L11 - Chemical Kineticts And Stability Of Dosage Forms 1

Question 1

Why is drug stability important for pharmaceutical products?

Answer 1

They have to remain stable for as long as possible

Question 2

What does chemical degradation lead to?

Answer 2

• Leads to loss of active product
• potentially toxic degradation

Question 3

What may instability result in?

Answer 3

Reduced solubility and bioavailability

Question 4

What does chemical kinetics show us?

Answer 4

• how a drug degrades
• how formulation can be stabilised

Question 5

What are the common mechanisms of degradation?

Answer 5

• hydrolysis
• oxidation
• other pathways (isomerisation, photochemical degradation, polymerisation)

Question 6

What is hydrolysis? What can it be catalysed by? How to prevent it?

Answer 6

Most common pathway for drug breakdown
- can be H+ or OH- catalysed
- can modify drug structure to prevent it

Question 7

What drugs are susceptible to hydrolysis?

Answer 7

Aspirin, procaine (ester)
Penicillins (amide, lactam)
Benzodiazepines (lactam)

Question 8

What is oxidation commonly via? What is it catalysed by? How to prevent it?

Answer 8

• commonly via peroxy radical (ROO*)
• can be catalysed by action of UV, heat or trace metals
• use antioxidants to mop up radicals

Question 9

What is isomerisation?

Answer 9

Racemisation, where an enantiomerically pure compound becomes a racemic mixture

Question 10

How to prevent photochemical degradation?

Answer 10

• amber glass to block UV
• coat tablets with UV-absorbing polymer

Question 11

When can polymerisation occur?

Answer 11

At high concentrations

Question 12

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?

Answer 12

• 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

Question 13

What does the international council for harmonisation of technical requirements for pharmaceuticals for human use (ICH) do?

Answer 13

Agree on different strategies to test medicines to make sure that quality, safety and efficacy are suitable

Question 14

What are the routes of degradation?

Answer 14

• direct
• dynamic equilibrium
• competitive
• sequential

Question 15

What is molecularity?

Answer 15

The number of reactant molecules or ions which participate in the rate determining step

Question 16

What are the different types of molecularity of reactions?

Answer 16

• unimolecular // rate = k[A]
• bimolecular // rate = k[A][B] or [A]^2
• termolecular

Question 17

What is the law of mass action?

Answer 17

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

Question 18

What is the order of reaction?

Answer 18

The sum of the powers

Question 19

What is the order of each reactant?

Answer 19

The power of the reactant in the rate equation

Question 20

What is the molecularity like in single step reactions (elementary)?

Answer 20

Same as the order

Question 21

How to plot first order kinetics:

Answer 21

• 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

Question 22

What is the rate constant?

Answer 22

Describes the reaction profile for a particular set of experimental conditions

Question 23

What can the rate constant predict? What are the units?

Answer 23

• predicts reactivity
• units are dependent on order of reaction
• always a +ve number

Question 24

What is shelf life?

Answer 24

The time that a specific drug characteristic remains within a particular specification after manufacture when stored according to the label

t95%

Question 25

What can shelf life be based on?

Answer 25

The amount of drug remaining or the accumulation of degradation product

Question 26

First order kinetics step-by-step method:

Answer 26

• calculate ln values
• plot ln vs t
• calculate rate constant k from slope
• calculate half life
• calculate shelf-life

Question 27

When does a drug go through degradation?

Answer 27

Only when in solution

Question 28

What assumption is there for degradation in pharmaceutical suspensions?

Answer 28

Will remain constant assuming that Asolid -> Asolution is not rate-limiting
- total [A] decreases, [A]solution remains constant

Question 29

What is rate like in zero order kinetics?

Answer 29

Rate is independent of conc of reacting species
- [A] solution is constant
= rate is constant

Question 30

What is the important point for zero order kinetics?

Answer 30

Once the solid particles in suspension are fully solubilised by the solution, degradation will no longer follow zero order