{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:41:57Z","timestamp":1791330117201,"version":"4.3.1"},"reference-count":43,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T00:00:00Z","timestamp":1623283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["Research Project AMICO (code ARS01_00758)"],"award-info":[{"award-number":["Research Project AMICO (code ARS01_00758)"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Ketoprofen\u2013l-lysine salt (KLS) is a widely used nonsteroidal anti-inflammatory drug. Here, we studied deeply the solid-state characteristics of KLS to possibly identify new polymorphic drugs. Conducting a polymorph screening study and combining conventional techniques with solid-state nuclear magnetic resonance, we identified, for the first time, a salt\/cocrystal polymorphism of the ketoprofen (KET)\u2013lysine (LYS) system, with the cocrystal, KET\u2013LYS polymorph 1 (P1), being representative of commercial KLS, and the salt, KET\u2013LYS polymorph 2 (P2), being a new polymorphic form of KLS. Interestingly, in vivo pharmacokinetics showed that the salt polymorph has significantly higher absorption and, thus, different pharmacokinetics compared to commercial KLS (cocrystal), laying the basis for the development of faster-release\/acting KLS formulations. Moreover, intrinsic dissolution rate (IDR) and electronic tongue analyses showed that the salt has a higher IDR, a more bitter taste, and a different sensorial kinetics compared to the cocrystal, suggesting that different coating\/flavoring processes should be envisioned for the new compound. Thus, the new KLS polymorphic form with its different physicochemical and pharmacokinetic characteristics can open the way to the development of a new KET\u2013LYS polymorph drug that can emphasize the properties of commercial KLS for the treatment of acute inflammatory and painful conditions.<\/jats:p>","DOI":"10.3390\/ph14060555","type":"journal-article","created":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T13:31:39Z","timestamp":1623331899000},"page":"555","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Unexpected Salt\/Cocrystal Polymorphism of the Ketoprofen\u2013Lysine System: Discovery of a New Ketoprofen\u2013l-Lysine Salt Polymorph with Different Physicochemical and Pharmacokinetic Properties"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8390-6614","authenticated-orcid":false,"given":"Andrea","family":"Aramini","sequence":"first","affiliation":[{"name":"Research and Early Development, Domp\u00e9 Farmaceutici S.p.A., 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Bianchini","sequence":"additional","affiliation":[{"name":"Research and Early Development, Domp\u00e9 Farmaceutici S.p.A., 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuele","family":"Lillini","sequence":"additional","affiliation":[{"name":"Research and Early Development, Domp\u00e9 Farmaceutici S.p.A., 80131 Napoli, Italy"},{"name":"IMAST S.c.a.r.l.\u2014Technological District on Engineering of Polymeric and Composite Materials and Structures, 80133 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5392-6646","authenticated-orcid":false,"given":"Simone","family":"Bordignon","sequence":"additional","affiliation":[{"name":"Department of Chemistry and NIS Centre, University of Torino, 10125 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Tomassetti","sequence":"additional","affiliation":[{"name":"Research and Early Development, Domp\u00e9 Farmaceutici S.p.A., 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7990-7507","authenticated-orcid":false,"given":"Rubina","family":"Novelli","sequence":"additional","affiliation":[{"name":"Research and Early Development, Domp\u00e9 Farmaceutici S.p.A., 20122 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Mattioli","sequence":"additional","affiliation":[{"name":"Research and Early Development, Domp\u00e9 Farmaceutici S.p.A., 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1137-6973","authenticated-orcid":false,"given":"Larisa","family":"Lvova","sequence":"additional","affiliation":[{"name":"Department of Chemical Science and Technology, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2380-1404","authenticated-orcid":false,"given":"Roberto","family":"Paolesse","sequence":"additional","affiliation":[{"name":"Department of Chemical Science and Technology, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8734-6009","authenticated-orcid":false,"given":"Michele Remo","family":"Chierotti","sequence":"additional","affiliation":[{"name":"Department of Chemistry and NIS Centre, University of Torino, 10125 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0617-0233","authenticated-orcid":false,"given":"Marcello","family":"Allegretti","sequence":"additional","affiliation":[{"name":"Research and Early Development, Domp\u00e9 Farmaceutici S.p.A., 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1039\/C5CC08216A","article-title":"Pharmaceutical cocrystals: Along the path to improved medi-cines","volume":"52","author":"Duggirala","year":"2015","journal-title":"Chem. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6370","DOI":"10.1021\/acs.cgd.8b00933","article-title":"Creating Cocrystals: A Review of Pharmaceutical Cocrystal Preparation Routes and Applications","volume":"18","author":"Padrela","year":"2018","journal-title":"Cryst. Growth Des."