Naproxen Enantiomers Research Articles

Photophysical Probes To Assess the Potential of Cholic Acid Aggregates as Drug Carriers

The two enantiomers of the nonsteroidal antiinflammatory drug naproxen and of its methyl ester have been selected as representative probes with markedly different hydrophobicity to assess the potential of cholic acid aggregates as drug carriers by means of photophysical techniques. The different distribution of the probes between bulk solution and aggregates has been assessed by quenching of their singlet and triplet excited states by iodide and nitrite anions, respectively. This straightforward photophysical methodology can, in principle, be extended to a variety of drugs containing a photoactive chromophore.

Kinetic Study for Biphasic Recognition Chiral Extraction of Naproxen Enantiomers with Hydrophobic L-iso-butyl Tartrate and Hydrophilic Hydroxypropyl-β-Cyclodextrin

The kinetics of biphasic recognition chiral extraction of naproxen (HA) enantiomers was investigated to determine the extraction mechanism, with hydrophobic L-iso-butyl tartrate (L-IBTA) in the organic phase and hydrophilic hydroxypropyl-β-cyclodextrin (HP--CD) in the aqueous phase. The two-phase homogeneous reaction model was selected over the interfacial reaction model, because there is a clear physical solubility of naproxen enantiomers in both the aqueous phase and the organic phase. The reactions between the HA enantiomers and L-iso-butyl tartrate in a stirred cell fall in Regime 3; the extraction is accompanied by two fast chemical reactions in the diffusion film. The reactions have been found to be first order with respect to HA enantiomers and second order with respect to L-IBTA. The forward rate constants for S-HA and R-HA are 1.26 × 10−4 mol−2 m6 s−1 and 2.52 × 10−4 mol−2 m6 s−1, respectively. With the increase of HP--CD concentration in the aqueous phase, high enantioselectivity was obtained, but the extraction rates decreased. These data will be useful in the design of extraction processes.

An Examination of the Thermodynamics of Fusion, Vaporization, and Sublimation of Ibuprofen and Naproxen by Correlation Gas Chromatography

The vaporization enthalpies of (S)-ibuprofen and (S)-naproxen measured by correlation gas chromatography at T = 298.15 K are reported and compared with literature values. Adjustment of the fusion enthalpies of (RS)- and (S)-ibuprofen and (S)-naproxen to T = 298.15 K and combined with the vaporization enthalpy of the (S)-enantiomer of both ibuprofen and naproxen also at T = 298.15 K resulted in the sublimation enthalpies of both (S)-enantiomers. On the assumption that the vaporization enthalpy of the racemic form of ibuprofen is within the experimental uncertainty of the chiral form, the sublimation enthalpy of racemic ibuprofen was also evaluated. The vaporization and sublimation enthalpies compare favorably to the most of the literature values for the racemic form of ibuprofen but differ from the value reported for chiral ibuprofen. The literature values of (S)-naproxen are somewhat smaller than the values measured in this work. The following vaporization enthalpies were measured for (S)-ibuprofen and (S)-naproxen, respectively: ΔH(vap) (298.15 K), 106.0 ± 5.5, 132.2 ± 5.0 kJ·mol(-1) . Sublimation enthalpies of 122.7 ± 5.6 and 155.2 ± 7.1 kJ·mol(-1) were calculated for the (S)-enantiomers of ibuprofen and naproxen and a value of 128.9 ± 5.8 kJ·mol(-1) was estimated for the racemic form of ibuprofen.

