SEMINAR ONDRUG 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 Study3. FT-IR Spectroscopy4. DRS-Diffuse Reflectance Spectroscopy5. 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, LactoseoThermal stability was performed on ascorbic acid std.

samples, binary mix. of ascorbic acid & excipients, under N2 & air atmospheres.

oIR & X-Ray Diffractometry: No chemical interactionHowever 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 2 amine 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 Stearate 4.Polysorbate-20 5.Polysorbate-85 6.PEG-40 hydrogenated castor oil 7.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, Lactone

Basic componentEster 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 reactionParabens 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-oxidants Ascorbic acid: Incompatible with acid- unstable drugsNa bisulfite:+ Epinephrine Sulphonic acid dvt.

-Incompatible in Opthalmic solution containing Phenyl mercuric acetate

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

Preservatives Phenolic 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.No.

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 withAll.

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,

glutawthione 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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