Stability of drugs and medicines Flashcards
various factors affecting stability of drugs and medicines
Susceptibility to hydrolysis, oxidation, light degradation and other common chemical degradation reactions.
Identify and minimize drug excipient interactions.
Reaction mechanism and kinetics.
Shelf life by accelerated stability testing (stress testing)
acceptable level of therapeutics
therapeutic effect remains unchanged
toxicogical expectations
no significant increase in toxicity occurs
Define shelf life
*The shelf life is that length of time during which a pharmaceutical product retains acceptable chemical, physical and microbiological stability so that the product remains fit for its intended purpose.
Ideally >3yrs and < 5% loss in potency without exceeding allowed limits of toxic degradation productions
Factors measuring stability
-pH - acid and base catalysis tends to raise chemical degradation. Extreme pH changes cause epimerisation
Many (not all) drugs are stable pH4-8 (epimer=one pair of stereoisomers)
Temperature - high temperature can induce oxidation, reduction and hydrolysis
Humidity - promotes hydrolysis, oxidation/reduction reactions and encourage microbial growth
Light - photons provide energy leading to radical formation, oxidation and polymerisation reactions. Photolysis of covalent bonds can also occur
Dosage form - solid usually more stable than liquid dosage form
Oxygen - promotes autoxidation
Metal ions - promotes oxidation
Factors measuring stability
-pH - acid and base catalysis tends to raise chemical degradation. Extreme pH changes cause epimerisation
Many (not all) drugs are stable pH4-8 (epimer=one pair of stereoisomers)
Temperature - high temperature can induce oxidation, reduction and hydrolysis
Humidity - promotes hydrolysis, oxidation/reduction reactions and encourage microbial growth
Light - photons provide energy leading to radical formation, oxidation and polymerisation reactions. Photolysis of covalent bonds can also occur
Dosage form - solid usually more stable than liquid dosage form
Oxygen - promotes autoxidation
Metal ions - promotes oxidation
Causes of chemical instability
Hydrolysis Oxidation Dimerisation and polymerization Isomeric change Photodegradation
Hydrolysis
Often the most common cause of drug instability. It involves nucleophilic attack of labile bonds by water.
Reactivity ranking: lactam > ester > amide > imide
Hydrolysis is a first order reaction.
pH dependent
Oxidation
Oxidation reactions tend to be complex, giving a variety of degradation products.
Oxidation taking place at ambient temperature in presence of molecular oxygen is called autoxidation. This reaction typically involves free radicals:
RH→ R. + H. (initiation)
R. + O2.→ RO2- (propagation)
RO2. + RH → ROOH + R.
The hydroperoxides (ROOH) react further to produce stable oxidation products. In the termination phase, the availability of oxygen or drug diminishes, the rate of reaction slows and free radicals combine to produce unreactive end-products.
How is oxidation promoted and stopped?
Oxidation is promoted by presence of oxygen ,oxidizing agents, light and trace metals
Antioxidants are generally used in formulations to suppress oxidation An effective antioxidant is more readily oxidized than the drug.
Example. Ascorbic acid (vitamin C) undergoes a rapid oxidation in solution to dehydroascorbic acid. The reaction is reversible but dehydroascorbic acid is irreversibly hydrolysed to form diketogulonic acid.
EDTA as a stabilising agent
Generally 0.005% and 0.1%
Chelates trace metal ions to minimise metal ion catalysed oxidation
Can also enhance action of preservatives such as benzalkonium chloride
Photodegradation
The energy associated with an electromagnetic radiation increases as wavelength decreases (UV > VIS > IR)
Natural sunlight (wavelength range 290-780nm) cause photodegradation of drug through its highest energy range (290-320nm).
Light-induced degradation is called photolysis.
Storage to prevent photodegradation
STORAGE statement in BP2013
“In an airtight container, protected from light.
