SEMINAR ON

DRUG EXCIPIENT COMPATIBILTY STUDY

(As a part of preformulation study)

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INTRODUCTION

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• INCOMPATIBILITY-Definition-3 Types

• OBJECTIVE OF THE STUDY-Why to screen excipients?

1.need to minimize no of model formulations2.provide rational basis for selecting excipients3.Formulation stability studies are time consuming.

-Goal of the study( Identify the excipients that)1.are compatible with API2.do not have impact on the stability of API

-Importance1.Stabity of formulation can be maximised.2.Helps to avoid surprise problems.3.Essential for IND submission.4.Bridges drug discovery and drug development

COMPATIBILITY TESTS

• 2 Aspects of compatibility tests are:1. Identification of compatible excipients for a formulation.2. Identification of stable storage conditions

• 2 Types:1. Solid state reactions:

- much slower and difficult to interpret.2. Liquid state reactions:

- easier to detect- Acc. to Stability Guidelines by FDA following conditions should be evaluated for solutions or suspensions

1. Acidic or alkaline pH.2. Presence of added substances3. High oxygen and nitrogen atmospheres.4. Effect of stress testing conditions.

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STEPS IN COMPATIBILITY STUDY

There are THREE steps to consider.

1. Sample preparation

2. Storage

3. Method of analysis

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SAMPLE PREPARATION

• FOR SOLID STATE REACTIONS: SampleA: -mixture of drug and excipient SampleB: -SampleA+ 5% moisture SampleC: -Drug itself without excipients

o All the samples of drug-excipient blends are kept for 1-3 weeks at specified storage conditions.

o Then sample is physically observed .o It is then assayed by TLC or HPLC or DSC.o Whenever feasible, the degradation product are identified

by MASS SPECTROSCOPY, NMR or other relevant analytical techniques.

o To determine Solid state stability profile of a new compound….

o To test the Surface Oxidation…..

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SAMPLE PREPARATION

FOR LIQUID STATE REACTIONS:

o Place the drug in the solution of additives.

o Both flint and amber vials are used.

o This will provide information about

-Susceptibility to oxidation.

-Susceptibility to light exposure.

-Susceptibility to heavy metals.

o In case of oral liquids, compatibility with ethanol, glycerin ,sucrose, preservatives and buffers are usually carried out.

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STORAGE CONDITION

The storage conditions used to examine compatibility can very widely in term of temp. & humidity, but a temp. of 50°c for storage of compatibility sample is considered appropriate.

Some compounds may require high temp. to make reaction proceed at a rate that can be measured over a convenient time period.

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ANALYTICAL TECHNIQUES USED TO DETECT

DRUS-EXCIPIENT COMPATIBILITY

1. Thermal methods of analysis

– DSC- Differential Scanning Calorimetry

– DTA- Differential Thermal Analysis

2. Accelerated Stability Study

3. FT-IR Spectroscopy

4. DRS-Diffuse Reflectance Spectroscopy

5. Chromatography

– SIC-Self Interactive Chromatography

– TLC-Thin Layer Chromatography

– HPLC-High Pressure Liquid Chromatography

6. Miscellaneous

– Radiolabelled Techniques

– Vapour Pressure Osmometry

– Flourescence Spectroscopy

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DSC- DIFFERENTIAL SCANNING

CALORIMETRY

o DSC is widely used to investigate and predict any physico-chemical interaction between drug and excipients involving thermal changes..

o METHOD

-The preformulation screening of drug-excipient interaction requires (1 : 1)Drug:excipient ratio, to maximize the likehood of observing an interaction.

-Mixture should be examined under N2 to eliminate oxidative and pyrrolytic effects at heating rate ( 2, 5 or 100 c / min) on DSC apparatus.

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EXAMPLE: DSC IN OFLOXACIN

TABLETS

Trace 1 of figure 1-4 shows peak at 278.330C. (melting endothermic

peak of Ofloxacin).

Trace 3 (Physical mixture of Ofloxacin & Lactose) shows absence of

peak at 278.330C and slight pre shift in Lactose peaks.

DSC RESULT-- INCOMPATIBLE

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Trace 5 (Physical mixture of Ofloxacin & Starch) shows an

early onset at 268.370C. But no other changes in

thermogram.

