Drug stability in Pharmaceutical products
Pharmaceutical products are assigned a shelf life which determines the time when a product is considered to be safe and effective under storage condition. Stability studies should be based on the basis of pharmaceutical R&D and regulatory requirements. Degradation studies reveal the intrinsic chemical properties of the API while formal stability studies establish the retest date. The shelf life is derived from stability studies
Introduction Importance And Need Of Stability Testing
Solid State Stability
pH Stability Profile
USP defines stability of pharmaceutical product as, “extent to which a product retains with in specified limits and throughout its period of storage and use (i.e. shelf life). The capacity or the capability of a particular formulation in a specific container to remain with in particular chemical , microbiological , therapeutically , and toxicological specifications.
Drug stability is defined as the ability of the pharmaceutical dosage form to maintain the physical, chemical, therapeutic and microbial properties during the time of storage and usage by the patient. The purpose of stability studies is to provide evidence on how the quality of the active substance or pharmaceutical product varies with time under the influence of a variety of environmental factor such as temperature, humidity and light .
Chemical and physical degradation of drug substances may change their pharmacological effects, which is then affecting on their therapeutic and toxicological effect.
Pharmaceuticals products are used therapeutically based on their efficacy and safety, they should be stable.
Maintenance of quality until the time of usage or until their expiration date.
The quality should be maintained under the various conditions that pharmaceuticals encounter, during production, storage in warehouses, transportation and storage in hospitals as well as in the home.
Types of stability
TYPES OF STABILITY TESTING
Degradation of active drug leads to lowering of quantity of the therapeutic agent in the dosage form.
A toxic product formation may takes place due to decomposition instability of drug product can lead to a decrease in its BIOAVAILABILITY.
Changes in PHYSICAL APPEARANCE of given dosage form may takes place.
Degradation may increase or decrease the POTENCY of drug.
TYPES OF DEGRADATION PATHWAYS
Loss of volatile compounds
Loss of water
Absorption of water
LOSS OF VOLATILE COMPOUNDS
Some of volatile components alcohol, ether, Iodine, volatile oils, Camphor menthol etc escape from the formulations exposé them degraded.
EXAMPLE: Some types of tablets (Nitroglycerine tablets) Aromatic water
PREVENTION: Such product should be placed in well closed container. Temperature should be proper.
LOSS OF WATER
Water loss from liquid preparation (o/w emulsion) leads to changes in stability. It causes crystallization of drug product . which may lead to increase in potency , and decrease in weight.
EXAMPLE : Water evaporates from na2so4 .BORAX. Creams: especially oil/water, they become dry by loss of water.
PREVENTION: Products should be placed in well-closed container.
ABSORPTION OF WATER
Hygroscopic drugs absorb the water from external atmosphere causing the physical degradation. Effervescent powders and tablets will deteriorate if stored in a moist atmosphere.
EXAMPLE: Powders: Liquification and degradation may occur as a result of absorption of water Suppositories which base made from hydrophilic substances as Glycerin, Gelatin, and polyethylene glycol. The consistency of these forms becomes jelly-like appearance.
PREVENTION: Products should be placed in well-closed container and in dry place.
Drugs when loose water, become saturated and crystal growth occurs. Crystallization is enhanced in porous tablets.In solutions after super saturation crystal growth occurs.
EXAMPLE: Injection of calcium glucconate In suspensions crystals settle down and caking occurs and suspension becomes unstable. Ophthalmic preparations.
PREVENTION: SOLUTIONS-Stabilizers are added SUSPENSION- ·Incorporation of surface active agent ·By increasing viscosity of suspending material.
Polymorphs show significant differences in important physiochemical properties such as solubility, dissolution rate and melting point. In polymorphic changes crystal forms are changed. This may cause change in solubility and possibly crystalline growth in aqueous suspension.
EXAMPLE: Cortisone acetate suspension.
PREVENTION: suspension –suspending agent like methyl cellulose & ethyl cellulose.
When molecules are exposed to electromagnetic radiation they absorb light (photons) at characteristic wavelength which cause increase in energy which can cause decomposition.
EXAMPLE: Sodium nitropruside in aqueous solution (which is administered by IV infusion for management of acute hypertension). Iodine
PREVENTION: Use of amber colored bottles. Storing the product in dark, packaging in cartons also act as physical barrier to light.
Colour changes indicate chemical or photochemical decomposition of the active ingredients, dyes or other ingredients. Colour changes are of two types.
1) Loss of colour
2) Development of colour
EXAMPLE: Phenolphthalein color changes as the PH changes. It is colorless in acidic solution and pink in basic. ascorbic acid tablet turn yellowish brown.
PREVENTION: • Protect the product from light and air • Avoid the using reducing substances as additives. COLOUR CHANGES .
isomerization (also isomerisation) is the process by which one molecule is transformed into another molecule which has exactly the same atoms, but the atoms have a different arrangement e.g. A-B-C → B-A-C (these related molecules are known as isomers).
