Methods for Forming and Crystallizing Organic Salts particularly Pharmaceutical Salts

 

Most Common Method for Forming Salts

Mixing  stoichiometric proportions of acid and base in a suitable solvent; then

1. Cooling to a lower temperature
2. Adding a miscible anti-solvent or liquefied gas
3. Adding an immiscible  or partially miscible anti-solvent
4. Drowning out in a miscible anti-solvent
5. Slowly adjusting the pH
6. Use of the common ion effect to decrease the salt’s solubility

Other Methods

1. Exchange of Ammonium Salt with Nonvolatile Base

An exchange between ammonium salt and another non-volatile cation to give a more insoluble salt of an anionic drug.

2. Exchange of formate or acetate or thiocyanate salt with a non-volatile acid

3. Double Decomposition Reactions

Metathetical reactions between a salt solubilize by the presence of a particular cation and a second salt solubilized by the presence of a particular anion giving one insoluble salt and one soluble salt from which the insoluble salt is recovered by filtration and washing.  

The use of metal salts of 2-ethyl hexanoic acid for the basification of organic acids is an example.

Methods for 

1. Direct addition

Addition of a solution of the salt-forming acid or base slowly into a solution or slurry of the pharmaceutical product whose salt is sought.

2. Inverse addition

Addition of the pharmaceutical salt capable species, either as a solid or as a solution into at least a full equivalent quantity of the salt-forming reagent.

3. Slow addition of poorly soluble neutral species by extraction

Extraction of the pharmaceutical salt capable species from a Soxhlet extractor by hot solvent and quench of the extracted species by an excess of the salt-forming reagent in the boiler of the extraction apparatus.

4. Impinging Streams of Salt Solution and Anti-solvent

5. Impinging Streams of Acid and Base
   

Methods for Precipitating Pharmaceutical Salts

Crystallization by Diffusion of an Ant-iSolvent

Dissolution of the salt in a mixture of solvents followed by the addition of an immiscible third solvent creating two phases in both of which the salt is insoluble.

Partial Evaporation of a Single Volatile Solvent

Partial Evaporation of a Mixed Solvent System

      Dissolving the pharmaceutical salt in a mixed solvent of a less volatile poorer solvent and a more volatile better solvent and then removing the better solvent by distillation of evaporation..

Lyophilization/Inorganic Salt Removal

Lyophilisation (freeze-drying) of a solution. Dissolution in methanol and filtration to remove inorganic salts.

Slurry to Slurry

Transformation from a slurry of the slightly soluble pharmaceutical acid or base candidate into a slurry of the desired salt form until a method of solution analysis shows equilibrium.

Precipitation by pH Adjustment

Dissolving of the pharmaceutical candidate in a partially aqueous solution followed by adjustment of the pH gradually by the hydrolysis of a solution component. For example: methyl acetate and base giving acetate and methanol; ethyl carbamate and acid giving ammonium carbon dioxide and ethanol.

Solvent Expansion

Dissolving the pharmaceutical salt or making the pharmaceutical salt in solution and then exposing the solution to a volatile anti-solvent so that the composition slowly becomes more insoluble