In vitro evaluation of water-insoluble silicates and polyvinylpyrrolidone-vinyl acetate as oral carriers for amorphous ritonavir: dissolution enhancement and the role of phosphatidylcholine

Abstract

Porous silicates have been investigated as drug carriers to promote the solubility and in vitro dissolution of poorly water-soluble drugs, owing to their potential to adsorb drug molecules in the amorphous form within their structural cavities. This study aimed to evaluate the efficiency of bentonite (BT), Aeroperl 300 Pharma (AP), and Florite PS-200 (FR) as water-insoluble silicate drug carriers, and the polymer polyvinylpyrrolidone-vinyl acetate (PVPVA) in improving the dissolution of ritonavir (RTV). The effect of phosphatidylcholine (PC) as a water-insoluble excipient on drug dissolution was also investigated. Multiple linear regression analysis of the dissolution data was performed to identify the factors influencing dissolution, complemented by mechanistic simulations of the best-performing carrier. The in vitro dissolution rank order of carriers with a 30% drug load (DL) based on % dissolved_300min was AP = FR > PVPVA = BT in the absence of PC, and AP > FR > PVPVA > BT with PC. The extent of dissolution for all formulations increased in the presence of PC, with the AP and FR formulations exceeding that of marketed formulations. High drug load did not significantly affect the dissolution profile of silicate formulations, but it reduced dissolution from PVPVA solid dispersion. In silico results showed that silicate pore size governed RTV release, with open pores forming fewer hydrogen bonds, allowing more facile RTV release. The significant improvement in RTV dissolution with AP and FR supports the use of these carriers for poorly soluble drugs as alternatives to traditional polymers, especially for formulations with high drug loads.

Introduction

Many small-molecule drug candidates suffer from poor aqueous solubility, leading to an increased use of enabling technologies to mitigate this issue (Shah and Taylor, 2024). Amorphous solid dispersion (ASD) is an approach used to formulate Biopharmaceutical Classification System (BCS) Class II and Class IV drugs. Traditional binary ASDs consist of an amorphous drug molecularly dispersed in a polymer matrix, which acts as a crystallization inhibitor in the solid state and a supersaturation promoter in the liquid state (Bhujbal et al., 2021, Dhumal et al., 2024).

Water-insoluble drug carriers such as clays and silicas have recently been explored as alternatives to polymers to improve drug solubility and dissolution profiles. These silicate carriers are characterized by large surface areas owing to their porous structures. Drug molecules are both adsorbed on the surface and intercalated into the pores of the carrier to form a drug-carrier composite of amorphous drug (Van Speybroeck et al., 2010a). The confined pores prevent drug recrystallization (Bukara et al., 2016, Heikkilä et al., 2007, Van Speybroeck et al., 2010a). When the composite comes into contact with the buffer, the amorphous drug dissolves into the medium (Van Speybroeck et al., 2010b).

Common techniques for preparing drug-silicate composites are solvent impregnation and melt intercalation. Solvent impregnation involves dropwise addition of a drug solution (e.g., drug in methanol) to the drug carrier with continuous trituration until the solvent has evaporated. In this technique, the drug solution penetrates the carrier pores; upon solvent evaporation, the drug remains embedded in the pores in the amorphous state. Melt intercalation involves melting the drug in the presence of a carrier at a slightly higher temperature than the drug’s melting point (Shen et al., 2002). It can be performed either by hot melt extrusion (HME) or vacuum compression molding (VCM) (Liu et al., 2020). It is solvent-free and scalable, but the drug must not be thermolabile. To the best of our knowledge, VCM has not been previously applied to prepare ternary drug-polymer-silica composites.

The findings of Baek et al. demonstrated that bentonite is a promising drug carrier to improve sorafenib solubility. In vivo rat studies showed that the sorafenib-bentonite composite increased bioavailability 3-fold relative to Nexavar (Baek et al., 2023). A similar study from the same group showed that the incorporation of PC boosted drug release from quetiapine-bentonite composites to address the partial drug release from bentonite (Baek et al., 2022). Dening and Taylor explored ordered mesoporous SBA-15 as a delivery vehicle for RTV (Dening and Taylor, 2018). The silica successfully maintained RTV in an amorphous form, but drug release was incomplete because of the adsorption equilibrium between silica and the dissolution medium. The presence of bile salts in the dissolution medium enhanced drug release from silica (Dening and Taylor, 2018). Bukara et al. conducted the first-in-human clinical study to evaluate the bioavailability-enhancing potential of mesoporous silica, with fenofibrate as a model drug. When normalized for dose, the fenofibrate-silica formulation showed a significant increase in the rate and extent of drug absorption as compared to Lipanthyl (Bukara et al., 2016).

