stability of drugs

• what is the importance of the stability of drugs?

  • Important for the patient: If the medicine decomposes, treatment will be ineffective or decomposition products may be toxic.
  • Important for the pharmacist: Financial loss if stock expires (BBD: best before date).
  • Need Long shelf-life and appropriate storage conditions. To make sure it doesn’t decompose quickly.
• what should be considered (mechanisms) when looking at the stability of drugs?

  Degradation via Hydrolysis and Free Radical Oxidation
• which functional groups of drugs are degraded via hydrolysis?

  Esters, amides.
• hydrolysis of esters:

  • slow hydrolysis of esters under neutral conditions
  • hydrolysis of esters: catalysed by acid or base
• example of an ester: aspirin?

  Hydrolysis to salicylic acid and ethanoic acid

  
• describe this pH rate profile of aspirin.

  • from the profile, it shows that aspirin gets catalysed by acid (pH1) and base (pH 11)
  • most stable at pH 2.5, hence formulated as free acid (not salt) and so stable in the stomach environment.

  
• amide hydrolysis:

  more stable to hydrolysis than esters because of the resonance structure

  
• hydrolysis of cyclic amides:

  • beta-lactam ring is less stable
  • this ring in penicillins can hydrolyse due to steric strain in the 4-membered ring
  • the cyclic is forced to have a bond angle of 90º due to the cyclic 4-membered ring and so less stable and more susceptible to hydrolysis (unstable)
  • reason why it needs special formulations e.g. suspensions → they also have to make it up on-site and on-demand
  • lactic cleaves to inactive penicllinoic acid
• how to minimise hydrolysis:

  1. More stable in the solid form-

  • Penicillins are powders: The pharmacist adds water to give a suspension.

  2.  Know pH rate profile of hydrolysis-

  • Formulate medicine at a pH where the 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.
• which drugs are susceptible to free radical oxidation?

  • 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
• Free radicals:

  • FREE RADICAL: reactive species with an unpaired electron in the 2nd shell (only 7 electrons)
• formation of free radicals can be catalysed by what?

  • light
  • metal
  • oxygen
• formation of free radicals - light:

  • Absorption of light energy (eg sunlight) can cleave a susceptible bond in a drug to give a ‘stabilised’ RADICAL & hydrogen radical
  • Homolytic bond cleavage:

  
• a way to prevent the formation of free radicals via light:

  Prevention-Packaging: store medicines in blister packs, brown bottles or cardboard cartons to protect from light.
• Formation of free radicals: OXYGEN-

  ...

  A) peroxide

  B) oxygen

  
• preventing the formation of free radicals via oxygen:

  • Prevention: Exclude oxygen
  • store medicines in well-filled, tightly-closed containers
  • add an inert gas e.g. nitrogen
• Formation of free radicals: METALS-

  e.g. with iron

  A) accept

  
• prevention of the formation of free radicals via metals:

  • Prevention: add a metal chelating agent, e.g. ethylenediaminetetraacetate (EDTA)

  
• free radical oxidation of Catechol-

  • oxidation off catechol is more rapid at basic pH
  • adrenaline contains the catechol group - formulated as the tartaric acid salt, to keep it at an acidic pH

  A) red/brown

  
• free radical oxidation of aromatic amines:

  ...

  A) dimer

  B) coloured

  
• free radical oxidation of polyunsaturated compounds:

  • an autoxidation reaction
  • occurs when butter goes rancid/ rubble goes brittle

  A) omega-3

  
• prevention of autoxidation/free radial oxidation:

  • Radicals (e.g. peroxyl ROO.) will form, therefore to avoid their self-propagation, TRAP with an ANTI-OXIDANT.
  • Mops up radicals or forms STABILISED radicals that do not continue the chain reaction.
  • e.g. VITAMIN C (ASCORBIC ACID)
  • e.g. BHT (butylated hydroxytoluene)
  • e.g. Vitamin E (alpha-tocopherol)