Abstract 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 < 15 and F2 > 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.

中文翻译：

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延长溶出度双丙戊酸钠片的制备：一种绿色无溶剂制粒技术

摘要 目的：双丙戊酸钠（DVS）具有吸湿性、苦味和体内半衰期短等特点，是一种具有挑战性的药物。本研究旨在使用无溶剂热熔制粒 (HMG) 工艺生产稳定的掩味 DVS 每日一次片剂。方法：使用六种可熔脂质粘合剂（compritol® 888 ATO、蜂蜡、gelucire® 50/13、precirol® ATO5、硬脂醇和geleol®）的实验室规模高剪切混合制粒机用于制备片剂。对颗粒剂和片剂进行质量控制测试，并采用 Box-Behnken 的设计来研究粘合剂浓度、叶轮速度和制粒时间对药物溶出度的影响。对选定批次进行货架和加速稳定性评估、味道评估和体内药代动力学研究。结果：结果表明DVS片剂制备成功，药物的体外溶出度与结合剂浓度成反比。蜂蜡和 compritol® 片剂显示出与市售产品 Depakote® 500 ER 片剂相似的溶出曲线（F1 < 15 和 F2 > 50）。与基于亲水基质的未包衣片剂相比，所选批次的水分含量较低 (<2%)，并成功掩盖了苦味。体内药代动力学研究表明，与市售产品相比，蜂蜡和 Compritol® 片剂的相对生物利用度值分别为 95.6% 和 118%。结论：无溶剂 HMG 工艺可用于配制 24 h 延长溶出度的 DVS 片剂，具有掩蔽苦味和高稳定性，