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5292","DOI":"10.1039\/C8CE00707A","article-title":"Pharmaceutical cocrystallization: An effective approach to modulate the physicochemical properties of solid-state drugs","volume":"20","author":"Dai","year":"2018","journal-title":"CrystEngComm"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1021\/mp060126o","article-title":"Cocrystal or Salt: Does It Really Matter?","volume":"4","author":"Fasulo","year":"2007","journal-title":"Mol. Pharm."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"8375","DOI":"10.1039\/C4CE00797B","article-title":"Cocrystals of telmisartan: Characterization, structure elucidation, in vivo and toxicity studies","volume":"16","author":"Chadha","year":"2014","journal-title":"CrystEngComm"},{"key":"ref_6","first-page":"1889","article-title":"Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved medicines?","volume":"35","author":"Zaworotko","year":"2004","journal-title":"Chem. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1021\/acs.cgd.0c00661","article-title":"Can We Identify the Salt\u2013Cocrystal Continuum State Using XPS?","volume":"21","author":"Tothadi","year":"2021","journal-title":"Cryst. Growth Des."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1021\/acs.cgd.9b01299","article-title":"Selective Synthesis of a Salt and a Cocrystal of the Ethionamide\u2013Salicylic Acid System","volume":"20","author":"Bernasconi","year":"2019","journal-title":"Cryst. Growth Des."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1039\/b509162d","article-title":"Tape and layer structures in cocrystals of some di- and tricarboxylic acids with 4,4\u2032-bipyridines and isonicotinamide. From binary to ternary cocrystals","volume":"7","author":"Bhogala","year":"2005","journal-title":"CrystEngComm"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6362","DOI":"10.1039\/c2ce26055g","article-title":"Acid\u2013base crystalline complexes and the pKa rule","volume":"14","year":"2012","journal-title":"CrystEngComm"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1021\/mp0601345","article-title":"The Salt\u2212Cocrystal Continuum: The Influence of Crystal Structure on Ionization State","volume":"4","author":"Childs","year":"2007","journal-title":"Mol. Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4150","DOI":"10.1021\/acs.cgd.8b00597","article-title":"First Comparative Study of the Three Polymorphs of Bis(isonicotinamide) Citric Acid Cocrystals and the Concomitant Salt 4-Carbamoylpyridinium Citrate Isonicotinamide","volume":"18","author":"Stainton","year":"2018","journal-title":"Cryst. Growth Des."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1107\/S2053229617017909","article-title":"The effect of amino acid backbone length on molecular packing: Crystalline tartrates of glycine, \u03b2-alanine, \u03b3-aminobutyric acid (GABA) and DL-\u03b1-aminobutyric acid (AABA)","volume":"74","author":"Losev","year":"2018","journal-title":"Acta Crystallogr. C Struct. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1039\/C7CE02204B","article-title":"A salt or a co-crystal\u2014When crystallization protocol matters","volume":"20","author":"Losev","year":"2018","journal-title":"CrystEngComm"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1039\/C8CE01076E","article-title":"Robust bulk preparation and characterization of sulfamethazine and saccharine salt and cocrystal polymorphs","volume":"21","author":"Perumalla","year":"2019","journal-title":"CrystEngComm"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1039\/C8CE02066C","article-title":"Living in the salt-cocrystal continuum: Indecisive organic complexes with thermochromic behaviour","volume":"21","author":"Jones","year":"2019","journal-title":"CrystEngComm"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1021\/mp070001z","article-title":"An Overview of Pharmaceutical Cocrystals as Intellectual Property","volume":"4","author":"Trask","year":"2007","journal-title":"Mol. Pharm."},{"key":"ref_18","first-page":"10","article-title":"Polymorphism: The Phenomenon Affecting the Performance of Drugs","volume":"1","author":"Raza","year":"2014","journal-title":"SOJ Pharm. Pharm. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Seo, K.-S., Bajracharya, R., Lee, S.H., and Han, H.-K. (2020). Pharmaceutical Application of Tablet Film Coating. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12090853"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1080\/03007995.2018.1466697","article-title":"Predicting rapid analgesic onset of ibuprofen salts compared with ibu-profen acid: Tlag, Tlow, Tmed, and a novel parameter, TCmaxRef","volume":"34","author":"Miles","year":"2018","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1007\/s40265-015-0392-z","article-title":"Advances in NSAID Development: Evolution of Diclofenac Products Using Pharmaceutical Technology","volume":"75","author":"Altman","year":"2015","journal-title":"Drugs"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2618","DOI":"10.1007\/s12325-019-01053-x","article-title":"Towards an Effective and Safe Treatment of Inflammatory Pain: A Delphi-Guided Expert Consensus","volume":"36","author":"Varrassi","year":"2019","journal-title":"Adv. Ther."},{"key":"ref_23","unstructured":"Silverstein, R.M., Webster, F.X., Kiemle, D.J., and Bryce, D.L. (2015). Spectrometric Identification of Organic Compounds, Wiley."