stability of medicines 2 Flashcards
What does stability mean? (chemistry terms)
capacity of a product to remain within specifications
to ensure potency, quality or purity
What is chemical degradation?
- Decomposition of
chemical moiety - Due to effects of
moisture, oxygen,
light & heat - Results in loss of
active drug
What is physical degradation?
- Formulation-specific
- Caking in
suspensions, phase
separation in
emulsions - Hardness &
brittleness of tablets
What is microbial degradation?
- Microbial
contamination - Metabolism of drug
molecule - Physical spoilage of
dosage form - Infection-causing
What may drug instability cause?
- Inconsistent dosage
- Undesired change in performance – dissolution/bioavailability
- Changes in physical appearance of the dosage form
- Product failures
What are 4 chemical degradation reactions?
- Hydrolysis
- Oxidation
- Photodegradation
- Polymerisation and dimerisation
What happens in hydrolysis?
- Most common chemical degradation
- Water present in many pharmaceuticals
- As ingredient or contaminant
- Carboxylic acid derivatives are common in medicines
- Esters and amides
What functional groups are prone to hydrolysis?
Ester
Amide
Imide
Urea
Lactone
Lactam
What is the rate of hydrolysis reduced by?
- Dry formulations (powder for reconstitution, solid dosage form)
- Adjusting pH to maximum stability in aqueous solution
- Storage temperature
- Coating
- Choice of packaging
What else reduces hydrolysis rate?
- Complexation
- Caffeine (a xanthine) complexes with local
anesthetics, such as benzocaine and procaine - Surfactants
- Drug molecules become trapped in the
micelle - Hydrolytic groups such as OH cannot
penetrate the micelle and reach the drug
molecules
What happens in oxidation?
- Second most common pathway for drug breakdown
- Oxidation = removal of H, loss of e-, addition of O
- Generally occurs via the action of free radicals
- Highly reactive species possessing one or more unpaired electrons
- Generated by the action of light energy (UV), heat or trace metals such as Fe2+
or Cu+
What happens in auto-oxidation?
- Uncatalysed and proceeds slowly under the influence of molecular oxygen
- Reaction of free radicals with drugs or biomolecules leads to the
formation of peroxyl radicals, which initiate and propagate auto- oxidation
What functional groups are more prone to auto oxidation?
Phenols
Catechols
Aldehydes
Thiols
Thioethers
What does circumvention of auto-oxidation do?
- Remove initiators
- Chelation of trace metals with chelating
agents: ethylene diamine tetraacetic acid
(EDTA), citric acid & tartaric acid - Exclude O2
- Sparge liquids with inert gases such as
nitrogen to displace oxygen
What does circumvention of auto-oxidation do? (only addition of…)
- Add free-radical scavengers/antioxidants
- Butylated hydroxytoluene (BHT) more readily oxidised than oils, used to
stabilise fatty/oily products - Ascorbic acid possesses lower redox potential than drug, more readily
oxidised
What occurs in photochemical degradation?
Energy of a photon increases with decreasing wavelength
*UV light has high energy which can catalyse reactions
What reactions might UV light induce?
*Oxidation
*polymerisation
* Ring Rearrangement
What happens in polymerisation?
- A process by which two (dimerisation) or more identical drug
molecules combine together to from a complex molecule - UV radiation induces the polymerisation of chlorpromazine (in anoxic
conditions)
What is photolysis and what occurs during this?
- Decomposition by light
- Photolysis of the pentacyanonitrosylferrate (II) ion in sodium
nitroprusside (administered by IV infusion for the management of
acute hypertension) - Protected from light, stable for ~1 year
- Exposed to normal room light, a shelf life of only 4 hours
How to prevent photolysis/ photochemical effects?
- Exclude from light by
- Storing in the dark
- Packaging in foil
- Filter out light by
- Storage in amber glass or
- Coating tablets with pigmented polymers
What is a zero order reaction?
Drug molecule A →product of degradation
= rate of degradation of A Is independent of the concentration of the reactants
What does a zero order reaction graph look like?
picture
What is a first order reaction?
*the rate of degradation of A is directly proportional to its concentration
What does a first order reaction graph look like?
picture
What is a pseudo zero order reaction, what happens?
if the degradation of A follows first order kinetics
observed rate constant is an expression for zero order reaction
How does a second order reaction work?
A+B → product degradation
the rate of degradation A is directly proportional to its concentration and the concentration of reactant B
second order reaction graph?
picture
What happens in pseudo first order reactions?
if B is very high (h2o) or constant (fixed pH)
How much degradation is allowed in medicines?
- 5 – 10% loss limit over total shelf life (~ 5 years)
What is degradation of medicines/ shelf life dependant on?
*Toxicity of
degradation products
*Physical properties of
dosage form
*Aesthetics
(look & feel)
Justification of expiry date and storage conditions
Simply store product under various conditions
* Assess instability at the end of storage period→ TAKES TOO LONG
↓
* Industry/regulatory authorities have evolved specific testing protocols
* Accelerated/stress testing
