alternate crystalline forms.

Polymorphic transformations during wet granulation can be divided to

1) Conversion of a metastable form to the stable form;

2) Conversion of the stable form to a metastable form; or

3) Conversion of an unsolvate form to a solvate form.


Use of granulating liquid which will not produce polymorphic

conversion.

Moderate/Optimum condition for drying.

The preparation of tablets by THE MELT GRANULATION PROCESS

was investigated to enhance chemical stability of a highly water-soluble

drug substance, dipeptidylpeptidase IV (DPP-IV) inhibitor

(Compound I), that is susceptible to degradation in presence of moisture.

Melt granulation with a lipophilic binder (hydrogenated castor oil)

improved the stability of the drug, while still maintaining immediate-

API molecule

Polymorph 1 Polymorph 2


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54

release characteristics of the drug product.With higher binder levels, the

sensitivity of the drug to degradation under humidity conditions

decreased. It is postulated that the lipophilic binder coated drug particles

at the surface protecting them from the influence of moisture. The

granules had good flow properties and good compressibility and tablets

prepared from them exhibited low weight variation and low friability.

(IJPS, oct 2009, Vol 381, Pg.56-61)

The effect of some processing and formulation variables on the stability

of tablets containing a crystalline salt of a triazine derivative was studied.

The salt has a relatively low melting point and a low microenvironmental

pH due to the weakly basic nature of the parent compound (pKa = 4.0).

This compound decomposes through acid-catalyzed hydrolysis. A full

factorial design was used to study the effect of three variables on tablet

stability: aqueous wet granulation, ball milling of the salt and filler prior

to manufacturing, and the inclusion of sodium carbonate in the

formulation as a pH modifier. In addition to the factorial design

experiments, a batch of tablets was prepared by wet granulation, using

sodium bicarbonate as the pH modifier. Stability of tablets was adversely

affected by wet granulation. However, stability was greatly improved by

wet granulation in the presence of sodium carbonate.The use of sodium

bicarbonate as a pH modifier resulted in only marginal enhancement of

tablet stability, suggesting that a higher microenvironmental pH than that

provided by sodium bicarbonate is needed to maximize stability.Milling

was found to have no effect.

EFFECT OF ADDITIVES:- The amorphous character is common in the polymeric molecules used as

excipients. For example, sugars usually exist in the amorphous state e.g. as a

result of milling, spray drying or freeze drying. Amorphous sugars are highly

hygroscopic and at high RHs they may sorb large amounts of water causing

crystallization of that sugar. This process can have significant consequences for

the stability of pharmaceutical formulations, because the presence of only small

amounts of amorphous material can affect the interaction between the powder

and other components of a formulation.

Optimizing the selection of excipients in the formulation could reduce

transformation during manufacturing and storage of final dosage forms.


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55

INSTABILITY of APIs and excipients may be broadly classified as:-

CHEMICAL INSTABILITY (like Hydrolysis, Oxidation and

Deamidation) or

PHYSICAL INSTABILITY (like Polymorphism,

Pseudopolymorphism or Crystallization).


Avoid use of excipients which produce instability.

Minimum numbers of excipients should be used.

Use of excipient with multiple action.

Eg:- SURFACTANTS:-

Presence of surfactants may either increase or decrease the

stability.LIKE presence of micelles of CETYL

TRIETHYLAMMONIUM BROMIDE & CETYL PYRIDINIUM

CHLORIDE inhibits degradation of aspirin by hydrolysis which is

acid catalyzed reaction in contrast increase the degradation of base

catalzsed reaction.

COMPLEXING AGENTS:-

Complexing agents increase the stability.Aromatic esters like

benzocaine,procaine & tetracaine can be stabilised in solution form by

the addition of 1-5% caffiene because of formation of complex.

ANTIOXIDANTS & CHELATING AGENTS:-

These agents generally increase stability by decreasing the rate of

reaction.

EFFECT ON STABILITY IN PRESENCE OF OTHER

DRUGS:- Sometimes presence of one drug affects either physical or chemical

stability of other drug.

Eg:-

1. Yuxingcao injection when mixed with 6 drugs at temp. 25°c & analysed

using uv following observation done:-

YUXINGCAO + PENICILLIN = PRECIPITATION

YUXINGCAO + GANCYCLOVIR= PRECIPITATION

YUXINGCAO + OFLOXACIN = NO CHANGE

YUXINGCAO + RIBAVIRIN = NO CHANGE

YUXINGCAO + CEPHRADIN = NO CHANGE FOR 2 HRS &

DECREASE IN CONTENT WITHIN 24 HRS.


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56

YUXINGCAO + ACYCLOVIR = DECREASE IN CONTENT WAS

OBSERVED.

(CA,VOL-151,5th

OCT 2009,Pg no-1970,321538p)

2. When fosfomycin sodium & gatifloxacin were mixed & analysed by UV

spectroscopy it was found that content & spectra of UV spectra changed

significantly.

(CA,VOL-151,5th

OCT 2009,Pg no-1970,321539q)

3. Stability of cefotiam in moxifloxacin injection. Stable for 8hrs at 25° C

& 37°C.

(CA, VOL-151,12th

OCT 2009,Pg no-1906,344130p)

RADIATIONS:- Not common variable.

Employed in the sterilization of pharmaceutical product so, its effect on

stability of drug should be considered.


Avoid irradiation if sterilization by other ways is possible.

Formation of various products on irradiation of diazepam in a

methanolic solution was inhibited by ascorbic acid.

γ - Irradiation Effects on Stability of Poly(lactide-co-glycolide)

Microspheres Containing Clonazepam.

The influence of CLO on PLGA radiolysis mechanisms and the

identification of possible irradiation markers were investigated.

Microspheres were prepared by means of a spray-drying method.

Radiolysis mechanisms were investigated by using electronic

paramagnetic resonance (EPR) analysis.

Polymer/CLO spin transfer reactions suggest that CLO had a

radiostabilising effect on the polymeric matrix.


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57

ENVIRONMENTAL FACTORS:-

TEMPERATURE:- Study of decomposition of the product at elevated temperature should be done to

know the temperature dependency of reaction.

It helps in predicting the stability of the product at ordinary shelf temperature.

Rate of reaction is denoted for each 10° c rise in temperature accelerated study is

done to decrease the time period for stability study.

At 37° c it takes 100 days for degradation & for 80° c it takes 25 days for

degradation.

Temperature is one of the primary factors affecting the drug stability.

As temperature increases a greater available free energy leads to a more

rapid reaction and typically a 10° C increase in temperature produces a

two to five fold increase in decay.

It catalyses hydrolysis, oxidation & thermal reaction follows just after initiation

of photolytic reaction.

The most satisfactory method for expressing the influence of temperature

on

reaction velocity or rate is the quantitative relation proposed by Arrhenius:

K = A * e-Ea/RT

Where, K = specific rate of degradation

A = Frequency Factor

Ea = Arrhenius Activation Energy

R = Gas Constant

T = Absolute Température

Logarithmically it can be expressed as:

Log K = log A - Ea/ 2.303 RT


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58

From the graph of K 1/T one can determine Ea from slope and A from intercept.

LOG K

1/T

Limitations of Arrhenius relationship for prediction of stability of products:

1. At higher temp., there is less relative humidity & O2 solubility , thus

hindering the predictability of RT stability of drug sensitive to presence of

moisture and oxygen.

2. For dispersed systems, viscosity is decreased as temp. is increased

and physical characteristics may be altered, resulting in potentially

large errors in prediction of stability .

3. Different degradation mechanisms may predominate at different

temperatures, thus making stability prediction marginal at best.


Pharmaceutical product should be stored within the temperature range in

which they are stable.

They should not be exposed to extremes of temperature.

Usually they should be stored at low temperature if they lack sufficient

stability at room temperature.

There are few drugs on which freezing has an adverse effect, so freezing

should be avoided unless until it is stable at such temperatures.

SLOPE = -Ea/2.303R

INTERCEPT

= LOG A


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59

HUMIDITY:- Higher humidity may lead to moisture adsorption.

As relative humidity is increased stability is decreased for drusgs which

are highly sensitive to hydrolysis.

Higher humidity increases ageing process through interaction of drugs

with excipients.

It can affect the stability of pharmaceuticals by,

Hydrolytic degradation

Isomerization

Crystallization

Affecting flow and compaction properties etc.

Figure: Water vapour adsorption and deliquescence of a water soluble

solid particle.

EFFECT OF MOISTURE CONTENT ON THE STORAGE

STABILITY OF LIPOPLEX FORMULATIONS CONTAINING

THIOBARBITURIC ACID DERIVATIVES WAS FOUND.

TEMPERATURE CHOOSEN WERE RT,40°C & 60 °C FOR 3

MONTHS.

RESULTS:-

AT ROOM TEMPERATURE – CONCENTRATION WAS

MAINTAINED .

AT HIGHER MOISTURE CONTENT – 1.93 LOWER TBA

DERIVATIVES.

AT LOWER MOISTURE CONTENT – LITTLE HIGHER TBA

DERIVATIVES.

(JPS,VOL-98,NO-9,SEPT 2009,Pg no-3301)


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60


Maintenance of controlled humidity condition

Moisture proof packaging.

OXIDATION:-

LIGHT:- BOTH ARE SAME AS DISCUSSED IN PREFORMULATION

(PHYSICO-CHEMICAL FACTORS).

pH The change of more than 10 fold in rate constants result in just shift of 1

pH unit.

So, before formulating the drug in solution , K versus pH should be

studied & optimum pH at lowest value of rate constant is to be found out.

Hydrogen ion catalysis occurs at lower pH & hydroxyl at higher Ph.

K

pH WAY FOR STABILIZATION:

Maintenance of stable pH by use of appropriate buffer salts.

The effect of salt form on the stability of an ester prodrug of a

IIb/IIIa receptor antagonist was investigated. The pH of maximum stability for the ester prodrug is approximately 4. The mesylate salt is thought to provide lower microenvironment pH, closer to the pH of maximum stability, than the acetate salt. Stability of drug

MAXIMUM

STABILITY AT

THIS pH


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61

product manufactured using the mesylate salt (DMP 755) was studied and compared with that for the acetate salt (DMP 754). Formulations contained disodium citrate as a pH modifier to control formulation pH, since solid state stability for this compound is dependent on the microenvironment pH. The pH modifier was not able to achieve adequate microenvironment pH control for the DMP 754 drug product when added using a dry manufacturing process. While DMP 754 required the use of a pH modifier added in solution during wet granulation in order to improve drug product stability, DMP 755 was able to achieve similar results using the dry granulation process. Stability of DMP 755 drug product was independent of effectiveness of the pH modifier. This study showed that the choice of the salt form may provide an alternative for maximizing drug product stability.

EFFECT OF SOLUBILITY:- Applicable to drugs in solution form.

Eg:- Penicillins are very unstable in aqueous solution because of hydrolysis of β-

lactam ring.


Stabilised by using insoluble salts of API.

Formulate the drug in suspension dosage form.

EFFECT OF IONIC STRENGTH:- The rate of reaction can be influenced by the ionic strength of the solution

in accordance with the following equation:

log k = log k0 + 1.02ZA ZB

Where,

ZA & ZB - charges carried by the reacting species in solution

U- the ionic strength

K- rate constant at infinite dilution.

&

Where,

U = ½ 2


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62

ZA,ZB = +ve

ZA,ZB = 0

ZA,ZB = -ve

Drugs with positive charge undergoes H

+ion catalysis & in this

increase in ionic strength caused by the addition of salt increases

rate of reaction.

If the drug is neutral change in ionic strength will have no effect.

Drugs with negative charge undergoes OH- ion catalysis & in this

increase in ionic strength caused by the addition of salt decreases

rate of reaction.

EFFECT OF PACKAGING COMPONENTS:- Most commonly employed are

CONTAINERS:

Glass, Plastic, Metal

CLOSURES:-

Rubber

CONTAINERS:

1) GLASS

PROBLEMS:

a) Release of alkali

b) Release of Insoluble flake

logk-logk0


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63

REMEDY FOR PREVENTION OF RELEASE OF ALKALI:-

By decreasing soda content

Siliconization of surface.

By replacing sodium oxide with other oxides.

Surface treatment by sulphur-di-oxide in presence of water-vapour &

heat.

REMEDY FOR PREVENTION OF RELEASE OF INSOLUBLE

FLAKE:-

Flake formation can be prevented by using borosilicate glass

Pretreatment of the container with dilute acid.

2) PLASTIC

HIGH MOLECULAR WEIGHT POLYMERS LIKE POLYETHYLENE,

POLYPROPYLENE, POLYSTYRENE, PVC ETC

PROBLEMS:

a) Permeation of moisture

b) Leaching

c) ADSORPTION OR ABSORPTION

d) CHEMICAL/PHYSICAL REACTION OF CONTENTS OF

CONTAINERS WITH PRODUCTS.

REMEDY:

Lining of the container with an epoxy resin eliminates this

problem but

has to be evaluated separately for each product .

(epoxy lining doesnot prevent sorption of phenyl mercuric nirate).

Stablity of FENTANYL 5µg/ml diluted with 0.9% sodium

chloride injection & was stored in polypropylene syringes….

It was found that above solution was stable for 90 days in

controlled ambient conditions when stored protected from light..

(CA, 5th

Oct, 2009,vol-151,pg no-1973,321560q)

3) METALS

Metals commonly used are tin , plastic coated tin , tin-coated lead ,

aluminum and coated aluminum .

PROBLEMS:

a) Reactivity

1. TIN + CHLORIDE ERROSION

2. ALUMINUM + FATTY ALCHOL WHITE


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64

ENCRUSTATION

REMEDY: Application of an epoxy lining to internal surfaces of aluminum

tubes was found to make them more resistant to attack .

CLOSURES:-

a) RUBBER

PROBLEMS:

a) Sorption of API into rubber.

b) Extraction of one or more components of rubber into vial solution .

Leached extractive in the solution can cause:-

a. Interference with chemical analysis of drug.

b. Affects toxicity & pyrogenicity of injectables.

c. Can cause drug inactivation.

d. Can cause physical instability so,to prevent such intereferences.

REMEDY:

Epoxy lining applied to rubber stoppers

- reduction results in amount of extractive leached from stopper but

no effect on sorption of preservative from solution .

- However use of Teflon – Coated rubber stoppers essentially

prevents sorption and leaching of the rubber stopper .


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65

NEW STABILIZATION TECHNIQUE:-

SUPERCRITICAL FLUID:-

• Near the critical points, supercritical fluids possess liquid like densities and

gas like transport properties.

• CO2 -choice for pharmaceutical application

Dry powders of Stable Protein Formulations from aqueous solutions

Prepared using Supercritical CO(2)-assisted Aerosolization

Use of a new supercritical carbon dioxide-assisted aerosolization

coupled with bubble drying technology.

Two model proteins, lysozyme and lactate dehydrogenase (LDH).

In the absence of excipients, lysozyme was observed to undergo

perturbations of secondary structure observed by solid-state infrared

spectroscopy. In the presence of sucrose, this unfolding was minimized.

The more labile LDH suffered irrecoverable loss of activity on

reconstituting in the absence of carbohydrate stabilizers.

LDH could be stabilized through with the addition of sucrose, and

almost complete preservation of activity was achieved with the further

addition of a surface active agent, such as Tween 20.


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PRIOR STUDY QUESTIONS:-

1. Enlist various processing factors affecting stability of formulation ?

2. Describe effect of particle size reduction (or milling) on stability of

formulation product and stabilization against the same?

3. Describe effect of radiation on stability of formulation product and

stabilization against the same?

4. Effect of RH on stability and stabilization against the same?

5. What is process induced transformation? Discuss the effect of wet

granulation, compression and excipients on the stability?

6. Discuss the effect of temperature, light and RH on the stability and

stabilization against the same?

7. Note on the influence of packaging components on the dosage form

stability?

NEW STUDY QUESTIONS:-

1. What is the effect of pH & ionic strength on the stability of drug?

2. Write a note on effect of blending on solid as well as liquid dosage

form?

3. Explain the effect of freeze drying on the stability?

4. What are the effects of polymeric film coating & amorphous mobility

on the stability of drug?

5. Note on effect of additives on stability?

6. Note on effect of presence of other drugs?

7. Explain the effect of solubility on stability with examples &

stabilization techniques?

8. Write a note on various stabilization techniques employed for the

stability of pharmaceutical dosage form?


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67

REFERENCES

1. THE THEORY AND PRACTICE OF INDUSTRIAL PHARMACY

BY LEON LACHMAN, HIBERT A. LIBERMAN AND JOSEPH L.

KANIG.

2. PHYSICAL PHARMACY BY ALFRED MARTIN.

3. MODERN PHARMACEUTICS BY MARCEL DEKKER, CH-6.

4. www.drugdeliverytech.com

5. www.sciencedirect.com

6. www.informaworld.com

7. JPS,VOL-98,NO-7,JULY,2009,pg no-2936

8. IJPS, oct 2009, Vol 381, Pg.56-61 9. JPS,VOL-98, NO-10,OCT 2009, pg no-3387

10. JPS,VOL-98,NO-9,SEPT.2009,Pg no-3319

11. CA,VOL-151, NO-14, NOV 2009, Pg no-1954, 321346z

12. JPS,VOL-98,NO-9,SEPT 2009,Pg no-2935

13. CA,VOL-151,5th

OCT 2009,Pg no-1970,321538p

14. CA,VOL-151,5th

OCT 2009,Pg no-1970,321539q

15. CA, VOL-151,12th

OCT 2009,Pg no-1906,344130p

16. JPS,VOL-98,NO-9,SEPT 2009,Pg no-3301

17. JPS, , VOL. 94 , SEPT 2005

18. CA, VOL-151,5th

Oct, 2009, pg no-1973,321560q

aiche.confex.com/aiche/2008/techprogram/P124994.HTML

http://www.drugdeliverytech.com/

http://www.sciencedirect.com/

http://www.informaworld.com/

SEMINAR on

Regulatory requirement

related to stability testing

PREPARED BY: MANAVADRIYA HIMANSHU GUIDED BY: Dr R.K PARIKH

M.PHARM: I ROLL NO: 02

DEPARTMENT OF PHARMACEUTICS AND

PHARMACEUTICAL TECHNOLOGY

L. M. COLLEGE OF PHARMACY, AHMEDABAD- 09

Paper 910101 regulatory requirement related to stability testing

M.Pharm-І-2009-10 HIMANSHU

Department of pharmaceutics and pharmaceutical technology,LMCP

List of Contents:

Contents

Introduction

Over view of ICH guidelines

Climate zones

SUPAC guidelines

Photo stability testing of new drug

substance & products

Bracketing and metrixing of new drug

substance & products

Impurity profile

References




STABILITY[2,3,4]

: “The capacity of a drug product to remain within specifications

established to ensure its identity, strength, quality and purity”.

PURPOSE OF STABILITY STUDY[2,3,4]:

To provide evidence of how the quality of drug substances or products varies with

time under the influence of environmental factors. (temperature, humidity and

light)

To establish a re-test period for the drug substances or the shelf-life for the drug

products and recommended storage conditions.

To ensure that drug products retain their full efficacy until the end of their

expiration date.

Most important guidelines are[2,3,4]

Food and Drug Administration (FDA)

International Conference on Harmonization (ICH)

European Union Guidelines (EU)

Japanese Guidelines (MHW)

World Health Organization (WHO) Guidelines

Currently ICH guidelines are most commonly accepted which provides information on

stability testing within the areas of European Union (EU), Japan, and United States.

Overview of ICH guideline for stability testing…

Stability Q1A

(R2)

Stability Testing in New Drugs and

Products (Revised guideline)

Q1B Photo-Stability Testing

Q1C Stability testing: New Dosage Forms

Q1D Bracketing and Matrixing Designs for

Stability Testing of Drug Substances

and Drug Products

Q1E Evaluation of Stability Data

Q1F Stability Data Package for

Registration in Climatic Zones III and

IV

Analytical

validation

Q2A Definitions and Terminology

Q2B Methodology

Impurities Q3A Impurity Testing in New Drug

Substances

Q3B Impurities in Dosage Forms:

Addendum to the Guideline on

Impurities in New Drug Substances

Q3C Impurities: Residual Solvents




Pharmacopeias Q4 Pharmacopeial harmonization

Biotechnology

Quality

Q5A Viral Safety Evaluation

Q5B Genetic Stability

Q5C Stability of Biotechnology Products

Q5D Cell Substrates

Specification Q6A Specifications, Test Procedures, and

Acceptance Criteria for New Drug

Substances and Products

Q6B Biotechnological substance

GMP Q7A GMP for active pharmaceutical

ingredients

Development Q8 Pharmaceutical development

Management Q9 Quality Risk Management

STABILITY

GUIDELINE

S1(A) Guidelines on The Need For

Carcinogenicity studies of

pharmaceuticals

S1(B) Testing for carcinogenicity of

pharmaceuticals

S1(C) Dose selection for carcinogecity

studies of pharmaceuticals

S2A Guidance on specific aspect of

regulatory genotoxicity test for

pharmaceuticals

S2B Standard for genotoxicity testing for

pharmaceuticals

S(3A) Note for guidance on

Toxicokinetics

S(3B) Pharmacokinetic:- Guidance for

repeated dose tissue distribution

studies

S4 Duration of Chronic Toxicity

testing in Animals

S5 Detection of Toxicity To

Reproduction for Medicinal product




and toxicity to male fertility

S6 Preclinical Safety Evaluation Of

Biotechnology derived

Pharmaceuticals

S7 Safety Pharmacology studies for

Human Pharmaceuticals

S8 Immunotoxicity studies for Human

Pharmaceuticals

EFFICACY

GUIDELINES

E1 The Extent of Population Exposure

to Assess clinical Safety

E2(A) Clinical safety Data management

E2(B) Implementation working group

E2C Clinical safety Data management :-

periodic safety update reports &

marketed drugs

E2(D) Post aproval safety data

manegemant :- Definations and

Standards for expedited reporting

E2(E) Pharmacovigillance Planning

E2(F) Development safety update report

E3 Structure and content of clinical

study reports

E4 Dose response Information to

support drug regisitration

E5 Ethnic factors in the acceptability of

foreign clinical data

E6 Guideline for Good Clinical

Practice

E7 Studies in support of Specific

Population

E8 General Consideration For Clinical

Trials

E9 Stastical Principles For Clinical

Trials

E10 Clinical Investigation of medicinal

products In The Pediatric

population

E11 Principles Of Clinical Evaluation of

New Anti-hypertensive drugs




E12 The Clinical Evaluation of

proarrythmic potential for Non-

Antiarrythmic drugs

E13 Definations of genomic biomarkers,

pharmacoecononomics,

pharmacogenetics, Genomic DATA

& sample coding categories

MULTIDISCIP

LINE-

GUIDELINES

M1 Maintenance of The ICH Guideline

on non-clinical safety studies for the

conduct of human clinical trials for

pharmaceuticals

M2 Electronic Transmission of

Individual Case Safety Reports

Message Specification

M3 Organisation of the Common

Technical Document for the

Registration of Pharmaceuticals for

Human Use

INTERNATIONAL CLIMATIC ZONES AND CLIMATIC

CONDITIONS[1,2,3,4]

Climatic

Condition

Zone I

Temperate

Zone II

Mediterranean

(sub-tropical)

Zone III

Hot/dry or

Hot/moderate

RH

Zone IV

Very

hot/humid

Mean

Annual

Temperature

< 20°C 20.5-24°C >24°C >24°C

Kinetic

Mean

Temperature

(Virtual

temperature)

21°C 26°C 31°C 31°C

Mean

Annual

Relative

Humidity

45% 60% 40% 70%




REQUIREMENT OF TEMPERATURE DEPENDED ON TYPE OF

TESTING

TYPE OF

STUDY

TEMPERATURE

RELATIVE

HUMIDITY

TIME

DURATION

Long term 25°C ± 2°C /60% RH ± 5%

RH

12 months

Intermediate 30°C± 2°C /65% RH ± 5%

RH

6 months

Accelerated 40°C± 2°C/ 75% RH ± 5%

RH

6 months

DIFFERENT TEMPERATURE REQUIREMENT DEPEND UPON

TYPE OF DOSAGE FORMS

FOR

DISTINCT

PRODUCTS

TYPE OF STUDY

AST IST LST

Solid oral DF,

solids for

reconstitution,

dry

&lyophilized

powders in glass

vials

40°C ± 2°C

75 % ± 5%RH

40°C±2°C

75 % ± 5% RH

40°C±2°C

75 % ± 5% RH

Liquids in glass

bottles ,vials,

sealed glass

ampoules which

provide an

impermeable

barrier to water

loss

40°C ± 2°C

Ambient

Humidity

30°C±2°C

Ambient

humidity

25°C±2°C

Ambient

Humidity

Drug products

in

semipermeable

40°C ± 2°C

NMT 25 %

RH

30°C±2°C

65 % ± 5%

RH

25°C±2°C

40 % ± 5% RH

Or 30°C±2°C




containers 35 % ± 5% RH

SUPAC GUIDELINES[1,2,3,4]

1) Stability Testing for New Drug Applications(NDA)

A. Drug Substance

B. Drug Product

2) Stability Testing for Abbreviated New Drug Applications(ANDA) A. Drug Substance Stability Data Submission

Supporting information may be provided directly to the drug product ANDA or by

reference to an appropriately referenced drug master file (DMF).

For ANDA bulk drug substances- on a minimum of one pilot-scale batch.

ANDA bulk drug substances produced by fermentation- on three production batches,

at least two of which should be generated from different starter cultures.

B. Drug Substance Testing

A program for stability assessment may include storage at accelerated, long-term,

and, if applicable, intermediate stability study storage conditions (refer to IV.G. of

the ICH Q1A Guidance and Section II.A. of this guidance).

C. Drug Product

As per ICH Q1 A [Section II.B.]

D. ANDA Data Package Recommendations

Accelerated stability data at 0, 1, 2, and 3 months. A tentative expiration dating

period of upto 24 months will be granted based on satisfactory accelerated stability

data unless not supported by the available long-term stability data.

Long-term stability data

Additional stability studies

accelerated stability study.

E. Stability Study Acceptance

3) Stability Testing For Investigational New Drug Applications The amount of information needed to achieve that assurance will vary with

o The phase of the investigation,

o The proposed duration of the investigation,

o The dosage form.

A. General

Supportive stability data for changes to an approved drug application (i.e. post

approval changes) required .

If change does not alter the stability of the drug product, the previously approved

expiration dating period can be used.

But now SUPAC-IR, MR , SS guidance are followed for stability studies .

Provides 5 stability data package types .

B. Change in Manufacturing Process of the Drug Substance




Carried out at approved manufacturing site .

Should be supported by the submission of sufficient data to show that such change

does not compromise the quality , purity , or stability of the drug substance and the

resulting drug product

Special concerns are there for biological products.

C. Change in Manufacturing Site

Site changes consists of change in location site of :

Manufacture

Packaging operations

Analytical testing laboratory both of company owned and contract

manufacturing.

Sufficient data to show that such a change does not alter the characteristics or

compromise the quality, purity, or stability of the drug substance or drug product

may be necessary.

