{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T16:16:55Z","timestamp":1773677815905,"version":"3.50.1"},"reference-count":35,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2019s Horizon 2020 Marie Sk\u0142odowska-Curie research and innovation program","award":["955756"],"award-info":[{"award-number":["955756"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Lipid-based formulations (LBFs) are enabling formulations for poorly water-soluble, mostly lipophilic drugs. In LBFs, the drug is pre-dissolved in the formulation which can consist of lipids, surfactants, and\/or cosolvents. In cases where the administration of high amounts of a drug is required, exceeding the drug solubility in the lipidic vehicle at the administration temperature, supersaturated LBFs are an option. The standard method described in the literature for inducing supersaturation in LBFs is to dissolve the drug substance in the lipidic vehicle at an elevated temperature, e.g., at 60 \u00b0C, and then subsequently let the formulation cool to ambient temperature before administration (heat-based approach). In this work, an alternative approach to induce supersaturation in LBFs was investigated in order to evaluate if higher drug loads, i.e., the concentration of drug dissolved in the vehicle, could be reached compared to the loading obtainable via heating. Methods: A volatile solvent that is miscible with the lipid matrix and in which the compound has a high solubility is added to the lipid matrix, after which the solvent is evaporated. Both approaches were compared in this work investigating two different LBFs loaded with the BCS-class II drugs celecoxib and fenofibrate. Results: When inducing supersaturation by heat, drug loads of 238% for celecoxib and 278% for fenofibrate could be achieved relative to the solubility at ambient temperature. Using the solvent-based approach, drug loads of up to 475% for celecoxib and 557% for fenofibrate could be prepared in the LBFs using dichloromethane (DCM) as the volatile solvent. However, those highly supersaturated preparations showed suboptimal physical stability and quickly led to precipitation when the LBFs were stored at ambient temperature. In addition, selected formulations were analyzed with GC-headspace to determine the residual DCM after solvent evaporation using a vacuum evaporator. This analysis revealed that the DCM content exceeded regulatory requirements, with up to 21,883 ppm DCM in the formulations. Conclusions: Overall, the relatively high residual DCM concentration and the suboptimal physical stability do not make the approach easily usable for generating supersaturated lipid-based formulations.<\/jats:p>","DOI":"10.3390\/pharmaceutics17060702","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T03:30:19Z","timestamp":1748489419000},"page":"702","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Application of Solvent Evaporation to Generate Supersaturated Lipid-Based Formulations: Investigation of Drug Load and Formulation Quality"],"prefix":"10.3390","volume":"17","author":[{"given":"Felix","family":"Paulus","sequence":"first","affiliation":[{"name":"Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium"},{"name":"Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jef","family":"Stappaerts","sequence":"additional","affiliation":[{"name":"Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8238-6984","authenticated-orcid":false,"given":"Annette","family":"Bauer-Brandl","sequence":"additional","affiliation":[{"name":"Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk","family":"Lauwers","sequence":"additional","affiliation":[{"name":"Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liesbet","family":"Smet","sequence":"additional","affiliation":[{"name":"Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eline","family":"Hermans","sequence":"additional","affiliation":[{"name":"Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4894-7765","authenticated-orcid":false,"given":"Ren\u00e9","family":"Holm","sequence":"additional","affiliation":[{"name":"Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Jacobsen, A.-C., Visentin, S., Butnarasu, C., Stein, P.C., and di Cagno, M.P. (2023). Commercially Available Cell-Free Permeability Tests for Industrial Drug Development: Increased Sustainability through Reduction of In Vivo Studies. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15020592"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.ejps.2013.04.002","article-title":"Biopharmaceutical classification of poorly soluble drugs with respect to \u201cenabling formulations\u201d","volume":"50","author":"Buckley","year":"2013","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.ejps.2006.04.016","article-title":"Formulation of poorly water-soluble drugs for oral administration: Physicochemical and physiological issues and the lipid formulation classification system","volume":"29","author":"Pouton","year":"2006","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S93","DOI":"10.1016\/S0928-0987(00)00167-6","article-title":"Lipid formulations for oral administration of drugs: Non-emulsifying, self-emulsifying and \u2018self-microemulsifying\u2019 drug delivery systems","volume":"11","author":"Pouton","year":"2000","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"105452","DOI":"10.1016\/j.ejps.2020.105452","article-title":"Exploring impact of supersaturated lipid-based drug delivery systems of celecoxib on in vitro permeation across Permeapad\u24c7 membrane and in vivo absorption","volume":"152","author":"Ilie","year":"2020","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1080\/03639045.2020.1721526","article-title":"Supersaturated lipid-based drug delivery systems\u2014Exploring impact of lipid composition type and drug properties on supersaturability and physical stability","volume":"46","author":"Ilie","year":"2020","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"105691","DOI":"10.1016\/j.ejps.2020.105691","article-title":"Exploring precipitation inhibitors to improve in vivo absorption of cinnarizine from supersaturated lipid-based drug delivery systems","volume":"159","author":"Ilie","year":"2021","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Koehl, N.J., Henze, L.J., Kuentz, M., Holm, R., and Griffin, B.T. (2020). Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12060564"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.ejpb.2019.07.002","article-title":"Fenofibrate oral absorption from SNEDDS and super-SNEDDS is not significantly affected by lipase inhibition in rats","volume":"142","author":"Michaelsen","year":"2019","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1208\/s12248-015-9832-7","article-title":"The Effect of Digestion and Drug Load on Halofantrine Absorption from Self-nanoemulsifying Drug Delivery System (SNEDDS)","volume":"18","author":"Michaelsen","year":"2016","journal-title":"AAPS J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"106634","DOI":"10.1016\/j.ejps.2023.106634","article-title":"Digestion is a critical element for absorption of cinnarizine from supersaturated lipid-based type I formulations","volume":"192","author":"Paulus","year":"2023","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1208\/s12248-016-0038-4","article-title":"Influence of drug load and physical form of cinnarizine in new SNEDDS dosing regimens: In vivo and in vitro evaluations","volume":"19","author":"Siqueira","year":"2017","journal-title":"AAPS J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.jconrel.2012.02.027","article-title":"In vitro and in vivo performance of novel supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS)","volume":"160","author":"Thomas","year":"2012","journal-title":"J. Control Release"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"119264","DOI":"10.1016\/j.ijpharm.2020.119264","article-title":"Enhancement of abiraterone acetate oral bioavailability by supersaturated-silica lipid hybrids","volume":"582","author":"Schultz","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ejpb.2017.12.012","article-title":"Supersaturated silica-lipid hybrids (super-SLH): An improved solid-state lipid-based oral drug delivery system with enhanced drug loading","volume":"125","author":"Schultz","year":"2018","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1124\/jpet.118.254466","article-title":"Supersaturated Silica-Lipid Hybrid Oral Drug Delivery Systems: Balancing Drug Loading and In Vivo Performance","volume":"370","author":"Schultz","year":"2019","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.ejpb.2023.11.001","article-title":"Functionalized calcium carbonate (FCC) as a novel carrier to solidify supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS)","volume":"193","author":"Merchant","year":"2023","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"105357","DOI":"10.1016\/j.ejps.2020.105357","article-title":"Enhancing the oral bioavailability of simvastatin with silica-lipid hybrid particles: The effect of supersaturation and silica geometry","volume":"150","author":"Meola","year":"2020","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Almasri, R., Joyce, P., Schultz, H.B., Thomas, N., Bremmell, K.E., and Prestidge, C.A. (2020). Porous nanostructure, lipid composition, and degree of drug supersaturation modulate in vitro fenofibrate solubilization in silica-lipid hy-brids. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12070687"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Bennett-Lenane, H., O\u2019shea, J.P., Murray, J.D., Ilie, A.-R., Holm, R., Kuentz, M., and Griffin, B.T. (2021). Artificial Neural Networks to Predict the Apparent Degree of Supersaturation in Supersaturated Lipid-Based Formulations: A Pilot Study. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13091398"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"106556","DOI":"10.1016\/j.ejps.2023.106556","article-title":"Lipid based formulations as supersaturating oral delivery systems: From current to future industrial applications","volume":"189","author":"Holm","year":"2023","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1208\/s12248-012-9433-7","article-title":"Supersaturated Self-Nanoemulsifying Drug Delivery Systems (Super-SNEDDS) Enhance the Bioavailability of the Poorly Water-Soluble Drug Simvastatin in Dogs","volume":"15","author":"Thomas","year":"2013","journal-title":"AAPS J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2733","DOI":"10.2174\/1381612821666150428125046","article-title":"Supersaturation as a Tool For Skin Penetration Enhancement","volume":"21","author":"Cilurzo","year":"2015","journal-title":"Curr. Pharm. Des."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"105262","DOI":"10.1016\/j.ejps.2020.105262","article-title":"Polymer\/lipid interplay in altering in vitro supersaturation and plasma concentration of a model poorly soluble drug","volume":"146","author":"Peng","year":"2020","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"657","DOI":"10.3109\/02652048.2013.774445","article-title":"Enhanced payload of lipid nanocarriers using supersaturated solution prepared by solvent-mediated method","volume":"30","author":"Nguyen","year":"2013","journal-title":"J. Microencapsul."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8801","DOI":"10.2147\/IJN.S149717","article-title":"Supersaturable solid self-microemulsifying drug delivery system: Precipitation inhibition and bioavailability enhancement","volume":"12","author":"Quan","year":"2017","journal-title":"Int. J. Nanomed."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0939-6411(96)00037-9","article-title":"Residual solvents in pharmaceutical products: Acceptable limits, influences on physicochemical properties, analytical methods and documented values","volume":"43","author":"Witschi","year":"1997","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_28","unstructured":"ICH Expert Working Group (2023, November 24). ICH Guideline Q3C (R8) on Impurities: Guideline for Residual Solvents Step 5, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 2021. ICH Q3C (R8) Residual Solvents\u2014Scientific Guideline. Available online: https:\/\/www.ema.europa.eu\/en\/ich-q3c-r8-residual-solvents-scientific-guideline."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11095-020-02877-x","article-title":"Residual Solvents in Nanomedicine and Lipid-Based Drug Delivery Systems: A Case Study to Better Understand Processes","volume":"37","author":"Dikpati","year":"2020","journal-title":"Pharm. Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Gr\u00fcne, L., and Bunjes, H. (2024). Solubility of Poorly Soluble Drugs in Phosphatidylcholine-Based Drug Delivery Systems: Comparison of the Loading Capacity in the Bulk Formulation and Its Dispersed State. Pharmaceuticals, 17.","DOI":"10.3390\/ph17030400"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1021\/mp9000876","article-title":"Ethanol\u2212Drug Absorption Interaction: Potential for a Significant Effect on the Plasma Pharmacokinetics of Ethanol Vulnerable Formulations","volume":"6","year":"2009","journal-title":"Mol. Pharm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"104858","DOI":"10.1016\/j.yrtph.2020.104858","article-title":"Evaluation of the carcinogenicity of dichloromethane in rats, mice, hamsters and humans","volume":"120","author":"Dekant","year":"2021","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"119473","DOI":"10.1016\/j.ijpharm.2020.119473","article-title":"Optimization of the manufacturing process of a complex amphotericin B liposomal formulation using quality by design approach","volume":"585","author":"Liu","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2505","DOI":"10.1016\/j.apsb.2021.05.014","article-title":"Pharmaceutical amorphous solid dispersion: A review of manufacturing strategies","volume":"11","author":"Bhujbal","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Salim, M., Fraser-Miller, S.J., B\u0113rzi\u0146\u0161, K., Sutton, J.J., Gordon, K.C., and Boyd, B.J. (2023). In Situ Monitoring of Drug Precipitation from Digesting Lipid Formulations Using Low-Frequency Raman Scattering Spectroscopy. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15071968"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/6\/702\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:41:26Z","timestamp":1760031686000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/6\/702"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,27]]},"references-count":35,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["pharmaceutics17060702"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17060702","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,27]]}}}