Ketoprofen Enantiomers Research Articles

Enantiomeric separation of ketoprofen using Frovatriptan as a chiral derivatizing reagent

AbstractWe established a validated high‐performance liquid chromatography method utilizing Frovatriptan as a chiral derivatizing agent to separate the enantiomers of ketoprofen from commercially available tablet formulations. The chiral derivatizing agent facilitated the synthesis of diastereomeric derivatives of ketoprofen, which were separated on a reversed‐phase C18 column using a mobile phase composed of acetonitrile and 0.1% trifluoroacetic acid under gradient elution from 30% to 70% of acetonitrile. The method demonstrated a limit of detection and quantitation of 2.52 and 8.31 ng/ml for the derivatives, respectively. Validation of the method was performed following the guidelines set by the International Council for Harmonisation to ensure accuracy, precision, and reliability, making it suitable for pharmaceutical industry applications. Notably, this study introduces the novel application of Frovatriptan as a chiral derivatizing agent in high‐performance liquid chromatography for the separation of ketoprofen enantiomers.

Development of a capillary electrophoretic method for determination of ketorolac enantiomers in human plasma using cationic β-cyclodextrin derivative as a chiral selector.

A novel approach for the separation of ketorolac enantiomers by capillary electrophoresis is presented. A cationic β-cyclodextrin derivative based on imidazole was synthesized and used as a chiral selector in the background electrolyte. The influence of pH and ionic strength of background electrolyte, as well as cationic β-cyclodextrin derivative concentration on the resolution of ketorolac enantiomers, was investigated. The highest value of the resolution for ketorolac enantiomers was 1.46 when the background electrolyte consisted of 25mM NaH2 PO4 (pH 6.4) with 1mM 1-butyl-3-β-cyclodextrinimidazolium tosylate. Additionally, the possibilities of cationic derivatives for the separation of ketoprofen enantiomers were shown (peak resolution 1.06). The two-step preconcentration mode was developed to reduce the limit of detection of individual enantiomers. The proposed approach was successfully applied to determine ketorolac enantiomers in tablet "Ketorol express" and human plasma. The calibration range of ketorolac enantiomers for plasma samples was 0.25-2.50μg/ml with coefficients of determination ≥ 0.99. The relative standard deviation both of the peak area and migration time was less than 15%, as well as the accuracy ranged from 90.1% to 110.2% for both analytes. The limits of detection were 44 and 55ng/ml for R- and S-ketorolac. The quantity of ketorolac in plasma was verified with high-performance liquid chromatography.

Immobilized Lipase in Resolution of Ketoprofen Enantiomers: Examination of Biocatalysts Properties and Process Characterization

In this study, lipase from Aspergillus niger immobilized by physical immobilization by the adsorption interactions and partially interfacial activation and mixed physical immobilization via interfacial activation and ion exchange was used in the kinetic resolution of the ketoprofen racemic mixture. The FTIR spectra of samples after immobilization of enzyme-characteristic signals can be seen, and an increase in particle size diameters upon immobilization is observed, indicating efficient immobilization. The immobilization yield was on the level of 93% and 86% for immobilization unmodified and modified support, respectively, whereas activity recovery reached around 90% for both systems. The highest activity of immobilized biocatalysts was observed at pH 7 and temperature 40 °C and pH 8 and 20 °C for lipase immobilized by physical immobilization by the adsorption interactions and partially interfacial activation and mixed physical immobilization via interfacial activation and ion exchange, respectively. It was also shown that over a wide range of pH (from 7 to 10) and temperature (from 20 to 60 °C) both immobilized lipases retained over 80% of their relative activity, indicating improvement of enzyme stability. The best solvent during kinetic resolution of enantiomers was found to be phosphate buffer at pH 7, which obtained the highest efficiency of racemic ketoprofen methyl ester resolution at the level of over 51%, followed by enantiomeric excess 99.85% in the presence of biocatalyst obtained by physical immobilization by the adsorption interactions and partially interfacial activation.