The data should include a side-by-side comparison of all attributes to demonstrate

comparability and equivalency of the drug substance or drug product manufactured

at the two facilities.

New manufacturing locations should have a satisfactory cGMP inspection.

D. Change in Formulation of the Drug Product

Historically, all changes in drug product formulation were grouped together and

required extensive stability documentation, usually submitted as a prior-approval

supplement.

An exception was the detection of a color from a product that could be reported in an

annual report without supporting stability data

E. Addition of a New Strength for the Drug Product The addition of a new strength for an approved drug product will generally

require the submission of a prior-approval supplement.

Demonstration of equivalent stability between the approved drug product and the

new strength will allow extension of the approved drug product expiration dating to

the new strength.

New strengths intermediate to those of an approved drug product may be supported

by bracketing/Matrixing studies (See Section VII.G. and VII.H.).

F. Change in Manufacturing Process and/or Equipment for the Drug Product

Can be supported by the submission of sufficient data to show that such a change

does not alter the characteristics or compromise the stability of the drug product.

The standard stability commitment to conduct and/or complete the stability studies

on the first three production batches produced by the revised manufacturing process

in accordance with the approved stability protocol is necessary.

If the data are found acceptable, the approved expiration dating period may be

retained.

G. Change in Batch Size of the Drug Product A key question : whether the change involves a change in equipment or its mode of

operation, or other manufacturing parameters described for the approved batch size.

Table 19 presents the recommended stability data packages for a variety of batch size

situations not involving equipment or mode of operation changes.




If an equipment change is part of the batch size change, please refer to Change in

Manufacturing Process of the Drug Product (Section IX.F.).

H. Reprocessing of a Drug Product Stability data submitted should take into account the nature of the reprocessing

procedure and any specific impact that might have upon the existing stability profile

of the drug.

The expiration dating period for a reprocessed batch should not exceed that of the

parent batch, and the expiration date should be calculated from the original date of

manufacture of the oldest batch.

Reprocessing range from repackaging to regrinding and recompressing tablets.

Any batch of the drug product that is reprocessed should be placed on accelerated

and long-term stability studies using the approved protocol to generate a Type 2

stability data package.

I. Change in Container and Closure of the Drug Product

The first factor used in determining the stability data package recommendation is

whether or not the protective properties of the container/closure system are affected

by the proposed change.

Protective properties of the container/closure system include,

moisture permeability,

oxygen permeability,

light transmission.

Changes that may affect these properties should be supported by a greater amount of

data to support the change.

The second factor is the nature of the dosage form itself. A solid dosage form will

generally be less affected by a container change than a liquid dosage form




PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND

PRODUCTS[1,4]

1. GENERAL

The ICH Harmonized Tripartite Guideline covering the Stability Testing of New Drug

Substances and Products notes that light testing should be an integral part of stress

testing.

A. Preamble

The intrinsic photostability characteristics of new drug substances and products should be

evaluated to demonstrate that, as appropriate, light exposure does not result in

unacceptable change.

Normally, photostability testing is carried out on a single batch of material.

Under some circumstances these studies should be repeated if certain variations and

changes are made to the product (e.g., formulation, packaging).

The guideline primarily addresses the generation of photostability information for

submission in Registration Applications for new molecular entities and associated drug

products. The guideline does not cover the photostability of drugs after administration

(i.e. under conditions of use).

A systematic approach to photostability testing is recommended covering, as appropriate,

studies such as:

i) Tests on the drug substance;

ii) Tests on the exposed drug product outside of the immediate pack;

and if necessary ;

iii) Tests on the drug product in the immediate pack;

and if necessary ;

iv) Tests on the drug product in the marketing pack.

The formal labeling requirements for photolabile drug substances and drug products are

established by national/regional requirements.

B. Light Sources

The light sources described below may be used for photostability testing.

The applicant should maintain an appropriate control of temperature to minimize the

effect of localized temperature changes.

Option 1

Any light source that is designed to produce an output similar to the D65/ID65 emission

standard such as an artificial daylight fluorescent lamp combining visible and ultraviolet

(UV) outputs, xenon, or metal halide lamp.

D65 is the internationally recognized standard for outdoor daylight as defined in ISO

10977 (1993). ID65 is the equivalent indoor indirect daylight standard.

For a light source emitting significant radiation below 320 nm, an appropriate filter(s)

may be fitted to eliminate such radiation.

Option 2




For option 2 the same sample should be exposed to both the cool white fluorescent and

near ultraviolet lamp.

1. A cool white fluorescent lamp designed to produce an output similar to that specified

in ISO 10977(1993) ; and

2. A near UV fluorescent lamp having a spectral distribution from 320 nm to 400 nm

with a maximum energy emission between 350 nm and 370 nm; a significant

proportion of UV should be in both bands of 320 to 360 nm and 360 to 400 nm.

C. Procedure

For confirmatory studies, samples should be exposed to light providing an overall

illumination of not less than 1.2 million lux hours and an integrated near ultraviolet

energy of not less than 200 watt hours/square meter to allow direct comparisons to be

made between the drug substance and drug product.

DECISION FLOW CHART FOR PHOTOSTABILITY TESTING OF DRUG PRODUCTS

2. DRUG SUBSTANCE

For drug substances, photostability testing should consist of two parts: forced degradation

testing and confirmatory testing.

The purpose of forced degradation testing studies is to evaluate the overall

photosensitivity of the material for method development purposes and/or degradation

pathway elucidation.




This testing may involve the drug substance alone and/or in simple solutions/suspensions

to validate the analytical procedures.

In these studies, the samples should be in chemically inert and transparent containers.

In these forced degradation studies, a variety of exposure conditions may be used,

depending on the photosensitivity of the drug substance involved and the intensity of the

light sources used.

For development and validation purposes it is appropriate to limit exposure and end the

studies if extensive decomposition occurs.

For photostable materials, studies may be terminated after an appropriate exposure level

has been used.

Under forcing conditions, decomposition products may be observed that are unlikely to

be formed under the conditions used for confirmatory studies.

Confirmatory studies should then be undertaken to provide the information necessary for

handling, packaging, and labeling.

Normally, only one batch of drug substance is tested during the development phase, and

then the photostability characteristics should be confirmed on a single batch if the drug is

clearly photostable or photolabile.

If the results of the confirmatory study are equivocal, testing of up to two additional

batches should be conducted.

Samples should be selected as described in the Parent Guideline.

A. Presentation of Samples

Care should be taken to ensure that the physical characteristics of the samples under test

are taken into account and efforts should be made, such as cooling and/or placing the

samples in sealed containers, to ensure that the effects of the changes in physical states

such as sublimation, evaporation or melting are minimized.

All such precautions should be chosen to provide minimal interference with the exposure

of samples under test. Possible interactions between the samples and any material used

for containers or for general protection of the sample, should also be considered and

eliminated wherever not relevant to the test being carried out.

As a direct challenge for samples of solid drug substances, an appropriate amount of

sample should be taken and placed in a suitable glass or plastic dish and protected with a

suitable transparent cover if considered necessary.

Solid drug substances should be spread across the container to give a thickness of

typically not more than 3 millimeters.

Drug substances that are liquids should be exposed in chemically inert and transparent

containers.

B. Analysis of Samples

At the end of the exposure period, the samples should be examined for any changes in

physical properties (e.g., appearance, clarity, or color of solution) and for assay and

degradants by a method suitably validated for products likely to arise from photochemical

degradation processes.

Where solid drug substance samples are involved, sampling should ensure that a

representative portion is used in individual tests. Similar sampling considerations, such

as homogenization of the entire sample, apply to other materials that may not be

homogeneous after exposure.

The analysis of the exposed sample should be performed concomitantly with that of any

protected samples used as dark controls if these are used in the test.




C. Judgement of Results

The forced degradation studies should be designed to provide suitable information to

develop and validate test methods for the confirmatory studies.

These test methods should be capable of resolving and detecting photolytic degradants

that appear during the confirmatory studies.

When evaluating the results of these studies, it is important to recognize that they form

part of the stress testing and are not therefore designed to establish qualitative or

quantitative limits for change.

The confirmatory studies should identify precautionary measures needed in

manufacturing or in formulation of the drug product, and if light resistant packaging is

needed.

When evaluating the results of confirmatory studies to determine whether change due to

exposure to light is acceptable, it is important to consider the results from other formal

stability studies in order to assure that the drug will be within justified limits at time of

use (see the relevant ICH Stability and Impurity Guidelines).

3. DRUG PRODUCT

(It is same as that described in drug substances)

4. ANNEX

A. Quinine Chemical Actinometry

The following provides details of an actinometric procedure for monitoring exposure to a

near UV fluorescent lamp (based on FDA/National Institute of Standards and Technology

study).

For other light sources/actinometric systems, the same approach may be used, but each

actinometric system should be calibrated for the light source used.

Prepare a sufficient quantity of a 2 per cent weight/volume aqueous solution of quinine

monohydrochloride dihydrate (if necessary, dissolve by heating).

Option 1: Use 20 ml colourless ampoules (seal hermetically).

Shape and Dimensions for ampoule specifications.

Option 2: Use 1 cm quartz cell.

For both the options, prepare sample and control wrap in aluminum foil to protect completely

from light, and measure their absorbance At and Ao respectively at 400nm using 1cm path

length. Measure the change in absorbance.

The length of exposure should be sufficient to ensure a change in absorbance of at least 0.9.




BRACKETING AND MATRIXING DESIGNS FOR STABILITY TESTING OF

NEW DRUG SUBSTANCES AND PRODUCTS[1,4]

1. GUIDELINES

1.1 General

A full study design is one in which samples for every combination of all design factors

are tested at all time points.

A reduced design is one in which samples for every factor combination are not all tested

at all time points.

A reduced design can be a suitable alternative to a full design when multiple design

factors are involved. Any reduced design should have the ability to adequately predict the

retest period or shelf life.

During the course of a reduced design study, a change to full testing or to a less reduced

design can be considered if a justification is provided and the principles of full designs

and reduced designs are followed.

1.2 Applicability of Reduced Designs

Reduced designs can be applied to the formal stability study of most types of drug

products, although additional justification should be provided for certain complex drug

delivery systems where there are a large number of potential drug-device interactions.

Whether bracketing or matrixing can be applied depends on the circumstances.

Data variability and product stability, as shown by supporting data, should be considered

when a matrixing design is applied.

Bracketing and matrixing are reduced designs based on different principles. Therefore,

careful consideration and scientific justification should precede the use of bracketing and

matrixing together in one design.

1.3 Bracketing

Bracketing is the design of a stability schedule such that only samples on the extremes of

certain design factors (e.g., strength, container size and/or fill) are tested at all time points

as in a full design. The design assumes that the stability of any intermediate levels is

represented by the stability of the extremes tested.

The use of a bracketing design would not be considered appropriate if it cannot be

demonstrated that the strengths or container sizes and/or fills selected for testing are

indeed the extremes.

1.3.1 Design Factors

Design factors are variables (e.g., strength, container size and/or fill) to be evaluated in a

study design for their effect on product stability.

1.3.1.1 Strength

Bracketing can be applied to studies with multiple strengths of identical or closely related

formulations.

Examples




(1) capsules of different strengths made with different fill plug sizes from the same

powder blend,

(2) tablets of different strengths manufactured by compressing varying amounts of the

same granulation, and

(3) oral solutions of different strengths with formulations that differ only in minor

excipients (e.g., colourants, flavourings).

In cases where different excipients are used among strengths, bracketing generally should

not be applied.

1.3.1.2 Container Closure Sizes and/or Fills

Bracketing can be applied to studies of the same container closure system where either

container size or fill varies while the other remains constant.

The characteristics such as container wall thickness, closure geometry, surface area to

volume ratio, headspace to volume ratio, water vapour permeation rate or oxygen

permeation rate per dosage unit or unit fill volume should be compared to select the

extremes which may affect the product stability.

With justification, bracketing can be applied to studies for the same container when the

closure varies. Justification could include a discussion of the relative permeation rates of

the bracketed container closure systems.

1.3.2 Design Considerations and Potential Risks

If, after starting the studies, one of the extremes is no longer expected to be marketed, the

study design can be maintained to support the bracketed intermediates.

Before a bracketing design is applied, its effect on the retest period or shelf life estimation

should be assessed. If the stability of the extremes is shown to be different, the

intermediates should be considered no more stable than the least stable extreme (i.e., the

shelf life for the intermediates should not exceed that for the least stable extreme).

1.3.3 Design Example

An example of a bracketing design is given in Table 1. This example is based on a

product available in three strengths and three container sizes. In this example, it should be

demonstrated that the 15 ml and 500 ml high-density polyethylene container sizes truly

represent the extremes. The batches for each selected combination should be tested at

each time point as in a full design.

Table 1: Example of a Bracketing Design

Strength 50 mg 75 mg 100 mg

Batch 1 2 3 1 2 3 1 2 3

Container

size

15 ml T T T T T T

100 ml

500 ml T T T T T T

Key: T = Sample tested

1.4 Matrixing

Matrixing is the design of a stability schedule such that a selected subset of the total

number of possible samples for all factor combinations would be tested at a specified time

point.




At a subsequent time point, another subset of samples for all factor combinations would

be tested.

The design assumes that the stability of each subset of samples tested represents the

stability of all samples at a given time point. The differences in the samples for the same

drug product should be identified as, for example, covering different batches, different

strengths, different sizes of the same container closure system, and possibly, in some

cases, different container closure systems.

When a secondary packaging system contributes to the stability of the drug product,

matrixing can be performed across the packaging systems.

Each storage condition should be treated separately under its own matrixing design.

1.4.1 Design Factors

Matrixing designs can be applied to strengths with identical or closely related

formulations. Examples (same as bracketing).

With justification, matrixing designs can be applied, for example, to different strengths

where the relative amounts of drug substance and excipients change or where different

excipients are used or to different container closure systems.

1.4.2 Design Considerations

A matrixing design should be balanced as far as possible so that each combination of

factors is tested to the same extent over the intended duration of the study and through the

last time point prior to submission.

However, due to the recommended full testing at certain time points, it may be difficult to

achieve a complete balance in a design where time points are matrixed.

In a design where time points are matrixed, all selected factor combinations should be

tested at the initial and final time points, while only certain fractions of the designated

combinations should be tested at each intermediate time point.

If full long-term data for the proposed shelf life will not be available for review before

approval, all selected combinations of batch, strength, container size, and fill, among

other things, should also be tested at 12 months or at the last time point prior to

submission.

In addition, data from at least three time points, including initial, should be available for

each selected combination through the first 12 months of the study.

For matrixing at an accelerated or intermediate storage condition, care should be taken to

ensure testing occurs at a minimum of three time points, including initial and final, for

each selected combination of factors.

1.4.3 Design Examples

Examples of matrixing designs on time points for a product in two strengths (S1 and S2) are

shown in Table 2. The terms “one-half reduction” and “one-third reduction” refer to the

reduction strategy initially applied to the full study design. For example, a “one-half

reduction” initially eliminates one in every two time points from the full study design and a

“one-third reduction” initially removes one in every three. In the examples shown in Table 2,

the reductions are less than one-half and one-third due to the inclusion of full testing of all

factor combinations at some time points as discussed in section 2.4.2. These examples

include full testing at the initial, final, and 12-month time points. The ultimate reduction is

therefore less than one-half (24/48) or one-third (16/48), and is actually 15/48 or 10/48,

respectively.




Table 2: Examples of Matrixing Designs on Time Points for a Product

withTwo Strengths

“One-Half Reduction”

Time point (months) 0 3 6 9 12 18 24 36

S

t

r

e

n

g

t

h

S1 Batch 1 T T T T T T

Batch 2 T T T T T T

Batch 3 T T T T T

S2 Batch 1 T T T T T

Batch 2 T T T T T T

Batch 3 T T T T T


“One-Third Reduction”

Time point (months) 0 3 6 9 12 18 24 36

S

t

r

e

n

g

t

h

S1 Batch 1 T T T T T T

Batch 2 T T T T T T

Batch 3 T T T T T T T

S2 Batch 1 T T T T T T T

Batch 2 T T T T T T

Batch 3 T T T T T T


Additional examples of matrixing designs for a product with three strengths and three

container sizes are given in Tables 3a and 3b. Table 3a shows a design with matrixing on

time points only and Table 3b depicts a design with matrixing on time points and factors. In

Table 3a, all combinations of batch, strength, and container size are tested, while in Table 3b,

certain combinations of batch, strength and container size are not tested.

Tables 3a and 3b: Examples of Matrixing Designs for a Product with Three

Strengths and Three Container Sizes

3a Matrixing on Time Points

Strength S1 S2 S3

Container size A B C A B C A B C

Batch 1 T1 T2 T3 T2 T3 T1 T3 T1 T2






3b Matrixing on Time Points and Factors

Strength S1 S2 S3

Container size A B C A B C A B C

Batch 1 T1 T2 T2 T1 T1 T2



Time-point

(months)

0 3 6 9 12 18 24 36

T1 T T T T T T T

T2 T T T T T T

T3 T T T T T T

S1, S2, and S3 are different strengths. A, B, and C are different container sizes.

1.4.4 Applicability and Degree of Reduction

The following should be considered when a matrixing design is contemplated:

knowledge of data variability

expected stability of the product

availability of supporting data

stability differences in the product within a factor or among factors

number of factor combinations in the study

In general, a matrixing design is applicable if the supporting data indicate predictable

product stability and also when the supporting data exhibit only small variability.

However, where the supporting data exhibit moderate variability, a matrixing design

should be statistically justified.

If the supportive data show large variability, a matrixing design should not be applied.

1.4.5 Potential Risk

Due to the reduced amount of data collected, a matrixing design on factors other than

time points generally has less precision in shelf life estimation and yields a shorter shelf

life than the corresponding full design.

In addition, such a matrixing design may have insufficient power to detect certain main or

interaction effects, thus leading to incorrect pooling of data from different design factors

during shelf life estimation.

If there is an excessive reduction in the number of factor combinations tested and data

from the tested factor combinations cannot be pooled to establish a single shelf life, it

may be impossible to estimate the shelf lives for the missing factor combinations.

A study design that matrixes on time points only would often have similar ability to that

of a full design to detect differences in rates of change among factors and to establish a

reliable shelf life.




This feature exists because linearity is assumed and because full testing of all factor

combinations would still be performed at both the initial time point and the last time point

prior to submission.

2.5 Data Evaluation

Stability data from studies in a reduced design should be treated in the same manner as

data from full design studies.

IMPURITY PROFILE[1,4]

ICH guidelines:

Impurities Q3A Impurity Testing in New Drug

Substances

Q3B Impurities in Dosage Forms:

Addendum to the Guideline on

Impurities in New Drug Substances

Q3C Impurities: Residual Solvents

IMPURITIES IN NEW DRUG SUBSTANCES

1. PREAMBLE

This document is intended to provide guidance for registration applications on the content

and qualification of impurities in new drug substances produced by chemical syntheses

and not previously registered in a region or member state. It is not intended to apply to

new drug substances used during the clinical research stage of development.

The following types of drug substances are not covered in this guideline:

biological/biotechnological

peptide,

oligonucleotide,

radiopharmaceutical,

fermentation product and semi-synthetic products derived therefrom,

herbal products, and crude products of animal or plant origin.

Impurities in new drug substances are addressed from two perspectives:




Chemistry Aspects include classification and identification of impurities, report

generation, listing of impurities in specifications, and a brief discussion of analytical

procedures; and

Safety Aspects include specific guidance for qualifying those impurities that were not

present, or were present at substantially lower levels, in batches of a new drug substance

used in safety and clinical studies.

2. CLASSIFICATION OF IMPURITIES

Impurities can be classified into the following categories:

Organic impurities (process- and drug-related)

Inorganic impurities

Residual solvents

Organic impurities can arise during the manufacturing process and/or storage of the

new drug substance. They can be identified or unidentified, volatile or non-volatile, and

include:

Starting materials

By-products

Intermediates

Degradation products

Reagents, ligands and catalysts

Inorganic impurities can result from the manufacturing process. They are normally

known and identified and include:

Reagents, ligands and catalysts

Heavy metals or other residual metals

Inorganic salts

Other materials (e.g., filter aids, charcoal)

Solvents are inorganic or organic liquids used as vehicles for the preparation of

solutions or suspensions in the synthesis of a new drug substance. Since these are

generally of known toxicity, the selection of appropriate controls is easily

accomplished.

IMPURITIES IN NEW DRUG PRODUCTS

INTRODUCTION

1.1 Objective of the guideline

This document provides guidance for registration applications on the content and

qualification of impurities in new drug products produced from chemically synthesised

new drug substances not previously registered in a region or member state.

1.2 Scope of the guideline

This guideline addresses only those impurities in new drug products classified as

degradation products of the drug substance or reaction products of the drug substance

with an excipient and/or immediate container closure system.

Impurities arising from excipients present in the new drug product or extracted or leached

from the container closure system are not covered by this guideline.




This guideline also does not apply to new drug products used during the clinical research

stages of development.

The following types of products are not covered in this guideline:

biological/biotechnological products

Peptides

Oligonucleotides

Radiopharmaceuticals

fermentation products and semi-synthetic products derived therefrom

herbal products, and crude products of animal or plant origin.

2. RATIONALE FOR THE REPORTING AND CONTROL OF DEGRADATION

PRODUCTS

The applicant should summarise the degradation products observed during manufacture

and/or stability studies of the new drug product.

This summary should be based on impurities arising from the interaction with excipients

and/or the immediate container closure system.

In addition, the applicant should summarise any laboratory studies conducted to detect

degradation products in the new drug product.

3. ANALYTICAL PROCEDURES

The registration application should include documented evidence that the analytical

procedures have been validated and are suitable for the detection and quantitation of

degradation products.

In particular, analytical procedures should be validated to demonstrate specificity for the

specified and unspecified degradation products.

As appropriate, this validation should include samples stored under relevant stress

conditions: light, heat, humidity, acid/base hydrolysis, and oxidation.

The quantitation limit for the analytical procedure should be not more than ( ) the

reporting threshold.

Degradation product levels can be measured by a variety of techniques, including those

that compare an analytical response for a degradation product to that of an appropriate

reference standard or to the response of the new drug substance itself.

Reference standards used in the analytical procedures for control of degradation products

should be evaluated and characterised according to their intended uses. The drug

substance can be used to estimate the levels of degradation products.

4. REPORTING DEGRADATION PRODUCTS CONTENT OF BATCHES

Analytical results should be provided in the registration application for all relevant

batches of the new drug product used for clinical, safety, and stability testing, as well as

batches that are representative of the proposed commercial process.

Quantitative results should be presented numerically.

For each batch of the new drug product described in the registration application, the

documentation should include:

Batch identity, strength, and size

Date of manufacture

Site of manufacture

Manufacturing process

Immediate container closure




Degradation product content, individual and total

Use of batch (e.g., clinical studies, stability studies)

Reference to analytical procedure used

Batch number of the drug substance used in the new drug product

Storage conditions for stability studies

5. LISTING OF DEGRADATION PRODUCTS IN SPECIFICATIONS

The specification for a new drug product should include a list of degradation products

expected to occur during manufacture of the commercial product and under

recommended storage conditions.

Stability studies, knowledge of degradation pathways, product development studies, and

laboratory studies should be used to characterise the degradation profile.

The selection of degradation products in the new drug product specification should be

based on the degradation products found in batches manufactured by the proposed

commercial process.

Those individual degradation products with specific acceptance criteria included in the

specification for the new drug product are referred to as "specified degradation products"

in this guideline.

Specified degradation products can be identified or unidentified.

A rationale for the inclusion or exclusion of degradation products in the specification

should be presented.

This rationale should include a discussion of the degradation profiles observed in the

safety and clinical development batches and in stability studies, together with a

consideration of the degradation profile of batches manufactured by the proposed

commercial process.

In summary, the new drug product specification should include, where applicable, the

following list of degradation products:

Each specified identified degradation product

Each specified unidentified degradation product

Any unspecified degradation product with an acceptance criterion of not more than ( )

the identification threshold

Total degradation products.

6. QUALIFICATION OF DEGRADATION PRODUCTS

Qualification is the process of acquiring and evaluating data that establishes the

biological safety of an individual degradation product or a given degradation profile at the

level(s) specified.

The level of any degradation product present in a new drug product that has been

adequately tested in safety and/or clinical studies would be considered qualified.

Therefore, it is useful to include any available information on the actual content of

degradation products in the relevant batches at the time of use in safety and/or clinical

studies.

Degradation products that are also significant metabolites present in animal and/or human

studies are generally considered qualified.

Degradation products could be considered qualified at levels higher than those

administered in safety studies based on a comparison between actual doses given in the

safety studies and the intended dose of the new drug product.




Justification of such higher levels should include consideration of factors such as: (1) the

amount of degradation product administered in previous safety and/or clinical studies and

found to be safe; (2) the increase in the amount of the degradation product; and (3) other

safety factors, as appropriate.

REFERENCE:

1. ICH HARMONISED TRIPARTITIE GUIDELINES

www.ich.org

2. Drug Stability: Principles and Practices, 3rd Edition, edited by Jens T. Carstensen and C.

T. Rhodes; chapter-13 & 17.

3. Remington, The Science and Practice of Pharmacy; 21st Edition, volume-1, chapter-

4. Stability of drugs and dosage forms by Sumie yoshika & valentio stella; chapter- 6; page

no- 205

5. 17. Food and Drug Administration for immediate release consumer media: 888-Info-

FDA. May 6, 1998.

6. Chemical Works of Gedeon Richter Ltd., P.O.B. 27, H-1475 Budapest, Hungary(Talanta

44 (1997) 1517-1526)

http://www.ich.org/

PAPER 910101 CHAPTER 4 STABILITY STUDIES

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APPLICATIONS OF

MICROCALORIMETRY

IN STABILITY STUDIES

GUIDED BY: PREPARED BY:

Dr.R.K.PARIKH SHWETA IYER

M-PHARM SEM-I

ROLL NO-8

2009-2010

DEPARTMENT OF PHARMACEUTICS & PHARMACEUTICAL TECHNOLOGY

L.M. COLLEGE OF PHARMACY, AHMEDABAD-09


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INTRODUCTION:

Calorimetry is the science of heat. It is concerned with how a given material responds to temperature

changes on both the atomic and macroscopic level. This varies widely from substance to substance, and

reveals important information about the arrangement and interaction of the atoms.

Calorimetry or Microcalorimetry is the measurement of the heat evolved or absorbed by a chemical or

physical process. Since heat evolved or absorbed is directly proportional to the rate of the process, it

serves to study rate & extent of reactions.

Microcalorimetry is the calorimetry of small samples, specifically microgram samples (or thereabouts).

These are much more challenging to study than big mass of material because

(1) The time scale for changing the temperature is much faster and

(2) The probes you attach to the sample to measure it takes away a greater proportion of the heat

involved.

Therefore, MICROCALORIMETRY is an advanced form of Calorimetry.

Calorimetry of microgram of Sample.

Power detection limit for microcalorimeter approaches a few microwatt.

It is 10,000 times more sensitive than DSC.

