Drug and Product Stability


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By: katteanupama (25 month(s) ago)

Thank u Mr. Rajkiran and it wud b sent to the asked mail id soon.

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excellent presentation. madem please send the this stability ppt. thrinadh_81@rediffmail.com

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Drug and Product Stability: 

Drug and Product Stability Presented by: K. Anupama M. Pharm [Q.A], 1 st yr S.G.V.U, Jaipur


STABILITY Stability is defined as the capacity of a drug substance or drug product to remain within the established specifications to maintain its identity, strength, quality and purity through out the retest or expiration dating period.

Objective of stability studies in Preformulation: 

Objective of stability studies in Preformulation The objective of stability study is to determine the shelf life, namely the time period of storage at a specified condition within which the drug product still meets its established specifications.


WHY STABILITY STUDY IS DONE? Stability is an essential factor of quality, safety and efficacy of a drug product. A drug product, which is not of sufficient stability, can result in changes in physical features (like hardness, dissolution rate, phase separation etc) as well as chemical characteristics (formation of high risk decomposition substances). The Chemical stability of drug is of great importance since it becomes less effective as it undergoes degradation. Also drug decomposition may yield toxic by products that are harmful to the patient. Microbiological instability of a sterile drug product could also be hazardous.

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Stability evaluation of drug substance or drug product is the key to drug quality as it determines the efficacy of any drug or dosage form. Stability assessment of drug products and drug substances are mandated by regulatory agencies across the globe. In fact, stability-testing issues are responsible for a number of audit findings by regulatory agencies. Stability testing problems are regularly cited in warning letters and sometimes results in costly product recall.

Importance of Stability Study: 

Importance of Stability Study Stability testing provides evidence that the quality of drug substance or drug product changes with time under the influence of various environmental conditions such as temperature, relative humidity etc. The stability study consists of a series of tests in order to obtain an assurance of stability of a drug product, namely maintenance of the drug product packed in it specified packaging material and stored in the established storage condition within the determined time period.

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Wherever possible the commercial pharmaceutical product should have a shelf life of 3 years. The potency should not fall below 95% under the recommended storage conditions and the product should still look and perform as it did when first time manufactured. The intrinsic stability of the drug helps to advice on ; Formulation approaches Types of excipients Specific protective additives Packaging

Stress conditions used in preformulation stability assessment: 

Stress conditions used in preformulation stability assessment Test Conditions SOLID Heat 4,20,30,40,40/75%RH,50 and 75 Moisture uptake 30,45,60,75 and 90% RH at RT Physical stress Ball milling AQUEOUS SOLUTION pH 1,3,5,7,9 & 11 at RT & 37 C. Reflux in 1M HCl &1M NaOH Light UV(254&366nm) and Visible(south facing window) at RT Oxidation Sparging with oxygen at RT;UV may accelerate breakdown.

Drug Degradation : 

Drug Degradation Drug degradation occurs by four main processes : Hydrolysis Oxidation Photolysis Trace metal catalysis

Various factors affecting drug stability : 

Various factors affecting drug stability The various factors affecting drug stability are as follows; Temperature Order of reaction Hydrolysis The influence of pH Solvolysis Oxidation Chelating agents Photolysis Solid state stability Hygroscopicity

1.Temperature : 

1.Temperature Thermal effects are superimposed on all 4 degradation chemical processes. Typically a 10 º C increase in temperature can produce a 2-5 fold increase in decay. Often the increase in reaction rate with temperature follows an Arrhenius type relationship: a plot of the log of the rate of reaction against the reciprocal of absolute temperature yields a straight line. The Arrhenius equation given in the form: Arrhenius Equation: K = A e-Ea/RT E : activation energy; R: gas constant a logK = logA - (E a /2.303RT) Plotting the rate of reaction (K) against 1/T allows the calculation of rate at any temperature and therefore a prediction of shelf-life (t 90 , time to 90% potency). This forms the basis of many accelerated stability tests.

