Experimental Electron Density and Neutron Diffraction Studies on the Polymorphs of Sulfathiazole

Abstract

High resolution X-ray diffraction data on forms I–IV of sulfathiazole and neutron diffraction data on forms II–IV have been collected at 100 K and analyzed using the Atoms in Molecules topological approach. The molecular thermal motion as judged by the anisotropic displacement parameters (adp’s) is very similar in all four forms. The adp of the thiazole sulfur atom had the greatest amplitude perpendicular to the five-membered ring, and analysis of the temperature dependence of the adps indicates that this is due to genuine thermal motion rather than a concealed disorder. A minor disorder (∼1–2%) is evident for forms I and II, but a statistical analysis reveals no deleterious effect on the derived multipole populations. The topological analysis reveals an intramolecular S–O···S interaction, which is consistently present in all experimental topologies. Analysis of the gas-phase conformation of the molecule indicates two low-energy theoretical conformers, one of which possesses the same intramolecular S–O···S interaction observed in the experimental studies and the other an S–O···H–N intermolecular interaction. These two interactions appear responsible for “locking” the molecular conformation. The lattice energies of the various polymorphs computed from the experimental multipole populations are highly dependent on the exact refinement model. They are similar in magnitude to theoretically derived lattice energies, but the relatively high estimated errors mean that this method is insufficiently accurate to allow a definitive stability order for the sulfathiazole polymorphs at 0 K to be determined.

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

“…The study of intramolecular interactions is very important in the design of pharmaceutical drugs, particularly in the context of conformationally flexible molecules. Conformation-controlling intramolecular interactions in drug molecules have a direct influence on the binding modes of the drugs with the respective targets [53,54,55]. In particular, intramolecular peri-interactions have been widely studied in the literature in naphthalene and other related systems [56][57][58][59][60].…”

Synthesis, Antimicrobial, and Docking Investigations of Remarkably Modified Sulfathiazole Derivatives

“…Both the amido and the imino tautomeric forms exist in a state of equilibrium in the liquid state, however, the imino tautomer is exclusively found in the solid phase. According to a recent study on the sulfathiazole polymorphism two intramolecular interactions are constantly observed; one between the thiazole sulfur atom (S δ+ ) and an oxygen (O δ− ) in the sulfone group, while the other interaction is attributed to the thiazole ring NH proton with the sulfone oxygen atom in the imino tautomer [29].…”

Oriented Crystallization on Organic Monolayers to Control Concomitant Polymorphism

“…Therefore crystallization of sulfathiazole (SULF) on organic thiol SAMsh as been used to investigate controlled oriented crystallization with polymorph selectivity, and the approachh as been compared to conventional crystallization methodst hat nucleate concomitantp olymorphs. [35] The molecular flexibility of the CÀSÀNb ond ( Figure 2a)a nd possible formation of different supramolecular synthons are the two key reasonsf or concomitant polymorphism of SULF ( Figure 3). SAM surfaces like ÀCOOH, ÀOH, pyridine and benzo-thiazolea re employedt og row crystalso fS ULF from isopropanol under controlled experimental conditions.…”