{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T01:49:33Z","timestamp":1785462573039,"version":"3.56.0"},"reference-count":33,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T00:00:00Z","timestamp":1732665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Pimozide is a first-generation antipsychotic used in the treatment of schizophrenia, Gilles de la Tourette syndrome, and other chronic psychoses. Its in vivo efficacy is limited by poor solubility and consequent poor bioavailability. Therefore, adipic acid was used as a coformer for the preparation of a binary product with improved pharmaceutical properties. The thermal behavior of the liquid-assisted grinding products of compositions included in the range 0.1 &lt; XPMZ &lt; 0.9 has been interpreted using a thermo-dynamic model according to which the two components originate a new crystalline entity in molar ratio pimozide:adipic acid 0.66:0.33, which forms an eutectic system with adipic acid. The model was confirmed using the quantitative analysis of the melting peaks and using the X-ray diffraction measurements from powders and single crystals. In particular, the latter have demonstrated that the new entity resulting from the pimozide:adipic acid 0.66:0.33 composition is actually salt [PMZH]2[adipate]. The crystalline product was characterized, from a pharmaceutical perspective, in terms of solubility and wettability (contact angle). Then, a tablet formulation was developed, and its dissolution behavior was compared to a commercial product considered as a reference. The new entity showed improved pharmaceutical properties in terms of solubility and wettability compared to the pure drug in both deionized water and bio-relevant fluids simulating oral administration in fed and fasted conditions. The tablets containing the new crystalline form can make this virtually insoluble drug available for absorption within minutes regardless of the variability in gastric conditions.<\/jats:p>","DOI":"10.3390\/molecules29235610","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T08:17:42Z","timestamp":1732695462000},"page":"5610","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pimozide and Adipic Acid: A New Multicomponent Crystalline Entity for Improved Pharmaceutical Behavior"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8561-7831","authenticated-orcid":false,"given":"Alessandra","family":"Buscarini","sequence":"first","affiliation":[{"name":"Department of Chemistry, Physical Chemistry Section & C.S.G.I. (Consorzio Interuniversitario per lo Sviluppo dei Sistemi a Grande Interfase), University of Pavia, Via Taramelli 16, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1360-540X","authenticated-orcid":false,"given":"Michael J.","family":"Zaworotko","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences and Bernal Institute, University of Limerick, V94 T9PX Limerick, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8355-396X","authenticated-orcid":false,"given":"Cati\u00facia R. M. O.","family":"Matos","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences and Bernal Institute, University of Limerick, V94 T9PX Limerick, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizia","family":"Grepioni","sequence":"additional","affiliation":[{"name":"Dipartimento di Chimica \u201cGiacomo Ciamician\u201d, Universit\u00e0 di Bologna, Via Selmi 2, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Contini","sequence":"additional","affiliation":[{"name":"Dipartimento di Chimica \u201cGiacomo Ciamician\u201d, Universit\u00e0 di Bologna, Via Selmi 2, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1064-7196","authenticated-orcid":false,"given":"Doretta","family":"Capsoni","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Physical Chemistry Section & C.S.G.I. (Consorzio Interuniversitario per lo Sviluppo dei Sistemi a Grande Interfase), University of Pavia, Via Taramelli 16, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2975-4362","authenticated-orcid":false,"given":"Valeria","family":"Friuli","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1408-8846","authenticated-orcid":false,"given":"Lauretta","family":"Maggi","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1958-2998","authenticated-orcid":false,"given":"Giovanna","family":"Bruni","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Physical Chemistry Section & C.S.G.I. (Consorzio Interuniversitario per lo Sviluppo dei Sistemi a Grande Interfase), University of Pavia, Via Taramelli 16, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Gonz\u00e1lez-Rodr\u00edguez, A., Monreal, J.A., Natividad, M., and Seeman, M.V. (2022). Seventy years of treating delusional disorder with antipsychotics: A historical perspective. Biomedicines, 10.","DOI":"10.3390\/biomedicines10123281"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2165\/00003495-197612010-00001","article-title":"Pimozide: A review of its pharmacological properties and therapeutic uses in psychiatry","volume":"12","author":"Finder","year":"1976","journal-title":"Drugs"},{"key":"ref_3","first-page":"CD001949","article-title":"Pimozide for schizophrenia or related psychoses","volume":"3","author":"Sultana","year":"2000","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1111\/j.1600-0447.1975.tb00019.x","article-title":"Pimozide in the treatment of monosymptomatic hypochondriacal psychosis","volume":"52","author":"Riding","year":"1975","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/S0190-9622(08)80767-0","article-title":"Pimozide in delusions of parasitosis","volume":"22","author":"Damiani","year":"1990","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"339","DOI":"10.2165\/00128071-200405050-00007","article-title":"Pimozide in dermatologic practice: A comprehensive review","volume":"5","author":"Cynthia","year":"2004","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_7","first-page":"752","article-title":"Antipsychotic pimozide is a potent Ca2+ channel blocker in heart","volume":"37","author":"Enyeart","year":"1990","journal-title":"Mol. Pharmacol."