stability in preformulation
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STABILITY IN
PREFORMULATION
Presented By
MITHA ANN THAMPY
M PHARM FIRST YEAR
NEHRU COLLEGE OF PHARMACY
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CONTENTS
1. STABILITY
2. OBJECTIVES OF STABILITY STUDIES
3. FACTORS AFFECTING STABILITY
4. STABILITY PROBLEMS AND ITS PREVENTION
5. REFERENCES
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STABILITY
Stability of pharmaceutical product may be definedas the capability of a particular formulation in a
specific container/closure system to remain within its
physical, chemical, microbiological, therapeutic and
toxicological specification. The stability of the drug substance is first assessed in
the preformulation stage.
A drug product must satisfy stability in terms of
chemical, therapeutic, toxicological and physicalcharacteristics
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OBJECTIVES OF STABILITY STUDIES
To gather information during preformulation stage to
produce a stable product.
To determine maximum expiration date.
To get an idea of storage condition.
To determine the packaging components.
To determine the retest period of pharmaceuticals.
To determine transport conditions.
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FACTORS AFFECTING STABILITY
Extrinsic factors- Temperature
- Light
- Gases
- Moisture Intrinsic factors
- pH
- Complexation
- Microbial GrowthBoundary factors
- Container composition
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EXTRINSIC FACTORS
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ENERGY OF ACTIVATION AND
REACTION TYPES
10
2-3 kcal/mole----------
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LIGHT
Activate molecules and enhance rate of decompositionPhotochemical decomposition due to absorption of
sunlight ( visible - blue, violet and uv 500 300nm )
Exposure of sunlight colour change of product
- degrade packaging- chemical decomposition of
active ingredient
Test procedure test sample in open petridishes or
clear containers- control sample in light resistantcontainers
- placed into temperature monitoredcabinets for 4 weeks
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Drugs undergo zero order kinetics
eg. Chlorpromazine, reserpine, colchicine
Drugs undergo first order kinetics
eg. Adriamycin, furosemide, nefidipine
Examples of photochemical degradation
- colour fading of tablets and liquids- conversion of ergosterol to vitamin D
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GASES
Oxygen and carbon dioxide affect stability of drug
Oxygen oxidation potency loss / colour change
eg. Ascorbic acid dehydroascorbic acid
CO2 - potency losseg.Sodium hexobarbitone iv injection hydrolysis solution CO2
(basic pH)
hexobarbitone precipitate
(acidic pH )
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MOISTURE
Absorption of moisture increases the weight of product
- dose diluted decreases potency
eg Deliquescent substances CaCl2 ,K2CO3
Gelatin capsules absorb moisture and become soft
Test procedure expose to various range of humidities
- test carried out on final packaged product
and unpackaged product
- To get information regarding formulationadjuvant, type of environment suitable for
a drug & type of package needed
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pH Rate of hydrolytic reactions vary with pH
- Hydrogen ion catalyses predominantly at lower pH- Hydroxyl ion catalysis operates at higher pH range
pH can also influence the rate of oxidation.
- system less readily oxidized when the pH is low.
Test procedure product samples are kept at pH 2 12 at55 90 0c for 2 weeks
- plot pH rate profile ( log k vs. pH )
- point of inflection of such a plot represents
pH of optimum stability
- point is useful in the development of
stable dosage form
eg. Aspirin buffered solution is maximum stable at a pH of 2.4,
above a pH of 10 the decomposition rate rapidly increases.16
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COMPLEXATION
Complex formation reduces the rate of hydrolysisand oxidation.
e.g. caffeine complexes with local anesthetics, such asbenzocaine, procaine and tetracaime - reduction in
rate of hydrolytic degradation.
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MICROBIAL GROWTH
o Threat to stability - degradation of drug dosage
impotency
o Evaluating microbiological stability
chemical assays of preservatives- Microbial challenge tests
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BOUNDARY FACTORS
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CONTAINER COMPOSITION
The container and closure are particularly important in
affecting product stability.