L-cysteine capped silver nanoparticles as chiral recognition sensor for ketoprofen enantiomers.

A simple, inexpensive but effective approach for visual chiral recognition of ketoprofen enantiomers was developed using L-cysteine capped silver nanoparticles (L-Cys-AgNPs) as a colorimetric sensor. Upon the addition of R-ketoprofen to L-Cys-AgNPs, rapid aggregation occurred, and the solution changed color from yellow to green. However, the presence of S-ketoprofen did not induce any color change. The results were characterized using UV-Vis, FESEM, FT-IR, SERS, and zeta potential measurements. The chiral assay described in this work is easily distinguished with the naked eyes or using a UV-Vis spectrometer. The sensor revealed a good linear response to ketoprofen enantiomers in the concentration range of 8.33-33.3μM with a detection limit of 4.52 μM and relative standard deviation of 3.73%. The proposed method was utilized for the determination of ketoprofen racemic mixtures in water samples and commercial tablets. The method excels by its simplicity, low cost, and good availability of materials.

New Studies on Dexketoprofen

Abstract Introduction. Dexketoprofen(DEX) belongs to nonsteroidal anti-inflammatory drugs (NSAIDs) and has analgesic, anti-inflammatory, and antipyretic properties. DEX is an enantiomer of ketoprofen (S+) and has a stronger effect than ketoprofen. It is highly effective even after the administration of small doses. The therapy with DEX does not cause serious side effects and is additionally tolerated by the body. Aim. The review aimed to find original scientific publications on DEX in recent years and its therapeutic efficacy, safety, and tolerability. Method. A systematic review of scientific articles published no earlier than 2015 was carried out. Materials from the PubMed, Google Scholar, and Medline Complete databases were used. The literature review was carried out in November 2021. Among the publications found, 28 scientific articles were selected for analysis. Results and discussion. Over the recent years, there have been many publications about DEX. Articles describing new data on DEX in the treatment of pain were analyzed, compared with other drugs and mesotherapy, the latest reports of its combination with tramadol and thiocolchicoside were reviewed, and a new slow release form of DEX and new therapeutic applications of this drug were investigated. After analyzing all the studies, it was found that DEX produced similar or more effective analgesia compared to other drugs and reduced the need for emergency medications. In addition, it was noted that using DEX in combination therapy was far better than taking it alone, and was also found to be effective in raising the epileptic threshold. Mesotherapy achieved higher results in the treatment of pain symptoms compared to DEX. The side effects that appeared as a result of the use of DEX therapy were not life-threatening. Conclusion. The results of the review confirm that DEX is a very good analgesic, which is more potent than paracetamol and diclofenac sodium while having similar effects to dexmedetomidine and lidocaine. DEX in combination with tramadol or thiocolchicoside is more effective than when the two drugs are used alone. Scientists are working on the long-acting DEX and are looking for new applications of the drug in epilepsy and oncology.

Dexketoprofen Pharmacokinetics is not Significantly Altered by Genetic Polymorphism.

