Cocrystal strategies to achieve excellent physiochemical performance under different environmental stress were highlighted here. The lattice energy and the energy barrier of degradation reactions are two pillars in a stable cocrystal construction.

A four-membered square-shaped H-bonding structure was successfully designed to synthesize vitamin D₃ co-crystals. The co-crystallization process was found to be conformationally selective to result in topochemically stable materials.

Two packing polymorphs of drug–drug co-crystals between VD₂ and VD₃ exhibit dramatically different properties. Form A presents superior physicochemical properties compared with VD₂ or VD₃ themselves.