DRUG EXCIPIENTS COMPATABILITY STUDIES

BY:Kinjan Mehta

Introduction • Compatibility study is the most important part of any

pre-formulation testing of proposed dosage form, and it is necessary that it should be carried out before the development of first formulation of proposed dosage form with a new drug or new formulation of existing API.

• This is required due to the following reasons:• • Formulation stability studies are time consuming

and expensive• • Need to minimize the number of model formulations• • Provide rational basis for selecting excipients used

in model formulations

Importance of Drug Excipient Compatibility Study:•Stability of the dosage form can be

maximized. •It helps to avoid the surprise problems.• It bridges the Drug discovery and Drug

development. •Drug excipient compatibility study data is

essential for IND (investigational new drug) submission

Goal of drug-excipients compatibility study:• 1.To find out the excipients that are incompatible

with the API• 2.To find out that excipients do not have any impact

on the stability of the API• 3.To find out the excipients that can stabilize the

unstable API• 4.To assign a relative risk level to each excipients

within a functional• 5.To design and develop selective and stability-

indicating analytical methods to determine the impurities, wherein the

• dosage strength difference is very large.

Mechanism of drug-excipients(s) interaction:

•Drug-excipient(s) interaction occurs more frequently than excipient-excipient interaction. Drug-excipients can be classified as:

PHYSICAL CHEMICAL BIOPHARMACEUTICAL

1.Solid dispersion

2.Complexation

3.adsorption

By chemical interaction with the excipent and

API through chemical

degradation pathway.

Designs of traditional excipient compatibility experiments:• Attributes of API Preformulation Profiles:• Prior to the initiation of any solid-state excipient

compatibility testing of a potential drug candidate, it is best to generate a preformulation profile of the API.

• This profile should include pHsolubility profiles, pH-stability profiles, pKa determination, and generation of log P information, as well as knowledge about degradation products formed in the solution state under acidic, basic, oxidative, and oxidative/free radical stress conditions.

Relevant solid-state parameters of the API:•Thermal and thermal/humidity stability• Hygroscopicity• Thermal calorimetric behaviour• Single crystal or crystal packing

information• Particle-size distribution and surface area• Crystal habit and/or amorphous content• Hot-stage polarized light microscopy data• Photostability•Effects of mechanical aggravation

Attributes of Excipients:• Information about excipients is critical in the initial planning

and interpretation of the excipient compatibility results.• The two key parameters of excipients that are important to

the compatibility formulator are:• 1.The ability of the excipients to absorb water at variable

humidity and• 2.The PH of the excipient will impart in the solid-state

• Other key solid-state experimental information useful to gather on the excipients includes:

• Known incompatibilities of excipients• Known stabilization effects of excipients• Reactive impurities in excipients• Mechanical properties of the excipients

Known incompatabilities with functional

group.Functional group Incompatibility Type of reaction

Primary amineMono & Di-

saccharidesAmine-Aldehyde &Amine-Acetal

Ester, Lactone

Basic componentEster base hydrolysis,

Ring opening,

AldehydeAmine,

Carbohydrate

Aldehyde-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

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

INTERACTION WITH CO SOLVENT

Sr.No. DRUG EXCIPIENT INTERACTION

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

Sr.No. DRUG EXCIPIENT INTERACTION

1. Lidocaine Unpurified sesame oil

Degradation of lodocaine

2.

Calcium chloride, phenytion sodium,

tetracycline hydrochloride

Soybean oil Incompatible withAll.

WITH OILS AND LIPIDS

SURFACTANTS AND CHELATING AGENTS

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.

Dexamathasone, Estradiol,

Iterleukin-2 & Proteins and

Peptides

Modified cyclodextrins,

Solubilize and stabilize drugs without apparent compatibility problems.

BUFFERS,ANTIMICROBIALS & ANTIOXIDENTS

Chlorpromazine EXCIPIENT INTERACTION

Recombinant human

interferon gamma

Tris buffer Form stable complex with N-nitrosourea and retard the degradation of this agent.

Chlorpromazine

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

formation of two degradation products that can cause serious

cardiotoxicities

Compatability tests are categorized are:

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.

Typical modalities in compatibility studies:•A) study execution•B) general steps and discussion

Compability studies

Proactive/explatory

retrospective

Binary and ternary

mixtures

N-1 formulatio

ns

Mini formulations

STEPS IN COMPATIBILITY STUDY

There are THREE steps to consider.1. Sample preparation2. Storage 3. Method of analysis

Background info. And literature review

Study design

Sample preparation

Incubation at stressed condition

Analysis and data interpretation

SAMPLE PREPARATION• FOR SOLID STATE REACTIONS:

SampleA: -mixture of drug and excipientSampleB: -SampleA+ 5% moistureSampleC: -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…..

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.

STORAGE CONDITIONThe 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.

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

DSC- DIFFERENTIAL SCANNING CALORIMETRYoMETHOD -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.

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

Trace 5 (Physical mixture of Ofloxacin & Starch) shows an early onset at 268.370C. But no other changes in thermogram. DSC RESULT-- COMPATIBLE

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.

ACCELARETED STABILITY STUDY

o Different formulations of the same drug are prepared.

o Samples are kept at 40ºC / 75 % RH.

o Chemical stability is assessed by analyzing the drug content at regular interval.

o Amt. of drug degraded is calculated.

o % Drug decomposed VS

time(month) is plotted.

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.

• 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)

TLC AND HPTLC

oTLC is generally used as confirmative test of compatibility after performing DSC.

oS.P. consist of powder (Silica, Alumina, Polyamide, Cellulose & Ion exchange resin) adhered onto glass, plastic or metal plate.

oSolution of Drug, Excipient & Drug: Excipient mixture are prepared & spotted on the same baseline at the end of plate.

oThe plate is then placed upright in a closed chamber containing the solvent which constitutes the M.P.

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.

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

INCOMPATIBLE IMPURITIES

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

• Eg. DCP- sometimes iron may be present in DCP as impurities and it is incompatabile with MECLIZINE HCL (NMT 0.04%)

• HYDROPEROXIDES (HPO): evaluation of HPO in ommon pharmaceutical execipients:

• Polydone• PVC• Polysorbate 80• HPC

Contains substantial conc. Of HPO with

significant bacth to batch or manufacturer to

manufactuer variatians

•While MCC, lactose, high mol.wt. PEG contains less amount of HPOS.

•5% PVP was shown responsible for n- oxide formation rafloxicin HCl due to high HPO content.

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