Expedited Tablet Formulation Development of a Highly Soluble Carbamazepine Cocrystal Enabled by Precipitation Inhibition in Diffusion Layer.

Abstract

To address the problem of precipitation of a poorly soluble drug during dissolution of highly soluble cocrystals by preparing granules intimately mixed with a water-soluble polymer. Effectiveness of polymers as precipitation inhibitors during the dissolution of carbamazepine-nicotinamide (CBZ-NCT) cocrystal was assessed based on induction time of crystallization from a supersaturated solution in presence of different polymers at two concentrations. Dissolution was evaluated by both intrinsic dissolution rate (IDR) and USP dissolution method. Powder manufacturability was assessed using a shear cell and compaction simulator to assess flowability and tabletability, respectively. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) was the most effective polymer against precipitation of CBZ and the IDR of a 1:1 (w/w) CBZ-NCT/HPMCAS mixture was the highest. The final formulation of 1:1 CBZ-NCT/HPMCAS granule exhibited excellent flowability, good tabletability, and significantly improved drug release rate than cocrystal formulations without HPMCAS or the CBZ formulation. The particle engineering strategy of modifying the diffusion layer on the surface of highly soluble cocrystal with a polymer is effective for inhibiting premature precipitation of CBZ. Assisted with predictive tools for characterizing powder flowability and tabletability, the design of high quality tablet product with improved drug release rate and manufacturability can be achieved in an efficient manner.