Cocrystal Engineering of Itraconazole with Suberic acid via Rotary Evaporation and Spray Drying

Abstract

Cocrystallization represents an emerging approach to tackle the issues associated with pharmaceutical product performance and processing, owing to its capability of modifying a variety of physicochemical properties. In this study, we sought to modify the crystal form of itraconazole (ITZ) with suberic acid (SUB) via rapid solvent removal methods, namely rotary evaporation and spray drying. A phase pure ITZ-SUB cocrystal, which could not be obtained by traditional cocrystallization methods, was successfully prepared by rotary evaporation. The new cocrystal was confirmed by powder X-ray diffraction, differential scanning calorimetry, and Fourier-transform infrared spectroscopy. Spray drying was further employed for particle engineering of ITZ-SUB to achieve optimal pulmonary delivery. By manipulating the critical processing parameters, inhalable ITZ-SUB agglomerates with a mass median aerodynamic diameter of 2.56 ± 2.27 μm and fine particle fraction of 64.10% w/w were reproducibly prepared. The inhalable powders contained mainly coamorphous ITZ-SUB, while a small portion of cocrystals still exists. Compared with the raw ITZ, the intrinsic dissolution rate of the ITZ-SUB cocrystal was ∼39 times faster, and a significantly larger fraction of ITZ-SUB agglomerates was dissolved after 180 min of the test. Besides, both products remained stable after 1-month storage at 60 °C.