Lamivudine salts with 1,2-dicarboxylic acids: A new and a rare synthon with double pairing motif fine-tuning their solubility

Abstract

Structures of the anti-HIV drug lamivudine with 1,2-dicarboxylic acids are assembled with in-plane ionic pairs held together by two hydrogen bonds in which the protonated cytosine moiety of the drug acts as donor to both oxygens of the carboxylate motif of the counterion, through a two-point 2-aminopyridinium-carboxylate synthon. Here, we report two lamivudine salts featuring hydrogen bonding donation from cytosine to both carboxylate and carboxyl groups of the 1,2-dicarboxylic acid counterions. Two drug molecules are paired in the plane with the same counterion unit giving rise to a planar trimer and a planar tetramer in the structures of lamivudine hydrogen phthalate hemihydrate and lamivudine hydrogen 4,5-dichlorophthalate, respectively. Furthermore, a new heterosynthon was found in the first salt. This new synthon can be described as a four-point one of two-point 2-aminopyridinium-carboxylate and 2-aminopyridinium-carboxyl synthons fused together. Likewise, the synthon responsible for the assembly of lamivudine hydrogen 4,5-dichlorophthalate is rare in the CSD. It has the 2-aminopyridinium-carboxylate pairing and a bifurcated hydrogen bond involving the hydrogen of the amino group on an opposite side relative to the imine proton and both carboxyl oxygens. In addition, water solubility of both lamivudine salts prepared here and of known ones, namely, lamivudine hydrogen phthalate and lamivudine salicylate monohydrate, were determined in this study. All were less soluble than the lamivudine form II (free base). Such solubility behavior appears to be related to the lipophilicity of the counterions. Moreover, the unexpected heterosynthons play a fine-tuning role in the slightly higher solubility of lamivudine hydrogen phthalate hemihydrate and lamivudine hydrogen 4,5-dichlorophthalate when compared to the antecedent salts.