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‘The reaction rate can then be calculated at any temperature and allows a prediction of shelf life at room temperature by extrapolation.’ This assumption forms the basis of accelerated stability tests. However this mechanism of chemical breakdown often changes with temperature which can be indicated by a discontinuity or ’knee joint’ in the Arrhenius plot. This is not easily detected and would invariably lead to erroneous conclusions based on elevated temperature data to predict shelf lives at room temperature or under refrigeration. Reactions often change at about 50degree celsius and this is a sensible ceiling.

2.Order of Reaction : 

2.Order of Reaction The time course of degradation depends on the number of reactants, whose concentration influences the rate. It is more convenient to express reaction rates in terms of time. The most common is the HALF LIFE[ the time at which the concentration has halved (t1/2 ). Values for a wide range of drug degradation reactions are 10-100 kcal/mol but are usually in the range of 15-60 kcal/mol. Most occur by 1 st order kinetics but some are zero order(e.g. aspirin in aqueous suspension) and few are 2 nd order (e.g. chlorbutol hydrolysis).

3. Hydrolysis: 

3. Hydrolysis The most likely cause of drug instability is Hydrolysis. Water plays a dominant role and in many cases it is implicated passively as a solvent vector between two reacting species in solution. Hydrolytic reactions involve nucleophilic attack of labile bonds, e.g. lactum >ester>amide> imide by water on the drug in solution and are first order. When this attack is by a solvent other than water, it is known as Solvolysis .

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A number of conditions catalyse the breakdown ; The presence of OH- The presence of H3 O+ The presence of divalent metal ions Ionic hydrolysis( protolysis ) is quicker than molecular Heat Light Solution polarity and ionic strength High drug concentrations

4.Influence of pH: 

4.Influence of pH The degradation of most drugs is catalysed by extremes of pH, i.e. high[H3O+] and [OH-] and many drugs are most stable between pH 4 and 8. It is important for injections that there is low buffer capacity to prevent unnecessary challenge to the homeostatic pH of blood. Weakly acidic and basic drugs are most soluble when ionized and it is then that instability is most likely as they are charged. This leads to a problem as many potent drugs are extremely poorly soluble and pH ionisation is the most used method to obtain a solution.

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In some cases, the inclusion of a water miscible solvent in the formulation will increase stability by: Suppressing ionisation Reducing the extreme of pH required to achieve solubility. Reducing water activity by reducing the polarity of the solvent, e.g. 20% propylene glycol in chlordiazepoxide HCl injection. Reactions in aqueous solutions are usually catalysed by pH and this is monitored by measuring the degradation rates against pH, keeping temperature, ionic strength and solvent concentration constant. Suitable buffers include acetate, citrate, lactate, phosphate and ascorbate (an intrinsic antioxidant).

5. Solvolysis: 

5. Solvolysis As mentioned earlier that where the solvent is not water, then breakdown is termed as ‘ solvolysis ’. Furthermore the definition can be extended to include any change in solvent polarity (usually measured as dielectric constant) as a result of increased ionic strength. E.g. Phenobarbitone and aspirin If a compound produces degradation products which are more polar then addition of a less polar solvent will stabilize the formulation. If the degradation products are less polar then the vehicle should be more polar to stabilize the solvent

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With the hydrolysis of non polar ,neutral drugs like steroids , the transition state will be non polar with no net charge. In this case solvents will not effect the rate of decompositon and can be used with impunity to to increase solubility.

6. Oxidation: 

6. Oxidation Oxidation is controlled by the environment i.e. light, trace metals, oxygen and oxidizing agents. Oxidation is loss of electrons and an oxidizing agent must be able to take the electrons. ANTIOXIDANTS: Most of the antioxidants function by providing electrons or labile H+ , which will be accepted by any free radicle to terminate the chain reaction. A prerequisite for effective antioxidant activity in any particular preparation is that the antioxidant is more readily oxidized than the drug.

7. Chelating agents: 

7. Chelating agents Chelating agents are complexes which form complex salts by a single bond provided by a lone electron pair. Chelating agents are capable of forming more than one bond. For e.g. Ethylene diamine is a bidentate (2 links), tripyridyl is tridentate (3 links) and ethylene diamine tetra-acetic acid is hexadentate (6) which makes it particularly effective as a pharmaceutical chelating agent.