PRINCIPLE OF MICROCALORIMETRY: Microcalorimetry works on the principle that all physical and chemical processes are accompanied by a heat

exchange with their surroundings. So when a reaction occurs a temperature gradient is formed between the

sample and its surroundings. The resulting heat flow between the sample and its surroundings, is measured as a

function of time.

When any reaction takes place, heat will be generated or absorbed by the molecules reacting.

In isothermal microcalorimetry heat input in sample cell adjusted to keep T constant. So,

Exothermic reaction will result in negative peaks (less heat is needed while the reaction

proceeds)

Endothermic reactions will result in positive peaks (more heat is needed while the reaction

proceeds)

CALORIMETERS:

A calorimeter is a device used for calorimetry, the science of measuring the heat of chemical

reactions or physical changes as well as heat capacity. The word calorimeter is derived from the

Latin word calor, meaning heat.

http://en.wikipedia.org/wiki/Calorimetry

http://en.wikipedia.org/wiki/Science

http://en.wikipedia.org/wiki/Chemical_reaction



http://en.wikipedia.org/wiki/Physical_change

http://en.wikipedia.org/wiki/Heat_capacity

http://en.wikipedia.org/wiki/Latin

http://en.wikipedia.org/wiki/Heat


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Differential scanning calorimeters, isothermal microcalorimeters, titration calorimeters and accelerated

rate calorimeters are among the most common types.

A simple calorimeter just consists of a thermometer attached to a metal container full of water

suspended above a combustion chamber.

WORKING:

To find the enthalpy change per mole of a substance A in a reaction between two substances A and B, the

substances are added to a calorimeter and the initial and final temperatures(before the reaction started and after

it has finished) are noted. Multiplying the temperature change by the mass and specific heat capacities of the

substances gives a value for the energy given off or absorbed during the reaction. Dividing the energy change

by how many moles of A were present gives its enthalpy change of reaction.

This method does not account for the heat loss through the container or the heat capacity of the thermometer

and container itself. In addition, the object placed inside the calorimeter show that the objects transferred their

heat to the calorimeter and into the liquid, and the heat absorbed by the calorimeter and the liquid is equal to the

heat given off by the metals.

SCHEMATIC DIAGRAM OF MICROCALORIMETER

In its most basic form a microcalorimeter consists of three parts: a thermal mass that absorbs the x-ray and

converts the energy to heat, a thermometer to measure the temperature rise of the thermal mass, and a thermal

link to a heat sink to allow the absorbed energy to escape from the thermal massThe energy resolution of a

microcalorimeter is limited by fluctuations in its thermal energy content; a simple thermodynamic analysis

gives the energy resolution as:

http://en.wikipedia.org/wiki/Enthalpy

http://en.wikipedia.org/wiki/Temperature

http://en.wikipedia.org/wiki/Specific_heat_capacity

http://en.wikipedia.org/wiki/Energy


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dE = (kT2C)

1/2

where k is the Boltzmann constant, T is the heat sink temperature, and C is the heat capacity of the detector. In a

more detailed analysis of a microcalorimeter with a resistive thermometer, the resolution given above is

modified by a multiplicative factor of order one that depends primarily on the temperature sensitivity of the

thermometer.

Energy, E, are incident upon a thermal mass of heat capacity C. A thermometer measures the temperature rise

of the thermal mass. A thermal link with conductance, G, connects the thermal mass to a heat sink allowing the

absorbed energy to leak away with a time constant equal to C/G.

TYPES OF CALORIMETERS:

1. ADIABATIC CALORIMETER:

No heat exchange takes place between the calorimetric vessel and its surroundings. The amount of heat that is

evolved or absorbed in an ideal adiabatic calorimeter is equal to the product of the measured temperature

change and the heat capacity of the vessel, including its content. No adiabatic calorimeter is truly adiabatic -

some heat will be lost by the sample to the sample holder. Examples of adiabatic calorimeters are:-

THT EV-Accelerating Rate Calorimeter

HEL Phi-Tec

A simple Dewar flask

Systag FlexyTSC a successor of their SIKAREX unit - the electronics of which could be used to apply a

feedback system to heat the sample holder to give a result closer to true adiabaticy, however as the sample

holder is an open ended glass tube, one soon loses the sample as a great deal of smoke.

2. REACTION CALORIMETERS:

A reaction calorimeter is a calorimeter in which a chemical reaction is initiated within a closed insulated

container. Reaction heats are measured and the total heat is obtained by integrating heatflow versus time. This is

the standard used in industry to measure heats since industrial processes are engineered to run at constant

temperatures. Reaction calorimetry can also be used to determine maximum heat release rate for chemical

process engineering and for tracking the global kinetics of reactions. There are four main methods for

measuring the heat in reaction calorimeter :

a) Heat flow calorimetry:

http://en.wikipedia.org/wiki/Dewar_flask



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The cooling/heating jacket controls either the temperature of the process or the temperature of the jacket. Heat

is measured by monitoring the temperature difference between heat transfer fluid and the process fluid. In

addition fill volumes (i.e. wetted area), specific heat, heat transfer coefficient have to be determined to arrive at

a correct value. It is possible with this type of calorimeter to do reactions at reflux, although the accuracy is not

as good.

b) Heat balance calorimetry

The cooling/heating jacket controls the temperature of the process. Heat is measured by monitoring the heat

gained or lost by the heat transfer fluid.

c) Power compensation The thermal power from an exothermic process is balanced by a known cooling power (usually Peltier effect

cooling), alternatively by a decrease of heating power. Endothermic processes are balanced by a known thermal

power released in a heater or by reversing the Peltier effect current.

Power compensation uses a heater placed within the vessel to maintain a constant temperature. The energy

supplied to this heater can be varied as reactions require and the calorimetry signal is purely derived from this

electrical power.

d) Constant flux

Constant flux calorimetry (or COFLUX as it is often termed) is derived from heat balance calorimetry and uses

specialized control mechanisms to maintain a constant heat flow (or flux) across the vessel wall.

3. BOMB CALORIMETERS:

A bomb calorimeter is a type of constant-volume calorimeter used in measuring the heat of combustion of a

particular reaction. Bomb calorimeters have to withstand the large pressure within the calorimeter as the

reaction is being measured. Electrical energy is used to ignite the fuel; as the fuel is burning, it will heat up the

surrounding air, which expands and escapes through a tube that leads the air out of the calorimeter. When the

air is escaping through the copper tube it will also heat up the water outside the tube. The temperature of the

water allows for calculating calorie content of the fuel.

In more recent calorimeter designs, the whole bomb, pressurized with excess pure oxygen (typically at 30atm)

and containing a known mass of sample (typically 1-1.5 g) and a small fixed amount of water (to absorb

produced acid gases), is submerged under a known volume of water (ca. 2000 ml) before the charge is (again


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electrically) ignited. The bomb, with sample and oxygen, form a closed system - no air escapes during the

reaction. The energy released by the combustion raises the temperature of the steel bomb, its contents, and the

surrounding water jacket. The temperature change in the water is then accurately measured. This temperature

rise, along with a bomb factor (which is dependent on the heat capacity of the metal bomb parts) is used to

calculate the energy given out by the sample burn. A small correction is made to account for the electrical

energy input, the burning fuse, and acid production (by titration of the residual liquid). After the temperature

rise has been measured, the excess pressure in the bomb is released.

4. CONSTANT PRESSURE CALORIMETER:

A constant-pressure calorimeter measures the change in enthalpy of a reaction occurring in solution during

which the atmospheric pressure remains constant.

An example is a coffee-cup calorimeter, which is constructed from two nested Styrofoam cups having holes

through which a thermometer and a stirring rod can be inserted. The inner cup holds the solution in which of the

reaction occurs, and the outer cup provides insulation. Then

where

Cp = Specific heat at constant pressure

ΔH = Enthalpy of solution

ΔT = Change in temperature

W = mass of solute

M = molecular mass of solute

5. DIFFERENTIAL SCANNING CALORIMETER:

In a differential scanning calorimeter (DSC), heat flow into a sample—usually contained in a small

aluminium capsule or 'pan'—is measured differentially, i.e., by comparing it to the flow into an empty reference

pan.

http://en.wikipedia.org/wiki/Enthalpy

http://en.wikipedia.org/wiki/Solution

http://en.wikipedia.org/wiki/Atmospheric_pressure

http://en.wikipedia.org/wiki/Styrofoam

http://en.wikipedia.org/wiki/Thermometer

http://en.wikipedia.org/wiki/Thermal_insulation

http://en.wikipedia.org/wiki/Heat_flow

http://en.wikipedia.org/wiki/Aluminium


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In a heat flux DSC, both pans sit on a small slab of material with a known (calibrated) heat resistance K. The

temperature of the calorimeter is raised linearly with time (scanned), i.e., the heating rate dT/dt = β is kept

constant. This time linearity requires good design and good (computerized) temperature control. Of course,

controlled cooling and isothermal experiments are also possible.

Heat flows into the two pans by conduction. The flow of heat into the sample is larger because of its heat

capacity Cp. The difference in flow dq/dt induces a small temperature difference ΔT across the slab. This

temperature difference is measured using a thermocouple.

A modulated temperature differential scanning calorimeter (MTDSC) is a type of DSC in which a small

oscillation is imposed upon the otherwise linear heating rate.

This has a number of advantages. It facilitates the direct measurement of the heat capacity in one measurement,

even in (quasi-)isothermal conditions. It permits the simultaneous measurement of heat effects that are

reversible and not reversible at the timescale of the oscillation (reversing and non-reversing heat flow,

respectively). It increases the sensitivity of the heat capacity measurement, allowing for scans at a slow

underlying heating rate.

6. ISOTHERMAL TITRATION MICROCALORIMETER:

In an isothermal titration calorimeter, the heat of reaction is used to follow a titration experiment. This

permits determination of the mid point (N) of a reaction as well as its enthalpy (delta H), entropy (delta S) and

of primary concern the binding affinity (Ka)

The technique is gaining in importance particularly in the field of biochemistry, because it facilitates

determination of substrate binding to enzymes. The technique is commonly used in the pharmaceutical industry

to characterize potential drug candidates

7. X-RAY MICROCALORIMETER:

In 1982, a new approach to non-dispersive X-ray spectroscopy, based on the measurement of heat rather than

charge, was proposed by Moseley et al. (1984). The detector, and X-ray microcalorimeter, works by sensing the

heat pulses generated by X-rayphotons when they are absorbed and thermalized. The temperature increase is

directly proportional to photon energy. This invention combines high detector efficiency with high energy

resolution, mainly achievable because of the low temperature of operation. Microcalorimeters have a low-heat-

capacity mass that absorbs incident X-ray (UV, visible, or near IR) photons, a weak link to a low-

temperature heat sink which provides the thermal isolation needed for a temperature rise to occur, and a

http://en.wikipedia.org/wiki/Heat_flux




http://en.wikipedia.org/wiki/Thermocouple

http://en.wikipedia.org/wiki/Titration

http://en.wikipedia.org/wiki/Biochemistry

http://en.wikipedia.org/wiki/Enzyme

http://en.wikipedia.org/wiki/X-ray_spectroscopy

http://en.wikipedia.org/wiki/Photons

http://en.wikipedia.org/wiki/Heat_sink


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thermometer to measure change in temperature. Following these ideas, a large development effort started. The

first astronomical spacecraft that was designed, built and launched with embarqued cryogenic

microcalorimeters was Astro-E2. NASA as well as ESA have plans for future missions (e.g.,IXO) that will use

some sort of micro-calorimeters.

8. HEAT LOSS CALORIMETER:

The heat developed inside the cell is collected by the inner copper cup. Then, it flows through the silicone-

rubber which serves as a thermal resistor and the outer copper cup, to the flowing water surrounding the outer

copper cup.

9. HIGH ENERGY PARTICLE CALORIMETER: It is a component of a detector that measures

the energy of entering particles.

10. THERMAL MICROCALORIMETER:

A thermal detector in principle is a very sensitive calorimeter which measures the energy deposited by a single

interacting particle through the corresponding temperature rise. For this mechanism to be really effective the

detector must have a very small heat capacity: this is accomplished by using suitable materials (dielectrics,

superconductors below the phase transition, ...) and by running the detector at low temperatures (usualluy below

100 mK) in a refrigerator (we use dilution refrigerators).

Precautions to be taken for efficient working: 1. The materials used on the device must not react with each other.

2. The membrane must be robust enough to survive deposition of thin films.

3. The leads going off the membrane must be made of a material and be of a size which compromises

between low electrical resistance and low thermal conductance (so they don't carry away too much heat), and

the thermal conductivity should have a weak temperature dependence.

4. Care should be taken when positioning features on the chip to avoid capacitance between elements of the

circuit.

There are many commercial types of equipment available; few of them are as under

1. TRONAC solution calorimeter

2. LKB Thermal Activity Monitor

3. Thermometric 2277 Thermal Activity Monitor

http://en.wikipedia.org/wiki/Astro-E2

http://en.wikipedia.org/wiki/NASA

http://en.wikipedia.org/wiki/ESA

http://ixo.gsfc.nasa.gov/

http://en.wikipedia.org/wiki/Particle_detector

http://en.wikipedia.org/wiki/Energy

http://en.wikipedia.org/wiki/Subatomic_particle

http://crio.mib.infn.it/wig/silicini/setup.html#crio


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Applications of Microcalorimetry Microcalorimetry is highly useful in following fields,

1. Stability testing.

2. Studies of powder wettability (by immersion and adsorption).

3. Sorption reactions

4. Crystal properties.

5. Dissolution of tablets and powders.

6. Excipient compatibility.

7. Direct in vitro studies of biological response.

8. To monitor rate and extent of physical and chemical processes.

9. To study powder surface energetics.

10. As a useful tool for solving shelf life problems in the food and pharmaceutical

industry.

11. Rapid screening of excipients.

12. Microorganism – Drug interaction

13. Food – Drug interaction.

14. Lymphoma cell – drug interaction.

15. Cyclodextrin – drug interaction.

16. Water – Excipient interaction

17. Drug – Excipient interaction.

18. In identification of polymorphs.

APPLICATIONS IN STABILITY STUDIES:

CONVENTIONAL METHODS FOR STABILITY STUDY

At present, the standard method used for stability analysis of a solid state pharmaceutical product is HPLC.

In summary, the concentration of parent compound and/or the concentration of any daughter compounds

produced are determined as a function of storage time.

The method has certain drawbacks.

Often not very sensitive to small changes in concentration.

It requires a certain degree of method development to establish a sample preparation and analysis protocol

It relies on the dissolution of the solid product.

This last drawback can cause distortions in an assay as a result of rapid acceleration

of decomposition when a compound is in a solvated state.

Because of the poor sensitivity of the technique, it is necessary to perform the experiment over an extended

time frame to allow sufficient reaction to take place. Hence, samples are stored under elevated temperature

and humidity after preparation to accelerate the potential decomposition.


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The samples are then assayed over a period of time that can range from a few weeks to many months to give

reaction snapshots along the decomposition profile.

For each storage condition, a rate constant, (k), is calculated. By plotting lnk against 1/T using the Arrhenius

relationship, it is possible to extrapolate back to ambient temperature and hence determine the rate constant

at that temperature.

where k is the rate constant, A is the Arrhenius factor or pre-exponential constant, Ea is the activation energy, R

is the gas constant, and T is the temperature. This technique for the determination of stability has been accepted

as normal practice for many years.

LIMITATIONS OF ARRHENIUS EQUATION

It does, however, rely on some assumptions that are not necessarily true in all cases. It is assumed that the

Arrhenius plot gives a linear relationship. This may not be true for many reasons.

If there are two competing reactions occurring simultaneously, then they will both have an associated

activation energy leading to an incorrect extrapolation & thus a major error in calculating the ambient rate

constant.

Finally, if the reaction does not go by a first order reaction, it is necessary to determine a different rate

equation that gives an improved understanding of the system under study. This is not always

straightforward, and, for solid state reactions, can be very complex.

The rate of decomposition at room temperature may be too slow to asses accurately the rate of

disappearance of the drug substance or appearance of a decomposition product. A useful approach is often to

study the rate of decomposition at higher temperature and to assume that the rate of decomposition at storage

temperature may be extrapolated from the high-temperature data by using the Arrhenius equation.

The high-temperature stability testing may not be feasible each time and thus stability study at room

temperature is must.

The rate of any decomposition reaction is very slow and difficult to measure so long term study is must.

Microcalorimetry can measure heat changes at microwatt levels and thus can be used for stability testing

at room temperature.

EXAMPLES: Few drugs for which stability study can be performed using microcalorimetry are Aspirin, PAS, and

some ß-lactam antibiotics

Microcalorimetry is applied to study the thermodynamic stability of Proteins present in the pool water of

some reverse micelles (Lysozyme, Cytochrome-c and Ribonuclease).

By using Microcalorimetry, stability study of ampicillin in aqueous Solutions as a function of conc. of

ampicillin, pH & temperature was carried out

Determination of decomposition mechanism of lovastatin by measuring rate of heat production at

different temperature & time was carried out by microcalorimetry.


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- Lovastatin degraded by an auto-catalytic mechanism in presence of oxygen.

Microcalorimetry is used to correlate the decomposition rate of several Cephalosporins in solids &

aqueous solution states.

The activation energy, determined by Microcalorimetry & a degradation rate Determined at a single

elevated temperature by HPLC.

Testing of physical stability of drug:-

Microcalorimetry has proved to be an effective analytical technique for characterizing micronised

compounds. It can be used to detect the presence of metastable regions not detectable by X-ray diffraction.

Furthermore, the kinetic of ―recrystalisation‖ of these regions can be studied, making a prediction of physical

stability possible. Thus the application of Microcalorimetry in the pharmaceutical development has a great

potential.

Determination of amorphous contents or crystallinity of pharmaceutical drugs and excipients:

The amorphous regions can alter the physical properties of the

material, which may have an impact on further pharmaceutical processes or the

quality of the material.

Microcalorimetry is a very sensitive way to measure amorphous contents well below

1%. The heat of recrystallization of the amorphous parts can be measured and by a

suitable calibration the amorphous content can be determined. Solution calorimetry is

able to measure directly the heat change caused by the dissolution of a crystalline or

partially crystalline powders. The observed heat of solution is a function of the

variability in crystallinity displayed. The quantification of amorphous contents, however, requires the

availability of pure amorphous and pure crystalline standards.

Amorphous content of lactose (hydrophilic) and Erythromycin (lypophilic) was assessed by isothermal

microcalorimetry.

Temperature was fixed at 22°C and humidity at 40% RH


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Microcalorimetric spectra of Erythromycin in Chloroform

Microcalorimetric spectra of Erythromycin in Benzene

Amorphous-crystal transition behavior of erythromycin


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Identification of Stable & Metastable forms:

Example: Microcalorimetric specra of Tripalmitin

In the case of Tripalmitin, the first heating run shows the sample as received is in the stable form. On

cooling, a metastable modification crystallizes out, whose melting point lies lower than that of the

thermodynamically stable form. In the second heating run, the metastable modification first melts and then

immediately begins recrystallization into the stable modification, which melts again at the higher temperature.

The lower onset temperature and slightly lower heat of fusion observed for the stable form in the second heating

experiment are caused by incomplete crystallization.

To study the thermal stability of antibodies:

DSC was used to study the thermal stability of antibodies that were being engineered for improved potency. In

this study, we demonstrated a correlation between decreased thermal stability based on DSC data, and greater

aggregation formation during accelerated stability studies (at 60°C). The SEC-HPLC stability data agree quite

well with the stability predicted by DSC, suggesting that the thermal stability data obtained from DSC

correlates with protein stability. Information derived from DSC can indicate potential long-term stability issues,

thus making the technique a useful tool in the screening and selection of engineered proteins.

Monitoring the stability of heat sensitive substances:

Example: Vitamin A is very sensitive to chemical degradation caused by oxygen, light, heat, and other stress

factors. If light and oxygen are excluded, the dominant degradation reaction for vitamin A derivatives is heat-

induced formation of kitols, that is, dimers or higher oligomers.

The vitamin A stability of a given sample can easily be predicted from the initial heat flow in a simple

microcalorimetry experiment. Compared to conventional stability tests, this offers savings of money and time.


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Determination of product shelf-life:

A new technique Microcalorimetry has been developed to determine stability of low molecular weight materials

in both aqueous and non-aqueous solvents. Its primary application areas include drug formulation and stability.

Estimates of product stability are often made using accelerated thermal decomposition studies at high

temperatures followed by extrapolation of the data to the temperature of interest.

When the temperature range under investigation is much higher than the temperature of interest, the

extrapolation of results is less certain, since the mechanism of decomposition can be different at different

temperatures.

Identifying optimal pH conditions to stabilize pharmaceutical proteins in solution formulations:

The utility of microcalorimetry as a rapid screening tool for assessing the solution stability of high molecular

weight pharmaceutical proteins was evaluated by using model recombinant antibodies, Protein I and Protein II.

Changes in the transition midpoint, Tm, were monitored as a function of pH and/or in the presence of excipients,

and results were compared with traditional accelerated stability data from samples that were analyzed by size

exclusion chromatography (SEC). The data from microcalorimetry were well correlated with those from SEC

for predicting both optimal solution pH as well as excipient effects on solution stability.

Identification of compatible exipient to stabilize drug molecule:

Microcalorimetry is a power full and easy to use tool for rapid screening of excipients for formulation

development. If the sum of the heat out put of the compound and the excipient alone is not equal to the heat

output of a binary blend then there is a potential compatibility issue.

Example 1 Long-term stabilization potential of PVP for amorphous lactose in spray-dried composites.

Study was done to investigate the potential of PVP to inhibit the crystallization of amorphous lactose

during storage of the composites up to 6 months. Short-term stability was assessed by microcalorimetry over 10

days and long-term stability by storage in desiccators with different relative humidities for 3 and 6 months.

Example 2 Microcalorimetry was used to study the effect of menadione & prednisone on the stability of the

microemulsions. The stability was not changed in the presence of drugs.

Example 3

Chemical & physical processes accompanying Cyclodextrin-drug interactions are usually endothermic or

exothermic in nature so they can be studied by microcalorimetry.

Determination of Biomaterials Stability:

Used to study stability of implants.


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Stability of UHMWPE, CaSO4 bone void filler, and buffered saline was studied using microcalorimeter.

One major finding was that radiation sterilization increases the oxidation rate of UHMWPE

7X-10X compared to EtO, and the rate difference persists after 9 years of post-sterilization shelf storage and/or

clinical TJA implantation. Oxidation embrittles UHMWPE.

Direct information on the stability and biological activity of immobilized proteins:

Give insight on the thermodynamic consequences of the immobilization in most experimental conditions,

ranging from multipoint covalent attachment to simple absorption.

assess the effects of the immobilization, support environment, and the type of entrapment on the active site

reflected as differences in the binding capacity of specific ligands.

Determination of Oxidation of Polymers:

The deterioration of polymeric materials is often caused by oxidation and typically manifested

by gradually increasing yellowing and embrittlement.This cause instability of polymers which can be efficiently

detected by microcalorimeters.

Example: study of oxidation of polyamide 6 film.

Measurement of the Kinetics of Slow Reactions:

Processes degrading or otherwise changing the properties of materials often occur too slowly to be readily

measured by conventional chemical analyses but can be measured in a relatively short period of time by heat

conduction calorimetry.

Determination of critical moisture content in hygroscopic substances:

Presence of moisture & amount of moicture determines the stability of the sample.

Example: Two extremely water-soluble substances (flupentixol,2HCl and Lu 25–109, water solubility over

1000 mg/ml) and a hydrophobic substance (sertindole, approximately 10 μg/ml) were examined for critical

moisture content by microcalorimetry.

The values determined by isothermal microcalorimetry showed results similar to various weighing methods.

This is known as characterization of hygroscopic property of API.

Determination of surface energetic of crystal:

Isothermal microcalorimetry gas flow vapour sorption experiments can be used to assess the surface energetics

of crystals, the formation and/or loss of hydrates as a function of humidity and the onset of deliquescence, and

to identify the presence of amorphous content in powders.

This directly or indirectly gives idea about the stability of the crystal substance.


SHWETA IYER

107

M.PHARM SEM –I


Characterisation of adsorption & absorption into powders:

Adsorption of gases, liquids or solids onto solid surfaces can cause change in physical properties & can affect

stability of the substance. This can be effectively determined by microcalorimetry as surface properties changes

the heat properties.

Example: Adsorption isotherms were constructed from the cumulative heat as a function of humidity using a

perfusion microcalorimetry. It was possible to differentiate among different samples of .ALPHA.-lactose

monohydrate.

Characterisation of browning reaction:

An isothermal microcalorimeter can be utilized to characterize a model solid-state interaction.

Example:The degradation of the HIV protease inhibitor, DMP 450, in a binary mixture with hydrous lactose

was followed in the presence of 5% additional water. Heat produced in the microcalorimeter sample vessel from

either chemical or physical change (Browning reaction) is channeled through extremely sensitive thermopile

blankets and is measured as it flows into infinite heat sinks.

Identification of stable polymorph:

The polymorphic behavior of organic substances is driven by thermodynamic and kinetic factors. Therefore

several solid phases may coexist.

Example: Polymorphic behavior of Donepezil Hydrochloride

Three polymorphs were identified (II, III and V) by DSC curves and thermodynamically stable form III

was determined (the highest: melting point, enthalpy and true density).

DSC curves of amorphous and polymorphic forms II, III and V.


SHWETA IYER

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M.PHARM SEM –I


INTERPRETATION AND TREATMENT OF MICROCALORIMETRIC DATA

It is difficult to determine rate constants, order of reaction and enthalpy of reaction from the

microcalorimetric output data. Recently Willson has described a general procedure for the determination of

both thermodynamic and kinetic parameters from microcalorimetric output data.

The procedure takes a kinetic equation for a particular reaction, and modifies it such that it applies directly

to microcalorimetric data. This is achieved by recognition of the fact that the total heat evolved during the

course of a reaction (Q) is equal to the total number of moles of material reacted (Ao) multiplied by the

change in molar enthalpy for that reaction ( H).

Q = A0 H ……………..(1)

Similarly, the heat evolved at time t (q) is equal to the number of moles of material reacted (x) at time t

multiplied by the change in molar enthalpy for that reaction.

q = x H ………………(2)

Eq. (2) may be substituted into a general rate expression of the form dx/dt to give an expression of the form

dq/dt (or power). For example, the general rate expression for a simple, first-order, A B process is given

by Eq. (3).

…………… (3)

Substitution of Eq. (2) into Eq. (3) yields,

………. (4)

This modified rate expression may be used to fit power–time data recorded using the microcalorimeter.

INNOVATIONS:

o MULTI-CHANNEL "CHIP CALORIMETERS" that operate in the Nano range (watts, material

concentration) with high throughput potential. Drug studied is Benzoyl Peroxide.


SHWETA IYER

109

M.PHARM SEM –I


REFERENCE:

Wikipedia

Encyclopedia Vol. 02 Page no. 247.,239

JPS 91,2, 2002 Page no. 417-422)

Microsc Microanal 11(Suppl 2), 2005

Meas. Sci. Technol. 1 (1990) 680-686.

Pure Appl. Chem., Vol. 73, No. 10, pp. 1625–1639, 2001.

