Guiding excipient selection for amorphous solid dispersions by combining an in vitro-in-silico approach – II: Supersaturation and drug release

There is a growing industrial need for quick and early screening of amorphous solid dispersions (ASDs). While new technologies are emerging, including in-silico predictions and high-throughput experimentation, a significant gap exists due to a lack of comparative data. The aim of this work was thus to compare experimental data with calculations obtained by the Conductor like Screening Model for Real Solvents (COSMO-RS). A small-scale high throughput method based on solvent casting was used to evaluate the release behavior and precipitation inhibition capacity of ASDs of griseofulvin and nifedipine in the presence of ten pharmaceutically relevant polymers. COSMO-RS was then used to investigate the interaction strength between drug and polymer by means of drug activity coefficients. A stronger interaction would result in better supersaturation maintenance. This was reflected in our results and a good alignment between calculations and experimental performance was observed. COSMO-RS effectively differentiated between polymers with strong precipitation inhibition (PI) functionality and separated those with weaker efficacy for most of the ASDs studied. This pre-selected list of polymers can serve as a foundation for additional studies on all relevant drug development quality attributes, from stability to manufacturing.

1. Introduction

1.1. Polymer selection in amorphous solid dispersions

An increasing number of new active pharmaceutical ingredients (APIs) in modern drug discovery exhibit poor water solubility, which can negatively affect their absorption (Kawakami, 2012). The extent of drug absorption via the oral route primarily depends on three factors: solubility, dissolution rate, and intestinal permeability. The preparation of amorphous solid dispersions (ASDs) offers a promising solution to dissolution and absorption challenges (Zhang et al., 2019, Wolbert et al., 2022, Rumondor et al., 2009). ASDs are systems in which the API is dispersed within a polymeric matrix; due to their high free energy they can significantly improve the apparent aqueous solubility relative to the compound’s thermodynamic solubility (Taylor, 2016). Additionally, the presence of polymeric carriers can improve API wetting, further enhancing dissolution rate and oral absorption. Selecting the right polymeric carrier is key to obtaining the desired API release from the formulation, delaying precipitation in vitro and in vivo, as well as enabling an acceptable shelf life (Wyttenbach et al., 2013). The choice of polymer can greatly influence the dissolution behavior of an ASD by affecting the dissolution rate as well as the amount of dissolved drug, both of which are key for effective administration within the gastrointestinal transit time (Fdukeck et al., 2013). Besides the drug dissolution kinetics influenced by the polymer, several other aspects must be investigated to ensure good performance of the final formulation. After early pre-formulation and profiling of drug candidates, different ASD screening assays can be carried out to select candidate excipients that meet several formulation requirements. Early ASD development screening may be oriented towards aspects such as apparent solubility, physical stability and supersaturation maintenance to reach early-phase clinical trials. At a later stage, further quality aspects such as manufacturability, long-term physical stability, regulatory requirements and cost-of-goods have to be considered. For example, API-polymer miscibility should be considered at an early stage, as it is generally a prerequisite for physical stability. Another key factor is solubility and potential amorphous drug loading of the API in the polymer, as this affects the degree of supersaturation, possibly supersaturation maintenance due to drug affinity to the polymer, and finally the achievable dose strength. Here, the development stage and drug availability play key roles. For instance, larger quantities of API and polymer are needed for formulation development and supply in later stages of clinical development. Amorphous solid dispersions are typically produced through hot melt extrusion, spray drying or, less commonly, lyophilization (Han et al., 2023, Baird and Taylor, 2012). Each of these manufacturing methods comes with specific requirements for the polymer, as outlined in the literature (Bhujbal et al., 2021). Furthermore, the pH profile of the polymer may be important, especially when an enteric polymer is required for targeted release. Another point to consider is API permeability: good permeability leads to rapid drug absorption. In such cases, maintaining supersaturation for long periods of time may not be as critical as for less permeable drugs or when the dose is relatively low. In summary, while polymer selection for a final drug product has to be based on multiple formulation parameters, an early-stage ASD screening assay can focus on a specific performance factor such as drug supersaturation, which was the focus of the present work.

1.2. Novel tools to support early development of amorphous formulations

High throughput screening methods are increasingly used in the pharmaceutical field, which has greatly facilitated screening not just in drug discovery but also in early formulation development, for example to identify suitable polymers in supersaturating formulations (Dai et al., 2007, Warren et al., 2010). Miniaturized ASD screening is becoming more established in pharmaceutical firms, and solvent casting is typically employed for subsequent physical and chemical analysis (Chiang et al., 2012, Shanbhag et al., 2008). Nevertheless, selecting the appropriate excipient remains a time-consuming and costly process, often constrained by limited API availability, especially in the early stages of development (Wyttenbach et al., 2013). This emphasizes the need for non-empirical methods such as computational models to help guide excipient selection, and such computational methods have gained wide attention in the pharmaceutical field to support drug development. Molecular dynamics simulations (MDs), for instance, have often been used to gain mechanistic understanding of drug-excipient interactions in ASDs ([AuthorError] et al., 2024, Xiang and Anderson, 2014). Ditzinger et al used MDs to gain structural insights into the interaction between fenofibrate, lysine and sodium-CMC as extruded ASD formulations (Ditzinger et al., 2020). Apart from such force-field based molecular simulations, the conductor-like screening model for real solvents (COSMO-RS) is of particular interest as it combines quantum-chemical surface calculations with statistical thermodynamics (Klamt and Eckert, 1999). In a study by Price and colleagues, COSMO-RS as a fragment-based approach, has been successfully used to select precipitation inhibitors (Price et al., 2019). More recently, COSMO-RS was employed for ternary ASDs and Antolovic and co-workers utilized COSMO-SAC (Segment Activity Coefficient) to predict the compatibility between APIs and polymers (Antolovic et al., 2024, Niederquell et al., 2024). The latter research incorporated both the solubility and miscibility of the API with the polymer, finding that while the model tended to slightly overestimate API solubility in the polymer, the overall predictions were reasonable (Antolovic et al., 2024). From a qualitative perspective, the model also correctly ranked polymers based on their API compatibility. The aim of the present study was therefore to evaluate COSMO-RS as a support tool for high-throughput screening methods, to guide excipient selection in the early stages of ASD development.

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2. Materials and methods

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