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

ELEONORA FREIRE; GRISELDA POLLA; RICARDO BAGGIO

ACTA CRYSTALLOGRAPHICA SECTION C-CRYSTAL STRUCTURE COMMUNICATIONS

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2016 vol. 72 p. 910 - 916

0108-2701

Lamotrigine is a drug used in the treatment of epilepsy and related convulsivediseases. The drug in its free form is rather inadequate for pharmacological usedue to poor absorption by the patient, which limits its bioavailability. On theother hand, the lamotrigine molecule is an excellent hydrogen-bonding agentand this has been exploited intensively in the search for better formulations. Theformulation presently commercialized (under the brand name Lamictal) israther complex and includes a number of anions in addition to the activepharmaceutical 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+C14H9O4S2H2O, (I), and theanhydrate, C9H8Cl2N5+C14H9O4S2, (II), contain a lamotriginium cation (L),a hydrogen dithiodibenzoate monoanion (D) and, in the case of (I), a disorderedsolvent water molecule. Both L and D present their usual configurationsseverely twisted around their central C?C and S?S bonds, respectively. Thesupramolecular structure generated by the many available donor and acceptorsites is characterized by a planar antisymmetric motif of the form D?L?L?D, i.e.the structural building block. Although this characteristic motif is extremelysimilar in both structures, its conformation involves different donors andacceptors in its R22(8) central L?L homosynthon. The lateral R22(8) D?Lheterosynthons are, on the other hand, identical. These substructures are furtherconnected by strong hydrogen bonds into broad two-dimensional structures, inturn weakly linked to each other. Even if the homo- and heterosynthons in (I)and (II) are rather frequent in lamotrigine structural chemistry, the compositetetrameric synthon appears to be much less common. The occurrence of thesemotifs among lamotrigine salts and cocrystals is analyzed.