L11 - Chemical Kineticts And Stability Of Dosage Forms 1 Flashcards
Why is drug stability important for pharmaceutical products?
They have to remain stable for as long as possible
What does chemical degradation lead to? (2)
- Leads to loss of active product
- potentially toxic degradation
What may instability result in?
Reduced solubility and bioavailability
What does chemical kinetics show us? (2)
- how a drug degrades
- how formulation can be stabilised
What are the common mechanisms of degradation? (3)
- hydrolysis
- oxidation
- other pathways (isomerisation, photochemical degradation, polymerisation)
What is hydrolysis? What can it be catalysed by? How to prevent it?
Most common pathway for drug breakdown
- can be H+ or OH- catalysed
- can modify drug structure to prevent it
What drugs are susceptible to hydrolysis? (3)
Aspirin, procaine (ester)
Penicillins (amide, lactam)
Benzodiazepines (lactam)
What is oxidation commonly via? What is it catalysed by? How to prevent it?
- commonly via peroxy radical (ROO*)
- can be catalysed by action of UV, heat or trace metals
- use antioxidants to mop up radicals
What is isomerisation?
Racemisation, where an enantiomerically pure compound becomes a racemic mixture
How to prevent photochemical degradation? (2)
- amber glass to block UV
- coat tablets with UV-absorbing polymer
When can polymerisation occur?
At high concentrations
Why is it important to know:
- what the degradation mechanism is?
- what the products are and are they safe?
- How stable the drug is in a given formulation
- at what temp it should be stored at?
- should it be stored in a dark place?
- what packaging?
- what is its shelf life?
- can limit the degradation
- is it toxic to the patient
- max stabalisation for long term
- is it susceptible to high temp?
- it is susceptible to photolitic degradation?
- have to consider moisture and gas impermeability
- API - how long is it effective or safe to take
What does the international council for harmonisation of technical requirements for pharmaceuticals for human use (ICH) do?
Agree on different strategies to test medicines to make sure that quality, safety and efficacy are suitable
What are the routes of degradation? (4)
- direct
- dynamic equilibrium
- competitive
- sequential
What is molecularity?
The number of reactant molecules or ions which participate in the rate determining step
What are the different types of molecularity of reactions? (3)
- unimolecular // rate = k[A]
- bimolecular // rate = k[A][B] or [A]^2
- termolecular
What is the law of mass action?
The rate of a chemical reaction is proportional to the product of the molar conc of each reactant raised to a power equal to the number of molecules
What is the order of reaction?
The sum of the powers
What is the order of each reactant?
The power of the reactant in the rate equation
What is the molecularity like in single step reactions (elementary)?
Same as the order
How to plot first order kinetics:
-requires curve to be integrated as a function of time // ln[A] vs t
= because otherwise gradient has to be measure continuously over small time intervals
What is the rate constant?
Describes the reaction profile for a particular set of experimental conditions
What can the rate constant predict? What are the units?
- predicts reactivity
- units are dependent on order of reaction
- always a +ve number
What is shelf life?
The time that a specific drug characteristic remains within a particular specification after manufacture when stored according to the label
t95%
What can shelf life be based on?
The amount of drug remaining or the accumulation of degradation product
First order kinetics step-by-step method: (5)
- calculate ln values
- plot ln vs t
- calculate rate constant k from slope
- calculate half life
- calculate shelf-life
When does a drug go through degradation?
Only when in solution
What assumption is there for degradation in pharmaceutical suspensions?
Will remain constant assuming that Asolid -> Asolution is not rate-limiting
- total [A] decreases, [A]solution remains constant
What is rate like in zero order kinetics?
Rate is independent of conc of reacting species
- [A] solution is constant
= rate is constant
What is the important point for zero order kinetics?
Once the solid particles in suspension are fully solubilised by the solution, degradation will no longer follow zero order
