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ASeminarOn“DRUG STABILITY” SUBMITTED TO MUMBAI UNIVERSITY ByMs. Swati S. Bharati(F.Y.M.Pharm) Under the Guidance ofDr. BHUSHAN RANEHOD (Pharmaceutics)
SHRI. D.D. Vispute College of Pharmacy & Research CenterPANVEL(2016-2017)
CONTENTS...Introduction Importance And Need Of Stability TestingDegradation PathwaysKinetic StabilitySolution StabilitySolid State StabilitypH Stability ProfileConclusionReference
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INTRODUCTION
STABILITY: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.
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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
DRUG STABILITY
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IMPORTANCE 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.19/11/2016 5
NEED
NEED OF STABILITY STUDIES
Quality varies with
time Shelf life of drug product
Storage condition
Container closure
suitabilityPrevention of expenses
Essential quality
attributes
Safety point of view of patient
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Where stability studies takes place....... Drug discovery development
New chemical
entity
Preclinical studies including:
•chemistry•Physical properties•Biologicali. Pharmacologyii. ADMEiii. Toxicology•Preformulationi. Bulk characterizationii. STABILITY ANALYSISiii. Solubility analysis
Clinical studies
Postmarketing
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Types of stability•
CHEMICAL
PHYSICAL
Types of stability
THERAPEUTIC
TOXICOLOGICALMICROBIOLOGICAL
GENOTOXIC
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TYPES OF STABILITY TESTING
• Stability condition Study
SR.
NO.
STUDY STORAGE CONDITION
TESTING TIMING
(MONTH)
Minimum Time
Period Covered
By Data At Submissio
n1 LONG TERM
(Ambient) 25º C ± 2º C 60%RH ± 5%
0, 3, 6, 9, 12, 18, 24, 36, 48, 60.
12 months
2 INTERMEDIATE (controlled)
30º C ± 2º C 60%RH ± 5%
0, 3, 6, 9, 12. 6 months
3 ACCELERATED(Short term)
40º C ± 2º C 75%RH ± 5%
0,1, 2, 3, 6, 9. 6 months
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DEGRADATION PATHWAYSDegradation 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.
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TYPES OF DEGRADATION PATHWAYS
Degradation
Pathways
PHYSICAL
TOXICOLOGIACAL
THERAPEUTIC
MICROBIOLOGICAL
CHEMICAL
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PHYSICAL DEGRADATION
LOSS OF VOLATILE COMPOUNDS
LOSS OF WATER
ABSORPTION OF WATER
CRYSTAL GROWTH
POLYMORPHISMS
COLOUR CHANGES
PHOTOLYSIS
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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 waterPREVENTION:Such product should be placed in well closed container.Temperature should be proper.
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LOSS OF WATERWater 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.
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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 waterSuppositories 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.
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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 glucconateIn suspensions crystals settle down and caking occurs and suspension becomes unstable.Ophthalmic preparations.
PREVENTION:SOLUTIONS-Stabilizers are addedSUSPENSION-·Incorporation of surface active agent·By increasing viscosity of suspending material
CRYSTAL GROWTH
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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
POLYMORPHISMS
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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.
PHOTOLYSIS
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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
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HYDROLYSIS
ISOMERIZATION
RACEMIZATION
EPIMERIZATION
DECARBOXYLATION
ELIMINATION
OXIDATION
CHEMICAL DEGRADATION
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1 • ESTER
2 • AMIDE
3 • BARBITURATES, HYDANTOINS & IMIDES
4 • CARBON NITROGEN BOND CLEAVAGE
HYDROLYSIS
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- Involve Acyl – Acid Cleavage.
EXAMPLE :
aspirin ,atropine, physostigmine & procaine..
REACTION:
ESTER
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AMIDES• Amide bonds are less susceptible to hydrolysis
than ester bonds.• The leaving group, an amine, is a poorer leaving
group. It involves cleavage of amide linkage to give an amine instead of alcohol as in case of esters.
EXAMPLE:
Chloramphenicol , Barbiturates
REACTION:
RCONHR(amide) + H2O RCOOH + NH2-R(AMINE)
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BARBITURATES, HYDANTOINS & IMIDES
• Barbiturates, hydantoins, and imides contain functional groups related to amides but have a tendency to be more reactive.
• Barbituric acids such as barbital, phenobarbital and amobarbital, undergo ring-opening hydrolysis.
REACTION:
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C-N BOND CLEAVAGE• Benzodiazepines such as diazepam, oxazepam, and
nitrazepam undergo ring opening due to reversible hydrolysis of the amide and azomethine bonds.
