Preparation of 5-ASA-Loaded Eudragit® S100 Nanoparticles by Emulsion-Based Methods: Comparison between Solvent Evaporation and Supercritical Fluid Extraction

Abstract

Breaking away from the limitations of conventional solvent evaporation (SE), supercritical fluid extraction of emulsions (SFEE) offers a transformative approach to the production of polymeric nanoparticles. In this study, both SFEE and SE were applied to formulate nanoparticles composed of Eudragit® S100 loaded with 5-aminosalicylic acid (5-ASA), a drug widely used in the treatment of inflammatory bowel disease (IBD).

Highlights

Nanoparticles of 5-ASA were successfully prepared using emulsion-based SE and SFEE

Eudragit® S100 was used as a pH-sensitive polymeric coating material

Both methods produced nanometric particles with high encapsulation efficiency

Rapid drug released was observed in acidic medium, favoured by high surface area

SFEE enables low-residue, sterile nanoparticles in continuous production

A comparison was made between the two methods in terms of particle size distribution, encapsulation efficiency, residual solvent content, and morphology. Formulation efforts focused on obtaining a stable emulsion. A mixed organic phase was required: acetone to dissolve the polymer and a second solvent to solubilise the drug, underscoring the formulation challenge. Among the solvents evaluated, dimethyl sulfoxide (DMSO) was selected due to its ability to maximise 5-ASA solubility, enhance emulsion stability, and its classification as a low-risk Class 3 solvent. SFEE resulted in larger particle sizes (D50 = 165 nm) and slightly lower encapsulation efficiency (EE = 84%) compared to SE (D50 = 85 nm, EE = 99%).

Despite the high boiling point of DMSO, SFEE achieved a significant reduction in residual solvent content (< 4%) versus 21% in SE particles. Both particles showed similar release profiles, with a rapid release of 5-ASA under acidic conditions despite being formulated with a pH-sensitive polymer. This behaviour was likely attributed to the nanometric size and high surface area of the particles, which favoured rapid drug diffusion.

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Materials and reagents

5-Aminosalicylic acid (5-ASA, ≥ 95.0%, CAS [89–57–6], Sigma-Aldrich, Spain), acetic acid (≥ 99.0%, CAS [64–19–7], Sigma-Aldrich, Spain), acetone (≥ 99.9%, CAS [67–64–1], Fisher Scientific, Spain), carbon dioxide (CO₂, ≥ 99.95%, CAS [124-38-9], Carburos Metálicos, Air Product, Spain), dialysis membranes (3500 KDa, diameter 22 cm, Medicell, UK), dichloromethane (DCM, 99.9%, CAS [75–09–2], Scharlab, Spain), dimethyl sulfoxide (DMSO, 99.9%, CAS [67,68], Scharlab, Spain), Eudragit® S100 (EU S100, kindly donated by Evonik Industries, Germany), hydrochloric acid (HCl, ≥ 99.0%, CAS [7647-01-0], Sigma-Aldrich, Spain), methanol (≥ 99.0%, CAS [67–56–1], Sigma-Aldrich, Spain), potassium di-hydrogen phosphate (≥ 99.0%, CAS [7778-77-0], Panreac, Spain), sodium lauryl sulphate (≥ 99.0%, CAS [151-21-3], Sigma-Aldrich, Spain), sodium phosphotungstic acid (2%, CAS [12501-23-4], Panreac, Spain), tetrahydrofuran (THF, ≥ 99.8%, CAS [109-99-9], Scharlab, Spain), and Tween 80 (polyoxyethylene (20) sorbitan monooleate, CAS [9005-65-6], Scharlab, Spain) were used as received in this work.

Table 1. Overview of nanoparticle formulations for 5-ASA-based drug delivery using different coatings and preparation techniques.

Coating	Technique	Size (nm)	Encapsulation efficiency (%)	Loading (%)	Reference
Carboxymethyl cellulose/gum rosin hybrid nanoparticles	Nanoprecipitation and crosslinking with glutaraldehyde	~ 267	-	-	[11]
Intestinal organoids containing Poly Lactic-co-Glycolic Acid (PLGA) nanoparticles	Double-emulsion (water/oil/water)-based solvent evaporation/extraction	200 - 300	33 - 45	-	[12]
Aloe vera polysaccharide/acrylonitrile nanoparticles	Free radical polymerization method using persulfate/ascorbic acid and methylenebisacrylamide as the redox initiator and crosslinker respectively	~ 50	-	-	[13]
Thiolated chitosan/alginate composite microparticulates coated by Eudragit® S100	Ionic gelation and the polyelectrolyte complexation	3.5×104	~ 66	~ 16	[6]
Silicon dioxide nanoparticles	Micro-emulsion	90	-	~ 14	[14]
Eudragit® FS	Melt extrusion	4×105 - 1 ×106	-	10 - 30	[7]
Bioadhesive agents, Carbomer 940 and hydroxypropyl cellulose, by extrusion/spheronization method and coated with Surelease® as inner layer for waterproof and with Eudragit® S100 as outer layer for pH control	Extrusion/spheronization and coated by a fluid bed coater	7×105	-	-	[15]
MCM-41 silicas functionalized by amino and by amino and carboxylic groups and alginate coating	Sol–gel	100	-	-	[16]
Xylan/ Eudragit® S100	Interfacial cross-linking polymerisation and/or spray-drying	(2 - 10) ×104	~ 25	-	[8]
Eudragit® S100	Solution enhanced dispersion by supercritical fluids (SEDS)	140 - 400	3 - 61	3 - 22	[9]
Poly Lactic-co-Glycolic Acid (PLGA)	SEDS and nanoprecipitation	135 - 210	-	-	[10]
Chitosan crosslinked with sodium tripolyphosphate and coated with carrageenan	Ionotropic gelation	570 - 3570	~ 40	-	[17]
Hemoglobin	Desolvation	220	-	0.5	[18]
Sodium alginate and chitosan on the surface of 5-ASA nanocrystals, and Eudragit® S100 was coated on the outermost layer.	Layer-by-layer self-assembly	352	95	86	[19]
Chitosan bound ginger nanocarriers	Physical adsorption	94	59	57	[20]

David Vizcaya, Diego F. Tirado, Albertina Cabañas, Dolores R. Serrano, Lourdes Calvo, Preparation of 5-ASA-Loaded Eudragit® S100 Nanoparticles by Emulsion-Based Methods: Comparison between Solvent Evaporation and Supercritical Fluid Extraction, The Journal of Supercritical Fluids, 2025, 106753, ISSN 0896-8446, https://doi.org/10.1016/j.supflu.2025.106753.