accelerated stability studies

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factors influencing stability studies, USP type of studies, storage con


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Accelerated stability studies:

Accelerated stability studies Submitted by Y.AKHILA(Y18MPH352) Under the guidance of M.GAYATRI RAMYA M.Pharm (Ph.D.) A.N.U. College of pharmaceutical sciences


Introduction Factors of degradation According to USP types of stability Types of stability studies Testing protocol Representative protocol Conclusion References CONTENTS:


Pharmaceutical products tend to deteriorate on storage. The shelf- life of a pharmaceutical product is the period of time during which, if stored correctly, it is expected to retain acceptable chemical, physical and microbiological stability. Pharmaceuticals should be formulated and stored in a way that minimize degradation. The following factors are relevant to most mechanisms of degradation. INTRODUCTION


TEMPERATURE: The rate of degradation reactions is markedly influenced by temperature. Storage of the product in a refrigerator at ( 2-8 degree cent.) is an option if the product is unstable at room temperature. Using a freezer at ( less than -15degree cent.) to store unstable formulations is sometimes adopted, however, this makes storage and distribution of the product inconvenient. LIGHT: Containers made from tinted glass protect the product from light to some extend because they allow less ultraviolet light to penetrate than those which are untinted.


Replacing an aqueous solvent in a formulation with a non aqueous one is a potential means of avoiding hydrolysis. The dielectric constant can influence the rate at which charged species react. However, the practical considerations of choosing a solvent for a formulation, such as toxicity and compatibility with the drug, usually outweigh consideration of any effect due to the solvents dielectric constant. Solid dosage forms are usually more stable than liquid ones. Injection formulations of unstable drugs, such as penicillin's, can be formulated as freeze-dried powders, which are reconstituted with water or saline immediately before administration. SOLVENT:


Oxidation reactions are less influenced by temperature than most other degradation reactions, so low temperature storage may be less successful as a stabilization option. Containers with an inert gas such as nitrogen before they are sealed will reduce the amount of oxygen in the product. Chelating agents are usually used in combination with an antioxidant. Antioxidants act in one of two ways. OXYGEN


1. Act as oxygen scavengers: oxygen is removed from the formulation by reacting preferentially with the antioxidant. 2. To terminate free radicals: The antioxidant form free radical which is relatively unreactive and so cannot contribute to free radical propagation. Sodium metabisulphite and ascorbic acid are examples of water soluble antioxidants used in aqueous formulation.

Types of USP stabilities physical stability:

Most of the drugs are due to changes in the physical properties of the dosage form, either spoiling the products appearance or reducing its effectiveness. The other potential problems are loss of drug due to sorption or contamination of the product by extractable from the container. Molecules of the drug or other formulation component may be lost from a formulation by adsorption onto the surface of the container or closure or by the absorption of molecules into plastic containers . E. g. Diazepam. Types of USP stabilities physical stability

Microbiological stability:

Deterioration due to the presence of microorganisms can either render the product harmful to the patient or have an adverse effect on the products properties. Injection products generally need to be used immediately the container is opened and products for use in the eye have a short in- use life once opened . M icrobiological stability


Stability studies are classified into three types, based on the temperature and humidity employed during the studies. These are Long term stability studies Intermediate stability studies Accelerated stability studies TYPES OF STABILITY STUDIES


Study Storage conditions Minimum time period covered by data of submission Long term (ambient) 25℃ ±2℃ 60% RH ±5% 12 months Intermediate (controlled) 30℃± 2℃ 60%RH ±5% 6 months Accelerated 40℃±2℃ 75%RH ±5% 6 months


Preformulation assessment At this stage, potential degradation mechanisms and degradation products are identified and the development of stability- indicating assay is commenced. The solid- state stability is also studied by storing drug at high temperature, either on its own or combined with potential excipients which may be used in a solid dosage form. ACCELERATED STABILITY TESTING ( STRESS TESTING)

Temperature cycling:

Temperature cycling studies involve storing the product at alternating high and low temperatures. These are often designed to subject liquid products to repeated freezing. For eg. This may reveal the product stability problems because it potentially accelerates physical deterioration of the product. Temperature cycling

Photostability testing:

The study is performed within the cabinet which has a controlled temperature, typically of 25degree cent. Initially photostability studies are carried out using pure drug, spread over the base of shallow containers and directly exposed to the light. After a period of storage, the material is chemically analysed to assess the degree of photodegradation . Photostability testing


This involves storing the drug under predicted worst-case conditions of temperature and humidity in controlled-temperature cabinets or rooms. Samples are removed at intervals and tested over a minimum period of 12 months. Any protocol should be designed to ensure that the product remains of adequate quality throughout its proposed shelf-life at the proposed storage conditions when it is marked. LONG-TERM STABILITY TESTING

Climatic zones:

To simply the long term stability testing of a product for the global market, four climatic zones have been defined. Climatic zone I : Temperature climate, includes Canada, New Zealand, northern Europe, Russia, United Kingdom. Climatic zone II : Subtropical and Mediterranean climate, include Japan, southern Europe, USA, southern Africa, parts of South America. Climatic zones


Climatic zone III: Hot and dry climate, includes Argentina, Australia, Botswana, Middle East, northern Africa. Climatic zone IV: Hot and humid climate, includes Brazil, much of central Africa including Ghana and Nigeria, Indonesia, Nicaragua, the Philippines, Malaysia.

Long term test conditions for the various climatic zones, as defined by WHO (2009):

Climatic zone Definition L ong term test conditions Temperature (degree cent) Relative humidity(% R.H) I Temperature climate 21 45 II Subtropical and Mediterranean climate 25 60 III Hot and dry climate 30 35 IVA Hot and humid climate 30 65 IVB Hot and very humid climate 30 75 Long term test conditions for the various climatic zones, as defined by WHO (2009)


Intermediate studies are conducted at 30℃ / 65% RH and designed to moderately increase the rate of chemical degradation or physical changes for a drug substance intended to be stored long term at 25℃. Generally these studies are conducted when the accelerated studies for general case (40℃/ 75%RH) failed to meet the acceptance criteria. INTERMEDIATE TESTING


Because the packaging of a product may affect its stability, products which are undergoing long term stability testing should be stored in the exact packing that is intended to be used when the product is marketed. At least three separate batches of a finished pharmaceutical product should be placed on stability testing. This may allow any batch to batch differences in stability to be detected. Testing should be performed at least every three months in the first year, every six months in the second year and annually thereafter. TESTING PROTOCOL:


To reduce the amount of routine testing, it is common practice in industry using the same conditions as required for climatic zone II testing i.e. under slightly harsher conditions that are actually required for zone I. For the product where refrigerated storage is envisaged, the 5 degree centigrade storage condition represents realistic storage conditions experienced in a refrigerator. REPRESNTATIVE PROTOCOL:


Stability testing is now the key procedural component in the pharmaceutical development program for a new drug as well as new formulation. Stability tests are carried out so that recommended storage conditions and shelf life can be included on the label to ensure that the medicine is safe and effective throughout its self life. Therefore, the stability tests should be carried out following proper scientific principles and after understanding of the current regulatory requirements and as per the climatic zone. CONCLUSION


Aulton’s Pharmaceutics. The design and manufacture of medicines. Theory and practice of industrial pharmacy by L achman . REFERENCES



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