Dexketoprofen is the (S)-(+)-enantiomer of racemic ketoprofen, a nonsteroidal anti-inflammatory drug used for the management of different types of pain. To the best of our knowledge, no article was published to date on dexketoprofen pharmacogenetics. Thence, in this work, we aimed to explore the influence of sex, race and several single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (e.g. CYP or UGT) or transporters (e.g., ABC or SLC) in the pharmacokinetics and safety of dexketoprofen to explore whether dosing adjustments based on genetic polymorphism would be beneficial for its prescription. For this regard, 85 healthy volunteers enrolled in three bioequivalence clinical trials were genotyped for 46 SNPs in 14 genes. Women showed lower AUC adjusted by dose/weight (AUC/DW) and higher Vd/F and Cl/F than men (p < 0.05 in univariate and multivariate analysis). CYP1A2*1B allele, CYP2B6 IM/PM and CYP2D6 IM/PM phenotypes were related to drug accumulation (AUC/DW or Cmax/DW) compared to the CYP1A2*1 allele, CYP2B6 NM/RM and CYP2D6 NM/UM phenotypes (p < 0.05 in the univariate analysis). ABCB1 C1236TT, C3435TT and G2677A/TA/T alleles were related to lower Cmax/DW compared to C, C, and G alleles (p < 0.05 in univariate and multivariate analysis). ABCB1 C1236TT allele was also related to lower AUC/DW (p < 0.05 in multivariate analysis). The remaining studied transporter genes (ABCC2, SLC22A1, and SLCO1B1) and metabolizing enzyme genes (CYP3A5, CYP2C19, CYP2C9, CYP2C8, CYP3A4, CYP2A6, and UGT1A1) were unrelated to dexketoprofen pharmacokinetic variability. We conclude that dexketoprofen pharmacokinetics can be influenced by several polymorphisms, although there is not a clear pharmacogenetic predictor that would justify individualization of therapy based on its genotyping. Further studies should be conducted to confirm the role of SNPs in CYP2B6, CYP2D6, CYP1A2 and ABCB1 on the pharmacokinetic variability of dexketoprofen. Current evidence on dexketoprofen pharmacogenetics does not justify its inclusion in pharmacogenetic guidelines.

Enantioseparation on a new synthetic β-cyclodextrin chemically bonded chiral stationary phase and molecular docking study.

A novel β-cyclodextrin derivative chemically bonded chiral stationary phase (EDACD) was synthesized by the reaction of mono-6-ethylenediamine-β-cyclodextrin with the active alkyl isocyanate, anchoring to silica gel. After the successful analysis and characterization using scanning electron microscopy, Fourier transform infrared spectra, solid-state nuclear magnetic resonance spectra, elemental analysis, and thermogravimetric analysis techniques, the enantioselective performance of the as-prepared EDACD column was evaluated by non-steroidal antiinflammatory drugs and flavonoids under the reversed-phase HPLC condition. The factors that affected enantioseparation including mobile phase compositions and buffers were investigated in more detail. As a result, EDACD showed a satisfactory enantioselectivity for the tested drugs. With the mobile phase of acetonitrile and 20-mM ammonium formate adjusted to pH4.0 using formic acid (85:15, v/v) at the flow rate of 0.6mLmin-1, the enantiomers of ibuprofen, carprofen, naproxen, indoprofen, ketoprofen, eriocitrin, naringin, and narirutin were separated with the best resolutions of 1.53, 1.64, 3.72, 2.40, 0.50, 0.61, 0.58, and 0.52. To adjust the proportion of acetonitrile to 80% (by volume), the enantiomers of pranoprofen and flurbiprofen were completely resolved with the best resolutions of 1.60 and 1.59. Additionally, by the study of the molecular docking, hydrogen bonding and inclusion complexation were believed to play an important role in chiral recognition. As a new material, EDACD will have a wider application in the analysis of chiral compounds.

Adrenergic modulation of dexketoprofen antinociception in murine formalin orofacial pain

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in pain whose mechanism of action is the inhibition of cyclooxygenase enzymes (COXs), however, there are evidence of other mechanisms of action, such as the inhibition of substance P, interaction with systems NO, monoaminergic and others. The objective of the present work was to study the participation of a-1 (prazosin) and a-2 (yohimbine) adrenoceptors antagonists in the antinociception of dexketoprofen, the S (+) enantiomer of ketoprofen. The antinociception evaluation was thru the mice orofacial formalin assay. Dexketoprofen (DEX) induced a dose-related antinociception 3.40 times more potent in phase I than in phase II. Prazosin i.p. decreased of the antinociception of DEX, 2.01 times in phase I and 4.02 times in phase II. Administered i.t. reduced the antinociception 5.30 times in phase I and 6.20 times in phase II. Yohimbine i.p. induced a reduction of the ED50 of 3.40 times in phase I and 4.50 times in phase II, after i.t. administration the reduction was 5.30 times in phase I and 6.20 times in phase II. The mechanism of antinociception induced by DEX is mediated by the activation of α-1 and α-2 adrenergic receptors at supraspinal and spinal levels.

