Gupta Piyush, Chawla Garima, Bansal Arvind K
Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research, Sector 67, Phase X, S.A.S. Nagar, Punjab-160062, India.
Mol Pharm. 2004 Nov-Dec;1(6):406-13. doi: 10.1021/mp049938f.
Glassy pharmaceuticals, characterized by excess thermodynamic properties, are theoretically more soluble than their crystalline counterparts. The practical solubility advantage of the amorphous form of celecoxib (CEL) is lost due to its proclivity to lose energy and undergo solvent-mediated devitrification. Theoretical assessment of solubility advantage using differences in isobaric heat capacities (Cp) revealed a 7-21-fold enhancement in the solubility of the amorphous form over that of the crystalline state of CEL. The present study attempts to unveil these differences between experimental and theoretical solubility using thermodynamic parameters such as free energy, enthalpy, and entropy. Amorphous CEL exhibited 1.3-1.5 times enhancement in Cp over that for the crystalline form. The zero and critical molecular mobility regions, represented by Kauzmann temperature (TK) and glass transition temperature (Tg), were found to lie near 246 and 323 K, respectively, for amorphous CEL. The fictive temperature (Tf), an indicator of the configurational entropy of glass, was determined for glassy CEL, signifying the retention of considerable molecular mobility in the glassy phase that may favor nucleation even below Tg. Further, the estimation of various thermodynamic quantities and strength/fragility parameters (D = 11.5 and m = 67.0) postulated the classification of glassy CEL into moderately fragile liquid, as per Angell's classification. A comprehensive understanding of such thermodynamic facets of amorphous form would help in rationalizing the approaches toward development of stable glassy pharmaceuticals with adequate solubility advantage.
玻璃态药物具有过量的热力学性质，理论上比其晶态对应物更易溶解。塞来昔布（CEL）无定形形式的实际溶解优势因倾向于能量损失和发生溶剂介导的失透而丧失。利用等压热容（Cp）差异对溶解优势进行理论评估表明，CEL无定形形式的溶解度比其晶态形式提高了7至21倍。本研究试图利用自由能、焓和熵等热力学参数揭示实验溶解度和理论溶解度之间的这些差异。无定形CEL的Cp比晶态形式提高了1.3至1.5倍。对于无定形CEL，分别由考兹曼温度（TK）和玻璃化转变温度（Tg）表示的零分子迁移率区域和临界分子迁移率区域分别位于246 K和323 K附近。确定了玻璃态CEL的虚构温度（Tf），它是玻璃构型熵的指标，这表明在玻璃态相中保留了相当大的分子迁移率，即使在Tg以下也可能有利于成核。此外，根据安吉尔分类法，对各种热力学量以及强度/脆性参数（D = 11.5和m = 67.0）的估计将玻璃态CEL归类为中等脆性液体。对无定形形式的这种热力学方面的全面理解将有助于合理化开发具有足够溶解优势且稳定的玻璃态药物的方法。
