Recent Techniques to Improve Amorphous Dispersion Performance with Quality Design, Physicochemical Monitoring, Molecular Simulation, and Machine Learning

Abstract

Amorphous solid dispersions (ASDs) represent a promising formulation strategy for improving the solubility and bioavailability of poorly water-soluble drugs, a major challenge in pharmaceutical development. This review provides a comprehensive analysis of the physicochemical principles underlying ASD stability, with a focus on drug–polymer miscibility, molecular mobility, and thermodynamic properties. The main manufacturing techniques including hot-melt extrusion, spray drying, and KinetiSol^® dispersing are discussed for their impact on formulation homogeneity and scalability. Recent advances in excipient selection, molecular modeling, and in silico predictive approaches have transformed ASD design, reducing dependence on traditional trial-and-error methods. Furthermore, machine learning and artificial intelligence (AI)-based computational platforms are reshaping formulation strategies by enabling accurate predictions of drug–polymer interactions and physical stability. Advanced characterization methods such as solid-state NMR, IR, and dielectric spectroscopy provide valuable insights into phase separation and recrystallization. Despite these technological innovations, ensuring long-term stability and maintaining supersaturation remain significant challenges for ASDs. Integrated formulation design frameworks, including PBPK modeling and accelerated stability testing, offer potential solutions to address these issues. Future research should emphasize interdisciplinary collaboration, leveraging computational advancements together with experimental validation to refine formulation strategies and accelerate clinical translation. The scientists can unlock the full therapeutic potential with emerging technologies and a data-driven approach.

Introduction

There are several advanced techniques to improve drug release performance of poorly soluble drugs. Notable ones are glycosylation [1], specific group engagement [2], co-crystallization [3], complexation, and more intriguing methods [4]. Amongst them amorphous solid dispersion (ASD) has been one of the preferred strategy formulations for poorly soluble drugs classified under biopharmaceutical classification system (BCS) Class II and Class IV [5]. The bioavailability of poorly soluble drugs primarily depends on their solubility and dissolution profile in biological fluids [6]. The drug crystals are converted into an amorphous form, which enhances its solubility, dissolution rate, and bioavailability [7]. In ASD systems, the crystalline drug is incorporated into a suitable polymer carrier, resulting in transformation into an amorphous state, which eliminates the need to break the crystal lattice [8]. Consequently, the amorphous form of many poorly soluble drugs attains substantially higher apparent solubility and a markedly faster dissolution rate [9]. However, producing the amorphous form requires significant energy input, rendering it susceptible to phase separation and recrystallization during manufacturing and storage [10].

The molecular mobility of the amorphous state increases upon exposure to ambient temperature and humidity, promoting recrystallization [11]. The crystalline drugs possess a well-defined, ordered structure with strong intermolecular bonds, conferring superior stability and predictable physicochemical behavior such as solubility, drug release, and melting point depression [12]. The intermolecular arrangement within crystals, extending in all directions, results in single or polycrystalline forms at the micron scale [13]. Molecules can adopt different conformations within the lattice, a phenomenon known as polymorphism [14]. Therefore, different polymorphic forms of the same drug exhibit distinct physicochemical properties. Different polymorphic forms exhibit distinct melting points. Thermal energy input drives structural reorganization toward more thermodynamically stable configurations, while accelerated cooling kinetics allow preservation of metastable crystalline arrangements before complete liquefaction occurs [15].

The amorphous form lacks long-range order and defined shape. Its molecular arrangement is unpredictable, leading to high intermolecular energy and metastability [16]. The amorphous forms possess higher free energy compared to their crystalline counterparts due to increased Gibbs free energy, which translates to greater apparent solubility and is advantageous for poorly soluble drugs. However, the amorphous form is thermodynamically unstable and tends to recrystallize over time or under stress conditions [17]. The absence of long-range order in the amorphous state results in short-range molecular interactions that promote clustering and nucleus formation [18,19].

This review investigates the physical stability of ASDs from a physicochemical perspective, considering thermodynamic, kinetic, and environmental aspects. The thermodynamic factors influencing ASD stability include drug solubility in the polymer, phase separation, drug–polymer compatibility, glass transition temperature, and drug–polymer interactions [20]. The kinetic factor associated with stability can estimate the molecular mobility, nucleus formation, and nucleus growth [21]. Environmental factors, such as temperature and humidity, can affect the physical stability of the amorphous form through both thermodynamic and kinetic mechanisms. Environmental conditions may induce polymorphic transformations, altering drug behavior [22]. Additional factors, including suboptimal formulation component selection, thermal and manufacturing stresses, and increased molecular mobility, can promote crystal precipitation, coarsening, and aging, ultimately diminishing dissolution rate and bioavailability [23]. Moreover, this review focuses especially on the recent development tools related to multiscale simulations, artificial intelligence (AI)—machine learning (ML), computation tools, and molecular modeling. Additionally, the impact of the tools is also discussed to perform efficiently high-throughput screening, predict ASD optimization, improve evaluation, and assess risk management [24,25,26,27,28,29,30,31]. The stable ASD products require careful selection of formulation components, manufacturing procedures, process parameters, and packaging [32].

ASDs are commonly classified into three generations: first generation (amorphous drug only), second generation (polymeric carrier), and third generation (amorphous carrier with surfactant) [33]. They are typically prepared by solvent evaporation or heat-congealing. Among these, spray drying, hot-melt extrusion, and KinetiSol® are widely used for industrial-scale production. Currently, 48 drug products containing ASDs, representing 36 unique amorphous drugs, have been approved by the U.S. FDA and are commercially available. These dosage forms include tablets, capsules, and granules. Table 1 summarizes commercially available drug products manufactured using ASD technology. The spray drying and hot-melt extrusion (HME) are most common industrial methods. The historical trend shows an increase in approval of ASDs since the early 2000s. The major polymers are the industry workhorses, most notably HPMCAS and PVP-VA64. Most ASDs are formulated as tablets [34].

Table 1. Trends in amorphous solid dispersion drug products approved by the U.S. Food and Drug Administration (FDA) through 2023.

Solid-state characterization techniques are employed to investigate the thermodynamic and kinetic properties of the amorphous form. The crystallinity in ASDs is typically assessed by differential scanning calorimetry (DSC), Raman spectroscopy, infrared (IR) spectroscopy, and powder X-ray diffraction (PXRD) [35]. Advanced imaging technologies such as nano-tomography and terahertz spectroscopy enable investigation of intermolecular interactions between polymer and drug at the submicron scale [36,37]. These innovative characterization methods facilitate prediction of dissolution properties, elucidation of recrystallization patterns, and evaluation of stability outcomes [11,38,39,40]. In addition, classic theories, molecular modeling, and machine learning approaches for assessing physical stability factors are introduced and discussed [41].

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Excipients mentioned in the paper: PVP, HPMC, PVP-VA 64, HPMCAS, HPC

Bhatta, H.P.; Han, H.-K.; Maharjan, R.; Jeong, S.H. Recent Techniques to Improve Amorphous Dispersion Performance with Quality Design, Physicochemical Monitoring, Molecular Simulation, and Machine Learning. Pharmaceutics 2025, 17, 1249. https://doi.org/10.3390/pharmaceutics17101249

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