Crystal structure from X-ray powder diffraction data, DFT-D calculation, Hirshfeld surface analysis, and energy frameworks of (RS)-trichlorme-thia-zide.

Robert A Toro,Analio Dugarte-Dugarte,José Antonio Henao,Jacco Van De Streek,Graciela Díaz De Delgado,José Miguel Delgado

doi:10.1107/s2056989021013633

Abstract

The structure of racemic (RS)-trichlorme-thia-zide [systematic name: (RS)-6-chloro-3-(di-chloro-meth-yl)-1,1-dioxo-3,4-di-hydro-2H-1λ6,2,4-benzo-thia-di-azine-7-sulfonamide], C8H8Cl3N3O4S2 (RS-TCMZ), a diuretic drug used in the treatment of oedema and hypertension, was determined from laboratory X-ray powder diffraction data using DASH [David et al. (2006 ▸). J. Appl. Cryst. 39, 910-915.], refined by the Rietveld method with TOPAS-Academic [Coelho (2018 ▸). J. Appl. Cryst. 51, 210-218], and optimized using DFT-D calculations. The extended structure consists of head-to-tail dimers connected by π-π inter-actions which, in turn, are connected by C-Cl⋯π inter-actions. They form chains propagating along [101], further connected by N-H⋯O hydrogen bonds to produce layers parallel to the ac plane that stack along the b-axis direction, connected by additional N-H⋯O hydrogen bonds. The Hirshfeld surface analysis indicates a major contribution of H⋯O and H⋯Cl inter-actions (32.2 and 21.7%, respectively). Energy framework calculations confirm the major contribution of electrostatic inter-actions (E elec) to the total energy (E tot). A comparison with the structure of S-TCMZ is also presented.

Highlights

Diurese, Metahydrin, Naqua, Triflumen, as well as with the generic trichlormethiazide name
Given our interest in the structure of materials involved in pharmaceutical formulations or with potential pharmaceutical applications, it was decided to undertake the structure determination of the racemic form of this active pharmaceutical ingredient (API)
The refinement of the final structural model using powder diffraction data recorded showed bond distances and angles within the range suggested in the statistical analysis performed with the Mogul geometry check (Bruno et al, 2004)

Summary

Chemical context

Trichlormethiazide (TCMZ), systematic name 6-chloro-3-(dichloromethyl)-1,1-dioxo-3,4-dihydro-2H-16,2,4-benzothiadiazine-7-sulfonamide (C8H8Cl3N3O4S2), is a diuretic drug derived from thiazide, the precursor of a classic family of diuretic compounds, discovered in the 1950s. The difference is the substitution of one hydrogen atom of the methylene group by a CHCl2 dichloromethyl group Thiazide diuretics and their derivatives are primarily used in the treatment of mild to moderate hypertension and oedema associated with Na+ and K+ retention and expansion of the extracellular fluid volume. They increase Ca2+ excretion, a potentially useful effect in patients with hypercalciuria, a condition that could lead to the formation of kidney stones (Mene, 2004). Given our interest in the structure of materials involved in pharmaceutical formulations or with potential pharmaceutical applications, it was decided to undertake the structure determination of the racemic form of this active pharmaceutical ingredient (API)

Structural commentary

Supramolecular features

Database survey

Computational studies

Findings

Spectroscopic and thermal characterization