In vitro kinetic release study of ketoprofen enantiomers from alginate metal complexes

BackgroundTo explore the release behavior of ketoprofen enantiomers from alginate-metal-complexes. Five mathematical models of drug release kinetics were investigated.ResultsBeads of alginate-metal complexes, loaded with racemic ketoprofen, were prepared by the ionotropic method. Divalent (Ca, Ba, Zn) and trivalent (Fe, Al) metals were used in the preparation of single-metal and mixed-metal alginate complexes. In vitro release experiments were carried out in an aqueous phosphate buffer medium at pH = 7.4. The concentrations of ketoprofen released enantiomers were determined using chiral HPLC technique. The obtained data were used to simulate the release kinetic of ketoprofen enantiomers using various mathematical models. The Korsmeyer-Peppas model was the best fit for Ca, Al, and Fe beads. Moreover, alginate-iron beads tend to release the drug faster than all other cases. In contrast, the drug release for alginate-barium complex was the slowest. The presence of barium in alginate mixed-metal complexes reduced ketoprofen release in the case of Fe and Zn, while it increased the release in the case of Al complex.ConclusionIn all the studied cases, ketoprofen showed very slow release for both enantiomers over a period exceeded 5 h (10 days in some cases). The release rate modification is possible using different multivalent metals, and it is also feasible by using two different metals for congealing either consecutively or simultaneously.

The Effect of Enantiomer Elution Order on the Determination of Minor Enantiomeric Impurity in Ketoprofen and Enantiomeric Purity Evaluation of Commercially Available Dexketoprofen Formulations.

In a recent study, opposite enantiomer elution order was observed for ketoprofen enantiomers on two amylose-phenylcarbamate-based chiral columns with the same chemical composition of the chiral selector but in one case with coated while in the other with an immobilized chiral selector. In the present study, the influence of this uncommon effect on method validation parameters for the determination of minor enantiomeric impurity in dexketoprofen was studied. The validated methods with two alternative elution orders for enantiomers were applied for the evaluation of enantiomeric impurity in six marketed dexketoprofen formulations from various vendors. In most of these formulations except one the content of enantiomeric impurity exceeded 0.1% (w/w).

Comparative Theoretical Study of Stability, Lypophilicity, Dipole Moments, Acidity and Spectroscopic Properties of Non-Steroidal Anti-Inflammatory Drugs: Ibuprofen, Ketoprofen and Flurbiprofen

A comparative theoretical study of some physicochemical properties of R and S enantiomers of ibuprofen, ketoprofen and flurbiprofen is undertaken in order to understand their reactivity. To do this, DFT and TD-DFT methods at the B3LYP/6-311G(d,p) level theory are used. The partition coefficient determined is 3.72 for ibuprofen, 2.81 for ketoprofen and 4.12. for flurbiprofen. That means that these NSAIDs are characterized by a high lipophilicity. The calculated Gibbs energies show that the R enantiomer is the most stable in the case of ibuprofen and the S enantiomer in the case of ketoprofen and flurbiprofen. The study of acidity shows that S enantiomer of ibuprofen and R enantiomers of ketoprofen and flurbiprofen are the most acidic enantiomers. TD-DFT calculations show that, the absorption maxima (λmax) of ibuprofen and flurbiprofen correspond to the HOMO→LUMO transition. For ketoprofen, these are associated with the transition HOMO→LUMO+1. These results elucidate the reactivity of the investigated NSAIDs and could help to establish a classification their efficacy.

Spectroscopic studies for the inclusion complexation of ketoprofen enantiomers with β-cyclodextrin.

