Co-crystallization for enhanced dissolution rate of nateglinide: In vitro and in vivo evaluation

Nateglinide is a non-sulphonylurea which was approved for treatment of type II diabetes mellitus. Its pH dependent slow dissolution resulted in variable oral bioavailability. This work presents Co-crystallization as a strategy for enhanced dissolution rate of nateglinide. The study was extended to investigate the effect of this dissolution enhancement on the hypoglycemic effect of the drug in diabetic rats. Sucralose was utilized as a co-crystal co-former at two different molar ratios (1:1 and 1:2, drug to sugar). The co-crystal formulations were prepared utilizing wet co-grinding technique in presence of acetone. The Co-crystallization process was monitored using infrared spectroscopy, thermal analysis and X-ray diffraction. Drug dissolution was monitored before and after processing with and without sucralose. The optimum co-crystalline product was evaluated for hypoglycemic effect with reference to the unprocessed drug. The study revealed polymorphic conversion of nateglinide after precipitation from acetone. Co-crystals were formed with 1:2 drug to sucralose (molar ratio) being optimum for co-crystallization process. The developed co-crystals exhibited fast drug dissolution and resulted in faster and more extensive reduction in blood glucose level compared with the unprocessed drug. The study thus introduced co-crystallization technique for enhanced dissolution rate and hypoglycemic efficacy of nateglinide.

191