7 research outputs found
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<sup>+</sup>Br<sup>–</sup>)·0.5H<sub>2</sub>O], 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<sup>+</sup>Cl<sup>–</sup>)·0.5H<sub>2</sub>O, 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><sub>a</sub> 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><sub>a</sub> = 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>2<sub>1</sub>/<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