DSC RESULT-- COMPATIBLE

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Trace 7 (Physical mixture of Ofloxacin & PVP) shows no change in

position of endothermic peak for PVP but there is increase in peak

area and size & shape of peak for Ofloxacin is also decreased.

DSC RESULT-- INCOMPATIBLE

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Trace 9 (Physical mixture of Ofloxacin & Talc) shows

combine features of each component but there are

evident changes in onset.

DSC RESULT-- COMPATIBLE

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DSC STUDY IN ASCORBIC ACID

FORMULATION

oExcipients: Sod. Crosscarmellose, MCC, Lactose

oThermal stability was performed on ascorbic acid std.

samples, binary mix. of ascorbic acid & excipients, under

N2 & air atmospheres.

oIR & X-Ray Diffractometry: No chemical interaction

However thermal stability of p’ceutical formulations are

different.

oTemp. of beginning of thermal dregradation for Ascorbic

acid is lowered of about 50C for MCC & 100C for Na-

crosscarmellose & Lactose.

oSuch facts must be considered for storage planning of

tablets. (Ref: C.A. vol:146, No:25,

June18,2007,507180t)

LIMITATIONS OF DSC

o If thermal changes are very small, DSC can’t be used.

o DSC can not detect the incompatibilities which occur after long term storage.

Eg. MCC / ASPIRIN…

o Not applicable if test material exhibits properties that make data interpretation difficult.

o ADVANTAGES:

-Fast

-Reliable and very less sample required.

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DIFFERENTIAL THERMAL

ANALYSIS(DTA)

Thermal Analysis is useful in the investigation of solid-state interactions.

It is also useful in the detection of eutectics.

Thermograms are generated for pure components and their physical mixtures with other components.

In the absence of any interaction, the thermograms of mixtures show patterns corresponding to those of the individual components.

In the event that interaction occurs, this is indicated in the thermogram of a mixture by the appearance of one or more new peaks or the disappearance of one or more peaks corresponding to those of the components.

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DTA( DRUG:ENALAPRIL MALEATE)

FORMULATION RESULT

OF DTA

(interaction)

SHELF

LIFE

INFERENCE

F1 (Avicel) + 3 ½ month Least suitable

F2 (Spray dried

lactose)

–– 1 yr and 3

month

Ideal

F3 (Emcompress) + 8 month Not recommended

F4 (A-tab) + 9 ½ month Not recommended

(Ref:I.J.P.E.,Jan:2000,153)

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ACCELARETED STABILITY STUDY

oDifferent formulations of

the same drug are

prepared.

oSamples are kept at 40ºC

/ 75 % RH.

oChemical stability is

assessed by analyzing the

drug content at regular

interval.

oAmt. of drug degraded is

calculated.

o% Drug decomposed VS

time(month) is plotted.

DIFFUSE REFLECTANCE

SPECTROSCOPY

• Principle: “Penetration of a portion of incident radiation flux into the interior of the solid sample, return of some portion of radiation to the surface of sample following partial absorption and multiple scattering at boundary of individual sample particles.”

• Detects the decomposed products, along with physical and chemical adsorption of excipients on to A.P.I. and vice versa.

• Example: Ethanol mediated interaction between dextroamphatamine sulphate and spray dried lactose in solid–solid mixture:

• Discoloration of powdered mixture was accelerated by 2amine and by storage at elevated temp. Two new absorption maxima were observed at 340 nm & 295 nm resply.

• A + L = A–L A–HMF

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DIFFUSE REFLECTANCE

SPECTROSCOPY

A shift in the diffuse reflectance spectrum of the drug due to the presence of the excipient indicates physical adsorption.

whereas the appearance of a new peak indicates chemisorption or formation of a degradation product.

DRS is more useful than HPLC assay to detect surface discoloration due to oxidation or reaction with excipients.

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SELF INTERACTIVE

CHROMATOGRAPHY

• SIC is useful for proteinous drug and excipients.

• METHOD:-

• SIC is a modified type of affinity chromatography.

• Here,drug is made immobilized as the SP & soln. to be tested( excipient soln.) acts as MP.

• Measure Rt (Retention time) & compare with non –retained marker.

