Polymorphism in Cannabinol Piperazine Cocrystals: Structural, Morphological, and Energetic Perspectives

Polymorphism remains a major challenge in the development of pharmaceutical solid products as even small changes in the crystal arrangement can influence key properties such as stability and solubility. In this study, we mechanochemically prepared a novel cannabinol piperazine cocrystal, which exists in three polymorphic forms. The formation of these polymorphs was systematically investigated by varying the solvents, temperature, and milling time during the ball mill experiments. Interestingly, the phenomenon of disappearing polymorphs was observed under repeated milling. To get insights into the polymorphic behavior and assess the relative stability of the forms, we analyzed their crystal structures, morphologies, and hydrogen bond motifs and performed particle energy calculations using density functional theory. The theoretical results show good correlation with the experimental data and provide valuable and deep insights into the polymorphic behavior and the disappearance of the metastable form. Overall, this work highlights the importance of integrating structural analysis with energetic evaluations to rationalize and predict polymorph stability and transformations.