Effect of Particle Size and Morphology on the Dehydration Mechanism of a Non-Stoichiometric Hydrate

Abstract

A hydrated form of 7-methoxy-1-methyl-5-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-a]quinolin-4-amine (designated Form B) exhibits moisture sorption behavior that is very strongly affected by particle size and morphology. When studied pre- and post-micronization, the simple rate of dehydration at ambient temperature is faster by >2 orders of magnitude after micronization. Complementary techniques were employed to understand this behavior including environmental X-ray powder diffractometry (XRPD), gravimetric vapor sorption (GVS), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy (HSM), single-crystal X-ray diffractometry (SCXRD), and solid-state nuclear magnetic resonance (SSNMR). Solid-state kinetics analysis of thermal data revealed that dehydration of the nonmicronized material follows a two-step consecutive reaction with the first step being a diffusion limited reaction and the second step being a first order reaction, whereas the micronized material follows a simple one-step <i>n</i>th order reaction. The crystal structure of Form B was determined, and the difference in dehydration kinetics was linked to narrow and staggered water channels observed along the crystallographic <i>a</i>-axis. Micronization cleaves slip planes that are approximately perpendicular to the long-axis of the water channels, allowing for easier egress and causing drastic changes in moisture sorption properties. Morphology predictions suggest that Form B has a tendency to have high aspect ratios along the <i>a</i>-axis, the longest axis of the columnar-shaped crystals, so that the rate of dehydration is limited by long channel systems. The crystal structure shows two crystallographically distinct water molecules with slightly different hydrogen bonding networks. SSNMR experiments are used to directly observe the preferential dehydration of one water molecule, and density functional theory and Monte Carlo sorption calculations are used to probe energetic differences between the water environments