Pharmaceutical salts of venetoclax with dicarboxylic and sulfonic acids: solid-state characterization and dissolution performance†

Abstract

This study focuses on enhancing the aqueous dissolution of venetoclax through salt formation. Venetoclax, a BCS class IV B-cell lymphoma-2-selective inhibitor, exhibits very low solubility and bioavailability. Given its multiple protonable groups, salt formation was explored to improve its dissolution properties. Dicarboxylic and sulfonic acids were selected as counterions for salt screening. Ten salts were synthesized and characterized using powder X-ray diffraction, nuclear magnetic resonance spectroscopy, thermogravimetric analysis, and differential scanning calorimetry. Intrinsic dissolution rate measurements demonstrated that all salts dissolve faster than the parent drug. The crystal structures of venetoclax, venetoclax fumarate, venetoclax oxalate, and venetoclax napsylate, which all solvated with acetonitrile, and unsolvated venetoclax tosylate were elucidated and described.