High-Throughput Screening of Amorphous Solid Dispersions: A Systematic Approach to Enhance Bioaccessibility of a Poorly Soluble Drug

Abstract

Poor aqueous solubility and thereby poor and/or variable bioavailability of drug candidates is frequently overcome by developing enabling formulations such as amorphous solid dispersions (ASDs). This study proposes a systematic, miniaturized approach to evaluate the ASD developability of an active pharmaceutical ingredient (API) based on i) assessment of glass forming ability ii) assessment of the supersaturation potential of the neat API by supersaturation/permeation testing, iii) selection of an appropriate ASD carrier system using high-throughput dissolution screening of ASD films and iv) performing high-throughput dissolution/permeation testing of ASD films. The model drug candidate, RO6897779, exhibited good glass forming ability. Eight pharmaceutical polymers (CAP, Eudragit® E, Eudragit® L100, HPMC 100LV, HPMCAS-M, PVP K25, PVP VA64, and Soluplus®) were screened as ASD carriers by high-throughput dissolution testing at drug loads of 20, 30 and 40% [w/w]. Due to poor performance of the binary systems, ternary ASDs containing Soluplus® were prepared at surfactant loads of 4, 6 and 8% [w/w] and subsequently, high-throughput dissolution/permeation studies were conducted on selected compositions. The composition containing RO6897779 at a drug load of 20% in Soluplus®[w/w] with the addition of 6% [w/w] SDS yielded the best performance, but was inferior to the permeation of supersaturated neat RO6897779. Further studies should be conducted to assess the ability of this four-step, miniaturized approach to predict optimal ASD formulations over a broad range of API physicochemical properties.

Introduction

Amorphous solid dispersion (ASD) formulations are a popular formulation strategy for improving oral absorption of drugs that suffer from poor aqueous solubility, as evidenced by the increasing numbers of marketed ASD products (Moseson et al., 2024). Compared to the crystalline form of a drug, the amorphous form benefits from being in a high-energy form. This is reflected in a higher kinetic solubility and faster dissolution rate, thereby serving as an effective bio-enabling formulation approach (Alonzo et al., 2010, Kanaujia et al., 2015, Schittny et al., 2020).

When considering ASDs as a formulation strategy for a drug, it is critical to assess whether the compound possesses suitable attributes for this approach. It has been established that a good glass forming ability (GFA), and physical stability of the glassy state are prerequisite drug properties when determining the potential of a crystalline drug to be formulated as an ASD (Janssens and Van den Mooter, 2009, Kawakami et al., 2012). These properties can be evaluated experimentally by e.g., differential scanning calorimetry (DSC) (Baird et al., 2010, Blaabjerg et al., 2017) or be predicted based on parameters such as molecular weight, flexibility, complexity, number of rotational bonds and number of hydrogen bonds (Mahlin and Bergstrom, 2013, Mahlin et al., 2011, Trasi et al., 2014). Closely related to GFA is the propensity of the drug to supersaturate in solution (Blaabjerg et al., 2018). This important parameter can be evaluated experimentally to predict the potential bioavailability benefit of the amorphous form.

As a consequence of the high free energy associated with the amorphous state, the system is thermodynamically unstable and will eventually convert to a crystalline state over time (Bhugra and Pikal, 2008). To kinetically stabilize the drug in the amorphous state, a water-soluble polymeric matrix is often utilized, in which the amorphous drug can be dispersed. Here, the amorphous state is stabilized through interactions with the polymer, increased microviscosity and decreased molecular mobility (Janssens and Van den Mooter, 2009, Newman et al., 2012, Baghel et al., 2016). In addition to improving the physical stability of the amorphous phase, the use of pharmaceutical polymers as matrix formers in ASDs can improve the dissolution kinetics, and inhibit precipitation of the drug from the supersaturated state (Warren et al., 2010). Thus, high concentrations can be maintained in the intestinal lumen in vivo and increase the driving force for absorption (Schittny et al., 2020).

During the early stages of drug product development, the use of a rapid and miniaturized approach to formulation screening can accelerate the process while sparing resources (Hu et al., 2013, Mosquera-Giraldo et al., 2021, Page et al., 2022, Wyttenbach et al., 2013). The use of miniaturized formulation screening approaches allows for investigations into the dissolution behavior and physical stability of a large number of combinations of drug, polymer and drug loading (DL), whilst maintaining a high throughput and low material expenditure. Based on the screening outcome, ASD compositions of interest can be selected for further evaluation and scale up. For example, Screening of Polymers for Amorphous Drug Stabilization (SPADS) has been proposed for screening ASD formulations (Wyttenbach et al., 2013). This approach, in combination with the refined Developability Classification System (rDCS), has recently been shown to be an effective preformulation tool. When applied, the approach can help to guide decision-making during the early stages of formulation development (Senniksen et al., 2025).

