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This paper reports the development of a rapid method for the enantioselective analysis of the nonsteroidal anti-inflammatory drug ibuprofen in human plasma by capillary electrophoresis employing the anionic cyclodextrin-modified electrokinetic chromatography mode. Sample cleanup was carried out by acidification with HCl followed by liquid-liquid ex...
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... enantiomeric separation of IBU was optimized by varying the type and concentration of the CD used as chiral selector, type and concentration of buffer solutions and the pH. IBU is an acidic drug (Fig. 1), so it will be negatively charged at background electrolyte (BGE) pH above the pK a value (pk a = 4.4). In preliminary experi- ments, various natives (a-, b-and g-CD) and neutral CD derivatives (hydroxypropyl-b-CD, TMb-CD and ampho- teric b-CD) were investigated under basic conditions (pH.7.0), but chiral recognition was not obtained ...
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... Numerous techniques have been employed to separate single enantiomers from racemic mixtures in chiral drugs (chiral selective processes (racemic to single enantiomers)). These methods include supercritical fluid chromatography [3], gas chromatography [4], capillary electrophoresis [5], high-performance liquid chromatography [6], diastereomeric crystallization, and biocatalysis. Chromatographic techniques are widely used to isolate drug enantiomers due to their ability to generate large quantities of products. ...
... The optimized structures of R-/S-ibuprofen incorporated into the BNNT (R/S@BNNT) in aqueous media were shown in Fig. 2f and g, respectively. The adsorption rate of two enantiomers into the BNNT (10,5) shows that S-ibuprofen reacts with the inner wall of nanotube with slightly higher interaction energy (− 50.824 kcal/mol) rather than the R-Ibuprofen (− 50.197 kcal/mol). The equilibrium distance between the nearest atoms of S-/R-Ibuprofen and the BNNT sidewall was estimated about 2.589/2.871 ...
... Our firstprinciples finding reveals that the outer surface demonstrated more ability for separating between two enantiomers of ibuprofen rather than inner sidewall. As a comparison, the enantioseparation of BNNT (10,5) has been found to be significantly stronger than its isoelectronics counterpart, CNT (10,5), as reported in our previous research work [2]. The estimated ΔU 0 for ibuprofen/CNT(10,5) with similar calculations procedure, DFT-D3/revPBE model of theory, was found about 0.0 and 0.2 (kcal/mol) for outer surface and interior sidewall of pristine CNT (10,5), respectively. ...
The separation of drug enantiomers in pharmaceutical industry is one of great importance since most organic compounds are chiral. In this study, the separation of ibuprofen enantiomers and the interaction between right-handed (R) and left-handed (S) isomers of ibuprofen with the outer surface as well as internal sidewall of a chiral boron nitride nanotube (BNNT(10,5)) was evaluated. The geometry optimizations and total energy calculations were performed with DFT–D3/revPBE-GGA method for various adsorption configurations. Our first-principles findings showed that interaction strength of the incorporated enantiomers into the BNNTs was higher than ones adsorbed onto the outer surface of nanotube. Also, the interaction energy difference between two enantiomers interacting with inside and outside of the BNNT was about 0.63 and 1.25 kcal/mol, respectively. This finding indicated the more ability of outer surface of BNNT in efficient enantioseparation of Ibuprofen isomers rather than inner site. Furthermore, in order to model a realistic system, tight-binding density functional molecular dynamics (DFTB–MD) simulation was performed at room temperature, and the results were consisted with the DFT–D3 findings. The nudged elastic band (NEB) method was also used to evaluate the activation energy barrier for incorporation of ibuprofen into the BNNT cavity. Our molecular simulation findings are reliable to offer beneficial information about the potential application of chiral BNNTs in enantiomer molecules adsorption and separation.
... Also, there are a number of methods described in the literature for IB drug. These included direct and indirect liquid chromatographic methods [16], supercritical-fluid direct chromatography [17], and a combination of micellar electrokinetic chromatographic separation with mass spectrometric detection [18], capillary electrophoresis [19], diffused reflectance and FT-IR spectroscopy [20], and gas chromatography [21]. ...
