Caprolactam Cocrystals: Bridging Virtual Screening to Experimental Solid-State Forms and Stability

This study revisits and expands the field of lactam cocrystals to include additional structural analogues of sulfonamides and evaluates the potential of virtual screening methods. Cocrystallization of lactams is driven by both lactam–lactam and lactam–API interactions. Four cocrystals, SA/CLCC, SG/CLCC, DDS/CLCC-I, and DDS/CLCC-II, were experimentally produced, including two novel ones, SG/CLCC and DDS/CLCC-II. The structures of the new multicomponent phases were successfully solved using powder X-ray diffraction data complemented by DFT-d calculations. Calorimetric analysis confirmed that DDS/CLCC-II is the high-temperature polymorph and is enantiotropically related to DDS/CLCC-I. Virtual screening methods, including molecular complementarity, multicomponent hydrogen-bond propensity, and molecular electrostatic potential maps, demonstrated utility but were limited by the molecular properties of the chosen coformer class. Crystal structure prediction on the other hand proved to be the most reliable computational approach, successfully identifying cocrystallization outcomes in all three systems and matching the experimental 1:1 cocrystal structures with computationally generated ones. The experimental investigations revealed that cocrystallization could reduce, but not completely prevent, the sublimation tendency of ε-caprolactam. Solubility tests showed no improvement in API solubility, as the cocrystals disintegrated into their individual components within the shortest time of contact with water. Thus, this work sheds light on lactam cocrystallization, highlighting the strengths and limitations of current predictive approaches, as well as the challenges that need to be addressed in experimental work.