Functional group orientation-dependent conformational polymorphism in 5-fluorocytosine–L-malic acid cocrystals

The study of pharmaceutical cocrystal polymorphism is attracting increasing interest, as variations in intermolecular interactions and packing arrangements between an active pharmaceutical ingredient (API) and the same cocrystal former (CCF) directly impact the extent to which cocrystals can tailor the API’s properties. However, the number of reported cases of cocrystal polymorphism remains relatively limited. Herein, we propose that orientational variability of hydrogen bond donors or acceptors on either the API or the CCF may drive the formation of cocrystal polymorphs. To substantiate this hypothesis, 5-fluorocytosine (5-FC) and L -malic acid ( L -MAL) were selected as the model cocrystallization system, and two distinct 2:1 polymorphs (form Ⅰ and form Ⅱ) were ultimately identified. Crystal structural analysis revealed that the two cocrystals share consistent supramolecular interactions; however, the divergent orientations of carbonyl and hydroxyl groups in L -MAL induce distinguishable hydrogen bonding configurations and molecular stacking patterns, which strongly validates the proposed origin of cocrystal polymorphism. Lattice energy calculations, polymorphic transformation studies, and melting point data collectively confirmed that these two polymorphs exhibit a monotropic thermodynamic relationship, with the high- Z ’ form Ⅱ ( Z ’ = 2) being the thermodynamically stable crystalline phase. Under higher relative humidity condition (90 % RH), an obvious phase transformation of form Ⅰ was observed within one week, whereas form Ⅱ maintains its phase stability for at least four weeks. Such performance difference between these two cocrystals further underscores the practical significance of cocrystal polymorph screening.