Metal-Organic Framework with Dual Active Sites in Engineered Mesopores for Bioinspired Synergistic Catalysis.

Here we report the design of an enzyme-inspired metal-organic framework (MOF), 1-OTf-Ir, by installing strong Lewis acid and photoredox sites in engineered mesopores. Al-MOF (1), with mixed 2,2'-bipyridyl-5,5-dicarboxylate (dcbpy) and 1,4-benzenediacrylate (pdac) ligands, was oxidized with ozone and then triflated to generate strongly Lewis acidic Al-OTf sites in the mesopores, followed by the installation of [Ir(ppy)2(dcbpy)]+ (ppy = 2-phenylpyridine) sites to afford 1-OTf-Ir with both Lewis acid and photoredox sites. 1-OTf-Ir effectively catalyzed reductive cross-coupling of N-hydroxyphthalimide esters or aryl bromomethyl ketones with vinyl- or alkynyl-azaarenes to afford new azaarene derivatives. 1-OTf-Ir enabled catalytic synthesis of anticholinergic drugs Pheniramine and Chlorpheniramine.

In situ immobilization of sulfated-ß-cyclodextrin as stationary phase for capillary electrochromatography enantioseparation.

In this work, a novel sulfated-ß-cyclodextrin (S-ß-CD) coated stationary phase was prepared for open-tubular capillary electrochromatography (OT-CEC). The capillary was developed by attaching polydopamine/sulfated-ß-cyclodextrin (PDA/S-ß-CD) onto the gold nanoparticles (AuNPs) coated capillary which was pretreated with polydopamine. The results of scanning electron microscopy (SEM) and energy dispersive X-ray analysis spectroscopy (EDS) indicated that polydopamine/sulfated-ß-cyclodextrin was successfully fixed on the gold nanoparticles coated capillary. To evaluate the performance of the prepared open tubular (OT) column, the enantioseparation was carried out by using ten chiral drugs as model analytes. Under the optimal conditions, salbutamol, terbutaline, trantinterol, tulobuterol, clorprenaline, pheniramine, chlorpheniramine, brompheniramine, isoprenaline and tolterodine were baseline separated with the resolution (Rs) values of 3.25, 1.76, 2.51, 1.89, 3.17, 2.17, 1.99, 1.72, 2.01 and 3.20, respectively. Repeatability of the column was studied, with the relative standard deviations for run-to-run, day-to-day and column-to-column lower than 5.7%.

Enantioselective analysis of pheniramine in rat using large volume sample stacking or cation-selective exhaustive injection and sweeping coupled with cyclodextrin modified electrokinetic chromatography.

For the aim of simultaneously performing the enantioseparation and determination of the trace enantiomers in plasma samples, enantioseparation by HPLC using five kinds of chiral stationary phases were initially investigated. But unfortunately, enantioseparation could not be detected in reversed mobile phase mode with all the five columns. For this reason, two simple, economical and highly efficient online preconcentration methods, large volume sample stacking and sweeping (LVSS-sweeping) and cation-selective exhaustive injection and sweeping (CSEI-sweeping) both followed by the cyclodextrin modified electrokinetic chromatography (CDEKC) were examined in the present work. Parameters affecting the enantioseparation and enhancement efficiency of these two injection modes were monitored in detail, and migration order of the two enantiomers was identified by circular dichroism (CD) and HPLC. Upon optimization, two enantiomers were best separated with the improvement of sensitivity reaching 160-fold and 4000-fold respectively for LVSS-sweeping and CSEI-sweeping comparing with the normal CDEKC separation. Then the optimal condition of CSEI-sweeping-CDEKC was validated and showed high sensitivity (10 ng/mL for lower limit of quantification, LLOQ), satisfactory accuracy (96.8-111.6%) and precision (relative standard deviation, RSD within 9.4%). This demonstrated it to be a suitable strategy for the rapid enantioselective determination and quantitative analysis of pheniramine enantiomers in plasma samples. Therefore, the method was further applied in the enantiomeric analysis of pheniramine in rat pharmacokinetics and plasma protein binding investigations. Stereoselectivity in pharmacokinetics as well as plasma protein binding were observed, suggesting that the stereoselective protein binding might be responsible for the stereoselectivity in pharmacokinetics.