D. A. Wollman, K. D. Irwin, G. C. Hilton, L. L. Dulcie, N. F. Bergren, Dale E.

Newbury, and John M. Martinis, internet article.

. Drug stability by carstensen pg. 09

www.acta.chemsoc.si/pdf

www.sciencedirect.com

www.springerprotocols.com

www.pubs.acs.org

www.ecmjournal.org

www.informahealth.com

www.ingentaconnect.com

www.springerjournal.com

JPS, VOL-97, July 2007

Int.JPS 117(1995) 253-256

http://www.sciencedirect.com/

http://www.springerprotocols.com/

http://www.pubs.acs.org/

http://www.ecmjournal.org/

http://www.informahealth.com/

http://www.ingentaconnect.com/

http://www.springerjournal.com/

PAPER-910101 CHAPTER- 4 COSMETIC AND DENTALPRODUCTS STABILITY STUDY BY: JIGNASHA R. BHURIA

110

FORMULATION AND

EVALUATION OF VARIOUS

COSMETIC AND DENTAL

PRODUCT

GUIDED BY: - PRESENTED BY:- Dr.R. K. Parikh Jignasha R. Bhuria M. Pharm Sem-1 Batch:-2009-2010 Roll no:-05

DEPARTMENT OF PHARMACEUTICS AND

PHARMACEUTICAL TECHNOLOGY, 2009-2010


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COSMETIC PRODUCT

LIST OF CONTENTS:-

CONTENTS DEFINITION

CLASSIFICATION

INGREDIENTS OF COSMETICS

FORMULATION

QUALITY CONTROL

COSMOCEUTICALS

1) DEFINITION:- The term cosmetics have been derived from the term ―COSMETIKOS‖ which

means the skill to decorate. Thus cosmetics is the art of decorating yourself to look beautiful.

According to D & C Act:- Cosmetics mean any articles meant to be rubbed, poured, sprinkled or sprayed on or introduced into or otherwise applied to any part of the human body for cleansing, beautifying, promoting attractiveness or altering appearance and include any article intended for use as a component of cosmetic. Soap is not covered under cosmetic product.

2) CLASSIFICATION OF COSMETICS:-


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3) INGREDIENTS OF COSMETICS:- 1. Water 2. Oils, Fats, Waxes 3. Humectants 4. Surfactants 5. Preservatives 6. Perfumes And Colors 7. Herbal Or Plant Material 8. Functional Raw Materials

1. WATER: - It is the main ingredient of cosmetics formulation. Thus stability and

quality of final product is dependant on the purity of water used so pure water should be used in manufacturing of cosmetics. Pure water on large scale can be manufactured by any of the methods mentioned below. Ion exchange system Distillation Reverse osmosis

2.OIL, FATS and WAXES:- These are used in preparation of creams,

lotions, brilliantine, hair oil, lipsticks etc. The source of oil, fat & wax can be mineral source & animal source. The source and example is given below.

Source:-1) Mineral source -mineral oil -paraffin and petroleum jelly 2) Animal source -wool fat -bees wax, Spermaceti

OILS:-

Name of oil (Vegetable)

Use in cosmetics

Almond Creams (emollient)

Arachis Hair oil, Brilliantines

Castor Lip stick, hair oil cream ,lotion

Olive Bath oils ,creams lotions

Type of mineral oil

Use in cosmetics product

Light liquid paraffin

In bath oil, hair oil,lotions,creams,brilliantine

Heavy liquid paraffin

In bath oil, hair oil,lotions,creams,brilliantine (emollient)


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• waxes:- The commonly used waxes in preparation of cosmetics Include bees

wax, spermaceti,ceresin,ozokerite wax

3. HUMECTANTS:- This is added to prevent drying out of cosmetics

(e.g. o/w creams)

Type of

Humectant

Examples

1.Inorganic

Calcium chloride (not used now due to compatibility problems)

2.Metal organic

Sodium lactate (used in sunscreen lotions)

3.Organic

Polyethylene glycol, Propylene glycol, glycerol, sorbitol, mannitol, glucose

4. SURFACTANTS: - Surfactants lower one or more boundary tensions at interface

in the system. one common feature of surfactant is that they all are amphipathic molecules containing a hydrophobic part & a hydrophilic part. Used in cosmetics to impart following functions. DETERGENCY, WETTING, FOAMING, EMULSIFICATION, SOLUBILIZATION Surfactants on basis of their ionic behavior can be divided into following 4 types:-

Type of surfactant

Examples

1.Anionic Fatty acid soaps, alkyl sulphates, alkyl sulphonates, polyethylene glycol ester,alkyl ether sulphates taurines,sarcosinates etc.

2.Cationic Alkyl trimethyl ammonium salts, Dialkyl dimethyl ammonium salts alkyl pyridinium salts, quaternised diamine salts.

3. Non ionic Alkanolamides,alkyl polyglycol ether, thioethers, alkyl polyethyleneimine amides.

4.Ampholytic Betains, alkylimidazolines, acyl peptides,etc.

5. PRESERVATIVES:- Used to prevent spoilage which occurs due to

1) Oxidation of oils 2) Microbial growth

• Unused cosmetics are usually contaminated wit PSEUDOMONAS but used cosmetics are contaminated with STAPHYLOCOCCI,FUNGI,YEAST

• Types of preservatives :- 1) Anti microbial agents:- e.g. .Benzoic acid, formaldehyde, cresol, phenol,

thiomersol,phenyl mercuric salts. Etc.


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2) Antioxidants :- Gallic acid, methyl gallate,BHA,BHT,Tocopherol, citric acid,Ethanolamine,lecithin,ascorbic acid, sodium sulphite,

Sodium metabisulphite 3) Antioxidant synergists: - Enhance the efficacy of antioxidants. examples

include:-ascorbic acid, citric acid, phosphoric acid 4) UV absorbers:-These are mainly used in products which are vulnerable

to visible or UV light. By incorporating UV absorbers colorless containers can be used if deterioration is due to UV light only.

6. PERFUMES:- The word perfume has been derived from ―per‖ means through

and ―fumum‖ means smoke. It suggests that early perfumes were pleasant smells obtained by burning wood and grass etc.

Source of perfume Example Natural (Animal source)

Musk ,civet, Ambergris, Castroreum etc.

Natural (Plant source)

Rose ,jasmine, lemon, lavender etc.

Aroma chemical Eugenol, Farnesal, Rose oxide, Citral ,Limonene

Floral base Rose base, Jasmine base

Woody base Citrus base(in colognes),spice base, oriental base, fruity base ,etc

7. COLORS: - It defined as visual sensation caused by a definite wavelength by an

object by one/more phenomenon of emission, reflection, refraction, transmission. Colors can be classified into three classes:- a) Natural colors:- Plant source :- e.g. Saffron, turmeric Animal source:-e.g. Cochineal (red) b) Inorganic colors:- e.g. Iron oxides, chromium oxides, carbon black,

titanium dioxide, zinc oxide etc. c) Coal tar colors:-Tartrazine, amaranth, Erythrosine, Indigocarmine. etc.

8.HERBAL OR PLANT MATERIAL:-These herbal or plant materials are used in

different cosmetics preparations. NAME USE IN COSMETICS

Almond Facial and body scrubs

Azadiracta Tooth paste and skin care

Comfrey Creams and lotions

Tulsi Skin cream and lotions

Cucumber Masks, toner, cleanser

Henna Dyeing of hair


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Amla Shampoo

Jasmine Hair oil

Lemon Skin tonic, cleansers

Apricot Facial and body scrubs

9. FUNCTIONAL RAW MATERIALS:- These agents contribute towards

some functional property .

TYPE EXAMPLE & USE

VITAMINS

Vit C (antioxidant in emulsion),vit A, Vit E (skin beautification)

AMINO ACIDS AV HILL MP TT (all essential amino acids)

ANTI INFLAMMATORY AGENTS

Allantoin (hand cream & lotion) Cade oil(eczema& psoriasis),Calamine

SUNSCREEN AGENTS

PABA, Vitamin C, Quinine salts Coumarin derivatives

ANTIDANDRUFF Selenium, cadmium sulphide, ZPTO

(4) FORMULATION COSMETICS FOR SKIN

Function:- 1) To provide decoration

2) To supplement natural functions of skin

Type of cosmetics used for skin:-

1. Skin cream 2. Lotion 3. Face powder & Compacts 4. Skin colorants 5. Body powder 6. Face pack & Masks 7. Bath Preparations (bath salt,oil,powder,foam)


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8. Astringents &Skin tonics (antiperspirants, astringent lotion, preshave & after shave lotion, colognes)

1. CREAMS: - These are the solid or semisolid preparation which is either a

o/w or w/o type emulsion.

TYPES OF CREAMS: A. Cleansing cream B. Massage creams C. Night creams D. Moisturizing creams E. Foundation creams F. Vanishing creams G. All purpose creams

A) CLEANSING CREAM:- Cleansing cream is required for removal of facial make up, surface grime, oil, water and oil soluble soil efficiently mainly from the face & throat.

Characteristic of a good cleansing cream:-

1) Be able to effectively remove oil soluble & water soluble soil, surface oil from skin.

2) Should be stable &have good appearance. 3) Should melt or soften on application to the skin 4) Should spread easily without too much of drag. 5) Its physical action on skin & pore openings should be that of flushing rather

than absorption Type of cleansing cream:-

I.) Anhydrous type:- It contains mixture of hydrocarbon, oils and waxes. It also contains cetyl alcohol, spermaceti, cocoa butter, fatty acid esters etc. Not popular. Mineral oil-80 gm, Petroleum jelly– 15gm

Ozokerite wax -5 gm Preservative and perfumes –q.s

Note :- Formation crusty surface is avoided by adding Ozokerite & petrolatum (prevent bleeding of mineral oils.) Opaque character obtained by adding Zno, mg.stearate, Tio2

II.) Emulsified type:- They can be either o/w or w/o type.

Common Ingredients:- Oil phase…………………..Spread easily Waxes……………………..Give appropriate thixotropy Emollient material…………likes cetyl alcohol, spermaceti, lanolin Water phase with preservative Different types:-

(1) Cold Cream:- Cooling effect is produced due to slow evaporation of the water contained in the formulation. These are w/o type.


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(2) Beeswax Borax type:- These contain high percentage of mineral oil. These are o/w type. This cream contains high amount of mineral oil for cleansing action. Basically these are o/w type emulsion. After the cream is being rubbed into the skin sufficient quantity of water evaporates to impart a phase inversion to the w/o type. The solvent action of the oil as external phase imparts cleansing property. In this type of cream borax reacts with free fatty acids present in the bees wax and produces soft soap which acts as the emulsifying agent and emulsifies the oil phase .

A typical formulation:-

Bees wax -2 gm Borax-2 gm Almond oil -50 gm Rose water 35.5 gm Lanolin– 0.5gm preservative and perfume –q.s

B) NIGHT & MASSAGE CREAM:- These are generally applied on the skin and left for several hours say overnight and assist in the repair of skin which has been damaged by exposure to various elements or exposure to detergent solution or soap. The mostly have a moisturizing & a nourishing effect of affected skin. These also contain vitamins and hormones basing on the application. This cream give better look to the skin and prevent dryness.

A typical formulation

• Mineral oil-38gm Borax 1gm Petroleum jelly-8gm Water 35gm White bees wax-15gm Perfume & preservative q.s Paraffin wax – 1.0gm Lanolin 2gm

C) VANISHING CREAM:- These are named so as they seem to vanish when applied

to the skin. High quantity of stearic acid as oil phase used.This provides an oil phase which melts above body temp, and crystsllises in a suitable form, so as to invisible in use and give a non greasy film.

• Main component is emollient esters ,stearic acids

• Part of stearic acid is saponified with an alkali & rest of stearic acid is emulsified this soap in large quantity of water.

• The quality of cream depends on the amount of acid saponified & nature of alkali used.

• NaoH makes harder cream than koH.

• Borax makes cream very white but product has tendency to grain.

• Pearliness can be attained using liq.paraffin, cocoa butter, starch, castor oil, almond oil.

• Ammonia solution has a tendency to discolor creams made with it after some time.

• Cetyl alcohol improves texture and stability at low temperature without affecting sheen.

A typical formulation


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Stearic acid 15gm Glycerin 5gm KOH 0.5 gm water 75.82 gm NaOH 0.18 gm preservative &perfume q.s Cetyl alcohol 0.50 gm Propylene glycol 3.0gm

Stearic acid has whiteness like snow so some times the preparation is called as SNOW. D) FOUNDATION CREAM:-

• Applied to skin to provide a smooth emollient base or foundation for the application of face powder & other make up preparations. They help the powder to adhere to skin. They are almost o/w type.

Types: 1) Pigmented 2) Unpigmented A typical formulation

• Lanolin 2 gm Propylene glycol 8gm

• Cetyl alcohol 0.50 gm water 79.10 gm

• Stearic acid 10gm Perfume &preservative q.s

• KoH 0.40 gm E) HAND & BODY CREAM:-

• The repeated or constant contact with soap and detergent damages & removes film of sebum thus this cream is used to impart following functions to the skin.

• The function of these creams are - Replace/reduce water loss. - Provide oily film to protect the skin. - Keep the skin soft, smooth but not greasy. Type:-

a) Liquid cream:-consistency is of liquid nature b) Solid creams:- Consistency is higher

c) Nonaqueous type:-Not containing any aqueous medium. A typical formulation a.) Isopropyl myristate - 4 gm Mineral oil -- 2 gm Stearic acid – 3.gm Emulsifying wax - .275 gm Lanolin - 2.5 gm b.) Glycerin -3.0 gm


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Triethanolamine – 1 gm Water -84.225 gm

Perfume and Preservative -q.s (F) ALL PURPOSE CREAMS:- All purpose means it is suitable for hands, face and body. They are w/o types. Formula:- Oil phase Water phase Mineral oil 18% Water 61.3% Lanolin 2% Glycerol 5% Petroleum jelly 2% Magnesium sulphate 0.2% Ozokerite 7 % Perfume, preservative q.s Paraffin wax 3%

2) LOTIONS :- (I) Cleansing lotion

A typical formulation Mineral oil 38%, Bees wax 2%,

Triethanolamine stearate 8%, Water to make 100% Preservative & Perfumes –q.s

Note :- Triethanolamine discolors on standing so it should be made in situ using calculated amount of stearic acid and Triethanolamine. O/W lotion have tendency to increase in viscosity with ageing (this is prevented by using ethoxylated cholesterol)

(II) Sunscreen lotions :- These lotion has property of protecting the skin from

sun burning. An ideal sunscreen agent should have following properties. Absorb light over the range of 200-400 nm. Be stable to heat, light & perspiration Be nontoxic & nonirritant Not be rapidly absorbed Be neutral Be readily soluble in suitable vehicles.

US dept of health has recommended following ingredients to be used as sunscreen agents. They absorb U.V radiation.

CYCLOFORM MONOGLYCERYL PARA AMINO BENZOATE DIGALLOYL TRIOLEATE BENZYL SALICYLATE BENZYL CINNAMATE

And few others are PABA, cinnamic acid derivatives, coumarin derivatives, Quinine salts, uric acid derivatives. A typical formulation Glyceryl p-amino benzoate 3.0 % Glycerin 5.0 % Alcohol 10 %


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Methyl cellulose 0.5 % Perfume q.s

Water to make 100 %

3.POWDERS:- These are categorized as face powder, body powder, and Compacts. The powders should have following properties:- Must have good covering power so can hide skin blemishes. Should adhere perfectly to the skin & not blow off easily. Must have absorbent property. Must have sufficient slip to enable the powder to spread on the skin by the puff . The finish given to the skin must be preferably of a matt or peach like character.

The raw materials used to manufacture of various powders are classified with example as follows:-

RAW MATERIAL FOR POWDER

IMPARTING

EXAMPLE

Covering prop Titanium dioxide,zno,kaolin,zn stearate

Adhesion prop Mg.stearate,talc,mg & ca salt of myristic acid

Slip & Softness Zn/mg undecanate,aluminium hydrosilicate

Absorbency prop Starch, colloidal kaolin,bentonite,pptd chalk

Peach like finish Rice starch,silica,powdered silk

Frosted look Guanine, bismuth oxychloride,mica,Zn,Al

Color & perfumes Iron oxides

FACE POWDER:- Types of Face Powders:-

A. Loose face powder B. Compact face powder C. Talcum powder

D. Baby powder

A) LOOSE FACE POWDER :- The essential feature of a good face powder includes Covering power, slip, Adhesiveness, Absorbency, Bloom, Coloring, Perfuming.


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Type:-

b) Light type

c) Medium type

d) Heavy type

Type of face powder

purpose & composition

LIGHT Dry skin, contains large amount of talc

MEDIUM Normal or moderately oily skins, lesser talc & zinc oxide

HEAVY Extremely oily skins ,low talc but higher amount of Zinc oxide

TYPICAL FORMULATION OF FACE POWDERS:-

LIGHT POWDER MEDIUM POWDER HEAVY POWDER

Talc ---------63gm Talc---------39.7gm Talc---------20.0gm

Kaolin --------20 gm Kaolin-------39.5 gm Kaolin(light)-20 0gm

Cal. carbonate(l) 5 gm Cal. carbonate(l) 5 gm . Cal. carbonate(l) 39 g

Zinc oxide ---5.0gm Zinc oxide ---7.0gm Zinc oxide ---15.0gm

Zinc stearate-5.0gm Zinc stearate-7.0gm Mg.stearate—5.0gm

Mg.carbonate—1.0gm Mg.carbonate—1.0gm Color ------0.5gm

Color ------0.5gm Color ------0.2gm Perfume------0.5gm

Perfume------0.5gm Perfume------0.6gm

B) COMPACT FACE POWDER:-

It is a dry powder which has been compressed into a cake. The pressure for

compaction is very important. The powder must come off easily when rubbed with puff.


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Type of binder Examples

1) Dry binder Zn/Mg.stearate

2) Oil binder (water repellant )

Mineral oil, isopropyl myristate, Lanolin derivative

3) Water soluble binder PVP, CMC, Cellulose, Acacia, Tragacanth

5) Emulsion binder Triethanolamine stearate, Glycerol monostearate

(C) TALCUM POWDER:- It is used as an adsorbent for making the skin from the

excess moisture. Light magnesium carbonate added to mix perfume. Formula:- Zinc oxide ………………………. .. 50 Zinc stearate ……………………… 50

Chlorhexidine diacetate ………3 Light magnesium carbonate.100 Talc ……………….797 Perfume……………………….0.2 D) BODY POWDER:- It consists of mainly talc, with small portion of a metallic stearate, precipitated chalk, magnesium carbonate(light). Talcum/body powders containing antiseptic substances are also used for prickly heat, and fungus infections. Boric acid act as antiseptic.

A typical formulation Talc - 75 gm Aluminum stearate – 4 gm Colloidal Kaolin –10 gm Boric acid – 0.3 gm Colloidal silica--- 5 gm Perfume --- 0.7 gm Magnesium Carbonate- 5 gm

3. SKIN COLORANTS:- It includes a) Lipsticks b) Rouge

a) LIPSTICK:-These are basically dispersions of coloring matter in a base consisting

of a suitable blend of oils, fats, waxes, suitably perfumed and flavored, moulded in the form of a stick. Ideal character of lipstick includes:-

Should cover the lips adequately with some gloss and last for long time. It should make the lips soft. The film must adhere firmly to the lips without being brittle.& tachy.


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Should have high retention of color intensity without any change in shade.

Should be completely free from grittiness & free from drying. Nonirritating to the lips. Desirable degree of plasticity & have a pleasant odor and flavor.

• Classification of raw materials:-

1) Wax mixtures (bees, candeilla, carnauba, ceresin, Ozokerite wax) 2) Oil mixtures (castor, paraffin, THFA, isopropyl myristate) 3) Bromo mixture 4) Colors 5) Preservatives

Types of lipsticks 1) Transparent lipstick 2) Liquid lipstick 3) Lip rouge 4) Lip jelly 5) Lip salve 6) Lip glosses A typical formulation of lipstick.

Castor oil 54 gm

Lanolin (anhydrous) 11 gm

Candeilla wax 9 gm

Isopropyl myristate 8 gm

White beeswax 5 gm

Carnauba wax 3 gm

Ozokerite wax 3 gm

Eosin 2 gm

Lakes 5 gm

Rose flavor q.s

Antioxidant q.s

Preservative q.s

b) SKIN ROUGE: - These are the cosmetics preparations used to apply a color to

the cheeks. The color may vary from the palest of pinks to the deep blue reds .The tint or color may be achieved using water insoluble colors such as iron oxides and certain organic pigments or by using water soluble organic colors which actually stain the skin. Types :-

Powder rouges Wax based rouges (Stick rouge) Emulsion cream rouges Liquid rouges


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Powder Rouges Stick rouge

Talc…………………………….40 Zinc oxide……………………..10 Magnesium carbonate……….20 Pigment………………………..14 Lanolin………………………...30 Perfume………………………..2

Carnauba wax…………………3 Candelilla………………………6 Ozokerite………………………1.5 Bees wax………………………1.5 Hexadecyl stearate……………10 Isopropyl myristate…………….8 Castor oil……………………….65 BHA……………………………..0.02 Color……………………………5

Emulsion cream rouge (vanishing type) Liquid rouge

Stearic acid…………………….15 Potassium hydroxide………….0.5 Sod. Hydroxide………………..0.18 Glycerin………………………..8 Water…………………………..76 Pigment, Perfume & Preserative……………………q.s

(A) Iso stearic acid…………….0.02 Mineral oil………………….30 Iso propyl myristate………..5 Colloidal silica……………..1 Color………………………...3 (B) Water………………………..48.3 Triethanolamine……………4 Perfume…………………….0.2

(4) ANTIPERSPIRANTS & DEODORANTS:- Anti perspirants:- Aluminium chlorhydrate used which has antibacterial and astringent action. Aluminium chloride and Zirconium compounds are also used as antiperspirants. Deodorants:--11 ( Hexachlorophene) - TMTD (Tetra methyl triuram disulphide) - Bithionol - Bromosalicylanilide - Diaphene - Neomycin ( Antibiotic) - Ion-exchange resin used like Amberlite - Metal chelates like 1,3 Diketones used which chelate copper, aluminium, Mg compounds.

COSMETICS FOR HAIR:- Includes following type of preparations:-

1. Shampoo 2. Hair tonics & Conditioners 3. Hair colorants and hair color remover 4. Hair grooming preparations 5. Depilatory & Epilatory 6. Shaving soaps & creams 7. Hair wave sets & lacquers ,rinses

1. SHAMPOO Ideal characters of a shampoo:-

Should effectively and completely remove the dust, excessive sebum.


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Should effectively wash hair. Should produce a good amount of foam The shampoo should be easily removed by rinsing with water. Should leave the hair non dry ,soft, lustrous with good, manageability. Should impart a pleasant fragrance to the hair,. Should not make the hand rough and chapped. Should not have any side effects or cause irritation to skin or eye.

Composition of shampoo:-

1) Principal surfactant (anionic type) Non ionic surfactant has sufficient cleansing property but have low foaming power. Cationic are toxic. So anionic are preferred. 2) Secondary surfactant (anionic or ampholytic detergent) They modify detergent and surfactant properties of principal surfactant. 3) Antidandruff agents (selenium, cadmium sulfide, ZPTO) 4) Conditioning agent (lanolin, oil, herbal extract, egg, amino acids) 5) Pearlescent agents (substituted 4 methyl coumarins) 6) Sequestrants (EDTA) Added because Ca, Mg salts are present in hard water. Soaps cause dullness by deposition of Ca, Mg soaps on hair shaft. This prevented by EDTA. 7) Thickening agents (alginates, PVA, MC) 8) Colors, perfumes and preservatives

Types of shampoo:- 1) Liquid cream shampoo 2) Solid cream and gel shampoo 3) Powder shampoo 4) Antidandruff shampoo 5) Aerosol foam shampoo

Formulation of shampoo:-

Liquid Cream shampoo Solid cream and Gel Shampoo

SLS 30% PEG 400 Distearate Mag. Stearate Dist. Water Ninol AB 21 Oleyl alcohol Perfume PEG 400 distearate and Mg stearate used to convert clear liquid shampoo to liquid cream shampoo. Ninol AB 21- Thickening agent Oleyl alcohol- Conditioning agent

SLS………………………20% Coconut monoethanolamide….1% Propylene glycol monostearate..2% Stearic acid…………………….5% Sodium hydroxide……………0.75% Water, perfume, Colour…….100


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1) Powder shampoo 2) Antidandruff shampoo

Henna powder ………… 5 gm Borax …………………….15 gm Sod. carbonate ………… 25 gm Pot. Carbonate ………….. 5 gm Soap powder…………….. 50 gm Perfume …………………. q.s.

Selenium disulphide…… 2.5 gm Bentonite ......…………… 5 gm Sod. Lauryl Sulphates ... 40 g Water ………………… 52.5 gm Perfume……………… q.s.

Aerosol Shampoo:- SLS………………………………………….30% Triethanolamine lauryl stearate…………..5% Polyethylene glycol stearate………………3% Perfume……………………………………..0.3% Water…………………………………………100 90 parts of above packed with 2 parts of propellant 12 and 8 parts of propellant 14.

2) CONDITIONERS:- These are the preparations used after shampooing to render

the hair more lustrous, easy to comb, and free from static electricity when dry. Conditioners are usually based on cationic detergents and fatty materials like lanolin, or mineral oil.

3) HAIR COLORANTS:-These are used either to hide gray hair or to change the

color of the hair . An ideal hair dye should have following properties:-

Should be nontoxic to the skin or hair, should not impair natural gloss and texture.

Should not be a dermatitic sensitizer. The color imparted must be stable to air, light, water, shampoo. Should be easy to apply.

Hair dyes are divided into 1) Vegetable Example is Henna 2) Metallic Example:- Lead dyes, Bismuth dyes, Silver dyes, Copper, nickel, cobalt salts Formula:- (Lead dyes) Precipitated sulphur……………….1.3% Lead acetate………………………..1.6% Glycerine…………………………….9.6% Rose water………………………….87.5% 3) Synthetic organic dyes They are of two types. a) Semipermanent dye. b) Permanent dyes Thyoglycolic acid……50% Paraphenylene diamne dye NH3 solution(PH 9.2)…100%

HAIR DYE REMOVER:- Formula:- Formamidine sulfinic acid……………….1.5% PVP…………………………………………5%


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Ethylene glycol monobutyl ether………..5% Ammonium carbonate……………………1% Ammonia…………………………………..0.5% CMC………………………………………..2.5% Water up to ……………………………….1oo Formamidine sulfinic acid is acting as hair dye remover.

4) HAIR GROOMING AIDS :-These are important group of cosmetics which are

used both by men and women to keep their hair in order for good looking, &enhance overall appearance. Types:-

1. Brilliantines & Hair oils 2. Hair setting lotions 3. Hair creams 4. Hair lacquers or sprays

5) DEPILATORIES:- • These are the preparations that remove superfluous hair by chemical

breakdown. This removes hair at the neck of the hair follicle and thus has advantage over razor shaver which removes hair on a level with the surface of epidermis.