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PRINCIPLE:-For different mobile phases (i.e. different excipients) the injected

drug have different interactions (may be repulsive or attractive)

with the SP of drug leads to shift in retention time (Rt)

When interaction is

repulsive,a sharper

peak is obtained at a

shorter retention

time

When no net

interaction between

the immobilized

drug,Rt=dead volume

of column.

When attractive

interactions,it will

have longer retention

time& wider peak

FIGURE-1 FIGURE-2 FIGURE-3

TLC AND HPTLC

o TLC is generally used as confirmative test of compatibility

after performing DSC.

o S.P. consist of powder (Silica, Alumina, Polyamide, Cellulose

& Ion exchange resin) adhered onto glass, plastic or metal

plate.

o Solution of Drug, Excipient & Drug: Excipient mixture are

prepared & spotted on the same baseline at the end of plate.

o The plate is then placed upright in a closed chamber

containing the solvent which constitutes the M.P.

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TLC AND HPTLC

Any change in the chromatograph such as the appearance of a new spot or a change in the Rf values of the components is indicative of an interaction.

The technique may be quantitated if deemed necessary. If significant interaction is noticed at elevated temperatures, corroborative evidence must be obtained by examining mixtures stored at lower temperatures for longer durations.

Among the advantages of thin-layer chromatography in this application are:

Evidence of degradation is unequivocal.

The spots corresponding to degradation products can be eluted for possible identification.

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HPLC AND FLUORESCENT

MEASUREMENT

• HPLC (high pressure liquid chromatography)

Characteristics:

-The APIs and model compounds of diversified chemical structure was studied.

-Elution rate: 7.5 ml/hr at ambient temp.

-Allows the detection and quantification of impurities, which span a wide range of polarities, including nonpolar compounds.

• FLUORESCENT MEASUREMENT:

-This technique is restricted to those compounds, which can generate florescence. As the no. of such compounds are restricted, this method is used in Analysis and not in preformulation

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• VAPOR PRESSURE OSMOMETRY & EQUILIBRIUM DIALYSIS

• Principle: ‘samples of solutions and pure solvent are introduced into a temperature-controlled enclosure, which is saturated with solvent vapor.Since the vapor pressure of solution is lower than that of solvent, solvent vapor condenses on solution sample causing its temperature to rise. The temperature rise is predicted by Clausis –Clapcyron equation.’

• Characteristics: Either liquid or solid sample and must be soluble in organic

solvent or in water Sample must not undego association in solution. Sample size is approx. 3 gms for multiple analysis. Measures a no. of avg. mole. Wt. of about 10,000 Daltons. This method measures interactions, & records the interaction

caused by variation of particle no.

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• RADIO LABELLED TECHNIQUES:

It is important when the API is having radio–

activity.

Method is carried out by using either 3H or 13C.

Highly sensitive method but the cost of carrying out

the method & the availability of well established

other techniques & methods, this method is

generally not preferred.

INCOMPATIBLE IMPURITIES

o Chemical impurity profiles -Very important in influencing the long term chemical stability.

Eg:-(1) Evaluation of Hydroperoxides ( HPO) in common

pharmaceutical excipients.

POVIDONE Contains substantial conc. PEG 400 of HPOs with significant HPC batch to batch or mfger

POLYSORBATE 80 to mfger variations.o While MCC, Lactose, High M.wt PEG, Polyxamer contains

less amt. of HPOs.o 5% PVP responsible for N-oxide formation of Raloxifen

HCl, due to high HPO content.

(Ref: J.Ph.Sci,vol:97,Jan:2007,106)

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(2) DCP – Sometimes, IRON may be present in

DCP as impurities. It is incompatible with

MECLIZINE HCl . (Fe NMT 0.04%)

(3)Gelatin is also containing IRON as

impurities, Dark spots may occur in the shell

due to the migration of water soluble iron

sensitive ingredients from fill material into the

shell.

