Similarity and Diversity: Cocrystallization of Baricitinib with Four C4-Dicarboxylic Acids

The structural resemblance strategy is an often-employed principle to guide the discovery of novel pharmaceutical cocrystals and salts. Here, baricitinib (BAR) was selected as a model compound due to the existence of abundant heterocyclic nitrogen sites (proton acceptor sites) to form crystalline complexes with four structurally similar and pharmaceutically acceptable C4-dicarboxylic acids, maleic acid (MAL), fumaric acid (FUM), succinic acid (SUC), and L-tartaric acid (TAR). Crystal structures, intermolecular interactions, and physicochemical properties of each resulting form were analyzed to demonstrate the similarity and diversity. BAR-MAL and BAR-TAR are two salts with stoichiometric ratios of 2:2 and 2:1, respectively. BAR-FUM and BAR-SUC are isostructural cocrystals with a stoichiometric ratio of 1:0.5. All of these new solid-state forms demonstrated excellent phase stability against hydration, reduced hygroscopicity, and slight solubility improvements, supporting their usage as alternative forms of BAR for generic drug development.