Capillary electrophoretic enantioseparation of basic drugs using a new single-isomer cyclodextrin derivative and theoretical study of the chiral recognition mechanism.

A novel single-isomer cyclodextrin derivative, heptakis {2,6-di-O-[3-(1,3-dicarboxyl propylamino)-2-hydroxypropyl]}-ß-cyclodextrin (glutamic acid-ß-cyclodextrin) was synthesized and used as a chiral selector in capillary electrophoresis for the enantioseparation of 12 basic drugs, including terbutaline, clorprenaline, tulobuterol, clenbuterol, procaterol, carvedilol, econazole, miconazole, homatropine methyl bromide, brompheniramine, chlorpheniramine and pheniramine. The primary factors affecting separation efficiency, which include the background electrolyte pH, the concentration of glutamic acid-ß-cyclodextrin and phosphate buffer concentration, were investigated. Satisfactory enantioseparations were obtained using an uncoated fused-silica capillary of 50 cm (effective length 40 cm) × 50 µm id with 120 mM phosphate buffer (pH 2.5-4.0) containing 0.5-4.5 mM glutamic acid-ß-cyclodextrin as background electrolyte. A voltage of 20 kV was applied and the capillary temperature was kept at 20°C. The results proved that glutamic acid-ß-cyclodextrin was an effective chiral selector for studied 12 basic drugs. Moreover, the possible chiral recognition mechanism of brompheniramine, chlorpheniramine and pheniramine on glutamic acid-ß-cyclodextrin was investigated using the semi-empirical Parametric Method 3.

Alternative method for determination of contaminated heparin using chiral recognition.

Since 2008 a significant amount of work has focused on the development of methods to analyze contaminated heparin. This work focuses on utilizing heparin's ability to serve as a chiral selector as a means for determining contamination. Specifically, the effect of contamination on the separation of pheniramine and chloroquine enantiomers was explored. Separations were conducted using heparin contaminated with chondroitin sulfate at varying levels. For each pair of enantiomers, electrophoretic mobility and resolution were calculated. For pheniramine enantiomers, an increase in contamination leads to a decrease in the electrophoretic mobility and resolution. A linear relationship between contamination level and electrophoretic mobility of the pheniramine enantiomers was observed for the entire contamination range. A linear relationship was also found between contamination level and resolution of the enantiomers between 0 and 70 percent contamination. For the separation of chloroquine enantiomers, it was found that at low levels of contamination, the resolution of enantiomers was increased due to the secondary interaction between the chloroquine enantiomers and the chondroitin sulfate. Results of this study illustrate the potential of using chiral recognition as a means to determine heparin contamination as well as the improvement of the chiral resolution of chloroquine with the additional of low levels of chondroitin sulfate A.

Enantiomeric separation and simulation studies of pheniramine, oxybutynin, cetirizine, and brinzolamide chiral drugs on amylose-based columns.

Solid phase extraction (SPE)-chiral separation of the important drugs pheniramine, oxybutynin, cetirizine, and brinzolamide was achieved on the C18 cartridge and AmyCoat (150 x 46 mm) and Chiralpak AD (25 cm x 0.46 cm id) chiral columns in human plasma. Pheniramine, oxybutynin, cetirizine, and brinzolamide were resolved using n-hexane-2-PrOH-DEA (85:15:0.1, v/v), n-hexane-2-PrOH-DEA (80:20:0.1, v/v), n-hexane-2-PrOH-DEA (70:30:0.2, v/v), and n-hexane-2-propanol (90:10, v/v) as mobile phases. The separation was carried out at 25 ± 1 ºC temperature with detection at 225 nm for cetirizine and oxybutynin and 220 nm for pheniramine and brinzolamide. The flow rates of the mobile phases were 0.5 mL min(-1). The retention factors of pheniramine, oxybutynin, cetirizine and brinzolamide were 3.25 and 4.34, 4.76 and 5.64, 6.10 and 6.60, and 1.64 and 2.01, respectively. The separation factors of these drugs were 1.33, 1.18, 1.09 and 1.20 while their resolutions factors were 1.09, 1.45, 1.63 and 1.25, and 1.15, respectively. The absolute configurations of the eluted enantiomers of the reported drugs were determined by simulation studies. It was observed that the order of enantiomers elution of the reported drugs was S-pheniramine > R-pheniramine; R-oxybutynin > S-oxybutynin; S-cetirizine > R-cetirizine; and S-brinzolamide > R-brinzolamide. The mechanism of separation was also determined at the supramolecular level by considering interactions and modeling results. The reported SPE-chiral high-performance liquid chromatography (HPLC) methods are suitable for the enantiomeric analyses of these drugs in any biological sample. In addition, simulation studies may be used to determine the absolute configuration of the first and second eluted enantiomers.

