(T1230-12-69) Impact of Aluminum Oxide Nanocoating on Release Behavior of Posaconazole/HPMCAS Amorphous Solid Dispersions

Purpose: Atomic layer coating (ALC) is emerging as a novel strategy to inhibit crystallization in amorphous solid dispersion (ASD) upon storage. ALC is a solvent free, layer-by-layer technique in which a nanoscale film ( < 10-100 nm) is applied to the surface of a substrate. Following application of an aluminum oxide coating of 5-40 nm, high drug loading amorphous solid dispersion (ASD) formulations, which were otherwise found to crystallize in < 1 month at accelerated storage conditions, were stable for 1-2 years. The surface engineering strategy is highly successful because surface crystallization, which is orders of magnitude faster than bulk (interior) crystallization, is inhibited. In this study, the impact of aluminum oxide atomic layer coatings on release performance of ASD particles is examined.

Methods: Posaconazole and hydroxypropyl methylcellulose acetate succinate (HPMCAS, MF grade) were selected as a model drug and polymer to prepare ASDs of 25% and 50% drug loading (DL). Hot melt extrusion was used to prepare the ASDs, which were then milled into two sieve fractions ( < 106 µm, 106-250 µm), and aluminum oxide nanocoatings (10-40 nm thickness) were applied using ALC. Two types of dissolution studies were conducted. First, release performance was conducted in a two-stage dissolution setup, representing simple gastric and intestinal conditions, to investigate the impact of the aluminum oxide coating in both acidic and neutral conditions. Second, release performance in a single-stage dissolution experiment in pH 6.5 buffer was conducted to correlate to results found in the two-stage dissolution setup. The persistence of the aluminum oxide coating was determined in each buffer system by imaging studies using scanning electron microscopy/energy dispersive X-ray analysis (SEM/EDX).

Results: Non-sink dissolution studies were conducted for ASD systems with and without aluminum oxide coatings at 8 µg/mL posaconazole concentration dose condition, equivalent to the amorphous solubility of posaconazole at pH 6.5. As shown in Figure 1A and 1B, release profiles of the coated systems are similar to that of the neat system of both 25% and 50% DL. Release rates were found to be faster for the smaller particle size ASDs. The 50% DL formulation has limited release, consistent with its high DL. Similar release performance trends were observed during pH shift dissolution studies (Figure 1C and 1D). The appearance of the coating on particles exposed to aqueous media was examined by SEM/EDX (Figure 2). The coating is identified by Al and O elements, and C, O, and F elements are found in the ASD formulation (F is found only in the drug). While not highlighted in this figure, deposition of buffer salts onto the dried particles can also be observed by elemental imaging. Imaging could only be conducted in conditions where the particle did not dissolve rapidly. Following immersion, the coating begins to crack and flake off. In pH conditions where release is favored (pH 6.5, where the polymer is ionized), the presence of the coating does not alter behavior of the underlying particle. The particle without coating forms continuous drug-containing domains, presumably due to the release of the polymer leaving behind amorphous drug. These continuous domains can be observed where the coating has disappeared.

Conclusion: Earlier studies in our laboratory have demonstrated that atomic layer coatings of aluminum oxide inhibit surface crystallization, sufficient to extend the stability of a high drug loading ASD from < 1 month to over 24 months (graphically presented in Figure 3). In this study, non-sink dissolution testing was conducted on posaconazole/HPMCAS ASD formulations, and it was found that release performance was unaffected by the presence of the coating. Upon immersion in aqueous media, the coating fractures and flakes off, enabling hydration and release of the underlying ASD particle. This study supports the broad applicability of atomic layer coatings for surface modification of pharmaceutical materials.

Acknowledgements:Funding for the study was provided by Applied Materials.


Figure 1. Dissolution profiles (single stage) of (A) 25% DL and (B) 50% DL posaconazole/HPMCAS ASDs with and without aluminum oxide coatings conducted in pH 6.5 phosphate buffer at 8 µg/mL dose concentration. Dissolution profiles (pH shift) of (C) 25% DL and (D) 50% DL posaconazole/HPMCAS ASDs with and without aluminum oxide coatings conducted in pH 1.6 and pH 6.5 phosphate buffer at 8 µg/mL dose concentration.


Figure 2. SEM/EDX imaging of 25% DL and 50% DL posaconazole/HPMCAS ASDs with or without aluminum oxide coatings following immersion in pH 1.6 or pH 6.5 media for 30-60 minutes. Spatial distribution of the elements carbon (C), oxygen (O), aluminum (Al), and fluorine (F) are highlighted.


Figure 3. Dissolution profiles (single stage) of (A) 25% DL and (B) 50% DL posaconazole/HPMCAS ASDs with and without aluminum oxide coatings conducted in pH 6.5 phosphate buffer at 8 µg/mL dose concentration.