},{"key":"ref_8","first-page":"5399","article-title":"Inhibition of human breast cancer cell proliferation in tissue culture by the neuroleptic agents pimozide and thioridazine","volume":"50","author":"Strobl","year":"1990","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3421","DOI":"10.1182\/blood-2009-11-255232","article-title":"The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors","volume":"117","author":"Nelson","year":"2011","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"17593","DOI":"10.18632\/oncotarget.4307","article-title":"The neuroleptic drug pimozide inhibits stem-like cell maintenance and tumorigenicity in hepatocellular carcinoma","volume":"8","author":"Chen","year":"2017","journal-title":"Oncotarget"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"768","DOI":"10.7150\/ijbs.14718","article-title":"Inhibition of wnt\/\u03b2-catenin signaling in hepatocellular carcinoma by an antipsychotic drug pimozide","volume":"12","author":"Fako","year":"2016","journal-title":"Int. J. Biol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.molliq.2015.12.054","article-title":"Novel pimozide-\u03b2-cyclodextrin-polyvinylpyrrolidone inclusion complexes for Tourette syndrome treatment","volume":"215","author":"Hriday","year":"2016","journal-title":"J. Mol. Liq."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Singh, M., Barua, H., Jyothi, V.G.S.S., Dhondale, M.R., Nambiar, A.G., Agrawal, A.K., Kumar, P., Shastri, N.R., and Kumar, D. (2023). Cocrystals by Design: A rational coformer selection approach for tackling the API problems. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15041161"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"875","DOI":"10.3109\/03639045.2014.971027","article-title":"Solubility and dissolution enhancement strategies: Current understanding and recent trends","volume":"41","author":"Jain","year":"2015","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1208\/s12249-009-9189-2","article-title":"Improving Tenoxicam Solubility and Bioavailability by Cosolvent System","volume":"10","author":"Yeh","year":"2009","journal-title":"AAPS PharmSciTech"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.ijpharm.2010.03.059","article-title":"Solubility enhancement of hydrophobic compounds by cosolvents: Role of solute hydrophobicity on the solubilization effect","volume":"393","author":"Miyako","year":"2010","journal-title":"Int. J. Pharm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1358\/mf.1998.20.3.485666","article-title":"Micronization: A method of improving the bioavailability of poorly soluble drugs","volume":"20","author":"Chaumeil","year":"1998","journal-title":"Methods Find Exp. Clin. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/978-1-4615-3002-2_2","article-title":"Microemulsion formation with some typical surfactants","volume":"15","author":"Ogino","year":"1993","journal-title":"Surf. Colloid Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1107\/S2052519213016989","article-title":"Structure and properties of domperidone and its succinate salt","volume":"69","author":"Bruni","year":"2013","journal-title":"Acta Cryst. B"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3690","DOI":"10.1016\/j.xphs.2021.08.009","article-title":"Zaltoprofen\/4,40-Bipyridine: A case study to demonstrate the potential of Differential Scanning Calorimetry (DSC) in the pharmaceutical field","volume":"110","author":"Bruni","year":"2021","journal-title":"J. Pharm. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/s10973-020-09749-x","article-title":"Probenecid and benzamide: DSC applied to the study of an impossible pharmaceutical system","volume":"145","author":"Bruni","year":"2021","journal-title":"J. Therm. Anal."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1016\/j.xphs.2018.11.033","article-title":"Enhancing the Pharmaceutical Behavior of Nateglinide by Cocrystallization: Physicochemical Assessment of Cocrystal Formation and Informed Use of Differential Scanning Calorimetry for Its Quantitative Characterization","volume":"108","author":"Bruni","year":"2019","journal-title":"J. Pharm. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2358","DOI":"10.1208\/s12249-018-1064-6","article-title":"Investigation of Cyclodextrin-Based Nanosponges for Solubility and Bioavailability Enhancement of Rilpivirine","volume":"19","author":"Rao","year":"2018","journal-title":"AAPS PharmSciTech"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gupta, D., Bhatia, D., Dave, V., Sutariya, V., and Varghese Gupta, S. (2018). Salts of therapeutic agents: Chemical, physicochemical, and biological considerations. Molecules, 23.","DOI":"10.20944\/preprints201804.0187.v1"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/j.addr.2007.05.010","article-title":"Salt formation to improve drug solubility","volume":"59","author":"Serajuddin","year":"2007","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.ijpharm.2012.11.028","article-title":"Use of pharmaceutical salts and cocrystals to address the issue of poor solubility","volume":"453","author":"Elder","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_27","unstructured":"U.S. FOOD & DRUG (2024, June 03). Regulatory Classification of Pharmaceutical Co-Crystals, Available online: https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/regulatory-classification-pharmaceutical-co-crystals."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6973","DOI":"10.1021\/acs.cgd.8b01159","article-title":"Salts, Cocrystals, and Ionic Cocrystals of a \u201cSimple\u201d Tautomeric Compound","volume":"18","author":"Wang","year":"2018","journal-title":"J. Cryst. Growth Des."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"14052","DOI":"10.1039\/D3CC04313D","article-title":"Crystal engineering: From promise to delivery","volume":"59","author":"Braga","year":"2023","journal-title":"Chem. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1107\/S2053273314026370","article-title":"SHELXT-Integrated Space-Group and Crystal-Structure Determination","volume":"71","author":"Sheldrick","year":"2015","journal-title":"Acta Crystallogr. Sect. A Found. Adv."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1107\/S0021889808042726","article-title":"OLEX2: A complete structure solution, refinement and analysis program","volume":"42","author":"Dolomanov","year":"2009","journal-title":"J. Appl. Crystallogr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1107\/S0021889807067908","article-title":"New Features for the Visualization and Investigation of Crystal Structures","volume":"41","author":"Macrae","year":"2008","journal-title":"J. Appl. Crystallogr."},{"key":"ref_33","unstructured":"(2023). USP43-NF38, United States Pharmacopeial Convention, Inc."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/23\/5610\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:40:35Z","timestamp":1760114435000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/23\/5610"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,27]]},"references-count":33,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["molecules29235610"],"URL":"https:\/\/doi.org\/10.3390\/molecules29235610","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,27]]}}}