Laboratory of Pharmaceutics, Faculty of Pharmaceutical Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8514, Japan.
Laboratory of Pharmaceutics, Faculty of Pharmaceutical Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8514, Japan.
Int J Pharm. 2021 Sep 25;607:120959. doi: 10.1016/j.ijpharm.2021.120959. Epub 2021 Jul 29.
Isosorbide (ISO) is an effective hyperosmotic agent that can be administrated orally and is used as a therapeutic agent for brain pressure drop, glaucoma, and Meniere's disease. However, the critical relative humidity (CRH) of ISO is about 48% RH at 25 °C, and it deliquesces in humid environments. In this study, we attempted to reduce the deliquescence of ISO using cocrystallization and analyze the water adsorption mechanism from the crystal structure. Four new ISO cocrystals with piperazine (PZ), hydrochlorothiazide (HCT), 3,5-dihydroxybenzoic acid (35DHBA), or gallic acid (GA) were identified. The dynamic vapor sorption analyses demonstrated that all the cocrystals showed higher CRHs than the ISO crystal. Although water adsorption below the CRH was observed for all cocrystals, the water molecules adsorbed in the ISO-PZ and ISO-GA cocrystals were lower than those in the ISO crystal. Investigation of the crystal structures suggested that the amount of water adsorbed might be related to the degree of exposure of the ISO hydroxyl groups on the crystal surface. Given the CRH, water adsorption below the CRH, thermal stability, apparent dissolution rate, and toxicity level of the coformer, the ISO-GA cocrystal is the most suitable for preparing a solid formulation of ISO.
异山梨醇（ISO）是一种有效的高渗剂，可口服给药，用于治疗脑压下降、青光眼和梅尼埃病。然而，ISO 的临界相对湿度（CRH）在 25°C 时约为 48%RH，并且在潮湿环境中会潮解。在这项研究中，我们试图通过共晶化来减少 ISO 的潮解，并从晶体结构分析其水吸附机制。鉴定了四种新的 ISO 共晶，分别为哌嗪（PZ）、氢氯噻嗪（HCT）、3,5-二羟基苯甲酸（35DHBA）或没食子酸（GA）。动态蒸汽吸附分析表明，所有共晶的 CRH 均高于 ISO 晶体。尽管所有共晶在 CRH 以下都观察到了水吸附，但 ISO-PZ 和 ISO-GA 共晶中吸附的水分子少于 ISO 晶体中的水分子。晶体结构的研究表明，吸附的水量可能与 ISO 羟基在晶体表面的暴露程度有关。考虑到 CRH、CRH 以下的水吸附、热稳定性、表观溶解速率和共晶形成剂的毒性水平，ISO-GA 共晶最适合制备 ISO 的固体制剂。
