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Determination of Ketorolac Tromethamine in Human Eye Samples by HPLC with Photo Diode-Array Detection
Abstract
A sensitive and selective reversed-phase HPLC method for analysis of ketorolac in aqueous and vitreous humor from the human
eye has been developed and validated. Chromatographic separation was achieved on a 250mm ×4.6mm i.d., 5-μm particle, C18 analytical column. Photo diode-array detection was performed at 314nm. Response was a linear function of ketorolac concentration
from 10 to 800ngmL−1. The limits of detection (LOD) and quantification (LOQ) were 3.0 and 10ngmL−1, respectively. Intra-day and inter-day bias were less than 2.05 and 2.28%, respectively, and intra-day and inter-day RSD
were no higher than 3.60 and 5.80%, respectively. Fluid obtained from patients eyes’ after topical application of Acular eye
drops before retina decolman surgery was analyzed by use of the method. The method enabled successful quantification of levels
of ketorolac in aqueous and vitreous humor.
... It also has antipyretic properties 20 times more potent than those of aspirin. 25 Ketorolac is marketed in the form of tromethamine salt (KET), which is suitable for oral, intramuscular, intravenous administrations, and as a topical ophthalmic solution. 10,[25][26][27] Like other NSAIDs, ketorolac has been implicated as a contributing cause of increased postoperative bleeding, renal failure, cardiovascular side effects, and gastritis. ...
... 25 Ketorolac is marketed in the form of tromethamine salt (KET), which is suitable for oral, intramuscular, intravenous administrations, and as a topical ophthalmic solution. 10,[25][26][27] Like other NSAIDs, ketorolac has been implicated as a contributing cause of increased postoperative bleeding, renal failure, cardiovascular side effects, and gastritis. The severity of these side effects is probably dose-related. ...
... Moreover, the pharmacological activity resides in the S (À) enantiomer, whereas the R (+) enantiomer has little or no activity. 25,26 Thus, individual determination of KET enantiomers is extremely important whether in bulk powders, pharmaceuticals, or biological media. ...
A novel method was developed for the simultaneous determination of guaifenesin (GUA) and ketorolac tromethamine (KET) enantiomers in plasma samples. Since GUA probably increases the absorption of coadministered drugs (e.g., KET), it would be extremely important to monitor KET plasma levels for the purpose of dose adjustment with a subsequent decrease in the side effects. Enantiomeric resolution was achieved on a polysaccharide-based chiral stationary phase, amylose-2, as a chiral selector under the normal phase (NP) mode and using ornidazole (ORN) as internal standard. This innovative method has the advantage of the ease and reliability of sample preparation for plasma samples. Sample clean-up was based on simply using methanol for protein precipitation followed by direct extraction of drug residues using ethanol. Both GUA and KET enantiomers were separated using an isocratic mobile phase composed of hexane/isopropanol/trifluoroacetic acid, 85:15:0.05 v/v/v. Peak area ratios were linear over the range 0.05-20 µg/mL for the four enantiomers S (+) GUA, R (-) GUA, R (+) KET, and S (-) KET. The method was fully validated according to the International Conference on Harmonization (ICH) guidelines in terms of system suitability, specificity, accuracy, precision, robustness, and solution stability. Finally, this procedure was innovative to apply the rationale of developing a chiral high-performance liquid chromatography (HPLC) procedure for the simultaneous quantitative analysis of drug isomers in clinical samples. Chirality 00:000-000, 2014. © 2014 Wiley Periodicals, Inc.
... The chromatographic techniques such as LC-MS [ 40 , 41 ], HPTLC [42] , polarographic method [43] , spectrophotometric method [44] and HPLC [45][46][47][48][49][50] have been reported in the prior art for the determination of bare/salt forms or combined drug forms of KEC from the human blood and serum samples; besides, a flow injection analysis (FIA) was also reported [51] . All the above-mentioned methods have several limitations, such as involvement of complex procedures, time-consuming protocols, and are expensive. ...
The ketorolac (KEC) is a non-steroidal anti-inflammatory drug (NSAID) which is a water-soluble non-opioid analgesic drug that exhibits antipyretic properties that helps in the treatment concerned with pain. The reports were found on the adverse effect of overdosage of KEC on health which makes to develop the simple, sensitive, and economic electroanalytical method for the trace level detection of KEC. In the present study, pencil graphite was employed as the electrode (PGE) for the electrochemical detection of KEC. The effects of different electrochemical parameters viz., pH of electrolyte, scan rate, and concentration etc., on KEC were explored through cyclic voltammetry (CV) and differential pulse voltammetry (DPV) techniques. The irreversible electrochemical reaction governed by the electrode process governed by the diffusion was attained by KEC at PGE. The linearity range was between 2.0 × 10−6 and 1.0 × 10−3 M, while the limit of detection was 4.59 × 10−7 M. The efficiency of the PGE was determined by analysing KEC in pharmaceutical drugs, and spiked real samples. The capability of the PGE towards the detection of KEC in presence of other chemicals was investigated by conducting an interference study. Hence, the proposed method can be applied for the determination of KEC in real biological and clinical samples.
