{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T00:31:12Z","timestamp":1776472272209,"version":"3.51.2"},"reference-count":35,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T00:00:00Z","timestamp":1734912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001824","name":"Czech Science Foundation","doi-asserted-by":"publisher","award":["21-05926X"],"award-info":[{"award-number":["21-05926X"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Apremilast (APR) is an anti-inflammatory drug commonly used in the treatment of psoriasis. In efforts to enhance its solubility, several cocrystals with similar structural features have been developed. This study investigates the cocrystallization of APR with four phenolic-type coformers: phenol, catechol, pyrogallol, and hydroxyquinol. These coformers differ in the number and position of their hydroxyl groups, with their melting points varying by as much as 100 \u00b0C. Four novel cocrystal forms were synthesized, purified, and characterized using X-Ray diffraction and thermal analysis techniques. Surprisingly, the resulting cocrystals exhibited minimal differences in their melting points. The molecular packing of APR appears to limit the network-forming potential of the hydroxyl groups, a conclusion supported by the solved crystal structures, Hirshfeld surface analysis, and differential scanning calorimetry (DSC) results.<\/jats:p>","DOI":"10.3390\/molecules29246060","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T10:06:52Z","timestamp":1734948412000},"page":"6060","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Apremilast Cocrystals with Phenolic Coformers"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1032-1763","authenticated-orcid":false,"given":"Yelizaveta","family":"Naumkina","sequence":"first","affiliation":[{"name":"Department of Solid State Chemistry, University of Chemistry and Technology, Prague, Technicka 5, 16628 Prague, Czech Republic"},{"name":"Chemical Engineering Department, National Research Tomsk Polytechnic University, Lenin Avenue 30, 634050 Tomsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2243-1349","authenticated-orcid":false,"given":"Bohumil","family":"Kratochv\u00edl","sequence":"additional","affiliation":[{"name":"Department of Solid State Chemistry, University of Chemistry and Technology, Prague, Technicka 5, 16628 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5938-9562","authenticated-orcid":false,"given":"Elena","family":"Korotkova","sequence":"additional","affiliation":[{"name":"Chemical Engineering Department, National Research Tomsk Polytechnic University, Lenin Avenue 30, 634050 Tomsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5925-6217","authenticated-orcid":false,"given":"Jan","family":"\u010cejka","sequence":"additional","affiliation":[{"name":"Department of Solid State Chemistry, University of Chemistry and Technology, Prague, Technicka 5, 16628 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Rahmani, M., Kumar, V., Bruno-Colmenarez, J., and Zaworotko, M.J. (2022). Crystal Engineering of Ionic Cocrystals Sustained by Azolium\u00b7Azole Heterosynthons. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14112321"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11514","DOI":"10.1021\/acs.chemrev.1c00987","article-title":"Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs","volume":"122","author":"Bolla","year":"2022","journal-title":"Chem. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.apsb.2021.03.030","article-title":"Pharmaceutical Cocrystals: A Review of Preparations, Physicochemical Properties and Applications","volume":"11","author":"Guo","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1107\/S2052520616003954","article-title":"The Cambridge Structural Database","volume":"72","author":"Groom","year":"2016","journal-title":"Acta Crystallogr. B Struct. Sci. Cryst. Eng. Mater."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1001\/jama.2020.4006","article-title":"Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: Review","volume":"323","author":"Armstrong","year":"2020","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"104520","DOI":"10.1016\/j.jddst.2023.104520","article-title":"Investigating the Influence of the Type of Polymer on Sustaining the Supersaturation from Amorphous Solid Dispersions of Apremilast and Its Pharmacokinetics","volume":"84","author":"Shetty","year":"2023","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_7","first-page":"1048","article-title":"Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases. Front","volume":"9","author":"Li","year":"2018","journal-title":"Pharmacology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5785","DOI":"10.1021\/acs.cgd.0c00393","article-title":"Formation of the First Non-Isostructural Cocrystal of Apremilast Explained","volume":"20","author":"Babor","year":"2020","journal-title":"Cryst. Growth Des."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"118639","DOI":"10.1016\/j.ijpharm.2019.118639","article-title":"Complex Methodology for Rational Design of Apremilast-Benzoic Acid Co-Crystallization Process","volume":"570","author":"Ondo","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3959","DOI":"10.1021\/acs.cgd.8b00301","article-title":"\u03c0-Philic Molecular Recognition in the Solid State as a Driving Force for Mechanochemical Formation of Apremilast Solvates and Cocrystals","volume":"18","author":"Dudek","year":"2018","journal-title":"Cryst. Growth Des."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1107\/S205252061900917X","article-title":"Understanding the Formation of Apremilast Cocrystals","volume":"75","author":"Dudek","year":"2019","journal-title":"Acta Crystallogr. B Struct. Sci. Cryst. Eng. Mater."