Acridine-Sulphonamide Compounds as Wound Antiseptics Clinical Trials of Flavazole

This work demonstrates how the thermodynamics of cocrystal formation from the pure, solid coformers can be directly determined from experimentally obtained calorimetric data, without involving solubility data or approximations of ideal solution. For the 1:1 cocrystal between the drug API sulfamethazine and salicylic acid, the melting temperatures and associated enthalpies of fusion have been determined for the coformers in their respective pure solid state and as an equimolar physical mixture and for the cocrystal, using differential scanning calorimetry. Heat capacities have been determined for the respective solid forms and their supercooled melts. The Gibbs energy for cocrystal formation and the enthalpic and entropic components have been determined as functions of temperature through a thermodynamic cycle. The Gibbs energy, enthalpy, and entropy of mixing have been estimated from the thermodynamic functions for cocrystal formation and fusion of the solid phases. The results show that the Gibbs energy for cocrystal formation is negative, i.e. the cocrystal is the stable solid phase in relation to a 1:1 mixture of the coformers throughout the temperature interval from room temperature to the cocrystal melting point, and becomes increasingly negative with increasing temperature. Cocrystal formation is an endothermic process, driven by the favorable entropy increase, and is accompanied by a 6% increase in molecular volume. At room temperature, liquid mixing of coformers is found to be weakly exothermic. The results qualitatively align with a previously reported analysis based on solubility data.

Section: Introductionmentioning

confidence: 99%

Calorimetric Determination of Cocrystal Thermodynamic Stability: Sulfamethazine–Salicylic Acid Case Study

Svärd

Ahuja

Rasmuson

2020

“…Sulfathiazole (STZ) (Figure ) is a model drug which is known to have at least five polymorphs, forms over 100 solvates and numerous adducts, and has more than 6000 STZ references in SciFinder. − STZ was also part of the first pharmaceutical application of a cocrystal when the 1:1 cocrystal of sulfathiazole and proflavine, branded as flavazole, was used as an antibacterial agent during the Second World War . Thus, it has been extensively investigated as a model system in polymorphism research and as a model cocrystal former. ,,− There are some inconsistencies in the nomenclature of sulfathiazole forms in the literature, and in this study the numbering of the polymorphic forms FI–FV is in accordance with that used by the Cambridge Crystallographic Data Centre (CCDC) …”

Section: Introductionmentioning

confidence: 99%

Mechanochemical Reaction of Sulfathiazole with Carboxylic Acids: Formation of a Cocrystal, a Salt, and Coamorphous Solids

Gniado

Erxleben

et al. 2014

The anhydrous solvent-free mechanochemical reaction of sulfathiazole, STZ, polymorphs I, III, and V with 10 carboxylic acids was monitored by powder X-ray diffraction (PXRD), attenuated total reflectance infrared (ATR-IR), and near-infrared (NIR) spectroscopy. A 1:1 cocrystal was observed with glutaric acid and the strongest acid, oxalic acid, gave a 1:1 salt. A principal components analysis of the glutaric acid NIR data showed that forms I and V proceeded to the cocrystal, but that form III transformed to form IV before cocrystal formation. The oxalic acid salt was formed via complete amorphization. The crystal structures of the cocrystal and the salt were determined. Sulfathiazole comilled with l-tartaric and citric acids gave coamorphous systems that were stable at 10% RH for up to 28 days. Comilling sulfathiazole with dl-malic acid gave mixtures of form V and the amorphous form.

“…SDs are the original class of PAs with an aniline ring covalently attached to a sulfonamide (SO 2 NHR) moiety as a structural core. SDs were the first compounds used to systematically treat and prevent bacterial and microbial infections, while thriving on synergistic effects stemming from a mixture of at least two PAs (e.g., co-trimoxazole: 1:5 mix of sulfamethoxazole and trimethoprim) . Owing to a drive by the field of pharmaceutics to investigate how intermolecular interactions between drug molecules dictate therapeutic efficacy, novel solid forms of SDs merit consideration to develop pharmaceutical co-crystals …”

Section: Introductionmentioning

confidence: 99%

Supramolecular Complexes of Sulfadiazine and Pyridines: Reconfigurable Exteriors and Chameleon-like Behavior of Tautomers at the Co-Crystal–Salt Boundary

Elacqua

Bučar

Henry

et al. 2012

We apply crystal engineering principles to prepare organic cocrystals and salts of sulfadiazine and pyridines. Pyridines are molecular building blocks utilized in crystal engineering that can disrupt the hydrogen bonded (amidine) N−H•••N (pyrimidine) dimer within the parent sulfa drug (SD) crystals, while providing access to both co-crystals and salts. We have synthesized four co-crystals and three salts of sulfadiazine involving N,N-dimethyl-4aminopyridine, 4-aminopyridine, 4-picoline, 4,4′-bipyridine, (E)-1,2-bis(4pyridyl)ethylene, 1,2-bis( 4-pyridyl)acetylene, and 4-(pyridin-4-yl)piperazine. Single-crystal X-ray analyses reveal three hydrogen-bond motifs, namely, dyads, rings, and chains based involving either (amidine/aniline) N−H•••N (pyridine/ pyrimidine), (pyridinium) + N−H•••N − (amidide), (aniline/piperazine) N− H•••O 2 S (sulfoxide) interactions, or a combination thereof. The hydrogen-bond motifs are assigned as D 1 1 (2), R 2 2 (8), R 2 2 (20), C 2 2 (17), and C 2 2 (13) graph sets. An analysis of the Cambridge Structural Database (CSD) reveals that the S−N bond length is generally shorter in complexes based on an anionic SD, which is consistent with the sulfonamide possessing greater S N character. From an analysis of SD-based structures involving our work and the CSD, we present a heretofore not discussed role of tautomers at the co-crystal−salt boundary. Specifically, the ability of tautomeric forms of SDs to display reconfigurable exteriors, and thereby act as chameleons, enables SDs to accommodate different co-formers by assuming different geometries and adopting different regions along the co-crystal−salt boundary.