Hydrogen-bonding synthons in lamotrigine salts: 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazin-2-ium 2-[(2-carboxyphenyl)disulfanyl]benzoate in its monohydrate and anhydrous forms

Abstract

Lamotrigine is a drug used in the treatment of epilepsy and related convulsive diseases. The drug in its free form is rather inadequate for pharmacological use due to poor absorption by the patient, which limits its bioavailability. On the other hand, the lamotrigine molecule is an excellent hydrogen-bonding agent and this has been exploited intensively in the search for better formulations. The formulation presently commercialized (under the brand name Lamictal) is rather complex and includes a number of anions in addition to the active pharmaceutical ingredient (API). The title salts of lamotrigine, namely 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazin-2-ium 2-[(2-carboxyphenyl)disulfanyl]benzoate monohydrate, C9H8Cl2N5+·C14H9O4S2−·H2O, (I), and the anhydrate, C9H8Cl2N5+·C14H9O4S2−, (II), contain a lamotriginium cation (L), a hydrogen dithiodibenzoate monoanion (D) and, in the case of (I), a disordered solvent water molecule. BothLandDpresent their usual configurations severely twisted around their central C—C and S—S bonds, respectively. The supramolecular structure generated by the many available donor and acceptor sites is characterized by a planar antisymmetric motif of the formD–L–L–D,i.e.the structural building block. Although this characteristic motif is extremely similar in both structures, its conformation involves different donors and acceptors in itsR22(8) centralL–Lhomosynthon. The lateralR22(8)D–Lheterosynthons are, on the other hand, identical. These substructures are further connected by strong hydrogen bonds into broad two-dimensional structures, in turn weakly linked to each other. Even if the homo- and heterosynthons in (I) and (II) are rather frequent in lamotrigine structural chemistry, the composite tetrameric synthon appears to be much less common. The occurrence of these motifs among lamotrigine salts and cocrystals is analyzed.