文献类型：期刊文献

英文题名：Novel pharmaceutical cocrystal of lenalidomide with nicotinamide: Structural design, evaluation, and thermal phase transition study

作者：Wang, Lijuan[1];Yan, Yizhen[1];Zhang, Xiangyang[1];Zhou, Xinggui[1]

机构：[1]East China Univ Sci & Technol, State Key Lab Chem Engn, Shanghai 200237, Peoples R China

年份：2022

卷号：613

外文期刊名：INTERNATIONAL JOURNAL OF PHARMACEUTICS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000736963200003)】；

语种：英文

外文关键词：Lenalidomide-nicotinamide cocrystal; Phase transition; Stability; Dissolution

摘要：Lenalidomide (LDM), widely used for the treatment of transfusion-dependent anaemia, has low oral bioavailability due to its poor aqueous solubility. Herein, we selected nicotinamide (NIC) as a coformer and synthesized a novel pharmaceutical cocrystal: lenalidomide-nicotinamide cocrystal (LNC) with a 1:1 stoichiometric ratio for enhancing the physicochemical properties of LDM, such as solubility and stability. For evaluating the ability to form cocrystal of LDM and NIC, a model of hydrogen-bond propensity (HBP) was utilized to calculate the hydrogen bond formation possibility for every hydrogen bond pair based on the existing structural information in the database. Afterward, solid-state grinding and liquid-assisted grinding methods were conducted to synthesize LNC, which were then characterized using powder X-ray diffraction, thermal and spectroscopic analysis. Besides, in the heating process, an interesting and anomalous phenomenon called thermal phase transition of the cocrystal was firstly observed and visualized by the hot stage microscope. Notably, the second thermal stage controlled by the vapor pressure of NIC was further determined experimentally and theoretically, which means that intermolecular hydrogen bonds gradually break when NIC occurs phase transition (from liquid to gas). Further, the physicochemical stability of cocrystal was proved reliable after being tested under accelerated stability conditions of 40 degrees C/75% RH for one month. Compared to lenalidomide and their physical mixture (molar ratio of 1:1), the dissolution and solubility of LNC have also been improved.