Atomic Layer Coating to Inhibit Surface Crystallization of Amorphous Pharmaceutical Powders

Abstract

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.

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

“…The Al 2 O 3 coatings were applied to prepare samples with thinner and thicker coatings. Thickness measurements were broadly consistent when estimated by TGA or imaged by TEM (Table , Figure ), and coatings appear highly conformal, consistent with our previous work. , …”

“…Further experiments which explore coating process controls and deposition rates may shed more light on this finding in the future. Our previous works have demonstrated that the coating effectively inhibits surface crystallization, , and our current investigation has shown that the coatings must be sufficiently permeable to water to facilitate rapid release. Combined, this requirement suggests that the optimal coating qualities consist of a relatively thin coating with a sufficient level of defects to facilitate both crystallization inhibition and dissolution performance.…”

“…It has a melting point of 168 °C and T g of 59 °C. HPMCAS is an enteric polymer with T g of 120 °C and p K a of 5.0. ,, HPMCAS M grade dissolves above pH 6.0, requiring a minimum ionization fraction to initiate dissolution …”

“…As the improvement of physical stability on ASDs has been broadly demonstrated, , the goal of this research study is to evaluate release behavior of ALC-coated ASDs and begin to develop a mechanistic framework. Herein, the impact of aluminum oxide atomic layer coatings on release performance of ASD particles is examined using posaconazole (PCZ) and HPMCAS as a model drug and polymer at 25% and 50% drug loading (DL).…”

“…Atomic layer coating (ALC) is emerging as a novel strategy to inhibit surface crystallization in amorphous solid dispersions 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 ASD formulations, which were otherwise found to crystallize in <1 month at highly accelerated open dish storage conditions, were stable for 6 months to over 2 years. , This surface engineering strategy is highly successful because surface crystallization, which is orders of magnitude faster than bulk (interior) crystallization, is inhibited. − In other studies, ALC has shown benefit for other surface-mediated phenomena, such as improved wettability, dispersibility, and powder flowability, as well as reduced agglomeration and hygroscopicity. ,− The impact of ALC on ASD crystallization behavior in solution environments is as of yet largely unexplored.…”