Screening for multicomponent amorphous solid dispersions increases the number of prototype formulation variants, amplifying the need for predictive, high-throughput methodologies to assess formulation feasibility. During screening, complex dissolution behavior may be observed, such as a switch from polymer-controlled release to drug-controlled release (Saboo et al., 2020, Saboo et al., 2019, Indulkar et al., 2019, Craig, 2002, Srividya and Ghosh, 2025), as well as changes in polymer hydration level (Wang et al., 2018) and formation of a separate polymer-rich phase in solution (Lange et al., 2025), thus leading to insufficient drug release.
Some studies have demonstrated that reliance on the apparently dissolved drug concentration during dissolution testing may lead to overestimation of in vivo exposure, as colloidally or excipient-associated drug may exhibit different permeation rates compared to the freely dissolved fraction (Dahan and Miller, 2012, Morita et al., 2024). In addition, the supersaturation–precipitation kinetics of drug substances were shown to be affected by the presence of an absorptive sink, which may alter the supersaturation-precipitation kinetics (Bevernage et al., 2012). Consequently, dissolution–permeation testing has been proposed as a more physiologically relevant and discriminative endpoint to guide the development and optimization of oral drug formulations (Nunes et al., 2023).

Despite increasing adoption of amorphous solid dispersions (ASDs) to enhance the bioavailability of poorly water-soluble drugs (Moseson et al., 2024), there remains a need for an integrated and systematic screening workflow for early-phase development. Current approaches often rely on fragmented assessments that do not account for the manifold challenges associated with ASD formulation. This study explores an integrated, systematic, and miniaturized approach to evaluate ASD developability in the early stages of preclinical development using the model drug RO6897779. The approach is based on i) assessment of glass forming ability, ii) assessment of the supersaturation potential of the neat API by supersaturation/permeation testing, iii) selecting an appropriate ASD carrier system on the basis of miniaturized dissolution screening of binary and ternary solvent-cast films and iv) performing high-throughput dissolution/permeation testing of solvent-cast ASD films in a 96-well PermeaPad plate set-up.

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Materials

RO6897779 was provided by F. Hoffmann – La Roche Ltd (Basel, CH). Polyvinylpyrrolidone (PVP) K25, vinylpyrrolidone-vinyl acetate copolymer (PVP VA64) and Soluplus® were kindly donated by BASF (Ludwigshafen, DE). Eudragit® E PO and L100 were purchased from Evonik (Essen, DE). AQOAT® Hypromellose Acetate Succinate-MMP (HPMCAS-MMP) was kindly donated by Shin-Etsu (Wiesbaden, DE). AFFINISOL TM Hypromellose (HPMC) 100LV was donated by Dupont de Nemours (Luzern, CH). Cellulose Acetate Phthalate (CAP), sodium dodecyl sulfate (SDS), dimethyl sulfoxide (DMSO), dioctyl sodium succinate (DOSS), acetone and dichloromethane were purchased from Sigma-Aldrich (Steinheim, DE). Sodium oleate (C18:1) was purchased from Tokyo Chemical Industry Co. LTD. (Tokyo, JP). Tocopherol polyethylene glycol succinate (TPGS) was purchased from PMC ISOCHEM (Vert-le-Petit, FR). NaH2PO4, NaCl, NaOH, and HCl were purchased from Merck KgaA (Darmstadt, DE). Acceptor sink buffer (ASB) and PCON GIT-0 lipid mixture were purchased from Pion (Billerica, MA, USA). 3F Biorelevant powder was purchased from Biorelevant.com Ltd. (London, UK), and used to prepare fasted state simulated intestinal fluid (FaSSIF-V1). Acetonitrile, Ethanol, formic acid and N-methyl-2-pyrrolidone (NMP) were purchased from VWR International (Rosny-sous-Bois Cedex, FR). Methanol was purchased from Honeywell Riedel-de Haën (Seelze, DE). The solvents and diluent used for ultra-performance liquid chromatography™ (UPLC) analysis, solvent-casting and solvent-shift tests were of analytical grade.

Malte Bøgh Senniksen, Justus Johann Lange, Wiebke Saal, Patrick O’Dwyer, Martin Kuentz, Brendan T. Griffin, Susanne Page, Jennifer Dressman, Nicole Wyttenbach, High-Throughput Screening of Amorphous Solid Dispersions: A Systematic Approach to Enhance Bioaccessibility of a Poorly Soluble Drug, European Journal of Pharmaceutical Sciences, 2025, 107401, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2025.107401.

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