Hot-melt extruded ibuprofen ternary solid dispersions using in-line UV–Vis: Impact of an ionizable polymer on thermodynamics and dissolution

Abstract

Amorphous solid dispersions (ASDs) remain a key strategy for enhancing the dissolution of poorly soluble APIs. Building on previous work with binary ibuprofen (IBU) blends, this study investigates the impact of incorporating poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), Eudragit EPO® (EPO), an ionizable third polymer into systems based on poly(vinylpyrrolidone-co-vinyl acetate), typically 60:40 VP:VA ratio, KOLVA64® (VA64), Polyvinylpyrrolidone, KOL17PF® (17PF) and hydroxypropyl methylcellulose acetate succinate, AQOAT AS-LMP (HPMCAS). Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) modeling was employed to predict solid–liquid (SLE) and liquid-liquid (LLE) phase equilibria using binary interaction parameters (k_ij). In comparison to Flory–Huggins’s theory, PC-SAFT predicted broader metastable regions, corresponding to up to threefold higher achievable ibuprofen loadings. ASDs (35 wt%) with increasing EPO concentration (0–32.5 wt%) were successfully extruded using in-line UV–Vis spectroscopy for real-time monitoring, with samples grouped according to polymeric composition by principal component analysis (PCA). Solid-state analyses (FTIR, XRD, DSC) of extrudate samples confirmed no recrystallisation for up to six months (25 °C/70% RH). Small-scale DSC experiments within the PC-SAFT-predicted unstable zone confirmed crystallinity (95 wt% for VA64-EPO and 17PF-EPO; 50 wt% for HPMCAS-EPO). Dissolution studies under acidic conditions revealed complete release of blends with ≥20 wt% EPO within 5 min, outperforming binary formulations and maintaining supersaturation for hours. At pH 6.8, no significant dissolution improvement was seen, providing additional evidence of a diffusion-controlled release dependent on pH and API-polymer interactions. Overall, this work presents a novel PC-SAFT-based, predict-first approach to ternary ASD design, enabling higher drug loadings and controlled pH-responsive release.

Introduction

Many modern active pharmaceutical ingredient (API) candidates exhibit poor aqueous solubility, creating an ongoing need for formulation strategies that can improve dissolution and enhance oral bioavailability. A common strategy to address this challenge is the formulation in the amorphous state, in which the API is converted into a higher-energy state with increased apparent solubility and the capacity to generate supersaturation upon dissolution (Li et al., 2019; Mantas et al., 2019). However, the thermodynamic instability inherent to amorphous materials poses a major limitation, as the API might recrystallize during storage or handling, compromising solubility, efficacy, and safety (Yu, 2001). Amorphous solid dispersions (ASDs) build upon this principle by molecularly dispersing the API within a miscible polymer matrix, preventing API nucleation and crystal growth, assuring the amorphous-state inherent solubility advantage.

Accurately predicting API–polymer miscibility remains central to the ASDs rational formulation design, as miscibility directly influences both solid-state stability and dissolution performance. Previous studies have demonstrated that the API solubility within a polymeric matrix can be estimated by examining the end-set temperatures of API–polymer blends of known composition (Tian et al., 2013). To date, Flory Huggins (FH) lattice theory is the more frequently used model to predict solid liquid (SLE) and liquid-liquid equilibrium (LLE) curves (Tian et al., 2013). Although less frequently employed, Kyeremateng empirical equation allows initial estimation of API solubility in polymer matrices and also provides risk zones during extrusion, useful to large-scale manufacturing (Kyeremateng et al., 2014). Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) incorporates explicit contributions from molecular size, shape, dispersion forces and association effects, enabling a physics-based approach and is becoming frequently more utilised (Anderson, 2018; Pavliš et al., 2023; Prudic et al., 2014a). The Tg serves as an indicator of molecular mobility and thermodynamic stability in amorphous systems. In solid dispersions, the observation of a single Tg is typically interpreted as evidence of miscibility between the API and polymer. Empirical Tg models such as Gordon–Taylor and Kwei assume ideal volume additivity, so deviations from their predictions are interpreted as evidence of interactions (Pezzoli et al., 2018). To more effectively capture non-linear trends, Brostow–Kalogeras quadratic model provides a useful alternative (Kalogeras and Brostow, 2009), allowing additional insights about components interactions. The information obtained from these small-scale experiments is particularly valuable during formulation development for hot-melt extrusion (HME), where miscibility, melt rheology, and thermal behaviour strongly influence processability and final product performance.

