Drug excipient compatibility

SEMINAR ONDRUG EXCIPIENT COMPATIBILTY STUDY

(As a part of preformulation study)

PREPARED BY

NISARG PATEL

(M.PHARM-SEM-I)

DEPARTMENT OF PHARMACEUTICS & PHARMACEUTICAL TECHNOLOGY

SMT.B.N.B SWAMINARAYAN PHARMACY COLLEGE,SALVAV-VAPI

SMT.BNB SWAMINARAYAN PHARMACY COLLEGE,VAPI 1

INCOMPATIBILITY DEFINATION - When we mix two or more API and / or excipient with each other & if they are antagonistic & affect adversely the safety, therapeutic efficacy, appearance or elegance then they are said to be incompatible.

Types Of Incompatibility Physical incompatibility:- It involves the change in the physical form of the formulation which involves color changes, liquefaction, phase separation or immiscibility.

Chemical incompatibility:- It involves undesirable change in formulation which is due to formation of new chemical comp. with undesirable activity or our formulation undergoes hydrolysis, oxidation, reduction, precipitation, decarboxylation, racemization.



Therapeutic incompatibility:- It is type of in vivo compatibility. It involves change in therapeutic response of the formulation which is undesirable to patient as well as physician.

OBJECTIVES:

Drug: active part of dosages form and it is mainly responsible for therapeutic value.

Excipient:substances which are included along with drugs being formulated in a dosage form so as to impart specific qualities to them.

Incompatibility- general aspects

►inactivation of drug through either decomposition or loss of drug by its conversion to a less favorable physical or chemical form.

►It affects safety, therapeutic efficacy, appearance or elegance.

►When we mix two or more API and / or excipient with each other & if they are antagonistic & affect adversely the safety, therapeutic efficacy, appearance or elegance then they are said to be incompatible.

COMPATIBILITY TESTS Aspects of compatibility tests are:

1. Identification of compatible excipients for a formulation.

2. Identification of stable storage conditions

Types:1. Solid state reactions:

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

- easier to detect- The Stability Guidelines by FDA following conditions should be evaluated for solutions or suspensions1. Acidic or alkaline pH.2. Presence of added substances3. High oxygen and nitrogen atmospheres.4. Effect of stress testing conditions.


STEPS IN COMPATIBILITY STUDYThere are THREE steps to consider.

1. Sample preparation2. Storage 3. Method of analysis


SAMPLE PREPARATION FOR SOLID STATE REACTIONS:SampleA: -mixture of drug and excipientSampleB: -SampleA+ 5% moistureSampleC: -Drug itself without excipients

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

Then sample is physically observed . It is then assayed by TLC or HPLC or DSC.Whenever feasible, the degradation product are identified by MASS SPECTROSCOPY, NMR or other relevant analytical techniques.

To determine Solid state stability profile of a new compound….To test the Surface Oxidation……


SAMPLE PREPARATION

FOR LIQUID STATE REACTIONS:oPlace the drug in the solution of additives.oBoth flint and amber vials are used.oThis will provide information about

-Susceptibility to oxidation. -Susceptibility to light exposure.

-Susceptibility to heavy metals.

oIn 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

COMPATIBILITY1. 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 CALORIMETRY

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

oMETHOD -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


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


Trace 9 (Physical mixture of Ofloxacin & Talc) shows combine features of each component but there are evident changes in onset. DSC RESULT-- COMPATIBLE



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.

LIMITATIONS OF DSCoIf thermal changes are very small, DSC can’t be used.oDSC can not detect the incompatibilities which occur after long term storage.

Eg. MCC / ASPIRIN… oNot applicable if test material exhibits properties that make data interpretation difficult.

oADVANTAGES:-Fast-Reliable and very less sample required.



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.

TLC AND HPTLCoTLC is generally used as confirmative test of compatibility after performing DSC.

oStationary Phase 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.


TLC AND HPTLCAny 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.


INCOMPATIBLE IMPURITIES

oChemical impurity profiles -Very important in influencing the long term chemical

stability.

Eg:-

(1) Evaluation of Hydroperoxides ( HPO) in common pharmaceutical excipients.

POVIDONE It all 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.

o5% PVP responsible for N-oxide formation of Raloxifen HCl, due to high HPO content.



(2)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 excipientsop-Glycoprotein is membrane associated transport protein. It is an efflux pump lies in

tissue membranes.

oSome 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



Known IncompatibilitiesFunctional group Incompatibility Type of reaction

Primary amine Mono & Di-saccharides Amine-Aldehyde &Amine-Acetal

Ester, Lactone Basic component

Ester base hydrolysis, Ring opening,

Aldehyde Amine, Carbohydrate Aldehyde-Amine, Schiff base Or Glycosylamine formation

Carboxyl Base Salt formation

Alcohol Oxygen Oxidation 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 reducedPhenol, Tannic acid &Salicylic acid

Softening & Liquifaction

Sulphonamide & Dithranol DiscolorationFilm coating Migration of PEG from tablet film

coating, leading to interaction with core component

DRUG EXCIPIENT COMPATIBILTY STUDY IN AEROSOLS

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

oPropellent 11 is trichloromonofluoromethane.

oHCl corrodes the Al-container.



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.


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.

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.


Surface active agentsPolysorbate 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.



Sr.No.

DRUG EXCIPIENT INTERACTIONOBSERVED

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

CO

SOL

VE

NT

S

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


DRUG EXCIPIENT INTERACTIONOBSERVED

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,

glutawthio and

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.


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

REFERENCES

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


o Write a note on Drug Excipient compatibility study

oElaborate the necessity of drug-excipient compatibility study with examples.Discuss how it is carried out.

oExplain the importance of Drug-excipient compatibility


QUESTION BANK


Date post:	14-Apr-2017
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Drug excipient compatibility

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