Once the container has been opened, its contents are to be used as soon as possible; any part of the contents not used at once should be protected by an atmosphere of inert gas”
Photolysis occurs via what mechanism(s)
Many photolysis reactions involve oxidation, although other mechanisms may occur (for instance, hydrolysis may be catalysed by light).
More ways to affect stability
- isomeric change
- dimerisation and polymerisation
dimerisation and polymerisation
Reaction of a drug molecule with another molecule of the same drug may result in the formation of a dimer or a polymer.
e.g. Amoxicillin ; amino group can attack β-lactam ring to give dimer. A potential source of related substance
Problems with protein and peptide drugs
Examples: Monoclonal antibodies (trastuzumab), Insulin, vaccines (influenza). Mostly parenteral administration.
Same causes of chemical degradation as drugs but with additional concerns:
Denaturation of conformation
Aggregation
Cross-linking
Stability of protein and peptide drugs is dependent on the amino acid sequence
Guidelines for API in the finished dosage
ICH (International Conference on Harmonisation
FDA (food drug administration)
EMEA (European Agency for the evaluation of Medicinal products)
Problem – Proteins and Peptides are largely excluded. Validating structural conformation and efficacy on large molecules is tricky.
Susceptible amino acids to:
1) oxidation
2) deamidisation
1) oxidation - Methionine, Cysteine
2) deamidisation -Asparganine, Glutamine
Problem with Tryptophan
Photosensitive and oxidation prone
Explain the strategy for lowering temperature to increase stability
Slows down reaction rates for most drugs
Can promote oxidation (liquid dosage)
freezing and thawing can affect protein drugs dramatically
How to control pH
add buffer components to make use of optimum pH range
Why add chelators and antioxidants?
e.g. EDTA, ascorbic acid, citric acid, tocopherol
often used in combo to slow down oxidation reactions
Why add a co-solvent?
reducing the aqueous with another solvent can reduce hyrolysis
Why add a co-solvent?
reducing the aqueous with another solvent can reduce hyrolysis
Why add inert gas?
Prevents autoxidation
Why add complexing agent?
Addition of complexing agent can slow down hydrolysis
e.g. caffeine in the case of procaine
Hydrolysis susceptible drugs
lidocaine
procaine
Oxidation susceptible drugs
ascorbic acid
chloramphenicol
calcitonin
Isomerisation susceptible drugs
tetracycline
adrenaline
photolysis susceptible drugs
Retinol
Adrenaline
Decarbazine
Polymerisation susceptible drugs
Amoxicillin
Ceftazidime
Sources of microbial contamination
- Environment :Water , air, ventilation
- Raw materials, containers and closures
- Personnel
- Instruments and apparatus
Deterioration due to microorganisms can render the product not only inactive but also very harmful to the patient
Microbial contamination affects sterility of products. examples:
- Injection products and eye drops have short in-use life once the container is opened.
Strictly controlled through :
manufacturing practice, preservatives packaging and storage instructions
Zones of world
Conditions
Zone 1: Temperature climate e.g. Canada, north Europe , Russia & uk
Zone 2: Subtropical & Mediterranean e.g. Japan, USA,
Zone 3: Hot & dry climate e.g. Australia , Middle east
Zone 4: Hot & humid e.g. Central Africa, Nigeria, Malaysia
Accelerated stability testing
In accelerated stability testing, the drug is stored at elevated temperatures (e.g. 40 ,50 ,600C and the reaction rate is calculated in a short time period (from minutes to days depending on the relative stability of the drug). The Arrhenius equation is used to predict the reaction rate at a realistic storage temperature.
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Limitations of accelerated stability testing
kinetics of degradation may change at higher temperatures
(ex. at elevated temperatures, the concentration of dissolved oxygen tends to decrease.
Additional complex reactions may take place at higher temperatures
Temperature may change the nature of the dosage form
(ex. melting of some solid ingredients at elevated temperature)
Change in physical properties with unpredictable effect.
(ex. changes in viscosity, reduction of the moisture level in a solid dosage form, etc.)
