Halide counterions in FDA-approved pharmaceutical salts

Salification is one of the most attractive tools to modulate the physicochemical properties of poorly water-soluble drugs. The halogen acids such as hydrochloric, hydrobromic, and hydroiodic acids contribute extensively in salifying poorly water-soluble basic drugs. Analysis of the orange book from 1939 to 2022 revealed approval of ∼600 pharmaceutical salts of new chemical entities (NCEs) over the last nine decades. The contribution of halides as a counterion was the highest, up to 32% (∼187 from 600). Upon detailed study, salts prepared with hydrochloric acid dominated among all halide counterions (Cl−, Br−, F−, I−), contributing to ∼29%. Our analysis shows that methamphetamine HCl is the first halide salt approved and launched in 1943. This review answers the fundamental question of why halide counterion dominates over the other in pharmaceutical salts. The researchers cannot avoid using halogen acids in salt screening experiments despite their corrosive and hazardous nature. The reason being it will affect the discovery and development of drugs significantly. The risk associated with their use may be minimized by controlling the salification process, adding strong acids, selecting the appropriate stoichiometric ratio, and using rigorous analysis to control residual acids in the product. Herein, we review the halide-based FDA-approved pharmaceutical salts with a critical discussion and insights on the role of salification in modulating biopharmaceutical properties.