pre formulation stability studies

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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 bestto put them together with drug.

To know that no toxic substance are formed



Consequently, the preformulation scientist must try todefine those study designs and condition that show the

greatest probability of success.

Therefore, the objective of preformulation stabilityprogram 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



1. Solid state stability of the drug

2. Compatibility studies (stability in the presence of

excipients )

3. Solution phase stability.( including stability in

gastrointestinal fluids and granulating solvents)



SOLUTION STABILITY

The primary objective of this phase of preformulationresarch is to identify conditions necessary to form astable solution. This includes effects of pH, ionicstrength, 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 90

0

C )andthe degraded samples are used to confirm assayspecificity 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, cosolventand ionic strength.

Since most solution pharmaceuticals are intended forparental routes of admistration.

For parenteral route – pH studies are conducted at aconstant ionic strength that is compactable with thephysiological medium.



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

Ionic strength () = ½ m1z1

2

Where,

m1 – molar concentration of the ion,

z1 – valency,

In the solution, stability studies are carried out for :

1. Cosolvents

2. pH profile rate



COSOLVENTS

Cosolvents may be needed to achieve drugconcentration that are necessary for analytic sensitivity,or to produce a defined initial condition.

Stability solutions produced are placed in flint glassampoules(sealed) and stored at constant temperatures.

Some of the ampoules may be stored at variety of temperatures to provide data for calculating activationenergies.



Light sensitive sample solution samples may be stored in

amber and yellow green glass container.

Potential for oxidation is intially unknown, some of thesolution samples should also be subjected to further testing

1. With an excessive headspace of oxygen,

2. With a headspace of an inert gas such as helium or

nitrogen,3. With inorganic antioxydant such as sodium

metabisulphate,

4. With organic antioxydent such as butylated hydroxy

toluene-BHT.



pH RATE PROFILE

Stability data generated at each pH and temp are analyzedkinetically to yield apparent decay rate constant (k) .

Arrhenius plot is constructed by plotting log k Vs

reciprocal of absolute temp at which each particular buffersolution was stored during stability test.

Shelf life can be obtained from appropriate kinetic

equationsEg : for 1st order decay process

t10% = -ln 0.90/k 1 = 0.105/k 1

Where t10% is the time for 10% decay



Solutions undergo accelerated decompositions uponaddition 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 ioncatalyst.



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:

1. Elevated temperature studies

2. Stability under high humidity conditions

3. Stability to oxidation,hydrolysis4. Photolytic stability



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 Arrheniustreatment to determine rate of degradation at lowtemperatures.

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 45°C and the rate is less than 1% per yearbelow 35°C.



If humidity affects drug stability, then stability data obtainedat various humidity's may be linearised with respect tomoisture by:-

KH = [gpl].K0

Where [gpl] is the concentration of water in atmosphere ingrams per liter.

K0 is the decay rate constant at zero relativehumidity.



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, Lactamsand Amides.

ExamplesCLASS EXAMPLE

Ester Aspirin

Amide ChloramphenecolLactum Methicillin

Lactone Spironolactone

Sulphonamide 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 productshould 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 degradationwhich 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 STATESTABILITY OF A NEW DRUG

The weighed samples are place in open screw capped vials and areexposed directly to various temperatures, humidity's and lightintensities for up to 12 weeks .

Samples usually consist of three 5-10 mg weighed samples at eachdata point for HPLC analysis and approximately 10-50 mg of sample for polymorph evaluation by differential scanningcalorimetry of IR

All these can be overcome by following ways:

The stability of Penicillins can be increased by reducing itssolubility, 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

1. Chromatographic techniques using either HPLC or TLC

2. Differential thermal analysis

3. Diffuse reflectance spectroscopy



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

50% Mixture

Excipient

DSC

NoInteraction

Interaction

TLC

SignificantBreakdown?

YesAlternateExcipients

No

Recommend

Excipients



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 :

1. Lachman L, Liebermann HA, Kanig JL. The theory and practiceof industrial pharmacy. 3rd edition. Bombay, Varghese publishinghouse;1991P.

2. Liebermann HA, Lachman L, Schwartz JB. Pharmaceutical

dosage forms:Tablets vol one. 2

nd

ed. New york.Basel: MarcelDekker,Inc;2005.p. 43-7

3. Banker S.G. and Rhodes T.C., Modern p. Modern Parmaceutics4th Edn, Marcel Dekker, Inc. New York, Vol. 121, p.178-82

4. http://books.google.co.in/books?id=RQJq3aosg34C&pg=PA4&lpg=PA4&dq=example+for+a+drug+undergone+preformulation+stablity+studies&source=bl&ots=R1FgUB1Cpl&sig=b7U_XVX6IfObgtKSWpUZaChTn5c&hl=en&ei=LaJ_SreuMMqAkQXo-9mGAw&sa=X&oi=book_result&ct=result&resnum=7#v=onepage&q=&f=false[cited on 2009 aug10]



THANK

U

pre formulation stability studies

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