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Glass
- Glass is resistant to chemical and physical change
and is the most commonly used material.
Limitations Overcome
1. Its alkaline surface use of Borosilicate glass
2. Ions may precipitateinsoluble crystals from the glass
the use of buffers
3. Permits the transmission oflight which may acceleratedecomposition.
Amber coloured glass
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Plastics
The problems with plastic are:
1. Migration of the drug through the plastic into the
environment.
2.Transfer of environmental moisture, oxygen, and otherelements into the pharmaceutical product.
3.Leaching of container ingredients into the drug.
4.Adsorption of the active drug or excipients by the plastic.
Overcome:1. Minimize by overwrapping
2. Leaching can be reduced by coating with Teflon
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Metals
- Various alloys and aluminium tubes may be utilized ascontainers for emulsions, ointments, creams and pastes.
- Limitation:They may cause corrosion and precipitation inthe drug product.
- Overcome: Coating the tubes with polymers may reducethese tendencies.
Rubber
- It has the problems of extraction of drug ingredients and
leaching of container ingredients.- The pretreatment of rubber vial stoppers and closures with
water and steam reduces potential leaching.
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STABILITY PROBLEM AND ITS
PREVENTION
Physical instability
Chemical instability
Therapeutic instability
Microbiological instability
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PHYSICAL DEGRADATION
Loss of volatile constituents
Loss of water
Absorption of water
Crystal growth
Polymorphism
Colour changes
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LOSS OF VOLATILE CONSTITUENTS
Medicinal agents such as iodine, camphor, menthol, ethanol,
anaesthetic ether, chloroform tendency to evaporate from
product
Nitroglycerine loose its potency volatilisation of medicament
Prevention
1. keep product in well closed container
2. store in cool place
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LOSS OF WATER
Decrease in weight, rises in concentration andincreases potency
Loss of water depends on temperature and humidity
eg. Efflorescent substances borax, quinidine
sulphate, caffeine
Prevention
1. keep product in well closed container
2. store in cool place
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ABSORPTION OF WATER
Absorption of moisture increases the weight of product
- dose diluted decreases potency
eg. Deliquescent substances CaCl2 ,K2CO3
Gelatin capsules absorb moisture and become soft
Prevention
1. keep product in well closed container
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CRYSTAL GROWTH
Fluctuation in temperature causes crystal growth Seen in - supersaturated solution
e.g. 10% w/v Calcium gluconate solution
- suspension
Prevention1. select suitable storage condition to prevent
temperature fluctuation
2. increase the viscosity of the product
3. include surface active agents in formulations
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CHEMICAL INSTABILITY
Hydrolysis
Absorption of CO2Decarboxylation
PolymerizationIsomerization
Oxidation
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HYDROLYSIS
- means splitting by water
Drug type Examples
Esters Aspirin, alkaloids
Dexmethasone sodium phosphate
Nitroglycerin
Lactones Pilocarpine
Spironolactone
Amides Chloramphenicol
Lactams Penicillins
Cephalosporins34
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Prevention
1. By adding Buffers
- maintain pH having maximum stability and
therapeutic activity
- Optimum pH selected should between 3.5 and 5
e.g. Boric acid buffer
2. Complexation3. Suppression of solubility
- achieved by adding
oAdditives e.g. Citrate, dextrose, sorbitol & gluconate
o Converting into salt forme.g. Penicillin Procaine Penicillin
o Converting into water insoluble derivative.