... Ketorolac tromethamine works by blocking the production of prostaglandins, compounds that cause pain, fever and inflammation [3]. Ketorolac tromethamine (C 19 H 24 N 2 O 6 ) has a molecular weight 376.4 g/mol and it was estimated by various analytical methods such as spectrophotometry [4][5][6], HPTLC [7,8], voltammetry [9], fluorophotometry [10], HPLC [11][12][13] and in biological fluids such as human plasma [14], human serum [15], human eye samples [16], serum and synovial fluids [17] and post mortem blood samples [18] in the literature. In the present study the authors have proposed five UV spectrophotometric methods for the determination of Ketorolac tromethamine in pharmaceutical dosage forms and the methods were validated as per ICH guidelines [19]. ...
... Literature survey reveals that Ketorolac tromethamine was estimated by various analytical methods such as HPLC [4][5][6], HPTLC [7,8], fluorophotometry [9], voltammetry [10], spectrophotometry [11][12][13] and in biological fluids such as human serum [14], human plasma [15], human eye samples [16], post mortem blood samples ...
... A number of analytical methods have been investigated for the determination of KTL either alone or in its salt form or combination with other drugs, such as liquid chromatography-mass spectrometry (LC-MS/MS) [4], high-performance thin-layer chromatography [5], LC-MS [6], and high-performance liquid chromatography (HPLC) [7][8][9][10][11]. KTL has been determined in blood after a solid-phase extraction by gas chromatography-MS after derivatization using diazopropane [12]. ...
Objectives: The study has been carried to investigate the electro-oxidation mechanism and to develop a selective and sensitive method for determination of ketorolac (KTL), a non-opioid analgesic drug,.Methods: A simple electro analytical method was used for the determination of ketorolac (KTL) using glassy carbon electrode by cyclic and differential pulse voltammetric techniques (DPV). The effect of various experimental parameters such as accumulation time, pH, scan rate, on the voltammetric responses of KTL was evaluated.Results: In the optimized conditions, variation of peak current with respect to concentration was studied and the calibration curve of the peak current vs. KTL concentration was drawn with a linear range of 10- 350 μM with an excellent detection limit of 8.08×10-8 M. This method was successfully tested for the determination of KTL in pharmaceuticals and human urine samples.Conclusion: From the results, it was observed that, the selected method is rapid, sensitive and low cost.
... The mechanism of action is to inhibit prostaglandin biosynthesis and given systemically does not cause pupil constriction. [6][7][8] In India, it is marketed under the trade name of Acular LS and Ketorol gel. Several studies for the estimation of the Ketorolac Tromethamine drug using various techniques have been utilized like Simultaneous Reverse phase high pressure liquid chromatographic (RP-HPLC) method used for estimation of ketorolac tromethamine in ophthalmic dosage forms 9 , Simultaneous spectrophotometric estimation of Ofloxacin and Ketorolac Tromethamine in tablet dosage forms 10 ; Simultaneous estimation of combination diclofenac sodium, famotidine and ketorolac tromethamine has also been reported. ...
... Meanwhile it possesses the inhibitory effect on platelet aggregation. After intramuscular injection, the analgesic effect is similar to Article Related Abbreviations: ACN, acetonitrile; CSP, chiral stationary phase; CTMB, cellulose tris- (4-methylbenzoate); FA, formic acid; HAc, acetic acid; MeOH, methanol; TFA, trifluoroacetic acid the same amount of morphine [5]. The chiral center endows Ketorolac chirality and its clinical application is in the form of racemate. ...
Ketorolac has been widely applied in clinical medicine for its antipyretic, analgesic and anti‐inflammatory pharmacological activity. Research showed that the analgesic effect of the S enantiomer is 230 times stronger than that of the R enantiomer. Getting the high‐purity S enantiomer of Ketorolac has profound significance but still remains a challenging topic. In this work, the separation of the R and S enantiomers of Ketorolac was investigated on polysaccharide‐based chiral stationary phases. Chiralcel AD‐H, OD‐H, OJ‐H and AS‐H columns were evaluated using polar organic and normal phase mode, respectively, in which the OJ‐H column showed the best performance with high selectivity and resolution for Ketorolac with α = 2.43 and RS = 9.04 by using methanol/formic acid (100:0.1, v/v) as the mobile phase. The influences of acid additive, composition of mobile phase and temperature were examined. The coating amount of cellulose tris‐(4‐methylbenzoate) has significant influence on the sample loadability. The high loadability of chiral stationary phases coated with 40% of cellulose tris‐(4‐methylbenzoate) allows preparative separation up to 16 mg on an analytical column of 250 × 4.6 mm id in a single run for Ketoroac using methanol/formic acid (100:0.1, v/v) as mobile phase, which shows a potential application in industrial preparation.
... Different methods were developed for determining KTC including the HPLC method in human plasma samples (11), HPTLC (12), HPLC in human eye and tablet dosage form (13), the fluorimetric method using stopped-flow sequential injection analysis (14), the HPLC method in tablet dosage forms (15), and spectrophotometric methods (16,17). ...
