Getsoian A, Lodaya R M, Blackburn A C
Pharmaceutical Sciences, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA.
Int J Pharm. 2008 Feb 4;348(1-2):3-9. doi: 10.1016/j.ijpharm.2007.06.053. Epub 2007 Oct 22.
To emphasize the fact that solvents can be either critical or immaterial in crystallizing specific polymorphs, a method for obtaining multiple polymorphs of a compound using only one solvent is demonstrated. By varying the crystallization temperature and level of supersaturation, three of the four polymorphs of carbamazepine (CBZ; 5H-dibenz [b,f]azepine-5-carboxamide) were crystallized from cumene (isopropyl benzene). Form III, also referred to as the primitive monoclinic form, was produced at temperatures below 60 degrees C from supersaturated solutions concentrated at less than twice the solubility of that form. When the supersaturation was increased to twice the solubility of form III at temperatures below 60 degrees C, form II, also referred to as the trigonal form, was produced. Form I, also referred to as the triclinic form, was produced regardless of the level of supersaturation at temperatures above 80 degrees C. Between 60 degrees C and 80 degrees C, mixtures of forms were produced. Competition slurries were employed to establish the transition temperature to be between 79 degrees C and 82 degrees C for the enantiotropically related forms III and I. These results indicate that crystallization of CBZ from cumene can either be under thermodynamic control or affected by the kinetics of crystallization of metastable forms. This raises the question about the importance of solvent diversity when looking for polymorphs, suggesting that a rational experimental design can be used to greatly reduce the number of solvents and crystallization conditions. The results of this one-solvent polymorph screen correlate somewhat with a phase-solubility diagram for CBZ.
为强调溶剂在特定多晶型物结晶过程中可能至关重要或无关紧要这一事实,展示了一种仅使用一种溶剂获得化合物多种多晶型物的方法。通过改变结晶温度和过饱和度,卡马西平(CBZ;5H - 二苯并[b,f]氮杂䓬 - 5 - 甲酰胺)的四种多晶型物中的三种从异丙苯中结晶出来。III型,也称为原始单斜晶型,在低于60摄氏度的温度下,由浓度低于该晶型溶解度两倍的过饱和溶液生成。当在低于60摄氏度的温度下将过饱和度增加到III型溶解度的两倍时,生成II型,也称为三角晶型。I型,也称为三斜晶型,在高于80摄氏度的温度下,无论过饱和度水平如何都会生成。在60摄氏度至80摄氏度之间,会生成多种晶型的混合物。采用竞争浆液法确定对映变体相关的III型和I型之间的转变温度在79摄氏度至82摄氏度之间。这些结果表明,卡马西平从异丙苯中的结晶过程既可以受热力学控制,也可以受亚稳晶型结晶动力学的影响。这就引出了在寻找多晶型物时溶剂多样性的重要性问题,表明可以采用合理的实验设计来大幅减少溶剂和结晶条件的数量。这种单溶剂多晶型筛选的结果与卡马西平的相溶解度图有一定关联。