• Desirable Characters of an ideal depilatory preparation are:- Selective in action Efficient and rapid action in few minutes. Non toxic and non allergic to the skin. Odorless Easy to apply Stable Non staining

• INGREDIENTS :- includes 1. Inorganic sulphates (Sod,calcium,barium sulphide,Strontium sulphide)

2. Thioglycollates: - (Calcium.thioglycollate & Lithium thioglycollate) 3. Stannites: - sodium stannite 4. Enzymes:-Keratinase (3-4%) 5. Humectant: - Glycerol,Sorbitol ,Propylene glycol

FORMULATION Name of ingredient Amount

1.Strontium sulphide 20.0 gm

2.Talc 20.0gm

3.Methyl cellulose 3.0 gm

4.Glycerin 15.0 gm

5.Water 42.0 gm

6.Perfume q.s

7. Preservative q.s


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6) EPILATORIES:-

Epilation is longer lasting or even can be of permanent nature. This is achieved by plucking the hair out and removing the root either by tweezers, threading,or by waxing.

• it is a permanent or long lasting effect (done by plucking the hair out, removing the root)

• Camphor-impart cooling effect to reduce discomfort of hair pulling.

• Local Anaesthetics:- overcomes discomfort and pain

FORMULATION

Rosin 70 gm

Bees wax 20 gm

Ozokerite 10 gm

Perfume q.s

7) SHAVING PREPARATIONS: - These are preparations used to carryout

shaving. Type

a) Ued before shaving b) Used after shaving

Preparations before shaving includes 1) Lather shaving creams 2) Brushless shaving cream 3) Shaving soaps (solid, cream) 4) Aerosol preparation Preparation after shaving is Aftershave lotion SOAP BAR SOAP CREAM

I Ingredients A amount I Ingredients A Amount

S Stearic acid 49 gm A. A. 䦋

C Coconut oil 1 13 gm 1. Stearic acid 30 gm

C Caustic potash 22 gm 2. Coconut oil 10 gm

C Caustic soda 12 gm 3. Palm kernel oil 05 gm

W Water 1.25 gm B. B.

S Sodium dioxy stStearate (50%)

o.75 gm

1. Pot. hydroxide 07 gm

S Sorbital liquid 1.25 gm 2. Sod. hydroxide 1.5 gm

G Glycerol 0.75 gm 3. Water 36.5 gm

P Perfume q.s 4. Perfume q.s


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P Preservative q.s 5. Preservative q.s

1) BRUSHLESS SHAVING CREAM – Here Lathering with shaving brush is avoided. Formulation of brushless shaving cream

INGREDIENTS AMOUNT

1. Stearic acid 16 gm

2. Mineral oil 14 gm

3. Spermaceti 2 gm

4. Glycerin 6 gm

5. Dil .ammonia solution 2 gm

6. Water 6 gm

7. Perfume q.s

8. Preservative q.s

2) LATHER SHAVING CREAM:- Lathering with shaving brush is required.

INGREDIENTS A AMOUNT (%)

Stearic acid 28

Coconut oil 12

Palm oil 5

Pot. hydroxide 6.5

Sod. hydroxide 1.5

Glycerin 10

Perfume q.s

Preservative q.s

Water to make 100

AFTER SHAVE PREPARATION:- Main purpose of shave preparation is to confer a pleasant feeling of comfort and well being after shaving. This is achieved by giving slight coolness, anaesthesia, tautness or emolliency to skin. At the same time it should be aseptic also. Formula:-( Antiseptic after shave lotion) Hyamine……………………………..0.25% Alcohol……………………………….40%


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Menthol………………………………0.005% Benzocaine………………………….0.025% Water…………………………………59.72% Perfume………………………………q.s

COSMETICS FOR NAILS:- Includes

1. Nail polishes 2. Nail lacquers & removers 3. Nail bleaches & Stain removers 4. Cuticle remover & softener 5. Fingernail elongations

1 ) NAIL POLISHES:- A distinction between nail polishes and lacquer is that in nail polish exert the abrasive action. Due to friction it draw the blood to numerous capillaries of nail bed and increasing blood supply, and exert stimulating effect to growth of nail. Examples are stannic oxide, talc, precipitated chalk. Silica exert abrasive action. Formula:- Stannic oxide………………………90% Powdered silica…………………….8% Butyl stearate………………………2% Pigment & Perfume…………….. ..q.s 2) NAIL LACQUERS :-

• These are the preparations that cover the nail with a water and air impermeable layer which normally remains for days.

• A good Nail lacquer should fulfill the following characters:-

1) Must be innocuous to the nail & the skin 2) Must be easy and inconvenient to apply 3) Product should be stable on storage 4) The product should produce a good &satisfactory film.

• COMPOSITION:- 1) Film former:-Nitro cellulose, Cellulose nitrate (mostly used), Cellulose acetate, cellulose acetobutyrate, Ethyl. Cellulose. 2) Resins :- Give film more body, gloss, depth, adhesion

Natural - Gum damar, Benzoic acid, Gum copal, Shellac Synthetic - Sulphonamide –Formaldehyde Resins

3) Solvents:-Mix of solvent is preferred, Mixing middle b.p solvents like alcohols, acetates,and aromatic solvents rate of evaporation can be retarded. 4) Diluents:- 5) Plasticizers :- Dibutyl phthalate, Castor oil ,n-butyl stearate, castor oil 6) pearlescent material :-Guanine crystals

(R.I-1.8), mica flakes, Ti02, Platelets coated with bismuth oxychloride.


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7) colors and perfumes

Formulation (Nail Lacquer)

INGREDIENT AMOUNT

Nitrocellulose 16 gm

Resin 9 gm

plasticizer 4.8 gm

Solvent 60.5 gm

Color 0.5 gm

Perfume q.s

b) LACQUER REMOVERS:- These are also called as nail cleansers which is applied to remove nail lacquers. FORMULATION OF LACQUER REMOVERS

Ingredients Amount

Butyl acetate 15 gm

Ethylene glycol monoethyl ether

80 gm

Propylene glycol ricinoleate

05 gm

Perfume q.s

c) CUTICLE REMOVERS AND SOFTENERS:- Cuticle preparations either soften or remove the cuticles.

COSMETICS FOR EYES:- Includes following preparations

1. Eye shadow 2. Mascara 3. Eyebrow pencil 4. Eye cream 5. Eye liners 6. Kajal

1) EYE SHADOW:- • Give a back ground of color to the eye

• Formulated as cream, liquid, powder or stick.

• Ultramarine(20 part)& Ti02 --- (BLUE)

• Iron oxide(30 part) &Ti02 (5 part)-- (BROWN)


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Ingredients Amount

petroleum jelly 47.5 gm

Liquid lanolin 4.5 gm

Bees wax 4.5 gm

Micro crystalline wax

8.5 gm

Isopropyl myristate 35 gm

2) EYE LINER:-

Types 1) Pencil type

2) Liquid type (suspension in a base containing film forming material) 3) Cake eye liners Formulation of Cake type eyeliner

Kaolin 5%

Zn Stearate 12%

Ppted Caco3 7 %

Pigment 10%

Talc to make 100 %

3) EYE BROW PENCIL:-

• Contain high proportion of wax to increase M.P so that these can be moulded into sticks.

Ingredient Amount

Bees wax 25%

Ozokerite 25%

Butyl stearate 8%

Lanolin 2%

Castor oil 25%

Mineral oil 15%

Perfume q.s


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Antioxidant q.s

4) MASCARA:- • Black pigmented preparation for applying to eye lashes or eye brows ,it darkens

the eye lashes & gives an illusion of their density and length.

• Type:- Cake , Cream , Liquid Formulation:-

Carbon black

55 %

Coconut oil sodium soap 25%

Palm oil –sodium soap 22.5%

7) QUALITY CONTROL OF COSMETICS :- We all know that ―Price of a product is quickly forgotten but the quality is remembered‖ so quality control plays a vital role regarding monitoring different parameters that may affect quality &also helps in producing quality product every time. Includes :-

1) RAW MATERIAL CONTROL 2) INTERMEDIATE PRODUCT CONTROL 3) FINISHED PRODUCT CONTROL 4) PACKAGING MATERIAL CONTROL

1) Q.C OF RAW MATERIAL:- • Done by determination of Bioburden

The bacterias that are monitored in raw materials include:-

• Enterobacteriaceae

• E.Coli

• Salmonella

• Pseudomonas aeruginosa

• Staphylococcus aureus

2) Q.C OF INTERMEDIATES AND BULK FINISHED PRODUCT:- Basing on the type of product few typical processing parameters are continuously to ensure quality final product. few of them have been enlisted here. a) CREAMS & LOTIONS:-

Mechanics, perfume addition temp addition of phases Viscosity Temp of filling


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rate of cooling b) FACE POWDER

Uniformity of mixing Apparent density Shade ,color Compression pressure (compacts)

c) LIPSTICKS Color match Texture Softening point Breaking point test

d) SHAMPOO:- -Foam & foam stability -Detergency & coloring action -Wetting action -Eye irritation -Oral toxicity

e) NAIL LACQUER:- Color match, Drying rate, Non volatile content, Smoothness, Gloss, Hardness, abrasion resistance, adhesion etc.

Sampling size for final Q.C:-

No of packaging No of packing selected

Up to 3 Each

4-50 03

51-150 04

151-300 05

301-500 06

>500 07

8) COSMOCEUTICALS: - These are cosmetics with therapeutic &

disease fighting property


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The following substances are now recognized having cosmoceutical potentials

1) Polysacharides :-Fom Tamarind extract and skin beneficial acids from Coriander extract provide moisture-lipid balance preventing dryness and itching 2

2) Wheat Germ Oil guard skin against free radical damage. 3) Moringa Extract protects your skin against dust and harmful pollutants. 4) Galanga Oil * protects skin from harmful UV rays and fights pimple in acne

prone skin. Skin beneficial fatty acids from Coriander boost the deposition of skin proteins, enhancing tissue repair

5) Cococin provides wholesome freshness and nourishment of natural tender coconut water. Natural growth promoters like kinetin and amino acids in Cococin® impart natural conditioning, suppleness and glow to the skin.

6) Ubiquinone(CO.Q.10) rejuvenates and increases the oxygen uptake into the cells.

7) Tetrahydrocurcuminoids, patented molecule from turmeric in combination with potent antioxidants - Alpha lipolic acid and Ubiquinone reduces fine lines, wrinkles, crow's feet, minimizes the UV induced signs of photo aging and pigmentation, leaving behind blemish-free, youthful skin.

8) Isoflavons from Soy impart luster and brightness to the skin by improving skin thickness, skin blood circulation, increased desquamation resulting in excellent surface texture and softness.

9) Tetrahydropiperine as Cosmoperine from Pepper improves the dermal penetration of the actives,

MISCELLANEOUS ISSUES:- SKIN TESTING:-

Type of cosmetic Preparation

Suspected agent to cause harm

CREAMS Mercurial & Salicylic acid

DEODORANT Phenolic antimicrobials, Aluminium.chloride

DEPILATORIES Sulphides of alkali (R.A)

HAIR DYE Ammonia solution

COLD WAVE LOTIONS Thioglycollates


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LIPSTICK Bromofluorescein dye ( cause Cheilitis)

HAIR & BATH Prep Agent which cause eye irritation

4) TEN SYNTHETIC COSMETIC INGREDIENTS TO AVOID:- Organic consumers association has given the following list of chemicals that are to be avoided in preparation of cosmetics.

1. Imidazolidinyl Urea and Diazolidinyl Urea 2. Methyl and Propyl and Butyl and Ethyl Paraben 3. Petrolatum 4. Propylene Glycol 5. PVP/VA Copolymer 6. Sodium Lauryl Sulfate 7. Stearalkonium Chloride 8. Synthetic Colors Example: FD&C Red No. 6 / D&C Green No. 6 9. Synthetic Fragrances 10. Triethanolamine

Newer approaches Hair Growth-accelerating preparation containing chlorogenic acid or its

isomer for treating androgenic alopecia and its formulation. Cosmetic composition contain in caffeine ,acetic acid and sodium

hyaluronate for preventing alopecia.

(chemical abstract-151-2009)

DENTAL PRODUCTS LIST OF CONTENTS

1) Introduction 2) The teeth and common problem 3) Causes of oral health problems 4) Classification 5) Formulation of dentifrices 6) Type of dentifrices

1. Tooth pastes 2. Tooth powders 3. Solid blocks 4. Liquid preparations 5. Mouth wash

7) Topical anesthetics 8) Tartar reducing product 9) Mechanical method for plaque control 10) Safety 11) Dental care product 12) Newer approaches


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INTRODUCTION

dentifrice a preparation for cleansing and polishing the teeth; it may contain a therapeutic agent, such as fluoride, to inhibit dental caries.

A substance, such as a paste or powder, for cleaning the teeth.

Etymology: L, dens + fricare, to rub a pharmaceutic compound used with a toothbrush for cleaning and polishing the teeth. It typically contains a mild abrasive, detergent, flavoring agent, fluoride, and binder. Other common ingredients are deodorants, humectants, desensitizers, and various medications to prevent dental caries. Also called toothpaste. dentifrice (toothpaste) n a pharmaceutical compound used in conjunction with the toothbrush to clean and polish the teeth. Contains a mild abrasive, a detergent, a flavoring agent, a binder, and occasionally deodorants and various medicaments designed as caries preventives (e.g., antiseptics). Two type of Dentifrice

1. Simple cleansing dentifrices 2. Therapeutics dentifrices: Therapeutic dentifrices may contain the

bactericidal, bacteriostatic, enzyme inhibiting or acid neutralizing qualities of the drugs or chemicals.

The teeth and common problem 1. Bad Breath If you suffer from bad breath, you are not alone. Bad breath, also called halitosis, can be downright embarrassing. According to dental studies, about 85% of people with persistent bad breath have a dental condition that is to blame. Gum disease, cavities, oral cancer, dry mouth and bacteria on the tongue are some of the dental problems that can cause bad breath. Using mouthwash to cover up bad breath when a dental problem is present will only mask the odor and not cure it. If you suffer from chronic bad breath, visit your dentist to rule out any of these problems. 2. Tooth Decay Did you know tooth decay, also known as cavities, is the second most prevalent disease in the United States (the common cold is first). Tooth decay occurs when plague, the sticky substance that forms on teeth, combines with the sugars and / or starches of the food we eat. This combination produces acids that attack tooth enamel. The best way to prevent tooth decay is by brushing twice a day, flossing daily and going to your regular dental check ups. Eating healthy foods and avoiding snacks and drinks that are high in sugar are also ways to prevent decay. 3. Gum (Periodontal) Disease Studies have shown that periodontal disease, also known as gum disease, is linked to heart attacks and strokes. Gum disease is an infection in the gums surrounding the

http://medical-dictionary.thefreedictionary.com/toothpaste

http://dentistry.about.com/od/badbre3/Bad_Breath_Causes_Preventions_and_Treatment_of_Bad_Breath.htm

http://dentistry.about.com/od/dentalhealth/tp/preventing_cavities.htm

http://dentistry.about.com/od/gumdisease/Gum_Disease_Periodontitis_and_Gingivitis.htm


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teeth. Gum disease is also one of the main causes of tooth loss among adults. There are two major stages of gum disease: gingivitis and periodontitis. Regular dental check ups along with brushing at least twice a day and flossing daily play an important role in preventing gum disease. 4. Oral Cancer Oral cancer is a serious and deadly disease that affects millions of people. In fact, the Oral Cancer Foundation estimates that someone in the United States dies every hour of every day from oral cancer. Over 300,000 new cases of oral cancer are diagnosed every year, worldwide. This serious dental disease, which pertains to the mouth, lips or throat, is often highly curable if diagnosed and treated in the early stages. 5. Mouth Sores There are several different types of mouth sores and they can be pesky and bothersome. Unless a mouth sore lasts more than two weeks, it is usually nothing to worry about and will disappear on its own. Common mouth sores are canker sores, fever blisters, cold sores, ulcers and thrush. 6. Tooth Erosion Tooth erosion is the loss of tooth structure and is caused by acid attacking the enamel. Tooth erosion signs and symptoms can range from sensitivity to more severe problems such as cracking. Tooth erosion is more common than people might think, but it can also be easily prevented. 7. Tooth Sensitivity Tooth sensitivity is a common problem that affects millions of people. Basically, tooth sensitivity means experiencing pain or discomfort to your teeth from sweets, cold air, hot drinks, cold drinks or ice cream. Some people with sensitive teeth even experience discomfort from brushing and flossing. The good news is that sensitive teeth can be treated. 8. Toothaches and Dental Emergencies I can't think of much worse than suffering from a toothache. While many toothaches and dental emergencies can be easily avoided just by regular visits to the dentist, we all know that accidents can and do happen. Having a dental emergency can be very painful and scary. Fortunately, you can do several things until you are able to see your dentist. 9. Unattractive Smile While an unattractive smile is not technically a "dental problem," it is considered a dental problem by people who are unhappy with their smile and it's also a major reason that many patients seek dental treatment. An unattractive smile can really lower a person's self-esteem. Luckily, with today's technologies and developments, anyone can have a beautiful smile. Whether it's teeth whitening, dental implants, orthodontics or other cosmetic dental work, chances are that your dentist can give you the smile of your dreams.

http://dentistry.about.com/od/oralcancer/Oral_Cancer_Mouth_Throat_Tongue_and_Neck_Cancer.htm

http://dentistry.about.com/od/cankersores/Mouth_Sores_Canker_Sores_Fever_Blisters_Ulcers_Thrush.htm

http://dentistry.about.com/od/tootherosion/Tooth_Erosion_Causes_Symptoms_and_Prevention_of_Tooth_Erosion.htm

http://dentistry.about.com/od/dentalfactsfaqs/f/toothsensitiv.htm

http://dentistry.about.com/od/toothachesemergenci2/Toothaches_and_Dental_Emergencies.htm

http://dentistry.about.com/od/cosmeticdentistry/Teeth_Whitening_and_Cosmetic_Dentistry.htm


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Causes of oral health problems 1)Pellicle The pellicle is rapidly formed on all freshly cleaned tooth surfaces by the deposition and absorption of some salivary proteins. It is less than 0.1 mm thick and is invisible to the naked eye. 2)Plaque Following the deposition of pellicle on a freshly cleaned tooth surface, plaque forms rapidly. Plaque is an invisible sticky film of bacteria, salivary proteins, and polysaccharides that accumulates on everyone's teeth. It is not washed away by the saliva, and the composition of bacteria depends upon the host, the site in the mouth and the age of the plaque layer. In the event of poor oral hygiene, plaque ages and there is a shift in bacterial population to more harmful organisms as the plaque age. 3)Dental calculus (tartar) Dental plaque may itself become mineralized and this hard deposit is called calculus. It accumulates on the tooth surface mainly at the gingival margin opposite the salivary ducts. It is a hard mineral deposit, containing predominantly calcium and phosphate, very tightly bound to the tooth surface. Once it has formed, it is virtually impossible to remove it except by a dental hygienist.

CLASSIFICATION OF DENTAL PRODUCTS

Dental preparations are classified as follows-

Classification depending on Dental Problems. I. Products for carries control.

a. Systemic fluoride b. Topical fluoride

i. Dentifrices ii. Gel iii. Rinses iv. Miscellaneous

II. Products for plaque control. a. Chemical agents

i. Dentifrices ii. Mouth washes

b. Mechanical products i. Tooth brushes ii. Dental floss iii. Other aids to plaque removal.

III. Products for tooth surface hypersensitivity. IV. Topical anesthetic. V. Halitosis


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TOOTHPASTE INGREDIENTS AND MANUFACTURE Requirements of a toothpaste/dentifrice

The major requirements of oral preparations, especially toothpastes, have been summarized on many occasions in the past. For a toothpaste, these requirements were: 1. When used properly, with an efficient toothbrush, it should clean the teeth adequately, that is, remove food debris, plaque and stains. 2. It should leave the mouth with a fresh, clean sensation. 3. Its cost should be such as to encourage regular and frequent use by all. 4. It should be harmless, pleasant and convenient to use. (It should conform to the EC Cosmetics Directive in that it is 'not liable to cause damage to human health when applied under normal usage conditions'.) 5. It should be capable of being packed economically and should be stable in storage during its commercial shelf-life. 6. It should conform to accepted standards in terms of its abrasivity to enamel and dentine. 7.Claims should be substantiated by properly conducted clinical trials.

These requirements remain valid today, with perhaps only the priority and emphasis placed on any individual point being changed.

To achieve this it is necessary to have a high solid suspension in a stable viscous form and therefore gelling agents or thickening polymers have to be incorporated.

To prevent it from drying out it also becomes necessary to add humectants to the system. Finally, colours (if desired), and preservatives (if necessary), are also added, creating a complex matrix of ingredients which can be classified as a 'simple' cosmetic toothpaste, i.e. 1. Cleaning and polishing agents (abrasives). 2. Surfactant (cleaning and foaming). 3. Humectants. 4. Binding (gelling) agents. 5. Sweetener. 6. Flavouring agents. 7. Minor ingredients (colours, whitening agents, preservatives).

In such a complex system many interactions can take place depending upon internal and external factors. Even the 'simple' formulations require extensive stability testing, over a range of temperatures and time, in order to be confident that the product quality does not change upon storage. Only in this way can the manufacturer have a high degree of confidence that the product seen by the consumer is of premium quality.

'A dentifrice should be no more abrasive than is necessary to keep the teeth clean - that is free of accessible plaque, debris and superficial stain'. (American Dental Association, 1970.) Thus, considerable performance testing on the final formulation is necessary.


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Ingredients used in toothpastes All ingredients generally have specifications approved for use in foodstuffs or are special grades available for dental preparations, especially abrasives. 1. Cleaning and polishing agents (abrasives) Clearly the main purpose of the cleaning and polishing agent is to remove any adherent layer on the teeth, and the materials normally considered are given below. (a) Dental grade silicas (SiO2)n.

In a relatively short period of time silica has generally become the abrasive of choice because it offers great flexibility to the formulator.

It can be produced to a high state of purity giving excellent compatibility with therapeutic additives and flavours.

Varying the particle size can alter the finished product abrasivity. Clear gels can be formulated by carefully matching the refractive indices of

silica used with the liquid phase of the toothpaste. Silica can also give additional thickening properties to the dental cream if

extremely fine particle sizes are used (silica thickeners). When used in toothpastes, silica is generally incorporated at levels between 10

and 30%. (b) Dicalcium phosphate dihydrate (DCPD) CaHPO4-2H2O.

DCPD is one of the most commonly used dental cream abrasives, perhaps because it gives good flavour stability.

It is normally white in colour and gives toothpaste which generally does not require additional whitening agents.

The main drawback is that it is only fully compatible with sodium monofluorophosphate as the fluoride source because of the presence of free calcium ions. Formulating with other therapeutic fluoride sources does not appear to have been successful.

The abrasive is usually formulated at levels between 40% and 50% to give relatively dense toothpaste.

(c) Calcium carbonate CaCO3. Calcium carbonate is probably one of the most commonly used dental cream

abrasives. Precipitated calcium carbonate (chalk) is available with a white or off-white

colour and both particle size and crystalline form can be varied, depending upon its conditions of manufacture.

As a result of its structure and calcium content, precipitated calcium carbonate is incompatible with sodium fluoride, but is stable with the less reactive sodium monofluorophosphate.

Calcium carbonate is also used at levels between 30% and 50% to give a relatively dense paste.

(d) Sodium bicarbonate (or baking soda NaHCO3). Sodium bicarbonate has a unique 'salty' mouth-feel that tends to polarize

consumers, many finding it attractive possibly due to its heritage as a cleaner/deodorizer.

It is a very mild abrasive, usually used at a 5-30% level, in combination with other abrasives such as silica or calcium carbonate to achieve the required cleaning action.

(e) Hydrated alumina Al2O3 • 3H2O or Al(OH)3.


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Hydrated alumina is relatively inert, cost-effective, and available as a white amorphous solid.

It has good compatibility with sodium monofluorophosphate and other ingredients added to give a therapeutic benefit.

The abrasive is usually formulated at levels between 40% and 50% to give a relatively dense paste.

(f) Other abrasives. Insoluble sodium metaphosphate (IMP) (NaPO3)x, is available as a free-flowing

white powder, with moderate abrasivity and good compatibility with flavour oils, sodium monofluorophosphate and ionic fluoride sources (stannous and sodium fluorides).

it is now only used in extremely limited amounts. Calcium pyrophosphate (CPP), Ca2P2O7, was the original abrasive purposely

developed for its compatibility with stannous fluoride to give the first commercially available therapeutic dentifrice containing fluoride (America Dental Association, Council on Dental Therapeutics, 1960). 2. Surfactants

Surfactants are used in the toothpaste to aid in the penetration of the surface film on the tooth by lowering the surface tension.

They also provide the secondary benefits of providing foam to suspend and remove the debris, and the subjective perception of toothpaste performance.

They often have better foaming properties, and are more compatible with other ingredients since their pH range is essentially neutral.

They are also available with a higher degree of purity that can eliminate some of the bitter flavour components that affect taste.

In general, surfactants are used at a concentration of around 1-2% by weight in the dental cream.

(a) Sodium lauryl sulphate (SLS) This has been the main surfactant of choice, used in nearly all toothpaste

brands. However, while alternative surfactants have been considered, and will continue

to be looked at and developed, none is in widespread use since all have some disadvantages compared to SLS. 3. Humectants

Humectants are used to prevent the paste from drying out and hardening to an unacceptable level.

At the same time they give shine and some plasticity to the paste. Generally only two major humectants are considered for use in toothpaste,

often in combination with small amounts of additional minor humectants. (a) Glycerin, CH2OHCHOHCH2OH.

Glycerin is still the humectant used in greatest bulk quantity in toothpaste. It is one of the best humectants, producing a shiny, glossy product.

It is stable, non-toxic, available from both synthetic and natural sources, and provides a useful sweetening function to the paste.

(b) Sorbitol, CH2OH(CHOH)4CH2OH. Sorbitol syrup (approximately 70%) is also extensively used throughout the

industry and is sometimes considered superior to glycerin depending upon the formulation.

It also imparts sweetness, and is a stable humectant.


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(c) Propylene Glycol, CH3CHOHCH2OH and Polyethylene Glycol, CH2OH(CHOH)nCH2OH.

Propylene glycol and polyethylene glycol are not normally used as the sole humectant in a paste since they are more expensive and, in the case of propylene glycol, can impart a slightly bitter taste.

They are more generally used in relatively small amounts in combination with either glycerin or sorbitol.

The amount of humectant in any formula obviously has to be adjusted depending upon the other constituents of the formula (especially abrasive nature), but generally the total humectant loading is in the range 10-30% by weight.

(d) Xylitol (CH2OH(CHOH)3CH2OH). Xylitol is a polyol equivalent of sorbitol, but with a five-carbon chain instead of

six. Like sorbitol it is a naturally occurring material with a relative sweetness equal to sugar.

Currently its high cost and limited availability restrict its use. 4. Gelling agents

Gelling or binding agents are hydrophilic (water-loving) colloids which disperse and swell in the water phase of the toothpaste and are necessary to maintain the integral stability of the paste and prevent separation into component phases.