8. Photolysis: 

8. Photolysis PHOTOLYSIS: It means chemical decomposition caused by light or other electromagnetic radiation. The energy associated with radiation increases as wavelength decreases. So, the energy of UV visible is greater than that of the IR and is independent of temperature. When molecules are exposed to EMR, they absorb light at particular wavelength which causes an increase in energy which can; cause decomposition Be retained or transferred Be converted to heat Result in light emission at new wavelength.

9. Solid state Stability: 

9. Solid state Stability Many of the processes of composition apply generally, particularly when the drug is in solution. However, certain important distinctions arise with the stability of drugs in solid state e.g. in tablets & capsules. This inadequacy of Information regarding solid state stability is due to complexities of formulated system and the difficulties in obtaining the quantitative data. In all solid dosage forms , there will be some moisture and certainly in tablets significant percentage, typically 2% is required to facilitate good compression

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This free water acts as vector for chemical reaction between drug and excipients and the adsorbed moisture films are saturated with drug when compared to the dilute solutions encountered in injectables . Stability under high humid conditions: Solid drug samples can be exposed to different relative humidity conditions by keeping them in laboratory desiccators containing saturated solutions of various salts. The closed desiccators in turn are kept in oven to provide constant temperature. The preformulation data of this nature are useful in determining if the material should be protected and stored in controlled low humidity environment or non aqueous solvent be used during formulation.

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Photolytic Stability Exposure of drug 400 and 900 foot-candles of illumination for 4 and 2 week periods respectively is adequate to provide some idea of photosensitivity. Resulting data may be useful in determining if an amber colored container is required or if color masking dye should be used in the formulation . Stability to Oxidation : Drug’s sensitivity to oxidation can be examined by exposing it to atmosphere of high oxygen tension. Samples are kept in desiccators equipped with three-way stop cocks, which are alternatively evacuated and flooded with desired atmosphere. The process is repeated 3 or 4 times to ensure 100% desired atmosphere.

Compatibility study: 

Compatibility study The described preformulation screening of drug excipients interaction requires only 5mg of drug in a 50% mixture with the excipients to maximize the likelihood of obscuring an interaction . Mixtures should be examined under nitrogen to ultimate oxidation and paralytic effect at a standard heating rate on DSC, over a temperature range, which will encompass any thermal changes due to both the drug and appearance or disappearance one or more peaks in themograms of drug excipient mixtures are considered of indication of interaction

Absorption behavior : 

Absorption behavior It is essential to test the in vivo behavior of the new drug for successful formulation of a dosage from good bioavailability. Partial in vivo and in vitro test are designed to study pharmacokinetic profile of the drug.


Hyrgoscopicity A substance which absorbs sufficient moisture from the atmosphere to dissolve itself is deliquescent. A substance that loses water to form a lower hydrate or becomes anhydrous is termed as efflorescent . Most of the pharmaceutical compounds are usually either impassive to the water available in the atmosphere or lose or gain water from the atmosphere depending on the Relative Humidity(RH). Materials unaffected by RH are termed non- hygroscopic where as those in dynamic equilibrium with water in the atmosphere are Hygroscopic.

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The constant sinusoidal change in day and night temperatures is the major influence. For this reason pharmaceutical air conditioning is set below 50% RH and very hygroscopic products e.g. effervescents which are particularly moisture sensitive are stored and made below 40%. Tablets and Capsules must be hydrophyllic to facilitate wetting and the process of deaggregation and drug dissolution. They must have good limited hygroscopicity to ensure good chemical and physical stability under all reasonable climatic conditions. Good packaging will accommodate moisture challenge, e.g. glass bottles, foil blisters & dessicant .

Stability Assessment: 

Stability Assessment The testing protocols used in preformulation to ascertain the stability of formulated products must be performed in solution and in the solid state since the same drug will be used in both an injection and a capsule. Accelerated stability testing The accelerated stability studies are designed to increase the rate of chemical degradation or physical change of a Drug Substance (DS) / Active Pharmaceutical Ingredient (API) or Drug Product (DP) using exaggerated storage conditions. The purpose of the study is to monitor any degradation reactions which than will help to predict the shelf life of a Drug Substance (API) or Drug Product (DP) under the defined (ICH) storage conditions.

