D

• Why salt?

  Drug absorption in humans is greater than 90% 

  High solubility 
• Techniques to improve solubility

  Salt forms

  Solid dispersion

  Co-crystals: formed by hydrogen bonding

  Micronation: increasing the surface area for more material in solution
• Pros

  increase solubility, dissolution rate, bioavailability, melting point, photostability, taste, processability, synthesis and purification
• Cons

  decrease active % API, decrease chemical stability, increase number of polymorphs, corrosiveness and additional manufacturing steps 
• Salt formation

  Any weak acid + strong base 

  Any weak base + strong acid 

  pKa criteria should not be less than 5 
• Why salt dissolve better (acid equation)

  Weak acid disassociates to form cation and anion 

  React weak acid with base forms sodium salt of acid and water 

  The sodium salt can be disassociated in sodium ions and conjugate base (A-) which accepts a proton to form a free acid 

  Increasing pH 

  This is why acidic salt will dissolve easier 
• Why salt dissolves better (basic equation)

  Base with acid (HCI) gives the conjugate acid 

  Introduce the conjugate base in water forming the free base 

  Conjugate acid BH+ donated a proton B H+ into the solution to form more hydrogen ions 

  This decreases the pH 

  Dissolution of basic salt causes decrease in pH

  pH drop increase dissolution of sakt 
• selection of salt former

  For a transfer of a proton to acid weak base, the pKa of acid must be less than of the weak base 

  pKa has different yields of salt 
• Salt forming criteria

  pKa of drug not less than 5 

  Reactivity potential has to be at least 3 units 

  -       Greater than 3 forming a salt 

  -       Lower than 0 is co-crystals 
• Salt former classes

   

  First-class salt formers 

  -       Physiological 

  -       Biochemical pathways 

  -       E.g., hydrochlorides and sodium 

   

  Second-class salt formers 

  -       Not naturally occurring but commonly used 

  -       Non-toxic 

  -       Sulphuric acid 

   

  Third-class salt former 

  -       Not naturally occurring 

  -       Not in common use 

  -       Special circumstances to solve a particular problem 
• salt screening

  -       A small amount of drug in a solvent 

  -       Solution of potential counterion 

  Solvent selection (Class. 1): non-toxic and environmentally friendly 

  Salt crystals: optical inspection, cooling or heating encourages crystals to be formed 
• Salt analysis

   x-ray diffraction to look at polymorphism 

  Hot-stage microscopy (HSM) to look at crystallinity and melting point 

  Differential scanning calorimetry (DSC) to look at the enthalpy of fusion and melting point 

  TGA (thermogravimetric analysis) 

  DVS (dynamic vapour sorption): hygroscopicity 
• Decision tree

  Tier 1: hygroscopicity if it is high then discard it 

  Tier 2: Physical stability and polymorphs, if it is poor discard it 

  Tier 3: thermal stability if it is poor discard it