Halogenation effects of pheniramines on the complexation with beta-cyclodextrin.

This study investigated the inclusion complexes of beta-cyclodextrin with pheniramine and its halogenated derivatives chlorpheniramine and brompheniramine both experimentally and theoretically to characterize the effects of a halogenated phenyl ring on the intermolecular interactions. Fourier transform infrared and nuclear magnetic resonance (NMR) experiments provided evidence of the formation of inclusion complexes and NMR were conducted to evaluate the apparent binding constants. The two-layered hybrid ONIOM method, ONIOM(B3LYP/6-31G(d):PM3), was adopted to optimize the geometry. The linear relationships between the calculated and experimental values for frequencies (with a scaling factor of 0.96) and for magnetic properties (with a scaling factor of 1.05) demonstrate that the quantum chemical calculations were consistent with the experimental spectra. Additionally, the calculated binding energies were consistent with the experimental results: the stability order of the complexes and the trend of the binding energy is: brompheniramine>chlorpheniramine>pheniramine; S-enantiomer>R-enantiomer. Natural Bond Orbital analysis further demonstrated three major electronic delocalizations--from the substituent on the phenyl moiety of pheniramine to beta-CD and from beta-CD to the phenyl and amine moieties in pheniramine--which were the dominant intermolecular forces that were responsible for the substantially different binding strengths. Geometrical data and the partial charge distribution obtained by NBO analysis are provided as supplementary data.

Chiral separation of alkylamine antihistamines in pharmaceuticals by capillary isotachophoresis with charged cyclodextrin.

Cyclodextrin-mediated capillary isotachophoresis (ITP) in cationic regime of the separation was developed for the separation and quantitation of alkylamine antihistamine dimethindene (DIM) and pheniramine (PHM) enantiomers in various pharmaceutical preparations (capsules, oral drops, gel, granulated powder). Several electrolyte systems of different compositions and pH were examined. The optimized chiral ITP electrolyte system was consisted of 10 mmol/L potassium acetate adjusted to pH 4.8 with acetic acid, containing 4 mmol/L negatively charged CE-beta-CD (chiral selector) as the leading electrolyte with electroosmotic flow (EOF) suppressing additive, 0.2% (w/v) methylhydroxyethylcellulose (m-HEC), and 5 mmol/L beta-alanine as the terminating electrolyte. The proposed electrophoretic method was successfully validated. It was convenient for the sensitive, simple, rapid, and highly reproducible assay of these antihistamine enantiomers. The calibration graphs relating the ITP zone length to the concentration of DIM and PHM enantiomers were rectilinear (r = 0.999) in the range 40.0-200.0 mg/L of each enantiomer. The relative standard deviations (RSD) were 0.75% for DIM(1), 0.63% for DIM(2), 1.05% for PHM(1), and 0.83% for PHM(2) (n = 6) when determining 100 mg/L DIM and PHM, respectively, standard solutions. According to the validation procedure based on the standard addition technique the recoveries were 97.66-98.34%. Good quantitation was obtained in short analysis time (a single analysis took about 12 min). The minimal sample pretreatment and low running costs make the proposed ITP method a good alternative to commonly used analytical methods (CZE, HPLC). The obtained results suggest that the proposed method is suitable for routine assay of dimethindene and pheniramine enantiomers in various pharmaceuticals.

Enantioselective determination of pheniramine in pharmaceuticals by capillary electrophoresis with charged cyclodextrin.

