In the Context of Polymorphism: Accurate Measurement, and Validation of Solubility Data
In the Context of Polymorphism: Accurate Measurement, and Validation of Solubility Data
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DOI：
10.1021/acs.cgd.9b00529
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发表时间：
2019-07-01
影响因子：
3.8
通讯作者：
Lopez-Mejias, Vilmali
中科院分区：
文献类型：
--
作者：
Marrero, Victor R. Vazquez;Berrios, Carmen Pinero;Lopez-Mejias, Vilmali
多晶型化合物的溶解度测量通常伴随着溶剂介导的相变。在本研究中，采用不饱和溶液的溶解度测量来研究氟芬那酸（FFA 形式 I 和 III）、托芬那酸（TA 形式 I 和 II）以及唯一已知形式的尼氟酸 (NA) 的两种最稳定多晶型物的溶解度。使用多热法测量了四种同系醇（甲醇、乙醇、1-丙醇、正丁醇）的溶解度（278.15 至 333.15 K）。已确定这些化合物的溶解度随着温度的升高而增加。 FFA 晶型 I 和 III 的溶解度曲线在所有四种溶剂中相交于 315.15 K（42 摄氏度），这代表了对映体对的转变温度。在TA的情况下，由于快速溶剂介导的相变，无法在任何溶剂中可靠地获得形式II的溶解度。还测定了唯一已知形式的 NA 的溶解度，并且没有观察到 NA 的其他多晶型物。使用修正的 Apelblat 和 lambda h 模型方程将 FFA（I 型和 III 型）、TA（I 型）和 NA 在这四种溶剂中的实验溶解度数据相关联。获得的相关和实验确定的溶解度数据可用于（i）指导多晶型化合物溶解度的准确测定，（ii）评估溶剂在介导转化中的作用，以及（iii）提供设计这些药物化合物的高级结晶过程的途径。
Solubility measurements for polymorphic compounds are often accompanied by solvent-mediated phase transformations. In this study, solubility measurements from undersaturated solutions are employed to investigate the solubility of the two most stable polymorphs of flufenamic acid (FFA forms I and III), tolfenamic acid (TA forms I and II), and the only known form of niflumic acid (NA). The solubility was measured from 278.15 to 333.15 K in four alcohols of a homologous series (methanol, ethanol, 1-propanol, n-butanol) using the polythermal method. It was established that the solubility of these compounds increases with increasing temperature. The solubility curves of FFA forms I and III intersect at, similar to 315.15 K (42 degrees C) in all four solvents, which represents the transition temperature of the enantiotropic pair. In the case of TA, the solubility of form II could not be reliably obtained in any of the solvents because of the fast solvent mediated phase transformation. The solubility of the only known form of NA was also determined, and no other polymorphs of NA were observed. The experimental solubility data of FFA (forms I and III), TA (form I), and NA in these four solvents was correlated using the modified Apelblat and lambda h model equations. The correlated and experimentally determined solubility data obtained serves to (i) guide the accurate determination of the solubility for polymorphic compounds, (ii) assess the role of the solvent in mediating transformations, and (iii) provide a route to engineer advanced crystallization processes for these pharmaceutical compounds.