Structures of human plasma β–factor XIIa cocrystallized with potent inhibitors

Key Points The first crystal structure of human plasma β-FXIIa in its active state is presented. The conformational lability of FXIIa is discussed. These novel structural data provide molecular insight into β-FXIIa interaction with its substrates and inhibitors.

A new solvate of furosemide with dimethylacetamide

The loop diuretic furosemide is used widely in the treatment of congestive heart failure and edema, and is practically insoluble in water. The physicochemical and pharmacokinetic properties of drugs can be modified by preparing the drug in an appropriate solid-state form. A new solvate of furosemide with dimethylacetamide (DMA) {systematic name: 4-chloro-2-[(furan-2-yl)methylamino]-5-sulfamoylbenzoic acidN,N-dimethylacetamide disolvate}, C12H11ClN2O5S·2C4H9NO, (I), is reported. The channeled structure formed on slow crystallization contains DMA solvent molecules in its channels. This structure adds to the evidence of varied conformations observed across all known structures, so supporting the idea that this flexible molecule has conformational lability. The current structure also differs from those of other previously known furosemide solvates in the number of solvent molecules per furosemide molecule,viz. 2:1 instead of 1:1. Desolvation of (I) gives the most stable form of furosemide,i.e.Form I.

Chirality sensing and discrimination of lysine derivatives in water with a dyn[4]arene

For sensing purposes, we took advantage of the conformational lability of a dyn[4]arene receptor for the generation of induced circular dichroism outputs in the presence of various lysine derivatives.

[1,1-(η2-dppe)-3-(NC5H5)-closo-1,2-RhSB9H8]: conformational lability and reactivity with H2 upon protonation

The {SB9H8(NC5H5)}-to-{Rh(dppe)} linkage is labilized upon protonation leading to a closo ↔ nido tautomerism; non-rigidity and higher Lewis acidity, induced by the proton, make possible the H2 activation on the cationic rhodathiaborane.

Furosemide solvates: can they serve as precursors to different polymorphs?

The importance of polymorphism of molecular crystals is hard to overestimate, especially when dealing with compounds used as materials or drugs. Different polymorphs of a drug substance may have different properties related to their manufacturing, therapeutic usage, or storage (density, hygroscopicity, melting points, thermal stability, solubility, rate of dissolution, surface free energy, toxicity, bioavailability, tabletting, etc.). Different polymorphs, solvates, and co-crystals can be patented, and this opens the way for a competition with brand drugs. Since the energies of different polymorphs are sometimes very close, producing desirable crystalline forms is quite a challenge and can also be complicated by the phenomena of concomitant polymorphism (when several polymorphs crystallize simultaneously from the same batch), or erratic and poorly reproducible (when crystallization gives different polymorphs even at seemingly identical experimental conditions). The aim of the present study was to crystallize various solvates of furosemide, to check whether these solvates can be used as precursors for producing different polymorphs of pure furosemide on their subsequent decomposition upon heating, and to search any correlation between the crystal structures of the solvates and on the furosemide polymorphs produced by desolvation. Four solvates of furosemide with tetrahydrofuran, dioxane, dimethylformamide, and dimethylsulfoxide were crystallized. The detailed structural analysis of furosemide-containing crystal structures showed that the molecule of furosemide has a high conformational lability because of the rotations of the sulfamoyl and furanylmethylamino fragments. Some of the furosemide conformations were shown to be stabilized by the intramolecular N–H···Cl H-bond. Desolvation of the four solvates was studied by TG and X-ray diffraction and was shown to give different products depending on the precursor and particle size.