Cyclodextrin (CD)-mediated capillary zone electrophoresis (CZE) in hydrodynamically closed separation system was developed for the separation and quantitation of pheniramine (PHM) enantiomers. Several parameters affecting the separation were studied, including the type and concentration of chiral selector, carrier cation and counterion, and the pH of the buffer. A high effectivity of oppositely migrating carboxyethyl-beta-cyclodextrin (CE-beta-CD) to separate the PHM enantiomers was demonstrated in detail. The optimized chiral analysis of the antihistamine drug was performed in a buffer consisted of 20 mmol/l epsilon-aminocaproic acid adjusted to pH 4.5 with acetic acid, containing negatively charged CE-beta-CD (2.5 mg/ml) as chiral selector and 0.2% (w/v) methylhydroxyethylcellulose (m-HEC) as an electro-osmotic flow (EOF) suppressor. Acceptable validation criteria for sensitivity, linearity, precision, accuracy/recovery were included. The proposed CZE method was successfully applied to the assay of PHM in pharmaceutical formulations using dioxopromethazine as an internal standard.

Chiral separation of pheniramine-like 3-phenyl-3-heteroarylpropylamines by CE and HPLC methods.

Analytical CE and HPLC methods were developed for the chiral separation of halogen-substituted 3-phenyl-3-(2-pyridyl)propylamines 1-4 (1: 3-(4-fluorophenyl) approximately, 2: 3-(3,4-difluorophenyl) approximately, 3: 3-(4-chlorophenyl) approximately, 4: 3-(3,4-dichlorophenyl) approximately ), 3-(4-fluorophenyl)-3-(2-thiazolyl)propylamine (5), and 3-(4-fluorophenyl)-3-(1-benzylimidazol-2-yl)propylamine (6), which are building blocks for the preparation of very potent arpromidine-type histamine H(2) receptor agonists. All amines were enantioseparated by CE with resolutions of at least 1.8 using alpha-, beta-, or gamma-cyclodextrin (CD) as chiral selectors. With heparin as buffer additive for CE the optical antipodes of 1-4 and 6 were separated with resolutions > or = 1.8. On RP-18 columns the separation of the (+)-(S)-acetylmandelic acid amides of racemic 2 (R = 0.9, alpha = 1.07) and the thioureas prepared by addition of 6 to 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate (R = 2.0, alpha = 1.20) was successful, whereas the diastereomeric ureas prepared from 3 and (+)-(S)-1-(1-naphthyl)ethyl isocyanate could not be resolved. Separation of the diastereomeric isoindoles prepared from 1-5, o-phthaldialdehyde and 2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranoside was achieved on a RP-18 phase (R > or = 0.4, a > or = 1.02). Direct separation of the enantiomers of 3 and 4 was achieved on a Cyclobond I column (R > or = 0.9, alpha > or = 1.07). alpha- and beta-CD were also useful as mobile phase additives for HPLC (3 and 4: RP-18 column, beta-CD, R > or = 0.4, alpha > or = 1.03; 3: RP-18 column, alpha-CD: R = 0.5, alpha = 1.04).

Solubilization of salicylamide and acetaminophen by antihistamines in aqueous solution.

The effect of self-association of the antihistaminic drugs pheniramine, chlorpheniramine, and brompheniramine as their maleate salts on the solubilization of salicylamide and acetaminophen in aqueous solution has been investigated. The total solubility of salicylamide increased nonlinearly at lower antihistamine concentrations (less than 0.4 M), but reached limiting linearity (slope = 0.34 mol/mol of antihistamine) at higher concentrations (up to 0.8 M). Salicylamide solubility increases are approximately 10-fold at high concentrations (0.6-0.8 M) of antihistamine, while acetaminophen solubility increases are about fivefold at similar antihistamine concentrations. The solubilization data were analyzed with a stepwise self-association model. Based on a dimer model, the experimental and theoretical log excess salicylamide solubility profiles were in good agreement (r2 = 0.982) except at the lowest chlorpheniramine maleate concentrations. Such deviation at the lowest concentrations increased when trimer and 11-mer models were utilized. To account for this deviation, a monomer-dimer model based on interaction with both the chlorpheniramine maleate monomer and dimer was proposed. This model was in excellent agreement (r2 = 0.996) with the solubility data.