title: Improving lithium therapeutics by crystal engineering of novel ionic cocrystals.
abstract: Current United States Food and Drug Administration (FDA)-approved lithium salts are plagued with a narrow therapeutic window. Recent attempts to find alternative drugs have identified new chemical entities, but lithium's polypharmacological mechanisms for treating neuropsychiatric disorders are highly debated and are not yet matched. Thus, re-engineering current lithium solid forms in order to optimize performance represents a low cost and low risk approach to the desired therapeutic outcome. In this contribution, we employed a crystal engineering strategy to synthesize the first ionic cocrystals (ICCs) of lithium salts with organic anions. We are unaware of any previous studies that have assessed the biological efficacy of any ICCs, and encouragingly we found that the new speciation did not negatively affect established bioactivities of lithium. We also observed that lithium ICCs exhibit modulated pharmacokinetics compared to lithium carbonate. Indeed, the studies detailed herein represent an important advancement in a crystal engineering approach to a new generation of lithium therapeutics.
authors.affiliation: Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida , Tampa, Florida 33612, United States.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Smith
authors.forename: Seol-Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Naga K
authors.initials: NK
authors.lastname: Duggirala
authors.forename: Jingji
authors.initials: J
authors.lastname: Jin
authors.forename: Lukasz
authors.initials: L
authors.lastname: Wojtas
authors.forename: Jared
authors.initials: J
authors.lastname: Ehrhart
authors.forename: Brian
authors.initials: B
authors.lastname: Giunta
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zaworotko
authors.forename: R Douglas
authors.initials: RD
authors.lastname: Shytle
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007477:Ions / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008094:Lithium / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D007477:Ions; D009569:Nitric Oxide; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3