Phosphatidylcholine (PC) is a phospholipid that is usually extracted from soybeans and egg yolk, but can also be produced synthetically. Owing to its surface-wetting and emulsifying/solubilizing properties, PC and other phospholipids have been used in drug delivery systems for poorly water-soluble drugs (Li et al., 2015). A study by Jo et al. involved the preparation of a PC-based dispersion using solvent evaporation to enhance celecoxib dissolution (Jo et al., 2019). PC alone enhanced celecoxib’s solubility. However, due to the sticky nature of PC, the silica Neusilin US2 was used to convert the PC dispersion to a powdered form for oral solid administration. In a similar manner, Yeo et al. also incorporated silica to address the formulation’s sticky behavior (Yeo et al., 2020).

Ritonavir was selected as the model compound because it is a good glass former. It is a weakly basic (pKa values of 1.8 and 2.6), poorly water-soluble drug typically used in combination with other antiviral drugs (Xu et al., 2018).

The primary goal of the current study was to evaluate the use of silicates as drug carriers to improve RTV’s dissolution and to compare their overall dissolution performance with that of traditional RTV ASD made with the polymer PVPVA and with commercial formulations. It was hypothesized that, at high drug load, silica would provide higher drug dissolution than polymer since drug release from a non-dissolving carrier is not coupled to dissolution of the carrier itself.

Three chemically distinct water-insoluble carriers were selected to test this hypothesis across a deliberate gradient of surface area. Bentonite (BT), a naturally occurring clay/silicate, along with the synthetic silicas Aeroperl 300 Pharma (AP) and Florite PS-200 (FR), were selected as a silicate drug carriers. AP is a colloidal silicon dioxide, whereas FR is a calcium silicate. PVPVA was also studied as a traditional polymer to make RTV ASD formulations. Here, BT, AP, and FR are collectively referred to as silicates, and solvent impregnation was used to fabricate binary composites from these silicates. VCM was used to fabricate binary and ternary PVPVA ASDs in this study. BT, AP, FR and PVPVA are collectively referred to as ‘carriers’. The impact of PC on the extent of dissolution of RTV formulations was also studied. Dissolution profiles of the formulations were compared to those of commercial RTV crushed tablets and powder. To identify the factors affecting dissolution, both positively and negatively, a multiple linear regression was carried out using dissolution data of binary formulations.

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Materials

Ritonavir was purchased from Chem Shuttle (Burlingame, CA, USA). Bentonite NF grade was obtained from Spectrum Chemical Mfg. Corp. (New Brunswick, NJ, USA). Aeroperl 300 Pharma was a gift from Evonik Industries AG (Essen, Germany). Florite PS-200 was generously donated by Tomita Pharmaceuticals Ltd. (Tokyo, Japan). PVPVA (Kollidon VA 64, copovidone) was obtained from BASF Corporation (Jessup, MD, USA). L-α-Phosphatidylcholine (Mol. Wt. = 790.15 g/mol) was purchased from Sigma-Aldrich (St. Louis, MO, USA). Aurobindo Ritonavir tablets (Aurobindo Pharma USA, NJ, USA), Packets of Norvir oral powder and Norvir Tablets (AbbVie; North Chicago, IL, USA) were commercially obtained. All other reagents were of analytical grade and obtained from Sigma-Aldrich (St. Louis, MO, USA).

Gaurav Dhumal, Adélaïde Savoy, Martin Kuentz, James E. Polli, In vitro evaluation of water-insoluble silicates and polyvinylpyrrolidone-vinyl acetate as oral carriers for amorphous ritonavir: dissolution enhancement and the role of phosphatidylcholine, International Journal of Pharmaceutics, Volume 704, 2026, 127399, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.127399.