Faculty of Pharmaceutical Science, Toho University.
Chem Pharm Bull (Tokyo). 2023;71(8):633-640. doi: 10.1248/cpb.c23-00109.
Nobiletin (NOB) is a flavonoid with attractive pharmaceutical characteristics, including anti-Alzheimer's, anti-inflammation, and anti-cancer properties, but it has low solubility in water, resulting in reduced bioavailability. Its solubility must be improved to develop NOB as a drug. Cocrystal engineering can change the physicochemical properties of an active pharmaceutical ingredient and generate remarkable drug candidates that are superior in drug formulation. In this report, extensive co-crystal screening of NOBs with 31 cocrystal formers (coformers) with various functional groups was carried out by the liquid-assisted grinding method. As a result, four cocrystals (NOB with urea (URE), oxalic acid, gallic acid and salicylic acid) and one solvate crystal (NOB with formic acid (FOR)) were found. Powder X-ray diffraction and thermal analysis revealed the unique crystal morphology of all the obtained samples. In addition, the crystal structures of two of them (NOB-URE and NOB-FOR) were determined by single crystal X-ray diffraction. The results revealed that NOB-URE and NOB-FOR are new cocrystals or solvate crystals consisting of molar ratios of 1 : 2 and 1 : 0.73, respectively. In NOB-URE, we could observe a transient increase in solubility due to supersaturation, suggesting that URE is one of the better coformers of NOB.
川陈皮素（NOB）是一种具有吸引力的药物特性的类黄酮，具有抗老年痴呆症、抗炎和抗癌特性，但它在水中的溶解度低，导致生物利用度降低。必须提高其溶解度，才能将其开发成药物。共晶工程可以改变活性药物成分的物理化学性质，并生成在药物配方中更优越的显著候选药物。在本报告中，通过液辅助研磨法对具有各种功能基团的 31 种共晶形成剂（共晶形成剂）的 NOB 进行了广泛的共晶筛选。结果发现了四个共晶（NOB 与尿素（URE）、草酸、没食子酸和水杨酸）和一个溶剂化物晶体（NOB 与甲酸（FOR））。粉末 X 射线衍射和热分析揭示了所有获得样品的独特晶体形态。此外，其中两个（NOB-URE 和 NOB-FOR）的晶体结构通过单晶 X 射线衍射确定。结果表明，NOB-URE 和 NOB-FOR 是由摩尔比为 1：2 和 1：0.73 组成的新共晶或溶剂化物晶体。在 NOB-URE 中，我们可以观察到由于过饱和而导致的溶解度暂时增加，这表明 URE 是 NOB 的较好共晶形成剂之一。
