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法莫替丁药物共晶:结构和生物药剂学评价。

Pharmaceutical Cocrystals of Famotidine: Structural and Biopharmaceutical Evaluation.

机构信息

University Institute of Pharmaceutical Sciences, Panjab University Chandigarh-160014, India.

University Institute of Pharmaceutical Sciences, Panjab University Chandigarh-160014, India.

出版信息

J Pharm Sci. 2022 Oct;111(10):2788-2798. doi: 10.1016/j.xphs.2022.04.018. Epub 2022 May 1.

Abstract

Famotidine (FMT) an anti-ulcer drug, recently being repurposed in COVID-19 treatment, suffers from poor aqueous solubility and restricted bioavailability (<40%). To conquer the limitations endured by this potent anti-ulcer agent, two novel 1:1 cocrystals of FMT, namely Famotidine-Sorbic Acid (FSOR) and Famotidine-Syringic Acid (FSY), were synthesized using the liquid-assisted grinding method and evaluated. Distinct DSC thermograms and PXRD patterns advocate the existence of a new crystalline form. The unique organization of the hydrogen-bonded network, in the prepared cocrystals, is inferred by variation in characteristic vibrational frequencies in FT-IR spectroscopic analysis and supported by crystal structure determination. FSOR cocrystallize in orthorhombic PNCB and FSY in triclinic P 1 crystal system. Further, a significant amplification in the solubility (9 to 5-fold) and dissolution (8 to 5-fold) of FMT in cocrystalline form, with simultaneous augmentation in peak plasma concentration (2 to 1.5-fold higher) and relative bioavailability (approx. 200% to 135%). This is associated with the remarkable increment in their anti-ulcer and anti-oxidant potential. Thus, the study illustrates that cocrystallization as a worthy approach in the efficient delivery of neutral compounds suffering from inadequate solubility crisis.

摘要

法莫替丁(Famotidine,FMT)是一种抗溃疡药物,最近被重新用于 COVID-19 的治疗,但它的水溶性差,生物利用度有限(<40%)。为了克服这种强效抗溃疡剂所面临的限制,我们采用液相辅助研磨法合成了 FMT 的两种新型 1:1 共晶物,即法莫替丁-山梨酸(FSOR)和法莫替丁-丁香酸(FSY),并对其进行了评估。明显不同的 DSC 图谱和 PXRD 图谱表明存在新的晶体形式。在制备的共晶物中,氢键网络的独特组织通过特征振动频率在 FT-IR 光谱分析中的变化推断出来,并得到晶体结构确定的支持。FSOR 以正交 PNCB 结晶,FSY 以三斜 P1 晶体系统结晶。此外,FMT 在共晶形式中的溶解度(提高 9 至 5 倍)和溶解速率(提高 8 至 5 倍)显著提高,同时峰值血浆浓度(提高 2 至 1.5 倍)和相对生物利用度(提高约 200%至 135%)也有所提高。这与它们抗溃疡和抗氧化潜力的显著增强有关。因此,该研究表明,共晶化是解决中性化合物溶解度不足危机的有效方法。

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