Inclusion complexes of R-ketoprofen and S-ketoprofen enantiomers with β-cyclodextrin (β-CD) in aqueous solution were studied using various spectroscopic techniques such as Raman, FTIR, UV and fluorescence. The different relative intensities and characteristic band shifts of the two enantiomers from Raman spectra suggests different interaction when complexed with β-CD. Raman experiments revealed a noticeable diminishing of the CC vibration and ring deformation, which indicate the embedding of ketoprofen inside the β-CD cavity. It's revealed that distinct differences between R- and S-ketoprofen in the presence of β-CD at neutral pH. The stoichiometry ratio and binding constant of the inclusion complexes were calculated using Benesi-Hildebrand plot. Both enantiomers showed stoichiometry ratio of 1:1 inclusion complex with β-CD. The binding constant of R-ketoprofen (4088M-1) is higher than S-ketoprofen (2547M-1). These values indicated that β-CD formed inclusion complexes more preferentially with R-ketoprofen than S-ketoprofen. Results demonstrated that β-CD can be used as a promising chiral selector for ketoprofen enantiomers.

Back Cover: Multifunction covalent coatings for separation of amino acids, biogenic amines, steroid hormones, and ketoprofen enantiomers by capillary electrophoresis and capillary electrochromatography

Back Cover: Multifunction covalent coatings for separation of amino acids, biogenic amines, steroid hormones, and ketoprofen enantiomers by capillary electrophoresis and capillary electrochromatography

Multifunction covalent coatings for separation of amino acids, biogenic amines, steroid hormones, and ketoprofen enantiomers by capillary electrophoresis and capillary electrochromatography

AbstractIn this study, the preparation process of multifunctional coating based on imidazole and β‐cyclodextrin has been developed. The synthesis includes several steps: activation of fused silica capillary walls via alkali, then process of silylation and finally functionalization with imidazole and β‐cyclodextrin derivative. The latter step was carried over 22 h at 100°C at 750 mg/mL concentration of p‐toluenesulfonyl‐β‐cyclodextrin. It was established that the coatings thus obtained are stable within pH 2–7 range but decompose in alkaline medium. The stationary phase developed in this study allows simultaneous separation of hydrophobic and hydrophilic analytes. Chiral separation of ketoprofen enantiomers was also achieved with the newly developed covalent coating. It was found that covalent coating based on imidazole and β‐cyclodextrin exceeded the dynamic coatings of similar structure in terms of repeatability, analysis time and the limits of detection.

Evaluating the enantiospecific differences of non-steroidal anti-inflammatory drugs (NSAIDs) using an ecotoxicity bioassay test battery

Wastewater treatment plants are a major pathway for pharmaceuticals to the aquatic environment. Many pharmaceuticals, including non-steroidal anti-inflammatory drugs (NSAIDs), are chiral chemicals and the biological activity of their enantiomers can differ. Few studies have assessed the effects of different NSAID enantiomers on non-target organisms. However, this information is important for environmental risk assessment to ensure that the effects of more potent enantiomers are not overlooked. In the current study, enantiomers of naproxen, ibuprofen, ketoprofen and flurbiprofen were evaluated in bioassays with bacteria, algae and fish cells. All enantiomers induced bacterial toxicity, with (R)-naproxen more toxic than (S)-naproxen (EC50 0.75 vs 0.93 mg/L) and (S)-flurbiprofen more toxic than (R)-flurbiprofen (EC50 1.22 vs 2.13 mg/L). Both (R)-flurbiprofen and (S)-flurbiprofen induced photosystem II inhibition in green algae, with (R)-flurbiprofen having a greater effect in the assay after 24 h (EC10 5.47 vs 9.07 mg/L). Only the (R)-enantiomers of flurbiprofen and ketoprofen induced ethoxyresorufin-O-deethylase (EROD) activity in fish cells, while (S)-naproxen was 2.5 times more active than (R)-naproxen in the EROD assay. While enantiospecific differences were observed for all assays, the difference was less than an order of magnitude. This indicates that the risk of overlooking the effect of more potent NSAID enantiomers is minor for the studied test systems and supports the use of racemic (or single enantiomer) effect data for environmental risk assessment. However, further investigation of the (R)-enantiomer of commonly used NSAID ketoprofen is recommended as it was at least six times more potent in the EROD assay than the inactive (S)-ketoprofen.

