Cocrystallization of Dolutegravir Sodium via Liquid-Assisted Grinding: Preparation, Characterization, and Ex vivo Evaluation

Introduction: Dolutegravir sodium is a second-line antiretroviral drug recommended by the World Health Organization for the treatment of people living with human immunodeficiency virus (HIV) who have failed a first-line regimen. It exhibits poor aqueous solubility and classified as Class II drug as per Biopharmaceutics Classification System. Additionally, it has low oral bioavailability (<50%). Cocrystallization is a promising approach to enhance solubility and bioavailability by forming supramolecular synthons with suitable coformers. Method: Cocrystals of dolutegravir sodium were prepared using xylitol, nicotinamide, and sorbic acid by the liquid assisted grinding method with ethyl acetate as the solvent. Prepared cocrystals were evaluated for solubility, dissolution, FTIR, DSC, PXRD, and Ex vivo study by everted intestine method. Results: Solubility was enhanced by 2.38, 2.91, and 5.01-fold with xylitol, nicotinamide, and sorbic acid, respectively. At 60 minutes, dissolution rates were 27.99 ± 2.5% (pure drug), 49.06 ± 2.56% (xylitol), 61.97 ± 3.24% (nicotinamide), and 96.54 ± 4.61% (sorbic acid). Dolutegravir:sorbic acid (1:1) cocrystals exhibited a distinct endothermic peak at 177.22 °C in DSC and intense PXRD peaks at 4.55°, along with unique peaks at 10.61°, 12.61°, 12.23°, 15.09°, 16.24°, 21.56°, 24.76°, and 25.27°. Ex vivo studies showed intestinal transport of 29.59 ± 4.93% for the pure drug and 72.51 ± 5.70% for the cocrystal. Conclusion: Cocrystals of dolutegravir sodium with sorbic acid were successfully prepared and evaluated. The solubility and dissolution rate of the prepared cocrystals were significantly increased. FTIR, DSC, and PXRD analyses confirmed the formation of a new crystalline structure. Furthermore, the Ex vivo study demonstrated a significant improvement in drug transport across the intestinal membrane.