{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T03:01:50Z","timestamp":1781060510734,"version":"3.54.1"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004312","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Salt selection is critical in pharmaceutical development. Glutaric acid, an endogenous dicarboxylic acid, offers potential advantages as a counterion but is underexplored in pharmaceutical applications. The nonclinical safety of glutaric acid as a pharmaceutical counterion was assessed using LY3972406 hemi-glutarate hemi-hydrate (HG) as a model, with direct comparison to the LY3972406-hydrochloride (HCl) salt. Comprehensive safety assessments included genetic toxicology (Ames, in vitro and in vivo micronucleus tests), hazard evaluation (phototoxicity, and dermal and corneal irritation), and repeat-dose toxicity studies in rats and dogs. Comparative studies evaluated LY3972406-HCl versus LY3972406-HG, and chronic studies assessed glutaric acid alone and as part of the LY3972406-HG salt. Glutaric acid was nongenotoxic. LY3972406-HG showed no phototoxicity and only mild, nonadverse dermal and ocular irritation in hazard assessments. Glutaric acid was well-tolerated by rats and dogs in repeat-dose toxicity studies, with no treatment-related adverse effects. When LY3972406-HG was administered at glutaric acid equivalent doses up to 31\u2009mg\/kg\/d, all findings were nonadverse, and likely attributable to the active pharmaceutical ingredient LY3972406. Glutaric acid demonstrates a favorable nonclinical safety profile with no genotoxicity and was tolerated at up to 40\u2009mg\/kg\/d in chronic toxicity studies. Direct comparison with HCl salt confirmed equivalent safety and exposure profiles, supporting glutaric acid as a viable alternative to HCl in pharmaceutical development. Glutaric acid is a promising pharmaceutical counterion that lacks regulatory safety data. This first comprehensive Good Laboratory Practice-compliant nonclinical safety evaluation supports the viability of glutaric acid as an alternative pharmaceutical counterion to hydrochloride salts in drug development.<\/jats:p>","DOI":"10.1093\/toxsci\/kfag059","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T11:33:13Z","timestamp":1779190393000},"source":"Crossref","is-referenced-by-count":0,"title":["Safety evaluation of glutaric acid as a novel pharmaceutical salt for first-in-human dosing"],"prefix":"10.1093","volume":"209","author":[{"given":"Kelle M","family":"Franklin","sequence":"first","affiliation":[{"name":"Department of Toxicology\/Pathology, Eli Lilly and Company , Indianapolis, IN 46285,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahamat","family":"Aboulmali","sequence":"additional","affiliation":[{"name":"Department of Toxicology\/Pathology, Eli Lilly and Company , Indianapolis, IN 46285,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"2026060922561271900_kfag059-B1","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1021\/op000018u","article-title":"Salt selection and optimisation procedures for pharmaceutical new chemical entities","volume":"4","author":"Bastin","year":"2000","journal-title":"Org Process Res Dev"},{"key":"2026060922561271900_kfag059-B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/jps.2600660104","article-title":"Pharmaceutical salts","volume":"66","author":"Berge","year":"1977","journal-title":"J Pharm Sci"},{"key":"2026060922561271900_kfag059-B3","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1177\/01926233221129233","article-title":"Extraintestinal pathogenic Escherichia coli causes necrohemorrhagic pneumonia in multiple research dogs","volume":"50","author":"Coe","year":"2022","journal-title":"Toxicol Pathol"},{"key":"2026060922561271900_kfag059-B4","first-page":"49","volume-title":"Appraisal of the Safety of Chemicals in Food, Drugs and Cosmetics (Editorial Committee, ed.)","author":"Draize","year":"1959"},{"key":"2026060922561271900_kfag059-B5","doi-asserted-by":"publisher","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":"2026060922561271900_kfag059-B6","volume-title":"Registration dossier: glutaric acid (CAS No. 110-94-1)","author":"European Chemicals Agency (ECHA)","year":"2022"},{"key":"2026060922561271900_kfag059-B7","volume-title":"Registration dossier: adipic acid (CAS No. 124-04-9)","author":"European Chemicals Agency (ECHA)","year":"2022"},{"key":"2026060922561271900_kfag059-B8","volume-title":"Glutaric acid (CAS No. 110-94-1)","author":"GESTIS International Limit Values","year":"2022"},{"key":"2026060922561271900_kfag059-B9","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/0378-5173(86)90055-4","article-title":"Salt selection for basic drugs","volume":"33","author":"Gould","year":"1986","journal-title":"Int J Pharm"},{"key":"2026060922561271900_kfag059-B10","doi-asserted-by":"publisher","DOI":"10.34865\/mb11094e5_3or","volume-title":"MAK value documentation \u2013 translation of the German version from 2019. 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