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PURPOSE: The purpose of the present study was to investigate the dissolution profiles of cocrystals with cis-trans isomeric coformers. Previously, the carbamazepine (CBZ) cocrystals with even-carbon dicarboxylic acids showed higher supersaturation than those with odd-carbon ones, attributed to particle surface solution-mediated phase transformation (PS-SMPT) to CBZ dihydrate (CBZ DH). However, it has been unknown whether this odd-even pattern holds for cis-trans isomeric coformers. METHOD: CBZ cocrystals with maleic acid (MLE) and fumaric acid (FUM) (CBZ-FUM anhydrate (CBZ-FUM AH) and monohydrate (CBZ-FUM H2O)) were employed as model cocrystals. Hydroxypropylãmethylcellulose (HPMC), polyvinylpyrrolidone, and polyethylene glycol 6000 (PEG) were used as precipitation inhibitors. Dissolution tests were performed under a non-sink condition. Residual particles were analyzed by powder X-ray diffraction, differential scanning calorimetry, polarized light microscope, and scanning electron microscope. RESULTS: All cocrystals showed little supersaturation in the absence of a polymer. In 0.1% HPMC, CBZ-FUM AH showed significant supersaturation, whereas CBZ-MLE and CBZ-FUM H2O did not for the first two hours. HPMC reduced the initial dissolution rate of CBZ-MLE and CBZ-FUM H2O while inducing the highest supersaturation among the polymers after 96 h. The particle surface changed from a smooth plane to a striped pattern, but little or no CBZ DH was detected. CONCLUSION: The cocrystals with cis-trans isomeric coformers showed different dissolution profiles. HPMC increased the dissolution rate of CBZ-FUM AH by inhibiting PS-SMPT but reduced the dissolution rate of CBZ-MLE and CBZ-FUM H2O without inducing PS-SMPT. The striped pattern was suggested to be due to surface etching rather than PS-SMPT.
Assuntos
Carbamazepina , Polímeros , Solubilidade , Cristalização , Carbamazepina/química , Difração de Raios X , Derivados da Hipromelose/química , Varredura Diferencial de CalorimetriaRESUMO
In the asymmetric unit of the title compound, [CrF2(C5H5N)4][ZnCl3(C5H5N)]·H2O, there are two independent complex cations, one tri-chlorido-(pyridine-κN)zincate anion and one solvent water mol-ecule. The cations lie on inversion centers. The Cr(III) ions are coordinated by four pyridine (py) N atoms in the equatorial plane and two F atoms in a trans axial arrangement, displaying a slightly distorted octa-hedral geometry. The Cr-N(py) bond lengths are in the range 2.0873â (14) to 2.0926â (17)â Å while the Cr-F bond lengths are 1.8609â (10) and 1.8645â (10)â Å. The [ZnCl3(C5H5N)](-) anion has a distorted tetra-hedral geometry. The Cl atoms of the anion were refined as disordered over two sets of sites in a 0.631â (9):0.369â (9) ratio. In the crystal, two anions and two water mol-ecules are linked via O-Hâ¯Cl hydrogen bonds, forming centrosymmetric aggregates. In addition, weak C-Hâ¯Cl, C-Hâ¯π and π-π stacking inter-actions [centroid-centroid distances = 3.712â (2) and 3.780â (2)Å] link the components of the structure into a three-dimensional network.
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Reversed-phase liquid chromatography (RPLC) is the analytical tool of choice for monitoring process-related organic impurities and degradants in pharmaceutical materials. Its popularity is due to its general ease-of-use, high performance, and reproducibility in most cases, all of which have improved as the technique has matured over the past few decades. Nevertheless, in our work we still occasionally observe situations where RPLC methods are not as robust as we would like them to be in practice due to variations in stationary phase chemistry between manufactured batches (i.e., lot-to-lot variability), and changes in stationary phase chemistry over time. Over the last three decades several models of RPLC selectivity have been developed and used to quantify and rationalize the effects of numerous parameters (e.g., effect of bonded phase density) on separation selectivity. The Hydrophobic Subtraction Model (HSM) of RPLC selectivity has been used extensively for these purposes; currently the publicly available database of column parameters contains data for 750 columns. In this work we explored the possibility that the HSM could be used to better understand the chemical basis of observed differences in stationary phase selectivity when they occur - for example, lot-to-lot variations or changes in selectivity during column use. We focused our attention on differences and changes in the observed selectivity for a pair of cis-trans isomers of a pharmaceutical intermediate. Although this is admittedly a challenging case, we find that the observed changes in selectivity are not strongly correlated with HSM column parameters, suggesting that there is a gap in the information provided by the HSM with respect to cis-trans isomer selectivity specifically. Further work with additional probe molecules showed that larger changes in cis-trans isomer selectivity were observed for pairs of molecules with greater molecular complexity, compared to the selectivity changes observed for simpler molecules. These results do not provide definitive answers to questions about the chemical basis of changes in stationary phase chemistry that lead to observed differences in cis-trans isomer selectivity. However, the results do provide important insights about the critical importance of molecular complexity when choosing probe compounds and indicate opportunities to develop improved selectivity models with increased sensitivity for cis-trans isomer selectivity.
