Polymer Selection for Esomeprazole Solid Dispersions: Drug–Polymer Compatibility Assessed by Forced Degradation, ATR-FTIR, and DFT Calculations

Abstract

Esomeprazole (ESO) is susceptible to degradation under stress conditions, making polymer selection important for stable solid dispersions. This study evaluated ESO compatibility with five polymers: three grades of hydroxypropyl methylcellulose acetate succinate (HPMCAS-LMP, HPMCAS-MMP, and HPMCAS-HMP), hydroxypropyl methylcellulose phthalate (HPMCP-55), and methacrylic acid–ethyl acrylate copolymer (1:1; Eudragit^® L100-55). Esomeprazole, polymers, and binary mixtures were stored at room temperature and subjected to forced thermal degradation at 60 °C for 16 days. Spectral changes were assessed by visual inspection and attenuated total reflectance–Fourier transform infrared (ATR-FTIR) spectroscopy using the fractional change index (FCI), normalized root-mean-square deviation (NRMSD), and relative maximum spectral difference (relative Max Δ). Density functional theory (DFT) calculations examined interaction energies, non-covalent interactions (NCIs), frontier molecular orbitals, and HOMO–LUMO-based reactivity descriptors. Combining quantitative ATR-FTIR analysis under thermal stress with DFT provides complementary experimental and molecular-level insights into ESO–polymer interactions, including an experimental comparison of three HPMCAS grades. The ESO–HPMCAS-MMP mixture showed the smallest spectral deviations. DFT indicated favorable interactions and relatively low chemical reactivity for the modeled ESO–HPMCAS complex. These findings support the preliminary consideration of HPMCAS-MMP for further formulation studies, although additional evidence is needed to establish comparative chemical compatibility and stability.

Introduction

Proton pump inhibitors (PPIs) are a class of acid-suppressing drugs characterized by a substituted benzimidazole–pyridine chemical structure [1]. They are widely used in the treatment of acid-related gastrointestinal disorders, including peptic ulcers, Zollinger–Ellison syndrome, gastroesophageal reflux disease (GERD), and Barrett’s esophagus [2]. Among PPIs, esomeprazole is widely used for the treatment of acid-related gastrointestinal disorders. However, its pharmaceutical development presents several challenges. Like other PPIs, esomeprazole is sensitive to acidic environments, light, temperature, oxidative conditions, and the presence of other salts [3,4,5,6]. These factors can affect its chemical stability, creating challenges during the manufacture, transportation, and storage of pharmaceutical dosage forms. In addition, the low aqueous solubility of esomeprazole can limit its dissolution and, consequently, its bioavailability [7,8,9]. This limited aqueous solubility is partly associated with the solid-state properties of PPIs and the stability of their crystalline forms [10,11].

Several pharmaceutical formulation strategies have therefore been proposed to address these challenges, including enteric-coated minitablets with optimized disintegrant content, cyclodextrin inclusion complexes, nanosuspensions for intravenous administration, and amorphous solid dispersions (ASDs) [12,13,14,15,16]. Among these approaches, ASDs are particularly promising because they can modify the crystalline state of the drug while enhancing its dissolution and potentially improving its bioavailability [17]. However, despite their advantages, ASDs present several formulation and stability challenges, including physical instability, drug–polymer phase separation, moisture sensitivity, limited drug loading, and difficulties in maintaining supersaturation during dissolution. Among these, recrystallization of the amorphous drug during storage remains a major concern, as it can compromise the enhanced solubility and dissolution performance provided by the ASD, making the selection of a suitable polymer essential for maintaining the amorphous state and protecting the active pharmaceutical ingredient (API) [18].

Previous studies have explored solid dispersion systems of esomeprazole and its salts using different polymeric carriers and preparation techniques. For example, Esomeprazole zinc has been formulated with polyethylene glycol (PEG 4000 and PEG 6000) and polyvinylpyrrolidone (PVP K30) using solvent-based methods [19,20], resulting in an amorphous drug state and improved dissolution. In addition, solid dispersions of esomeprazole magnesium have also been prepared using hydroxypropyl methylcellulose (HPMC), with the incorporation of alkalizers to improve the stability of the acid-labile drug in gastric conditions [21].

