PRODUCT STABILITY

PRESENTED BY:Shweta patil

256213885024M.PHARMACY(ANALYSIS)

GUIDED BY:YASMEEN MADAMM.PHARMA

MALLA REDDY COLLEGE OF PHARMACYMAISAMMAGUDA,DHULPALLY SEC-BAD-14

CONTENTS

INTRODUCTION

ARRHENIUS EQUATION

ACTIVATION ENERGY

SHELF LIFE

ACCELERATED STABILITY TESTING

LIMITATIONS OF ACCELERATED STABILITY

ADVANTAGES

INTRODUCTION

Stability of pharmaceutical product may be defined as the capability of a particular formulation to remain in a specification.

The container/closure system in which the product will remain within its physical, chemical, microbiological, therapeutic and toxicological specification

Stability:

But the stability studies for any formulation is time consuming and economical.

Accelerated stability studies is the study of stability by the accelerating the parameters like

• Temperature• Humidity• Light

NEED FOR STABILITY TESTING:

Provide evidence as to how the quality of the drug product varies with time.

Establish shelf life for the drug product.

OBJECTIVES:Main objective of the accelerated stability studies

To predict the best formulation.

To know the shelf life of the formulation.

To provide quality formulations.

Essential quality attribute.

Determine closure system suitability.

Safety point of view of patient.

Prevention of economical repercussion.

Arrhenius equation :

It explains the effect of temperature on rate of a reaction.According to Arrhenius, for every 10º rise in temperature, the speed of reaction increases about 2-3 times.

k = A e -Ea / RTWhere k=specific rate constant

A=frequency factorEa= activation energyR=ideal gas constantT=absolute temperature

Arrhenius factor is the frequency of molecular collisions occuringbetween the molecules.

Take log on both sides,ln k = ln A –Ea/RT ln e (2)

Converting equation (2)to log 10 log k = log A – Ea/2.303RT

By using Arrhenius equation at time zero and at any time it can be

ln = ln ko – Ea/R(1/T - 1/T0)

Estimation of k:1.Reaction is conducted at several temperatures.2.Concentrations is determined at different time period.3.Order of reaction is identified.4.From slope of line k is calculated.

slope=-k2.303

Log(a)

Time(s)

ACTIVATION ENERGY:

Activation energy is the minimum energy that a molecule should possess so that the molecular collisions produce the product.

The activation energy of a reaction is usually denoted by Ea, and given in units of kilojoules per mole.

A graph can be drawn by taking log k on y-axis and reciprocal temperature (1/T) on x-axis.

A straight line is obtained, the slope of the line is negative and the magnitude is Ea / 2.303 R.

The intercept corresponds to log A

All the constants in the Arrhenius equation can be obtained from the graph.

y-axis=lnk slope=-EA/R

x-axis=1/T

SHELF LIFE:

t90 or t0. 9 : Time required to reduce the concentration of the reactant to 90% of its initial concentration.

Stability of formulation can be determined by shelf life.

t90=0.105/k

where k=specific rate constant

SHELF LIFE :

Maximum and minimum time at which potency mustbe atleast 90% of label claim at the temperature indicated in order to predict a shelf life of two years at room temperature.

Temperature Maximum time For study

Minimum time for study

37*c 12 months 6.4months

45*c 8.3 months 2.9 months

60*c 4.1months 3 weeks

85*c 0.6 weeks 25 days

Calculation of shelf life:Example: Shelf life of Aspirin suspension A prescription for liquid aspirin is called for it contains 325mg/5ml or 6.5g/100ml. Solution of aspirin at 25*c is 0.33g/100ml.therefore suspension will

definitely be suspension. Other ingredients in prescription cause the product to have PH of

6. 1st order rate constant for aspirin degradation is 4.5 x10-6 sec-1. Calculate zero order rate constant. Determine shelf life assuming that product is satisfactory until at

the time at which it has decomposed to 90% of its original concentration at 25*c

K0= k x (Aspirin in solution)

=(4.5 x 10-6 sec-1) x (0.33g/100ml)

Ko = 1.5 x 10-6 g/100ml sec-1

t90 = 0.10(A)0/k0

=0.10 x 6.5g/100ml1.5 x 10-6g/100ml

=5days

Accelerated stability testing:

It involves studies designed to increase the rate of chemicaldegradation or physical change of active substances or drug productBy using exaggerated storage condition as part of formal,definitive Storage programme.

