Co-crystal formation with active pharmaceutical ingredients has recently been considered an effective alternative to control the physical properties of a drug. Although several studies have been carried out on solvent-drop grinding as a means of co-crystal formation, little is available on the use of solid-liquid equilibrium measurements for co-crystal crystallization design.

A model system, nicotinamide and trans-cinnamic acid, is herein used to illustrate the challenges of solid phase discovery and control in a polymorphic co-crystal system. Crystallization of the stable and metastable co-crystal solid phases from solution, as well as through other techniques, is explored. Three component phase diagrams are presented to aid crystallization process design for scale-up.