Combining high throughput ASD screening with the rDCS to streamline development of poorly soluble drugs

Abstract

Poor aqueous solubility and slow dissolution rate of active pharmaceutical ingredients (APIs) are often encountered challenges during oral drug development, leading to variable and insufficient bioavailability. To overcome these challenges, a so-called “enabling” formulation strategy is often pursued. Among these, amorphous solid dispersions (ASDs) are established as an effective means of improving drug absorption. However, evaluating the outcome of in vitro ASD screening approaches and relating this to the expected bioavailability increase can be difficult if not done systematically. Here we show, for the first time, how the combination of a high throughput ASD screening method with the refined Developability Classification System (rDCS) can streamline the formulation of poorly soluble APIs as ASDs. Using the Screening of Polymers for Amorphous Drug Stabilization (SPADS) approach to rapidly prepare ASD films, the improvement in dissolution performance of three APIs (befetupitant, celecoxib and itraconazole) was investigated with eight polymeric carriers. The results showed that the concentration of dissolved API was highly dependent on both the carrier and the drug load. For the APIs studied, Eudragit E, HPMC 100LV and Soluplus showed especially advantageous effects as carriers. Translating these results into the rDCS framework allowed for the visualization of the left-shift (more favorable for absorption) in classification. Several ASD films were classified as rDCS class I, showing a major improvement from the initial IIb classification of the pure API. This novel approach could be expanded to include a diverse set of screening methods for enabling formulation strategies, where the rDCS can allow for a direct comparison and support formulation selection.

Introduction

Introduced in 2010, the developability classification system (DCS) is recognized as a powerful tool during the early stages of drug development (Butler and Dressman, 2010). Depending on its biopharmaceutical profile, an active pharmaceutical ingredient (API) can be classified in one of four classes, with class II being further divided into IIa and IIb for APIs with dissolution rate limited and solubility limited absorption, respectively (Butler and Dressman, 2010). Since its introduction, the DCS has been further evolved into the refined developability classification system (rDCS), introducing inter alia a decision tree that is based on both standard and customized investigations. To address the fact that during preclinical development, the dose of an API is rarely already established, the rDCS encourages the use of a wide potential dose range of 5, 50 and 500 mg (Rosenberger et al., 2018). Recently, the rDCS has received attention related to drugs which show supersaturation and precipitation effects (Beran et al., 2024) as well as to guide the design of oral formulations (Beran et al., 2024).

For APIs with a dose classified as rDCS class IIb or IV, where solubility-limited absorption is anticipated, an enabling formulation is frequently sought to ensure sufficient in vivo exposure. Amorphous solid dispersions (ASDs) represent one such enabling formulation. The ASD approach aims to increase bioavailability by harnessing the high energy state of the amorphous API to achieve not only a faster dissolution rate but also supersaturation in the gastrointestinal tract (Babu and Nangia, 2011), (Van den Mooter, 2012). Ideally, an ASD is a molecular dispersion of the API within an amorphous carrier. The carrier, typically a hydrophilic polymer, impedes crystallization of the API in the solid state and can also serve to stabilize supersaturated solutions of the API upon dissolution (Van den Mooter, 2012, Brouwers et al., 2009, Baghel et al., 2016). For a detailed review of the mechanisms behind the bioavailability enhancement of ASDs the reader is referred to the comprehensive publication by Schittny et al (Schittny et al., 2020). For information regarding the manufacturing strategies available for ASDs the reader is referred to the thorough review of Bhujbal et al (Bhujbal et al., 2021).

Different approaches exist to screen potential ASD candidates for bioavailability enhancement and stability such as in silico methods (Walden et al., 2021, Walter et al., 2024, Antolovic et al., 2024) and melt-based screening methods (Auch et al., 2018, Shadambikar et al., 2020, Lauer et al., 2018). To efficiently screen a range of ASD candidates with different carriers and drug loads for their ability to improve bioavailability, a film casting approach is often utilized, such as the Screening of Polymers for Amorphous Drug Stabilization (SPADS) workflow (Wyttenbach et al., 2013). By utilizing 96-well microtiter plates to conduct film casting and dissolution testing, a wide range of samples can be investigated concurrently, with a small consumption of API. In the present study, three poorly water-soluble drugs (befetupitant, celecoxib and itraconazole) and eight different polymers were investigated. The polymers were chosen to reflect the variety of the carriers used in marketed ASD products as well as including polymers that are more novel for this purpose. Together, the polymers represent a wide range of functional moieties, hydrophilicity, glass transition temperatures and molecular weights.

This study sets out to combine the SPADS dissolution assay with rDCS classification. The proposed workflow i) classifies the APIs according to rDCS to identify the need for solubility improvement, ii) presents a detailed approach to dissolution screening of ASD films and iii) utilizes the rDCS to visualize the outcome of the screening approach. By combining these two approaches, the most suitable ASD strategy for a given poorly soluble drug can be identified, thus guiding decision-making during the early stages of formulation development.

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Materials

Crystalline befetupitant was provided by F. Hoffmann – La Roche Ltd (Basel, CH). Crystalline celecoxib was purchased from AA Blocks LLC (San Diego, CA, USA). Crystalline itraconazole was purchased from Chemieliva Pharmaceutical CO., Ltd (Chongqing, PRC) (Table 1.). 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 ™ Hypromellose (HPMC) 100LV kindly donated by Dupont de Nemours (Luzern, CH), Cellulose Acetate Phthalate (CAP) was purchased from Sigma-Aldrich (Steinheim, DE) (Table 2.). NaH2PO4, NaCl, NaOH and HCl were purchased from Merck KgaA (Darmstadt, DE). 3F Biorelevant powder was purchased from Biorelevant.com LTD (London, UK), and used to prepare fasted state simulated intestinal fluid (FaSSIF-V1). The solvents and diluent used for ultra performance liquid chromatography™ (UPLC) analysis were of an appropriate grade. Acetonitrile, formic acid and N-methyl-2-pyrrolidone (NMP) were purchased from VWR International (Rosny-sous-Bois cedex, FR).

Table 2. Selected polymeric carriers and their properties.

Malte Bøgh Senniksen, Nicole Wyttenbach, Susanne Page, Jennifer Dressman, Combining high throughput ASD screening with the rDCS to streamline development of poorly soluble drugs, European Journal of Pharmaceutical Sciences, 2025, 107130, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2025.107130.

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