An Investigation into the Morphology of Loxapine in a Thermal Aerosolization Process from Crystalline to Amorphous

Abstract

A highly pure aerosol of the antipsychotic drug, loxapine, can be thermally generated through vaporization from a thin coating of loxapine on a stainless steel substrate with the formation of a condensation aerosol. Because loxapine can exist in two polymorphic forms, the morphological time course from loxapine drug substance to coating on the substrate (intermediate product) and ultimately to the aerosol was investigated using differential scanning calorimetery, X-ray diffraction (XRD), Fourier transform infrared, and Raman spectroscopy. Monoclinic and orthorhombic crystalline forms of loxapine were confirmed by single crystal and powder XRD. A mixture of both loxapine crystalline polymorphs was formed on the substrate, independent of the initial loxapine crystalline morphology, and demonstrated to be stable. The loxapine aerosols generated from the thermal aerosolization process were demonstrated to be amorphous, regardless of the initial polymorph of loxapine active pharmaceutical ingredient used. In humans, the amorphous aerosol was reported to be rapidly absorbed and the particle size resulted in rapid delivery to the deep lung.