Fabrication of extended-dissolution divalproex tablets: a green solvent-free granulation technique

Objective: Divalproex sodium (DVS) is a challenging drug owing to its hygroscopicity, bitter taste, and short in vivo half-life. This study aims to produce stable taste masked DVS once daily tablets using solvent free hot melt granulation (HMG) process. Methods: A lab scale high shear mixer granulator employing six meltable lipid binders (compritol®888 ATO, beeswax, gelucire®50/13, precirol® ATO5, stearyl alcohol, and geleol®) was used for the preparation of tablets. Quality control tests were performed on granules and tablets, and Box–Behnken’s design was adopted to investigate the effect of binder concentration, impeller speed, and granulation time on the drug dissolution. Shelf and accelerated stability evaluation, taste assessment, and in vivo pharmacokinetic study were conducted on the selected batches. Results: Results revealed that DVS tablets were successfully prepared, and that the in vitro dissolution of the drug was inversely proportional to the binder concentration. Beeswax and compritol® tablets showed similar dissolution profiles to the marketed product Depakote® 500 ER tablets (F1 50). The selected batches showed lower moisture content (<2%) and successfully masked the bitter taste compared to uncoated tablets based on a hydrophilic matrix. The in vivo pharmacokinetic study delineated relative bioavailability values for Beeswax and Compritol® tablets of 95.6% and 118%, respectively, compared to the marketed product. Conclusion: The solvent free HMG process can be employed to formulate 24 h extended dissolution DVS tablets with masked bitter taste and high stability, and comparable or higher bioavailability than the marketed product.研究目的：丙戊酸钠（Divalproex sodium, DVS）因兼具吸湿性、苦味及体内半衰期较短的特性，属于制备难度较高的药物。本研究旨在采用无溶剂热熔制粒（hot melt granulation, HMG）工艺，制备兼具稳定性与良好口感掩蔽效果的每日一次给药DVS缓释片剂。 研究方法：本研究采用实验室级高剪切混合制粒机，以六种可熔融脂质黏合剂（Compritol®888 ATO、蜂蜡、Gelucire®50/13、Precirol® ATO5、硬脂醇及Geleol®）为辅料制备片剂。对制得的颗粒与片剂开展质量控制检测，并采用Box-Behnken设计，考察黏合剂用量、叶轮转速及制粒时间对药物溶出度的影响。对筛选得到的批次，分别进行货架期稳定性、加速稳定性评价、口感评估及体内药代动力学研究。 研究结果：结果显示，DVS缓释片剂可成功制备，且药物体外溶出度与黏合剂用量呈负相关。蜂蜡组与Compritol®组片剂的溶出曲线与市售参比制剂Depakote® 500 ER缓释片相似（相似因子F1=50）。相较于采用亲水基质的未包衣片剂，筛选批次的水分含量更低（<2%），且可有效掩蔽药物苦味。体内药代动力学研究表明，以市售制剂为对照，蜂蜡片剂与Compritol®片剂的相对生物利用度分别为95.6%与118%。 研究结论：无溶剂热熔制粒工艺可用于制备24小时缓释溶出的DVS片剂，该制剂兼具优异的苦味掩蔽效果与高稳定性，且生物利用度不低于甚至优于市售参比制剂。