The present work describes new spectrophotometric methods for the simultaneous determination of phenylephrine hydrochloride and ketorolac tromethamine in their synthetic mixtures. The applied chemometric techniques are multivariate methods including classical least squares, principal component regression, and partial least squares. In these techniques, the concentration data matrix was prepared by using the synthetic mixtures containing these drugs dissolved in distilled water. The absorbance data matrix corresponding to the concentration data was obtained by measuring the absorbances at 16 wavelengths in the range 244-274 nm at 2 nm intervals in the zero-order spectra. The spectrophotometric procedures do not require any separation steps. The accuracy, precision, and linearity ranges of the methods have been determined, and analyzing synthetic mixtures containing the studied drugs has validated them. The developed methods were successfully applied to the synthetic mixtures and the results were compared to those obtained by a reported HPLC method.
... [5,6] A detailed survey of analytical literature for moxifloxacin hydrochloride revealed several methods based on varied techniques, viz, HPLC, [7][8][9][10] Spectrophotometry, [11,12] High-Performance Thin-Layer Chromatography (HPTLC). [13,14] Similarly, a survey of the analytical literature for ketorolac tromethamine revealed several methods like HPLC, [15,16] HPTLC, [17,18] LC/MS/MS (Liquid Chromatography-Mass Spectrometry-Tandem Mass Spectrometry), [19] capillary electro chromatography. [20] The published literature revealed spectrophotometric determination of moxifloxacin hydrochloride and ketorolac tromethamine in combination. ...
Background and Aim: A fixed dose combination of moxifloxacin hydrochloride and ketorolac tromethamine is used in ratio of 1:1 as eye drops for the treatment of the reduction of post operative inflammatory conditions of the eye. A simple, precise, and accurate High Performance Liquid Chromatographic (HPLC) method was developed and validated for determination of moxifloxacin hydrochloride and ketorolac tromethamine in eye drops. Materials and Methods: Isocratic HPLC separation was achieved on a ACE C 18 column (C 18 (5 μm, 150 mm×4.6 mm, i.d.)) using the mobile phase 10 mM potassium di-hydrogen phosphate buffer pH 4.6-Acetonitrile (75:25 v/v) at a flow rate of 1.0 mL/min. The detection was performed at 307 nm. Drugs were subjected to acid, alkali and neutral hydrolysis, oxidation and photo degradation. Moreover, the proposed HPLC method was utilized to investigate the pH dependent degradation kinetics of moxifloxacin hydrochloride and ketorolac tromethamine in buffer solutions at different pH values like 2.0, 6.8 and 9.0. Results and Conclusion: The retention time (t R ) of moxifloxacin hydrochloride and ketorolac tromethamine were 3.81±0.01 and 8.82±0.02 min, respectively. The method was linear in the concentration range of 2-20 μ/mL each for moxifloxacin hydrochloride and ketorolac tromethamine with a correlation coefficient of 0.9996 and 0.9999, respectively. The method was validated for linearity, precision, accuracy, robustness, specificity, limit of detection and limit of quantitation. The drugs could be effectively separated from different degradation products and hence the method can be used for stability analysis. Different kinetics parameters like apparent first-order rate constant, half-life and t 90 (time for 90% potency left) were calculated.
... [7][8][9][10] A few analytical and bioanalytical methods have been reported in the literature for the determination of KETO alone or in combination with other drugs. It includes determination of KETO in biological samples by using LC and LC/MS methods [11][12][13][14][15][16][17][18][19][20][21] as well as LC/MS/MS method, [22] in vivo metabolites identification, [23] spectrophotometric estimation of KETO by different methods, [24] determination of KETO by HPTLC, [25] determination of KETO and its impurities by capillary electrochromatography, [26] assay of KETO in pharmaceutical matrices using differential pulse polarography, [27] derivative adsorptive chronopotentiometry, [28] and high-performance liquid chromatography (HPLC) methods. [29][30][31] The hydrolytic degradation behavior of KETO was studied under acidic and alkaline conditions by Salaris et al. [32] One acid hydrolysis product was identified that is listed in British Pharmacopoeia as impurity H, chemically known as methyl (1RS)-5-benzoyl-2,3dihydro-1H-pyrrolizine-1-carboxylate (Scheme 1, structure K-8). ...
Ketorolac, a nonsteroidal anti-inflammatory drug, was subjected to forced degradation studies as per International Conference on Harmonization guidelines. A simple, rapid, precise, and accurate high-performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (LC/ESI/Q/TOF/MS/MS) method has been developed for the identification and structural characterization of stressed degradation products of ketorolac. The drug was found to degrade in hydrolytic (acidic, basic, and neutral), photolytic (acidic, basic, and neutral solution), and thermal conditions, whereas the solid form of the drug was found to be stable under photolytic conditions. The method has shown adequate separation of ketorolac tromethamine and its degradation products on a Grace Smart C-18 (250 mm × 4.6 mm i.d., 5 µm) column using 20 mM ammonium formate (pH = 3.2): acetonitrile as a mobile phase in gradient elution mode at a flow rate of 1.0 ml/min. A total of nine degradation products were identified and characterized by LC/ESI/MS/MS. The most probable mechanisms for the formation of degradation products have been proposed on the basis of a comparison of the fragmentation of the [M + H]+ ions of ketorolac and its degradation products. In silico toxicity of the drug and degradation products was investigated by using topkat and derek softwares. The method was validated in terms of specificity, linearity, accuracy, precision, and robustness as per International Conference on Harmonization guidelines. Copyright © 2014 John Wiley & Sons, Ltd.
