{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:37:47Z","timestamp":1760146667819,"version":"build-2065373602"},"reference-count":42,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T00:00:00Z","timestamp":1732752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Institute for Science and Technology Development (LPIT), Bandung Institute of Technology","award":["564\/IT1.B07.5\/TA\/2024","JP22K05032","JP24H00005"],"award-info":[{"award-number":["564\/IT1.B07.5\/TA\/2024","JP22K05032","JP24H00005"]}]},{"name":"JSPS KAKENHI","award":["564\/IT1.B07.5\/TA\/2024","JP22K05032","JP24H00005"],"award-info":[{"award-number":["564\/IT1.B07.5\/TA\/2024","JP22K05032","JP24H00005"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Piperine (PPN) is a natural compound with an anti-inflammation effect and low solubility. Hence, some molecular modifications have improved its solid-state character, including cocrystal formation. However, the salt structure has yet to be widely studied. In this research, PPN was reacted with toluene sulfonic acid (TSA), which was expected to increase its solubility and anti-inflammatory effects. This experiment used solid-state reactions and analysis, including thermal analysis, infrared spectroscopy, and powder X-ray diffractometry, to characterize the new multicomponent solid phase. Next, single crystal R-ray diffractometry was used to determine the final three-dimensional conformation structure. After that, the salt, which can be reproduced by wet grinding, was tested for improved stability and anti-inflammatory effects. As a result, the PPN\u2013TSA multicomponent solid was confirmed as a solid salt with monoclinic packing, exhibiting better solubility and anti-inflammation effects. Thus, this new organic salt has the potential for further phytochemical compound development.<\/jats:p>","DOI":"10.3390\/molecules29235631","type":"journal-article","created":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T07:28:01Z","timestamp":1732778881000},"page":"5631","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Development of a New Salt of Piperine with Toluene Sulfonic Acid and Its Anti-Inflammation Effect In Vivo"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5069-0343","authenticated-orcid":false,"given":"Ilma","family":"Nugrahani","sequence":"first","affiliation":[{"name":"School of Pharmacy, Bandung Institute of Technology, Bandung 40132, Indonesia"},{"name":"Center of Halal Studies, Bandung Institute of Technology, Bandung 40132, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ari","family":"Sartinah","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Bandung Institute of Technology, Bandung 40132, Indonesia"},{"name":"Faculty of Pharmacy, Halu Oleo University, Kendari 93231, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9809-1411","authenticated-orcid":false,"given":"Hidehiro","family":"Uekusa","sequence":"additional","affiliation":[{"name":"School of Science, Tokyo Institute of Technology, Tokyo 152-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuto","family":"Abekura","sequence":"additional","affiliation":[{"name":"School of Science, Tokyo Institute of Technology, Tokyo 152-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Slamet","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Jenderal Achmad Yani University, Cimahi 40531, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9879-6112","authenticated-orcid":false,"given":"Kusnandar","family":"Anggadiredja","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Bandung Institute of Technology, Bandung 40132, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8293921","DOI":"10.1155\/2020\/8293921","article-title":"The role of inflammation in the pathogenesis of osteoarthritis","volume":"2020","author":"Chow","year":"2020","journal-title":"Mediat. Inflamm."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Ali, K.A., Maity, A., Roy, S.D., Pramanik, S.D., Das, P.P., and Shaharyar, M.A. (2023). Insight into the Mechanism of Steroidal and Non-Steroidal Anti-Inflammatory Drugs, Academic Press.","DOI":"10.1016\/B978-0-323-99855-0.00004-X"},{"key":"ref_3","first-page":"349","article-title":"Anti-inflammatory treatments for chronic diseases: A review","volume":"12","author":"Laveti","year":"2013","journal-title":"Inflamm. Allergy-Drug Targets Former. Curr. Drug Targets-Inflamm. Allergy Discontin."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Bindu, S., Mazumder, S., and Bandyopadhyay, U. (2020). Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem. Pharmacol., 180.","DOI":"10.1016\/j.bcp.2020.114147"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.intimp.2013.06.025","article-title":"Piperine inhibits IL-\u03b2 induced expression of inflammatory mediators in human osteoarthritis chondrocyte","volume":"17","author":"Ying","year":"2013","journal-title":"Int. Immunopharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"100027","DOI":"10.1016\/j.medidd.2020.100027","article-title":"Piperine: A comprehensive review of methods of isolation, purification, and biological properties","volume":"7","author":"Tiwari","year":"2020","journal-title":"Med. Drug Discov."