Racemization refers to partial conversion of one enantiomer into another. It involves the optically active form of a drug into its enantiomorph.
It occurs with the compound having more than one asymetric carbon atom in the molecule. At equilibrium, both epimers are present, but not in equal proportion.
EXAMPLE: Under prolonged storage solution containing ergometrine is decomposed by hydrolysis and isomerized to ergometrinine.
Elimination of CO2 from compound. Drug substances having a carboxylic acid group is sometimes susceptible to decarboxylation,
EXAMPLE: 4-Aminosalicylic acid procain.
In elimination, reaction some groups of the substance is eliminated.
EXAMPLE: Trimelamol eliminates its hydroxymethyl groups and forms formaldehyde.
Removal of an electropositive atom, radical or electron, or the addition of an electronegative atom or radical. Oxidation is controlled by environment i.e., light, trace elements, oxygen and oxidizing agent.
TYPES of OXIDATION
Auto-oxidation: Oxidation in which the oxygen presents in the air is involved. This process proceeds slowly under the influence of atmospheric oxygen.
Photo-Oxidation: Oxidation in which removal of the electron is involved without presence of O2.
EXAMPLE:Adrenaline,Riboflavin and Ascorbic Acid etc.
- Chelating agent: EDTA
- Antioxidant agent :Citric Acid,Tartaric Acid,Ascorbic Acid,Iso ascorbic acid,potassium and sodium salts of metabisulfites.
Contamination of a product may sometimes cause a lot of damage and sometimes may not be anything at all. -Thus it is dependent on the type of microbe and its level of toxicity it may produces. -If parenterals or ophthalmic formulations are contaminated, it may cause serious harm.
Source of microbial contamination :Water & air Container & closure Raw material.
Suitably designing the containers
Usually using single dose containers
Sticking to proper storage conditions
Adding an antimicrobial substance as preservative.
Therapeutic effect must be changed due to hydrolysis, isomerisation or epimerization .
some product may produces toxic during degradation’s
Kinetics deals with the study of the rate at which processes occur and mechanism of chemical reactions It involves the study of rate of change and the way in which this rate is influenced by the concentration of reactants, products, and other chemical species that may be present, and by factors such as solvents, pressure, and temperature.
Kinetics applies to:
- Drug action at molecular level
- Elimination processes.
Rate & order of reaction
- Rate: The speed or velocity of a reaction with which a reactant or reactants undergoes a change. • It is determined by the change in the concentration of the reactants or products as a function of time.
- Order of reaction :The number of concentrations that determine rate. • The way in which the concentration of the reactant influences the rate.
Types of order of reaction
Zero order of reaction:Rate is constant and is independent of the concentration of any of the reactants.
First order of reaction: The reaction rate of change is proportional to drug concentration.
Second order of reaction: Rate depends on the product of two concentration terms. When you have two components reacting with each other or one component reacting with itself.
Pseudo order of reaction :For some reactions, the rate of the reaction may be independent of the concentration of one or more of the reacting species over a wide range of reactions.
Overall order of reaction
Shelf life It is defined as the time required for the concentration of the reactant to reduce to 90% of its initial concentration .
Represented as t90 the units of time /conc.
t90 = (a-0.9a)/ ko = 0.1 a/ ko
Where, a = initial concentration. ko = specific rate constant for zero order reaction.
The main purpose of solution stability is identification of conditions necessary to form a stable solution Study. Includes – effects of pH, Ionic strength, Co-solvent, light , temperature and oxygen Interested experiments at extremes conditions of pH and temperature (0.01N HCl , water ,0.01N, NaOH all at 90°C).
Aqueous Buffers are used to provide wide range with constant levels of drug, co solvent and ionic strength Compatible with physiological media.
SOLID STATE STABILITY
The purpose of solid state stability is identifications of stable storage conditions for drug in the solid state and identification of compatible excipients for a formulations.
Affected by change in purity and crystallinity Initial bulk lots and newer lots– to be studied Solid state is slower and difficult to interpret than solution state TLC, UV-Vis, fluorescence
Polymorphic changes – DSC, IR or appearance changes like oxidation – surface discoloration
pH STABILITY STUDIES
The pH-stability profile is essential for understanding how the compound behaves in different environments and informs formulation development, process development, drug product stability and the route of administration of the molecule. To develop a pH-stability profile, it is important to develop stability-indicating assays for the intact drug at the various pH values to be studied.
Mr. Shiv Kumar is the Author and founder of pharmaceutical guidance, he is a pharmaceutical Professional from India having more than 14 years of rich experience in pharmaceutical field.
During his career, he work in quality assurance department with multinational company’s i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd, Panacea Biotec Ltd, Nectar life Science Ltd. During his experience, he face may regulatory Audit i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda,Kenya, Tanzania, Zimbabwe. He is currently leading a regulatory pharmaceutical company as a head Quality. You can join him by Email, Facebook, Google+, Twitter and YouTube