MOD 1

• DEFINE DRUG QUALITY


  the fitness of a medicine for its intended use
• what determines drug quality

  • how safe it is
• what determines drug quality

  how efficient it is
• Drug discovery process "pipeline"

  1. Discovery

  2. Non-clinical (safety)

  3. Clinical (efficacy and safety)

  4. Getting Drug Approved by FDA

  5. Manufacturing and distribution to the market
• Discovery stage


  Finding a drug lead and then synthesising an analogue [fragment fragment-based design]
• Non-clinical stage


  Testing on animals, good laboratory practices [GLP]
• Clinical stage


  Testing on humans, good clinical practices [GCP]
• Getting Drug Approved by FDA stage

  Approval by FDA
• Manufacturing and distribution to the market stage

  Manufacturing and distribution to the market
• Difference between Drug Discovery and Manufacture

  Discovery: identifying potential drug candidates; focus on efficacy, with limited concern for cost. Manufacture: optimizing drug production; focus on scalability, cost, and safety.
• Drug discovery (research and development)

  • Screening and scale up
  • Emphasis is on improving efficacy of chemical properties
  • Limited focus on the cost
• Drug manufacture (process development)

  • Scaling up - safety considerations
  • Toxicity of impurities are amplified
  • Low yield - purification issues
  • Optimising the drug's synthetic procedure
• Importance of packaging


  • Packing helps reduce degradation (UV radiation, heat etc)
  • Plays major role in the stability of the medicine
  • Helps reduce contamination
  • Ensures correct medication and dosage
  • Makes brands recognisable --> build trust w/ consumers
• Acid


  Proton donor
• pKa


  Measures strength of the acid - how easily a proton is lost
• Carboxylic acids


  • R-COOH
  • pKa values from 3-5
  • Carboxylic acids are acidic because of the polar RZ-H bond and a stabilised conjugate base (through resonance)
  • Forms a salt - helping w/ solubility
• Sulfonamides


  • Acidic because of polar N-H bond (creates dipole moment) (S-N and double bonded to O)
• Tetrazoles


  • 5 membered aromatic ring w/ 1 acidic proton
  • Bioisotere of carboxylic acid
• Enols


  • Alkene attached to alcohol
  • Polarised Z-H bond
  • Stability of the conjugate base depends on the R group
• Estimate the percentage ionisation of a drug with an acidic functional group at a specified pH
• Base


  Proton acceptor
• pKa (of a base)


  Measures the strength of the conjugate acid (the protonated form of a base)
• Amines


  • N-H
  • Aliphatic Amines are basic and have a pKa of 9-11
  • Aromatic amine - aromatic ring reduces basicity - weak base
  • Heterocyclic amines - the nitrogen is part of a ring (pKa 9-10/9-11)
• Imines


  • C=N
  • Double bond as opposed to amine
• Amine reactivity


  • Amines are reactive due to resonance
  • Polar bond creates a dipole moment - uneven spread of charge --> reactivity
  • Chemically stable but not biologically stable
  • More H bonds = higher melting and boiling point + more H bonds in solvent --> more soluble
• Alcohol


  • OH- (hydroxyl group)
  • Oxygen has two pairs of non bonded electrons
  • Good at hydrogen bonding
• Thiol


  • Very basic (weak acid)
  • SH - like alcohol but has sulfur instead
  • Stronger nucleophiles and more acidic than analogous alcohols (pKa 10)
• Types of carbonyl containing functional groups

  • Aldehyde
  • Carboxylic acid
  • Ketone
  • Amide
  • Imine
  • Ester

  
• Prodrug


  Drug in an inactive/significantly less active form which is preferentially activated at the drug target
• Prodrugs often involve ester hydrolysis - required for activation
• Prodrugs are types of esters
• Reasons why prodrugs are used

  • Get the drug across the membrane to where it needs to go - increasing lipophilicity
  • Improve oral bioavailability of a drug
  • Decrease off target toxicity of a drug
  • Increase Lipophilicity of a drug
  • Increase hydrophilicity of a drug
  • More specific targeting of a drug
  • Improve patient tolerance during administration of a drug (e.g. Taste)
  • Prolonged/slow release
• Hydrogen bonding


  Polar- requires very polar Z-H partner to be present (commonly O or N)
• Reactivity


  Uneven sharing of electrons creates a dipole moment --> reactivity
• Stability


  Dipole moment --> less stable
• Aldehyde


  • Can't hydrogen bond w/ itself because there is no hydrogen attached directly to the oxygen
  • Prone to further redox reactions because of the presence of the hydrogen atom = reactive

  
• Carboxylic acid


  • Uneven sharing of electrons creates a dipole moment à reactivity
  • Dipole moment à less stable
• Ketone


  • Ketones cannot H bond together --> because the C-H bind is not electronegative enough to create a dipole
  • Unreactive due to the presence of the alkyl group provides steric hinderance to nucleophilic attack
  • More stable than aldehydes because of alkyl group - used often in drugs

  
• Amide


  • Can hydrogen bind w/ themselves --> therefore have high boiling and melting points + good solubility
  • Chemically unreactive due to resonance (electron sharing)
  • Non bonding pair of electrons of the N are delocalised into the adjacent carbonyl group --> cannot be protonated = no basic properties
  • Much less reactive to nucleophiles @ the carbonyl carbon (C=O) that ketones, aldehydes and esters
  • Stable due to resonance (sharing of electrons)

  
• Imine


  • Polar but cannot H bind w/ itself because no hydrogen directly attached to the oxygen atom
  • Prone to hydrolysis because they have a polarised C=O bind and the C-O bond cannot be broken --> because it is between two electronegative atoms
  • Unstable because of lack of hydrogen bonds