Jayasankar Adivaraha, Good David J, Rodríguez-Hornedo Naír
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109-1065, USA.
Mol Pharm. 2007 May-Jun;4(3):360-72. doi: 10.1021/mp0700099. Epub 2007 May 8.
The purpose of this study is to determine the mechanisms by which moisture can generate cocrystals when solid particles of cocrystal reactants are exposed to deliquescent conditions (when moisture sorption forms an aqueous solution). It is based on the hypothesis that cocrystallization behavior during water uptake can be derived from solution chemistry using models that describe cocrystal solubility and reaction crystallization of molecular complexes. Cocrystal systems were selected with active pharmaceutical ingredients (APIs) that form hydrates and include carbamazepine, caffeine, and theophylline. Moisture uptake and crystallization behavior were studied by gravimetric vapor sorption, X-ray powder diffraction, and on-line Raman spectroscopy. Results indicate that moisture uptake generates cocrystals of carbamazepine-nicotinamide, carbamazepine-saccharin, and caffeine or theophylline with dicarboxylic acid ligands (oxalic acid, maleic acid, glutaric acid, and malonic acid) when solid mixtures with cocrystal reactants deliquesce. Microscopy studies revealed that the transformation mechanism to cocrystal involves (1) moisture uptake, (2) dissolution of reactants, and (3) cocrystal nucleation and growth. Studies of solid blends of reactants in a macro scale show that the rate and extent of cocrystal formation are a function of relative humidity, moisture uptake, deliquescent material, and dissolution rates of reactants. It is shown that the interplay between moisture uptake and dissolution determines the liquid phase composition, supersaturation, and cocrystal formation rates. Differences in the behavior of deliquescent additives (sucrose and fructose) are associated with moisture uptake and composition of the deliquesced solution. Our results show that deliquescence can transform API to cocrystal or reverse the reaction given the right conditions. Key indicators of cocrystal formation and stability are (1) moisture uptake, (2) cocrystal aqueous solubility, (3) solubility and dissolution of cocrystal reactants, and (4) transition concentration.
本研究的目的是确定当共晶反应物的固体颗粒暴露于潮解条件下（即吸湿形成水溶液时）水分能够生成共晶的机制。其基于这样一个假设，即吸水过程中的共结晶行为可以通过使用描述共晶溶解度和分子络合物反应结晶的模型从溶液化学推导得出。选择了含有形成水合物的活性药物成分（API）的共晶体系，包括卡马西平、咖啡因和茶碱。通过重量法蒸汽吸附、X射线粉末衍射和在线拉曼光谱研究了吸湿和结晶行为。结果表明，当与共晶反应物的固体混合物潮解时，吸湿会生成卡马西平 - 烟酰胺、卡马西平 - 糖精以及咖啡因或茶碱与二羧酸配体（草酸、马来酸、戊二酸和丙二酸）的共晶。显微镜研究表明，向共晶的转变机制涉及（1）吸湿，（2）反应物溶解，以及（3）共晶成核和生长。对宏观尺度下反应物固体混合物的研究表明，共晶形成的速率和程度是相对湿度、吸湿量、潮解物质以及反应物溶解速率的函数。结果表明，吸湿与溶解之间的相互作用决定了液相组成、过饱和度和共晶形成速率。潮解添加剂（蔗糖和果糖）行为的差异与吸湿量和潮解溶液的组成有关。我们的结果表明，在合适的条件下，潮解可以将API转化为共晶或使反应逆转。共晶形成和稳定性的关键指标是（1）吸湿量，（2）共晶在水中的溶解度，（3）共晶反应物的溶解度和溶解情况，以及（4）转变浓度。