... The AUC 0-8 h of the (S)-enantiomer (27.4 ± 12.4 ng h/mL, mean ± SD, n = 6) was ca. two times higher than that of the (R)-enantiomer (13.4 ± 5.7 ng h/mL), in agreement with the plasma/serum data in the literature [20,21]. The T max values of both enantiomers were 1.83 ± 0.68 h and the C max values were 5.09 ± 1.97 and 8.74 ± 3.30 ng/mL for the (R)-and (S)-enantiomers, respectively. ...
A method was developed and validated for the enantioselective determination of trace ibuprofen (IBU) in saliva using liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS) combined with the derivatization using a chiral ESI-enhancing reagent, (S)-1-(4-dimethylaminophenylcarbonyl)-3-aminopyrrolidine (DAPAP), and its isotope-coded analog, (2)H4-DAPAP (d-DAPAP). The DAPAP-derivatization enabled the highly sensitive detection [detection limit, 0.15fmol (equivalent to 30fg of intact IBU) on the column] and complete separation (resolution 3.1) of the IBU enantiomers. The use of d-DAPAP significantly improved the assay precision and accuracy; the intra- (n=5) and inter-assay (n=5) relative standard deviations did not exceed 6.2%, and good accuracy (101.3-106.1%) was obtained. The developed method was successfully applied to the quantitative analysis of IBU in saliva. Using this method, salivary concentration-time profiles of each enantiomer after a single oral administration of the racemic IBU to healthy subjects were obtained. The area under the salivary concentration-time curve of the (S)-enantiomer was ca. twice that of the (R)-enantiomer due to the unidirectional chiral inversion of the (R)- to (S)-enantiomer in vivo. Thus, saliva-based noninvasive pharmacokinetic analyses of IBU enantiomers were achieved by this method.
... The analysis of ibuprofen enantiomers in plasma by HPLC with UV detection or MS has been described using derivatization procedures with enantiomerically pure reagents [10][11][12][13][14], addition of chiral selectors as-cyclodextrins in the mobile phase [15] or columns with chiral stationary phases [2,[16][17][18]. Other methods using CE were also described in the literature [8,19]. The present study describes the development and validation of a sensitive and specific method by LC-MS/MS to quantify the enantiomers of ibuprofen using aliquots of only 200 L of plasma, liquid-liquid extraction and separation in a Chirex R 3005 column for the application in studies of kinetic disposition of ibuprofen enantiomers in rats. ...
... The method described by Hassan et al. [15] using-cyclodextrin in the mobile phase as a chiral selector and fluorescence detector report a LLOQ of 35 ng of each ibuprofen enantiomer/mL in plasma. Enantioselective methods for ibuprofen analysis by CE showed LLOQs of 100-200 ng of each enantiomer/mL using 1 mL aliquots of plasma [8,19]. The LLOQ of 25 ng of each enantiomer/mL in plasma obtained in the present investigation was sensitive enough to quantify ibuprofen enantiomers in rat plasma collected up to 8 h after the administration of a single oral dose of 25 mg/kg of the racemate. ...
A sensitive and selective method for the analysis of ibuprofen enantiomers by LC-MS/MS was developed and validated for the purpose of application in pharmacokinetic studies in small experimental animals. Aliquots of 200 μL plasma were submitted to liquid-liquid extraction with hexane/diisopropylether (50:50 v/v) in acid pH. Separation was accomplished in a Chirex® 3005 (250 × 4.6 mm, 5 μm) column at 25°C with a mobile phase that consisted of 0.01 M ammonium acetate in methanol at a flow rate of 1.1 mL/min. The mass spectrometer consisted of an ESI interface operating at negative ionization mode and multiple reaction monitoring. The transitions 205>161 and 240>197 were monitored for ibuprofen enantiomers and fenoprofen (internal standard), respectively. Method validation included the evaluation of the matrix effect, stability, linearity, lower limit of quantification, within-run and between-run precision and accuracy. The lower limit of quantification was 25 ng/mL for each ibuprofen enantiomer, and the calibration curves showed good linearity in the range 0.025-50 μg/mL. The method was successfully applied in the investigation of pharmacokinetic disposition of ibuprofen enantiomers in rats treated orally with 25 mg/kg of the racemate. Enantioselective kinetic disposition was observed with accumulation of (+)-(S)-ibuprofen in rats following single oral administration. This article is protected by copyright. All rights reserved.
