lecture 12-15

• Ester Hydrolysis


  1. Protonation of the carbonyl group

  2. Nu attack by water

  3. Proton transfers

  4. Final steps - what enables the C-O bond to break
• Water


  Can act as either an acid or a base
• Water catalyses the ester bond
• Acid catalysed ester hydrolysis

  1. Protonation of the carbonyl group

  2. Nu attack by water

  3. Proton transfers

  4. Final steps - what enables the C-O bond to break
• Base catalysed ester hydrolysis

  Hydroxide ion attack
• Products of ester hydrolysis

  Carboxylic acid and an alcohol
• Role of an acid

  Proton donor
• Role of a base

  Proton acceptor
• Alcohol


  Has a lone pair of electrons and can act as either an acid or a base
• Hotter


  Faster
• Ester hydrolysis in formulation vs in vivo
• Prodrug


  Drug in an inactive/significantly less active form which is preferentially activated at the drug target
• LogD


  Coefficient used to measure the lipophilicity of ionisable compounds
• LogP


  Coefficient used to measure the lipophilicity of the unionised species in water
• Pharmacophore


  The 3D spatial arrangement of functional groups that are responsible for a defined pharmacological activity
• Isostere


  Two drug molecules that are the same (a chemical group/part of a molecule which can be considered to be close to equivalent in physical and chemical properties to another chemical group)
• Bioisostere


  A chemical functional group which can replace another chemical group without significantly affecting biological activity of another drug (swapping out like for like)
• Quality assurance


  GLP + GCP + GMP
• Minimum required functions of Medsafe

  • Manufacturing, importation, exportation and wholesale and distribution are licensed and comply with GMP
  • Look to control things like counterfeits
  • Before medicines are marketed they assess their safety, efficacy and quality
• Main components of GMP

  • Production
  • People
  • Premises
• Role of documentation in GMP

  • Standard operating procedure
  • Manufacturing instructions
  • Records
  • Specifications
• Critical quality attributes used to ensure the specification of a manufactured drug

  • API and excipients
  • Identity - chemical and physical description (using spectroscopy)
  • Purity - Using spectroscopy) HPLC
  • Homogeneity - are the impurities below the acceptable safe level
  • Water content
  • Physiochemical properties
  • Microbial contamination
  • Stability
• Role of spectroscopy in drug quality control

  • Different regions of spectroscopy tell different parts of molecules
  • Fingerprint region - many peaks
  • Functional group region
  • Spectroscopy = detection and analysis of electromagnetic radiation
  • Spectroscopy can be used for drug identity, purity and to determine the structure
• Pharmacopoeia


  • Like drug encyclopaedia for known drugs
  • Provides: Verification of identity, Homogeneity (measurement of purity - not measuring the API), Purity
• Medicine dossier


  For unknown drugs
• Types of tests used to measure critical quality attributes

  • Proton or cNMR
  • Mass spectroscopy
  • IR spectroscopy
  • Melting point
• HPLC process


  1. Column is filled with a substance like silica

  2. Mobile phase is passed down column due to gravity

  3. High pressure pump attached to the top of the column generates a high pressure

  4. Stationary Phase - Particle size is kept uniform to obtain better performance

  5. Mobile Phase - Mixture of different solvents used - solvent used depends on which molecules are to be separated (can be polar or non polar)
• Difference between IR and UV spectrum

  • IR is for identifying the structure and functional groups in the drug
  • UV is for identifying the drug
• Interpreting IR spectrum


  • Fingerprint region - Many little peaks, below 1500 wave numbers
  • Functional group region - Can decipher the functional group, Certain frequency regions characteristics of certain bond types, When K starts increasing wave number and frequency shift to a large number --> can now interpret functional groups, Powerful for identifying carbonyl groups - double bond = more stretch