Choice of drug salt to optimise solubility

The choice of a particular salt of a dmg for use in formulations may depend on several factors. The solubility of the dmg in aqueous media may be markedly dependent on the salt form. The chemical stability rather than the solubility may be a criterion and in many cases this is dependent on the choice of salt, sometimes through a pH effect. Deliberate choice of an insoluble form for use in suspen- 

The large hydrophobic compound XIX, even as its hydrochloride salt, is poorly soluble and this is presumably the reason for its poor oral bioavailability. Similar conclusions were drawn several years ago for novobiocin. The acid salt administered at 12.5 mg kg to dogs was not absorbed, but the monosodium salt, which is about 300 times as soluble in water, produced plasma levels of 22 /rg cm after 3 hours. Unfortunately, the sodium salt is unstable in solution. An amorphous form of the acid produced even higher levels of dmg than the sodium salt, illustrating the fact that choice of salt and crystalline form of a dmg substance may be of critical importance. 

Some of the solubility differences obviously arise from differences in the pH of the salt solutions, which in the case of compound XIX ranged from 2.4 to 5.8 pH units. This is not atypical. The pH of solutions of salts of a 3-oxyl-1,4-benzodiazepine derivative at 5 mg cm ranged from 2.3 for its dihydrochloride, to 4.3 for the maleate, and to 4.8 for the methane sulfonate. 

Further examples of the solubility range in dmg salts and derivatives are shown in 

Salt AAelting point Solubility Saturated solution 

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