The heterogeneous crystallization of a novel solvate of clozapine base in the presence of excipients

Abstract

A new methanol solvate of clozapine base (CPB) has been identified. It exhibits different molecular arrangements and bonding environments at low and room temperatures, while still maintaining the same PXRD pattern throughout. Slurry experiments confirmed this CPB–MeOH solvate to be the thermodynamically stable form in suspension relative to CPB. The CPB–MeOH solvate was further characterised using TGA, DSC and VT-PXRD, with VT-PXRD confirming its conversion to CPB upon desolvation via heating. As confirmed by PXRD, CPB–MeOH solvate was also crystallized heterogeneously from MeOH in the presence of dextran (DEX), chitosan (CHT) and microcrystalline cellulose (MCC), with a significant reduction in induction time observed in the presence of all three excipients: 28, 18 and 15-fold in the presence of DEX, CHT, and MCC respectively. The CPB–MeOH solvate crystals in the resultant composite solids were desolvated to CPB upon heating to 120 °C for 6 h, causing their plate-like habit to deform to one containing pores and ridges. The accompanying increase in crystal surface area led to a 3 to 5-fold increase in the extent of CPB's dissolution from these desolvated CPB–MeOH crystals after 5 minutes and also after 1 h relative to normal CPB crystals. Therefore, the potential may exist to enhance the dissolution rate of a poorly-soluble active pharmaceutical ingredient (API), thereby improving its bioavailability, by crystallizing it as a solvate in the presence of an excipient heterosurface and thereafter desolvating the API crystals in the composite solid at high temperature. By so doing, it may no longer be necessary to mill such API crystals during drug formulation.