(R)-Profens are substrate-selective inhibitors of endocannabinoid oxygenation by COX-2

Cyclooxygenase-2 (COX-2) catalyzes the oxygenation of arachidonic acid and the endocannabinoids 2-arachidonoylglycerol and arachidonoylethanolamide. Evaluation of a series of COX-2 inhibitors revealed that many weak competitive inhibitors of arachidonic acid oxygenation are potent inhibitors of endocannabinoid oxygenation. (R) enantiomers of ibuprofen, naproxen and flurbiprofen, which are considered to be inactive as COX-2 inhibitors, are potent 'substrate-selective inhibitors' of endocannabinoid oxygenation. Crystal structures of the COX-2–(R)-naproxen and COX-2–(R)-flurbiprofen complexes verified this unexpected binding and defined the orientation of the (R) enantiomers relative to (S) enantiomers. (R)-Profens selectively inhibited endocannabinoid oxygenation by lipopolysaccharide-stimulated dorsal root ganglion (DRG) cells. Substrate-selective inhibition provides new tools for investigating the role of COX-2 in endocannabinoid oxygenation and a possible explanation for the ability of (R)-profens to maintain endocannabinoid tone in models of neuropathic pain.

Modeling multiple chemical equilibrium for reactive extraction of naproxen enantiomers with HP-β-CD as hydrophilic selector

Reactive extraction is an emerging technology for large-scale continuous resolution of drug enantiomers. The enantioselective extraction of R,S-naproxen by hydrophilic HP-β-CD in 1,2-dichloroethane was studied at 5 °C. The experimental data were described by a reactive extraction model with a homogeneous aqueous phase reaction of R,S-naproxen with HP-β-CD which couples a complete description of chemical equilibria in aqueous phase with the overall phase equilibria of the system. Important parameters of this model were determined experimentally. The physical distribution coefficients for molecular and ionic NAP were 0.041 and 1.730, respectively. Here we show that the efficiency of extraction depends strongly on two process variables including pH and HP-β-CD concentration. The model predictions are compared graphically with the results of previous experiments and there is a good agreement between each other. By the use of modeling and experiment, an optimized extraction condition with pH of 2.5 and HP-β-CD concentration of 0.1 mol/L was obtained with high enantioselectivity (α?) of 1.59 and performance factor (pf) of 0.049. The model gives a good means of predicting enantiomers partitioning over a range of experimental conditions.

Enantioselective analysis of ibuprofen, ketoprofen and naproxen in wastewater and environmental water samples

A highly sensitive and reliable method for the enantioselective analysis of ibuprofen, ketoprofen and naproxen in wastewater and environmental water samples has been developed. These three pharmaceuticals are chiral molecules and the variable presence of their individual ( R)- and ( S)-enantiomers is of increasing interest for environmental analysis. An indirect method for enantioseparation was achieved by the derivatization of the ( R)- and ( S)-enantiomers to amide diastereomers using ( R)-1-phenylethylamine (( R)-1-PEA). After initial solid phase extraction from aqueous samples, derivatization was undertaken at room temperature in less than 5 min. Optimum recovery and clean-up of the amide diastereomers from the derivatization solution was achieved by a second solid phase extraction step. Separation and detection of the individual diastereomers was undertaken by gas chromatography–tandem mass spectrometry (GC–MS/MS). Excellent analyte separation and peak shapes were achieved for the derivatized ( R)- and ( S)-enantiomers for all three pharmaceuticals with peak resolution, R s is in the range of 2.87–4.02 for all diastereomer pairs. Furthermore, the calibration curves developed for the ( S)-enantiomers revealed excellent linearity ( r 2 ≥ 0.99) for all three compounds. Method detection limits were shown to be within the range of 0.2–3.3 ng L −1 for individual enantiomers in ultrapure water, drinking water, surface water and a synthetic wastewater. Finally, the method was shown to perform well on a real tertiary treated wastewater sample, revealing measurable concentrations of both ( R)- and ( S)-enantiomers of ibuprofen, naproxen and ketoprofen. Isotope dilution using racemic D 3-ibuprofen, racemic D 3-ketoprofen and racemic D 3-naproxen was shown to be an essential aspect of this method for accurate quantification and enantiomeric fraction (EF) determination. This approach produced excellent reproducibility for EF determination of triplicate tertiary treated wastewater samples.

High resolution fluorescence excitation spectra of both enantiomers of naproxen in the gas phase: Are they equivalent or not?