P- Glycoprotin inhibitor excipients

o p-Glycoprotein is membrane associated transport protein. It is an efflux pump lies in tissue membranes.

o Some excipients have p-Glycoprotein efflux-pump inhibiting properties.

o EXAMPLES:- 1.PEG-32 lauric glycerides.2.Polysorbate-80 3.PEG-50 Stearate4.Polysorbate-205.Polysorbate-856.PEG-40 hydrogenated castor oil7.PEG-35 castor oil

(Ref: J.Ph.Sci.,vol:93,Nov:2004,2755)

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Known Incompatibilities

Functional group Incompatibility Type of reaction

Primary amine Mono & Di-saccharidesAmine-Aldehyde &

Amine-Acetal

Ester,

LactoneBasic component

Ester base hydrolysis, Ring

opening,

Aldehyde Amine, CarbohydrateAldehyde-Amine, Schiff base

Or Glycosylamine formation

Carboxyl Base Salt formation

Alcohol OxygenOxidation to Aldehyde

& Ketones

Sulfhydryl Oxygen Dimerization

Phenol Metal Complexation

Gelatin- Capsule Shell Cationic Surfactant Denaturation

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Excipient Incompatibility Type of reaction

Parabens Non ionic surfactants

(Polysorbate 80)

Micellization (Reduced

antimicrobial activity)

Plastic Containers Absorption of Parabens

Phenylmercuric

Nitrate

Anionic Emulsifying agents,

Suspending Agents, Talc, Na-

metabisulfite, Na-thiosulfate

Anti-microbial activity

Reduced

Halides Incompatible (forms less soluble

halogen compds)

PEG Penicillin & Bacitracin Anti-bacterial activity reduced

Phenol, Tannic acid &

Salicylic acid

Softening & Liquifaction

Sulphonamide & Dithranol Discoloration

Film coating Migration of PEG from tablet film

coating, leading to interaction with

core component

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DECS in solid dosage forms

Example 1:-

o Millard reaction:- is a non-enzymatic bimolecular browning reaction between reducing sugar and an amine.(Anhydrous lactose: no Millard reaction)

o Mechanism:-

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Example2:-

Effect of Excipients on Hydrate formation in

wet masses containing Theophylline

oDuring wet granulation Theophylline Shows

Pseudopolymorphic changes that may alter its

dissolution rate.In the presence of moisture

Theophylline monohydrate is formed which has slow

dissolution rate.

oDiluents Used:

1.α- Lactose monohydrate : Minimum water

absorbing capacity. So not able to prevent but

enhance Hydrate formation of Theophylline.

2.Silicified MCC : Highly water absorbing

capacity.Able to inhibit the formation of

Theophylline monohydrate at low moisture content.(Ref- J.Ph.Sci,vol:92,Jan:2003,516)

SILICIFIED MCC –as a multifunctional

pharmaceutical excipient

• Multifunctional excipient

• Characteristics offered by Prosolv are high compactibilty, high intrnsic flow, enhanced lubrication efficiency and improved blending properties.

• Provide tremendous advantages through out product life cycle.

• MCC is a dry binder- when comes in contact with water ,its compressibilty is decreased..but that is not the case with SMCC.

(Ref:CA,Vol:151,No:6,

August10,2009 ,131557w)

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DRUG EXCIPIENT COMPATIBILTY

STUDY IN AEROSOLS

o Example 1:- Interaction of propellent-11 with aqueous drug products.

o Propellent 11 is trichloromonofluoromethane.

o HCl corrodes the Al-container.

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Example2:

Beclomethasone- Hydroflouroalkane interactions:

BDP is a Steroidal drug used in Asthma

Manipulation of above interaction: BDP particles

coated with amphiphilic macromolecular excipient by

Spray drying.Therefore, prevention of aggregation

& production of physically stable

suspension with excellent

aerosolisation properties.(Ref: J. Ph.Sci.,VOL:95,May:2006,1060)

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oAnhydrous ethanol is corrisive to Al containers.

-Hydrogen produced in the reaction increases the

pressure of the container.So drugs containing polar

solvents tend to be corrosive to bare Al.

oFor containers which contain 2%Tin and 98% Lead

-Lead reacts with the fatty acids(for product

cont.soaps) to form Lead salts which cause valve

clogging.

DRUG EXCIPIENT COMPATIBILTY IN

PARENTERAL PRODUCTS

Anti-oxidantsAscorbic acid: Incompatible with acid- unstable drugs

Na bisulfite:+ Epinephrine Sulphonic acid dvt.