e.g Erythromycin propionate, Erythromycin stearate
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4. Removal of water
- achieved byo Storing drug in dry form
e.g. Streptomycin dry powder for injection
o Use water immiscible vehicle for dispersion of drug
e.g. Aspirin in silicone fluid
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ABSORPTION OF CARBON DIOXIDE
loss potency
eg. Sodium hexobarbitone iv injection
Amphetamine,KOH,NaOH,Ca(OH)2,MgO -
turbid solution
Prevention
- keep product in well closed container
- Manufacture product as dry sterile powder
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DECARBOXYLATION
Elimination of CO2from a compound Encountered when parenteral solutions of NaHCO3
are autoclaved
e.g. Sodium P- amino salicylic acid
Procaine hydrochloride
Prevention
- CO2 gas is passed into the solution for 1 min
prior to sealing
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POLYMERISATION
combination of 2 or more identical molecules to form
larger and more complex molecule
e.g. dextrose inj autoclaving 5 hydroxymethyl furfural
( straw coloured solution)
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OXIDATION
Removal of electropositive atom, radical or electron oraddition of electronegative atom or radical
Functional group Examples
Catechols Catecholamines (dopamine)
Ethers Diethylether
Thiols Dimercaprol (BAL)
Thioethers Chlorpromazine
Carboxylic acids Fatty acids
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Prevention : Oxidation is prevented by
1. Adding antioxidants
- break free radical chain reaction at the step of chain
propagation
2. Adding chelating agents
- form complexes with heavy metal ions and preventthem from catalyzing oxidative decomposition.
e.g. EDTA derivatives and salts, citric acid & tartaricacid.
Aqueous systems Oil systems
Sodium metabisulfite Ascorbyl palmitate
Sodium thiosulfate BHT
Ascorbic acid BHA
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3. Adding Buffers
- impart stability when oxidation catalysed by H+ or
OH- ions
4. Adding reducing agents
- employed at a concentration of .01 - .1 %
e.g. sodium and potassium metabisulphite
5. Adding surfactants- Nonionic, cationic and anionic surfactants when
added to solutions containing drugs form micelle and
the drug particles become trapped in the micelle
6. Environmental control measures- prevent exposure to light
- oxygen free environment
- low temperature storage
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Water gram-negative groups: Pseudomonas,
Xanthamonas, Flavobacterium
Air Mould spores: Penicillium, Aspergillus
Bacterial spores: Bacillus spp. Yeasts
Raw materials Micrococci
Starches Coliforms
Pigments Salmonella
MICROBIOLOGICAL INSTABILITY
Gums Actinomyces
Animal
products
Salmonella, Coliforms
Personnel Coliforms, Staphylococci, Sterptococci44
Prevention:
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Prevention:
(1) Suitably designing the containers
(2) usually using single dose containers
(3) sticking to proper storage conditions
(4) adding an antimicrobial substance as preservative
Preparation Preservative Concentration %w/v
Injections Phenol
CresolChlorocresol
0.5
0.30.1
Eye drops Chlorhexidine
acetate
Benzalkoniumchloride
0.01
0.01
Mixtures Benzoic acid
Methyl paraben
Alcohol
0.1
0.1
12-2045
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THERAPEUTIC INSTABILITY
Due to drug interactions ( effect of one drug is alteredby prior or simultaneous administration of another
drug or food)
Prevention
- proper adjustment of dosage
Generic name Potentiates Decreases Food
Bacampicillin
Beta adrenergic
Birth control pills
Probenicid
Sodium benzoate
Chloramphenicol
Erythromycin
Loperamide
Paromomycin
Tetracycline
Troleandomycin
alcoholic
beverages,acidic
fruits or
juices
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REFERENCES
Leon Lachman et.al, The Theory and Practice of IndustrialPharmacy, Varghese Publishing House, Bombay,3rd editionP. 190
C.V.S Subrahmanyam, Textbook of Physical pharmaceutics,Vallabh Prakashan, Delhi,2ndedition P. 51 - 69
Dr.Shyamala Bhaskaran, Industrial Pharmacy, BirlaPublications, Ist edition, P. 8 - 11
R.M. Mehta, Pharmaceutics ll, Vallabh Prakashan, Delhi,2ndedition P. 58
Conditions for Stability from:http://www.pharmacopeia.cn/v29240/usp29nf24s0c1191.html
Drug interactions from http://en.wikipedia.org/wiki/Listofdrug interactions
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