Two chiral conformers of the optically active molecule naproxen have been identified in its high resolution electronic spectrum, differing only in the orientation of the attached isopropionic acid group relative to the naphthalene ring. Both conformers exhibit b-type spectra, indicating that the S1 states of the isolated molecules are similar to those of other 2-substituted naphthalenes. The measured rotational constants of the left- and right-handed forms of both conformers are identical to within the experimental error, ±0.1MHz (∼1:109), indicating that they are enantiomers of each other, not diastereomers. The naphthyl ring with its attached methoxy group is insufficient to provide chiral discrimination.

An Evidence for the Chiral Discrimination of Naproxen Enantiomers: A Combined Experimental and Theoretical Study

Naproxen enantiomers possess strong room temperature phosphorescence (RTP) in β-cyclodextrin (β-CD) system with a small amount of 1,2-dibromoethane (1,2-DBE) under ambient conditions. The effects o...

Separation of Naproxen Enantiomers Using Hollow Fiber Molecularly Imprinted Membrane Chromatography

Abstract In this paper, the use of molecularly imprinted membrane (MIM) for chromatographic separation is described. Poly(vinylidene fluoride) hollow-fiber membranes were grafted on an imprinted polymer layer by using 4-vinylpyridine and trimethylolpropane triacrylate as monomer and crosslinker and were applied as the chromatographic media. During separation, naproxen enantiomers were separated efficiently, and the separation factor was 2.36. Molecularly imprinted membrane chromatography (MIMC) showed an apparently opposite transport behavior compared to molecularly imprinted polymer (MIP)-packed chromatography.

The adsorption of Naproxen enantiomers on the chiral stationary phase Whelk-O1 under reversed-phase conditions: The effect of buffer composition

The adsorption of the Naproxen enantiomers on the chiral stationary phase ( S,S)-Whelk-O1 from methanol–water 80:20 (v/v) solutions modified with the addition of acetic acid or an acetic acid–sodium acetate buffer was studied using elution chromatography. Adsorption was found to be best accounted for by a two-site model assuming different retention mechanisms for the two enantiomers. Under experimental conditions causing a considerable degree of solute dissociation, strong distortion of overloaded band profiles is observed. This phenomenon is explained by the superimposition of the adsorption and the dissociation equilibria. The effect of the buffer composition on the retention is discussed and the results compared with previous ones obtained with the same system. The proposed model explains all the principal features of the adsorption of Naproxen on Whelk-O1 that were found earlier. Moreover this model applies well in a wider range of buffer concentrations, encompassing both the eluents in which solute dissociation is suppressed and those in which dissociation is significant.

Equilibrium studies on reactive extraction of naproxen enantiomers using hydrophilic β-cyclodetrin derivatives extractants

A simple and low-cost method using liquid–liquid extraction coupled with complexation reactive technique has been developed for enantioselective separation of naproxen enantiomers. Three kinds of modified β-cyclodextrins including methyl-β-cyclodextrin (Me-β-CD), hydroxyethyl-β-cyclodextrin (HE-β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD), were selected as hydrophilic chiral selectors for extraction naproxen from organic phase to aqueous phase. A systematic study of the factors affecting chiral separation performance were investigated. The experiment results obtained show that, HP-β-CD, HE-β-CD and Me-β-CD has stronger recognition abilities for S-naproxen than those for R-naproxen. Among the β-CD derivatives studied, HP-β-CD has the strongest ability for chiral recognition and separation. Excellent enantioselectivity (a) of 1.59 is obtained under the optimal conditions of pH of 2.5 and temperature of 5 °C.