... Also, there are a number of methods described in the literature for IB drug. These included direct and indirect liquid chromatographic methods [16], supercritical-fluid direct chromatography [17], and a combination of micellar electrokinetic chromatographic separation with mass spectrometric detection [18], capillary electrophoresis [19], diffused reflectance and FT-IR spectroscopy [20], and gas chromatography [21]. ...
Ibuprofen (C15H18O2) is an anti-inflammatory drug. It is important to investigate its structure to know the active groups and weak bond responsible for its medical activity. Consequently in the present study, ibuprofen was investigated by mass spectrometry (MS) and thermal analyses (TAs) (TG/DTG and DTA), and confirmed by semi-empirical molecular orbital (MO) calculation using PM3 procedure, on the neutral and positively charged forms of the drug. These calculations included bond order, bond length, and bond strain, and charge distribution, heat of formation, and ionization energy. The mass spectra and thermal analysis fragmentation pathways were proposed and compared to each other to select the most suitable scheme representing the correct fragmentation pathway of the drug in both techniques. From the electron ionization (EI) mass spectra, the primary cleavage site of the charged molecule is because of the rupture of COOH group (the lowest bond order) followed by propyl group loss. The TAs of the drug revealed high response of the drug to the temperature variation with very fast rate. It decomposed in several sequential steps in the temperature range 25–360 °C. The initial thermal decomposition is similar to that obtained by MS fragmentation of the first rupture (COOH), then subsequent one of propyl loss, and finally of ethylene loss. These mass losses appear as endothermic peaks required energy values of −214.83, −895.95, and −211.10 J g−1, respectively. The order of these losses is also related to the values of the MO calculation parameters. Therefore, the comparison between MS and TA helps in the selection of the proper pathway representing the decomposition of this drug to give its metabolites in in vivo system. This comparison is also successfully confirmed by MO calculations.
... An important question stemming from the results of these studies concerns the in vivo concentration of ibuprofen in animal and human brain, and to what extent these concentrations inhibit Cox-1, Cox-2, and AA3? The steady-state level of ibuprofen in rat brain and plasma was estimated to be ~3.5 and ~180 μM (Mannila et al., 2005), and the level in human plasma reached ~100 μM after single dose of 600 mg (Jabor et al., 2002). Assuming that humans have a similar ratio of serum to brain ibuprofen, its level in human brain may be roughly estimated at ~1-3 μM. ...
... The values confirmed sensitivity of the method as they were calculated for 0.5 ml plasma and 0.05 ml urine. Moreover, the value of LOQ in plasma is lower than the LOQ of 0. 2 mg l −1 in 1.0 ml of plasma sample reported by Jabor et al. (2002). ...
... Recovery of the chiral analytes from plasma and urine after SPE procedure was in the range of 82-87%, 90-95% and 70-76% for IBP, IBP-OH and IBP-COOH enantiomers, respectively. The obtained values correspond to the literature data reporting 70-90% and higher recovery of IBP (Jabor et al. 2002) and IBP-OH and IBP-COOH (Tan et al. 1997). ...
The pharmacokinetics of ibuprofen enantiomers and its chiral metabolites, namely (R,S)-29-hydroxyibuprofen and (RR,RS,SR,SS)-29-carboxyibuprofen, was studied in healthy volunteers carrying different alleles coding cytochrome P450 (CYP) 4502C isoenzymes. Following administration of 400 mg of racemic ibuprofen, enantiomers of the parent compound and their metabolites were isolated from plasma and urine samples using solid-phase extraction and were quantified by the validated capillary zone electrophoresis method. The levels of the analytes in biological fluids were used to calculate their pharmacokinetic parameters in subjects with different variants of CYP2C8 and CYP2C9 isoenzymes. The analysis of each subject's genotype was carried out using polymerase chain reaction-restriction fragment length polymorphism. Impaired metabolism of ibuprofen enantiomers was associated with the presence of CYP2C8*3, CYP2C9*2 and CYP2C9*3 alleles. The greatest effect of mutated alleles on pharmacokinetics was observed in a subject with a CYP2C8*1/*3, CYP2C9*1/*2 genotype. This subject appeared to have lower value of clearance, greater area under the curve (AUC) and longer time t(0.5) in comparison with the wild-type.
... Hence, the production of active profens in enantiomerically pure forms, their optical purity control and stereoselective pharmacokinetic studies have become important tasks in the chiral drug development45678. These tasks could be more effectively conducted in high-throughput analysis mode by simultaneous enantioseparation of multiple profens in a single run9101112 rather than in more commonly employed individual profen analysis mode13141516171819202122232425. The accurate chiral discrimination of profens requires the use of high-resolution analytical methods. ...
