Amorphous Solid Dispersions (ASDs): The Influence of Material Properties, Manufacturing Processes and Analytical Technologies in Drug Product Development

Poorly water-soluble drugs pose a significant challenge to developability due to poor oral absorption leading to poor bioavailability. Several approaches exist that improve the oral absorption of such compounds by enhancing the aqueous solubility and/or dissolution rate of the drug. These include chemical modifications such as salts, co-crystals or prodrugs and physical modifications such as complexation, nanocrystals or conversion to amorphous form. Among these formulation strategies, the conversion to amorphous form has been successfully deployed across the pharmaceutical industry, accounting for approximately 30% of the marketed products that require solubility enhancement and making it the most frequently used technology from 2000 to 2020. This article discusses the underlying scientific theory and influence of the active compound, the material properties and manufacturing processes on the selection and design of amorphous solid dispersion (ASD) products as marketed products. Recent advances in the analytical tools to characterize ASDs stability and ability to be processed into suitable, patient-centric dosage forms are also described. The unmet need and regulatory path for the development of novel ASD polymers is finally discussed, including a description of the experimental data that can be used to establish if a new polymer offers sufficient differentiation from the established polymers to warrant advancement.

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Introduction
The oral route of drug administration is regarded as the most preferred route for medicines, with more than 85% of drugs sold around the world being administered orally. In this context, the properties of a drug molecule that govern oral absorption are critical to its development. The Biopharmaceutics Classification System (BCS) serves as a guide to predict oral absorption based on the aqueous solubility and permeability of a drug [1,2]. Poor solubility is among the primary causes of low bioavailability for orally administered drugs. Drugs that are slightly soluble to practically insoluble exhibit solubility of < 0.01% based on the description in the United States Pharmacopoeia (USP) [3]. In a comparison of solubility of 200 oral drugs of various origins as seen in Figure 1, 40–45% were very slightly soluble to practically insoluble, representing 33% of drugs listed in the US Pharmacopeia and 75% of compounds under development and 90% of new chemical entities were regarded as poorly soluble [4–11]. The improvement of solubility is therefore regarded as a key driver for greater bioavailability.

Figure 1. A comparison of the distribution of solubilities for 200 oral drugs from various regions of the world (very soluble drugs: over 1000 mg/mL; freely soluble drugs: 100–1000 mg/mL; soluble drugs: 33–100 mg/mL; sparingly soluble drugs: 10–33 mg/mL; slightly soluble drugs: 1–10 mg/mL; very slightly soluble drugs: 0.1–1 mg/mL; practically insoluble drugs: <0.1 mg/mL). Reproduced with permission from [4] T. Takagi et al, Molecular Pharmaceutics, published by American Chemical Society, 2006.

The Noyes–Whitney equation [12] relates mass transfer to the concentration gradient as

where D is the diffusion coefficient (cm2/s), A is the cross-sectional area, h is the thickness of the hydrodynamic diffusion layer and Cs is the solubility or maximum concentration. Under infinite dilution (sink), the concentration gradient approximates to solubility Cs,resulting in

For poorly soluble drugs, increasing aqueous solubility and the surface area are primary means of increasing the rate and extent of dissolution since parameters D and h are a function of extrinsic factors such as viscosity of dissolution medium and stirring rate. The approaches to improve dissolution rate may be broadly classified as physical and chemical as shown in Table 1.

Among these approaches, the conversion of drugs into an amorphous solid dispersion (ASD) form has gained widespread attention over the last few decades. The ASD of a drug molecularly dispersed in a polymeric matrix has been extensively utilized to improve solubility and bioavailability of poorly soluble drugs [19,25–27]. An ASD of vemurafenib (Zelboraf®) increased human bioavailability by about five-fold compared to the crystalline form [19]. However, since amorphous forms are thermodynamically unstable, the materials and technologies that enable ASD formation, the subsequent dosage form and the methods of characterization of these systems play a critical role in defining the quality, stability, processability and in-vivo performance of the ASD. There are over forty successfully launched ASD-based drug products in the market that point to an industrial relevance and increasing maturity and robustness of the ASD approach as seen from Figure 2. In this paper, the authors discuss the various aspects associated with development of ASDs from a molecule to a medicine including challenges associated with transfer from a laboratory setup to commercial manufacturing and the need for novel polymers that enable ASD-based medicinal dosage forms.

Iyer, R.; Petrovska Jovanovska, V.; Berginc, K.; Jaklič, M.; Fabiani, F.; Harlacher, C.; Huzjak, T.; Sanchez-Felix, M.V. Amorphous Solid Dispersions (ASDs): The Influence of Material Properties, Manufacturing Processes and Analytical Technologies in Drug Product Development. Pharmaceutics 2021, 13, 1682. https://doi.org/10.3390/pharmaceutics13101682