Lecture 11 - Chemical kinetics and stability of dosage forms 1 Flashcards
Why is it important that pharmaceutical products remain stable for as long as possible?
Chemical degradation leads to the loss of active product- loss of potency and potentially toxic degradation.
instability can also lead to reduced solubility and bioavailability.
Name five mechanisms of degradation of drugs
hydrolysis, oxidation, isomerization, photochemical degradation, polymerisation.
Hydrolysis is the most common pathway for drug breakdown. Why drugs may be degraded through hydrolysis?
aspirin, procaine (esters), penicillin’s (amide, lactam) and benzodiazepines (lactam)
Hydrolysis of drugs may be ……… or ……….. catalysed
H+
OH-
It may be possible to modify drug structure to prevent….
hydrolysis
Oxidation is common in drugs like…
steroids and sterols and polyene antibiotics (C=C), ethers and sulphur groups
Oxidation commonly occurs via
peroxy radical- ROO.
Oxidation can be catalysed by…
Can be catalysed by action of UV, heat or trace metals
Describe izomerization
Racemization- a pure enantiomer becomes a racemic mixture
Describe photochemical degradation. How can it be prevented?
amber glass to block UV- tablets can be coated with a UV absorbing polymer
Polymerisation of drugs occurs at ….
high concentration
give four routes of degradation.
- Direct (A –> B where K is the rate constant). This is what we will look at
- Dynamic equilibrium
- Competitive
- Sequential
What is the molecularity of a reaction??
the number of reactant molecules or ions which participate in the rate determining step
Molecularity of reaction:
Reactions maybe unimolecular, bimolecular or even termolecular. Give rate equations of each
Termolecular = Rate = [A]^3
Termolecular reactions are very rare in ………. . They occur more commonly in…?
solution
gas phase
What is the law of mass action?
When you have a number of reactants reacting together, the rate = rate constant multiplied by the concentration of reactants raised to a power equal to the number of molecules.
What does the order of reaction tell you?
tells you how the reactants concentration effects rate.
If you double the concentration of a reactant and the rate stays the same, the order with respect to that reactant is……..
0
If you double the concentration of a reactant and the rate doubles, the order with respect to that reactant is…
1
If you double the concentration of a reactant and the rate quadruples. the order with respect to that reactant is…
2
The overall order of reaction =
the sum of the powers of the reactants in the rate equation
We cannot just observe an equation to find order, we need to…
know the individual order of each reactant and we do this through experimentally working them out
The order is usually as small whole number but it can be….?
a fraction or zero
give the basic rate equation for a first order reaction.
- Rate= K[A]1
How could you find the rate of a first order reaction using a concentration-time graph? Write an equation for this.
The gradient of the tangent of the concentration-time graph of the first order reaction is the rate. The change in [A] divided by the change in time = Rate.
Rate = (Δ[A])/ΔT = K[A]
What is the integrated first order rate equation?
The units of the rate constant depend upon the
order of reaction
use the units given
K is always…
positive
Integrated equation for rate constant for a first order reaction
First order half life:
At half life, how much of the drug remains?
HALF the concentration of the drug
Half life for first order reaction equation
Define shelf life.
Shelf life of a medicine is the time that a specific drug characteristic remains within a particular specification after manufacture when stored according to the label.
Shelf life can be based upon one of two things..
- Can be based on the amount of drug remaining or the accumulation of degradation product.
shelf life may be estimated mathematically through
extrapolation
In our lectures, shelf-life was defined as…
95% of the label dose.
Give equation for shelf life of first order reaction.
In a first order reaction, shelf life is intendent of…
initial concentration of the drug.
We can find the ratio between half life and shelf life. Give the equation for first order.
Give the step by step method to find k, half life and shelf life using time and concentrations of a drug.
Calculate ln values from the data
Plot ln of residual % drug versus time on linear graph paper
Calculate rate constant k from slope (m = -k)
Calculate half-life (t½ = 0.693 / k)
Calculate shelf-life (t95% = 0.0513 / k)
Describe untrue/pseudo zero order. Use suspensions to explain.
- In a 1st order reaction, the rate decreases throughout the reaction because the concentration of A decreases.
- But, if drug A could be replenished, the rate would be a constant. For example, suspensions.
- In suspensions, there are solid undissolved particles and also a percentage of the drug in solution. The drug will only degrade in solution.
- A in solution is replenished by dissolution of solid drug particles- this keeps the concentration of A constant.
pseudo/untrue zero order:
The constant concentration = constant rate. Therefore, what would the concentration-time graph look like?
straight line with negative gradient.
What is the integrated zero order equation?
Graphical zero order K equation
Zero order half life equation
zero order shelf life equation
In zero order, the shelf life is indepedent of…..
initial concentration
Give the equation for ratio of half life to shelf life in zero order reactions
in pseudo zero order reactions, once the solid particles in suspension are fully solubilized in solution…?
Once the solid particles in suspensions are fully solubilized in solution, the degradation will no longer follow zero order. You then get first order degradation.
In first order reactions, a plot of ln[A] against time gives a straight line with a slope of = -k. How does this differ to zero order?
in zero order, a plot of [A] against time fives a straight line with a slope of = -k
In first order, K is described in terms of seconds-1. How does this differ to zero order
SI units of zero order = moles, litre, seconds
For first order, shelf life is independent of initial concentration. How does this differ to zero order?
Shelf life is dependent on initial concentration.
