TY - JOUR
T1 - Toward continuous crystallization of urea-barbituric acid
T2 - a polymorphic co-crystal system
AU - Powell, Keddon A.
AU - Bartolini, Giulia
AU - Wittering, Kate E.
AU - Saleemi, Ali N.
AU - Wilson, Chick C.
AU - Rielly, Chris D.
AU - Nagy, Zoltan K.
PY - 2015/10/7
Y1 - 2015/10/7
N2 - 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 state of controlled operation (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.
AB - 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 state of controlled operation (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.
UR - http://www.scopus.com/inward/record.url?scp=84943562216&partnerID=8YFLogxK
UR - http://dx.doi.org/10.1021/acs.cgd.5b00599
U2 - 10.1021/acs.cgd.5b00599
DO - 10.1021/acs.cgd.5b00599
M3 - Article
AN - SCOPUS:84943562216
SN - 1528-7483
VL - 15
SP - 4821
EP - 4836
JO - Crystal Growth and Design
JF - Crystal Growth and Design
IS - 10
ER -