PREFORMULATION STABILITY STUDIES

PRESENTED BY KADRI MOHAMMED PAYAM DEPT OF PHARMACEUTICS 1st M.MPHARM

INTRODUCTION

Stability is defined as the extent to which the drug substance retains within the specified limits throughout its storage period.

Preformulation stability studies are usually assessment of chemical stability of a new drug. These studies are conducted under condition typical for the handling, formulation, storage and administration of the drug candidate.

PURPOSE

To develop a stable dosage form To establish expiry date To study drug decomposition kinetics and to know more about the degraded products To collect the long term(12months) , intermediate (12months) and accelerated stability data (6 months)

To have an idea of what excipients to use, and how best to put them together with drug.
To know that no toxic substance are formed

Consequently, the preformulation scientist must try to define those study designs and condition that show the greatest probability of success. Therefore, the objective of preformulation stability program is to identify and help to avoid or control situation where the stability of the active ingredient may be compromised.

For drug substance to be developed in to tablet dosage form, this objective may be achieved by investigating the stability of the drug under the following three categories

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Solid state stability of the drug Compatibility studies (stability in the presence of excipients ) Solution phase stability.( including stability in gastrointestinal fluids and granulating solvents)

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SOLUTION STABILITY

The primary objective of this phase of preformulation resarch is to identify conditions necessary to form a stable solution. This includes effects of pH, ionic strength, co-solvent, light, temperature and oxygen on solution. In this experiments are carried out at the extremes of temp and pH (0.1N HCL and 0.1N NaOH at 900 C )and the degraded samples are used to confirm assay specificity and provide estimates for maximum rates of degradation.

This intial expriment should be followed by the generation of a complete pH-rate profile to identify the pH of maximum stability. Aqueous buffer are used to produce solutions over wide range of pH values with constant level of drug, cosolvent and ionic strength. Since most solution pharmaceuticals are intended for parental routes of admistration. For parenteral route pH studies are conducted at a constant ionic strength that is compactable with the physiological medium.

Ionic strength for any new buffer solution may be calculated from the following equation.

Ionic strength () = m1z12

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Where, m1 molar concentration of the ion, z1 valency, In the solution, stability studies are carried out for : Cosolvents pH profile rate

COSOLVENTS

Cosolvents may be needed to achieve drug concentration that are necessary for analytic sensitivity, or to produce a defined initial condition. Stability solutions produced are placed in flint glass ampoules(sealed) and stored at constant temperatures. Some of the ampoules may be stored at variety of temperatures to provide data for calculating activation energies.

Light sensitive sample solution samples may be stored in amber and yellow green glass container. Potential for oxidation is intially unknown, some of the solution samples should also be subjected to further testing

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With an excessive headspace of oxygen, With a headspace of an inert gas such as helium or nitrogen, With inorganic antioxydant such as sodium metabisulphate, With organic antioxydent such as butylated hydroxy toluene-BHT.

pH RATE PROFILE

Stability data generated at each pH and temp are analyzed kinetically to yield apparent decay rate constant (k) . Arrhenius plot is constructed by plotting log k Vs reciprocal of absolute temp at which each particular buffer solution was stored during stability test. Shelf life can be obtained from appropriate kinetic equations Eg : for 1st order decay process t10% = -ln 0.90/k1 = 0.105/k1 Where t10% is the time for 10% decay

Solutions undergo accelerated decompositions upon addition of acids or bases. These are catalysed by hydrogen or hydroxyl ions. Ex: pH profile rate of acid base catalysed hydrolysis of methyl-o-phenyl-2-piperidylacetate.Here at pH 1-3 there is a decrease in rate due to hydrogen ion catalysis. At pH 3-7 there is increase in rate due to hydroxyl ion catalyst.

SOLID STATE STABILITY

Objective is to find out a stable storage conditions and identification of compactable excepients for formulation Solid state stability refers to physical as well as chemical stability. Pharmaceutical solid degrade as a result of solvolysis, oxidation, photolysis and pyrolysis. The mechanisms of solid state degradation are complex and difficult to elucidate.

The common factors that cause solid state reactions are heat, light, oxygen and moisture. Various approaches for solid state state stability include: Elevated temperature studies Stability under high humidity conditions Stability to oxidation,hydrolysis Photolytic stability

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ELEVATED TEMPERATURE STUDIES

These samples are stored at higher temperatures and should be examined for physical and chemical changes at frequent intervals and any change, when compared to an apropriate , should be noted. Substantial changes is seen,samples stored at lower temperatures are examined. If no changes seen after 30 days at 600c, the stability is excellent.

This data obtained is extrapolated using the Arrhenius treatment to determine rate of degradation at low temperatures. Here logarithm of rate constant is plotted against reciprocal of absolute temperature. The plot is extrapolated to obtain the rate constant.

Example: Ergot alkaloids degrade completely within a year when stored above 45C and the rate is less than 1% per year below 35C.

STABILITY UNDER HIGH HUMIDITY

In the presence of moisture, many drug substances hydrolyze, react with excipients,or oxidize. Controlled humidity conditions are obtained using desiccators containing saturated solutions of various salts. The closed desiccators are placed in oven to provide a constant temperature. If the humidity doesnt effect the drug stability, then Arrhenius plot is used to produce the shelf life.

If humidity affects drug stability, then stability data obtained at various humidity's may be linearised with respect to moisture by:

KH = [gpl].K0

Where [gpl] is the concentration of water in atmosphere in grams per liter. K0 is the decay rate constant at zero relative humidity.

