Toward Continuous Crystallization of Urea-Barbituric Acid: A Polymorphic Co-Crystal System

Pharmaceutical co-crystals are multicomponent molecular systems typically formed through hydrogen bonding of a co-former molecule with the active pharmaceutical ingredient (API). Just as many single component molecular structures can exhibit polymorphism due to the geometry of hydrogen bond donors and acceptors, the same is true for pharmaceutical co-crystals. In this study, the selective co-crystallization of the desired polymorphic form of urea-barbituric acid (UBA) co-crystals (forms I and III) is demonstrated, applying a novel periodic mixed suspension mixed product removal (PMSMPR) crystallizer cascade. The process was monitored using an integrated process analytical technology (PAT) array consisting of Raman spectroscopy, attenuated total reflectance ultraviolet/visible (ATR-UV/vis) spectroscopy, focused beam reflectance measurement (FBRM), particle vision microscopy (PVM), and an in-house developed commercial crystallization process informatics system (CryPRINS) software tool to determine when a “s...

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