The formulation of drug with improved bioavailability is always challenging and indispensable in the field of pharmaceutics. The control of intermolecular interactions via crystal engineering approach and solid-state molecular recognition results in the formation of active drug molecules with modulated pharmacological benefits. Therefore, with the aim to improve the solubility and dissolution rate of the drug chlorpropamide (CPA), the mechanochemical liquid-assisted grinding (LAG) of the drug with several pharmaceutically accepted excipients was performed. This contributed to the discovery of six novel solid phases, namely salts, salt cocrystals and salt cocrystal hydrate─the salt of CPA with 3, 4-diaminopyridine (DAP); salt and salt cocrystal (SC) polymorph (Z″=3) with 1, 4-diazabicyclo [2.2.2] octane (DABCO); a salt, SC polymorph (Z″=9), and a SC hydrate (Z″=9) with piperazine (PIP). The formation of these salts and salt cocrystals are mainly guided by the strong hydrogen bonds with tunable strength having high electrostatic contribution. This attractive interaction brings the donor and the acceptor atoms close to each other for a facile proton transfer. Furthermore, the conformational constraints on the drug molecules, provided by the excipients via strong and directional hydrogen bonds, are quite impressive as this leads to the identification and characterization of “new conformational isomers” for the CPA molecules. The new crystalline phases exhibit enhanced intrinsic dissolution rate in comparison to that of the pure drug, the magnitude being 7, 131, and 120 folds for CPADAP, CPADABCO_II, and CPAPIP_III, respectively. Furthermore, it is interesting to note that the order of solubility is enhanced by 2.7-, 3-, and 7-fold, respectively, for the abovementioned salts. This also mirrors the trends in the magnitude of the binding energy, the higher magnitude being reflected in the lower solubility. Additionally, the in vivo experiments performed in SD rats results in the enhancement of the magnitude of the pharmacokinetic properties, when compared to the pristine drug. The concentration of the drug in CPADABCO_II and CPAPIP_III formulations exhibits 6- and 4-fold increments, respectively. Indeed, these results corroborate to the trends observed in the structural characterization, intermolecular energy calculations, solubility, and in vitro dissolution assessments.

中文翻译：

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晶体工程中的合成方法调节氯磺丙脲有机盐的理化性质


提高生物利用度的药物制剂一直是制药领域的挑战，也是不可或缺的。通过晶体工程方法和固态分子识别来控制分子间相互作用，从而形成具有调节药理功效的活性药物分子。因此，为了提高药物氯丙酰胺（CPA）的溶解度和溶出度，对该药物与几种药学上可接受的赋形剂进行了机械化学液体辅助研磨（LAG）。这有助于发现六种新型固相，即盐、盐共晶和盐共晶水合物——CPA与3, 4-二氨基吡啶（DAP）的盐；具有1, 4-二氮杂双环[2.2.2]辛烷(DABCO)的盐和盐共晶(SC)多晶型物(Z″=3)；盐、SC 多晶型物 (Z”=9) 和 SC 水合物 (Z”=9) 与哌嗪 (PIP)。这些盐和盐共晶体的形成主要由强氢键引导，氢键的强度可调，具有高静电贡献。这种有吸引力的相互作用使供体和受体原子彼此靠近，以便于进行质子转移。此外，赋形剂通过强而定向的氢键对药物分子提供的构象限制非常令人印象深刻，因为这导致了 CPA 分子“新构象异构体”的识别和表征。与纯药物相比，新晶相表现出增强的固有溶出速率，CPADAP、CPADABCO_II 和 CAPIP_III 的数量级分别为 7、131 和 120 倍。此外，有趣的是，上述盐的溶解度分别提高了 2.7 倍、3 倍和 7 倍。 这也反映了结合能大小的趋势，较高的大小反映了较低的溶解度。此外，与原始药物相比，在 SD 大鼠中进行的体内实验导致药代动力学特性的增强。 CPAABCO_II 和 CAPIP_III 制剂中的药物浓度分别增加了 6 倍和 4 倍。事实上，这些结果证实了在结构表征、分子间能量计算、溶解度和体外溶出评估中观察到的趋势。