Discovery of new cocrystals beyond serendipity: lessons learned from successes and failures

The past decade has witnessed remarkable progress in cocrystal research, by virtue of the desires to address problematic properties of drugs. Notwithstanding the rapid advancements in knowledge-based cocrystal design, such as by leveraging different in silico virtual screening tools, obtaining false-positive results wherein predicted cocrystals fail to materialize experimentally remains a common occurrence. While being less disconcerting than the false-negative, there is a need to comprehend the underlying reasons as to why cocrystal formers bearing supramolecular features that indicate a high probability of cocrystallization would eventually fail. This enigma is associated with the thermodynamic instability of cocrystals or requirement of a high activation energy for cocrystallization, thus rendering them elusive under conventional production. This review aims to address this knowledge gap by providing a holistic overview on the strategic design and preparation of elusive cocrystals, followed by highlighting the importance of process control on the critical factors, such as reaction kinetics, the presence of catalysts, and annealing conditions. The challenges pertaining to the characterization and clinical translation of elusive cocrystals are also covered. Finally, an empirical analysis of the Cambridge Structural Database was conducted to explore the elusive cocrystal formation through understanding the differential cocrystallization behaviors among a series of isomers and structurally similar coformers. The insights gained herein offer scientists a guide for conducting cocrystal screening in a more rational and effective manner, with the ultimate goal of expediting the development of novel drug cocrystals for future clinical use. A holistic understanding of reaction kinetics, the presence of catalysts, and annealing conditions can advance and accelerate the screening of elusive cocrystals, expediting the development of novel drug cocrystals for future clinical use.