Drug-Excipient Compatibility Studies

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DRUG – EXCIPIENT COMPATIBILITY STUDY [ PREFORMULATION STUDIES ]

CONTENTS: 

CONTENTS Objectives Types of Incompatibilities Definition Compatibility Tests Techniques for compatibility testing Chromatography Differential Thermal Analysis How to read Thermo gram ? Fluorescence measurement Diffuse Reflectance Spectroscopy Vapour pressure Osmometry Radiolabelled Technique Accelerated Storage Testings Incompatibility in Dosage forms Influence of Excipient on Antiseptic power of some Ointments Drug – Excipient Interaction in Parenteral formulation Preformulation studies – expected outcomes References

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Stable formulation And to provide Bio available dosage form The objectives of preformulation

Incompatibilities: 

Incompatibilities Physical incompatibility Chemical incompatibility Therapeutical incompatibility

Definition of …………………. : 

Definition of …………………. Incompatibility : Physical Chemical Therapeutical . Physical Incompatibility : Chemical Incompatibility : Therapeutical Incompatibility :

Molecular constant B/W API and Excipients: 

Molecular constant B/W API and Excipients Compatibility Tests :- Compatibility test for Solid dosage form Compatibility test for Liquid dosage form Aqueous solution compatibility Non-Aqueous solution compatibility

The Seven techniques commonly employed in Drug Excipient compatibility screening are :-: 

The Seven techniques commonly employed in Drug Excipient compatibility screening are :- Chromatography Differential Thermal Analysis Fluoroscence Measurement Spectroscopy Vapour Pressure Osmometry Radio Labelled Techniques Accelerated Storage Testing

The ratio of Drug : Excipient used in preformulation study: 

The ratio of Drug : Excipient used in preformulation study Van Dooren recommends ratio For Diluents 1:5 For Binder & Disintegrants 3:1 For Lubricant 5:1 For colourant 10:1 In present study a 1:1 ratio is used

Chromatography in Drug Excipient interaction studies: 

Chromatography in Drug Excipient interaction studies Any decomposition/ changes,if occurs then it is detected by HPLC or TLC. Changes in the chromatograph such as appearance of NEW SPOT or change in R f values or R t If significant interaction is noticed……………………

Advantages of HPLC or TLC: 

Advantages of HPLC or TLC Evidence of degradation. Spots or peaks isolation. Quantification to obtain Kinetic data. Example : Fluoxetine HCl + Spray dried Lactose N – formyl fluoxetine ( Maillard reaction)

Differential Thermal Analysis in D-E interaction studies: 

Differential Thermal Analysis in D-E interaction studies Advantage is it’s rapidity useful in Eutectics and other phase formulations. Thermo grams are generated for the pure components & their 1:3,1:1,3:1 physical mixture.

How to read Thermo gram ?: 

How to read Thermo gram ? In the event that indicates interaction…………………….. By the appearance of one or more new peaks or the disappearance of one or more peaks corresponding to those of the components. Example : Trimetazine HCl (TMZ) with commonly used tablet excipient like : Talc , DCP , Starch , Lactose , Stearic acid & Mg- Stearate . ( Ind. Drugs,2002,89,138)

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A comparative study of thermograms of Ofloxacin and it’s mixtures with selective Tablet excipient showed it to be compatible with Starch , talc , where as the study showed definite incompatibility with Lactose , Mg-stearate and PVP . (Int.J.of P’ceutical Excipient 2002,Vol.1,97)

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A comparative study of thermograms of Metoprolol and it’s mixtures with selective Tablet excipient showed it to be compatible with Eudragit , Aerosil , MCC , where as the study showed definite incompatibility with Stearic acid , Mg-stearate , Lactose , Primogel . (Ind.Drugs,1995,32,25)

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A comparative study of thermograms of Lomefloxacin and it’s mixtures with selective Tablet excipient showed it to be compatible with Lactose , DCP , Mg-stearate where as the study showed definite incompatibility with PVP K-30 , EC , SSG , MCC powder , Aerosil , NaCMC . (Int.J.of P’ceutical Excipient 2003,Vol.2,38)

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A comparative study of thermograms of Lamotrigine and it’s mixtures with selective Tablet excipient showed it to be compatible with Starch , Talc , MCC , EC , Mg-stearate and DCP where as the study showed definite incompatibility with Lactose . (Ind.Drugs,1995,32,25)

Fluorescence measurement :-: 

Fluorescence measurement :- This technique is restricted to those compounds,which can generate Fluorescence As the number of such compounds restricted,this method is used in Analysis and not in preformulation.

