{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T23:10:10Z","timestamp":1788217810430,"version":"build-2803163510"},"reference-count":113,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T00:00:00Z","timestamp":1733961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Romanian Ministry of Research, Innovation and Digitization\u2014Executive Agency for Higher Education, Research, Development and Innovation Funding (UEFISCDI)","award":["PN-III-P1-1.1-TE-2021-0244"],"award-info":[{"award-number":["PN-III-P1-1.1-TE-2021-0244"]}]},{"name":"Romanian Ministry of Research, Innovation and Digitization\u2014Executive Agency for Higher Education, Research, Development and Innovation Funding (UEFISCDI)","award":["PN 23 24 01 02"],"award-info":[{"award-number":["PN 23 24 01 02"]}]},{"name":"Romanian Ministry of Research, Innovation and Digitization\u2014Executive Agency for Higher Education, Research, Development and Innovation Funding (UEFISCDI)","award":["PN 23 24 01 05"],"award-info":[{"award-number":["PN 23 24 01 05"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Development of cocrystals through crystal engineering is a viable strategy to formulate poorly water-soluble active pharmaceutical ingredients as stable crystalline solid forms with enhanced bioavailability. This study presents a controlled cocrystallization process by cooling for the 1:1 cocrystal of Ketoconazole, an antifungal class II drug with the Fumaric acid coformer. This was successfully set up following the meta-stable zone width determination in acetone\u2013water 4:6 (V\/V) and pure ethanol. Considering the optimal crystallization data, laboratory scale-up processes were carried out at 1 g batch size, efficiently delivering the cocrystal in high yields up to 90% pure and single phase as revealed by powder X-ray diffraction. Biological assays in vitro showed improved viability and oxidative damage of the cocrystal over Ketoconazole on human dermal fibroblasts and hepatocarcinoma cells; in vivo, on Wistar rats, the cocrystal increased oral Ketoconazole bioavailability with transient minor biochemical transaminases increases and without histological liver alterations. Locally on Balb C mice, it induced no epicutaneuous sensitization. A molecular docking study conducted on sterol 14\u03b1-demethylase (CYP51) enzyme from the pathogenic yeast Candida albicans revealed that the cocrystal interacts more efficiently with the enzyme compared to Ketoconazole, indicating that the coformer enhances the binding affinity of the active ingredient.<\/jats:p>","DOI":"10.3390\/ijms252413346","type":"journal-article","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T06:29:30Z","timestamp":1733984970000},"page":"13346","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Ketoconazole-Fumaric Acid Pharmaceutical Cocrystal: From Formulation Design for Bioavailability Improvement to Biocompatibility Testing and Antifungal Efficacy Evaluation"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4046-7310","authenticated-orcid":false,"given":"Ioana","family":"Baldea","sequence":"first","affiliation":[{"name":"Department of Physiology, \u201cIuliu Ha\u0163ieganu\u201d University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remus","family":"Moldovan","sequence":"additional","affiliation":[{"name":"Department of Physiology, \u201cIuliu Ha\u0163ieganu\u201d University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9596-2899","authenticated-orcid":false,"given":"Andras-Laszlo","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Ross University School of Veterinary Medicine, Basseterre P.O. Box 334, Saint Kitts and Nevis"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2903-1535","authenticated-orcid":false,"given":"Pompei","family":"Bolfa","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Ross University School of Veterinary Medicine, Basseterre P.O. 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