Controlled isolation of a novel polymorphic form of chlorothiazide by spray drying†

Abstract

This study outlines a route to producing a novel polymorphic form of chlorothiazide (CTZ). CTZ was spray dried using three different atomising gas flowrate settings to determine whether it has any effect on the solid-state of CTZ. At a lower atomising gas flowrate, a new form of CTZ, CTZ form IV, was obtained in pure form, whereas at the highest atomising gas flowrate, a mixture of CTZ form I and CTZ form IV was obtained. The morphology of CTZ form I was prism-shaped, and the new form, CTZ form IV, consisted of spherical clusters, some of which were porous and some non-porous. As a result of the rapid drying process, acetone was trapped within the porous clusters and could be released by milling. CTZ form IV has been shown to be stable at room temperature and below 40% relative humidity (RH); however, after 1 week of stability under accelerated conditions of 40 °C/75% RH, CTZ form IV converted to CTZ form I. Also, at high temperatures between 150 °C and 175 °C, CTZ form IV converted to form I, with the simultaneous release of acetone upon its morphology change. This study demonstrates how spray drying can be useful to discover new forms of APIs by a controlled drying process.