Li Long, Yin Xian-Hong, Diao Kai-Sheng
Sichuan Kelun Pharmaceutical Research Institute Co., Ltd., Chengdu 610000, China.
College of Chemistry and Chemical Engineering, Guangxi University for Nationalities, Nanning 530006, China.
ACS Omega. 2020 Oct 1;5(40):26245-26252. doi: 10.1021/acsomega.0c04005. eCollection 2020 Oct 13.
Pemafibrate is a new generation of anti-hyperlipidemia drugs. However, its poor solubility in water (0.410 mg/mL at 25 °C) has limited its oral bioavailability. In this study, we aimed to improve the solubility and consequently the oral bioavailability of pemafibrate via a new polymorph. A new polymorph Form II was successfully obtained by controlling the crystallization temperature and characterized by multiple analysis methods. The thermodynamic properties of Form I and Form II are almost the same, the melting points of crystal Form I [differential scanning calorimetry (DSC) onset: 97.5 °C, melting entropy: -76 J/g] and crystal Form II (DSC onset: 96.6 °C, melting entropy: -80 J/g) are very close, and the crystallinity of both is very high. In pure water, Form II is about 1.9 times that of Form I in terms of the intrinsic dissolution rate (IDR) and powder solubility. In medium, the IDR characterization was performed in a pH 6.8 buffer. The solubility of this Form II in 0.1 M HCl (pH 1.0) and phosphate buffers (pH 6.8) was investigated, and the results showed that the solubility of Form II was 2.1 and 2.0 times that of Form I, respectively. The crystal structure of Form II shows that the hydrophilic carboxyl groups of the compound are arranged outside the unit cell, which may be the reason for the increased solubility. We also studied the pharmacokinetics of beagle dogs. The mean AUC of Form II is about 2.6 times that of Form I, indicating that the solubility and bioavailability of pemafibrate can indeed be improved by forming the new polymorph Form II. It may become an ideal solid form of active pharmaceutically ingredient suitable for pharmaceutical preparations, and it can be further studied in the later period.
匹伐他汀钙是新一代抗高血脂药物。然而，其在水中的溶解度较差（25℃时为0.410mg/mL），限制了其口服生物利用度。在本研究中，我们旨在通过一种新的晶型来提高匹伐他汀钙的溶解度，进而提高其口服生物利用度。通过控制结晶温度成功获得了一种新的晶型II，并采用多种分析方法对其进行了表征。晶型I和晶型II的热力学性质几乎相同，晶型I的熔点[差示扫描量热法（DSC）起始温度：97.5℃，熔化熵：-76J/g]和晶型II的熔点（DSC起始温度：96.6℃，熔化熵：-80J/g）非常接近，且两者的结晶度都很高。在纯水中，就固有溶解速率（IDR）和粉末溶解度而言，晶型II约为晶型I的1.9倍。在介质中，在pH 6.8缓冲液中进行IDR表征。研究了该晶型II在0.1M HCl（pH 1.0）和磷酸盐缓冲液（pH 6.8）中的溶解度，结果表明，晶型II的溶解度分别是晶型I的2.1倍和2.0倍。晶型II的晶体结构表明，该化合物的亲水性羧基排列在晶胞外部，这可能是溶解度增加的原因。我们还研究了比格犬的药代动力学。晶型II的平均AUC约为晶型I的2.6倍，表明通过形成新的晶型II确实可以提高匹伐他汀钙的溶解度和生物利用度。它可能成为适合药物制剂的理想活性药物成分固体形式，后期可进一步研究。