Diffuse Reflectance Spectroscopy in D-E interaction studies: 

Diffuse Reflectance Spectroscopy in D-E interaction studies Principle :- Physical mixtures are exposed to incident radiation, A portion of the incident radiation is partly absorbed and partly reflected in the Diffuse manner. Factors that are adequately controlled :- Packing density of the solid, Partical size, It’s crystal form.

A shift in the DRS indicates physical absorption, where as the appearance of a new peak indicates Chemisorptions or formation of degradation product.: 

A shift in the DRS indicates physical absorption, where as the appearance of a new peak indicates Chemisorptions or formation of degradation product. The method of preparation of the D-E mixture is very critical……. Lach and co workers used this technique for detection of interaction B/w Isoniazid with magnesium oxide and with Lactose at elevated temperatures.

Vapour pressure Osmometry :-: 

Vapour pressure Osmometry :- Principle : Solution of Sample and pure solvent are introduced in to a temperature controlled enclosure, which is saturated with solvent vapour . Since the Vapour pressure of solution is lower than that of solvent, solvent Vapour condenses on solution sample causing its temperature to rise. The temperature rise is predicted by Clausis – clapcyron equation. dlnP / dT = H vap /RT 2

Conditions :- Either Liquid or Solid must be soluble in organic Solvent or in water Sample must not undergoes association in solution. Sample size : 3gms: 

Conditions :- Either Liquid or Solid must be soluble in organic Solvent or in water Sample must not undergoes association in solution. Sample size : 3gms Example :- Sulphathiazole sodium & PVP K25 , PVP K90

Radiolabelled Technique :-: 

Radiolabelled Technique :- Highly sensitive method but the cost of carring out the method ,as well as the availability of well established other techniques and methods,this method is generally not prefered. It is important when the API is radio active. Method is carried out by using either 3 H or 13 C.

Accelerated Storage Testings :-: 

Accelerated Storage Testings :- More data in shorter time. Elimination of Unsatisfactory formulation early. Reduces the time for reaching the market by a successful product.

Objectives :-: 

Objectives :- Rapid detection of deterioration.

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Prediction of shelf life. To ensure that no unexpected changes has occurred. Common high stress are : Temperature Humidity Light

Example :- Maillard type condensation reaction.: 

Example :- Maillard type condensation reaction. Sorbitol ( Hygroscopic_at 65%humidity) Calcium carbonate incopatible with acidicdrugs , also with Tetracyclines . Degradation of Cephalothin sodium, Benzylpenicillin potassium Lactose (Aldehyde group) # 1 0 and 2 0 amines Freeze dried preparation

Residual moisture content may affect the stability of solid dosage form and powders. : 

Residual moisture content may affect the stability of solid dosage form and powders. Amorphous excipient crystalline form. The expelled water becomes available to react with API. INSTABILITY HOH of Methyl predinisolone Na saccinate with mannitol

INCOMPATIBILITY IN DOSAGE FORMS.: 

INCOMPATIBILITY IN DOSAGE FORMS. Sr. No. DRUG EXCIPIENT INTERACTION OBSERVED 1. Catecholamines Air and other oxidants Oxidation of Catecholamine 2. Any drug Metal ions Catalyze decomposition 3. Hydrocortisone Cupric ions Ketol (O) Glyoxal 4. Corticosteroids Trace metals Catalysis oxidative degradation 5. Ester or acyl compound 1 0 or 2 0 amines, alcohols, phenols Transacylation reaction

INFLUENCE OF EXCIPIENTS ON ANTISEPTIC POWER OF SOME OINTMENTS: 

INFLUENCE OF EXCIPIENTS ON ANTISEPTIC POWER OF SOME OINTMENTS Phenyl mercuric borate,Demiphen Powerful Bacteriostatic against S.aureus In presence of Cationic detergent bacteriostatic power increases. e.g.Formaldehyde, Boric acid with bradosol, Phenol with desogene. Anionic detergent increases the diffusion of the Antiseptic while non – ionic detergents decreased it.

