A Scalable Freeze-Dissolving Approach to Prepare Ultrafine Crystals for Inhalation: Mechanism and Validation

Abstract

Inhaled drug delivery has garnered increasing attention due to its inherent advantages including rapid onset of action, targeted delivery, high bioavailability, and reduced side effects, which holds promise for the treatment of localized lung diseases and systemic diseases. The currently dominant technologies for the preparation of inhalants are air flow pulverization, media milling, and spray drying, which encounter challenges such as inaccurate particle size control, inefficiency, instability, and difficulties in scaling up. The present study proposes a freezedissolving technique (FDT) for the preparation of inhalable microcrystals, comprising two essential steps: rapid freezing of microdroplets into iced pellets within seconds and subsequent dissolution of a solvent in the iced pellets to release the microcrystals in a suspension. By employing the FDT technique, griseofulvin, a representative inhalant, was successfully engineered into a bipyramidal morphology with a targeted particle size (<5 μm), minimal agglomeration (<3%), and an aspect ratio below 2, in which the solvent and stabilizer systems played pivotal roles in facilitating or impeding nucleation and crystal growth processes. To verify the universality of the FDT, six other typical inhalant preparation processes were successfully developed based on the FDT with a controllable crystal size between 1 and 10 μm. Furthermore, three out of the aforementioned seven model substances were randomly selected, and their preparation was scaled up by a factor of 100, yielding consistent results with those obtained at a smaller test scale. This study outlines the freeze-dissolving mechanism in ultrafine crystal formation and demonstrates that the FDT is a robust and scalable approach for the production of inhalants.