Stability of Medicines Flashcards
Stability
Capacity of a product to remain within specifications to ensure potency, quality or purity
Chemical degradation
- Decomposition of chemical moiety
- Due to effects of moisture, oxygen, light & heat
- Results in loss of active drug
Physical degradation
- Formulation-specific
- Caking in suspensions, phase separation in emulsions
- Hardness & brittleness of tablets
Microbial degradeation
- Microbial contamination
- Metabolism of drug molecule
- Physical spoilage of dosage form
- Infection-causing
Drug instability may cause
- Inconsistent dosage
- Undesired change in performance dissolution/bioavailability
- Changes in physical appearance of the dosage form
- Product failures
Chemical degradation reactions
- Hydrolysis
- Oxidation
- Photodegradation
- Polymerisation and dimerisation
Hydrolysis
- Most common chemical degradation
- Water present in many pharmaceuticals as ingredient or contaminant
- Carboxylic acid derivatives are common in medicines
Esters and amides
Imide
- N-H
- 2 Carbonyal
Urea
- 2x NH2
- Carbonyal group
Rate of hydrolysis is reduced by
- Dry formulations (powder for reconstitution, solid dosage form)
- Adjusting pH to maximum stability in aqueous solution
- Storage temperature
- Coating
- Choice of packaging
Hydrolysis reduction
Complexation
- Caffeine (a xanthine) complexes with local anesthetics, such as benzocaine and procaine
Hydrolysis reduction
Surfacant
- Drug molecules become trapped in the micelle
Hydrolytic groups such as OH cannot penetrate the micelle and reach the drug molecules
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+
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
- Initiation, Propogation and Termination
Prevent auto-oxidation
Remove initiators
Chelation of trace metals with chelating agents: ethylene diamine tetraacetic acid (EDTA), citric acid & tartaric acid
Prevent auto-oxidation
Exclude oxygen
Sparge liquids with inert gases such as nitrogen to displace oxygen
Prevent auto-oxidation
Add free radicals
- More readily oxidised at lower redox potention
Photochemical degradation
- Energy of a photon increases with decreasing wavelength inverse proportional
- UV light has high energy which can catalyse reactions
- UV light could cause oxidation, polymerisation
- Ring rearrangement
Polymerisation
- A process by which two or more identical drug molecules combine together to from a complex molecule
- UV radiation induces the polymerisation of chlorpromazine
Photolysis
- Decomposition by light
- last for a year without light
- 4 hours with light
Prevent photolysis
- Exclude from light
- Packaging in foil
- Filter out light by
- Storage in amber glass or Coating tablets with pigmented polymers
Zero order reaction
- Degradeation of drug increases as time increases regardless of concention of drug
First order
- Degradeation directally proportional to it concentration
- ln() funtion then it is first order
Pseudoreaction
- lots of solid dissolving degrade dependant on concentration but regardless of concentration
- Initially zero order to first
Second order
- The rate of degradation of A is directly proportional to its concentration and the concentration of the reactant B
- Length of half life increases with decreasing concentration
Acceptable degradeation
Toxicity of degradation products
Antifungal drug flucytosine degrades to fluorouracil (cyctotoxic)
Acceptable degradation
Physical properties of dosage form
Irreproducible dose
Acceptable degradation
Aesthetics (look & feel)
Adrenaline degrades to red adrenochrome (unsightly)
Acceptable degradedation
5-10% loss of overall limit
Expiry date
- Accelerated testing in extream conditions
- measure degradation
Arrhenius equation
Ae^-Ea/RT
Components of Arrenius equation
- ln(a) is y-intercept
- Gradient -Ea/R
- X intercept 1/T
Why Arrhenius?
Duning accelerated testing at high temperature measure degradeation
