A fundamental understanding of the interplay between ligand-removal kinetics and metal aggregation during the formation of platinum nanoparticles (NPs) in atomic layer deposition of Pt on TiO nanopowder using trimethyl(methylcyclo-pentadienyl)platinum(IV) as the precursor and O as the coreactant is presented. The growth follows a pathway from single atoms to NPs as a function of the oxygen exposure (P × time). The growth kinetics is modeled by accounting for the autocatalytic combustion of the precursor ligands via a variant of the Finke-Watzky two-step model. Even at relatively high oxygen exposures (<120 mbar s) little to no Pt is deposited after the first cycle and most of the Pt is atomically dispersed. Increasing the oxygen exposure above 120 mbar s results in a rapid increase in the Pt loading, which saturates at exposures >> 120 mbar s. The deposition of more Pt leads to the formation of NPs that can be as large as 6 nm. Crucially, high P (≥5 mbar) hinders metal aggregation, thus leading to narrow particle size distributions. The results show that ALD of Pt NPs is reproducible across small and large surface areas if the precursor ligands are removed at high P .

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The morphology, size and surface properties of pharmaceutical particles form an essential role in the therapeutic performance of active pharmaceutical ingredients (APIs) and excipients as constituents in various drug delivery systems and clinical applications. Recent advances in methods for surface modification, however, rely heavily on liquid-phase based modification processes and afford limited control over the thickness and conformality of the coating. Atomic layer deposition (ALD), on the other hand, enables the formation of conformal nanoscale films on complex structures with thickness control on the molecular level, whilst maintaining the substrate particle size and morphology. Moreover, this enables nanoengineering of surfaces of pharmaceutical particles also in the dry state. Successful nano-engineeering of crystal and amorphous surfaces of pharmaceutical particles is demonstrated in this study whereby functional properties, such as dissolution and dispersability, were tailored for drug delivery applications. This expands on our initial work on ALD of alumina on pharmaceutical particles within the lower micro-to higher nano-size ranges to here probe both crystalline and amorphous lactose substrate surfaces (d 50 3.5 and 21 um). In addition, both water and ozone coreactants were evaluated; the latter having not been evaluated previously for pharmaceutical particles.

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Ideal controlled pulmonary drug delivery systems provide sustained release by retarding lung clearance mechanisms and efficient lung deposition to maintain therapeutic concentrations over prolonged time. Here, we use atomic layer deposition (ALD) to simultaneously tailor the release and aerosolization properties of inhaled drug particles without the need for lactose carrier. In particular, we deposit uniform nanoscale oxide ceramic films, such as Al2O3, TiO2, and SiO2, on micronized budesonide particles, a common active pharmaceutical ingredient for the treatment of respiratory diseases. In vitro dissolution and ex vivo isolated perfused rat lung tests demonstrate dramatically slowed release with increasing nanofilm thickness, regardless of the nature of the material. Ex situ transmission electron microscopy at various stages during dissolution unravels mostly intact nanofilms, suggesting that the release mechanism mainly involves the transport of dissolution media through the ALD films. Furthermore, in vitro aerosolization testing by fast screening impactor shows a ∼2-fold increase in fine particle fraction (FPF) for each ALD-coated budesonide formulation after 10 ALD process cycles, also applying very low patient inspiratory pressures. The higher FPFs after the ALD process are attributed to the reduction in the interparticle force arising from the ceramic surfaces, as evidenced by atomic force microscopy measurements. Finally, cell viability, cytokine release, and tissue morphology analyses verify a safe and efficacious use of ALD-coated budesonide particles at the cellular level. Therefore, surface nanoengineering by ALD is highly promising in providing the next generation of inhaled formulations with tailored characteristics of drug release and lung deposition, thereby enhancing controlled pulmonary delivery opportunities.