Effect of the Ketoprofen Distribution in Cream-gels on the Formation of the Impurities

Introduction.The fixed combination of ketoprofen, methyl salicylate and levomenthol in the form of a cream-gel is rational. Ketoprofen forms salts with bases and esters with substances containing hydroxyl groups. Ketoprofen is practically insoluble in water, and the solubility of ketoprofen salts is much higher; this can lead to its different localization in the o/w emulsion and affect the profile of ketoprofen impurities resulting from esterification.Aim.The aim of the work is to study the effect of ketoprofen distribution in cream-gels on the formation of the impurities during storage.Materials and methods.Cream-gels with pH of 5,5 or 6,8 containing ketoprofen 2,5%, levomenthol 5% and methyl salicylate 10% have been studied. For their production, ketoprofen was dissolved in the mixture oflevomenthol – methyl salicylate or in the mixed solvent ofwater – propylene glycol (PG) – diethylene glycol monoethyl ether (DGME). The impurities have been identified by liquid chromatography and the distribution of ketoprofen between the phases of the emulsion and the content of impurities in cream-gels have been determined by the same method. The rheological characteristics of cream-gels have been studied by viscosity-rotating viscometer method, and their microstructure – by optical microscopy.Results and their discussion.The formation of ketoprofen esters with PG, DGME and levomenthol in cream-gels have been studied. Differences in the localization of ketoprofen in the phases of the o/w emulsion at pH 5,5 and 6,8 have been shown. The formed impurities have been identified by the retention times of their peaks on chromatograms, by UV spectra and mass spectra. It has been established that during storage the content of ketoprofen esters with PG, DGME and levomenthol increased, but their formation rate was lower at pH=6,8 as well as at the adding of ketoprofen as a salt with trometamol into the dispersion medium of cream-gel. However, this resulted in formation of three impurities that were identified by UV spectra as decomposition products of methyl salicylate. When storing cream-gels with pH=6,8, the content of decomposition products of methyl salicylate, which were not detected at pH=5,5, increased.Conclusion.When making a cream-gel, ketoprofen is advisable to dissolve in a mixture of methyl salicylate and levomenthol and standardize the pH about 5,5. It is rational to use hydrophilic solvents without hydroxyl groups as penetration enhancers and the impurity profile could be limited to the menthol esters of the enantiomers of ketoprofen as a result.

(S)-1-(1-Methylpyridin-2-yl)-3-aminopiperidine as a novel derivatization reagent capable of enantiomeric separation and enhanced ESI-MS/MS detection for chiral carboxylic acids

A novel derivatization reagent, (S)-1-(1-methylpyridin-2-yl)-3-aminopiperidine (MPAPp), was designed and developed for the enantiomeric separation by conventional reversed-phase liquid chromatography (LC) and the sensitive electrospray ionization-tandem mass spectrometry (ESI-MS/MS) detection of chiral carboxylic acids. MPAPp reacted with the carboxylic acids at 60 °C within 5 min in the presence of a condensation agent to produce the positively-charged and diastereomeric derivatives. The MPAPp-derivatization enabled the satisfactory enantiomeric separation not only of the α- and β-chiral carboxylic acids [ketoprofen (KET), etodolac and 3-hydroxypalmitic acid], but also of the γ-chiral carboxylic acid [2-(γ-carboxyethyl)-6-hydroxy-2,7,8-trimethylchroman (γ-CEHC)] with the resolution (Rs) values of 1.35–1.82. The derivatization also worked for the enantiomeric separation of the ε-chiral carboxylic acid [α-lipoic acid, separation factor (α) = 1.04]. The detection responses of the MPAPp-derivatives were 25–500-times greater than the intact carboxylic acids, therefore, the low femtomolar derivatives were fully detected. The trace detection of a γ-CEHC enantiomer (limit of detection, 1.9 fmol on column) in saliva was achieved by the MPAPp-derivatization followed by LC/ESI-MS/MS. The pharmacokinetic profiles of the KET enantiomers during/after the MOHRUS® patch application were also obtained from the saliva analysis using the MPAPp-derivatization based LC/ESI-MS/MS method, which was precise (intra- and inter-assay relative standard deviations, <6.6% and <4.6%, respectively) and accurate (96.2–105.3%) within the range of 35–280 pg/mL for each enantiomer.