Accelerated stability testing involves four types:

They are: Test at elevated temperature. Test at high level intensity Test at high partial pressure. Test at high relative humidity

Drug liquid preparation stored at 50, 60, 70,85, 100 and 121˚c. Also study performed at R.T. and or refrigerator

temp. Sampling:

First year- 3 month intervalSecond year- 6 month interval

Four climatic zones:Temperate zone 21˚c/45%RHMediterranean zone 25˚c/60%RHTropical zone 30˚c/70%RHDesert zone 30˚c/35%RH

Test at elevated temperature:

Drug substances fade or darken on exposing to light, can be controlled by using amber glass or opaque container.

By exposing drug substance to 400 & 900 (Foot candle)of illumination for 4 & 2 weeks to light and another sample examined protected from light .

Results found on appearance and chemical loss may be recorded.

Comparing color or using diffused reflectance spectroscopy for examination.

e.g. cycloprofen becomes very yellow after five days under 900 foot candles of light.

Test at high intensity of light:

Sensitivity of the drugs to atmospheric oxygen must be evaluated from which it should be packed in inert atmospheric condition with antioxidants is decided .

Here, high oxygen tension plays important role to investigate stability Usually ,40% of oxygen atmosphere allows for rapid evaluation.

Results were correlated with inert & without inert condition

Test at high partial pressure of oxygen :

Presence of moisture may cause hydrolysis and oxidation.

These reactions may accelerated by exposing the drug to different relative humidities.

Control humidity by Lab desiccators

Closed dessicator are placed in an oven to provide constant temperature.

Test at high relative humidity:

Storage condition of 40*C and relative humidity of 75% has been recommended for all the four zones for drug substances and drug products.

Studies carried out for 6 months.

Accelerated storage conditions must be at least 150C above the expected actual storage temperature and appropriate relative humidity

ACCELERATED STABILITY STUDIES

CLIMATIC ZONES/STORAGE CONDITIONS

CLIMATIC ZONES/STORAGE CONDITIONS

CLIMATIC ZONES/STORAGE CONDITIONS

Drug substances - intended for storage in a Refrigerator

CLIMATIC ZONES/STORAGE CONDITIONS

Drug products - General case

Valid only when the break down depends on temperature. The energy of activation obtained in the study should be

between 10 to 30 kcal/mole.

It is not useful when degradation is due to:Microbial contaminationPhotochemical reactionsDiffusionExcessive agitation

When the product looses its physical integrity at higher temperatures.

When the order changes at elevated..

Limitations of accelerated stability testing:

Advantages:

Storage conditions can be known.

Stability of product can be estimated.

Shelf life and expiry date can be known.

Key assurance of quality of pharmaceuticals.

Pharmaceutical products meet their specification for identifying purity, quality and strength throughout their defined storage period at specific storage condition.

SHELF LIFE ASSIGNMENT The validity of an assigned shelf life depends upon:

• Results of stability studies.• Whether the batches used in the stability studies

accurately model to be marketed.• Whether the analytical methodology was adequately

validated.

CONDITIONS: Assigning a shelf life is easier if results are available.

For full duration of proposed shelf life.

At maximum recommended storage condition.

For all formulations and manufacturing methods.

In exactly the packaging to be registered.

At all the sites of manufacture of finished product and API.

If these conditions are not met that’s when shelf life assignmentbecomes difficult.

There will be delays in approving the product.

SHELF LIFE DETERMINATION BASED ON ARRHENIUS PLOT

We keep several samples of the drug product at atleast three temperatures, such as 40,50 and 60*c.