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Cromatografia de Fase Reversa , Comércio , Reprodutibilidade dos Testes , Bases de Dados Factuais , Preparações FarmacêuticasRESUMO
The structure of the title compound, [CrCl2(C10H24N4)][Cr(HCONH2)2(C10H24N4)][ZnCl4]2 (C10H24N4 = 1,4,8,11-tetra-aza-cyclo-tetra-decane, cyclam; HCONH2 = formamide, fa), has been determined from synchrotron X-ray data. The asymmetric unit contains two independent halves of the [CrCl2(cyclam)]+ and [Cr(fa)(cyclam)]3+ cations, and one tetra-chlorido-zincate anion. In each complex cation, the CrIII ion is coordinated by the four N atoms of the cyclam ligand in the equatorial plane and two Cl ligands or two O-bonded formamide mol-ecules in a trans axial arrangement, displaying a distorted octa-hedral geometry with crystallographic inversion symmetry. The Cr-N(cyclam) bond lengths are in the range 2.061â (2) to 2.074â (2)â Å, while the Cr-Cl and Cr-O(fa) bond distances are 2.3194â (7) and 1.9953â (19)â Å, respectively. The macrocyclic cyclam moieties adopt the centrosymmetric trans-III conformation with six- and five-membered chelate rings in chair and gauche conformations. The crystal structure is stabilized by inter-molecular hydrogen bonds involving the NH or CH groups of cyclam and the NH2 group of coordinated formamide as donors, and Cl atoms of the ZnCl4 2- anion as acceptors.
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We investigate and report on the kinematics of photoisomerization processes of polymer composite thin films based on azo dye methyl red (MR) hosted in polymethylmethacrylate (PMMA) incorporated with Benzyl dimethyl ketal (BDK) as a photo-initiator. Understanding photoisomerization mechanisms is crucial for several optical applications such as Read/Write/Erase (WRE) optical data storage media, UV light Read/Write heads, and UV light sensors. The as-prepared polymer composite thin films are characterized using UV-Vis spectroscopy. Furthermore, Fourier transform infrared spectroscopy (FTIR) and scanning electron microscope (SEM) are employed to investigate the optical, chemical, and morphological properties of trans- and cis-states of PMMA-BDK-MR polymer composite thin films. The presence of the azo dye MR in the composite is essential for the efficient performance of the cis â trans cycles through illumination â thermal relaxation for Write/Read/Erase optical data storage and UV-light sensors. Moreover, UV-Vis and FTIR results confirm the hysteresis cycle of trans- and cis-states and that PMMA-BDK-MR thin films may be regarded as potential candidates for successful Write/Read/Erase optical data storage and UV-light sensors. In addition, the morphology of the thin film surface is investigated by SEM technique. The SEM images indicate that uncured surfaces of PMMA-BDK-MR thin films are inhomogeneous compared with the corresponding surfaces after curing. The transformation from inhomogeneous surfaces to homogeneous surfaces is attributed to the polymerization of thin films by UV curing.
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The NADPH oxidase NOX2 complex consists of assembled cytosolic and redox membrane proteins. In mammalian cells, natural arachidonic acid (cis-AA), released by activated phospholipase-A2, plays an important role in the activation of the NADPH oxidase, but the mechanism of action of cis-AA is still a matter of debate. In cell-free systems, cis-AA is commonly used for activation although its structural effects are still unclear. Undoubtedly cis-AA participates in the synergistic multi-partner assembly that can be hardly studied at the molecular level in vivo due to cellular complexity. The capacity of this anionic amphiphilic fatty acid to activate the oxidase is mainly explained by its ability to disrupt intramolecular bonds, mimicking phosphorylation events in cell signaling and therefore allowing protein-protein interactions. Interestingly the geometric isomerism of the fatty acid and its purity are crucial for optimal superoxide production in cell-free assays. Indeed, optimal NADPH oxidase assembly was hampered by the substitution of the cis form by the trans forms of AA isomers (Souabni et al., BBA-Biomembranes 1818:2314-2324, 2012). Structural analysis of the changes induced by these two compounds, by circular dichroism and by biochemical methods, revealed differences in the interaction between subunits. We describe how the specific geometry of AA plays an important role in the activation of the NOX2 complex.
