Impact of Aluminum Oxide Nanocoating on Drug Release from Amorphous Solid Dispersion Particles.

Atomic layer coating (ALC) is emerging as a particle engineering strategy to inhibit surface crystallization of amorphous solid dispersions (ASDs). In this study, we turn our attention to evaluating drug release behavior from ALC-coated ASDs, and begin to develop a mechanistic framework. Posaconazole/hydroxypropyl methylcellulose acetate succinate was used as a model system at both 25% and 50% drug loadings. ALC-coatings of aluminum oxide up to 40 nm were evaluated for water sorption kinetics and dissolution performance under a range of pH conditions. Scanning electron microscopy with energy dispersive X-ray analysis was used to investigate the microstructure of partially released ASD particles. Coating thickness and defect density (inferred from deposition rates) were found to impact water sorption kinetics. Despite reduced water sorption kinetics, the presence of a coating was not found to impact dissolution rates under conditions where rapid drug release was observed. Under slower releasing conditions, underlying matrix crystallization was reduced by the coating, enabling greater levels of drug release. These results demonstrate that water was able to penetrate through the ALC coating, hydrating the amorphous solid, which can initiate dissolution of drug and/or polymer (depending on pH conditions). Swelling of the ASD substrate subsequently occurs, disrupting and cracking the coating, which serves to facilitate rapid drug release. Water sorption kinetics are highlighted as a potential predictive tool to investigate the coating quality and its potential impact on dissolution performance. This study has implications for formulation design and evaluation of ALC-coated ASD particles.

Atomic Layer Coating to Inhibit Surface Crystallization of Amorphous Pharmaceutical Powders.

Preventing crystallization is a primary concern when developing amorphous drug formulations. Recently, atomic layer coatings (ALCs) of aluminum oxide demonstrated crystallization inhibition of high drug loading amorphous solid dispersions (ASDs) for over 2 years. The goal of the current study was to probe the breadth and mechanisms of this exciting finding through multiple drug/polymer model systems, as well as particle and coating attributes. The model ASD systems selected provide for a range of hygroscopicity and chemical functional groups, which may contribute to the crystallization inhibition effect of the ALC coatings. Atomic layer coating was performed to apply a 5-25 nm layer of aluminum oxide or zinc oxide onto ASD particles, which imparted enhanced micromeritic properties, namely, reduced agglomeration and improved powder flowability. ASD particles were stored at 40 °C and a selected relative humidity level between 31 and 75%. Crystallization was monitored by X-ray powder diffraction and scanning electron microscopy (SEM) up to 48 weeks. Crystallization was observable by SEM within 1-2 weeks for all uncoated samples. After ALC, crystallization was effectively delayed or completely inhibited in some systems up to 48 weeks. The delay achieved was demonstrated regardless of polymer hygroscopicity, presence or absence of hydroxyl functional groups in drugs and/or polymers, particle size, or coating properties. The crystallization inhibition effect is attributed primarily to decreased surface molecular mobility. ALC has the potential to be a scalable strategy to enhance the physical stability of ASD systems to enable high drug loading and enhanced robustness to temperature or relative humidity excursions.

Surface nanocoating of high drug-loading spray-dried amorphous solid dispersions by atomic layer coating: Excellent physical stability under accelerated storage conditions for two years.

Physical instability remains a major concern with amorphous solid dispersions (ASDs). In addition to bulk crystallization inhibition, another potential strategy to improve the physical stability of ASDs is surface engineering. However, coating processes are extremely challenging for ASD microparticles. Herein, we describe for the first time the application of atomic layer coating (ALC), a solvent-free technique, to deposit a pinhole-free, ultra-thin film of aluminum oxide onto the surface of spray-dried ASD particles containing high drug loadings of ezetimibe with hydroxypropyl methylcellulose acetate succinate. ALC affords excellent control over the thickness, uniformity and conformality of the coating at the atomic scale. The freshly prepared coated ASD powders exhibited less agglomeration, a lower hygroscopicity, as well as improved wettability, flowability and compressibility compared to the uncoated samples. Under accelerated storage conditions, crystallization was detected in the uncoated 50% and 70% drug loading ASDs after only a few days, whereas the coated samples showed no evidence of physical instability for two years. Consequently, there was a dramatic decrease in the drug release from the uncoated ASDs during storage, while little change was observed for the coated samples. Using ALC for surface nanocoating of ASD paves the way for the development of higher drug loading ASD without compromising physical stability, thereby reducing the pill burden.