... A detailed literature survey revealed that a number of methods are available for determination of KTR, SMP and SPP individual in serum by high-performance liquid chromatography (HPLC) [8][9][10][11][12][13][14][15][16][17] , gas chromatography mass spectrometry [18] , spectrophotometry [19,20] , liquid chromatography mass spectrometry [21] , and in pharmaceutical dosage form by HPLC [22][23][24][25] . ...
A sensitive, fast, and stability-indicating isocratic reverse-phase ultra-performance liquid chromatography method was developed and validated for quantitative simultaneous determination of sodium methylparaben, sodium propylparaben and ketorolac tromethamine in topical dosage forms. Separation of all peaks was achieved by using acquity ethylene bridged hybrid C18 (50×2.1 mm, 1.7 μ) as stationary phase, mobile phase used was triethylamine buffer (pH 2.5):tetrahydrofuran:methanol (665:35:300, v/v/v) with isocratic mode at a flow rate of 0.40 ml/min. All component were detected at 252 nm with 10 min run time. The described method was found to be linear in the concentration range of 248-744 μg/ml for ketorolac tromethamine, 20.8-62.4 μg/ml for sodium methylparaben and 2.38-7.13 μg/ml for sodium propylparaben with correlation coefficients more than 0.999. Method was validated in terms of specificity, linearity, accuracy, precision, solution stability, filter equivalency, and robustness as per International Conference on Harmonization guideline. Formulation was exposed to the stress conditions of peroxide, acid, base, thermal, and photolytic degradation and proven all components were well separated in the presence of degradants.
... It is indicated for the short-term management of moderate to severe pain. Literature survey showed that very few analytical methods have been reported for the estimation of ketorolac in single or in combination such as spectrophotometric [5] , flow injection analysis [6] , high-performance liquid chromatography (HPLC) [7][8][9][10][11][12][13][14][15] , high-performance thin layer chromatography (HPTLC) [16] and gas chromatography-mass spectrometry [17] , which are either less economical or less sensitive. For routine analysis, a simple, rapid and most sensitive analytical method is preferred. ...
A reliable, rapid and sensitive isocratic reverse phase high-performance liquid chromatography method has been developed and validated for assay of ketorolac tromethamine in tablets and ophthalmic dosage forms using diclofenac sodium as an internal standard. An isocratic separation of ketorolac tromethamine was achieved on Oyster BDS (150×4.6 mm i.d., 5 μm particle size) column using mobile phase of methanol:acetonitrile:sodium dihydrogen phosphate (20 mM; pH 5.5) (50:10:40, %v/v) at a flow rate of 1.0 ml/min. The eluents were monitored at 322 nm for ketorolac and at 282 nm for diclofenac sodium with a photodiode array detector. The retention times of ketorolac and diclofenac sodium were found to be 1.9 min and 4.6 min, respectively. Response was a linear function of drug concentration in the range of 0.01-15 μg/ml (R (2)=0.994; linear regression model using weighing factor 1/x (2)) with a limit of detection and quantification of 0.002 μg/ml and 0.007 μg/ml, respectively. The % recovery and % relative standard deviation values indicated the method was accurate and precise.
Ketamine Hydrochloride Ketanserin Ketobemidone Hydrochloride Ketoconazole Ketoprofen Ketorolac Tromethamine Ketotifen Fumarate References
Objective: The main objective of the present investigation was to develop a simple isocratic stability indicating reversed phase liquid chromatographic method and validate the proposed method and to apply it for the estimation of ketorolac tromethamine, a non-steroidal anti-inflammatory drug in pure and pharmaceutical formulations. Methods: Waters high performance liquid chromatographic 2695 series system, inertsil ODS, C18 (150 mm × 4.6 mm × 5.0 µ) column and UV-visible detector with photo diode array detection was adopted for the method development. The components were separated by injecting about 20 µL working standard solution of concentration 5 µg/mL, using mobile phase prepared by mixing buffer of 100 mM potassium dihydrogen orthophosphate solution of pH 4.5 and acetonitrile in the ratio 60:40 v/v at a flow rate of 0.8 mL/minute, and the components were detected at a wavelength of 316 nm. Results: The proposed method was validated as per ICH guidelines. The developed method was found to be precise, accurate, linear, robust and rugged. A study of forced degradation was carried out and found that the drug was stable under variety of degradation conditions. Conclusion: The proposed method was adopted for assay of pharmaceutical formulations and recommended for routine analysis in any quality control laboratory. © 2015, Asian Journal of Pharmaceutical and Clinical Research. All rights reserved.