We 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.

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 zeroorder,percent drug remaining versus time Will give a straight line.

Next we take the log k or log of reaction constant on y-axis. And 1/T x10-3 on x-axis and draw a best fit line.This line is the

Arrhenius plot.We extrapolate this line to get k at 25*c and from this we calculate the shelf life.

If the reaction is following zero-order Expiration date at 25*c(tx) Initial potency-minimum potency/reaction rate at 25*c

oytx -XY OK/

If the reaction is following first order:

Expiration date at 25*c(tx)=Log initial potency-log minimum potency

Reaction rate at 25*c

Where:

xyoy = initial constant

= final potency

ok = zero order kinetics

SHELF LIFE DETERMINATION BASED ON REAL TIMETESTING:

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

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.

Now plot the graph of % drug content on y-axis and time on x-axis along with confidence intervals minimum potency,there you fix the shelf life.

As an example : vitamin tablets stability confidence intervals at40*c(confidence intervals means a range of values so defined thatThere is a specified probability that the value of the parameters lies Within it.)

Time(months)

Results(mg/tablet)

Lowerlimit

Upperlimit

0 100.0 95.2 104.9

1 91.2 88.7 93.8

3 83.1 79.3 87.3

6 75.8 69.8 82.5

9 69.1 61.2 78.2

12 63.0 53.6 74.0

1(y -iy )

2n

2

y1 = predicted value at t1n = sample sizeYi = standard error of line

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

Confidence intervals

DruG%

Estimation of the shelf life(expiration period) of drugproducts

Shelf life is best defined as the time span over which the quality of a product remains with specifications .

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.

The two methods for estimating shelf life of pharmaceuticals when chemical degradation is the major contributor to degradation process and degradation can be adequately described by a rate expression.

Extrapolation from real-time data:

The woolfe equation has been used to Estimate the shelf life of a product from data obtained at the sameTemperature/conditions as those expected for the final product.

The time at which the drug content diverges from its Specifications is estimated by extrapolating the time course of Degradation at a specific temperature/condition. when the timeCourse of drug content(c) is represented by

tt ccb

Where t = Average of t c = Average of c b = constant

The woolfe equation allows one to estimate the confidence limit Of t as a function of C

SHELF LIFE ESTIMATION FROM TEMPERATUREACCELERATEDSTUDIES: In temperature-accelerated studies,shelf life at a storage

temperature T1 is estimated from the shelf life at an elevated temperature T2 ,according to

ln )1(T90t

)2(90 TtaE

R1T1

- 1

T2

Shelf life is reffered to as t90t1 when the lower specification limit of the content is 90%.

1/T is the temperature range when activation is constant .

Stability of drug also can be defined as the time from the date of manufacture and packaging of the formulation until its chemical or predetermined level of labelled potency and its physical characteristics have not changed appreciably.

Solid state stability

Provide a evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as….. temperature, Humidity and light.

Establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions.

Because physical, chemical or microbiological changes might impact the efficiency and security of the final product.

Why Stability…?

Drug Substances (DS) : The unformulated drug substance that may subsequently be formulated with excipients to produce the dosage form.

Drug Products (DP) :The dosage form in the final immediate packaging intended for marketing……. controlled and documented determination of acceptable changes of the drug substance or drug product

Stability tests are performed 0n:

Physical changes• Appearance• Melting point• Clarity and color of solution• moisture• Crystal modification (Polymorphism)• Particle size

Chemical changes• Increase in Degradation • Decrease of Assay

Microbial changes

What are the changes….?

Acidic & Basic conditions.

Dry heat exposure

UV radiation exposure

Influence of pH

Influence of temperature

Influence of ionic strength

Forced degradation studies:

Ideally any commercial pharmaceutical product should have a shelf life of 5 years and should not fall below 90-95% potency under recommended storage.

In designing a solid dosage form it is necessary to know the inherent stability of the drug substance, excipients to be used, formulation procedure.

