Solvatomorph and polymorph screening of clopamide drug and its copper(ii) complex crystals

Abstract

Clopamide ((4-chloro-N-2,6-dimethylpiperidin-1-yl)-3-sulfamoylbenzamide, LH) drug is used worldwide in the treatment of hypertension and oedema. Despite its medical application its structure has not yet been published. We report the crystal structure of clopamide anhydrate and hemihydrate and a structural landscape of different polymorphs and solvatomorphs of its copper(II) complexes. Our main challenge was the growth of single crystals for X-ray diffraction experiments and then the analysis of the molecular arrangements of the pure drug as well as the series of complexes organised by the coordination bond and by different secondary interactions. We present how the inclusion of water contributes to the crystal perfection of the drug crystals (1 and 2). The newly defined chalcogen bond is recognised in the clopamide anhydrate crystals being in competition with an intramolecular halogen bond. All Cu(II) complexes have a square-planar coordination geometry, in which copper(II) centres are surrounded by piperidine-N and carbonyl-O donor atoms in a five-membered chelate ring. The two ligands are in trans positions. The solvatomorph crystals, containing small homologous alcohols (3–6), have been found to be isostructural (P) with increasing size of void and unit cell volumes which terminates using n-butanol. In the solvent-free polymorph [CuL₂] crystals (7–9), the complex molecules form parallel columns strengthened by N–H⋯O interactions between the ligand sulfonamide groups. The arrangement of these columns in 7 (P) is similar to that of the solvate 3 (P), while 8 (P) transitions to 9 (R), where perfect threefold symmetry is realised, although leaving large empty spaces in the lattice. The columnal arrangement is preserved in the crystal containing dichloromethane (10) but the columns are no longer parallel. The solvate content and thermal behaviour of the crystals were studied by IR and thermoanalytical methods. The solution structure of the [CuL₂] complex was investigated in DMSO by EPR spectroscopy at 77 K. These results of the systematic comparison of several polymorphic and solvatomorphic crystal arrangements contribute to the better understanding of the structure-directing effects, which provide strategies to control the molecular self-assembly.