This book is a compilation of summarized analytical methods designed to serve the needs of pharmacologists, toxicologists, and other allied health professionals involved the development, use, or monitoring of pharmaceuticals. The summaries are structured monographs on 511 different drug entities detailing 964 different analytical methods, providing the reader with a thorough description of method validation. These analytical methods include not only high performance liquid chromatography (HPLC), but also gas chromatography (GC), immunoassay, electrophoresis, ultra performance liquid chromatography (UPLC) coupled with UV (UPLC-UV) detection and mass spectrometry (UPLC-MS/MS). With more detailed and complete summaries than sketchy and abbreviated formats used in the other books, this book provides a thorough description of method validation and results, as well as the operating parameters.
ABSTRACT
An isocratic, reversed phase-HPLC method was developed and validated for the quantitative determination of Ofloxacin and Ketorolac Tromethamine in combined-dosage form. A thermo hypersil BDS C18 (250mmx4.6mm, particle size 5µm) column with mobile phase containing water (pH - 2.8 adjusted with ortho phosphoric acid) and methanol in the ratio of 60: 40, v/v was used. The flow rate was 1.0 mL/min, column temperature was 30°C and effluents were monitored at 241 nm. The retention times of ofloxacin and ketorolac tromethamine were 4.671min and 5.751 min respectively. The correlation co-efficient values for both the ofloxacin and Ketorolac tromethamine were found to be 1. The proposed method was validated with respect to linearity, accuracy, precision, specificity, and robustness. Recovery of ofloxacin and Ketorolac tromethamine in formulations was found to be 100% confirms the non-interferences of the excipients in the formulation. Due to its simplicity, rapidness and high precision, the method can be successfully applied to the estimation of Ofloxacin and Ketorolac tromethamine in combined dosage form.
Keywords: RP-HPLC, Ofloxacin and Ketorolac Tromethamine.
A simple, precise, specific and accurate RP-HPLC method has been developed and Validated for the simultaneous determination of Moxifloxacin Hydrochloride and Ketorolac Tromethamine in Ophthalmic dosage form. The determination was carried out by using Hypersil BDS C 18 column (250mm×4.6 mm, 5µm).The Chromatographic separation was done with Acetonitrile: Buffer (pH:4) (60:40) as the mobile phase at a flow rate 1.0 ml/min and the eluent was monitored at 294nm. Buffer solution is prepared by using 0.05 mol Ammonium acetate and pH: 4 is adjusted by using OPA (Ortho Phosphoric Acid). The Retention time of Moxifloxacin Hydrochloride and Ketorolac Tromethamine were 3.54 and 5.62 respectively. Linearity for the Moxifloxacin and Ketorolac were found in the range of 10-90 µg/ml. The method was validated according to the ICH guidelines with respect to specificity, linearity (r 2 = 0.998), accuracy (102 to 98%), precision and robustness (RSD < 2%). The method was reproducible, with good resolution between Moxifloxacin Hydrochloride and Ketorolac Tromethamine and can be use for routine analysis.
A simple, rapid and selective RP-HPLC method was developed and validated for the determination of ketorolac and five piperazinylalkyl
ester prodrugs. A binary isocratic mobile phase composed of a mixture of 65:35 (v/v) 0.02M phosphate buffer (pH5.4) and acetonitrile was used on a C18 column (125×4mm, 5μm). The injection volume was 25μL and the detection wavelength was 314nm and the flow rate was 1.5mLmin−1. The method exhibited excellent linearity with R
2 of no less than 0.999 and intra-assay and inter-assay precision that were less than the maximum amount allowed according
to Horwitz equation. The accuracy was found to be within the allowed ±15%. The limits of detection for the analytes were between
0.060 and 0.220μg mL−1 and the limits of quantification were between 0.183 and 0.667μg mL−1. This method was used successfully for the study of the solubility, stability and partition coefficients of piperazinylalkyl
ester prodrugs of ketorolac.
A reversed-phase high-performance liquid chromatographic assay was used to study the bioequivalence of the anti-inflammatory drug (+/-)-ketorolac in human volunteers. Following deproteinization of human serum with 5% zinc sulphate solution, ketorolac was chromatographed on a 10-microns octadecylsilica column using acetonitrile-water as mobile phase and ultraviolet detection at 313 nm. Under these conditions the method was reproducible with a coefficient of variation of less than 5%. The assay procedure was linear in the range 0.25-1.5 micrograms/ml, with a sensitivity of 0.01 micrograms/ml ketorolac. The recovery of ketorolac from serum ranged from 90 to 95%.
