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.

Vibrational and thermal analyses of multicomponent crystal forms of the anti-HIV drugs lamivudine and zalcitabine

“…The solutions kept upon standing up to complete solvent matrix evaporation were prepared by dissolution of lamivudine (or zalcitabine in 5) either in isopropyl alcohol (1,(3)(4)(5) or directly in a 0.28 mol L −1 solution of hydrochloric acid in water (2). Except for the preparation of 2, a next step consisted of addition of another aqueous solution of either 0.28 mol L −1 hydrochloric acid only (1 and 5) or both 0.28 mol L −1 hydrochloric acid and 0.04 mol L −1 maleic acid (3).…”

A second monoclinic polymorph of caesium salicylate monohydrate

“…4 (4) ], comparing with À168.2 (3) in polymorph 1 and 179.3 (1) in the structure of the parent salicylic acid (Munshi & Guru Row, 2006). In all of the salicylate structures, including those of the anhydrous Li salt (Smith et al, 2013), the Li monohydrate salt (Wiesbrock & Schmidbaur, 2003b) and the K and Rb salt (Dinnebier et al, 2002) or salt adducts (Downie & Speakman, 1953), a short intramolecular phenolic O-HÁ Á ÁO carboxyl hydrogen bond is present. Symmetry codes: (i) x; y; z þ 1; (ii) x À 1; y; z þ 1; (iii) Àx þ 1; Ày þ 1; Àz þ 1.…”

Physical Stability Enhancement and Pharmacokinetics of a Lithium Ionic Cocrystal with Glucose

“…Even more recently, we reported the first organic anion (B -= salicylate and nicotinate) lithium ICCs with Lproline as a coformer. 29 Moreover, we reported that the blood and brain pharmacokinetics (PK) of one ICC, that of lithium salicylate and proline (LISPRO), are drastically different than the most commonly prescribed FDA approved lithium salt, lithium carbonate, in rats. Importantly, 6 we also demonstrated that this new speciation of lithium did not negatively affect the bioactivity of lithium in clinically relevant in vitro models.…”