Despite these previous studies, the compatibility of esomeprazole with polymers containing different functional groups remains insufficiently characterized, particularly for polymers considered for solid dispersion development. Previous studies have shown that polymer composition and acidic functional groups can influence drug–polymer interactions and the stability of proton pump inhibitors [22,23,24]. However, the comparative spectral responses of different HPMCAS grades in combination with esomeprazole under the same defined thermal-stress conditions have not been systematically established. In particular, comparing HPMCAS-LMP, HPMCAS-MMP, and HPMCAS-HMP can help determine whether the observed spectral changes differ among grades under the conditions investigated.

Accordingly, HPMCAS, HPMCP, and Eudragit® L100-55 were selected as representative pharmaceutical polymers with different chemical functionalities and established applications in solid dispersion systems [25,26,27,28]. In these polymers, acidic functional groups remain predominantly protonated under acidic conditions and become increasingly ionized as the pH rises in the intestinal environment, facilitating polymer dissolution in the small intestine [22,29,30]. However, the presence of acidic functional groups may also influence the stability of acid-labile PPIs [23,24].

Beyond their enteric functionality, polymer selection for hot melt extrusion (HME) also requires consideration of thermal and rheological properties, including glass transition temperature (Tg), thermal stability and degradation onset, softening or melt behavior, melt viscosity, and the resulting processing window between polymer softening and thermal degradation [27]. These characteristics are particularly relevant for thermolabile and hydrolysable drugs such as esomeprazole, for which excessive processing temperatures, prolonged residence times, or unfavorable shear conditions may increase the risk of drug degradation. Thus, the distinct chemical structures and physicochemical properties of HPMCAS, HPMCP, and Eudragit® L100-55 provide a relevant basis for investigating their drug–polymer interactions and their potential applicability to HME-based solid dispersion development.

Therefore, the present study aimed to preliminarily evaluate the compatibility of esomeprazole with three pharmaceutical polymers—HPMCAS, HPMCP, and Eudragit® L100-55—as a first step toward their subsequent evaluation for the development of an esomeprazole solid dispersion by HME. The study focused on assessing spectral changes following thermal stress using quantitative ATR-FTIR descriptors and exploring potential drug–polymer molecular interactions through complementary computational approaches. Quantitative ATR-FTIR analysis enables the comparison of changes in measured spectral profiles, whereas molecular docking and density functional theory (DFT) provide complementary perspectives on these interactions, allowing potential molecular associations to be explored alongside the energetic and electronic factors that may contribute to their stability [31]. By combining these approaches, the study aimed to establish a rationale for polymer selection and guide subsequent formulation studies, including the evaluation of thermal behavior, rheological properties, and processing performance during hot-melt extrusion (HME).

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Materials

Esomeprazole, used as the active pharmaceutical ingredient (API), was supplied by Nifty Labs (Hyderabad, Telangana, India). The pharmaceutical polymers employed in the physicochemical compatibility studies included three grades of hydroxypropyl methylcellulose acetate succinate (HPMCAS), namely HPMCAS-LMP (Low Medium Substitution), HPMCAS-MMP (Medium Medium Substitution), and HPMCAS-HMP (High Medium Substitution), together with hydroxypropyl methylcellulose phthalate (HPMCP-55). These polymers were obtained from Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan). Eudragit® L100-55 (methacrylic acid–ethyl acrylate copolymer, 1:1, Mw = 320,000) was obtained from Evonik Industries AG (Darmstadt, Germany).

Ahumada-Herazo, E.; Urrego A., J.R.; Baena-Aristizábal, C.; Carrascal, J.J.; Bernal Rodríguez, C.-A. Polymer Selection for Esomeprazole Solid Dispersions: Drug–Polymer Compatibility Assessed by Forced Degradation, ATR-FTIR, and DFT Calculations. Polymers 2026, 18, 2655. https://doi.org/10.3390/polym18212655