A Solubility Comparison of Neutral and Zwitterionic Polymorphs
A Solubility Comparison of Neutral and Zwitterionic Polymorphs
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DOI：
10.1021/cg5000205
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发表时间：
2014-04-01
影响因子：
3.8
通讯作者：
Nangia, Ashwini
中科院分区：
文献类型：
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作者：
Kumar, S. Sudalai;Nangia, Ashwini
选择了几种两性模型化合物和药物，如氨基苯甲酸（邻、Meta、帕拉）、N-芳基-2-氨基烟酸（三种异构体）、氨基水杨酸（Meta、帕拉）、氯尼辛和尼氟灭酸，得到它们的两性离子和中性多晶型物，目的是研究它们的X-射线晶体结构、溶解度和溶出速率以及稳定性。我们成功地结晶了2-和3-氨基苯甲酸（阿坝）、2-（对甲苯氨基）烟酸（TNA）和氯尼辛（CLX）以及4-和5-氨基水杨酸（4-阿萨为中性，5-阿萨为离子形式）的中性和离子多晶型物。中性和两性离子结晶多晶型物通过其独特的粉末X射线衍射（PXRD）、傅里叶变换红外、拉曼和ss-NMR光谱进行区分，并通过Hirshfeld表面分析进一步定量。通过差示扫描量热法和变温粉末X射线衍射监测相变。中性和两性离子多晶型物的溶解度和溶解速率的差异与它们的氢键（O-H中心点O、O-H中心点N和N+-H中心点O-）相关。离子形式的较快溶解速率归因于溶剂分子与两性离子官能团之间的较强的吸引力相互作用。尽管目前还没有通用的策略来结晶两性分子的离子多晶型物，但本研究显示了两性离子形式用于溶解度增强的优点。
Several amphoteric model compounds and drugs, such as isomers of aminobenzoic acids (ortho, meta, and para), N-aryl-2-aminonicotinic acids (three isomers), amino-salicylic acids (meta and para), clonixin, and niflumic acid, were selected to obtain their zwitterionic and neutral polymorphs with the objective to study their X-ray crystal structures, solubility and dissolution rate, and stability. We were successful in crystallizing neutral and ionic polymorphs for 2- and 3-aminobenzoic acid (ABA), 2-(p-tolylamino)nicotinic acid (TNA), and clonixin (CLX), as well as 4- and 5-aminosalicylic acid (4-ASA as neutral and 5-ASA in ionic form). The neutral and zwitterionic crystalline polymorphs were differentiated by their distinctive powder Xray diffraction (PXRD), Fourier transform infrared, Raman and ss-NMR spectroscopy, and further quantified by Hirshfeld surface analysis. Phase transitions were monitored by differential scanning calorimetry and variable temperature powder X-ray diffraction. The difference in solubility and dissolution rates of the neutral and zwitterionic polymorphs were correlated with their hydrogen bonding (O-H center dot center dot center dot O, O-H center dot center dot center dot N, and N+-H center dot center dot center dot O-). The faster dissolution rates of the ionic forms were ascribed to stronger, attractive interactions between the solvent molecules and the zwitterionic functional groups. Even as there is no general strategy yet to crystallize ionic polymorphs of amphoteric molecules, the present study shows the advantages of zwitterionic forms for solubility enhancement.