In Situ Monitoring of Stirring Effects on Polymorphic Transformations during Cooling Crystallization of Carbamazepine

Abstract

The influence of experimental conditions on polymorphic outcome and transformations during cooling crystallization of carbamazepine (CBZ) from anhydrous ethanol has been investigated. Stirring was found to be the most important controlling factor for the initial polymorphic outcome in solutions prepared using commercial CBZ powder. For quiescent conditions, a few large crystals of the metastable trigonal α form (II) initially appeared, undergoing subsequent slow transformation into the stable P-monoclinic β form (III). Under sufficiently vigorous stirring, the induction times observed were clearly defined by the onset of turbidity, which was due to formation of a large number of small form III prismatic crystals. In experiments with solutions prepared by using recrystallized CBZ, significantly shorter induction times were observed under stirring conditions: a large number of small form II needleshaped crystals initially formed at the onset of turbidity and then relatively rapidly transformed to small crystals of form III. This indicates a possible effect of impurities in the commercial CBZ powder inhibiting rapid nucleation of form II under stirring conditions. In situ monitoring of CBZ polymorphic outcome was performed using custom-built experimental setup for simultaneous measurement of intensity of transmitted and scattered light. Distinct pathways in two-variable intensity plots were observed for formation of each respective polymorph under stirring conditions. The same monitoring technique should be readily applicable to other systems.

Conundrum of γ glycine nucleation revisited: to stir or not to stir?

“…The effect of stirring on m-hydroxybenzoic acid solutions found that the proportion of the stable form decreases under intermediate agitation rates, accompanied by a large reduction in nucleation time of the metastable form. 7 The effect of stirring conditions on cooling crystallisation of carbamazepine from anhydrous ethanol was investigated by Sypek et al 8 In this study, crystals of form II were formed and then slowly transformed to crystals of form III under quiescent conditions. In the case of sufficiently vigorous stirring, the induction times observed were clearly defined by the onset of turbidity which was due to formation of a large number of small form III crystals.…”

“…However, there are numerous examples where agitation plays profound role in determining polymorphic outcome in crystallisation of pharmaceuticals and other molecular systems, such as carbamazepine, stearic acid, L-glutamic acid, m-hydroxybenzoic acid 7 or glycine. [8][9][10][11] In industrial applications it is vital to understand the impact of process conditions such as agitation on polymorphism in order to scale up crystallisation processes properly accounting for differences in agitation between labbased, pilot scale and plant scale processes.…”

Carbamazepine-Fumaric Acid and Carbamazepine-Succinic Acid Co-crystal Screening Using Solution Based Method

“…CBZ is a drug that used as anticonvulsant for treatment of epilepsy and trigeminal neuralgia [14]. CBZ can be classified in class 2 drugs under biopharmaceutics classification system (BCS) [15].…”

Pharmaceutical crystallization in Couette-Taylor crystallizer: A case study of polymorphism of amino acid L-glutamic acid

“…Since the conformation and packing of molecules in solution directly depended on the fluid hydrodynamic in crystallizer, the fluid hydrodynamic is certainly considered as the key factor to control the selective and phase transformation of polymorphism [7][8][9]. For example, Sypek et al [7] reported that the stable phase of carbamazepine was selectively obtained in stirred crystallization, whereas the unstable phase was preferably crystallized in a stagnant crystallization.…”

“…Since the conformation and packing of molecules in solution directly depended on the fluid hydrodynamic in crystallizer, the fluid hydrodynamic is certainly considered as the key factor to control the selective and phase transformation of polymorphism [7][8][9]. For example, Sypek et al [7] reported that the stable phase of carbamazepine was selectively obtained in stirred crystallization, whereas the unstable phase was preferably crystallized in a stagnant crystallization. As regards the phase transformation, Davey et al [8] indicated that the completed phase transformation of 2,6dihydroxybenzoic acid from unstable to stable phase required at least 20 days in a stagnant crystallization, but it was significantly reduced to only 2−3 days in stirred crystallization.…”