Determining the solubilities for benzoate, nicotinate, hydrochloride, and malonate salts of bedaquiline

Abstract

Determining the solubility of a compound is important for predicting its oral bioavailability, the medium to be used for dissolution, and solvents for cleaning during manufacturing. The solubilities of the newly synthesized benzoate, hydrochloride, nicotinate, and malonate salts of bedaquiline were elucidated, and the plausible reasons for the differences observed in their experimental aqueous solubilities were highlighted.The shake flask method was used to determine the experimental solubilities of the bedaquiline free base and all the salts in water, 0.01 N HCl, and pH 6.8 buffer. The molar and mole fraction solubility estimates of the salts were determined using equations for ideal and non-ideal situations. Furthermore, the relative contribution of the lattice and activity coefficient to the overall aqueous solubility of the salts were predicted graphically.The new salts ranked hydrochloride [0.6437 mg/mL] > malonate [0.0268 mg/ml] > nicotinate [0.0024 mg/mL] > benzoate [0.0004 mg/mL], showed improved aqueous solubility over the free base. The general solubility equation [GSE], fairly predicted the solubilities for the benzoate and malonate salts, but the ideal solubility equations provided poor estimates of their experimental values. Based on the ideal solubility estimates, the crystal lattice contributions of all salts were malonate > nicotinate > HCl > benzoate. However, using the activity coefficient values, the order of hydrophobicity of the bedaquiline salts was: benzoate > nicotinate > malonate > HCl.The salts forms of bedaquiline offered additional solubility as a function of their crystallinity and hydrophobicity.