They are probably the most widely variable components of toothpaste and the choice of gelling agent can greatly influence the dispersibility of the paste in the mouth, the generation of foam and, above all, the release of the flavor components.

Some formulations have combinations of gelling agents in order to achieve the desired consumer preferences. (a) Sodium Carboxymethyl Cellulose CMC.

Carboxymethyl cellulose is one of the preferred gelling agents for use in toothpaste.

It can be manufactured to a high state of purity, and tailor-made for an individual requirement by varying the degree of substitution on the cellulose chain.

This can give flexibility in terms of solubility, elasticity and some increased stability in the presence of electrolytes.

(b) Carrageenan.

It is a purified colloid, consisting of a mixture of sulfated polysaccharides and, as with all natural products, it can be of variable quality, which could cause a problem for any formulator.

Therefore, it is standardized either by repeated blending, or dilution with variable amounts of inert material.

Some flexibility in the gelling properties of carrageenan can be achieved by controlling the cations present by ion exchange.

(c) Miscellaneous gelling agents Xanthan - this is a polysaccharide produced by fermentation technology. It offers excellent properties for use in toothpaste since it gives a highly structured gel, relatively easily broken down when sheared, but which recovers rapidly.


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It is relatively insensitive to electrolytes and heat, but unfortunately it is generally incompatible with cellulosic materials because of contaminating enzymes that degrade cellulose. Hydroxy ethyl cellulose HEC - this is occasionally used as an alternative to carboxymethyl cellulose (CMC), especially when a greater electrolyte tolerance is required. Synthetic polymers - crosslinked acrylic acid polymers have become more intensively used in the past decade because of their useful thickening and suspending properties combined with their inertness and their stability to heat and ageing. Clays - colloidal clays, either natural processed bentonites or synthetic clays, have been used as binding agents because of their thixotropic properties. Depending upon the rest of the formula components (e.g. abrasive, amount of free water), the level of gelling agent added to a paste can vary from 0.5% to 2.0% by weight. 5. Sweetening agents

These are important for product acceptance, since the final product must be neither too sweet nor too bitter.

These ingredients must always be considered in partnership with the flavour because of their combined impact.

(a) Sodium saccharin. This is the sweetening agent in widest commercial use, and is generally used at

a level between 0.05% and 0.5% by weight. 6. Flavours

Flavours are probably the most crucial part of toothpaste because of consumer preferences.

The flavour is a blend of many suitable oils, with peppermint and spearmint being the major base components. These are nearly always fortified with other components such as thymol, anethole, menthol (to give a pleasant cooling effect), eugenol (clove oil), cinnamon, eucalyptol, aniseed, and wintergreen (to give a medicinal effect).

In addition, because the flavour is a mixture of sparingly soluble organic oils, its interactions with the other dentifrice components are often unpredictable and unexpected.

Taste and stability can be influenced greatly by both the other components of the dental cream, e.g. free water content, or absorption by the abrasive (perhaps to the surface), and also by the physical properties of the dental cream, e.g. pH,

viscosity etc., Depending upon the formulation, e.g. the abrasive nature and level, the

gelling agent used and the presence of therapeutic ingredients which may impact taste perception, the flavour level may vary from around 0.5% to 1.5% by weight. 7. Minor ingredients (a) Titanium Dioxide TiO2- Titanium dioxide may be added to give additional whiteness and brilliance to the paste. (b) Colours. Colours can be an integral part of the aspect of any toothpaste that may influence consumer preference and purchase intent. The EEC Cosmetics Directive (Annex IV) lists the permitted colours and only a small amount is necessary to create a large impact, <0.01% by weight.


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(c) pH regulators. Occasionally buffering systems need to be added to the dental cream to adjust the pH of the final finished product. (d) Sparkles. A recent introduction in the marketplace is the addition of small reflective mica particles to coloured transparent gel products. This gives toothpaste the appearance of containing 'sparkles' and is especially aimed at younger children. 8.Fluoride and other 'active' ingredients

The earliest fluoride dentifrices contained sodium fluoride. However, the fluoride was biologically unavailable because the calcium in the

dentifrice abrasive bound the fluoride and thus inactivated it. Although a number of dentifrices containing fluoride are on the market, not all

provide available fluoride because the abrasive systems that some dentifrices contain inactivate the fluoride.

Therefore, the product may contain as much fluoride as any other dentifrice but it is not available.

Also, if the product has a short shelf life, it will be ineffective if poor marketing gets it to the consumer too late.

For these reasons, only dentifrices approved by the Council on Scientific Affairs of the American Dental. Various topical fluoride preparations are available as given in the table.

Form of fluoride Preparations Concentration of fluoride

Acidulated phosphate fluoride

Topical solution Topical gel Mouth rinse Paste

1.23 % in 1 % phosphoric acid 1.23 % in 1 % phosphoric acid

0.02-0.04 % 1.2 %

Amine fluoride Dentifrices Mouth rinse

1.6 % 2.5 %

Sodium fluoride Topical solution Mouth rinse Dentifrice

2 % 2.5 %

0.2 % (weekly)

Sodium monofuorophosphate

Dentifrices 0.76 – 0.8 %

Stannous fluoride Topical solution Mouth rinse Paste Gel Dentifrices

8 % 0.1 % 8 %

0.4 % 0.4 %

Currently accepted dentifrices contain sodium monofluorophosphate,sodium fluoride, or, less frequently,stannous fluoride, all of which reduce caries by approximately 25% when used daily.

The composition of some popular tooth pastes is given in table.

Brand Fluoride Abrasive Sweetener Foaming agent


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Aim 0.8 % Na.MFP

10 % Hydrated silica xerogel

19 % Hydrated silica

67 % sorbitol 1.5 % SLS

Aim extra strength

1.2 % Na.MFP

Aqua fresh 0.76 % Na.MFP

12.6 % calcium carbonate 12 % silica

52.8 % sorbitol

1.15 % SLS

Colgate 0.76 % Na.MFP

48.76 % dicalcium phosphate

22 % glycerin 1.2 % SLS

stannous fluoride

dentifrices stained teeth, particularly in pits and fissures.

This stain is related to the tin in this compound, which adheres to plaque.

The significance of this staining and its esthetic problems have resulted in a decreased usage in dentifrices.

Stannous fluoride dentifrices are marketed in a plastic container because a reaction of stannous ions at an acid pH occurs when conventional soft metal tubes are used.

Dentifrices containing stannous fluoride as an active ingredient are no longer widely marketed; however,these formulations were the first to be evaluated for caries-reducing properties.

Effectiveness in caries reduction varied from 23 to 34%. Amine fluoride

amine fluorides also have strong plaque-reducing properties.

However, although the amine fluorides may be more effective for caries reduction than other forms of fluoride, the FDA has not allowed these products to be extensively tested in this country.

Sodium fluoride

Recent studies of sodium fluoride dentifrices formulated to ensure ready availability of fluoride ions have shown anticaries benefits similar to those obtained in clinical caries trials with dentifrices containing stannous fluoride and sodium monofluorophosphate.

Clinical caries trials conducted under wellcontrolled, daily supervised brushing conditions have reported reductions in dental caries of approximately 25–48%.

Sodium monofluorophosphate

A number of clinical studies have been conducted with dentifrices containing 0.76% monofluorophosphate (MFP).

The data from these controlled clinical studies of sodium MFP dentifrices have indicated reductions in dental caries ranging from approximately 17–42%.

Therapeutic effects of fluoride

Caries control M/A: fluoride ion can replace the hydroxyl ion in hydroxyapatite the major crystalline structure of enamel.


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The substituted crystals called fluorapatite is more resistant to acid, such as those produced by plaque bacteria.

As fluoride is also an antienzyme. It may inhibit enzymatic acid production by plaque bacteria.

Dental plaque control

Mainly stannous fluoride is used for this purpose. M/A: related to an alteration of bacterial aggregation and metabolism.

Caries sites

1. Pit-and-fissure caries develop initially in the fissures of the teeth, but can spread into the dentine

2. Smooth-surface caries are most common on interdental surfaces, but can occur on any smooth surface of the tooth

3. Root caries attack the cementum and dentine, which becomes exposed as gums recede

Sources of fluoride Topical agents Fluoridated water Other ingested source


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Fluoride effect on remineralization and demineralization of ename Promote remineralization1

Reduce demineralization2,3 Inhibitacid generation from plaque bacteria4

MECHANICAL PRODUCTS FOR PLAQUE CONTROL

Toothbrush Toothpaste Dental Floss Tongue Scraper

1. Toothbrush

The toothbrush is the primary dental hygiene product you need to take care of your teeth. First, the regular toothbrush alone provides a plethora of options. Toothbrushes come in various sizes and styles. Various brushes differ from the handle to the bristles. That’s why buying a toothbrush can be a confusing task.

In choosing a brush, most dentists recommends soft-bristled brushes more because these can best remove plaque and traces of food that gets stuck in the teeth. You should also choose a brush that does not have a big head. Small-


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headed brushes can reach the back areas of the mouth for thorough and complete mouth cleaning. You can also choose from squared heads or tapered ones.

As for the handle, you should go for brushes that provide good grip. The shape of the handles themselves differs a lot. But the most important part of the brush is the bristles. There are many forms of bristles, such as rippled, flat, trimmed, or domed ones. All these different types of bristles provide specific benefits that may help meet your needs.

Aside from regular brushes, however, you can also use power brushes, which is very popular among younger users. These powered brushes help clean the teeth better than children usually can.

2. Toothpaste

Another important choice you have to make is what toothpaste to use to go with that perfect brush. The toothpaste aisle in the supermarket is highly congested, and the different brands and kinds often differ in ways that are vague to consumers. That’s why it is even harder to choose a toothpaste than a toothbrush. The trick, however, is to follow the fluoride arrow. Look for a toothpaste that contains fluoride, and the brand usually doesn’t matter much. Fluoride is an essential ingredient that can provide strengthening for your teeth. Fluoride works by keeping cavities away and also by polishing tooth enamel.

Another clue to look for is the seal of approval by the American Dental Association, which will help lead you to safe and effective products that have passed clinical scrutiny. You can also consider your specific tastes, such as desensitizing toothpaste for sensitive teeth, whitening toothpaste for yellowing teeth, and tar-tar control toothpaste for those dealing with tar-tar problems.

3. Dental Floss

Another important dental hygiene product is dental floss, which is often neglected by a lot of people. Flossing should be done at least once daily, and benefits are far ranging. Flossing can help clean teeth and in between teeth to make sure no food debris are left. It can help you easily get rid of the food stuck irritatingly between your teeth, which can lead to tooth decay, gum disease, and accumulation of bacteria in the long run. Also, bacteria can lead to bad breath, so dental floss can help keep bad breath away.

4. Tongue Scraper

Another less popular product is the tongue scraper or tongue cleaner, which cleans the surface of the tongue to remove bacteria, food debris, fungi, and dead cells. The tongue is vulnerable to bacteria and fungi that can cause bad


150

breath, oral problems and even medical conditions. Tongue cleaners come in a general form, but one thing to note is that it should be used before brushing your teeth, since brushing might cause the stuff on your tongue to recede into the throat.

Tartar (Calculus)-Reducing Products A number of products, both dentifrices and mouthrinses,are available for reduction of supragingival calculus (tartar) in dental patients. Calculus reduction has been shown with dentifrices containing pyrophosphates, zinc salts, triclosan, and papain. The incidence of calculus formation ranges from 45 to 66%, with some variation between males and females and different age groups. Although supragingival calculus is not a major etiologic agent for gingivitis or periodontitis, its surface porosity provides an environment for plaque formation. In addition, it serves as a plaque-delivery system by holding plaque against gingival tissues. Although plaque formation has been well correlated with gingivitis and periodontitis, a similar correlation for calculus has not been reported. For this reason, the ADA does not offer an acceptance program for products that reduce calculus formation because this is considered to be a cosmetic issue, rather than an issue of disease. The mechanism of action of the calculus-reducing chemicals is related to the latter’s ability to inhibit crystal growth and interrupt the transformation of calcium phosphate (found in foods and saliva) into dental calculus. This effect may occur as follows: 1. The agents complex on the tooth surface to block receptor sites for calcium phosphate that precipitates from saliva and chemically absorbs to initiate calculus formation. 2. This same receptor site blockage also occurs in the calculus matrix as it begins to form. 3. The pyrophosphate complexes combine with free calcium in saliva to inhibit the attachment at the tooth surface (probably a secondary mechanism). TYPE OF DENTIFRICES

(A) Pastes form – Tooth paste (B) Powder form – Tooth powder (C) Solid blocks (D) liquids

(A) TOOTH PASTES Tooth pastes are most popular valuable and widely used preparations for cleansing the teeth. It has largest share of dental cleansing and care preparations. Tooth pastes are preferred over other dental preparations because of following reasons.

Easy to take and spread on the tooth brush


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No spillage or wastage Attractive consistency Proper distribution in mouth Available in wide varieties

A good tooth paste should have following characteristics

It must clean the dental surface properly without any scratches. Consistency should be such that it can be easily squeezed out of the tube to

spread on the brush, but should not penetrate in to the brush. The consistency should remain constant in wide range of temperature during

shelf life. It should be non toxic and should not sensitize buccal membrane. It should not interact with the container material. It should have pleasant taste and odour. It should have good appearance.

Formulation: Method: - 1 The binder, prewetted with the humectant, it is disperse in liquid portion containing the saccharin and preservative and allow swelling to form a homogeneous gel. The swelling may be accelerated by heat and agitation. The solid abrasive is added slowly to homogeneous gel and mixed in mixer until a paste formed. The flavour and detergent are added last and distributed uniformly. Excessive, aeration, particularly in the presence of detergent, should be avoided. The paste can then be milled, deairated and tubed. Method: - 2 The binder is premixed with solid abrasive, which is then mixed with the liquid phase, containing humectant, preservative and sweetener into a mixer. After formation of homogeneous paste, the flavour and detergent are added, mixed, milled deairated and tubed. (A) TOOTH POWDERS Tooth powders are oldest and simplest preparations. Over the years their market share has been reduced due to popularity of pastes, but steel they have a considerable market share. The main problems encountered with powders are-

Floating of powder in air during manufacturing. Formation of cake on storage Uneven distribution in mouth

Composition Tooth powders contain the following ingredients-

Abrasives Surfactants or detergents Sweetening agents Flavours Colours

Abrasives are used in manufacturing of tooth powders are similar to that of tooth pastes. Though lighter calcium carbonate is used in tooth paste but in tooth powders heavier grade calcium carbonate is used.


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Other ingredients are similar to that of tooth paste.

General procedure for manufacture

This is done by simple mixing First ingredients of small quantity are premixed and then mixed with other

ingredients. Ribbon type or agitator type of mixer are used. Flavour can be sprayed on to the bulk or can be premixed with part of some

abrasive.

(3) SOLID BLOCKS Solid dentifrice is like a soap preparation. Basically they consist of tooth powder suspended in a base of soap powder, water, and humectant. Solid detifrices provide a convenient and handy from of cleaning for the teeth. Formulation The soap first dissolved in a mixture of glycerin and water with the aid of heat. The powder (abrasive) is then mixed until soft mass formed. Mass is dried on trays, cut into blocks.

EVALUATION OF SOLID DENTAL PRODUCTS Identification of ingredients and estimation of their contents are essential components of overall quality control and evaluation of dental care products. The products, tooth pastes and tooth powders, can be basically classified into foam forming and non-foam forming. Some other special evaluation tests are as follows: Abrasiveness

Various tests have been designed and reported over the year, mostly on the set of extracted teeth. The teeth were mechanically brushed with pastes or powders and then the effects were studied by observation, mechanical or other means. Abrasive character normally depended on the particle size. So, study of particle size can also give such idea. Particle size This can be determined by microscopic study of the particles or by sieving or other means. Cleansing property This is studied by measuring the change in the reflectance character of a lacquer coating on the polyester film caused by brushing with a tooth cleanser (paste or powder). Also an in vivo test has been suggested in which teeth were brushed for two weeks and condition of teeth was assessed before and after use with the help of photo graphs. Consistency


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it is important that the product , paste, should maintain the consistency to enable the product press out from the container. Study of viscosity is essential for this. Rheology of powders is also important for proper flow of the powder from the container. PH of the product PH of the dispersion of 10 % of the product in water is determined by PH meter. Foaming character This test is specially required for foam forming tooth pastes or tooth powders. Specific amount of product can be mixed with specific amount of water and to be shaken. The foam thus formed is studied for its nature, stability, washability. Limit test for arsenic and lead This is very important as these are highly toxic metals. Specific tests are there to estimate these two metals; products may not have excess of such metals. Volatile matters and moisture A specific amount of the product required to be taken in a dish and drying is to be done till constant weight. Loss of weight will indicate percentage of moisture and volatile matters. Effect of special ingredients Special test should be done for the special ingredients if any, like antiseptics, enzymes, etc. for each one special and specific test are to be done. (4) LIQUID DENTAL PREPARATIONS

Use of liquid dentifrices are comparatively less than solid one. They are basically aqueous or hydroalcoholic solutions of surfactants with

additional components like Thickening agent Sweeteners Flavours etc.

They do not contain any abrasive as they will sediment Action of this preparation on dental surface is less but the cleansing effect is

more. Manufacturing process is making solution of all ingredients.

Formulations

Formula :1

Sodium myristate sulphate 4.0 gm

Methyl cellulose 4.0 gm

Saccharine sodium 0.1 gm

Flavouring oil 0.3 gm

Glycerin 5.0 gm

Alcohol 10.0 gm

Water 85.4 gm


154

HALITOSIS

Local factors, systemic factors, or a combination of both can cause halitosis.

It is estimated that 80% of all mouth odors are caused by local factors within the oral cavity, and these odors are most often associated with caries, gingivitis, and periodontitis.

Oral malodors occur because of the action of various microorganisms on proteinaceous substances, such as, exfoliated oral epithelium, salivary proteins, food debris, and blood.

Studies have shown that saliva from individuals who are free of dental disease produces malodor less rapidly than saliva from patients with dental disease.

It has also been observed that after prolonged periods of decreased salivary flow and abstinence from food and liquid malodors tend to be most severe.

Various oral bacteria produce products that are degraded to a number of compounds, foremost of which are sulfides and mucoproteins.

These compounds have been most often associated with oral malodor. Specifically, it appears that oral malodor usually results from the bacterial- mediated degradative processes of methyl mercaptan and hydrogen sulfide in oral air.

Ammonia is also produced but does not appear to contribute significantly to halitosis.

It has even been suggested that ammonia production may improve the odor of mouth air.

However, for many patients, systemic or local factors cannot be identified.

Tongue scraping has been shown to reduce malodor in some patients.

Mouthwashes and dentifrices can serve an esthetic function by reducing halitosis. They can accomplish this by masking malodors, acting as antimicrobial agents, or both.

There are no ADA-accepted products to reduce halitosis at this time.

Safety

While dentifrice products have a long history of safety, there is an ongoing concern associated with dental fluorosis due to fluoride ingestion in children under age six. Studies have shown that for children 1–3 years, 30–75% of the dentifrice is ingested, and for children 4–7 years 14–48% is ingested.

As with any OTC drug product, precautions need to be taken to prevent overdose. The FDA requires labeling of all fluoride dentifrice products to include a statement "to minimize swallowing use a pea-size amount in children under six."

Making childproof caps available on fluoride dentifrice products intended for use by children has been recommended.

Another approach would be to provide metered dentifrice delivery systems for children under age six, which could be set to dispense the correct amount of fluoride depending on the body weight of the child.


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Dental care products

Effervescent Polident Denture Cleansers

Non abrasive cleaning and antibacterial action in a soaking solution with oxidizing agents and detergents to remove food particles, stains and bacteria. Cleaning action is available in variants for 3 minutes, overnight and stain removing whitening and for partials.

Polident Fresh Cleanse Denture Foam Denture Cleansing foam provides non abrasive mechanical cleaning and antibacterial action and stain removal with detergents and a long lasting flavor

Polident Dentu-Paste and Dentu- Gel Denture Cleansers

Mechanical cleaning with a brush using these denture cleansers containing detergents and oxidizing agents


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Super Poligrip Denture Adhesive Cream

Poly(methylvinylether/maleic polymer cross linking salts to provide adhesion between denture and the alveolar ridge and the palate. The denture adhesive cream fills gaps between gum and denture for a strong hold and sealing out food particles

Super Poligrip Denture Adhesive Powder

Poly(methylvinylether/maleic polymer cross linking salts to provide adhesion between a denture and the alveolar ridge and the palate. The denture adhesive powder forms a strong, thin seal to keep out food particles

Super Poligrip Denture Adhesive Strips

Extruded strip with a Polyox/Carboxymethylcellulose system. The denture adhesive strips are pre cut to control the amount of the application.

Texas Dental Firm Offers Novel Tooth-Whitening Product Line Ultra-White Products, Inc., a tooth whitening product manufacturer in Texas,

now offers an attractive alternative to marginally effective over-the-counter tooth whitening product lines and costly dental treatments.

The company’s novel tooth whitening product affords users the ability to obtain custom application trays and whitening gels at a fraction of the cost normally associated with professional cosmetic dentistry and are far more effective than over-the-counter solutions.


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The company has a worldwide following with over 30,000 clients and is owned an managed by a practicing dentist.

NEWER FORMULATIONS OF DENTIFRICE FROM CHEMICAL

ABSTRACTS

Functional toothpaste containing nano sized silver. High Fluoride ion recovery dentifrice compositions. Stable Suspensions of composite material s for use as dentifrices

containing an antimicrobial organic acid salt. Application of water soluble chitosan in toothpaste & mouthwash. Dentifrice containing silica microparticles as the sole abrasives. Dentifrice compositions comprising alkyl galactoside derivatives

+nonionic disinfectants or +protein naturants or +vit- E gives strong coaggregation-inhibitory effect & antibacterial

effect against Fusobacterial & other dental caries & periodontal disease- causing bacteria.

QUESTIONS:- 1) Define cosmetics? Put some light on its origin and development through different ages.

2) Describe in brief the cosmetics products for skin?

3) Define shampoo? Write note about it?

4) Write a note on skin colorants?

5) Classify cosmetics with examples?

6) Define cosmoceutical? how it differs from cosmetics products? explain

7) Describe different nail preparations?

8) Write in detail about quality control of cosmetics including sampling size?

9) What is powder? classify powers ? Give formulation of any one type?

10) Classify raw materials of cosmetics? Write in brief about each with example?

REFERENCES:- 1. Harry’s Cosmeticology, by Ralph.G.Harry, and Leonard Hill books and

intertex publisher. 6th

edition.

2. 1) Cosmetics : Science and Technology : Edward Sagarin

3. 2) Cosmetic Science and Technology Series : Volume 19 :

Novel Cosmetic Delivery System : Shlomo Magdassi ,Elka

Touitou

4. Cosmetics: formulation, Manufacturing, Q.C:P.P SHARMA

5. A Handbook of cosmetics: B.M MITTAL, R.N SAHA

6. COSMETICS & TOILETORIES Journal

7. www.mydenturecare.com 8. www.ultracosmetics.com

9. www.health.howstuffworks.com

10. Encyclopedia of pharmaceutical sciences Vol.3

http://www.mydenturecare.com/

http://www.ultracosmetics.com/

http://www.health.howstuffworks.com/


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11. Hand book of cosmetics by Mitthal Cosmetics – Formulations, manufacturing

& quality control P.P.Sharma

12. Cosmetics –formulation by Poucher.

13. Chemical abstract vol-147.No 23 2007.

14. Chemical abstract vol-147.No 5 2007.

15. Chemical abstract vol-151,No 2009.

PAPER-910101 Chapter-8 KRUPA MEHTA

159

FORMULATION AND EVALUATION OF THE HERBAL INGREDIENTS AND OFFICIAL HERBAL DRUGS

Guided By: DR.R.K.PARIKH

Prepared By: KRUPA MEHTA SAURABH PATEL M.PHARM(SEM-1)


160

Classification of the ingredients 1)Solid

2)Semi solid

3)Liquid or Oil herbal

Solid Herbal Ingredients:

Senna,Digitalis,Cinchona,ipecacuanha,Ginger etc….

Semi solid Herbal:Aloes,Acacia,Tragacanth,Guar gum etc…

Liquid or Oil Herbal:Castor oil,Almond oil,Cedar oil all types of

oil include in the Oil herbal..

FORMULATION OF HERBAL INGREDIENTS

For the Solid preparation: Drugs are cleaned and dried.

They are coarsely powederd, weighed as per formula, and

then mix well..

For the Semi solid preparation: the preparation generally

have liquids, sugar or sugar candy, powders or certain

drugs, oil and honey..

Sugar or sugar candy dissolved in the liquid and strained to

remove the foreign particles. This solution boiled over a

moderate fire.when pressed between two figers or when it

sinks in water without getting easily dissolved, it should be

removed from the fire. Fine powders of drugs are then

added in small quantities and stirred continuously and

vigorously to form a homogenous mixture. Oil is

mentioned is added while the preparation is still hot and


161

mixed well. Honey , if mentioned is added when the

preparation is cool and miwed well..

For the Liquid preparation: for this preparation generally

steam distillation method is used. The drugs are cleaned

and coarsely powdered. Some quantity of water is added to

the drugs for soaking and kept over-night. This makes the

drugs soft and when boiled releases the essential volatile

principle easily. The vapour is condensed and collected in a

receiver. In the beginning, the vapour consists of only

steam and may not contain the essential principles of the

drugs. It should therefore be discarded. The last portion

also may not contain therapeutically essential substance

and should be discarded. The aliquots collected in between

contain the active ingredients and may be mixed together to

ensure uniformity of the product..

SUGGESTED EVALUATION METHODS

As mentioned earlier that the expiratory date can not be used for

the herbal formulations. This guidelines details out simple quality assessment parameters

as a means of evaluating “the best before use date”

EASIEST METHOD TO PREDICT DATE IS 1. To decide requisite condition and parameter to be monitored during

Processing Packing Storage condition

2. Selection of packing material 3. Exposing packs to challenging conditions to study behavior of

formulation in


162

A. STEPS

1. Batch size of at least 5% of the regular production batch is taken for testing.

2. Samples from one to three batches are selected. 3. The properly closed selected packs with one or more intended

packing material proposed for packing the formulation is recommended for such study.

4. Adequate numbers of sample are required. 5. If more than one packaging material are to be studied test for each

packaging material is required with the same batch.

B. CHALLEGING CONDITION FOR STORAGE OF PACKS FOR ACCELERATED STUDIES

AT 45 ± 2 0 C

AT 40 ± 2 0 C / 75% ± 5% RH

For comparison purpose one set of sample to be stored in a refrigerator below 25 0C

Samples are to be evaluated on pre decided parameter at 0, 1, 2, 3 and 6 months.

C. REAL TIME STUDY

Temperature = 30 0 C ± 2 0 C

Relative humidity = 65% ±5%

For long period of time.

