Carboxylic Acid Counterions in FDA-Approved Pharmaceutical Salts

Abstract

Salification is one of the powerful and widely employed approaches to improve the biopharmaceutical properties of drugs. The FDA's eighty-year trajectory of new drug approvals depicts around one-third of the drugs clinically used as their pharmaceutical salts. Among various cationic and anionic counterions used in FDA-approved pharmaceutical salts, the carboxylic acids have significantly contributed. A total of 94 pharmaceutical salts discovered during 1943-2020 comprises carboxylic acids as counterions with a major contribution of acetate, maleate, tartrate, fumarate, and succinate. Hydrocodone tartrate is the first FDA-approved carboxylate salt approved in 1943. Overall, the analysis shows that fifteen carboxylic acid counterions are present in FDA-approved pharmaceutical salts with a major share of acetate (18 drugs). This review provides an account of FDA-approved carboxylate salts from 1939 to 2020. The decade-wise analysis indicates that 1991-2000 contributed a maximum number of carboxylate salts (24) and least (3) in 1939-1950. The technical advantage of carboxylate salts over free-base or other counterions is also discussed. Graphical Abstract.

Keywords: US FDA; biopharmaceutical properties; carboxylic acid counterions; enhanced bioavailability; pharmaceutical salts; weakly basic drugs.