An indirect and a direct HPLC method for the quantification of the (R) and (S) enantiomers of ketorolac are described here. The indirect method employs the chiral amine (+)-R-1-(1-naphthyl)ethylamine to form disastereomeric amides; separation of the disastereomeric derivates is achieved by normal-phase HPLC with a mobile phase of ethyl acetate-hexane. The direct method uses a C18 solid-phase extraction column to extract ketorolac enantiomers from plasma; the reconstituted extract is then injected onto an alpha 1-acid glycoprotein chiral column using a mobile phase of isopropanol-phosphate buffer (0.05 M; pH 5.5). Both methods are reproducible, accurate, and stereospecific, and both have equivalent quantification limits (0.02 microgram ml-1 of plasma for each enantiomer), ranges (0.02-2.0 micrograms per aliquot of plasma), precision (% relative standard deviations of < or = 10.5% and < or = 10.8% for (R)- and (S)-ketorolac respectively), and accuracy (mean recoveries of 88.4-110% and 90.1-110% for (R)- and (S)-ketorolac respectively). Results of analyses of clinical samples by the two methods showed excellent agreement (slope near 1.0 and coefficients of correlation between 0.9740 and 0.9864 for both enantiomers).
To examine the effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of cystoid macular oedema (CMO) following cataract surgery.
Systematic literature review of randomised controlled trials (RCTs) that evaluated the effects of NSAIDs in the treatment of CMO following cataract surgery was done according to the Cochrane Collaboration methodology.
Seven trials involving a total of 266 participants were included. Four trials studied the effects of NSAIDs in chronic CMO while the other three trials examined the effect of NSAIDs in acute CMO. Little evidence of effectiveness was found for oral indomethacin and topical fenoprofen for chronic CMO in two small trials. Treatment with topical 0.5% ketorolac for chronic CMO was found to be effective in two trials. Three trials examined the effect of topical NSAIDs on acute CMO. The comparisons among these studies were of a NSAID to placebo, prednisolone or another NSAID. Because of considerable heterogeneity between these study designs, their results were not combined in a meta-analysis.
A positive effect of topical NSAID (0.5% ketorolac tromethamine ophthalmic solution) on chronic CMO was noted. However, there is not enough evidence to show the effectiveness of NSAIDs in acute CMO following cataract surgery.
The adsorption behavior of ketorolac on a hanging mercury drop electrode (HMDE) was explored by square-wave and cyclic voltammetry. The square wave voltammetric response of ketorolac depends on the parameters of the square wave voltammetry excitation signal as well as on the pH of the medium and the accumulation time. The drug was accumulated at HMDE and a well-defined peak was obtained at -1.41 V versus. Ag/AgCl (saturated KCl) in acetate buffer of pH 5.0. A square-wave adsorptive stripping voltammetric method for the quantitative determination of ketorolac was developed. The linear concentration range was 1x10(-10)-1x10(-8) when using 300 s accumulation at -0.8 V. The detection limit of ketorolac was 1.0x10 (-11)M . The precision was excellent with relative standard deviation of 3.85% at concentration of 5x10 (-8)M after 60 s accumulation time. Applicability to serum samples was illustrated. A detection limit of 14 ng per ml of serum was obtained.
A differential pulse polarographic method for the quantitative determination of ketorolac is described. Ketorolac is an antiinflamatory-analgesic agent that is directly electroreducible at the mercury electrode. The polarographic reduction is due to the reduction of the benzoyl moiety in the ketorolac molecule. For analytical purposes, a very well resolved diffusion controlled differential pulse polarographic peak obtained at pH 9 was selected. This peak was used to develop a new method for the determination of ketorolac in pharmaceutical dosage forms. Recovery study shows that the method is sufficiently accurate and precise to be applied in the individual tablet assay of commercial samples.
This paper describes analytical methods using high-performance liquid chromatography and gas chromatography-mass spectrometry
(GC-MS) for the isolation of the nonsteroidal anti-inflammatory drug, ketorolac. The drug is isolated from postmortem blood
using a hatched solid-phase extraction method on Amberlite XAD-2 resin. Derivatization of ketorolac using diazopropane was
necessary prior to GC-MS analysis. The methods were applied in the investigation of a death occurring shortly after the administration
of an intramuscular injection of ketorolac tromethamine. Death was attributed to an adverse reaction to the drug, resulting
in anaphylaxis and cardiac arrest.
A high-performance liquid chromatographic method for the determination of the enantiomers of ketorolac in human plasma has been developed. Plasma samples containing ketorolac were acidified and extracted into diethyl ether. The ethereal extract was evaporated to dryness and the residue reconstituted in mobile phase before injection onto a Chiral-AGP column. The mobile phase was 2-propanol-20 mM potassium dihydrogenphosphate buffered to pH 7 (0.5:99.5, v/v). Detection was by ultraviolet absorbance at 320 nm. The detection limit was 5 ng/ml for each enantiomer. The method has been applied to determine the concentration of ketorolac enantiomers during an infusion of the racemic drug and has proven to be rapid and sensitive.
