International Journal of Pharmaceutics 620 (2022) 121747 Available online 12 April 2022 0378-5173/© 2022 Elsevier B.V. All rights reserved. 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 Tu Van Duong a , Hanh Thuy Nguyen a , Fei Wang b , Miaojun Wang b , Pravin K. Narwankar b , Lynne S. Taylor a, * a Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, IN 47907, United States b Applied Materials, 3100 Bowers Ave, Santa Clara, CA 95054, United States A R T I C L E INFO Keywords: Solid dispersions High drug loading Atomic layer coating Atomic layer deposition Nanocoating Spray drying Stability ABSTRACT 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 engi- neering. However, coating processes are extremely challenging for ASD microparticles. Herein, we describe for the frst time the application of atomic layer coating (ALC), a solvent-free technique, to deposit a pinhole-free, ultra-thin flm 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 thick- ness, 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, fowability 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. 1. Introduction Amorphous solid dispersion (ASD) is one of the most promising ap- proaches to improve the dissolution and oral bioavailability of poorly water-soluble compounds (Leuner and Dressman, 2000; Van den Mooter, 2012). In order to achieve a stable ASD where drug crystalli- zation is avoided during product storage, a high amount of a polymer often needs to be used to form the dispersion, where the amount depends on the drug crystallization tendency and how this is modifed by addi- tion of a specifc polymer. There is an unmet need to improve the drug loading since large amounts of polymer can lead to large dosage sizes, which are diffcult for patients to swallow, or multiple dosage units, increasing the pill burden. To date, most research has been focused on crystallization inhibition in the bulk system, mainly by using a polymer with high glass transition temperature (T g ) that is able to form in- teractions with the drug (Van Duong and Van den Mooter, 2016; Van Duong and Van den Mooter, 2016). However, surface engineering of either the active pharmaceutical ingredient (API) particles or ASD powder offers another potential approach to stabilization against crys- tallization (Zhu et al., 2008; Zhu et al., 2010; Wu et al., 2007; Gui et al., Abbreviations: ALC, atomic layer coating; API, active pharmaceutical ingredient; ASD, amorphous solid dispersion; C max , peak drug concentration; DMSO, dimethyl sulfoxide; DSC, differential scanning calorimetry; FIB, focused ion beam; HMPCAS, hydroxypropyl methylcellulose acetate succinate; HPLC, high-perfor- mance liquid chromatography; LLPS, liquid-liquid phase separation; PBS, phosphate buffer solution; PXRD, powder X-ray diffraction; RH, relative humidity; SEM, scanning electron microscopy; TEM, transmission electron microscopy; T g , glass transition temperature; TGA, thermogravimetric analysis; TMA, trimethylaluminum; T max , time to reach the peak concentration; UV/vis, ultraviolet-visible. * Corresponding author. E-mail addresses: vduong@purdue.edu (T. Van Duong), nguye534@purdue.edu (H.T. Nguyen), Fei_C_Wang@amat.com (F. Wang), Miaojun_Wang@amat.com (M. Wang), Pravin_K_Narwankar@amat.com (P.K. Narwankar), lstaylor@purdue.edu (L.S. Taylor). Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm https://doi.org/10.1016/j.ijpharm.2022.121747 Received 22 February 2022; Received in revised form 5 April 2022; Accepted 9 April 2022