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

Divalproex sodium (DVS) is a challenging drug owing to its hygroscopicity, bitter taste, and short half-life. This study aims to produce stable taste masked DVS once daily tablets using solvent free hot melt granulation (HMG) process. A lab scale high shear mixer granulator employing six meltable lipid binders (compritol888 ATO, beeswax, gelucire50/13, 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 pharmacokinetic study were conducted on the selected batches. Results revealed that DVS tablets were successfully prepared, and that the 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 pharmacokinetic study delineated relative bioavailability values for Beeswax and Compritol tablets of 95.6% and 118%, respectively, compared to the marketed product. 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.