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Ácido Araquidônico/metabolismo , NADPH Oxidases/metabolismo , Fagócitos/enzimologia , Ácido Araquidônico/química , Fracionamento Celular , Membrana Celular/enzimologia , Membrana Celular/metabolismo , Sistema Livre de Células , Colorimetria , Ativação Enzimática , Isomerismo , Estrutura Molecular , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/química , NADPH Oxidases/isolamento & purificação , Neutrófilos/enzimologia , Fagócitos/imunologia , Proteínas Recombinantes de Fusão , Análise EspectralRESUMO
The structure of the title compound, [Cr(NCS)2(C2H8N2)2]2[ZnCl4], has been determined from synchrotron data. In the asymmetric unit, there are four independent halves of the Cr(III) complex cations, each of which lies on an inversion centre, and one tetra-chlorido-zincate anion in a general position. The Cr(III) atoms are coordinated by the four N atoms of two ethane-1,2-di-amine (en) ligands in the equatorial plane and two N-bound NCS(-) anions in a trans arrangement, displaying a slightly distorted octa-hedral geometry with crystallographic inversion symmetry. The Cr-N(en) and Cr-N(NCS) bond lengths range from 2.0653â (10) to 2.0837â (10)â Å and from 1.9811â (10) to 1.9890â (10)â Å, respectively. The five-membered metalla-rings are in stable gauche conformations. The [ZnCl4](2-) anion has a distorted tetra-hedral geometry. The crystal structure is stabilized by inter-molecular hydrogen bonds involving the en NH2 or CH2 groups as donors and chloride ligands of the anion and S atoms of NCS(-) ligands as acceptors.
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The cis-isomer of methyl orange (MO), stabilized in cationic premicelles, has been found to be fluorescence active when excited at wavelength ≤270nm. An intense fluorescence band with maximum at 575nm along with a broad moderate intensity band in the range of 370-530nm and a low intensity band at 361nm have been observed. The major band at 575nm has been attributed to S1âS0 (n-π(*)) fluorescence unlike the other azobenzenes where the S2âS0 (π-π(*)) fluorescence is usually reported. UV-Vis spectral and surface tension study indicate that the dye exists in the trans form in dye-surfactant ionpair (DSIP) at very dilute concentrations of the surfactant. But the polar cis-isomer is stabilized by micellization of the DSIPs as the concentration of the surfactant is increased. The fluorescence and hence the cis-isomer again disappear when normal micelles are formed above the normal CMC of the surfactant. It has been suggested that the symmetry forbidden S1âS0 (n-π(*)) transition of MO becomes allowed due to the formation of the twisted cis-form. TD-DFT calculations have been used as an auxiliary tool to identify the possible structures and electronic transitions responsible for the specific absorption and fluorescence properties of MO observed in presence of premicellar cationic surfactants.
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Compostos Azo/química , Corantes Fluorescentes/química , Micelas , Cátions/química , Fluorescência , Isomerismo , Modelos Moleculares , Tensoativos/químicaRESUMO
Objective Chiral recognition for the glimepiride and glimepiride-cis-isomer by applying three amino acid (D-Lysine,L-Glutamine and L-Tyrosine) as chiral probes based on electrospray ionization mass spectrometry (ESI-MS) was achieved.Methods glimepiride/glimepiride-cis-isomer solutions were mixed with three amino acid solutions.The complex was extracted by ESI-MS and then the fragmentation abundance was investigated applying collision induced dissociation (CID) by MS/MS,which is the basis of chiral recognition for glimepiride and glimepiride-cis-isomer.Results Chiral recognition effect was achieved with the recognition rate (R) 1.61,2.92 and 2.17 for D-Lysine,L-Glutamine and L-Tyrosine respectively.Conclusion 3 kinds ofchiral amino acids were used as probes to distinguish between stereoisomers,and rapid identification of glimepiride and glimepiride cis isomer by mass spectrometry come true for the first time.