The adsorption of Naproxen enantiomers on the chiral stationary phase ( [formula omitted])-Whelk-O1 under reversed-phase conditions: The effect of mobile phase composition

The adsorption of the Naproxen enantiomers on the Whelk-O1 chiral stationary phase from acidic (0.01 M CH 3COOH) methanol–water solutions was studied using the frontal analysis method and band profile calculations. The adsorption model that best accounted for these data is one assuming the coexistence of three types of adsorption sites, two of them being enantioselective, associated with the chiral selectors, the third type being the nonselective type of sites associated with residual surface silanol groups. The adsorption equilibrium is influenced by secondary processes that result in variations of the model parameters with the mobile phase composition. Several qualitative correlations between the model parameters and the methanol–water ratio were observed and are discussed.

Retention of Naproxen enantiomers on the chiral stationary phase Whelk-O1 under reversed-phase conditions. A reconsideration of the adsorption mechanism in the light of new experimental data

A model of adsorption of the Naproxen enantiomers on the ( S, S)-Whelk-O1 chiral stationary phase that we recently proposed was found to be inconsistent with new experimental data. A new model taking into account the variation of the dissociation coefficient of the analyte during elution of the band is discussed.

On the enantioselectivity of the mass transfer kinetics and the adsorption equilibrium of Naproxen on the chiral stationary phase ()-Whelk-O1 under reversed-phase conditions

The adsorption of the Naproxen enantiomers on a Pirkle-type chiral stationary phase (CSP) (R,R)-Whelk-O1 from 0.01M acetic acid solution in a methanol-water (85/15, v/v) mixture was studied using techniques of frontal analysis and elution chromatography. Adsorption was found to follow a model that assumes retention of a solute on two types of surface sites, enantioselective and nonselective. Some minor deviations from the classical bi-Langmuir model were found, but they were well accounted for by assuming the coexistence of two groups of enantioselective sites: sparse sites of strong affinity toward (R)-Naproxen and a more numerous type of low-energy sites exhibiting a somewhat different affinity toward the two enantiomers. Special consideration is paid to the adsorption of the methanol-water mixture on the surface of the CSP. The bonded organic layer exhibits hydrophobic properties, so the adsorbed layer is enriched in methanol throughout the whole range of mobile phase compositions. The study of the mass transfer kinetics was carried out by analyzing the dependence of the HETP on the flow velocity. It revealed the enantioselective character of the intraparticle transport processes. Other aspects of the column dynamics, such as axial dispersion, the external and internal mass transfer were also discussed.

Features of the adsorption of Naproxen on the chiral stationary phase ( S, S)-Whelk-O1 under reversed-phase conditions

Using elution chromatography, we studied the adsorption mechanism of the Naproxen enantiomers on the chiral stationary phase ( S,S)-Whelk-O1, from buffered methanol–water solutions. We propose an adsorption mechanism that assumes monolayer adsorption of the more retained enantiomer and the associative adsorption of the less retained one. The effects of the mobile phase composition on the adsorption of Naproxen are discussed. The combination of an elevated column temperature and of the use of an acidic mobile phase led to the degradation of the column and caused a major loss of its separation ability. The use of a moderately acidic mobile phase at temperature slightly above ambient did not produce rapid severe damages but, nevertheless, hampered the experiments and caused a slow gradual deterioration of the column.

Adsorption of naproxen enantiomers from solutions on chemically modified cellulose. The effect of a polar component of a liquid phase

The influence of mobile phase composition (hexane-ethanol with the addition of 0.1 vol.% of trifluoroacetic acid) on the adsorption of the naproxen enantiomers on a chiral adsorbent Chiralcel OJ-H was investigated. Methods of linear and nonlinear chromatography were used to investigate adsorption thermodynamics at infinite dilution and to measure adsorption isotherms for solutions containing 10 and 20 vol.% of ethanol. It was found that two groups of adsorption sites coexist on the surface of the adsorbent in contact with the mentioned solvent, strong and weak ones, with the strong adsorption sites contributing mainly to the adsorption of naproxen. The effect of ethanol content on the retention of naproxen consists of the change in the number of the strong adsorption sites and regulating solvation property of a solvent.