Samples are evaluated at 0,3,6,12,18,and 24 months

D. PARAMETERS TO BE EVALUATED

1. Appearance 2. Colour 3. Odour 4. Taste 5. Particle size 6. Flowability 7. Viscosity


163

8. Clarity 9. pH 10. Moisture content 11. Sedimentation 12. Flocculation 13. Emulsion breakage 14. Friability 15. Hardness 16. Extractive Values ( in selected solvents) 17. Volatile matter contents 18. Free fatty acids/ acidity 19. Peroxide values 20. Microbial parameters

Total viable count (TPC) Yeast and mould count ( YMC) Coil form count and other pathogens

21. Specific parameters applicable to formulation / dosage form

E. HOW TO DETERMINE THE CRITICAL PARAMETER

Done by intentionally exposing the formulation to such conditions promoting their degradation and determining the critical parameter.

eg. Churna have moisture content 3.5 % when it

increase up to 7-10 % start to look different and can start degradation.

Novel product paper code:910201

Vijay Makwana

.

164 PHARM PART – I (2009-10)

L.M.COLLEGE OF PHARMACY, AHMEDABAD - 09

SEMINAR

ON

Novel products

GUIDED BY: PRESENTED BY:

Dr. R. K. PARIKH Vijay Makwana

M.PHARM – I

ROLL NO. – 01

YEAR:-2009-10

DEPARTMENT OF PHARMACEUTICS & PHARMACEUTICAL TECHNOLOGY


Vijay Makwana

.

165 PHARM PART – I (2009-10)


CONTENTS

Introduction

Classification

Cream Preparations

Shaving Preparations

Lipsticks

Hair Products

Cosmetics For Nail

Deodarants

Facewash & Facemask

Dentifrices


Vijay Makwana

.

166 PHARM PART – I (2009-10)


Introduction

Definition: As per Drug and Cosmetic Act Cosmetic means “ Any article

intended to be rubbed, poured, sprinkled, or sprayed on or introduced

into or otherwise applied to the human body or over part there of for

cleaning, beautifying, promoting attractiveness or altering the

appearance.”

People use cosmetic for beautifying, promoting attractiveness, altering

the appearance and for the care of body , eyes, teeth, hair, face, skin

etc.

Cosmetic are mainly for two purpose

1.Care of body parts

2.Enhancing personal appeal of body.

Classification

Cosmetics are classified under two groups.

o Group-1.According to the part of the body on which they are

used.

o Group-2.According to their physical nature.

Group-1 further subdivided as follow:

A. For skin: e.g. Powder, Cream, Lotion, and Make up, Deodorant etc.

B. For Hair: e.g. Shampoo, Hair dressing and Brilliantine,Depilatories

etc

C. For Nails: e.g. Nail polish and it‟s remover

D. For Teeth and Mouth: e.g. Dentifrices, Mouth wash

Group-2 further divided as follows:

A: Aerosols: e.g. Perfume, Hair set etc.


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B: Cakes: e.g. Rouge, Toilet soap etc.

C: Emulsion: e.g. Cold cream, Vanishing cream, Cleansing cream

D: Jellies: Hand jelly, Brilliantine jelly etc.

E: Mucilages: e.g. Hand lotion etc.

F: Oils: e.g. Hair oils etc.

G: Paste: e.g. Tooth paste, Deodorant paste etc.

H: Powders: e.g. Face powder, Tooth powder, Talcum powder etc.

I: Solution: e.g. Shampoos, After shave lotion etc.

J: Sticks: e.g. Lipsticks, Deodorant sticks etc.

K: Suspension: e.g. Lotion etc

Cream Preparations

Cosmetic cream are emulsions and can be available in either O/W or

W/O form which may provide opportunity to choose the cream for oily or

for dry skin respectively

<A> Cold Creams

It‟ function is cooling effect on application due to evaporation of water

separated by breaking of W/O emulsion.

It is used as emollient creams. It is widely used in winter season.

Most popular cold cream is water-in-oil emulsion.

COMPOSITION OF COLD CREAM

White bees wax

Mineral oil

Triethanolamine

Glycerin


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Distilled water

Perfume

METHOD OF PREPARATION

First melt waxes, fats, and oils together at temperature 70° C.

Then take water, Glycerin and Triehanolamine in another beaker

and heat up to 70°C.

Then add melted fat to triehtnolamine solution and stir continuously

until cold and add perfume lastly.

<B> Cleansing Cream

Cleansing cream is water-in-oil emulsion used to clean the dirt, oil on

skin.

It also removes applied cosmetic such as face powder, cake make up

etc.

Cleansing cream possess following characteristics:

1. It should liquefy at body temperature.

2. It should have low viscosity.

3. It should leave the skin smooth, nongreasy and clean.

4. It should spread easily without dragging.

COMPOSITION OF CLEANSING CREAM

Beeswax

Paraffin

White petrolatum

Mineral oil

Borax


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Glycerin

Water


Same as cold cream.

<C> Vanishing Cream

It is oil-in-water emulsion.

It is applied to skin to provide a smooth emollient base before the

application of face powder and make up preparation.

They help the powder to adhere to the skin and act as protective to

prevent damaging effects by sun.

They mainly used to provide fairness to the skin.

The choice of alkali

is an important criteria in preparing vanishing cream.

COMPOSITION

Stearic acid

Cetyl alcohol

Potassium hydroxide

Glycerin

Methyl parahydroxybenzoate

Purified water

Perfume

The main ingredient of vanishing cream is excess stearic acid.


Melt the stearic acid and cetyl alcohol in a beaker.


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Then dissolve potassium hydroxide and methyl

parahydroxybenzoate in water in a separate beaker and add

glycerin to it.

Heat the above aqueous solution up to 70°C and add to melted

stearic acid and cetyl alcohol mixture.

Perfume is added to the emulsified mass when the temperature

cools down to 45°C.

Mix gently.

<D> All Purpose Cream

All purpose cream is a cream which combines the properties of

specialized cream.

It possesses function of foundation cream, cleansing cream, vanishing

cream.

All purpose cream is suitable for hand, face, and body.

COMPOSITION

Borax

Bees wax

Mineral oil

Stearic acid

Paraffin wax

Glycerin

Anti-oxidant

Preservative

Purified water

perfume


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First mix all oily material and melt at 70°C.

Then mix all aqueous material and heat up to 70°C temperature.

Then mix oily phase and aqueous phase. Stir continuously.

Then add perfume, preservative when temperature lowers to 40°C.

Shaving Preparation

Shaving preparation is used for the shaving of beard hair.

Most common problem associated with shaving is skin irritation.

The lather should have resistant to rapid drying.

It should rapid become softening properties.

It should produce skin lubrication.

It should produce sufficient foam and stable foam so shaving is done

comfortably.

Lather Shaving Cream

Shaving cream normally contain 30-50% of soap.

COMPOSITION

Stearic acid

Coconut oil

Potassium hydroxide

Sodium hydroxide

Glycerol

Water



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First melt stearic acid with coconut oil at 80°C temperature.

Mix potassium hydroxide and sodium hydroxide in glycerol and water

mixture.

Then mix both above mixture with continues stirring.

Cool slowly.

Evaluation Of Shaving Preparation

1. Lathering capacity

Stability

Shaking with water.

2. Beard softening ability

Definite amount taken and wetting effect seen and how much water

required for hydration on skin.

3. Damage to skin (superficially)

Aerosol Shaving Foam

The aerosol can filled with a soap solution, the concentrate, together

with liquid propellant under pressure.

This foam applied to the pre-wetted beard, is sufficiently stable to last

throughout the shaving process.

COMPOSITION

Stearic acid

Lauryl or stearyl alcohol

Sodium lauryl sulfate


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Glycerol

Triethanolanime

Water

Perfume


First melt fatty acid and alcohol together to 70° C temperature.

Mix glycerol, sodium lauryl sulfate, triethanolamine and water and

heat at 70°C.

Then mix above both mixture and stir continuously.

Add perfume when mixture is below 40°C.

Then fill in aerosol.

After Shave Product

It is applied on the face after shaving.

It‟s produce cooling effect.

It refreshes the skin.

It produces mild astringent effect.

They protect it from bacterial infection while it recovers from the slight

injury.

After Shave Lotion

COMPOSITION

Ethanol

Propylene glycol

Water

Fragrance


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Color


Mix perfume, propylene glycol and dissolve in alcohol.

Add water slowly with stirring.

Add color.

Then cool the mixture to 4°C and filter through a fine filter to give a

clear product.

Lipsticks

Lipsticks is the lip cosmetic molded into sticks, are essentially dispersions

of coloring matter in a base consisting of a suitable blend of oils, fats, and

waxes.

Lipstick is used to impart an attractive color and appearance to the lips.

It provides an oily protective film to prevent chapping and drying out of the

lips.

Lipsticks possess following characteristics:

An attractive appearance, a smooth surface of uniform color free from

defects.

Pharmacologically inert when applied topically.

Easy to apply, giving a film on the lips that is neither greasy nor too dry.

Its color is not permanent but easily washable.

Typical Lipsticks Formulation

Castor oil


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Carnauba wax

Bees wax

Candelilla wax

Octyldecyl stearoyl stearate

Lanolin oi

Mineral oil

Anti-oxidant

Color

Fragrance

Lipsticks Ingredient

COLORING MATERIALS

Color of lipsticks is one of the major selling points.

The color is imparted to the lips in two ways:

A. By staining the skin, which requires a dye in solution, capable of

penetrating the outer surface of the lips.

B. By covering the lips with a colored layer that serves to hide any

surface roughness and give a smooth appearance.

The color of lipsticks must be selected on the bases of Drug And

Cosmetic Act.

Typical proportion for color in lipsticks.

PIGMENTS

Both organic and inorganic pigments are used to create a full range of

shade.


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Titanium dioxide produces pink color.

IRON OXIDES

These are used for matching the brown shades.

Bismuth Oxychloride

It is dense, white pigment.

LIPID BASE MATERIAL

Quality of the lipstick during manufacturing, storage, and use will be

determined for the most part by the composition of the fatty base.

In the mould it must set quickly with good surface and good release

properties.

In use the stick must soften sufficiently in contact with the lips.

CASTOR OIL

It act as solvent for the waxes that give structure to lipsticks and

yielding sticks that have a fine crystalline structure, good stability, and

resistance to breakage.

It is excellent vehicle for pigment.

LIQUID FATTY ALCOHOL

These are good solvents for polar waxes.it act as co-solvents

between polar and nonpolar materials in formulation.

E.g. Isocetyl, isostearyl and octyldodecyl.

ESTERS

Esters are of many type including linear and branched alkyl esters of

mono, di, and tribasic fatty acid.

Lactate esters impart a slipepery yet nongreasy.


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E.g. triisostearyl trilinoleate, triisocetyl citrate.

MINERAL OIL

It has been used to provide a glossy surface to the sticks.

WAXES

Waxes are included in lipstick bases to provide the high melting

points or the hardness that are required to give satisfactory molding

properties.

It‟s ranges between 8% and 15% of the formulation.

E.g. Carnauba wax

Candelilla

Microcrystalline waxes

Beeswax

Manufacture Of Lipsticks

It consists of two stages:

(1)preparation of component blends

Melt all waxes at 85-95˚C and mix oily material then add color grind.

Blending of these intermediates used to form the lipstick mass.

(2)Molding of the lipstick mass into sticks.

The melted mass poured into mould sticks and lowers the temperature up

to 20˚C.

Evaluation Of Lipsticks

MELTING POINT


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Determined by capillary tube method by keeping the size of capillary,

lenth of fill and rate of heating constant.

Melting point should be more than 50 for safe handling.

BREAKING POINT

This test is done to determine the strengh of the lipsticks.

The lipsticks is held horizontally in a socket ½ inch above the base and

weight is applied on the lipstick.The weight is gradually inceased at

iterval of 30 seconds.

The weight at which lipstick breaks is considered as the breaking point.

The test shoul done at specific temperature (25˚C).

Hair Products

Brilliantine

Brillientines are employed to impart luster to the haiir and also keeping

them in the proper place.

They have to be applied to the dry hair after it has been waved.

They are avaliable in liquid form or viscous form.

Liqid form is liked by women because of ease of application on their long

hair while men like viscous creamy form.

LIQUID BRILLIANTINE

COMPOSITION

Olive oil

Sweet almond oil

Caster oil

Parahydroxybenzoic acid ester

Alcohol


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Perfume


Mix olive oil, caster oils and add almond oil mixture to it.

Dissolve the parahydroxybenzoic acid ester and perfume in alcohol.

Mix above both mixture and filter it.

Hair Straiteners

These preparation which are used to take curl or kink out of the hair and

and at the same time impart a sheen and perfume to the hair.

They are applied on the hair with the help of hard brush.

COMPOSITION

Petrolatum

Rosin

Perfume


Melt the rosin with petrolatum. Stir well. Cool slightly and add perfume at

45°C.

Depilatories

These preparations are employed for temporarily removing any undesired

hair above the outer surface of the skin.

Women are the main user of such type of preparation.

The action of depilatories is to dissolve the hair.

Intially, it is softened, sweeled and disperesed by the action of the

chemical.

These chemical may have irritating effect on the epidermis.


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The user should be advised to do the sensitivity test on a part of arm

which is devoid of hair, by applying a little deplilatory.

Depilatory Powder

COMPOSITION

Titanium dioxide

Barium sulfide

Wheat starch

Perfume


Mix all powder geometrically and add the perfume in it.

Cosmetics For Nails

Nails are protective covering of the finger toes.

The care of nails is referred to as manicuring. These preparetion used by

women.

Manicure preparation includes many preparations like nail polish, polish

remover, and nail bleach, cte.

Nail Polish

COMPOSITION

Nitrocellulose

Ethlyl acetate

Butyl acetate

Diethyl phthlate


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Camphor

Color

The color should be complying with the Drug and Cosmetic Act.


Dissolve the nitrocellulose and the camphor in the ethyl acetate.

Add the rest of ingredients along with color and perfume.

Mix both the mixture.

Nail Polish Remover

COMPOSITION

Butyl stearate

Ethyl acetate


Mix both preparations.

USE

Used for thr removal of polish on the nail.

Deodarant

There is a problem of the body odor from men and women because of

perspiration.

There are two types of deodarants, one is employed to

1.Deodorize perspiration without restricting its flow.


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2. Deodorize and prevent decomposition through bacteria inhibiting action.

Deodarants may be liquids, pastes, powders, sticks.

Deodarant Liquid

COMPOSITION

Oxyquinoline sulphate

Aluminium sulphate

Magnesium sulphate

Alcohol

Purified water

Perfume


Mixall three salta in purified water.

Dissolve perfume in alcohol.

Mix both mixture.

FACE MASK

Introduction

Face pack are topically applied preparation particular to facial area, either in

form of liquid or paste and allow to dry. With drying produce tightening effect and

warmth is experienced. This produces stimulating sensation after removal. As such

when they are removed, skin debris and blackheads may be removed along with

them.


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They have cleansing effect. They also improve circulation. They also have healing

power. This preparation are allow applied to face and allow to set.

Ideal Properties of the Preparations.

• They should form a smooth paste and should have pleasant odour.

• When applied to a face, they should dry out rapidly to form an

adherent coating on the face. However, the the coating should be such

which can be removed either by peeling off the face or by gentle

washing without causing pain.

• They should be capable of producing significant cleansing of the skin.

• They should produce sensation of tightening of the skin after

application.

• They should be non toxic to the skin.

Types of The Face Mask

High Viscosity Pastemasks

They contain high percentage of colloidal clay, kaolin or other suitable

solids dispersed in liquid vehicle.

Law Viscosity or Liquid Masks

They contain film forming hydrophilic colloids. They have less cleansing

capacity, Cleansing action can be improved by inclusion of detergent.

Formulation of Face Mask

While formulating face mask they should be an effort to produce product

which will have properties above mentioned.

There are five basic system, these systems are based on:

Waxes, Rubbers, Vinyl-resins, Hydrocolloids, Earths.

Wax Base Formulations

Usually wax based systems consists of paraffin wax , petroleum jelly and polar

materials like stearyl alcohols. These products are solids and are required to


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melt before application. These may be applied with brush while hot. When

waxes solidify, sensation of tightness is fill. Due to coating of wax profuse

perspiration is produce. This may lead to cleansing of follicular penings of the

skin by flushing out dirt and impurities. To facilitate application thixotropy is

imparted to the preparations.

Rubber Based Formulations

They form continuous and elastic film on the skin. Resultant film is water

impermeable , it interfere with skin respiration, and cause rise in temperature,

and also increase blood circulation to the skin.

Vinyl Resins Based Formulations

Vinyl resins like polyvinyl alcohol or polyvinyl acetate can form continuous

film.adsorbants are also added.

Hydrocolloids Based Formulations

They can be prepared in form of high viscosity solutions or in form of solid

gels. For formulating such type of face masks variety of gums can be usued

like gum acacia, gum tragacanth, guar gum, gelatine, carboxy methyl cellulose,

polyvinyl pyrolidone etc.

Hydrocolloids Based Formulations

Solid gel is required to be melt before application. Viscosity of gel can be

varied by changing the gum and its concentration. Plasticizer and humectants

also have to use. They are easy to apply.

Earths Based Formulations

They contains high percentage of solids. They may be prepared either as

powders or as pastes. Water is require before application, if mask is in form

of powder. These masks, on drying, harden on the skin and contract giving a

sensation of mechanical astringency. Absorbent clays produce cleaning effect.

Hydrocolloids may be added to stabilize the suspention of solids humectants and

plasticizers also added. Earths which are usued in the preparation include china

clay, colloidal kaolin, fuller‟s earth, bentonite etc.


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They also contain ingredients like astringents. Bleaching gents if required. An

oxygenated face mask can be prepared by incorporating peroxide like magnesium

peroxide. Oxygenated mask recommended for use by person having oily skin. In

powder form peel off type alginates can also be used. Sodium alginate can also be

used as gelling agent in powder form peel off packs. Sodium carbonate used as

gelling regulator. Titanium dioxide and zinc oxide can be used as opacifier.

Cellulose type thickeners used to modify plasticity.

Manufacture of Face Mask

If face mask are to be manufactured in powder form, all powders are blended in a

blender like ribbon blander. The powder mixture is then transferred to filling

machine. These may either be filled in bulk containers or in sachets. Manufacturing

of high viscosity face mask as follows:

Phase -A Phase -B Phase - C

Kaoline

Bentonite

ZnO

Sulpher

Cetrimide

Glycerile monostearate

Emulsifying wax

Cetyl alcohol

Mineral oil

Glycerine

Perfume

water

Menthol

Alcohol

Procedure

Prepare cream from phase – B by dispersing oily phase in water and glycerine

at 70 °C.

Mix powders and micronized it then stir into the cream base.

Gradually cool the mixture to 35 °C.

Finally mix menthol and perfume in alcohol and add to cream.

Low viscosity or liquid mask

They contains film forming hydrophilic colloids. They have less cleansing capacity.

Cleansing action can be increased by inclusion of detergent.


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Rx

Methocel, low viscosity

Glycerin

Water

Color

Perfume

preservative

Face mask for oily skin

Frequent and effective cleansing is recommended for oily skin…

To reduce the amount of sebum left on the skin to minimum and

To avoid the development of spots and pimps.

Emulsion cleansers are avoided since they tend to leave layer of oil on the skin.

Synthetic detergent can be used for cleansing of oily skin. This lotion cleanser may

be applied with a cotton ball or impregnated into a wipe fabric a total product.

Rx

A

Isopropyle palmitate

Polysorbate

Pyridoxine tripalmitate

B Water

Propelyne glycol

C

Penthenol

Ethanol

Eucalyptus

Face mask and exfoliating lotion

They are used for exfoliation of acne-prone skin rather than facial scrubs. The

following formulation makes use of keratolytic properties of salicylic acid as

exfoliating agent. Chamomile is used for its anti-inflammatory properties


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Rx

Water

Ethanol

Propylene glycol

Preservative

Chamomile extract

Salicylic acid

Perfume

Color

Procedure:

Dissolve preservative and propylene glycol.

Blend all the ingredient add water slowly and mix well.

Add perfume.

Medicated clear cleansing gel

Gel have become popular product for cleansing purpose. Carbopol gel is used in

next formula where alcohol provides antiseptic and astringent effect, allantoin is

added to as a soothing agent.

Rx

Carbopol-940

Water

Alcohol

Glycerine

Allantoine

Menthol


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Perfume

Procedure:

Hydrate carbopol In water.

Add remaining ingredients.

When completely homogeneous, neutralize to pH 6.5 with di-

isopropanolamine soln

Emulsion cleanser

Emulsion based cleansers are recommended for people with dry skin. Cleansing

creams, lotions and milk can be O/W or W/O emulsions which combines the

solvency of water and to effective cleaning of the skin. In doing this they also leave a

layer of emollient oil on the skin, leaving it feeling smooth, in contrast to the dry

sensation often feel after the use of synthetic detergent system.

FACE WASH

Introduction

Surfactant based face wash product have made significant impact on cleansing

market. Face wash generally contain mixture of surfactant which works

synergistically to produce foam. These preparations also contain moisturizing agent,

opacifier, thickener, perfume and water and appearance of product enhanced by

water soluble dyes.

Ingredients


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Mixture of surfactant used to produce foam. In past anion surfactant system such as

fatty alcohol other sulphates combined with fatty acid such as diethanolamides were

popular but they cause adverse reactions. This resulted in move to use anionic or

amphoteric surfactant such as alkyl betains, amido alkyl betains, sulphobetains and

N-alkyl-amino propionates. Silicone derivative have increased in popularity because

of their ability to impart smoothness.

Example of silicone include dimethicone copolyol and diquaternary polydimethyl

siloxane. Dimethicone copolyol also offer good skin feel.

moisturizers: moisturizers help the skin to maintain moisture content of the skin;

keeping it smooth and pliable. It include occlusive oils and wax like lanolin, paffin,

patrolatum, long chain alcohols and humectants include glycerol, propylene glycol

and ethoxylated sorbitol.

Polysorbate 20 and PEG-40,castor oil are use as co-solubilizers. PEG –distearate is

thickening agent.

BMR


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It should be based on master formula record which is prepared by R&D dept. BMR

required to maintain for each batch of product to be manufactured.

Before any process begins, check should be made to ensure that all work station

are clear of previous product.

During processing information should be recorded, signed and dated by persons

responsible for processing of operations.

Advances in skin care

Delivery system have expand from emulsion to microcapsule, multiple emulsion,

liposomes, cyclodextrin and polymeric systems.

A) microcapsule: they composed of hollow vesicle containing an active

ingredient.

B) liposomes: they are microscopic spherical vesicle in which the membranes

consist of a bilayer of amphiphilic molecules

Because of lipophilicity and particle size, microcapsule and liposomes efficiently

penetrates the skin, compared to classical emulsion

Because of the presence of amphiphile, they represents a safe way of delivering

actives such as moisturizers to deeper layer of skin.

Following formula based on liposomes using lecithin and acrylates as a emulsifying

agent.

A

Alkyl acrylate cross polymer

Carbomer

Capric triglycerides

Octyle stearates

Mineral oil

B Water

Glycerine

C NaOH

Lecithin


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Procedure:

Combine the ingredients of Part-A in vessel.

Mix the ingredients with rapid stirring to disperse the polymer.

Combine the ingredients of Part-B in vessel.

Add Part-B to Part-A slowly.

Mix for about 20 mins. to swell the polymer.

When emulsion is formed, add NaOH to maintain pH 7

Add preservative and mixed.

Cyclodextrin

They are starch derivative. They reduce skin penetration and so protect the skin

from undesirable properties of the active material.

Porous polymeric system

Release of active ingredient from skin surface by partitioning of the active ingredient

between the polymer and skin surface.

Evaluation test

Viscosity

Viscosity is an important in process quality control test.

Measurement of pH

Visual examination

It reveals the presence of any physical contaminants in product.

Microscopy


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This examination give information about uniformity of a particle size, carried on

regular basis.

Spot test

Specific reagent used to form colored complexes to detect, the presence of a

range anions and cations, confirm the presence of additives or presence of

contaminants.

Identification of raw materials

Analytical technique developed to identify raw materials

Efficacy testing

Foam testing

Shade testing

Pressure testing

Breakage testing

SUN SCREEN LOTION

Introduction

Earth‟s atmosphere absorbs all wavelengths of EMR below 295nm ;Of

wavelengths of radiation which reach earth‟s surface UV has highest energy.

Photo biologist divide sub-region of UV spectrum in descending order of

energy


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Far UV : 100-200nm

UVC: 200-280nm

UVB: 280-320nm

UVB region:

It is primary initiator of sun burn; also responsible for certain Skin cancer,

photodermatosis, premature skin aging and generation of melanin pigments.

On positive note it is also responsible for synthesis of Vitamin D synthesis.

UVA region:

Long term effects of this rays on dermal layers of human skin shows aging

of skin and capable of generating immediate skin pigmentation.

SUNSCREEN AGENTS

It must absorb UV light over a broad or specified part of UV spectrum.

Chemically stable

easy to formulate in to cosmetic vehicles and should be absorbed easily into the

skin

resistant to removal by water or sweat

must not require too frequent re-application to be effective

effective at law concentration

non toxic, non irritant and non sensitizing

Organic sunscreens

All allowable screening materials are catagorised by both US FDA and EC in

Europe.

PABA and derivatives

Cinnamates:octylmethoxycinnamates

Salicylates:methylsalicylates


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Anthranilates:methylsalicylates

Camphor derivatives.

Benzophenones:2-hydroxy 4-methoxy benzophenone.

Dibenzoyl methane:4 butyl 4‟methoxy dibenzoyl methane

Octocrylene:

Water soluble sunscreens

They become more effective by virtue of their skin penetrating properties.

2 hydroxy 4 methoxy benzophenone 5 sulfonic acid

2 phenyl benzimidazole 5 sulfonic acid

Inorganic sunscreens

Inorganic compound which has radiation scattering and reflective properties due to

its physical form. Natural minerals and pigments like talc, kaolin, metal oxides, TiO2

but choice depends on cosmetic acceptability. ZnO has good light barrier properties

Across both UV A and UVB range ;also to some extent visible spectrum. TiO2 has

similar effects to ZnO. Metallic oxides where used in combination with organic filters;

Also gives higher SPF products.

Water proofing agent

An important requirements of any sun screen products is that it should withstand

water; It is desirable that products is not easily washed off. There are official test for

standard of water resitance which improve in vitro SPF before and after immersion

for fixed period of time. It should retain at least 50% of its SPF after immersing in

water .

W/O lotion are inherently water resistant. Law level of water present as dispersed

phase are readily loss on application to skin to leave ; continuous oily phase spread

over the surface to gives water repellant film .W/O lotion often have greasy fill. O/W

lotion are cosmetically more elegant and have better skin effects.

Silicon oils are extremely resistant to water penetration ;are easily spreadable and

form continuous thin water repellant film on skin surface ;which is highly acceptable.


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Most widely used materials are dimethicone , cyclo methicone and trimethylsiloxy

silicate.

Recently polymeric film formers like PVP are excellent for imparting water resitant

to a formulation.

Plant layout


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METHOD OF MANUFACTURING

It involves heating the oily phase to dissolve oil soluble components material

satisfactorily.

Water phase heated similarly and both phases are then combined with mixing to

form emulsion. pH is adjusted to gel the water phase. Perfumes are added slowly

once emulsion cooled.