Plasma Concentrations of Ketoprofen and Meloxicam after Subcutaneous and Topical Administration in the Smoky Jungle Frog (Leptodactylus pentadactylus)

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for analgesia in veterinary patients; however, evaluation of NSAID pharmacokinetics in amphibians is limited. A wide variety of pharmacotherapeutics have been administered topically to the skin of anurans with limited empirical evidence of absorption or efficacy. Systemic absorptions of two NSAIDs, meloxicam and ketoprofen, were evaluated after subcutaneous and topical cutaneous administration in smoky jungle frogs (Leptodactylus pentadactylus). Eighty-four, 8 month old, 38.0 g (26.1–56.6 g) (median [range]) frogs were randomly assigned to receive one of four treatments, with 21 animals in each group: 1 mg/kg racemic ketoprofen administered either subcutaneously (SK) or topically (TK) or 0.2 mg/kg meloxicam administered either subcutaneously or topically. Plasma concentrations of meloxicam and the R- and S-enantiomers of ketoprofen were quantified at 3, 8, and 24 h after administration. At each time point, seven frogs per group were anesthetized for blood collection and then euthanized. Plasma samples were pooled within each group for drug quantification. Both enantiomers of ketoprofen were detectable in groups SK and TK, and plasma concentrations decreased from 3 to 24 h. The drop in concentration was less predictable for TK than for SK. Plasma concentrations of meloxicam were nondetectable at most time points by both routes. Topical absorption of ketoprofen is possible in frogs, although therapeutic levels have not been determined for this species.

Enantioselective analysis of ketoprofen in human saliva by liquid chromatography/tandem mass spectrometry with chiral derivatization

The enantioselective analytical method for trace ketoprofen (KET) in human saliva was developed for the first time using liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS) combined with a derivatization using a chiral reagent, (S)‑1‑methyl‑4‑(5‑(3‑aminopyrrolidin‑1‑yl)‑2,4‑dinitro‑phenyl)piperazine (APy‑PPZ). The APy‑PPZ derivatization enabled highly sensitive detection (detection limit, 0.5 fmol on column) and complete separation with high resolution (Rs = 4.3) of KET enantiomers. The calibration curves of both KET enantiomers in saliva were linear in the concentration range of 5–500 nM. The developed method showed good analytical performance with relative standard deviations (RSDs) below 2.6% and good accuracy (100.5–105.9%) through intra- and inter-assay and gave a potential for practical application to the quantitative determination of KET in human saliva.

Analyses of simulated moving bed with internal temperature gradients for binary separation of ketoprofen enantiomers using multi-objective optimization: Linear equilibria

Gradient operation of a simulated moving bed (SMB) can improve the separation and purification performance by adjusting adsorption strength in each individual zone according to its functional role. The feasibility of an internal temperature gradient (ITG) established by a difference between feed and desorbent temperatures for binary separation of ketoprofen enantiomers was investigated based on simultaneous optimization of purity and productivity of S-ketoprofen, the preferentially adsorbed species and desired product. ITG operation with a temperature difference of 20K has a unit productivity higher than isothermal mode by about 20%. Due to the combined effects of temperature transition and downstream dilution, concentration profile may exhibit a remarkable peak and a pattern of two-step drop in the temperature descending and ascending areas, respectively. Both areas, if properly located under optimal conditions, are favorable for unit productivity, which cannot be predicted by the direct use of triangle theory and average Henry’s constants. Modifications of the SMB operations to reduce solvent consumption were also discussed based on analyses of parametric sensitivity and internal concentration profiles.