Conventional ASDs typically rely on a single polymer to stabilise the API in its amorphous state, however, the incorporation of a third component has been increasingly explored as a strategy to further optimise the ASD performance (Baghel et al., 2016; Luebbert and Stoyanov, 2023; Trenkenschuh et al., 2024; Xie and Taylor, 2017). Surfactants have been shown to enhance supersaturation generation and dissolution rates (Guan et al., 2019), while also improving the physical stability of amorphous drugs by forming stronger intermolecular interactions and reducing recrystallisation tendency (Kapourani et al., 2021; Xie and Taylor, 2017). The inclusion excipients have also been reported to improve processability in HME, where modifications to the formulation can influence melt viscosity and extrusion behaviour (Trenkenschuh et al., 2024). Another valuable strategy relies on the addition of pH modifiers, such as sodium carbonate (Almotairy et al., 2021) and meglumine (Alhamhoom et al., 2024) to change dissolution microenvironment and improve pH-dependent dissolution.

Even though UV–Vis spectroscopy is generally less chemically specific than vibrational spectroscopic techniques such as Raman and NIR, it is more cost-effective and simpler to implement, particularly during early development phases (Mishra et al., 2025). In addition, the integration of multivariate data analysis has significantly expanded the applicability of UV–Vis, enabling the exploration of sample differences and pattern recognition, which is especially valuable for real-time process monitoring (Ríos-Reina and Azcarate, 2022). UV–Vis has been successfully applied to the evaluation of tablet critical quality attributes (Lillotte et al., 2021; Mészáros et al., 2020), cleaning monitoring and optimization (Steiner-Browne et al., 2024), and hot-melt extrusion (HME) monitoring (Bezerra et al., 2025; Schlindwein et al., 2018; Triboandas et al., 2024; Wesholowski et al., 2018). In this work, we aimed to assess UV–Vis as a tool for real-time monitoring and for identifying compositional patterns across different polymeric systems.

Ibuprofen (IBU) is a poorly soluble nonsteroidal anti-inflammatory drug that exhibits pH-dependent solubility due to its weakly acidic character (pKa ≈ 4.9). Eudragit® EPO (EPO), a cationic copolymer consisting of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (2:1:1 ratio), is soluble below pH 5 and has been widely used to enhance supersaturation, improve dissolution, and act as a release modifier for ionisable APIs across various pH conditions (Darwich et al., 2024; Fine-Shamir and Dahan, 2019). This raises the relevant question of whether additional acid–base (ion-pairing) interactions between the carboxyl group of IBU and the tertiary amine functionalities of EPO could enhance physical stability or improve dissolution when incorporated into ASDs formulated with non-ionisable polymers.

Following our earlier investigation using IBU with Kollidon® VA64 (VA64), Kollidon® 17PF (17PF), and HPMCAS to produce binary ASD systems (De Castro et al., 2025), this study examines whether the addition of EPO offers any advantage in terms of stability or dissolution performance of extrudates. To this end, we apply the thermodynamic models described above to predict SLE, LLE, Tg-based miscibility predictions, and we assess the dissolution behaviour of the resulting formulations under non-sink conditions in both acidic and basic pHs. This predict-first approach is further strengthened by the integration of In-line UV–Vis spectroscopy during extrusion, offering a novel, real-time validation of miscibility and establishing a direct link between thermodynamic predictions for ternary ASDs.

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Materials

IBU, Kollidon VA64, and Kollidon 17PF were obtained from BASF (Ludwigshafen, Germany). HPMCAS was provided by Harke ChemLink (UK), and Eudragit E PO by Evonik Pharma Polymers (Darmstadt, Germany). The API and polymers physicochemical properties are summarized in Table 1, and their chemical structures are shown in Fig. 1. True density (ρ), glass transition temperature (T_g), melting temperature (T_m), enthalpy of fusion (Δ_fusH), and heat capacity change (ΔC_p) were determined experimentally.

Table 1. Ibuprofen and polymers’ true density and calorimetric properties.

Matheus de Castro, Melissa Almeida, Christian Luebbert, Shadrack Joel Madu, Jatin Khurana, Mark Evans, Matthew Leivers, Gabriel Araujo, Mingzhong Li, Walkiria Schlindwein, Hot-melt extruded ibuprofen ternary solid dispersions using in-line UV–Vis: Impact of an ionizable polymer on thermodynamics and dissolution,
International Journal of Pharmaceutics: X, Volume 11, 2026, 100536, ISSN 2590-1567, https://doi.org/10.1016/j.ijpx.2026.100536.

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