stability of medicines 2

Question 1

What does stability mean? (chemistry terms)

Answer 1

capacity of a product to remain within specifications
to ensure potency, quality or purity

Question 2

What is chemical degradation?

Answer 2

• Decomposition of
  chemical moiety
• Due to effects of
  moisture, oxygen,
  light & heat
• Results in loss of
  active drug

Question 3

What is physical degradation?

Answer 3

• Formulation-specific
• Caking in
  suspensions, phase
  separation in
  emulsions
• Hardness &
  brittleness of tablets

Question 4

What is microbial degradation?

Answer 4

• Microbial
  contamination
• Metabolism of drug
  molecule
• Physical spoilage of
  dosage form
• Infection-causing

Question 5

What may drug instability cause?

Answer 5

• Inconsistent dosage
• Undesired change in performance – dissolution/bioavailability
• Changes in physical appearance of the dosage form
• Product failures

Question 6

What are 4 chemical degradation reactions?

Answer 6

• Hydrolysis
• Oxidation
• Photodegradation
• Polymerisation and dimerisation

Question 7

What happens in hydrolysis?

Answer 7

• Most common chemical degradation
• Water present in many pharmaceuticals
• As ingredient or contaminant
• Carboxylic acid derivatives are common in medicines
• Esters and amides

Question 8

What functional groups are prone to hydrolysis?

Answer 8

Ester
Amide
Imide
Urea
Lactone
Lactam

Question 9

What is the rate of hydrolysis reduced by?

Answer 9

• Dry formulations (powder for reconstitution, solid dosage form)
• Adjusting pH to maximum stability in aqueous solution
• Storage temperature
• Coating
• Choice of packaging

Question 10

What else reduces hydrolysis rate?

Answer 10

• Complexation
• Caffeine (a xanthine) complexes with local
  anesthetics, such as benzocaine and procaine
• Surfactants
• Drug molecules become trapped in the
  micelle
• Hydrolytic groups such as OH cannot
  penetrate the micelle and reach the drug
  molecules

Question 11

What happens in oxidation?

Answer 11

• Second most common pathway for drug breakdown
• 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+

Question 12

What happens in auto-oxidation?

Answer 12

• 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

Question 13

What functional groups are more prone to auto oxidation?

Answer 13

Phenols
Catechols
Aldehydes
Thiols
Thioethers

Question 14

What does circumvention of auto-oxidation do?

Answer 14

• Remove initiators
• Chelation of trace metals with chelating
  agents: ethylene diamine tetraacetic acid
  (EDTA), citric acid & tartaric acid
• Exclude O2
• Sparge liquids with inert gases such as
  nitrogen to displace oxygen

Question 15

What does circumvention of auto-oxidation do? (only addition of…)

Answer 15

• Add free-radical scavengers/antioxidants
• Butylated hydroxytoluene (BHT) more readily oxidised than oils, used to
  stabilise fatty/oily products
• Ascorbic acid possesses lower redox potential than drug, more readily
  oxidised

Question 16

What occurs in photochemical degradation?

Answer 16

Energy of a photon increases with decreasing wavelength
*UV light has high energy which can catalyse reactions

Question 17

What reactions might UV light induce?

Answer 17

*Oxidation
*polymerisation
* Ring Rearrangement

Question 18

What happens in polymerisation?

Answer 18

• A process by which two (dimerisation) or more identical drug
  molecules combine together to from a complex molecule
• UV radiation induces the polymerisation of chlorpromazine (in anoxic
  conditions)

Question 19

What is photolysis and what occurs during this?

Answer 19

• Decomposition by light
• Photolysis of the pentacyanonitrosylferrate (II) ion in sodium
  nitroprusside (administered by IV infusion for the management of
  acute hypertension)
• Protected from light, stable for ~1 year
• Exposed to normal room light, a shelf life of only 4 hours

Question 20

How to prevent photolysis/ photochemical effects?

Answer 20

• Exclude from light by
• Storing in the dark
• Packaging in foil
• Filter out light by
• Storage in amber glass or
• Coating tablets with pigmented polymers

Question 21

What is a zero order reaction?

Answer 21

Drug molecule A →product of degradation
= rate of degradation of A Is independent of the concentration of the reactants

Question 22

What does a zero order reaction graph look like?

Answer 22

picture

Question 23

What is a first order reaction?

Answer 23

*the rate of degradation of A is directly proportional to its concentration

Question 24

What does a first order reaction graph look like?

Answer 24

picture

Question 25

What is a pseudo zero order reaction, what happens?

Answer 25

if the degradation of A follows first order kinetics
observed rate constant is an expression for zero order reaction

Question 26

How does a second order reaction work?

Answer 26

A+B → product degradation
the rate of degradation A is directly proportional to its concentration and the concentration of reactant B

Question 27

second order reaction graph?

Answer 27

picture

Question 28

What happens in pseudo first order reactions?

Answer 28

if B is very high (h2o) or constant (fixed pH)

Question 29

How much degradation is allowed in medicines?

Answer 29

• 5 – 10% loss limit over total shelf life (~ 5 years)

Question 30

What is degradation of medicines/ shelf life dependant on?

Answer 30

*Toxicity of
degradation products
*Physical properties of
dosage form
*Aesthetics
(look & feel)

Question 31

Justification of expiry date and storage conditions

Answer 31

Simply store product under various conditions
* Assess instability at the end of storage period→ TAKES TOO LONG
↓
* Industry/regulatory authorities have evolved specific testing protocols
* Accelerated/stress testing