Crystal Polymorph Stability

For centuries, scientists have been captivated by the way molecules arrange themselves in the rigid beauty of crystals. Polymorphism, the ability of a compound to crystallize in more than one distinct lattice, is a central property of crystals as structure controls every material property relevant to their manufacture, durability, and performance. In the special case of active pharmaceutical ingredients, polymorph selection determines essential behaviors that range from solubility and hygroscopicity to tableting and long-term stability. Recent advances in molecular thermodynamics and analytics have radically expanded our understanding of polymorphic free energy landscapes. This review provides a comprehensive synthesis of up-to-date theoretical foundations of the relative stability of different polymorphs of a compound. Drawing on real-world case studies, we discuss challenges related to evaluation of crystal form stabilities. We conclude by highlighting necessary prospective developments in the fundamental understanding of polymorphism that focus on the roles of solvents, conformational variability, and entropy, and in the experimental approaches such as automation and the use of artificial intelligence.