STABILITY TO HYDROLYSIS

The most likely causes of drug instability is hydrolysis.

Drugs, which are susceptible to hydrolysis are: Penicillin's, Cephalosporin's, Aspirin, Chlormphenicol, Esters, Lactams and Amides. Examples CLASS EXAMPLE

Ester Amide Lactum Lactone Sulphonamide

Aspirin Chloramphenecol Methicillin Spironolactone Sulphapyrazine

The use of anhydrous vegetable oils, reduce the chance of hydrolytic decomposition Decomposition can be prevented in solution forms by suspending in non-aqueous vehicle rather than dissolving by them in aqueous solvent Storage under refrigeration is advisable for most preparations considered unstable due to hydrolysis For hydrolysable drug the pH of optimum stability is between pH 5 and 6

STABILITY TO OXIDATION

This test must be evaluate to establish if the final product should be packaged under inert atmospheric condition and if should contain an antioxident. Oxidative reactions are influenced by light and metal ions. Auto-oxidation is a common form of oxidative degradation which involves free radical mechanism. Antioxidants are used to overcome this problem some of them are sodium sulphite,ascorbic acid,butylhydroxyanisole.

Samples are stored in large 25 ml vials for injection, capped with Teflon lined rubber stopper and the head space flooded with dry oxygen. To confirm that the decay is caused by oxidation only and not due to reduced humidity another set of vials flooded with dry atmospheric nitrogen is used. These samples are than analyzed for chemical stability, polymorphic changes and discoloration

PHOTOLYTIC STABILITY

Many drug substance fade or darken on exposure to light. It can be readily controlled by using amber glass or opaque container or by using dye to mask the discoloration.

Drugs that are prone to photolysis reaction are ascorbic acid,sulphonamide,steroids.

Flint glass absorbs at 80% in 290-320nm and amber glass absorbs more than 95%.

DETERMINATION OF SOLID STATE STABILITY OF A NEW DRUG

The weighed samples are place in open screw capped vials and are exposed directly to various temperatures, humidity's and light intensities for up to 12 weeks . Samples usually consist of three 5-10 mg weighed samples at each data point for HPLC analysis and approximately 10-50 mg of sample for polymorph evaluation by differential scanning calorimetry of IR All these can be overcome by following ways: The stability of Penicillins can be increased by reducing its solubility, by using additives like citrates, dextrose, sorbitol etc.

Drugs, which are susceptible to acid base catalyzed hydrolysis, can be stabilized by determining the pH of maximum stability and by formulating the product at that pH. By using insoluble salt form of a solid dosage form or preparation of oral liquid dosage form by replacement of water by some other non aqueous solvents such as polyhydroxy alcohols. Eg: Acetaminophen solution contains high proportion of sorbitol and propylene glycol.

COMPATIBILITY STUDIES

Stability in presence of excipients.

A typical tablet contain binders, disintegrants, lubricants, and diluents.

In tablet compatibility of drug and excipient will depend on the nature of the excipient, and size and the potency of the tablet For eg:- Compound with bulk instability at high humidity should be formulated with anhydrous excipients. Similarly , pH of maximum stability should match with pH of aqueou solution of the drug and excipient.

The three techniques commonly employed in drug - excipient compatibility screening are Chromatographic techniques using either HPLC or TLC

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Differential thermal analysis

Diffuse reflectance spectroscopy

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CHROMATOGRAPHIC TECHNIQUES

Drug and excipients mixture are granulated with water and solvented at elivated temperature. Granulation is carried out so that mixture contain fixed amount of moisture at elevated temperatures. The samples are examined periodically for appearance and analyzed for any decomposition using HPLC and TLC.

DIFFERENTIAL THERMAL ANALYSIS

In this 5mg of drug is taken in a 50% mixture with excipient. It should be observed in presence of nitrogen to avoid oxidative and pyrrolytic effects at a standard heating rate on DSC apparatus.

Drug

No Interaction 50% Mixture DSC

Interaction Excipient TLC

Recommend Excipients

No

Alternate Excipients

Yes

Significant Breakdown?

DIFFUSE REFLECTANCE SPECTROSCOPY

Detect and monitor drug excipient interaction. Exposed to incident radiation Partly absorbed and partly refelected in a diffuse manner. Diffuse reflectance spectroscopy is used to investigate physical chemical changes occurring on a solid surfaces. A shift in the diffuse reflectance spectrum of the drug due to the presence of the excipients indicates physical absorption where as the appearnce of new peak indicates formation of degradation product.

REFERENCES :
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Lachman L, Liebermann HA, Kanig JL. The theory and practice of industrial pharmacy. 3rd edition. Bombay, Varghese publishing house;1991P. Liebermann HA, Lachman L, Schwartz JB. Pharmaceutical dosage forms:Tablets vol one. 2nd ed. New york.Basel: Marcel Dekker,Inc;2005.p. 43-7 Banker S.G. and Rhodes T.C., Modern p. Modern Parmaceutics 4th Edn, Marcel Dekker, Inc. New York, Vol. 121, p.178-82 http://books.google.co.in/books?id=RQJq3aosg34C&pg=PA4&l pg=PA4&dq=example+for+a+drug+undergone+preformulation+ stablity+studies&source=bl&ots=R1FgUB1Cpl&sig=b7U_XVX 6IfObgtKSWpUZaChTn5c&hl=en&ei=LaJ_SreuMMqAkQXo9mGAw&sa=X&oi=book_result&ct=result&resnum=7#v=onepa ge&q=&f=false[cited on 2009 aug10]

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THANK