... Most of the chiral CE analyses of profens were achieved employing mainly cyclodextrins (CDs) as the principal chiral selectors [5–25, 28, 29] added to background electrolyte (BGE). Single CD system approaches employed either uncharged CDs such as heptakis( methyl)-b-CD (TMbCD) [9–11, 14, 16, 19, 21, 24] , hydrox- ypropyl-b-CD [13, 21] and cyanoethylated b-CD [18], or charged CDs such as anionic sulfated b-CD [23], cationic b-CD-heptakis(6-methoxyethylamine) [12] and per- methyl-6-monoamino-6-monodexyl-b-CD (PMMAbCD) [25]. They were operated in the conventional normal polarity (NP) mode [10, 14, 19, 24] or more preferentially in the reversed polarity (RP) mode [9, 11–13, 16, 18, 21, 23]. ...
... The EMOs of weakly acidic profens in a given CD system were not reversed by just selecting an appropriate combination of pH and CD concentrations [13, 10]. They could be reversed by reversing the polarity of the high-voltage supply under the conditions of EOF suppression [9, 13, 16, 18, 21], EOF reversal [11], or anionic CD addition [5, 8, 15, 20, 22, 23, 25]. However, attempts to exploit the crosschecking, each EMO measured in the NP and RP modes for the accurate chiral discrimination, have rarely been made in chiral CE of profens [25]. ...
Simultaneous enantioseparations of nine profens for their accurate chiral discrimination were achieved by capillary electrophoresis (CE) in the normal polarity (NP) mode with a single cyclodextrin (CD) system and in the reversed polarity (RP) mode with a dual CD system. The single CD system in the NP mode employed heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin (TMbetaCD) added at 75 mM-100 mM 2-(N-morpholino)ethanesulfonic acid buffer (pH 6.0) as the optimum run buffer. The dual CD system operated in the RP mode used 30 mM TMbetaCD and 1.0% anionic carboxymethyl-beta-cyclodextrin dissolved in pH 3.0, 100 mM phosphoric acid-triethanolamine buffer containing 0.01% hexadimethrine bromide added to reverse the electroosmotic flow. Fairly good enantiomeric resolutions and the opposite enantiomer migration orders were achieved in the two modes. Relative migration times to internal standard under respective optimum conditions were characteristic of each enantiomer with good precision (< 2% relative standard deviation, RSD), thereby enabling to crosscheck the chemical identification of profens and also their accurate chiralities. The method linearity in the two modes was found to be adequate (r > or = 0.9991) for the chiral assay of the profens investigated. Simultaneous enantiomeric purity test of ibuprofen, ketoprofen and flurbiprofen in a mixture was feasible in a single analysis by the present method.
Besides the racemate, the S‐enantiomer of ibuprofen (Ibu) is used for the treatment of inflammation and pain. Since the configurational stability of S‐Ibu in solid state is of interest, it was studied by means of ball milling experiments. For the evaluation of the enantiomeric composition, a chiral CE method was developed and validated according to the ICH guideline Q2(R1). The addition of Mg²⁺, Ca²⁺, or Zn²⁺ ions to the background electrolyte (BGE) was found to improve Ibu enantioresolution. Chiral separation of Ibu enantiomers was achieved on a 60.2 cm (50.0 cm effective length) x 75 μm fused‐silica capillary using a background electrolyte (BGE) composed of 50 mM sodium acetate, 10 mM magnesium acetate tetrahydrate, and 35 mM heptakis‐(2,3,6‐tri‐O‐methyl)‐β‐cyclodextrin (TM‐β‐CD) as chiral selector. The quantification of R‐Ibu in the mixture was performed using the normalization procedure. Linearity was evaluated in the range of 0.68–5.49% R‐Ibu (R² = 0.999), recovery was found to range between 97 and 103%, the RSD of intra‐ and interday precision below 2.5%, and the limit of quantification for R‐ in S‐Ibu was calculated to be 0.21% (extrapolated) and 0.15% (dilution of racemic ibuprofen), respectively. Isomerization of S‐Ibu was observed under basic conditions by applying long milling times and high milling frequencies.
