Vemavarapu Chandra, Mollan Matthew J, Needham Thomas E
Pharmaceutical Sciences, Pfizer Global R&D, Ann Arbor, MI 48105, USA.
AAPS PharmSciTech. 2002;3(4):E29. doi: 10.1208/pt030429.
The purpose of this study was to test the utility of rapid expansion of supercritical solution (RESS) based cocrystallizations in inducing polymorph conversion and crystal disruption of chlorpropamide (CPD). CPD crystals were recrystallized by the RESS process utilizing supercritical carbon dioxide as the solvent. The supercritical region investigated for solute extraction ranged from 45 to 100 degrees C and 2000 to 8000 psi. While pure solute recrystallization formed stage I of these studies, stage II involved recrystallization of CPD in the presence of urea (model impurity). The composition, morphology, and crystallinity of the particles thus produced were characterized utilizing techniques such as microscopy, thermal analysis, x-ray powder diffractometry, and high-performance liquid chromatography. Also, comparative evaluation between RESS and evaporative crystallization from liquid solvents was performed. RESS recrystallizations of commercially available CPD (form A) resulted in polymorph conversion to metastable forms C and V, depending on the temperature and pressure of the recrystallizing solvent. Cocrystallization studies revealed the formation of eutectic mixtures and solid solutions of CPD + urea. Formation of the solid solutions resulted in the crystal disruption of CPD and subsequent amorphous conversion at urea levels higher than 40% wt/wt. Consistent with these results were the reductions in melting point (up to 9 degrees C) and in the DeltaH(f) values of CPD (up to 50%). Scanning electron microscopy revealed a particle size reduction of up to an order of magnitude upon RESS processing. Unlike RESS, recrystallizations from liquid organic solvents lacked the ability to affect polymorphic conversions. Also, the incorporation of urea into the lattice of CPD was found to be inadequate. In providing the ability to control both the particle and crystal morphologies of active pharmaceutical ingredients, RESS proved potentially advantageous to crystal engineering. Rapid crystallization kinetics were found vital in making RESS-based doping superior to conventional solvent-based cocrystallizations.
本研究的目的是测试基于快速膨胀超临界溶液（RESS）的共结晶在诱导氯磺丙脲（CPD）多晶型转变和晶体破坏方面的效用。利用超临界二氧化碳作为溶剂，通过RESS过程使CPD晶体重结晶。研究的用于溶质萃取的超临界区域为45至100摄氏度和2000至8000磅力/平方英寸。这些研究的第一阶段是纯溶质重结晶，第二阶段是在尿素（模型杂质）存在下CPD的重结晶。利用显微镜、热分析、X射线粉末衍射和高效液相色谱等技术对由此产生的颗粒的组成、形态和结晶度进行了表征。此外，还对RESS与从液体溶剂中蒸发结晶进行了比较评估。市售CPD（晶型A）的RESS重结晶导致多晶型转变为亚稳晶型C和V，这取决于重结晶溶剂的温度和压力。共结晶研究揭示了CPD +尿素共晶混合物和固溶体的形成。在尿素含量高于40% wt/wt时，固溶体的形成导致CPD晶体破坏并随后发生无定形转变。与这些结果一致的是CPD熔点降低（高达9摄氏度）和ΔH(f)值降低（高达50%）。扫描电子显微镜显示RESS处理后粒径减小高达一个数量级。与RESS不同，从液体有机溶剂中重结晶缺乏影响多晶型转变 的能力。此外，发现尿素掺入CPD晶格的量不足。RESS在控制活性药物成分的颗粒和晶体形态方面具有潜力，被证明对晶体工程具有潜在优势。发现快速结晶动力学对于使基于RESS的掺杂优于传统的基于溶剂的共结晶至关重要。