-Incompatible in Opthalmic solution containing Phenyl mercuric acetate

Edetate salts: Incompatible with Zn Insulin, Thiomerosal, Amphotericin & Hydralazine

PreservativesPhenolic Preservatives

-Lente- Insulin + Phenolic preservative Break-down of Bi-sulphide Linkage in Insulin structure.

-Protamine- Insulin + Phenolic preservative tetragonal oblong crystals which is responsible for prolong action of insulin.

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Surface active agents Polysorbate 80:

One must concern about the residual peroxide present in Polysorbate.

PS 80 Polyoxyethylene sorbitan ester of Oleic acid ( Unsatd.F.A)

PS 20 Polyoxyethylene sorbitan ester of lauric acid ( Satd.F.A)

So PS 20 is less prone to oxidation than PS 80.

Cosolvants Sorbitol

Increase the degradation rate of Penicillin in Neutral and Aqueous solutions.

Glycerol Increase the mobility of freeze-dried formulation leading to

peptide deamidation.

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Sr

.

N

o.

DRUG EXCIPIENTINTERACTION

OBSERVED

1.Nicotinamide &

dimethylisosorbide

Propylene-glycol Hemolysis (in vivo effect)

2.

Paclitaxel,

Diazepam,

Propaniddid and

Alfaxalone

Cremophor EL

(polyoxyl 35

castor oil)

Precipitation of Cremophor EL

COSOLVENTS

Sr.

No.DRUG EXCIPIENT INTERACTION

1. Lidocaine Unpurified

sesame oil

Degradation of

lodocaine

2.

Calcium chloride,

phenytion sodium,

tetracycline

hydrochloride

Soybean oil Incompatible with

All.

OIL

S A

ND

LIP

IDS

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DRUG EXCIPIENTINTERACTION

OBSERVED

Proteins Tween 80 and

other

nonionic

polyether

surfactants

Surfactants undergo oxidation and the

resultant alkyl hydroperoxides

formed contribute to the

degradation of protein.

Protein

formulations

Thiols such as

cystiene,

glutawthion

e asnd

thioglycerol

Most effective in stabilizing protein

formulations containing peroxide-

forming surfactants.

SURFACTANTS & CHELATING AGENTS

Dexamathasone,

Estradiol,

Iterleukin-2 &

Proteins and

Peptides

Modified

cyclodextrins,

Solubilize and stabilize drugs without

apparent compatibility problems.

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DRUG EXCIPIENT INTERACTION

N-nitrosourea Tris buffer Form stable complex with N-nitrosourea

and retard the degradation of this agent.

5-flurouracil Tris buffer Tris buffer will degrade 5-flurouracil,

causing the formation of two degradation

products that can cause serious

cardiotoxicities

Chlorpromazine Meta-cresol Incompatible

Recombinant

human interferon

gamma

Benzyl alcohol Benzyl alcohol caused the aggregation of

the protein

Cisplatin Sodium

metabisulfite

Sodium metabisulfite inactivates cisplatin

BUFFERS,ANTIMICROBIALS & ANTIOXIDENTS

JPS 2002, Vol. 91, No. 9-12, page 2283-2296.

REFERENCES

Pharmaceutical Dosage forms By Leon Lachman & Liberman Hand book of Pharmaceutical Excipients Remington’s Pharmaceutical Science,21st edition,2005. Modern Pharmaceutics by Banker & Rhodes,4th edition,2002. Theory and Practice of Industrial Pharmacy by Lachman & Lieberman.

Int. J. Ph.Exci., Vol-1, Jan-2000, 153.

Int. J. Ph.Exci., Nov-2002, 2283

Int. J. Ph.Exci.,jan-march,2003

J. Ph. Sci..,Vol-97, Jan-2007,106

J. Ph. Sci., Vol-95, May-2006, 976.

J. Ph. Sci., Vol-95, May-2006, 1060.

J. Ph. Sci., Vol-95, June-2006, 1342.

J. Ph. Sci., Vol-93, Jan-2004,132

J. Ph. Sci., Vol-93, Nov-2004, 2755.

J. Ph. Sci., Vol-92, May-2003, 516.

JPS 2002, Vol. 91, No. 9-12, page 2283-2296

C.A. vol:146, No:25,June 18 :2007,507180t

C.A. vol:147, No:4, July 23 :2007,79121

CA,Vol:151,No:6, August10,2009 ,131557w

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