Order of Addition and Other Variables in the Crystallizing or Precipitating Organic Ions as Salts

There are a variety of protocols available for bringing the particular cation and particular anion together that are expected to form a salt that either advantageously crystallizes or precipitates.

Mixing a Stoichiometric Ratio of Acid and Base in a Solvent and:

1. Cooling to a lower temperature
2. Adding a miscible anti-solvent or condensed soluble 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
7. Evaporating to dryness

The Above is the Most Direct and Obvious but there are Other Methods of Formation

1.   Exchange of Ammonium Salt with Nonvolatile Metal Chloride

Exchange an ammonium cation for a different but non-volatile cation selected to create a more insoluble salt of an organic anion and as a coproduct volatile/soluble ammonium chloride.

2. Exchange of formate/acetate/trifluoroacetate/thiocyanate Salt with a Non-volatile Acid

    These four anions have volatile protonated forms. If a     salt of one of these acids is mixed with an organic acid and evaporated to dryness the formic acid, acetic acid, trifluoracetic acid or thiocyanic acid will be driven off leaving a residue of the desired salt.

3. Double Decomposition Reactions

Metathetical reactions between a salt solubilized by the presence of a particular cation and a salt solubilized by the presence of a particular anion to give an insoluble and a 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 Mixing

1. Direct addition

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

2. Inverse addition

Addition of the 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 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

  This is a simultaneous mixing that gives small crystals    that avoids any grinding step to control crystal size

5. Impinging Streams of Acid and Base
   

    This is a simultaneous mixing that gives small crystals that avoids any grinding step to control crystal size  In this situation the neutralizing reaction occurs in the impinging streams.

Methods for Precipitating Salts

1. Crystallization by Diffusion of an Ant-Solvent

Dissolution of the salt in some solvent composition in which it is soluble followed by the addition of a partially immiscible anti-solvent creating two phases wherein the salt is soluble in neither. An example is to dissolve a compound in acetonitrile and then layer it with hexane. Some hexane migrates into the acetonitrile causing crystallization.

2. Partial Evaporation of a Single Volatile Solvent

  The classical method: The components are dissolved in a    volatile solvent and the solvent volume is reduced either by boiling or slowly by evaporation.

3. Lyophilization/Inorganic Salt Removal

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

4. Slurry to Slurry

The 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.

5. Precipitation by pH Adjustment

The dissolving of the pharmaceutical candidate in a partially aqueous solution is followed by the adjustment of the pH gradually by the hydrolysis of a solution component. For example, methyl acetate and base to give acetate and methanol; ethyl carbamate and acid giving ammonia, carbon dioxide, and ethanol.

6. 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.

  7. Evaporative Precipitation

 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.