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1107\/S2052252522005577","article-title":"Structure\u2013Property Relations of a Unique and Systematic Dataset of 19 Isostructural Multicomponent Apremilast Forms","volume":"9","author":"Babor","year":"2022","journal-title":"IUCrJ"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5945","DOI":"10.1039\/C8CE00689J","article-title":"Solid-State Characterization and Solubility Enhancement of Apremilast Drug\u2013Drug Cocrystals","volume":"20","author":"Wang","year":"2018","journal-title":"CrystEngComm"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1107\/S2053229617002984","article-title":"The Preparation, Characterization, Structure and Dissolution Analysis of Apremilast Solvatomorphs","volume":"73","author":"Wu","year":"2017","journal-title":"Acta Crystallogr. C Struct. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.31557\/APJCP.2019.20.9.2645","article-title":"In Vivo Anti Cancer Potential of Pyrogallol in Murine Model of Colon Cancer","volume":"20","author":"Revathi","year":"2019","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5534","DOI":"10.1021\/acs.cgd.8b00849","article-title":"Cocrystallization of Curcumin with Benzenediols and Benzenetriols via Rapid Solvent Removal","volume":"18","author":"Wong","year":"2018","journal-title":"Cryst. Growth Des."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3974","DOI":"10.1021\/acs.cgd.7b00599","article-title":"Crystal Engineering of Curcumin with Salicylic Acid and Hydroxyquinol as Coformers","volume":"17","author":"Sathisaran","year":"2017","journal-title":"Cryst. Growth Des."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.3109\/03639045.2013.804834","article-title":"Solid state manipulation of lornoxicam for co-crystals\u2014Physicochemical characterization","volume":"40","author":"Nijhawan","year":"2014","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3053","DOI":"10.1021\/acs.cgd.9b01688","article-title":"Drug\u2013drug cocrystals provide significant improvements of drug properties in treatment with progesterone","volume":"20","author":"Guo","year":"2020","journal-title":"Cryst. Growth Des."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4135","DOI":"10.1021\/cg200704s","article-title":"Fast Dissolving Curcumin Cocrystals","volume":"11","author":"Sanphui","year":"2011","journal-title":"Cryst. Growth Des."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.1107\/S1600576716016058","article-title":"CrystalCMP: An easy-to-use tool for fast comparison of molecular packing","volume":"49","author":"Rohlicek","year":"2016","journal-title":"J. Appl. Cryst."},{"key":"ref_22","unstructured":"Lide, D.R. (2005). CRC Handbook of Chemistry and Physics, CRC Press."},{"key":"ref_23","unstructured":"O\u2019Neil, M.J. (2013). The Merck Index\u2014An Encyclopedia of Chemicals, Drugs, and Biologicals, Royal Society of Chemistry."},{"key":"ref_24","unstructured":"Lide, D.R. (2007). CRC Handbook of Chemistry and Physics, CRC Press. [88th ed.]."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/0891-5849(95)02089-6","article-title":"Effects of metals, ligands and antioxidants on the reaction of oxygen with 1,2,4-benzenetriol","volume":"20","author":"Zhang","year":"1996","journal-title":"Free Radic. Biol. Med."},{"key":"ref_26","unstructured":"Bruker, S. (2002). SAINT, Bruker AXS Inc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1107\/S2053273314026370","article-title":"SHELXT\u2014Integrated Space-Group and Crystal-Structure Determination","volume":"71","author":"Sheldrick","year":"2015","journal-title":"Acta Crystallogr. A Found. Adv."},{"key":"ref_28","first-page":"435","article-title":"SIR92 a program for automatic solution of crystal structures by direct methods","volume":"27","author":"Altomare","year":"1994","journal-title":"J. Appl. Cryst."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1107\/S0021889803021800","article-title":"CRYSTALS Version 12: Software for Guided Crystal Structure Analysis","volume":"36","author":"Betteridge","year":"2003","journal-title":"J. Appl. Crystallogr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1107\/S0021889810025598","article-title":"CRYSTALS enhancements: Dealing with hydrogen atoms in refinement","volume":"43","author":"Cooper","year":"2010","journal-title":"J. Appl. Cryst."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1107\/S1600576719014092","article-title":"Mercury 4.0: From Visualization to Analysis, Design and Prediction","volume":"53","author":"Macrae","year":"2020","journal-title":"J. Appl. Crystallogr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"S13","DOI":"10.1017\/S0885715614000840","article-title":"The HighScore suite","volume":"29","author":"Degen","year":"2014","journal-title":"Powder Diffr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1107\/S1600576721002910","article-title":"CrystalExplorer: A program for Hirshfeld surface analysis, visualization and quantitative analysis of molecular crystals","volume":"54","author":"Spackman","year":"2021","journal-title":"J. Appl. Cryst."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1039\/B818330A","article-title":"Hirshfeld surface analysis","volume":"11","author":"Sparkman","year":"2009","journal-title":"CrystEngComm"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1107\/S0108768104020300","article-title":"Novel tools for visualizing and exploring intermolecular interactions in molecular crystals","volume":"60","author":"McKinnon","year":"2004","journal-title":"Acta Cryts. B"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/24\/6060\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:58:36Z","timestamp":1760115516000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/24\/6060"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,23]]},"references-count":35,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["molecules29246060"],"URL":"https:\/\/doi.org\/10.3390\/molecules29246060","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,23]]}}}