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.

目的：丙戊酸钠（Divalproex sodium, DVS）因吸湿性、苦味及体内半衰期短等特性，成为一款极具挑战性的药物。本研究旨在采用无溶剂热熔制粒（hot melt granulation, HMG）工艺，制备具有稳定掩味效果的DVS每日1次片剂。
方法：本研究采用实验室规模高剪切混合制粒机，选用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®，用于片剂的制备。对制得的颗粒与片剂开展质量检测，并采用Box-Behnken设计考察黏合剂浓度、叶轮转速及制粒时间对药物溶出行为的影响。对筛选得到的优化批次进行货架期稳定性与加速稳定性评价、口味评估及体内药代动力学研究。
结果：研究结果表明，成功制备得到DVS片剂，且药物的体外溶出度与黏合剂浓度呈负相关。蜂蜡组与Compritol®组片剂的溶出曲线与市售产品Depakote®500 ER片剂相似（F1值为50）。相较于未包衣亲水基质片，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显示，以市售Depakote®500 ER片剂为参比，蜂蜡组与Compritol®组片剂的相对生物利用度分别为95.6%与118%。
结论：无溶剂热熔制粒工艺可用于制备24小时持续溶出的DVS片剂，该制剂具备苦味掩蔽效果佳、稳定性高的优势，且生物利用度与市售产品相当甚至更优。