Assessment of the pharmaceutical active compounds removal in wastewater treatment systems at enantiomeric level. Ibuprofen and naproxen

The enantioselective degradation of ibuprofen and naproxen enantiomers was evaluated in five different wastewater treatment systems, including three constructed wetlands (vertical- and horizontal-flow configurations), a sand filter and an activated sludge wastewater treatment plant. In addition, injection experiments were carried out with racemic ibuprofen at microcosm- and pilot-scale constructed wetlands. Ibuprofen and naproxen have an asymmetric carbon atom and, consequently, two enantiomeric forms (i.e. S and R). The enantiomeric fraction (EF = S/(S + R)) in the raw sewage and effluents of various wastewater treatments were found to be compound-dependent (i.e. ibuprofen: EF influent = 0.73–0.90, EF effluent = 0.60–0.76; naproxen: EF influent = 0.88–0.90, EF effluent = 0.71–0.86). Of the two chiral pharmaceuticals, naproxen was the only one whose effluent EF correlated with its removal efficiency ( p < 0.05). The lack of correlation found for ibuprofen was attributable to the fact that its enantioselective degradation kinetics were different under prevailing aerobic and anaerobic conditions. Injection experiments of ibuprofen in constructed wetlands at microcosm and pilot-scale followed similar trends. Hence, under prevailing aerobic conditions, S-ibuprofen degraded faster than R-ibuprofen, whereas under prevailing anaerobic conditions, the degradation was not enantioselective. In summary, the naproxen EF measurements in wastewater effluents show that naproxen is a suitable alternative for evaluating the removal efficiency of treatment systems because its enantioselective degradation is similar under prevailing aerobic and anaerobic conditions.

Micro-Preparative Chromatographic Separation of Naproxen Enantiomers

Chromatographic micro-preparative separation of a racemic mixture of naproxen enantiomers using a chiral stationary phase of Chiralcel OJ-H has been studied. Optimum conditions for the separation have been found. It is shown that a special fraction collection scheme involving an intermediate region between the minimum between peaks and the maximum of the second peak should be used for the simultaneous recovery of both enantiomers. In this case, S- (0.12 mg) and R-naproxen (0.12 mg) with a purity of up to 99.4 and 94.5%, respectively, can be isolated in one run using a standard analytical column.

Features of the adsorption of naproxen enantiomers on weak chiral anion-exchangers in nonlinear chromatography

The retention mechanism of the enantiomers of naproxen on a Pirkle-type chiral stationary phase (CSP) was studied. This CSP is made of a porous silica grafted with quinidine carbamate. It can interact with the weak organic electrolyte naproxen either by adsorbing it or by ion-exchange. Using frontal chromatography, we explored the adsorption equilibrium under such experimental conditions that naproxen dissociates or cannot dissociate. Under conditions preventing ionic dissociation, the adsorption isotherms were measured, the adsorption energy distributions determined, and the chromatographic profiles calculated. Three different types of the adsorption sites were found for both enantiomers. The density and the binding energy of these sites depend on the nature of the organic modifier. Different solute species, anions, neutral molecules, solvent-ion associates, and solute dimers can coexist in solution, giving rise to different forms of adsorption. This study showed the unexpected occurrence of secondary steps in the breakthrough profiles of S-naproxen in the adsorption mode at high concentrations. Being enantioselective, this phenomenon was assumed to result from the association of solute molecules involving a chiral selector moiety. A multisite Langmuir adsorption model was used to calculate band profiles. Although this model accounts excellently for the experimental adsorption isotherms, it does not explain all the features of the breakthrough profiles. A comparison between the calculated and experimental profiles allowed useful conclusions concerning the effects of the adsorbate–adsorbate and adsorbate–solvent interactions on the adsorption mechanism.

Adsorption of naproxen enantiomers on chemically modified cellulose

Adsorption of naproxen enantiomers on the Chiralcel OJ-H chiral stationary phase, being tris(4-methylbenzoate) cellulose coated on silica gel, was studied. The thermodynamic characteristics of adsorption were measured. The adsorption isotherms are described by the Langmuir equation within the concentration range under study.