(T1430-02-12) Highly Controlled Drug Nanoparticles Generation by Vapor Jet De-sublimation

Purpose: Over 40% of marketed drugs suffer from poor aqueous solubility, limiting their therapeutic efficacy. Enhancing dissolution is critical for improving bioavailability and clinical outcomes. Conventional nanonization or amorphization methods –such as ball milling, high-pressure homogenization, and spray drying– improve dissolution but often require excessive solvents, excipients, and energy input. We present a simple, energy-efficient, solvent-free, additive manufacturing approach to generate drug nanoparticles with enhanced dissolution performance. Using griseofulvin (GSF) as a model compound, we demonstrate the production of amorphous nanoparticles with diverse morphologies (films, discrete nanoparticles, particle aggregates and fractal meshes) and improved dissolution without polymeric excipients. This platform also generalizes to other active pharmaceutical ingredients (APIs) and excipients (e.g., atovaquone, saccharin) and yield physically stable nanoparticles under accelerated storage conditions (40 ^oC, 75% RH).

Methods: A collimated, carrier-gas-driven molecular vapor jet was employed to induce continuous gas-phase nucleation and nanoparticle growth. Organic materials were vaporized, entrained by a carrier gas (e.g., nitrogen), and jetted toward a collection substrate. Resulting particles and films were characterized using scanning electron microscopy (SEM) and X-ray diffraction (XRD) to confirm morphology and amorphousness. Computational fluid dynamics (CFD) simulations (COMSOL Multiphysics) mapped supersaturation fields and predicted nucleation zones, guiding process optimization and reproducibility validation. Real-time particle trajectory visualization and collection allowed experimental validation of flow dynamics and deposition modeling. Dissolution testing was conducted in both fed state simulated intestinal fluid (FeSSIF) and fasted state simulated intestinal fluid (FaSSIF). Amorphous GSF nanoparticles and raw GSF were compared at a 100 µg/ml dose. Concentration-time profiles were used to quantify enhancement, highlighting the ability to achieve superior dissolution performance without relying on polymeric stablizers.

Results: The vapor jet method reproducibly generated GSF nanoparticles with tunable morphologies. SEMs and Particle size analysis quantified the morphology differences; XRD confirmed predominatnly amorphous content. CFD modeling closely matched experimental deposition profiles, supporting the proposed gas-phase nucleation mechanism. The platform successfully generalized to atovaquone and saccharin; Dissolution studies revealed significant performance improvements: In FeSSIF, amorphous GSF nanoparticles achieved over a 3-fold increase in concentration compared to raw GSF; In FaSSIF, where GSF solubility is lower, a 2-fold concentration increase was achieved. Importantly, these enhancements were obtained without any polymeric excipients, highlighting the intrinsic benefit of morphology control via gas-phase processing. Nanoparticles remained physically stable after two months at 40 ^oC and 75% RH, without any aggregation or recrystallization.

Conclusion: We developed a solvent-free, energy-efficient, and reproducible vapor jet platform that enables the fabrication of stable, excipient-free drug nanoparticles with significantly enhanced dissolution performance. Through tunable morphology control and real-time particle trajectory visualization, this method offers a scalable solution to address poor aqueous solubility challenges. The ability to achieve dissolution enhancement without polymeric additives improves formulation simplicity and expands opportunities for bioavailability improvement across a range of poorly soluble pharmaceutical compounds.

References: L. Kumari et al. Life 13, 1099 (2023).
R. Samineni et al. Turk J Pharm Sci 19, 706–713 (2022).

Acknowledgements: We thank the Michigan Center for Materials Characterization [(MC)2] for instrument support. We thank National Science Foundation [Grant numbers 2029139], Sublime, LLC, Bill and Melinda Gates Foundation for funding support. University of Michigan has applied for patents on aspects of technology described here, licensed it to Sublime, LLC, who co-sponsored the work; MS and UM hold equity in Sublime, LLC.