Rodríguez-Ruiz Christian, Montes-Tolentino Pedro, Domínguez-Chávez Jorge Guillermo, Morales-Rojas Hugo, Höpfl Herbert, Herrera-Ruiz Dea
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Cuernavaca 62209, Mexico.
Centro de Investigaciones Químicas, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Cuernavaca 62209, Mexico.
Pharmaceutics. 2022 Jan 30;14(2):334. doi: 10.3390/pharmaceutics14020334.
A cocrystal of the antihypertensive drug chlorthalidone (CTD) with caffeine (CAF) was obtained (CTD-CAF) by the slurry method, for which a 2:1 stoichiometric ratio was found by powder and single-crystal X-ray diffraction analysis. Cocrystal CTD-CAF showed a supramolecular organization in which CAF molecules are embedded in channels of a 3D network of CTD molecules. The advantage of the cocrystal in comparison to CTD is reflected in a threefold solubility increase and in the dose/solubility ratios, which diminished from near-unit values for to 0.29 for . Furthermore, dissolution experiments under non-sink conditions showed improved performance of CTD-CAF compared with pure CTD. Subsequent studies showed that CTD-CAF cocrystals transform to CTD form I where CTD precipitation inhibition could be achieved in the presence of pre-dissolved polymer HPMC 80-120 cPs, maintaining supersaturation drug concentrations for at least 180 min. Finally, dissolution experiments under sink conditions unveiled that the CTD-CAF cocrystal induced, in pH-independent manner, faster and more complete CTD dissolution when compared to commercial tablets of CTD. Due to the stability and dissolution behavior of the novel CTD-CAF cocrystal, it could be used to develop solid dosage forms using a lower CTD dose to obtain the same therapeutic response and fewer adverse effects.
通过淤浆法获得了抗高血压药物氯噻酮（CTD）与咖啡因（CAF）的共晶体（CTD-CAF），通过粉末和单晶X射线衍射分析发现其化学计量比为2:1。共晶体CTD-CAF呈现出一种超分子结构，其中CAF分子嵌入在CTD分子的三维网络通道中。与CTD相比，共晶体的优势体现在溶解度提高了三倍以及剂量/溶解度比值上，该比值从CTD的接近单位值降至CTD-CAF的0.29。此外，非漏槽条件下的溶出实验表明，与纯CTD相比，CTD-CAF的性能有所改善。后续研究表明，CTD-CAF共晶体转变为CTD晶型I，在预溶解的聚合物羟丙基甲基纤维素80 - 120厘泊存在的情况下可以实现CTD沉淀抑制，使药物过饱和浓度保持至少180分钟。最后，漏槽条件下的溶出实验表明，与CTD市售片剂相比，CTD-CAF共晶体以与pH无关的方式诱导CTD更快、更完全地溶解。由于新型CTD-CAF共晶体的稳定性和溶出行为，它可用于开发固体剂型，使用较低剂量的CTD即可获得相同的治疗效果且副作用更少。
