L17 - Drug Solubility and Dissolution Rate 2

• Kw

  
  

  (what is it? what's it equal to? what's the eqn?)

  The ionic product of water

  
  

  = 1 x 10^-14 at 25°C

  
  

  pKw = pKa + pKb
• Henderson-Hasselbalch equation

  
  

  (what does it show? what is it for weak acids and weak bases?)

  - shows degree of ionisation as a function of ph

  
  

  log [A-]/[HA] = pH - pKa

  
  

  
  

  log [B]/[BH+] = pH - pKa

  
• Dissolution rate


  The rate at which a solid substance dissolves in a solvent
• How can you increase the solubility of weak acids?


  - ionised forms are more soluble

  
  

  - so increase pH to increase % ionised form and increase solubilty

  
  

  - use a salt with +ve ions, eg sodium ibuprofen. Dissolution of a salt of a weak acid increases pH so more is ionised and solubility increases

  
• S0


  saturation solubility of undissociated acid/base

  
  

  aka intrinsic solubility
• What eqn can be used to predict solubility of a solution with weakly acidic drugs?

  log Cs-S0 / S0 = pH - pKa

  
  

  where Cs = total saturation solubility of weakly acidic drug. (conc at which solution is saturated)

  
  

  
  

  s0 = saturation solubility of UNionised form of drug

  
• What factors do you need to predict solubility of a weak acid/base?


  - pH of solution

  - pKa

  - S0: intrinsic solubility. Total solubility of UNIONISED form of the drug
• What's Cs (total saturation solubility) when pH = pKa?


  when pH = pKa, ph-pKa = 0 .

  
  

  So Cs = 2 x S0

  
• Henderson-Hasselbalch equation for a weak acid

  pH = pKa + log([A-]/[HA])
• Henderson-Hasselbalch equation for a weak base

  pH = pKa + log([B]/[BH+])
• % ionised form of a weak acid

  The percentage of a weak acid that is in the ionized form at a given pH
• % ionised form of a weak base

  The percentage of a weak base that is in the ionized form at a given pH
• Solubility of weak acids as a function of pH

  
  

  (what happens to it a) for each pH unit above pKa? b) as pH decreases below pKa? c) when pH=pKa?)


  a) increases x10 for each pH unit above pKa

  
  

  b) approaches S0

  
  

  c) solubility = 2x S0

  
• Solubility of weak bases as a function of pH

  
  

  (what happens to it a) for each pH unit above pKa? b) as pH decreases below pKa? c) when pH=pKa?)


  a) increases x10 for each pH unit below pKa

  
  

  b) approaches S0

  
  

  c) solubility = 2x S0

  
• Eg - Below what pH will phenobarbital ( a weak acid) begin to precipitate from a solution containing 1.3%w/v of Na phenobarbitol?

  
  

  Solubility of free acid = 0.005M

  pKa = 7.41

  Mw=254


  - convert to molar

  - substitute values into eqn

  
  

  pH = 8.37

  
• How can you increase the solubility of weak bases?


  - ionised forms are more soluble

  - sodecrease pH to increase % ionised form and increase solubilty

  - use a salt with -ve ions, eg lidocaine HCl. Dissolution of a salt of a weak base decreases pH so more is ionised and solubility increases

  
• What eqn can be used to predict solubility of a solution with weakly basic drugs?


  log s0 / (Cs - s0) = pH-pKa

  
  

  
  

  where Cs = total saturation solubility of weakly basic drug. (conc at which solution is saturated)

  
  

  
  

  s0 = saturation solubility of UNionised form of drug

  
• Eg at what pH will thioridazine (weak base) begin to precipitate from a solution containing 0.407% w/v of HCl salt?

  
  

  solubility of free base = 1.5x10^-6 M

  pKa = 9.5

  Mw = 407

  - convert to molar, then moles

  
  

  pH = 5.68

  
• What happens if the salt of a weak


  acidis used instead of the free form?- pH of solution increases

  - solubility increases

  - BUT if solution pH lowers, precipitation of free form acid may occur
• What happens if the salt of a weak


  baseis used instead of the free form?- pH of solution decreases

  - solubility increases

  - BUT if pH of solution is increased, precipitation of free base may occur