Dissolution of copovidone-based amorphous solid dispersions: Influence of atomic layer coating, hydration kinetics, and formulation

Abstract

Atomic layer coating (ALC) is an emerging, solvent-free technique to coat amorphous solid dispersion (ASD) particles with a nanolayer ceramic coating that has been shown to improve powder characteristics and limit drug crystallization. Herein, we evaluate the impact of aluminum oxide coatings with varying thickness and conformality on the release behavior of ritonavir/copovidone ASDs. Release performance of powders, neat tablets, and formulated tablets was studied. Confocal fluorescence microscopy (CFM) was used to visualize particle hydration and phase separation during immersion of the ASD in aqueous media. CFM revealed particle hydration requires defects for solvent penetration, but coatings, regardless of thickness, had minor impacts on powder dissolution provided defects were present. In tablets where less surface area is exposed to the dissolution media due to gel formation, slowed hydration kinetics resulted in phase separation of the drug from the polymer in coated samples, limiting release. Formulation with two superdisintegrants, crospovidone and croscarmellose sodium, as well as lactose achieved ∼90% release in less than 10 minutes, matching the uncoated ASD particles of the same formulation. This study highlights the importance of hydration rate, as well as the utility of confocal fluorescence microscopy to provide insight into release and phase behavior of ASDs.

Introduction

Bioavailability improvement can be achieved by formulating a poorly water-soluble drug as an amorphous solid dispersion (ASD) drug product which can create and maintain supersaturation.1, 2, 3 The ASD drug product intermediate consists of molecularly dispersed amorphous drug and polymer, while additional excipients are needed to formulate the ASD powder into an oral solid dosage form.4, 5, 6 This highlights the two major challenges and success criteria for the ASD formulation strategy: physical stability (i.e. preventing crystallization in the solid state) and optimized release performance (i.e. achieve supersaturation and prevent subsequent crystallization in solution).
Atomic layer coating (ALC) has emerged as a new, solvent-free particle coating technique.7,8 The ALC process deposits a nanoscale film onto the surface of a substrate in a layer-by-layer sequence of controlled chemical reactions.9, 10, 11 Typical ALC films have thicknesses on the order of <10-100 nm, and consist of metal oxides such as aluminum oxide or zinc oxide among others.12, 13, 14 In high drug loading ASD systems, ALCs of 5-40 nm film thickness have been found to inhibit surface crystallization upon storage in accelerated temperature and relative humidity conditions.12,13 The ALC strategy thus serves as a significant formulation intervention to promote physical stability of amorphous systems. Other particle properties such as wettability, dispersibility, and flowability have shown improvement upon coating, and agglomeration/hygroscopicity has been reduced.8,12,14, 15, 16

ALC-coated ASD systems have begun to be studied to understand the influence of the coating on the release process. Inorganic oxide coatings, such as TiO2, Al2O3, ZnO, and SiO2, have been shown to delay and slow rates of release from powders, having an increasing impact with greater thickness.7,16, 17, 18, 19, 20 Moseson et al. found that while Al2O3 coating thickness and defect density did affect water sorption, release was unaffected or improved whereby the coating prevented matrix crystallization in slow-releasing conditions.20 Although little work has been done on the impact of ALC on release from coated powders compressed into tablets, one study found the coating had no effect on dissolution rate of metformin HCl tablets.21 Furthermore, in terms of studying the impact of coatings on release from ASDs, only limited work has been performed, and only for hypromellose acetate succinate (HPMCAS)-based ASDs.12,20 Copovidone (polyvinylpyrrolidone/vinyl acetate copolymer, PVPVA), is widely used in ASDs, and undergoes significant gelation as part of the drug release process.22, 23, 24 The effect of ALC of ASD particles on gelation and subsequent release performance of PVPVA-based ASDs is thus largely unexplored, but likely to be important in dictating release behavior.

Drug release mechanisms from ASD systems are complex and have been found to be a function of polymer properties, drug loading, pH/ionization state, phase separation kinetics, and crystallization tendency, among other factors.25, 26, 27, 28, 29 For systems based on neutral polymers, such as PVPVA, release rates fall into two regimes. The polymer-controlled release regime is observed at low drug loadings (DL) that are below a critical drug loading termed the limit of congruency (LoC) and represents the optimal release regimen. The drug-controlled release regime is observed for DLs above the LoC, where release rates are comparatively slow, possibly leading to incomplete release.26,27,30 For PVPVA-based ASDs, the drug-controlled release regime typically occurs when the hydrophobic drug has phase separated to create a continuous amorphous layer blocking further hydration and therefore release.22,31 Adequate hydration is required for the polymer to swell, disentangle, and dissolve.

In this study, ritonavir (RTV) and PVPVA were selected as the model ASD system, as their phase behavior and release characteristics have been well-studied.22,27,32, 33, 34, 35 Because this system does not undergo rapid crystallization under storage or dissolution conditions, release mechanisms with ALC coating can be studied with fewer variables. This model system is a highly relevant ASD formulation to study, as it is found in several commercial drug products, including Norvir, Kaletra, Viekira Pak, and Paxlovid.6 RTV is a weakly basic drug with low aqueous solubility and is unionized under most physiological conditions (Table 1). PVPVA is the most common polymer used for ASD formulations, in particular for those made by hot melt extrusion.6,36 The polymer-controlled release regime (i.e., congruent release of RTV and PVPVA) has been observed from neat ASD tablets up to 25% DL.27

Herein, the impact of aluminum oxide atomic layer coatings on release performance of RTV and PVPVA ASDs at 10% and 20% DL was studied, where both DLs are below the reported LoC for this system, and therefore in the regime of polymer-controlled drug release.22,27 First, dissolution of ASD powders was investigated in pH 6.8 phosphate buffer. Second, release from neat ASD compressed into a tablet was evaluated in pH 6.8 phosphate buffer and 0.1 N HCl media. Reasons underlying observed differences in release behavior were further investigated using confocal fluorescence microscopy (CFM) in combination with fluorescent probes to study ASD hydration, gelation behavior, and coating barrier functionality upon exposure to the dissolution medium. The ASDs were then formulated into tablets with the goal of improving hydration kinetics and subsequent drug release rates.

Materials

Ritonavir (RTV) was obtained from ChemShuttle (Hayward, CA). Relevant physicochemical properties and solubility values are listed in Table 1.

Polyvinylpyrrolidone/vinyl acetate copolymer (copovidone, PVPVA, Kollidon VA64) and crospovidone (xPVP, Kollidon CL) were provided by BASF (Florham Park, NJ). Sodium starch glycolate (SSG, Explotab) was provided by JRS Pharma (Rosenberg, Germany). Croscarmellose sodium (CCS, Ac-Di-Sol) and microcrystalline cellulose (Avicel PH 102) were provided by Dupont.

Emily G. Benson, Dana E. Moseson, Shradha Bhalla, Fei Wang, Miaojun Wang, Kai Zheng, Pravin K. Narwankar, Lynne S. Taylor, Dissolution of copovidone-based amorphous solid dispersions: Influence of atomic layer coating, hydration kinetics, and formulation, Journal of Pharmaceutical Sciences, 2024, ISSN 0022-3549, https://doi.org/10.1016/j.xphs.2024.10.001.

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excipients formulation