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Accelerates stability testing requires the careful design of protocols which must define clearly the following: The temperature and humidity for storage Storage time before sampling The number of batches to be sampled The number of replicates within each batch A suitable light challenge Details of assay. Storage conditions during stability testing vary from company to company and even within a single company. Often different types of products are given different challenges.

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Two alternative stability protocol strategies are: Factorial analysis A structured approach 1. Factorial Analysis: It is an approach for gauging the likely effect of additional factors for which no simple descriptive relationship exists. For e.g. it may reasonably suspected that light and humidity degrade a freeze dried antibiotic powder. The powder is therefore stored under low and high stresses in sealed vessels over water or dessicant on windowsill and cup boards.. After a suitable time, the amount of decomposition is measured. A Structured Approach: A typical protocol is designed and plotted. At least 2-3 batches are tested in duplicate. Products are usually stores in their final container, such that if at this stage the pack has not been finalized, a number of pack materials can be tested.


STABILITY STORAGE TEST CONDITIONS AND STABILITY ROOMS Based on the analysis the world is divided in to 4 climatic zones. REGIONS ZONES l AND 2 ZONES 3 AND 4 EUROPE All countries AMERICA Argentina, Bolivia, Canada, Mexico, US Brazil, Columbia, Cuba, Jamaica ASIA Afghanistan, China, Iran, Nepal, Turkey Bahrain , Hong Kong, India, Oman , Pakistan, Srilanka , UAE AFRICA Egypt, Algeria, South Africa, Libya Angola, Benin, Congo, Uganda, Sudan, Somalia, Senegal

Worldwide zones and the temperature and humidity conditions : 

Worldwide zones and the temperature and humidity conditions Zone Mean kinetic temperature Yearly average humidity (%RH) Zone I ( Moderate) 21 ̊C 45 Zone II (Mediterranean) 25 ̊C 60 Zone III (Hot, dry) 30 ̊C 35 Zone IV (Very hot, moist) 30̊ C 70

Various dosage form considerations for Stability testing: 

Various dosage form considerations for Stability testing Dosage form Evaluation Tablets Appearance,colour,odour,assay,degradation products,dissolution,moisture and friability. Hard gelatin capsules Appearance,colour,odour,assay,degradation products,dissolution,moisture and microbial limits Soft gelatin capsules Appearance,colour,odour,assay,degradation products,dissolution,moisture and microbial limits,pH,leakage. Emulsions Appearance,colour,odour,assay,degradation products, microbial limits,PH,viscosity,preservative content and distribution of dispersed phase globules.

Stability Chambers: 

Stability Chambers Various types of stability chambers are used in stability studies. Some of them are:

Large stability chamber: 

Large stability chamber

Small stability chamber like : 

Small stability chamber like


Conclusions Preformulation stability studies are usually the first quantitative assessment of chemical stability of a new drug. These studies include both solution and solid state experiments under conditions typical for the handling, formulation, storage, and administration of a drug candidate as well as stability in presence of other excipients . The method of sterilization of parenteral products will be largely dependent on the temperature stability of the drug. Drugs having decreased stability at elevated temperatures cannot be sterilized by autoclaving but must be sterilized by another means, e.g., filtration. The effect of pH on drug stability is important in the development of both oral and parenteral dosage forms; acid labile drugs intended for oral administration must be protected from the highly acidic environment of the stomach

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Buffer selection for parenteral dosage forms will be largely based on the stability characteristics of the drug. Solid state studies may be severely affected by changes in purity and crystallinity . Solid state reactions are much slower and more difficult to interpret than solution state reactions, and it is customary to use stress conditions in the investigation of stability. GUIDANCE temperature at 5°C may be followed for as long as 6 months. The data obtained at elevated temperatures may be extrapolated using the Arrhenius treatment to determine the degradation rate at a lower temperature. Stability under High-Humidity Conditions In the presence of moisture, many drug substances hydrolyze, react with other excipeints , or oxidize. These reactions can be accelerated by exposing the solid drug to different relative-humidity conditions.


References: Wells J.I and M.E Aulton , The Drug Delivery System, p. 237-238 www.authorstream.com

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