W7 L1 - Drug Stability - notes made

Question 1

why is drug stability important

Answer 1

• For patient - If the medicine decomposes, treatment will be ineffective or decomposition products may be toxic.
• For pharmacist - Financial loss if stock expires (BBD: best before date).

Question 2

2 processes that affect stability

Answer 2

• hydrolysis
• free radical oxidation

Question 3

conditions for hydrolysis of esters

Answer 3

• slow hydrolysis under neutral conditions
• catalysed by acid or base

Question 4

which chemicals are susceptible to hydrolysis

Answer 4

esters

Question 5

are amides more or less prone to hydrolysis and why

Answer 5

• less prone so more stable
• resonance makes amide bond stronger and more stable

Question 6

why is aspirin not formulated as a salt

Answer 6

• most stable at pH 2.5
• salts would increase pH, making it more basic so aspirin would be less stable

Question 7

why are cyclic amides (beta-lactam rings) less stable

Answer 7

• steric strain due to 90 degree angles
• angles would normally be tetrahedral 109.5 or 120 for carbonyls
• Lactam cleaves to inactive penicillinoic acid

Question 8

Esters & beta-Lactam Drugs: How to minimise hydrolysis

Answer 8

1. More stable in the solid form-
   Penicillins are powders: Pharmacist adds water to give a suspension.
2. Know pH rate profile of hydrolysis-
   Formulate medicine at a pH where rate of hydrolysis is low.
3. More stable at low temperatures-
   Advise patient to store medicine in fridge to minimise hydrolysis.
4. Storage (Packaging)-
   Airtight container or blister packs, to keep out water.

Question 9

Drugs susceptible to free radical oxidation

Answer 9

• Drugs containing the phenol group, especially catechols.
  e.g. morphine, paracetamol, catecholamines (adrenaline).
• Drugs containing an aromatic amine
  e.g. prilocaine (local anaesthetic)
  or primaquine (malaria).
• Drugs (or excipients) with unsaturated groups
  e.g. ethyl oleate, vitamin A, Omega-3 fish oils

Question 10

free radical definition

Answer 10

reactive species with an unpaired electron in the 2nd shell (only 7 electrons)

Question 11

formation of free radicals is catalysed by

Answer 11

• light (via homolytic fission/cleavage)
• metals
• oxygen

Question 12

How do you prevent light from causing free radical oxidation

Answer 12

• blister packs
• brown bottles
• cardboard cartons to protect from light

Question 13

Formation of free radicals due to oxygen

Answer 13

• R* radical (from light) reacts with O=O to give a reactive peroxide radical (R-O-O.).
• Oxidation and degradation of drugs (see autoxidation of polyunsaturated compounds).

Question 14

How to prevent oxygen from causing free radical substitution

Answer 14

• Exclude oxygen
  -Store medicines in well filled, tightly-closed containers.
  -Add an ‘inert’ gas, e.g. nitrogen, carbon dioxide

Question 15

Formation of free radicals by metals

Answer 15

Transition metals can accept an electron and initiate RADICAL formation in drug R-H.
Fe3+ __+e___> Fe2+
R-H + Fe3+ _____> Fe2+ + R. + H+

Question 16

How to prevent metals from causing free radical substitution

Answer 16

• add a metal chelating agent, e.g. ethylenediaminetetraacetate (EDTA).
• chelating agent - a chemical compound that binds tightly to metal ions

Question 17

Another way of preventing free radical oxidation

Answer 17

• addition of anti-oxidants
• avoids self-propagation
• Mops up radicals or forms STABILISED radicals that do not continue the chain reaction.
  e.g. VITAMIN C (ASCORBIC ACID)

Question 18

GO OVER MECHANISMS ON THE PPT