Novel Hybrid Polymer-Lipid-Based Formulations for Enhanced Dissolution Rates of Poorly Water-Soluble Drugs: A Quality by Design (QbD) Approach via Hot Melt Extrusion

Abstract

This study presents a Quality by Design (QbD) strategy combined with Design of Experiments (DoE) to develop hybrid polymer–lipid hot-melt extruded (HME) formulations aimed at improving the dissolution rate and palatability of ibuprofen (IBU), a Biopharmaceutics Classification System (BCS) Class II drug with poor aqueous solubility. A fractional factorial design was applied to evaluate the influence of Eudragit EPO and Gelucire 48/16 (GLC) ratios on the preparation of IBU-loaded extrudates. Physicochemical characterisation of the micronised extrudates, using differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD), confirmed the formation of amorphous solid dispersions (98.0–99.8%). The DoE analysis demonstrated that the EPO/GLC ratio significantly affected crystallinity, particle size distribution, and dissolution performance. The optimised hybrid polymer–lipid formulations exhibited immediate drug release (> 80%) within 45 min. Furthermore, in vivo evaluation indicated effective taste masking and improved palatability.

Introduction

Enhancing the solubility of poorly water-soluble drugs remains a major challenge in pharmaceutical development, particularly for Biopharmaceutics Classification System (BCS) Class II compounds such as Ibuprofen (IBU) [1,2,3,4]. Hot melt extrusion (HME) has been proved a suitable technology to overcome this limitation by producing amorphous solid dispersions (ASDs) that significantly improve drug dissolution and bioavailability [5, 6]. One of the key advantages of HME lies in its ability to molecularly disperse the active pharmaceutical ingredient (API) into a polymer matrix, thereby enhancing solubility and stability [7,8,9]. Nowadays hot-melt extrusion (HME) is s widely recognised as an effective solvent-free, continuous technique for improving the physicochemical properties of challenging BCS Class II drugs through formation of ASDs and related drug-carrier systems [10,11,12,13,14,15]. Over the last two decades, HME has evolved into a versatile platform for numerus drug delivery systems including emerging processes such as 3D printing [16,17,18,19,20,21].

Along with polymer-lipid matrices, the use of inorganic porous carriers like Neusilin has become more popular as a way to improve the performance of hot-melt extruded amorphous solid dispersions [22]. Neusilin is a synthetic magnesium aluminometasilicate that has a large specific surface area and a mesoporous structure. It has several benefits, such as a strong ability to adsorb, better wettability, and better flowability [23, 24]. Neusilin helps the drug homogenize dispersions throughout the matrix when mixed with polymers like Eudragit EPO and lipid excipients like Gelucire 48/16. It also prevents the drug from recrystallising by reducing molecular mobility and keeps lipid domains stable throughout processing. Its porous shape lets molten lipids stick to it during extrusion, which reduces phase separation and makes it easier to handle the extrudates later [25]. Also, the synergistic interplay of polymer supersaturation processes, lipid-assisted solubilisation, and Neusilin-mediated surface dispersion may help poorly water-soluble drugs like ibuprofen dissolve better [25, 26]. From a Quality by Design (QbD) standpoint, the concentration (%w/w) and physicochemical characteristics of Neusilin are essential material attributes that affect dissolution rate, physical stability, taste-masking efficiency, and processability [27]. Therefore, they require a systematic assessment within a Design of Experiments framework to define a comprehensive formulation design space [12].

The incorporation of Quality by Design (QbD) principles and Design of Experiments (DoE) has greatly enhanced the development of HME extruded ASDs by improving product quality, consistency, and regulatory compliance [28]. DoE allows systematic optimisation of formulation and process parameters [29, 30] while reducing experimental workload compared to traditional one-factor-at-a-time approaches [31, 32]. Successful implementation of QbD, as outlined in ICH Q8, Q9, and Q10 guidelines [28, 33, 34], requires a clear understanding of the Quality Target Product Profile (QTPP) and identification of Critical Material Attributes (CMAs) and Critical Quality Attributes (CQAs) to ensure robust and reproducible product design.

In the present study, a Quality-by-Design (QbD) framework combined with Design of Experiments (DoE) was employed to systematically investigate the influence of formulation parameters—specifically, the ratio of Eudragit EPO to Gelucire 48/16 on the formation of Ibuprofen-loaded hot-melt extrudates and their amorphous solid dispersion characteristics. All processing parameters were maintained constant to isolate the effects of composition on product performance. The overall objective was to optimise IBU-based HME formulations for enhanced solubility, improved flowability, and effective taste masking.

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Materials

Ibuprofen (IBU) was supplied by Farmasino Pharmaceuticals Co., Ltd. (Nanjing, China). Eudragit EPO was obtained from Evonik Industries AG (Germany), Gelucire 48/16 (GLC) from Gattefossé (France), and Neusiline® US2 (NEU) from Fuji Chemical Industries Co., Ltd. (Japan). All materials were of analytical grade and used as received without further modification.

Kolipaka, S.S., Junqueira, L.A., Garg, V. et al. Novel Hybrid Polymer-Lipid-Based Formulations for Enhanced Dissolution Rates of Poorly Water-Soluble Drugs: A Quality by Design (QbD) Approach via Hot Melt Extrusion. AAPS PharmSciTech 27, 267 (2026). https://doi.org/10.1208/s12249-026-03530-3