Reversible Solid-State Hydration/Dehydration of Paroxetine HBr Hemihydrate: Structural and Thermochemical Studies

For active pharmaceutical ingredients (API) in the solid state, the occurrence of hydration/dehydration phase transitions may have implications upon the efficiency of the pharmaceutical product, once they are often accompanied by changes of physicochemical properties. Thus, it is important for pharmaceutical research and development to investigate these mechanisms based on the crystal structures of the API. In this work, beyond the structural characterization of a new salt of the antidepressant drug Paroxetine [an HBr hemihydrate, (PRX⁺Br^–)·0.5H₂O], by single crystal X-ray diffraction (SXRD), thermal analysis (DSC/TGA), and hot stage microscopy (HSM), we were able to perform a complete investigation toward the reversible hydration/dehydration solid phase transitions occurring for this salt. In addition, solubility measurements for the anhydrous and hemihydrate solid forms of the new salt are compared with those of its isostructural hydrochloride hemihydrate salt, (PRX⁺Cl^–)·0.5H₂O, for which hydration/dehydration processes are still not completely understood due to structure instability after dehydration

Cocrystal polymorphs and solvates of the anti-Trypanosoma cruzi drug benznidazole with improved dissolution performance

Benznidazole, the primary drug used in Chagas’ disease treatment, has known side effects, which may limit its widespread use. Its low solubility could negatively interfere in the bioavailability, even accentuating the toxic effects. Cocrystals have been extensively used to modify and optimize physicochemical properties, but, as single-component raw materials, they are susceptible to the phenomenon of polymorphism. In this work, we report a trimorphic cocrystal containing a 1:1 ratio of benznidazole and salicylic acid. The crystalline structures of three polymorphs were elucidated by single-crystal X-ray diffraction. Moreover, several isostructural solvates were also synthesized and analyzed. The same carboxylic acid-imidazole supramolecular heterosynthon is present in the four forms, but the main structural feature is an extended column based on amide-amide hydrogen bonds. Based on the crystalline structures, the trimorphic system was classified as conformational and packing polymorphism. Furthermore, the dissolution profiles of the stable forms were determined and shown a significant solubility improvement over the raw material

The Continuum in 5‑Fluorocytosine. Toward Salt Formation

5-Fluorocytosine (5-FC) was crystallized with complementary dicarboxylic acids, aiming to achieve a controlled synthesis of structures based on the Δp<i>K</i>_a rule proposed in the salt–cocrystal continuum study and to provide structural information helpful in the comprehension of its supramolecularity. Although 5-FC tends to be basic, p<i>K</i>_a = 3.26, only three salts are reported. In this way, new 5-FC salts were obtained, the fumaric, maleic and oxalic ones, all crystallizing in the monoclinic space group <i>P</i>2₁/<i>c</i>. In the 5-FC oxalate and fumarate cases, the acid molecules are placed on an inversion center in a fashion that each half molecule exhibits one terminal donor–acceptor site, leading to the constitution of a 5-FC–acid–5-FC heterodimer. Such a heterodimer is observed in only one donor–acceptor site of the maleate of 5-FC, whose acid molecule exhibits a closed chain architecture. Infrared and Raman spectra recorded for the three compounds complement the salt characterization on the basis of the extent of proton transfer. Thermal analysis evidence that the salt formation decreases the melting point of the new compounds, ranking this molecule as a coformer candidate to improve the physical properties of other drugs

Furosemide:Triethanolamine Salt as a Strategy To Improve the Biopharmaceutical Properties and Photostability of the Drug

With the purpose of enhancing the biopharmaceutical properties of the furosemide, a pharmaceutical salt was obtained and characterized by combining the drug and triethanolamine. The solid system was prepared using different techniques such as kneading, grinding, and slow evaporation. It was characterizated by X-ray powder diffraction, solid-state nuclear magnetic resonance, infrared and Raman spectroscopy, thermal analysis, and scanning electron microscopy. The results showed that the same pharmaceutical compound in solid state was obtained through the different preparation techniques. The crystalline structure was fully elucidated by single-crystal X-ray diffraction. The salt formation was confirmed by two-dimensional nuclear magnetic resonance experiments, which revealed the transference of the OH proton of the drug to triethanolamine. Besides, the solubility studies demonstrated an increase in the drug solubility attributed not only to a pH change but also to a soluble salt formation in solution. In addition, the combination of the drug with triethanolamine produces an enhancement of the chemical photostability, whereas the physical photostability and the hygroscopicity status were not modified. Finally, this new solid form of furosemide constitutes an interesting strategy to improve the biopharmaceutical properties and stability of furosemide, with potential application in pharmaceutical formulations

Temperature-Driven Isosymmetric Reversible Phase Transition of the Hormone Estradiol 17β Valerate

The hormone estradiol 17β valerate (E2V), used in hormone replacement therapy, undergoes a structural phase transition at 251.1 K on cooling. The crystalline structures of the low and room temperature phases were determined showing that neither the space group nor the site symmetry and number of atoms are altered. These phases are related by a large conformational reorientation of the valerate chain. In addition, thermal analysis, solid state nuclear magnetic resonance, and infrared spectroscopy show that the transformation is reversible, discontinuous, and first order, evidencing the occurrence of an isosymmetric phase transition, rare for organic compounds

The Effect of High Pressure on Polymorphs of a Derivative of Blatter’s Radical: Identification of the Structural Signatures of Subtle Phase Transitions

The effect of pressure on the α and β polymorphs of a derivative of Blatter’s radical, 3-phenyl-1-(pyrid-2-yl)-1,4-dihydrobenzo[e][1,2,4]triazin-4-yl, has been investigated using single-crystal X-ray diffraction to maximum pressures of 5.76 and 7.42 GPa, respectively. The most compressible crystallographic direction in both structures lies parallel to π-stacking interactions, which semiempirical Pixel calculations indicate are also the strongest interactions present. The mechanism of compression in perpendicular directions is determined by void distributions. Discontinuities in the vibrational frequencies observed in Raman spectra measured between ambient pressure and ∼5.5 GPa show that both polymorphs undergo phase transitions, the α phase at 0.8 GPa and the β phase at 2.1 GPa. The structural signatures of the transitions, which signal the onset of compression of initially more rigid intermolecular contacts, were identified from the trends in the occupied and unoccupied volumes of the unit cell with pressure and in the case of the β phase by deviations from an ideal model of compression defined by Birch–Murnaghan equations of state

The Effect of High Pressure on Polymorphs of a Derivative of Blatter’s Radical: Identification of the Structural Signatures of Subtle Phase Transitions

The effect of pressure on the α and β polymorphs of a derivative of Blatter’s radical, 3-phenyl-1-(pyrid-2-yl)-1,4-dihydrobenzo[e][1,2,4]triazin-4-yl, has been investigated using single-crystal X-ray diffraction to maximum pressures of 5.76 and 7.42 GPa, respectively. The most compressible crystallographic direction in both structures lies parallel to π-stacking interactions, which semiempirical Pixel calculations indicate are also the strongest interactions present. The mechanism of compression in perpendicular directions is determined by void distributions. Discontinuities in the vibrational frequencies observed in Raman spectra measured between ambient pressure and ∼5.5 GPa show that both polymorphs undergo phase transitions, the α phase at 0.8 GPa and the β phase at 2.1 GPa. The structural signatures of the transitions, which signal the onset of compression of initially more rigid intermolecular contacts, were identified from the trends in the occupied and unoccupied volumes of the unit cell with pressure and in the case of the β phase by deviations from an ideal model of compression defined by Birch–Murnaghan equations of state