• Benzodiazepinoxazoles(oxazole-condensed benzodiazepines) such as oxazolam, flutazolam, haloxazolam, and cloxazolam are undergo ring opening due to hydrolysis.
REACTION:
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PREVENTION OF HYDROLYSIS Packaging in suitable moisture resistant
packs such as strip packs and storage in controlled humidity and temperature.
Hydrolysis of certain drugs such as benzocaine and procaine can be decreased by the addition of specific complexing agent like caffeine to the drug solutions .
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ISOMERIZATION
Isomerisation is the process by which one molecule is transformed into another molecule which has exactly the same atoms, but the atoms are rearranged
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RACEMIZATION
Racemization refers to partial conversion of one enantiomer into another. It involves the optically active form of a drug into its enantiomorph.
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EPIMERIZATION
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DECARBOXYLATION
Elimination of CO2 from compound. Drug substances having a carboxylic acid group is sometimes susceptible to decarboxylation,
EXAMPLE:4-Aminosalicylic acidprocain
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ELIMINATION
In elimination, reaction some groups of the substance is eliminated.
EXAMPLE:Trimelamol eliminates its hydroxymethyl groups and forms formaldehyde.
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OXIDATION
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TYPES of OXIDATION
•Oxidation in which the oxygen presents in the air is involved.This process proceeds slowly under the influence of atmospheric oxygen.
AUTO-OXIDATIONExample:
oil, fat and unsaturated
compds
•Oxidation in which removal of the electron is involved without presence of O2.
PHOTO-OXIDATION
Example: adrenaline, riboflavin &
ascorbic acid etc.
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PREVENTION
• EDTAChelating agent
• CITRIC ACID , TARTARIC ACID • ASCORBIC ACID AND ISO-
ASCORBIC ACID, K OR NA SALTS OF METABISULFITE
Antioxidant agent
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MICROBIAL DEGRADATION
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.
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Source of microbial contamina
tion
Water & air
Container &
closure
Raw materi
al
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PREVENTION
Usually using single dose containers
Sticking to proper storage conditions
Adding an antimicrobial substance as preservative
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THERAPEUTIC DEGRADATION
Therapeutic effect must be changed due to hydrolysis, isomerisation or epimerization .
Example:Adrenaline
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Toxicological degradation
SOME DRUGS MAY PRODUCE TOXIC PRODUCT .EXAMPLE:TETRACYCLINE, CHLORAMPHENICOL
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Kinetic stability
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:StabilityIncompatibilityDissolutionAbsorptionDistribution Drug action at molecular levelElimination processes
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Rate & order of reaction
•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.
Rate
•The number of concentrations that determine rate.•The way in which the concentration of the reactant influences the rate.
Order of reaction
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Types of order of reaction•Rate is constant and is independent of the concentration of any of the reactants.
Zero order of reaction
•The reaction rate of change is proportional to drug concentration.
First 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.
Second 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.
Pseudo order of reaction
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Overall order of reaction
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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/ koWhere, a = initial concentration. ko = specific rate constant for zero order reaction.
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Shelf life
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SOLUTION STABILITY
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). Aq. Buffers are used to provide wide range with constant levels of drug, co solvent and ionic strength Compatible with physiological media
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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 crystallinityInitial bulk lots and newer lots– to be studiedSolid state is slower and difficult to interpret than solution stateTLC, UV-Vis, fluorescencePolymorphic changes – DSC, IR or appearance changes like oxidation – surface discoloration
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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.
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pH-stability studies
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CONCLUSION 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
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REFERENCEhttp://www.slideshare.net/GajananSanap/stability-studies-58779043on date15/10/2016
C.V.S Subrahmanyam “Textbook of Physical Pharmaceutics” vallabh prakashan, second edition, reprint 2007, page no: 13-50, 51-84.
http://www.slideshare.net/bknanjwade/drug-stability-and-stabilization- techniques. On date 19/10/2016http://uchpel.vscht.cz/files/uzel/0022888/Chemical%20and%20physical%20degradation%202015.pdf. On date 21/10/2016http://www.slideshare.net/alaaalfayez/stability-tests-for-pharmaceutical-products on date 19/10/2016http://cst-kh.edu.ps/staff/mabujamee/wp-content/uploads/2010/10/Unit-4-Drug-Stability.pdf.Cartensen J, Marcel Dekker “ Drug Stability Principles and Practises ”Informa healthcare, third edition,vol 107, 1990, page no:
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Thank you
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