},{"key":"ref_7","first-page":"176","article-title":"Evaluation of Analgesic, Anti-Inflammatory, and Antipyretic Activity of Piperine: An Experimental Study","volume":"12","author":"Dhargawe","year":"2021","journal-title":"Pharmacogn. Res."},{"key":"ref_8","first-page":"36","article-title":"Curcumin and piperine: A novel therapy in the management of osteoarthritis in Indian patient","volume":"18","author":"Faruqui","year":"2018","journal-title":"Pac. J. Med. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1007\/s10753-012-9448-3","article-title":"Anti-inflammatory effect of piperine in adjuvant-induced arthritic rats\u2014A biochemical approach","volume":"35","author":"Murunikkara","year":"2012","journal-title":"Inflammation"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1111\/1541-4337.12246","article-title":"Piperine\u2014The bioactive compound of black pepper: From isolation to medicinal formulations","volume":"16","author":"Gorgani","year":"2017","journal-title":"Compr. Rev. Food Sci. Food Saf."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"31","DOI":"10.22159\/ijap.2021v13i4.41596","article-title":"Recent strategies for improving solubility and oral bioavailability of piperine","volume":"13","author":"Salsabila","year":"2021","journal-title":"Int. J. Appl. Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Nugrahani, I., and Parwati, R.D. (2021). Challenges and progress in nonsteroidal anti-inflammatory drugs co-crystal development. Molecules, 26.","DOI":"10.3390\/molecules26144185"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Zaini, E., Fitriani, L., Ismed, F., Horikawa, A., and Uekusa, H. (2020). Improved solubility and dissolution rates in novel multicomponent system crystals of piperine with succinic acid. Sci. Pharm., 88.","DOI":"10.3390\/scipharm88020021"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.5958\/0974-360X.2020.00347.9","article-title":"Improving Dissolution rate of piperine by multicomponent system crystal formation with saccharin","volume":"13","author":"Zaini","year":"2020","journal-title":"Res. J. Pharm. Technol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e31548","DOI":"10.1016\/j.heliyon.2024.e31548","article-title":"Piperine-hydroxybenzoate as phytochemistry antiosteoarthritis combination: Structural, solubility, and in vivo antiinflammatory study","volume":"10","author":"Sartinah","year":"2024","journal-title":"Heliyon"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.saa.2016.05.042","article-title":"Salt or cocrystal of salt? Probing the nature of multicomponent crystal forms with infrared spectroscopy","volume":"167","author":"Ribeiro","year":"2016","journal-title":"Spectrochim. Acta A Mol. Biomol. Spectrosc."},{"key":"ref_17","unstructured":"National Center for Biotechnology Information (2023, July 01). PubChem Compound Summary for Piperine, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Piperine."},{"key":"ref_18","unstructured":"National Center for Biotechnology Information (2023, July 01). PubChem Compound Summary for p-Toluenesulfonic-Acid, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/p-Toluenesulfonic-acid."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3091","DOI":"10.2174\/138527211798357074","article-title":"Application of p-toluenesulfonic Acid (PTSA) in Organic Synthesis","volume":"15","author":"Baghernejad","year":"2011","journal-title":"Curr. Org. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ungur, D.T., Santiso-Quinones, G., Pop, M.M., Tamas, T.L., Guguta, C., Stam, D., Mija, A., and Iordache, C.A. (2023). Febuxostat\u2013p-Toluenesulfonic Acid Multi-Component Crystal: Characterization, Crystal Growth and Elucidation of the Salt\/Co-Crystal Nature. Crystals, 13.","DOI":"10.3390\/cryst13050836"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2199","DOI":"10.1007\/s11947-017-1994-0","article-title":"Sequential microwave-ultrasound-assisted extraction for isolation of piperine from black pepper (Piper nigrum L.)","volume":"10","author":"Gorgani","year":"2017","journal-title":"Food Bioprocess Technol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"158","DOI":"10.22146\/ijp.866","article-title":"Development of new isolation and quantification method of Piperine from white pepper seeds (Piper nigrum L.) using a validated HPLC","volume":"32","author":"Kusumorini","year":"2021","journal-title":"Indones. J. Pharm."},{"key":"ref_23","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_24","doi-asserted-by":"crossref","unstructured":"Solares-Briones, M., Coyote-Dotor, G., P\u00e1ez-Franco, J.C., Zerme\u00f1o-Ortega, M.R., de la O Contreras, C.M., Canseco-Gonz\u00e1lez, D., Avila-Sorossa, A., Morales-Morales, D., and Germ\u00e1n-Acacio, J.M. (2021). Mechanochemistry: A green approach in the preparation of pharmaceutical cocrystals. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13060790"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"121063","DOI":"10.1016\/j.ijpharm.2021.121063","article-title":"Cocrystals, salts, and salt-solvates of olanzapine; selection of coformers and improved solubility","volume":"608","author":"Gong","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"119694","DOI":"10.1016\/j.ijpharm.2020.119694","article-title":"Enhancing the solubility and permeability of the diuretic drug furosemide via multicomponent crystal forms","volume":"587","author":"Diniz","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1021\/acs.cgd.7b01538","article-title":"Multifunctional organosulfonate anions self-assembled with organic cations by charge-assisted hydrogen bonds and the cooperation of water","volume":"18","author":"Xing","year":"2018","journal-title":"Cryst. Growth Des."},{"key":"ref_28","first-page":"32","article-title":"Enhancement of solubilization and bioavailability of poorly soluble drugs by physical and chemical modifications: A recent review","volume":"2","author":"Chaudhary","year":"2012","journal-title":"J. Adv. Pharm. Educ. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"520","DOI":"10.54203\/scil.2023.wvj55","article-title":"Carrageenan-Induced Acute Inflammation on Back-Skin of Mice: Histopathological Features, Number of Inflammatory Cells, and Expression of COX-2, COX-1, and IL-6","volume":"13","author":"Widyarini","year":"2023","journal-title":"World\u2019s Vet. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"501","DOI":"10.26554\/sti.2023.8.3.501-508","article-title":"Increasing the Solubility and Anti-Inflammatory Activity of Curcumin by Cocrystallization","volume":"8","author":"Wicaksono","year":"2023","journal-title":"Sci. Technol. Indones."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5531","DOI":"10.1021\/acs.cgd.9b00249","article-title":"Cocrystal of apigenin with higher solubility, enhanced oral bioavailability, and anti-inflammatory effect","volume":"19","author":"Ma","year":"2019","journal-title":"Cryst. Growth Des."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nrd.2015.21","article-title":"From blood\u2013brain barrier to blood\u2013brain interface: New opportunities for CNS drug delivery","volume":"15","author":"Banks","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1002\/ptr.6855","article-title":"Piperine: A review of its biological effects","volume":"35","author":"Haq","year":"2021","journal-title":"Phytother. Res."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Nugrahani, I., Laksana, A.N., Uekusa, H., and Oyama, H. (2022). New organic salt from levofloxacin-citric acid: What is the impact on the stability and antibiotic potency?. Molecules, 27.","DOI":"10.3390\/molecules27072166"},{"key":"ref_35","first-page":"20170103","article-title":"A review on differential scanning calorimetry technique and its importance in the field of energetic materials","volume":"3","year":"2018","journal-title":"Phys. Sci. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.ejps.2018.02.020","article-title":"Zwitterionic cocrystal of diclofenac and L-proline: Structure determination, solubility, kinetics of cocrystallization, and stability study","volume":"117","author":"Nugrahani","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1107\/S2053273314026370","article-title":"SHELXT\u2013Integrated space-group and crystal-structure determination","volume":"A71","author":"Sheldrick","year":"2015","journal-title":"Acta Crystallogr. Sect. A Found. Adv."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1107\/S2053229614024218","article-title":"Crystal structure refinement with SHELXL","volume":"C71","author":"Sheldrick","year":"2015","journal-title":"Acta Crystallogr. Sect. C Struct. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Nugrahani, I., Kumalasari, R.A., Auli, W.N., Horikawa, A., and Uekusa, H. (2020). Salt cocrystal of diclofenac sodium-l-proline: Structural, pseudopolymorphism, and pharmaceutics performance study. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12070690"},{"key":"ref_40","first-page":"19","article-title":"Determination of azole antifungal medicines using zero-order and derivative UV spectrophotometry","volume":"66","author":"Ekiert","year":"2009","journal-title":"Acta Poloniae Pharm. Drug Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.1039\/C7CE00284J","article-title":"Solubility improvement of epalrestat by layered structure formation via cocrystallization","volume":"19","author":"Putra","year":"2017","journal-title":"Cryst. Eng. Comm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1055\/s-2007-967122","article-title":"Evaluation of the anti-inflammatory activity of luteolin in experimental animal models","volume":"73","author":"Ziyan","year":"2007","journal-title":"Planta Med."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/23\/5631\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:41:24Z","timestamp":1760114484000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/23\/5631"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,28]]},"references-count":42,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["molecules29235631"],"URL":"https:\/\/doi.org\/10.3390\/molecules29235631","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2024,11,28]]}}}