Drug Stability and Degradation Kinetics

Kinetics

The study of the rate at which processes occur

What are the key points of the rate of reaction?

- Defined by dC/dt

- dC = change in concentration

- dt = change in time

- Depends on reactant concentration, temperature, pH, and solvents/additives

What does it mean when a reaction order is "pseudo-"?

The true order of reaction is the next higher order

t1/2 = C0 / 2k

Zero-order

C = C0 - kt

Zero-order

t90 = C0 / 10k

Zero-order

C = C0 * e^(-kt)

First-order

log C = log C0 - kt / 2.303

First-order

t1/2= 0.693 / k

First-order

t90 = 0.105 / k

First-order

What are the key points of pseudo-zero-order reactions?

- Suspensions

- Drug degrades via first-order pathway

- Drug dissolves continuously in a zero-order pathway

- Maintains solution concentration at saturation level, despite loss due to degradation

kt = 1/C - 1/C0

Second-order

t1/2 = 1 / C0 k

Second-order

What are the key points of pseudo-first-order reactions?

- Second-order reaction, but appears to be first-order

- Concentration of second reactant does not change significantly

- Hydrolysis of ester drugs

Parallel (simultaneous) reactions

Two mechanisms occurring at the same time

Consecutive (series) reactions

Multiple steps and rate processes at different time points

What determines the overall rate of a reaction?

Slowest step

How is hydrolysis prevented?

- Coat tablets with polymers

- Prevent contact with water

How is oxidation prevented?

- Coat tablets with polymers

- Flush packaging with nitrogen and carbon dioxide

- Add antioxidants

- Package in a hermetically sealed container

- Prevent contact with oxygen

How is photolysis prevented?

Packaging in opaque or amber-colored container

What determines stability and shelf-life?

- t90

- Assume first-order unless stated otherwise (suspensions)

What are the key points of accelerated stability testing?

- Artificial stressors are introduced to accelerate reaction

- Mathematical conclusions are extrapolated

- Temperature and high humidity are most common stressors

Who sets the standard conditions for stability testing?

International Conference on Harmonization

What are the key points of the Arrhenius method?

- Models how reaction rate increases with temperature

- R = gas constant

- Ea = energy of activation

- The most complicated reaction on the equation sheet

How does temperature affect reaction rate?

- Doubles for every 10*C rise in temperature

- Alters the free energy of reactant

- Affects activation energy

How do solvents affect reaction rate?

- Alter the activity coefficient of the molecules

- Physiochemical parameters indirectly affect rate

How do additives affect reaction rate?

- Surfactants may increase or decrease degradation

- Complexing agents improve drug stability

What are the key points of efflorescent powders?

- Contain water that may be released due to stress

- Solid dosage form turns damp and pasty

What are the key points of hygroscopic and deliquescent drugs?

Absorb moisture from air

What are the key points of eutectics?

- Two substances that may liquefy when mixed

- Problem for solids and powders

- Advantage for liquids or semi-solids

What are the strategies for drugs prone to liquifaction?

- Tight containers

- Moisture absorber pouches

- Built-in moisture absorbers (magnesium carbonate)

What are the key points of polymorphism?

- Drugs that exist in different crystalline structures

- Different structures are not necessarily therapeutically the same

- Cocoa butter