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.addr.2017.07.001","article-title":"Pharmaceutical aspects of salt and cocrystal forms of APIs and characteri-zation challenges","volume":"117","author":"Chierotti","year":"2017","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1039\/b711551b","article-title":"Solid-state NMR studies of weak interactions in supramolecular systems","volume":"14","author":"Chierotti","year":"2008","journal-title":"Chem. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1107\/S0108270189004968","article-title":"K\u00e9toprof\u00e8ne","volume":"46","author":"Briard","year":"1990","journal-title":"Acta Crystallogr. C"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1039\/b910662f","article-title":"Chiral co-crystal solid solution: Structures, melting point phase diagram, and chiral enrichment of (ibuprofen)2(4,4-dipyridyl)","volume":"12","author":"Chen","year":"2010","journal-title":"CrystEngComm"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3973","DOI":"10.1002\/anie.201411520","article-title":"L-Lysine: Exploiting powder X-ray diffraction to complete the set of crystal structures of the 20 directly encoded proteinogenic amino acids","volume":"54","author":"Pa","year":"2015","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1515\/chem-2020-0028","article-title":"Disintegration, In vitro Dissolution, and Drug Release Kinetics Profiles of k-Carrageenan-based Nutraceutical Hard-shell Capsules Containing Salicylamide","volume":"18","author":"Pudjiastuti","year":"2020","journal-title":"Open Chem."},{"key":"ref_30","first-page":"12","article-title":"Taste Masking: A Unique Approach for Bitter Drugs","volume":"1","author":"Chauhan","year":"2017","journal-title":"J. Stem Cell Biol. Transplant."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1081\/DDC-120037477","article-title":"Taste Masking Technologies in Oral Pharmaceuticals: Recent Developments and Approaches","volume":"30","author":"Sohi","year":"2004","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_32","first-page":"731","article-title":"The impact of geographical location on taste sensitivity and preference","volume":"22","author":"Baharuddin","year":"2015","journal-title":"Int. Food Res. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"145","DOI":"10.3109\/03639045.2013.804833","article-title":"A review on the taste masking of bitter APIs: Hot-melt extrusion (HME) evaluation","volume":"40","author":"Maniruzzaman","year":"2013","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.3109\/03639045.2015.1118495","article-title":"Sucralose as co-crystal co-former for hydrochlorothiazide: Development of oral disintegrating tablets","volume":"42","author":"Arafa","year":"2015","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.ijpharm.2014.07.008","article-title":"Novel pharmaceutical cocrystal consisting of paracetamol and trimethylglycine, a new promising cocrystal former","volume":"473","author":"Maeno","year":"2014","journal-title":"Int. J. Pharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1016\/j.xphs.2017.09.013","article-title":"Evaluating Suspension Formulations of Theophylline Cocrystals with Artificial Sweeteners","volume":"107","author":"Aitipamula","year":"2018","journal-title":"J. Pharm. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.talanta.2012.04.013","article-title":"Salt release monitoring with specific sensors in \u2018in vitro\u2019 oral and digestive environments from soft cheeses","volume":"97","author":"Lvova","year":"2012","journal-title":"Talanta"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.bios.2016.01.050","article-title":"Electronic tongue for microcystin screening in waters","volume":"80","author":"Lvova","year":"2016","journal-title":"Biosens. Bioelectron."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Lvova, L., Jahatspanian, I., Mattoso, L.H., Correa, D.S., Oleneva, E., Legin, A., Di Natale, C., and Paolesse, R. (2020). Potentiometric E-Tongue System for Geosmin\/Isoborneol Presence Monitoring in Drinkable Water. Sensors, 20.","DOI":"10.3390\/s20030821"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1021\/acs.jpcb.5b11893","article-title":"Identification of Ion-Pair Structures in Solution by Vibrational Stark Effects","volume":"120","author":"Hack","year":"2016","journal-title":"J. Phys. Chem. B"},{"key":"ref_41","unstructured":"Falk, J.E. (1975). Porphyrins and Metalloporphyrins: A New Edition Based on the Original Volume by J. E. Falk, Elsevier."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/S0925-4005(97)00232-3","article-title":"Photocurable carbonate-selective membranes for chemical sensors containing lipophilic additives","volume":"44","author":"Levitchev","year":"1997","journal-title":"Sens. Actuators B Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1142\/S1088424609001510","article-title":"Corrole-based ion-selective electrodes","volume":"13","author":"Lvova","year":"2009","journal-title":"J. Porphyr. Phthalocyanines"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/6\/555\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:13:06Z","timestamp":1760163186000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/6\/555"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,10]]},"references-count":43,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ph14060555"],"URL":"https:\/\/doi.org\/10.3390\/ph14060555","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,10]]}}}