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

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• 作者：Keddon A. Powell ; Giulia Bartolini ; Kate E. Wittering ; Ali N. Saleemi ; Chick C. Wilson ; Chris D. Rielly ; Zoltan K. Nagy
• 刊名：Crystal Growth & Design
• 出版年：2015
• 出版时间：October 7, 2015
• 年：2015
• 卷：15
• 期：10
• 页码：4821-4836
• 全文大小：1121K
• ISSN：1528-7505

文摘

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 鈥渟tate of controlled operation鈥?(SCO) was achieved. Three different start-up strategies were employed and their ability to produce selectively a particular polymorphic form of UBA was evaluated. The experimental conditions for producing pure UBA form I were optimized, but pure UBA form III remained elusive. Off-line characterization of the UBA polymorphs was carried out using Powder X-ray Diffraction (PXRD) and Raman spectroscopy.