kilomentor

Kilomentor continues with his review of the properties and procedures for the manufacture of pharmaceutical salts. The procedures are among the most import in chemical process development and organic synthesis.

It would seem from looking at the names of pharmaceutical products that phosphate anion is a fairly frequently used pharmaceutical salt former, but closer examination reveals that there are actually very few ionic pharmaceutical phosphate salts. Among drug substances called phosphates, the majority are covalent phosphate esters of an alcohol functional group.

Nevertheless, there is a place for the phosphate salts because the monophosphate is probably the most hydrophilic anion used to make pharmaceutical salts. Dihydrogen phosphate anion contains two very polarized hydrogen-oxygen bonds that energetically prefer to exist in a hydrogen bonding, high dielectric medium. When this hydrophilic anion is combined with a large hydrophobic cation, the result is almost always an insoluble salt. To balance this advantage the following disadvantages must be weighed:

· These salts have a high propensity to give several different hydrate pseudopolymorphs.

· phosphoric acid as a viscous oil or very low melting solid that is difficult to manipulate quantitatively.

· phosphoric acid is not miscible with the non-polar organic solvents which are the preferred media for the hydrophobic base partner

· the acid’s hygroscopicity makes weighing more difficult.

Evidence of the hydrophilicity of phosphate is provided by its selection for use in a standard procedure for making those acid addition salts of acids, which are themselves in the neutral form poorly stable, such as nitrates, thiocyanates, perchlorates and fluoroborates.

The procedure is taken from Brandstrom and Gustavii, Acta Chemica Scandinavica 23 (1969) 1215-1218.

To a two phase mixture of 1M aqueous phosphoric acid and methylene chloride or chloroform, add the free base which thereupon dissolves in the aqueous acid. Add sodium nitrate, sodium thiocyanate, sodium perchlorate or sodium terafluoroborate; mix the phases and extract the salt, anion and protonated base, into the organic layer quantitatively. Because the phosphoric acid monoanion is so hydrophilic it does not compete with these anions for extraction into the lipophilic organic layer even though it is present in enormous excess. That phosphoric acid is the bulk acidifying agent used testifies to its preference for the aqueous phase. The pKas of phosphoric acid are K₁ =7.107 x 10^{-3 ;} K₂ =7.99 x 10^-8; K₃= 4.8 x 10^-13.

The literature provides another piece of evidence that ionic phosphates may be good choices for giving solid crystalline salts for a wide range of bases. Helene Perrier and Marc Labelle found the phosphates the second most preferred salts for isolating as salts a wide range of intermediates containing the 3-acylquinoline moiety [J. Org. Chem. (1999), 64, 2110-2113.

Some corroborative information about crystalline phosphate salts comes from an article analyzing salts found in the Cambridge structural Database. http://www.msm.cam.ac.uk/pfizer/pdf/Publications/P03%20(02)%20-%20Occurrence%20of%20Pharmaceutically%20Acceptable%20Anions%20and%20Cations%20in%20the%20Cambridge%20Structural%20Database.pdf

The phosphate dianion was found to have the highest percentage of its salts as hydrates of all the salts examined. According to the authors’ interpretation this suggests that increasing charge on a single ion leads to increasing hydrate formation. They reference another paper that suggests that hydrate formation is a result of an imbalance between the number of hydrogen bond donors and acceptors in a crystal. [Infantes l., Chisholm J. Motherwell S. Cryst. Eng. Comm. 2003, 5: 480-486.]

Some specific examples of procedures are given in the extended text below.

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• Pamoates or Embonates: crystalline Pharmaceutical Salts or Derivatives for Isolation and Purification
• Symmetrical Bis-N,N-(3-nitrophenyl)urea: A Super Co-crystal Former that might have applications in Product Purification.
• The Importance of the Molecular Weight of a Salt Former in choosing a Pharmaceutical Salt
• Reiterating the Objective of the Kilomentor Blog
• The process vision: an integrating strategy in pharmaceutical process development
• Phosphate Pharmaceutical Salts : Chemical Process Development & Organic Synthesis
• Green /Recyclable Solvents: Low Vapour pressure compositions for storage and recycling of solvents that are highly volatile or gaseous at room temperature
• Sulfate Pharmaceutical Salts
• Making the Hydrochloride Pharmaceutical Salt of Basic Drug Substances
• Kilomentor weighs in as “Pharmaceutical Manufacturing Goes Green”.
• Another Way to Separate Phenolics by Crystallizing of Co-crystals?
• The Complete Blog for the Preparation of Pharmaceutical Salts
• Inverted Filtration: A chemical synthesis laboratory technique particularly helpful at 5-10 litre scales.
• Recovering More Product by Crystallization in Organic Synthesis:Trituration with a Modified Water Phase as a Potential Chemical Process Development Method
• Kilomentor moves the discussion from Steam Distillation to other Co-distillations

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