Improved Manufacturability and In Vivo Comparative Pharmacokinetics of Dapagliflozin Cocrystals in Beagle Dogs and Human Volunteers

Dapagliflozin (DAP), which improves glycemic control in patients with type 2 diabetes mellitus, has poor physical properties against heat and moisture, thus hindering its manufacturing potential. The superior physicochemical properties of a recently developed cocrystal of DAP and citric acid (DAP cocrystal) in comparison with those of DAP and Forxiga®, a patented solvate form with propandiol monohydrate, were identified via structural analysis and moisture sorption isotherm.

For the first time, the formulation, manufacturability, and in vivo bioavailability of DAP cocrystals were successfully investigated to develop oral dosage forms that substitute Forxiga®. The intrinsic dissolution rate of DAP cocrystal was controlled by varying particle size distribution. Unlike the direct compression (DC), roller compaction (RC) was more preferable to obtain good flowability of dry granules for a continuous manufacturing system. The cocrystal structure was maintained throughout the stability assessment period. In Vitro dissolution pattern differences of the optimized DAP cocrystal tablet with RC and the reference tablet, Forxiga® 10 mg, were pharmaceutically equivalent within 5% in four different media.

Furthermore, comparative pharmacokinetic analysis confirmed that a 10 mg DAP cocrystal tablet with RC was bioequivalent to a 10 mg Forxiga® tablet, as assessed in beagle dogs and human volunteers.

Download the full article here: Improved Manufacturability and In Vivo Comparative Pharmacokinetics of Dapagliflozin Cocrystals in Beagle Dogs and Human Volunteers

or continue reading here: Cho, S.; Lee, J.; Yoo, Y.; Cho, M.; Sohn, S.; Lee, B.-J. Improved Manufacturability and In Vivo Comparative Pharmacokinetics of Dapagliflozin Cocrystals in Beagle Dogs and Human Volunteers. Pharmaceutics 2021, 13, 70.

Conclusions
In this study, the hydrogen bonds in DAP cocrystal structure was confirmed through XRD and FTIR. The physical properties of the cocrystal against heat and moisture were superior to those of DAP and DAP-PH. To improve granule flowability and achieve a continuous manufacturing system, optimization of the RC parameters was tested and established. Moreover, it was confirmed that the cocrystal structure was maintained during the entire stability test for the final selected formulation, RC-T4. Similar Forxiga^® 10 mg and RC-T4 PK patterns were identified in beagle dogs. Comparative PK studies of RC-T4 and reference tablets using crossover design in human volunteers showed bioequivalence with regard to the extent of bioavailability and C_max.

Keywords: dapagliflozin; cocrystal; dry granulation; manufacturability; stability; dissolution; comparative pharmacokinetics, Anhydrous lactose (Supertab 21AN) , Lactose monohydrate (Tablettose), Microcrystalline cellulose (Avicel PH-101), Microcrystalline cellulose (Vivapur 12), Mannitol (Pearlitol 100 SD), crospovidone (Polyplasdone XL), colloidal silicon dioxide (Aerosil 200 pharma), magnesium stearate, Opadry