For a drug substance, we need to study 3 categories of stabilities-1. Solid state stability of drug only2. Compatibility studies ( drug+ excipients )3. Solution phase stability

Stability

Solid state stability

It includes both physical and chemical stability.

Physical changes by polymorphic transitions and hygroscopicity.

Polymorphic transitions- It is the ability of the compound to Crystallize in one or more crystalline forms with different Internal lattices.

Hygroscopicity-It is the ability of the substance too attract and Hold water molecules from the surrounding environment.

Ex:Cellulose fibres,Sugar,Caramel,Glycerol,ethanolSulfuric acid.

Chemical changes such as solvolysis,oxidation,photolysisPyrolysis.

Solvolysis: It is a special type of nucleophilic solution or Elimination where nucleophile is a solvent molecule.

Oxidation: It is any chemical reaction that involves the movingOf electrons.

(or)Oxidation is gain of oxygen.

2fe 3o 3o + 3CO2+ CO2

Photolysis: The decomposition or separation of molecules by action of light.

Example: Decomposition of ozone to oxygen in the atmosphere

Example: Synthesis of chloromethane from methane and chlorine initiated by light.

Pyrolysis: It is a thermochemical decomposition of organic material at elevated temperature in the absence of oxygen. It involves simultaneous change of chemical composition and physical phase is irreversible.

pKa Melting point Crystal form Equilibrium moisture content. Solubility

Example- amorphous materials are less stable than their crystalline counterparts.

A relatively dense material may better withstand ambient stresses aminobenzylpenicillin trihydrate is more denser and stable than its amorphous form.

PHYSICAL CHANGES /INSTABILITY

Solid state reactions are generally slow and it is customary to use stress conditions in investigation of stability.

Data obtained under stress is then extrapolated to make prediction of stability.

High temperature can drive moisture out of a sample and render the material apparently stable otherwise prone to hydrolysis.

Example- Above 65% relative humidity the beta form of chlortetracycline hydrochloride transforms into alpha form.

CHEMICAL CHANGES/INSTABILITY

ELEVATED TEMPERATURE STUDIES

Tests are usually performed at 40 ,50 ,600C in conjuction with ambient humidity.

Higher temperatures are also used, samples kept at highest temperature examined for chemical and physical changes at weekly intervals- if no change is seen after 30 days at 600C Stability prognosis is excellent.

Arrhenius Treatment is used to determine the degradation rate at lower temperature.

K = Se-Ha /RT

where,k = specific rate of degradation.R = gas constant ( 1.987 calories degree-1mole).T = absolute temperature.S = frequency factor.

ARRHENIUS EQUATION (Effect of temperature)

o In presence of moisture, many drug substances hydrolyze react with other excipients or oxidize.

o These tests are performed by exposing the drugs to different relative humidity conditions

o Preformulation data of this type is helpful in determining if the material should be protected and stored in a controlled low-humidity environment or if aqueous based granulation should be avoided.

STABILITY UNDER HIGH HUMIDITY CONDITIONS

Many drugs fade or darken on exposure to light and this leads to an aesthetic problem which can be controlled by using: 1 Amber Glass Container2 Opaque Container3 Incorporating a Dye.

PHOTOLYTIC STABILITY

Stability to oxygen must be evaluated to establish that the final product should be packaged under inert atmosphere or it requires an antioxidant.

A 40% oxygen atmosphere allows for rapid evaluation

The samples are kept in dessicators.

Process is repeated 3-4 times to assure 100% of desired atmosphere.

STABILITY TO OXIDATION

Knowledge of stability of a formulation is very important for three primary reasons:

A Pharmaceutical product must appear fresh, elegant and professional for as long as it remains on the shelf.

Since some products are dispensed in multiple dose containers uniformity of dose of the active ingredient over time must be ensured .

The active ingredient must be available to the patient through out the expected shelf life of the preparation. A breakdown in the physical system can lead to non availability or of the medication to the patient.

CONCLUSION

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