Phosphate Pharmaceutical Salt Preparations

Kilomentor continues with his review of the properties and procedures for the manufacture of pharmaceutical salts.  The procedures are among the most important 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 is 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 difficult.

Evidence of the hydrophilicity of phosphate is provided by its selection as a reagent in a procedure for making  acid addition salts, wherein the acid salts being prepared are poorly stable, such as nitrates, thiocyanates, perchlorates, and fluoroborates. The procedure is taken from Brandstrom and Gustavii, Acta Chemica Scandinavica 23 (1969) 1215-1218. The method is:

To a two-phase mixture of 1M aqueous phosphoric acid and methylene chloride or chloroform, add the free base from which you want to make a salt. It thereupon dissolves in the aqueous phosphoric acid. Add sodium nitrate, sodium thiocyanate, sodium perchlorate, or sodium terafluoroborate; mix the phases. The salt between the base of choice and the chosen anion is extracted into the organic layer quantitatively, Because the phosphoric acid monoanion is so hydrophilic it does not compete with any of 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 procedure avoids actually handling any of nitric, thiocyanic, perchloric or fluoroboric acids.

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 isolation of 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 [see figure].  According to the authors’ suggested explanation 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 examples of making phosphate pharmaceutical salts are collected below.

WO/2006/033007

Example 1 :

Preparation and Characterization of Polymorphic Form IV (Methanol Solvate) of the phosphate salt of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H- azepino[5,4,3-cd]indol-6-one

A 500 mL round-bottom flask was charged with the compound 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1-, 3,4,5- tetrahydro-6H-azepino[5,4,3-cd]indol-6-one represented by formula 1 (1.65 g, 5.10 mmol, 1.0 equiv.) and methanol (200 ml). The mixture was agitated until a clear solution was obtained (~10 minutes). A 0.5 M phosphoric acid solution in methanol (11.0 ml, 5.87 mmol, 1.15 equiv., prepared by dissolving 0.7 g of 85% phosphoric acid in 11.0 mL of methanol) was added. The resulting mixture was stirred for 30 minutes at ambient temperature. The solids obtained were filtered and dried at 45°C to afford polymorphic Form IV of the phosphate salt of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H- azepino[5,4,3-cd]indol-6-one (1.43 g).

Comment:

A 15% excess of acid is used in the salt formation. It is not indicated whether the excess is required or useful. Presumably, this excess remains dissolved in the solvent, which is exclusively methanol.  A titrated molar solution of phosphoric acid in methanol is used to dispense the phosphoric acid.  This may be a useful solution to the problems working with neat phosphoric acid. The salt apparently precipitated from the homogenous solution without seeding, cooling, or the use of any anti-solvent.

WO/2005/0240027

Example 1

Preparation of Form I Carvedilol Dihydrogen Phosphate Hemihydrate

A suitable reactor is charged with acetone. The acetone solution is sequentially charged with carvedilol and water. Upon addition of the water, the slurry dissolves quickly. To the solution is added aqueous H3PO4. The reaction mixture is stirred at room temperature and carvedilol dihydrogen phosphate seeds are added in one portion. The solid precipitate formed is stirred, then filtered, and the collected cake is washed with aqueous acetone. The cake is dried under vacuum to a constant weight. The cake is weighed and stored in a polyethylene container.

Comment:

The order of addition in the example seems strange. Typically solid is added to a reactor followed by the addition of the solvent or solvents. This is particularly true on-scale because it is not safe to open a reaction charged with organic solvent because the vapor can be a fire hazard.  Perhaps the carvedilol is only soluble in a mixture of water and acetone.  It appears that just enough water is added to get a solution of the free base.  In this example, an aqueous solution of phosphoric acid is the reagent.  There is apparently no immediate solid formation. Carvedilol dihydrogen phosphate crystal seeds are added. The example does not teach, as it should, in what solvent they are slurried and what was done to properly wet the seeds. These are important experimental aspects that should not be ignored. Apparently cooling is not used to increase the precipitation of salt.  The wash solvent is not specified more than that it is aqueous acetone.  Often a mixture slightly richer in the poorer solvent is used in washing to make sure the solid is not partially redissolved.

Example 6

Form VI—Carvedilol Hydrogen Phosphate Preparation

A suitable reactor is charged with acetone. The acetone solution is sequentially charged with Carvedilol and water. Upon addition of the water, the slurry dissolves quickly. To the solution is added aqueous H3PO4 (at ½ the molar quantity of Carvedilol). The reaction mixture is stirred and allowed to crystallize. The solid precipitate formed is stirred and cooled, then filtered and the collected cake is washed with aqueous acetone.

Comment:

This is an unusual example of the formation of a 2:1 base phosphate salt.  The stoichiometry is controlled by limiting the amount of phosphoric acid.  Apparently, crystallization occurs without seeding. This phosphate may be the kinetically faster forming one and may explain the need for seeds in the previous example. Here cooling is used to increase the recovery of solid.

US4255582

EXAMPLE 3

Preparation of the phosphoric acid salt of (-)-a-{2-[bis(1-methylethyl)amino]ethyl}-a-phenyl-2-pyridineacetamide

To a solution of 214 parts (0.658 moles) of (-)-a-{2-[bis(1-methylethyl)amino]ethyl}-a-phenyl-2-pyridineacetamide in 790 parts of absolute ethanol is added a solution of 73 parts (0.626 moles) of 85% phosphoric acid in 160 parts of absolute ethanol. The crystalline precipitate which forms is filtered off and dried in air. The substance thus isolated is the phosphoric acid salt of (-)-a-{2-[bis(1-methylethyl)amino}-a-phenyl-2-pyridineacetamide, [a]_D +28.2.

Comment:

The solvent is ethanol. The phosphoric acid is derived from a convenient commercial form, an 85% phosphoric acid in water.

Dioxyline Phosphate

A solution of 5 g of 6,7-dimethoxy-3-methyl-1-(4-ethoxy-3-methoxybenzyl)isoquinoline in 100 ml of ethanol is treated with a solution of 1.5 g of phosphoric acid in 10ml of ethanol. Thereafter, 10 ml of water is added to effect complete dissolution and the reaction mixture is then cooled, and ether is added until precipitation of the salt is complete. The precipitate of 6,7-dimethoxy-3-methyl-1-(4-ethoxy-3-methoxybenzyl)isoquinoline phosphate is filtered off and recrystallized from 85% ethanol by addition to it of 2 volumes of diethyl ether.

Comment: As you can see, the almost exclusive solvents when working with phosphoric acid are methanol, ethanol or acetone.