Hot Melt Extruded Aceclofenac-Soluplus® Solid Dispersion: Mechanistic View of Miscibility and Drug-Carrier Interactions for Enhanced Dissolution

Abstract

Aceclofenac (ACF), a Non-Steroidal Anti-Inflammatory Drug (NSAID), is formulated with Soluplus® (SOLP) to enhance solubility and bioavailability. This study presents a distinct approach by utilizing Hot Melt Extrusion (HME) to prepare Aceclofenac-Soluplus® solid dispersion (ACF-SOLP), in contrast to the previously investigated nanoemulsion technique. The HME technique facilitates a uniform drug distribution within the polymer matrix, increasing ACF’s dissolution rate. Different weight ratios of ACF and SOLP were assessed with 1:8 (HM4), which proved to be the optimal choice. ACF is dispersed within SOLP in its amorphous state, and HM4 exhibited a significant increase in drug release as compared to pure ACF and its physical mixture. In vivo pharmacokinetic data of HM4 demonstrated a drastic improvement in the C_max (7.1 ± 0.14 µg/ml) and AUC (12.1 ± 1.30 µg-h/ml). Further, molecular dynamics simulation revealed that the polymer is widely dispersed within the supramolecular architecture of ACF-SOLP, with ACF positioned centrally, confirming the favorable interactions between the components. Leveraging the hydrophilic nature of the SOLP, the solid dispersion demonstrated enhanced dissolution of ACF, while HME synergistically reinforced the combination. This approach presents a compelling alternative to traditional methods, unlocking new possibilities for formulating poorly soluble drugs.

Introduction

Numerous solubility-enhancing techniques have been investigated in the last few years to tackle the solubility issues and aid in the oral delivery of BCS class II drugs [1]. Some of the strategies adopted for overcoming the poor solubility problems of drugs include size reduction of drugs by nanonization [2, 3], cocrystal formation [4, 5], conversion into inclusion complexes [6, 7], solid dispersion techniques [8, 9], and self-emulsifying drug delivery systems [10, 11]. The solid dispersion technique encompasses the dispersion of drugs within the carrier matrix, constituting a polymer at the molecular level [12]. The drug is dispersed in the matrix in its amorphous form, thus increasing drug solubility, as the amorphous form of the drug shows a greater extent of solubility than its crystalline counterparts. The presence of the polymer also imparts stability to the system. The preparation of amorphous solid dispersions (ASD) is straightforward and can hold many poorly soluble drugs within them [13, 14]. The transformation of drugs into solid dispersions induces amorphization, which is the key factor behind the significantly enhanced thermodynamic solubility of ASDs. Solvent evaporation and thermal fusion methods are the prime techniques for manufacturing solid dispersion. Another technique that is slowly gaining pace in the pharmaceutical field is the hot melt extrusion (HME) technique [15].

HME technique is a continuous process wherein the materials are fed into the equipment at high temperatures, more than polymers glass transition temperature (Tg) which are forced in between the rotating screws to enable the blending of the polymer and drug at a molecular level. The controlled process conditions, along with the combined effects of heat and mechanical forces, aid in forming a solid dispersion. Twin-screw extruders are often used, which provide continuous, vigorous mixing and a homogenous dispersion. The advantages of the HME technique, such as being a continuous process, a solvent-free technique, a closed system, and easy scalability, make it a widely sought-after platform technology in the pharmaceutical industry [16].

Based on this background, in the present work, the advantages of the HME technique were exploited to enhance the solubility of the BCS-II drug, Aceclofenac (ACF), by formulating it into a solid dispersion utilizing Soluplus® (SOLP) as a matrix. ACF is a non-steroidal anti-inflammatory drug (NSAID) prescribed for conditions such as rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. However, its poor aqueous solubility results in its limited bioavailability after oral administration [17]. Hence, improving its solubility remains a significant aspect of improving its therapeutic efficacy. Numerous efforts have been made to improve the solubility of ACF, such as incorporating them into cyclodextrin to form inclusion complexes [18, 19], various size reduction techniques to yield nanoparticles [3, 20], chitosan nanoparticles [21], co-crystals [22,23,24], and solid dispersion [25, 26]. However, HME presents a superior approach by offering a solvent-free, scalable, and continuous manufacturing process. Unlike nanonization, which may face stability concerns, or inclusion complexes that require specific host–guest interactions, HME ensures uniform dispersion of the drug within the polymer matrix, promoting enhanced amorphization, improved dissolution, and sustained drug release. This makes HME a promising alternative for developing stable and effective formulations of poorly soluble drugs [27,28,29,30,31,32].

A relatively new amphiphilic copolymer, SOLP is a graft copolymer comprising polyvinyl caprolactam (57% vinyl caprolactam) -polyvinyl acetate (30% vinyl acetate)-polyethylene glycol (13% PEG6000). Polyethylene glycol constitutes the hydrophilic part, whereas polyvinyl caprolactam and polyvinyl acetate form the lipophilic part of the polymer. The polymer is capable of solubilizing poorly soluble drugs by forming micelles. Above their critical micelle concentration, they tend to form larger micelles, resulting in turbid solutions. They can retain the drug in its supersaturated form for a prolonged period in the gastrointestinal tract, thereby preventing nucleation and crystallization and enhancing the dissolution. SOLP has been successfully utilized in amorphous solid dispersion using HME technology and has shown positive results [33,34,35,36,37].

The combination of ACF and SOLP nanoparticles has already been explored using the emulsion technique [38]; however, our approach employs HME to enhance the formation of a more uniform amorphous solid dispersion and control over particle size distribution, improving the drug’s dissolution rate and bioavailability. HME was compared with the fusion method, and molecular-level interactions were analyzed using molecular dynamics simulations to assess the strength and stability of the drug-polymer combination. These insights reinforce the potential of HME as a robust and efficient strategy for developing stable formulations.

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Materials

ACF and SOLP were generous gift samples from Lupin Research Park, Pune, India, and BASF Corporation, Mumbai, India, respectively. All the other chemicals used in the experiments were analytical grade.

U, L., Bharti, R., Narayan, R. et al. Hot Melt Extruded Aceclofenac-Soluplus® Solid Dispersion: Mechanistic View of Miscibility and Drug-Carrier Interactions for Enhanced Dissolution. AAPS PharmSciTech 26, 180 (2025). https://doi.org/10.1208/s12249-025-03173-w