Polymeric materials require careful addition and complete dissolution must be

ensured.

BMR (batch manufacturing record)

BMR is required to maintain for each batch manufactured. It should be based on

master formula records, which is prepared by R&D department.

Before any process begins check should be made to ensure that all work-station are

clear off previous products.

During processing information listed below should be recorded, signed and dated by

persons responsible for processing operations.

Name of the product

Batch number

Date of commencement and completion of significant intermediate stage

Name of person responsible for each stage product

Batch number, quantity, quality control report number of each ingredient

actually weighted

Amount of any recovered material added

In process control carried out their result and signature of persons who

performed

Theoretical yield and actual yield at appropriate stage of production

BPR (batch packaging record)


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Batch packaging record should be keep for each batch or part of batch

proceed.

Before any packaging operation begins; check should be made and recorded

that the equipment and work station are clear of previous product.

It is a part of batch process record.

Line clearance have to be obtained before carry out packaging operations.

WHO guidelines require that following information should be recorded at time

of each action.

Name, batch number & quantity of bulk finished product to be packaged

Theoretical yield, practical yield & reconciliation

Date & time of packaging operation,

Name of responsible person carrying out packaging

IPQC check and check for identity and conformity with packaging instruction

Evaluation of sunscreen lotion

S.P.F. (sunscreen protection factor)

Level of protection from sun burn afforded by sun product is described by sun

protection factor.

COLIPA SPF test method

Individual is exposed to source of UV radiation and comparing very law dose

of UV that is needed to produce reddening of human skin; 24 hour after

exposure.

SPF

Ratio of dose of energy required to produce a MED(minimum erythamal dose)

on protected skin to that required to produce MED on unprotected skin.


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SPF Testing in vivo

In vivo testing is typically carried on the skin of human volunteers, exposing

1cm2 sites on skin to increasing dose of radiation from xenon arc solar

stimulator; irradiated test sites are examined after 24 hour exposure. the sun

product examined similarly.

SPF testing also performed in vitro on research tool and also during early

screening process.

Standard for water resistance

The official test standard for water resistance involve an in vivo SPF testing

before and afterr immersing for a fixed period of time in a water.

If product retain at least 50% of its SPF following moderate activity in water, a

product is described to be described as water-resistant.

β- glucans

β- glucans are polysaccharides.

In skin care sunscreen products β- glucans found to reduce oxygen radical

formation and stimulate the langerhans cells in UV radiated skin, also stimulate

collagen synthesis, increase in epidermal turnover rate, reduction of fine wrinkles,

reduction in skin damage caused by detergent.


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Dentifrices

INTRODUCTION

Dental preparations are the preparation that is used for the cleansing of teeth.

These preparations are able to maintain the health of the teeth and gum. Various

dental care preparations or dentifrices are now a day available in the market for this

purpose. As we know that the health of the teeth and gum is very important for the

good general health, use of the dental care preparations or dentifrices is increased.

The teeth are grinder for food what we eat. These food particle if not removed

regularly may become pocket for the microbes to grow. So the removal of the food

particle from the teeth is very important for good general health. This can be

possible with the help of the dental and oral care preparation. Importance of

cleaning the teeth was probably realized along with need for maintenance of body

cleanliness. In ancient time chew sticks and sponges were used for the teeth

cleaning purpose. Material were used as ingredients of dentifrices at that time were

dried animal parts, herbs and plant parts, honey and minerals. Several items of the

early ingredients were found to be harmful, destroying teeth, irritating oral mucosa.

Some of these harmful substances were sulphuric acid, acetic acid, lead ores, and

abrasive minerals. Over the period of time, various studies on these substances

have helped to identify safe and useful dentifrices ingredients.

Dental Care preparations (Dentifrices) are:


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Tooth pastes

Tooth powders

Solid and Liquid dental preparation

Dentifrices may be a simple dentifrices or therapeutic dentifrices, later contain

additionally a therapeutic ingredients for some special functions like decrease the

occurrence of dental caries and help in control of periodontal disease. Therapeutic

dentifrices containing stannous fluoride are widely used products.

Tooth pastes and tooth powder are similar in composition except that tooth

pastes are made pasty by addition of suitable solvents.

Functions of Dentifrices:

Though the primary function of dentifrices is the cleaning of the accessible

surface of the teeth, but it can have some other functions also. The expected

functions of a dentifrices are as follows.

1. Cleaning the surface of teeth

2. Prevention of formation of dental plaque

3. Prevention of formation of calculus

4. Polishing of teeth

5. Reduction of occurrence of tooth decay

6. Reduction of periodontal diseases

7. Prevention of mouth odors

8. Freshening of breath


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Some commercial dentifrices may be performing all of the above functions and

some may be fulfilling partial function.

TOOTH PASTES

Tooth pastes are the most popular and widely used preparations for cleansing

the teeth. These preparations are more expensive than the tooth powder but still

they are more preferred.

Advantages:

Easy to take measured quantity

Easy to spread on the tooth brush

No spoilage or wastage

Attractive consistency

Proper distribution in the mouth

Ingredients:

Various ingredients are added in the toothpastes for fulfill the requirements or the

special function of the toothpastes in order to obtain the good product for the

consumers. Common ingredients used in the toothpastes are listed below:

1. Abrasive and polishing materials

2. Detergents and foaming materials

3. Humectants

4. Binding agents

5. Sweetening materials

6. Flavors

7. Preservatives

8. Special ingredients e.g. Therapeutic agents Colors Whitening agents Bleaches Lubricants


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Abrasive and polishing materials:

Abrasive and polishing materials are known as cleansing materials. They are

the main constituents of the toothpaste and tooth powders. It is hard powder but it

should not make scratches on the enamel of the teeth and gum. The abrasives and

polishing materials are responsible for the removal of the food particle from the

teeth. Abrasive and polishing material build up the half of the total weight of the

tooth pastes.

Materials that are used as abrasive and polishing materials are calcium

carbonate, tricalcium phosphate, Dicalcium phosphate, aluminium phosphate,

magnesium trisilicate. Calcium carbonate is available in different grade which are

vary in density, particle size, crystal form. calcium carbonate in the toothpastes

preparation is responsible for the alkalinity of the preparation. Dicalcium phosphate

dehydrate impart neutral pH to the tooth pastes. Aluminum hydroxide is also act as

abrasive materials and it is used with other abrasive materials. Dehydrate and

anhydrous dicalcium phosphate, tricalcium phosphate and calcium pyrophosphate

are important calcium salts used as abrasive in tooth pastes. Dicalcium phosphate

dehydrate is mostly used among them. These substances are mild abrasives. Both

dicalcium phosphates are odorless, tasteless and white. They are slightly soluble in

water. Tricalcium phosphate is also a tasteless, odorless white amorphous powder

and insoluble in water. It also impart mild abrasive and polishing effect.

Detergents and Foaming agents:

These materials are added in the toothpastes for causing wetting and

dispersion of the powdered materials in the toothpastes. Also detergents are

responsible for the cleansing of the teeth by lowering the surface tension. These

agents help to penetrate paste and abrasive in to the fine cracks and thus remove

the food particles. Apart from this, these agents are responsible for producing foam.

Though soaps are alkaline in nature but still they are used. Specially prepared

dental soaps are available in the market for use in tooth pastes. As soaps may have

odor or taste, tasteless or odorless soaps are to be added.

Materials that are used as detergents and foaming agents are Sodium Lauryl

sulphate, magnesium lauryl sulphate, diethyl sodium lauryl sulphosuccinate, sodium


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lauryl sarcosinate. Sodium laurylsarcosinate is also act as a bacteriostatic and

anticariogenic agents.

Humectants:

Humectants are added in the toothpastes formulation for prevention of drying

of the product and to impart the plasticity to the pastes. Humectant normally used in

the toothpastes formulation is varies from 5 to 10 % w/w. Actual amount that is to be

used in the formulation is depends on the specific gravity of the powder mass.

Materials that are used as humectants are glycerin, Sorbitol, propylene glycol

etc. amongst all glycerin is widely used in the toothpastes formulation as

humectants. Sorbitol prevents the separation of the water from the pastes and also

impart viscosity to the pastes.

Binding agents:

Binding agents are added in the toothpastes formulation to improve and

maintain the consistency of the product. Also these binding agents help to prevent

the separation of the toothpastes. Aqueous dispersion of the hydrocolloids are

viscous. These hydrocolloids are used in the range of 1-2.5%. Though once liquid

glucose and simple syrup were used but slowly they were replaced by mucilage of

various gums. An amount that is to be used in the formulation is depends on the

consistency wanted. Normally the gum is first mixed with sufficient quantity of

glycerine, alcohol before adding water. This is done to prevent the formation of

lumps.

Materials that are used as binding agents are gum tragacanth, karaya gum,

carboxy methyl cellulose, sodium alginate, carbopols, bentonite etc. Gum tragacanth

is still a widely used binding agent.

Sweetening materials:

Sweetening agents are added to impart good tastes to the product. Sodium

saccharine is widely used sweetening agents in toothpastes formulation. Amount of

the sweetener added is depends on the sweetness of the other ingredients.

Flavors;


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Essentially the flavors are incorporated in the toothpastes for test and for long tern

effect in the mouth. Flavors used are blending of suitable oils with the sweetening

agents to produce smooth but distinct tastes in the product and also the pleasant

smell in the mouth after use.

Flavors used are peppermint oil, clove oil, cinnamon oil, cassia oil, menthol etc.

Preservatives:

Toothpastes formulations are prone to microbial growth due to the presence of

gums and water, preservatives are added to prevent the microbial growth in the

product.

Examples of preservatives: Methyl parahydroxy benzoate with propyl parahydroxy

benzoate.

Special Ingredients:

Bleaches: Added in pastes to impart whitening effect to the pastes. Hey are

basically oxidizing agents. Examples are sodium perborate, magnesium peroxide,

stabilized hydrogen peroxide.

Lubricants: Lubricants are sometimes added in the tooth pastes to give softness to

the product that will help in the filling purpose or to facilitate the pastes to come out.

Color : Added in the pastes to give good appearance and to attract the customer

attention towards the products.

General Method of preparation:

First step in the preparation of toothpastes is to mix the gum with the

humectants.

Then binding agent is dispersed in the alcohol. If preservative is used it should

be dissolved in the water or glycerin.

Other powder ingredients are sifted together and added to mucilaginous

mixture with continuous gentle stirring.

Then the aqueous media is mixed and stirred to get the product.


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Flavor and detergents are added at the last.

TOOTH POWDERS

Tooth powders are oldest, simplest and cheapest preparation used for the

cleaning of the teeth. Over the years their market share has been reduced by

popularity and advantages of tooth pastes. The oldest tooth powder is reported to be

camphorated chalk.

Disadvantages:

Floating of powder in air during manufacturing

Formation of cake on storage


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Uneven distribution in mouth

Composition:

Basically, tooth powders contain the

following ingredients.

1. Abrasive and polishing materials

Abrasive used in the tooth powder is

same as used in the tooth pastes.

e.g. Calcium carbonate- heavier grade

Calcium pyrophosphate

Dicalcium phosphate

Tricalcium phosphate

Aluminum sulphate

2. Detergents or Surfactants

3. Sweetening materials

4. Flavors

5. Color (if required)

Method of Preparation:

Done by simple mixing

First ingredients of small quantity are premixed and then mixed with other

ingredients in ribbon type or agitator type of mixer.

Flavor can be sprayed on the bulk or premixed with part of some abrasive and

then mixed with the bulk.

Finally sieve the bulk mass to get tooth powder

Ingredients Quantity (gm)

Phenol 2.5

Kieselguhr 57.5

Calcium carbonate (heavy) 40.0

Flavor q.s.

Color q.s.


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EVALUATION OF DENTIFRICES:

Identification of ingredients and estimation of their contents are essential

components of overall quality control and

evaluation of dental care preparations.

Some special evaluation tests are as

follows:

Abrasiveness:

Various tests have been

designated and reported over the

years, mostly on the set of extracted

teeth. Teeth were mechanically

brushed with pastes or powders and

then the effect were studied by

observation, mechanical or other means. Abrasive character normally depends on

the particle size. So, study of particle size can also give such idea.

Particle size:

This can be determined by microscopic study of the particles or by sieving or

other means.

Cleansing property:

This is studied by measuring the changes in the reflectance character of a

lacquer coating on a polyester film caused by brushing with a tooth cleanser (paste

or powder). Also an in vivo test has been suggested in which teeth were brushed for

2 weeks and condition of teeth was assessed before and after use with the help of

photographs.

Consistency:

Ingredients Quantity

(gm)

Calcium carbonate (heavy)

92.5

Dental soap powder 6.0

Flavoring oil 1.0

Saccharine sodium 0.2

Color q.s.

Ingredients Quantity (gm)

Calcium carbonate (heavy) 76.0

Kaolin 11.9

SLS 2.0

Powdered pumice 10.0

Saccharine sodium 0.1

Flavor q.s

Color q.s.


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It is important that the product, paste, should be maintain the consistency to

enable the product press out from the container. Study of viscosity is essential for

this. Rheology of powders is also important for proper flow of the powders from the

container.

pH of the product:

pH of the dispersion of 10% of the product in water is determined by pH meter.

Foaming character:

This test is specially required for foam-forming tooth pastes or tooth powders.

Specific amount of product can be mixed with specific amount of water and to be

shaken. The foam thus formed is studied for its nature, stability and washability

Limit test for arsenic and lead:

This is very important as these are highly toxic metals. Specific tests are there

to estimate these two metals. However, if the raw materials are tested for the limit of

these two metals, product may not have excess of such metals.

Volatile matters and moisture:

A specific amount of the product required to be taken in a dish and drying is to

be done till constant weight. Loss of weight will indicate percentage of moisture and

volatile matters.

Effect of special ingredients:

Special tests should be done for the special ingredients if any, like antiseptic,

enzymes, etc. For each one special tests and specific test are to be done.

DETAL GELS

Dental gel is one type of dental care preparation that is used for the treatment of

various dental diseases. Thus dental gels are therapeutic dentifrices that contain


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one or more therapeutic agent that has special function to prevent periodontal

disease.

The systemic use of antibiotics to prevent dental disease has several

disadvantages. A prolonged administration of antibiotics increases the risk of

problems like, such as

antibiotic resistance

adverse drug reactions

like nausea, diarrhea and pseudomembranous colitis

As a result of these unwanted reaction, studies focusing on the development of

localized drug delivery systems for the release of antibiotics in the periodontal

pockets are becoming more frequent. This approach leads to higher concentrations

of the drug at the target sites, minimizing the potential systemic side effects.

Dental gels provide local delivery of antimicrobials in periodontal pockets may be

carried out with fibers, films, microparticles and gels made of biodegradable or

nondegradable polymers and have been proposed as effective methods to

administer antimicrobial agents in periodontal therapy .One class of hydrogels used

for controlled release of drugs in many pharmaceutical applications is represented

by the poloxamers, which are nonionic poly(ethylene oxide)-poly(propylene oxide)-

poly(ethylene oxide) triblock copolymers. Poloxamer 407 has been one of the most

extensively used copolymers. It has low toxicity, is compatible with other chemicals

and can solubilize drugs with different physicochemical properties. Additionally,

aqueous solutions of Poloxamer 407, at concentrations of 20% and above,

demonstrate a thermo reversible gelation behaviour, characterized by a critical

temperature. At temperatures under the critical one, Poloxamer solution is in the

form of a low-viscosity sol, while above it, when approaching body temperature, a

viscous transparent gel is formed.

Among the antimicrobials dental gels used for the treatment of periodontitis,

metronidazole dental gel particularly suitable due to following advantages.

Restricted spectrum of activity

Limited side effects, compared to those of tetracycline.


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RECENT INNOVATION

Metronidazole-containing dental gel for the treatment of periodontitis

Fluoride Dental Gels for dental caries prevention

Antimicrobial activity of dental gel on cariogenic bacteria

Dental sealant

Over the last few decades, several advancements have been made in caries

prevention. Along with systemic and topical fluoride, he increased acceptance and

use of pit and fissure sealants have without question had an impact on the

prevention of caries. Fluorides have been found extremely effective in preventing

caries on smooth surfaces of the teeth, but less effective on occlusal surfaces.

Sealants protect the occlusal surfaces, inhibiting bacterial growth and providing a

smooth surface that increases the probability that the surface will stay clean

Advances in the treatment of root dentine sensitivity:

Dentine hypersensitivity (DH) is characterized by „pain derived from exposed

dentine in response to chemical, thermal, tactile or osmotic stimuli which cannot be

explained as arising from any other dental defect or pathology.‟ A recent

modification to this definition has been made to replace the term „pathology‟ with the

word „disease‟ presumably with a view to avoid any confusion with other conditions

such as atypical odontalgia. Traditionally, the term dentine hypersensitivity was used

to describe this distinct clinical condition; however, several authors have also used

the terms cervical dentine sensitivity (CDS) or cervical dentine hypersensitivity

(CDH) or dentine sensitivity (DS), and root dentine sensitivity (RDS)/root dentine

hypersensitivity (RDH).


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Algorithm for the treatment of Dentine Hypersensitivity/Root Dentine Sensitivity by Practitioners is shown here:


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REFERENCES

A handbook of cosmetics by B.M. Mithal & R.N. Saha

J.B.Wilkinson, Harry‟s cosmeticology, Leonard Hill book, London, UK.

P.P.Sharma, cosmetics. Formulation, manufacturing and quality control,

Vandana publications, Delhi, India.

W.A. Poucher, Modern cosmetics, Vol-I,II & III, B.I. Publications, New Delhi,

India.

D.G. GILLAM & R. ORCHARDSON. Advances in the treatment of root dentine

sensitivity: mechanisms and treatment principles Endodontic Topics 2006, 13,

13–33

Nádia Araci Bou-Chacra, Sandra Sayuri Gobi, Mitsuko Taba Ohara, Terezinha

de Jesus Andreoli Pinto. Antimicrobial activity of four different dental gel

formulas on cariogenic bacteria evaluated using the linear regression method .

Revista Brasileira de Ciências Farmacêuticas Brazilian Journal of

Pharmaceutical Sciences vol. 41, n. 3, jul./set., 2005

Dental sealant . Access special supplemental issue, July 2001.

PAPER-910101 CHAPTER-8 OFFICIAL HERBALS KRUPA MEHTA

OFFICIAL

HERBAL DRUGS

Guided by:

Dr.r.k.parikh

Prepared by:

Krupa Mehta

m.pharm(sem-I)


HERBAL DRUGS:

Herbal drugs are widely used now-a-days..due to…

TRADITION:used through out history

COST: perceived as gentler and safer.

ACCESS: no prescription is necessary.

SYNERGISM: a view that multiple ingredients working together yield better results.

BUT…CASE AGAINST HERBAL DRUGS:

-Lack of FDA Regulations

-Lack of dose standardization

-Potential for toxicity and drug interaction.

But…still herbal drugs are widely used..even as pharmaceutical aids.

List of herbal drugs official in different pharmacopoeias are given here..

A look at the table indicates that IP has a long way to go to catch up, if one wishes to have high

/comparable number of herbals as in other Pharmacopoeiae, covered with quality monographs

for them.

Table 1. Recent Trend-Coverage of Herbal/Phytopharmaceuticals Monographs

in recent editions of Pharmacopoeiae

Sl No.

Category of monographs. In B.P

2005

In USP31/NF26[2nd

suppl]

In EP, 5th

Edn-2005.

In IP,2007.+IP addendum2008

1 Raw herbs 67 37 80 45

2 Excipients [Naturals.] 15 22 25 6

3 Processed herbs [extracts/V.oils /Essn.oils/Resins...]

60 61 54 15

4 Finished Products [Tinctures/Waters/syrups/tablets/Capsules/ear

drops…]

47 84 14 2

5 TOTAL 189 204 173 68


HERBAL DRUGS IP’07 BP’93 USPNF2006

ABSORBENT COTTON -

ACACIA (POWDER) (SYRUP)

ADHATODA(VASAKA/ADULASA) VINCOBLASTINE, CRISTINE

VINCRISTINE,BLASTINE, VINORELBINE

AGAR - -

ALLANTOIN - -

ALMOND OIL -

ALOE BARBALOIN BARBADOS & CAPE

AMALAKI/AMLA - -

AMARA - -

AMRITA(GUDUCHI/TINOSPORA/GILOE) - -

ANISE OIL - (ANISEED)

ARACHIS OIL (PEANUT/GROUNDNUT OIL)

ARJUNA - -

ARTIMISIA - -

ASHWAGANDHA(INDIAN GINSENG/WITHANIA)

- -

BACOPA(BRAHMI) - -

BALSAM OF TOLU - (SYRUP)

BASIL(TULSI) - -

BELLADONA (HERB,LEAF, POW, EXT)

(HERB) (LEAF,EXT, TAB,TINCTURE)

BENZOIN (TINCTURE) (SUMATRA) -

BHOI AMLA(PHYLLANTHUS) - -

BHRINGRAJ(ECLIPTA) - -

BLACK CURRANT(Ribes nigrum) - -

BLACK PEPPER(MARICHA) - -

CAFFEINE (ANHYDROUS)

CAMPHOR (RACEMIC) (SPIRIT)

CAPSICUM - - (OLEORESIN)

CARAWAY - (POW,OIL) -

CARDAMOM - (FRUIT,OIL) (OIL,SEED, TINC)

CASCARA - (POW) (EXT)

CASTOR OIL (EMUL.,CAP)

CATECHU - (POW) -

CEDAR OIL -

CHAMOMILE FLOWERS - -

CHASTE TREE - - (POW,EXT)

CHERRY - - (JUICE,SYRUP)

CHOCOLATE - - (SYRUP)

CINCHONA BARK - (POW)

CINNAMON - (POW,OIL) -



CLOVE (OIL,POW) (OIL)

CLOVER,RED - - (EXT,POW,TAB)

COCAINE -

COCILLANA - -

COCOA BUTTER - -

COCONUT OIL - -

CODEINE -

COLCHICINE (TAB)

COLEUS

COLOPHONY - -

CORIANDER - (POW,OIL) (OIL)

CORN - - (OIL,STARCH)

COTTONSEED OIL - -

CRANBERRY - - (LIQ PREP)

CURCUMA(HARIDRA/HALDI) (CURCUMIN) (PAPER)

DIGITALIS (TAB,DIGOL, DIGOXIN INJ, PAEDIA.)

(LEAF,POW, DIGOXIN, DIGITOXIN)

(CAP,POW,TAB, DIGITOXIN, DIGOXIN)

DILL OIL - -

ECHINACEA ANGUSTIFOLIA (E.PALIDA,E.PURPUREA)

- -

EMETINE (HCL,INJ) (HCL) (HCL)

EPHEDRINE - (ANHY, HCL) (HCL,SO4 )

ERGOT (ERGOTAMINE,METRINE, NOVINE)

- (NOVINE, TAMINE)

ETOPOSIDE (CAP,INJ) -

EUCALYPTUS OIL

EUGENOL

FENNEL OIL - -

FRANGULA BARK - -

FRIER’S BALSAM - -

GARCINIA(VILAYATI IMLI) - -

GARLIC(ALLIEUM SATIVUM) (POW,EXT, DR TAB)

-

GENTIAN - (POW) -

GINGER (POW) (POW,CAP,TINC)

GINKGO - -

GINSENG - - (AMERICAN, ASIAN)

GOKHRU - -



GUAR GUM - -

GUDMAR(GYMNEMA) - -

GUGGUL(COMMIFORA) (LIPID) - -

HAWTHORN LEAF WITH FLOWER - -

HORSE CHESTNUT - - (POW,EXT)

HYOSCYAMUS - (POW) -

INDIAN SQUILL - -

IPECACUANHA - (POW,PREP) -

ISPAGHULA(PLANTAGO) (HUSK) (BARK) (SEED)

KALMEGH(ANDROGRAPHIS) - -

KUNDURU(SALAKI GUM/ GUM OF BOSWELIA)

- -

LEMON OIL - (TERPENELESS, PEEL)

(TINC)

LINALOOL - -

LINSEED - (POW,OIL) -

LIQUORICE(MULETHI/YASTI/JETHIMADH) (POW) (POW,EXT)

LOBELIA POWDER - -

LONG PEPPER(CATKINS-BIG/SMALL) - -

MAIZE - (OIL,STARCH) -

MALT EXTRACT - -

MANDUKPARNI(CENTELLA/GOTUKOLA) - -

MANGO - -

MANJISTHA(INDIAN MADDAR/ Rubia cordifolia)

- -

MARITINE PINE - -

MATRICARIA FLOWERS - -

MATTO GROSSO IPECAC - -

MENTHA OIL - -

MILK THISTLE - - (POW,EXT,TAB, CAP)

MINT OIL-DEMENTHOLISED - -

MYROBALAN -BELLIRIC/BHIBHITAKI -CHEBULIC/HARAD/HARITAKI/ TERMINALIA

- -

- -

MYRRH - - (TOPICAL SOLU)

NETTLE STNGING - - (POW)

NUTMEG OIL -



OLIVE OIL - (POW,TINC)

OPIUM(PAPAVER) (RAW,TINC) (MORPHINE)

ORANGE - (OIL,PEEL,TINC, SYRUP,SPIRIT)

(OIL,PEEL,TINC, SYRUP,SPIRIT)

PACLITAXEL - -

PALM-KERNAL OIL - -

PAPAIN - -

PEPPERMINT OIL (LEAF,SPIRIT) (OIL,WATER, SPIRIT)

PHYSOSTIGMINE -

PICRORRHIZA(KUTKI) - -

PIPERIDINE - -

PODOPHYLLUM - (RESIN)

PSEUDOEPHEDRINE -

PSYLLIUM - - (HUSK,SUSP)

PUNARNAVA(HOGWEED/BORREHWIA) - -

PURPUREA - -

PYGEUM - -

PYRETHRUM - -

QUILLIA - (POW) -

RAPESEED OIL - -

RAWOLFIA(SARPGANDHA) - (RESERPINE)

RHATONY ROOT - (POW) -

RHUBARB - (POW) -

ROSE - - (OIL,OINTMENT)

SAFFLOWER OIL - -

SATAVARI(ASPARAGUS) - -

SATI(HEDYCHIUM) - -

SAW PALMETTO - -

SENNA(CASSIA) (LEAF,POW) (TINNEVELLY) (POW,EXT)

SESAME OIL -

SHELLAC(LAC) -

SOYA OIL - -

SOYBEAN OIL -

SPEARMINT OIL - -

SQUILL - -

ST. JOHN’S WART - -

STARCH - (POTATO)

STERCULIA LEAF - -

STRAMONIUM LEAF - -

SUNFLOWER OIL -



SUNTHI(SONTH) - -

TURPENTINE OIL - -

THEOBROMA OIL - -

THEOPHYLLINE -

THIO TEPA -

TOMATO - -

TRAGACANTH -

VALERIAN -

VANILLA - (VANILLINE) (TINC)

WHEAT - -

WINTERGREEN OIL - -

REFERENCES:

1.Indian pharmacopoeia,2007

2.British Pharmacopoeia,1993

3.USPNF,2006

4.www.expresspharmaonline.com

stability study

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