A chirally selective high-performance liquid chromatographic assay was developed to measure the R(+) and S(-) enantiomers of ketorolac in plasma for pharmacokinetic studies. Naproxen sodium [S(+) enantiomer] (10 micrograms) was used as an internal standard. Plasma samples (0.5 ml) were acidified (50 microliters of 4 M H3PO4 to pH 1.5), extracted into 0.4 ml of 10% pentan-2-ol in hexane and back-extracted into 0.15 ml of base (20 mM NaOH pH to 7-8), of which samples (5 microliters) were chromatographed on a 100 x 4 mm I.D. column packed with an HPLC chiral stationary phase based upon immobilized alpha 1-acid glycoprotein (Chiral AGP-CSP) with 4% propan-2-ol in 0.1 M NaH2PO4 pH 5.5, at 0.9 ml/min. Detection was at 325 nm and run time was 10 min. Retention times of R- and S-ketorolac and of S(+)-naproxen were 3.3, 4.8 and 6.4 min, respectively. The metabolite p-hydroxyketorolac was not resolved enantiomerically and had a retention time of 2.2 min. The assay was linear over the range 0.5-10 mg/l, with precisions < 5% C.V. Good separations (alpha > 1.35) and resolutions (Rs > 3.23) between peaks were achieved. The sensitivity could be extended to 35 micrograms/l with less precision by increasing the injection volume to 100 microliters.
Diclofenac sodium, famotidine and ketorolac tromethamine were determined by flow injection analysis (FIA) with spectrophotometric detection. The sample solutions (5-50 micrograms ml-1 of diclofenac sodium, 10-80 micrograms ml-1 of famotidine and 10-120 micrograms ml-1 of ketorolac tromethamine) in methanol were injected into a flow system containing 0.01% (w/v) of 2,4,dichloro-6-nitrophenol (DCNP) in methanol. The colour produced due to the formation of a charge transfer complex was measured with a spectrophotometric detector set at 450 nm. A sampling rate of 40 per hour was achieved with high reproducibility of measurements (RSD below 1.6%). The FIA method was applied to the determination of diclofenac sodium, famotidine and ketorolac tromethamine in pharmaceutical formulations.
A high-performance liquid chromatographic (HPLC) analytical method is described for the quantification of the (R)- and (S)-enantiomers of ketorolac when present together in human plasma. The method involves derivatization with thionyl chloride/(S)-1-phenylethylamine and subsequent reversed-phase chromatography of the diastereomeric (S)-1-phenylethylamides of (R)- and (S)-ketorolac. The method is suitable for the analysis of large numbers of plasma samples and has been applied in this report to a pharmacokinetic study of ketorolac enantiomers upon intramuscular administration of racemic drug to a human subject. The limit of quantification for each enantiomer of ketorolac is 50 ng/ml (signal-to-noise ratio > 10).
A simple, selective and sensitive method has been developed to determine ciprofloxacin in human aqueous humor. Separation of ciprofloxacin was carried out with pipemidic acid as internal standard using a Novapak C18 reversed-phase cartridge column (100 x 8 mm i.d., particle size 4 microns) and a mobile phase consisting of methanol-acetonitrile-citric acid (0.4 M) (3:1:10, v/v/v) at a flow rate of 1 ml min-1. The column effluent was monitored with fluorescence detection at 278 nm (excitation) and 450 nm (emission) after direct injection. The retention times were 4.88 min for pipemidic acid and 7.52 min for ciprofloxacin. The within-day and day-to-day reproducibilities were less than 7% for ciprofloxacin at 0.1 and 1 microgram ml-1 (n = 6). The mean recovery from aqueous humor was found to be 101.37 +/- 6.7% for ciprofloxacin at 0.1 micrograms ml-1 (n = 6 and the detection limit corresponding to a signal-to-noise ratio of 2.5:1 was 250 pg ml-1. The method was shown to be suitable for determining ciprofloxacin levels in human aqueous humor samples.
A reversed-phase high-performance liquid chromatographic method is described for the determination of ofloxacin in human aqueous humour; the method involves fluorescence detection (excitation at 290 nm; emission at 500 nm) after direct injection of samples. The method utilized a 100 mm x 8 mm i.d. cartridge column packed with 4 microns Novapak C18 with a mobile phase methanol-acetonitrile-0.4 M citric acid (3:1:10, v/v/v) and a flow rate of 1 ml min-1 at ambient temperature. The retention times for the internal standard pipemidic acid and for ofloxacin were 4.82 and 7.32 min respectively. The mean recovery (+/- ISD) from human aqueous humour was 103.24 +/- 4.45% for ofloxacin at 1 microgram ml-1 (n = 6). The within-day and day-to-day RSDs at 0.1 microgram ml-1 and 1 microgram ml-1 were less than 6.71% (n = 6) and the lower limit of reliable determination corresponding to a signal-to-noise ratio of 2.5:1 was 20 ng ml-1. The assay was shown to be suitable for measuring ofloxacin levels in human aqueous humour samples after topical, oral and intravenous administration.
A chemical and a stable-isotope analog, p-fluoroketorolac and [18O3]ketorolac respectively, were directly compared for applicability as internal standards for the determination of ketorolac in plasma samples using gas chromatography/mass spectrometry (GC/MS) with selective-ion-monitoring detection, following derivatization to form the methyl esters. This comparison involved analyzing ketorolac calibration standards and spiked plasma samples that contained both internal standard candidates. The response for ketorolac and each internal standard was monitored simultaneously and electronically integrated peak heights were obtained. Thus, for each analysis performed, a response ratio was obtained for each internal standard relative to an identical ketorolac response. Linearity of response for ketorolac calibration standards and accuracy for spiked plasma sample analysis were compared using each internal standard. The use of [18O3]ketorolac as the internal standard provided superior accuracy data for the analysis of ketorolac in plasma samples.
