{"title":"Novel cocrystal inclusion compound of bezafibrate with l-proline: preparation, characterization, and <i>in vitro</i>/<i>in vivo</i> evaluation.","authors":"Kangjie Wen, Hongguo Han, Tingyu Jin, Xingyi Zhu, Yunfen Hua","doi":"10.1080/03639045.2026.2741086","DOIUrl":null,"url":null,"abstract":"<p><strong>Context: </strong>Bezafibrate (BEZA) suffers from poor water solubility, which severely restricts its in vitro dissolution performance and further limits in vivo bioavailability.</p><p><strong>Objective: </strong>To improve the solubility and dissolution of BEZA and enhance its bioavailability.</p><p><strong>Methods: </strong>The cocrystal of BEZA and L-proline (L-Pro) (BEZA-L-Pro cocrystal) was prepared using liquid-assisted ball milling method. Additionally, the BEZA-L-Pro/hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion compound was prepared through neat ball milling. The preparation conditions were optimized. The formation of the cocrystal and inclusion compound was confirmed by powder X-ray diffraction, differential scanning calorimetry, Fourier-transform infrared spectroscopy and scanning electron microscopy. The stoichiometry of the inclusion compound was determined by phase solubility tests.</p><p><strong>Results: </strong>The optimal cocrystal preparation conditions were: BEZA to L-Pro molar ratio of 1: 1, ethanol as solvent, η of 0.8 μL/mg, milling speed of 150 rpm. The optimal inclusion compound preparation conditions were: BEZA-L-Pro to HP-β-CD molar ratio of 1: 1, milling speed of 200 rpm. The saturation solubility test showed that the saturation solubility of cocrystal and inclusion compound was 1.48 times and 3.91 times of BEZA, respectively. The dissolution test showed that the cumulative release rate of cocrystal and inclusion compound in acetate buffer solution (pH 4.5) within 120 min was 2.5 times and 4 times of BEZA, respectively. The in vivo study demonstrated that the bioavailability of cocrystal and inclusion compound was 1.4 times and 2 times of BEZA, respectively.</p><p><strong>Conclusion: </strong>The prepared BEZA-L-Pro cocrystal and BEZA-L-Pro/HP-β-CD inclusion compound can significantly improve the solubility and dissolution of BEZA, and enhance its bioavailability.</p>","PeriodicalId":11263,"journal":{"name":"Drug Development and Industrial Pharmacy","volume":" ","pages":"1-13"},"PeriodicalIF":2.6000,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Development and Industrial Pharmacy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/03639045.2026.2741086","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Context: Bezafibrate (BEZA) suffers from poor water solubility, which severely restricts its in vitro dissolution performance and further limits in vivo bioavailability.
Objective: To improve the solubility and dissolution of BEZA and enhance its bioavailability.
Methods: The cocrystal of BEZA and L-proline (L-Pro) (BEZA-L-Pro cocrystal) was prepared using liquid-assisted ball milling method. Additionally, the BEZA-L-Pro/hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion compound was prepared through neat ball milling. The preparation conditions were optimized. The formation of the cocrystal and inclusion compound was confirmed by powder X-ray diffraction, differential scanning calorimetry, Fourier-transform infrared spectroscopy and scanning electron microscopy. The stoichiometry of the inclusion compound was determined by phase solubility tests.
Results: The optimal cocrystal preparation conditions were: BEZA to L-Pro molar ratio of 1: 1, ethanol as solvent, η of 0.8 μL/mg, milling speed of 150 rpm. The optimal inclusion compound preparation conditions were: BEZA-L-Pro to HP-β-CD molar ratio of 1: 1, milling speed of 200 rpm. The saturation solubility test showed that the saturation solubility of cocrystal and inclusion compound was 1.48 times and 3.91 times of BEZA, respectively. The dissolution test showed that the cumulative release rate of cocrystal and inclusion compound in acetate buffer solution (pH 4.5) within 120 min was 2.5 times and 4 times of BEZA, respectively. The in vivo study demonstrated that the bioavailability of cocrystal and inclusion compound was 1.4 times and 2 times of BEZA, respectively.
Conclusion: The prepared BEZA-L-Pro cocrystal and BEZA-L-Pro/HP-β-CD inclusion compound can significantly improve the solubility and dissolution of BEZA, and enhance its bioavailability.
目的：提高贝扎贝特（BEZA）的溶解度和溶出度，提高其生物利用度。意义：BEZA溶解度差。本研究通过一种新的共晶包合化合物策略解决了这一限制。方法：采用液体辅助球磨法制备BEZA与l -脯氨酸（L-Pro）共晶（BEZA-L-Pro共晶）。通过球磨法制备了BEZA-L-Pro/羟丙基-β-环糊精包合物（HP-β-CD）。对制备条件进行了优化。通过粉末x射线衍射、差示扫描量热法、傅里叶变换红外光谱和扫描电镜证实了共晶和包合物的形成。包合物的化学计量学通过相溶解度试验确定。结果：最佳共晶制备条件为：BEZA与L-Pro的摩尔比为1:1，乙醇为溶剂，η为0.8 μL/mg，铣削速度为150 rpm。最佳包合物制备条件为：BEZA-L-Pro与HP-β-CD的摩尔比为1:1，铣削速度为200 rpm。饱和溶解度测试表明，共晶和包合物的饱和溶解度分别是BEZA的1.48倍和3.91倍。溶出试验表明，共晶和包合物在醋酸缓冲液（pH 4.5）中120 min内的累积释放率分别是BEZA的2.5倍和4倍。体内研究表明，共晶和包合物的生物利用度分别是BEZA的1.4倍和2倍。结论：制备的BEZA- l - pro共晶和BEZA- l - pro /HP-β-CD包合物可显著提高BEZA的溶解度和溶出度，提高其生物利用度。
期刊介绍：
The aim of Drug Development and Industrial Pharmacy is to publish novel, original, peer-reviewed research manuscripts within relevant topics and research methods related to pharmaceutical research and development, and industrial pharmacy. Research papers must be hypothesis driven and emphasize innovative breakthrough topics in pharmaceutics and drug delivery. The journal will also consider timely critical review papers.
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