Drug – Excipient Interaction in Parenteral formulation: 

Drug – Excipient Interaction in Parenteral formulation Excipients are added to parenteral formulation :- Solubilizers, Stabilizers, Tonicity agents. Control Drug delivery. Positive interaction b\w Drug & Excipient. Negative interaction Loss of solubility, Stability, bioavaibility.

Some formulation related problems :-: 

Some formulation related problems :- IV Drug delivery includes Hemolysis, Precipitation, Phlebitis and pain. Scientist must concentrate on Physical,Chemical – in vitro,as well as therapeutical – in vivo.

Surfactants :-: 

Surfactants :- Sr. No. Drug Excipient Interaction observed 1. Hydrophobic protein (humicolalanuginosa lipase) Tween 20 Precipitation of proteins 2. Proteins Tween 80 &other non ionic polyether surftants Degradation of proteins through oxidation

Co-Solvents :-: 

Co-Solvents :- Sr. No. Drug Excipient Interaction observed 1. Peptide containing drug Glycerol Peptide deamination 2. Penicillins Sorbitol Degradation rate increases 3. Nicotinamide & dimethyl isosorbide PG Hemolysis(in vivo effect)

Complexing & Chelating agents :-: 

Complexing & Chelating agents :- Sr. No. Drug Excipient Interaction observed 1. Dexamethasone,Estradiol Modified Cyclodextrins Increased solubility 2. Un identified wter soluble drug HP ß-Cyclodextrin &Sulfobutyl ether ß-Cyclodextrin Degradation of drug to its insoluble degrant form

Buffers :-: 

Buffers :- Sr. No. Drug Excipient Interaction observed 1. Minodronic acid Citrate & Tartarate Maintain both Physical & Chemical stability 2. N- nitroso Urea Tris buffer Incease stability 3. Peptide formulation Tris buffer Degrade to librate formaldehyde 4. 5 – Fluorouracil Tris buffer Enhance the degradation,serious cardiotoxicities

Antioxidants :-: 

Antioxidants :- Sr. No. Drug Excipient Interaction observed 1. Uracil type molecules Sodium Bisulfite Causes ester hydrolysis 2. Zinc insulin,thiomersal, amphotericin and hydralazine HCl Edetate salts Incompatible with all.

Antimicrobial Preservative :-: 

Antimicrobial Preservative :- Sr. No. Drug Excipient Interaction observed 1. Chlorpromazine Meta Cresol Incompatible 2. Recombinant human interferon gamma Benzyl alcohol Aggregation of protein 3. Insulin zinc suspension Phenol Destroy the Crystals 4. Neutral protamine insulin (NPH) Phenol Form tetragonal oblong crystals

Preformulation studies – expected outcomes: 

Preformulation studies – expected outcomes The product will: Meet specifications, including for assay, impurities & dissolution rate Be consistent within & between batches Have optimum chemical & physical stability Can be manufactured for the minimum cost consistent with quality As far as possible, is palatable to the patient Development costs are minimised: - Fewer formulations fail stability & BA studies

References :-: 

References :- Encyclopedia of P’ceutical technology, Vol. 19, pg 31~39 Pharmaceutics :The science of dosage form design by Michael E. Aulton J.L.Lach & L.D.Bighley, JPS 1970, 59, No.9, 1261~1264 J.Pharm.Sci.1982, 71, No.9, 1021~1026 Int.J.Pharm.2000, 149 Pg-141 J.Pharm.Sci.1998, 87, No.1,31~33 J.Pharm.Sci.191972, 61, 1770~1775 Indian Drugs 2002,Vol.39, No.3, 138~147 J.Pharm.Sci.2001, 90, 1, 79~88 Modern P’ceutics by Banker & Rhodes 3 rd Edi. 1996 J.Pharm.Sci. 1972, Vol. 60, pg 339~345 J.Pharm.Sci. 1952, Vol. 4, pg 418~419 J.Pharm.Sci. 1982, Vol. 71, pg 1193~1198 J.Pharm.Sci. 2002, Vol. 91, pg 2283~2296 Drug Development & Industrial Pharmacy 1998, Vol. 24, No.8

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