A method is described for the simultaneous analysis of 14 non-steroidal anti-inflammatory drugs (NSAIDS) in human serum using negative electrospray ionization-tandem mass spectrometry (ESI-MS/MS). After addition of internal standard and protein precipitation using acetonitrile, samples were transferred to autosampler vials for direct analysis without chromatography. Injection of an air bubble with the sample and a multiple reaction monitoring (MRM) method using argon collision-induced dissociation (CID) of analyte (M-H)- ions permitted integration of the product ion peak areas to produce reproducible quantitative data over the range of concentrations expected in serum during routine use of these drugs. The method permitted the analysis of 30 samples per hour. Two hundred fifty consecutive analyses did not adversely affect instrument sensitivity.
A High Performance Thin Layer Chromatography (HPTLC) method for quantification of ketorolac tromethamine, a non-narcotic and non-steroidal agent was developed. The mobile phase composition was chloroform-ethyl acetate-glacial acetic acid (3:8:0.1, v/v/v). Spectrodensitometric analysis of ketorolac tromethamine was carried out at 323 nm. The calibration curve was linear in the range of 200-700 ng. The mean values of slope, intercept and correlation coefficient were, 2941, 749583, 0.99. The method was validated for method precision, system precision, marketed sample analysis and recovery studies. The % CV for method precision studies was 1.98 (n = 6) and system precision study was 1.83 (n = 6). The average recovery was found to be 99.2%. Acid and base degraded products were adequately separated from the drug. The method was successfully used for the determination of drug from saliva. The results indicate that the method is simple, specific, selective and reliable for quantitative analysis of ketorolac tromethamine as bulk drug and from formulations. It can also be applied for the stability study of the drug and analysis of drug in biological fluids.
An improved high-performance liquid chromatographic method has been developed to measure human plasma concentrations of the analgesic nonsteroidal anti-inflammatory drug ketorolac for use in pharmacokinetic studies. Samples were prepared for analysis by solid-phase extraction using Bond-Elut PH columns, with nearly complete recovery of both ketorolac and the internal standard tolmetin. The two compounds were separated on a Radial-Pak C18 column using a mobile phase consisting of water-acetonitrile-1.0 mol/l dibutylamine phosphate (pH 2.5) (30:20:1) and detected at a UV wavelength of 313 nm. Using only 250 microl of plasma, the standard curve was linear from 0.05 to 10.0 microg/ml.
A reversed-phase high-performance liquid chromatographic method is described for the determination of betaxolol in human aqueous humour. Betaxolol and the internal standard metoprolol were extracted with cyclohexane and separated on a reversed-phase column (Luna C(18), 250 x 4.6 mm, 5 microm) with a mobile phase containing acetonitrile-phosphate buffer (40:60, v/v) at a flow-rate of 0.8 ml/min. The column effluent was monitored with a fluorescence detector at 227 nm (excitation) and 301 nm (emission). The retention times for metoprolol and betaxolol were 3.55 and 5.63 min, respectively. The recovery from aqueous humour was found to be 71.6% for betaxolol at 1.25 microg/ml. The within-day and day-to-day accuracy values were in the range of 96.17-105.2% for betaxolol at 0.1, 4 and 12 microg/ml (n=6), within-day and day-to-day precision values were less than 10% for betaxolol at the concentrations given above. The detection limit corresponding to the signal-to-noise ratio of 3:1 was 15 ng/ml. The presented method was suitable for measuring betaxolol levels in human aqueous humour samples obtained from patients after topical administration.
A simple, fast and selective micellar electrokinetic chromatographic (MEKC) method for the simultaneous assay of ketorolac tromethamine and its known related impurities (1-hydroxy analog of ketorolac, 1-keto analog of ketorolac and decarboxylated ketorolac), in both drug substance and coated tablets, is described. The compounds were detected at 323 nm, and flufenamic acid (FL) and tolmetin (TL) were chosen as internal standards to quantify ketorolac tromethamine and impurities, respectively. The multivariate optimization of the experimental conditions was carried out by means of the response surface study, considering as responses the resolution values and analysis time. The optimized background electrolyte (BGE) consisted of a mixture of 13 mM boric acid and phosphoric acid, adjusted to pH 9.1 with 1 M sodium hydroxide, containing 73 mM sodium dodecyl sulfate (SDS). Optimal temperature and voltage were 30 degrees C and 27 kV. Applying these conditions, all compounds were resolved in about 6 min. The related substances could be quantified up to the 0.1% (w/w) level. Validation was performed, either for drug substances and drug product, evaluating selectivity, robustness, linearity and range, precision, accuracy, detection and quantitation limits and system suitability.
Martindale The Complete Drug Reference
- S C Sweetman
- SC Sweetman