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1.
Biomed Chromatogr ; 33(10): e4611, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31145820

RESUMEN

In this study, a simple and reliable liquid chromatography coupled with Q-Exactive-Orbitrap-MS was developed and validated for detecting and quantifying cligosiban and its metabolites in dog plasma after oral administration. The plasma samples were pretreated with acetonitrile and separated on a Diamonsil C18 column (4.6 × 100 mm, i.d. 3 µm) with 0.1% formic acid in water and acetonitrile as mobile phase. The method was validated according to the guidance of the US Food and Drug Administration. The assay was linear over the tested concentration ranges with coefficients of correlation >0.995. The extraction recovery was >83.23% with RSD <15%. Precision was <9.31% and accuracy ranged from -4.40 to 10.20%. The method was free of matrix effects. Under the conditions used, four metabolites were detected and their identities were identified by accurate masses and fragment ions. M1 and M3 were further confirmed by reference standards. The biotransformation pathways included demethylation and glucuronidation. The validated method was further applied to quantify cligosiban, M1 and M3 in dog plasma. After oral administration, cligosiban was detectable in dog plasma and reached the maximum concentration at ~1.67 ± 0.58 h post-dose. It was rapidly eliminated with a half-life of 3.48 ± 0.80 h. M1 showed high plasma exposure with its area under the curve being 23.31% of that of cligosiban.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Piridinas/sangre , Piridinas/farmacocinética , Espectrometría de Masas en Tándem/métodos , Triazoles/sangre , Triazoles/farmacocinética , Administración Oral , Animales , Perros , Estabilidad de Medicamentos , Límite de Detección , Modelos Lineales , Masculino , Piridinas/administración & dosificación , Piridinas/química , Reproducibilidad de los Resultados , Espectrometría de Masa por Ionización de Electrospray/métodos , Triazoles/administración & dosificación , Triazoles/química
2.
J Sep Sci ; 39(17): 3302-10, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27390135

RESUMEN

We report the development and validation of a stability-indicating reversed-phase high-performance liquid chromatography method with precolumn derivatization for the separation and identification of the impurities of ripasudil hydrochloride hydrate, a novel protein kinase inhibitor. 2,3,4,6-Tetra-O-acetyl-ß-d-glucopyranosyl isothiocyanate was chosen as the derivatizing reagent and triethylamine was added as catalyst. 200 µL sample solution (1 mg/mL), 600 µL derivatizing reagent (1 mg/mL), and 200 µL triethylamine solution (1%, v/v) were mixed and reacted at 40°C for 30 min. The separation was achieved on an Inertsil C18 ODS-3 (250 mm × 4.6 mm, 5 µm) column using mobile phases including 10 mmol monopotassium phosphate buffer (pH 3.0) and methanol in gradient mode. The column temperature was adjusted at 25°C and the flow rate at 1 mL/min. The detection was carried out at 220 nm. Different precolumn derivatization conditions as well as the high-performance liquid chromatography conditions were optimized. Ripasudil hydrochloride hydrate and its four impurities were detected and quantitated, among which two new compounds were characterized. The proposed method was validated and proven to be selective, accurate, and precise and suitable for the quantitative analysis of ripasudil hydrochloride hydrate.


Asunto(s)
Cromatografía de Fase Inversa/métodos , Isoquinolinas/química , Isotiocianatos/química , Inhibidores de Proteínas Quinasas/química , Sulfonamidas/química , Cromatografía Líquida de Alta Presión/métodos
3.
J Sep Sci ; 39(7): 1232-41, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26843471

RESUMEN

High-performance liquid chromatography analysis of vonoprazan fumarate, a novel proton pump inhibitor drug revealed six impurities. These were identified by liquid chromatography with mass spectrometry. Further, the structures of the impurities were confirmed by synthesis followed by characterization by mass spectrometry, NMR spectroscopy, and infrared spectroscopy. On the basis of these data and knowledge of the synthetic scheme of vonoprazan fumarate, the previously unknown impurity was identified as 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methyldimethylamine, which is a new compound. The possible mechanisms by which these impurities were formed were also discussed. A high-performance liquid chromatography method was optimized in order to separate, selectively detect, and quantify all process-related impurities of vonoprazan fumarate. The presented method has been validated in terms of linearity, limits of detection, and quantification, and response factors and, therefore, is highly suitable for routine analysis of vonoprazan fumarate related substances as well as stability studies.


Asunto(s)
Contaminación de Medicamentos , Pirroles/química , Sulfonamidas/química , Cromatografía Líquida de Alta Presión , Estructura Molecular , Pirroles/síntesis química , Sulfonamidas/síntesis química
4.
J Sep Sci ; 37(11): 1248-55, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24616424

RESUMEN

The characterization of process-related impurities and forced degradants of alogliptin benzoate (Alb) in bulk drugs and a stability-indicating HPLC method for the separation and quantification of all the impurities were investigated. Alb was found to be unstable under acid and alkali stress conditions and two major degradation products (Imp-F and Imp-G) were observed. The optimum separation was achieved on Kromasil C18 (250 × 4.6 mm, 5 µm) using 0.1% perchloric acid (pH adjusted to 3.0 with triethylamine) and acetonitrile as a mobile phase in gradient mode. The proposed method was found to be stability indicating, precise, linear (0.10-75.0 µg/mL), accurate, sensitive, and robust for the quantitation of Alb and its process-related substances and degradation products. The structures of 11 impurities were characterized and confirmed by NMR spectroscopy, MS, and IR spectroscopy, and the most probable formation mechanisms of all impurities were proposed according to the synthesis route.


Asunto(s)
Benzoatos/química , Cromatografía Líquida de Alta Presión/métodos , Cromatografía de Fase Inversa/métodos , Piperidinas/química , Uracilo/análogos & derivados , Estabilidad de Medicamentos , Estructura Molecular , Uracilo/química
5.
Biomed Chromatogr ; 28(12): 1738-43, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24853720

RESUMEN

Vilazodone hydrochloride (CAS 163521-12-8) is polymorphic and has 15 crystal forms, referred to as I-XI and XIII-XVI. In the study, we prepared and performed structural identification of a new crystal form named XVII. To investigate this in vivo, a rapid and sensitive method based on liquid-liquid extraction, followed by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was developed and validated for the determination of vilazodone hydrochloride in dog plasma. This HPLC-MS/MS method was successfully applied to a bioavailability comparison of two crystal forms of vilazodone hydrochloride (IV and XVII) in six healthy beagles using a single-dose, two-way crossover design. The maximum plasma concentration (C(max)), the time taken to reach C(max), and the area under the concentration-time curve were determined following oral administration of 10 mg vilazodone hydrochloride (IV or XVII) to beagles. These analyses revealed no significant bioavailability differences between vilazodone hydrochloride forms IV and XVII in dogs.


Asunto(s)
Benzofuranos/sangre , Benzofuranos/farmacocinética , Cromatografía Liquida/métodos , Indoles/sangre , Indoles/farmacocinética , Piperazinas/sangre , Piperazinas/farmacocinética , Espectrometría de Masas en Tándem/métodos , Administración Oral , Animales , Benzofuranos/administración & dosificación , Benzofuranos/química , Disponibilidad Biológica , Perros , Femenino , Indoles/administración & dosificación , Indoles/química , Límite de Detección , Masculino , Piperazinas/administración & dosificación , Piperazinas/química , Reproducibilidad de los Resultados , Clorhidrato de Vilazodona
6.
J AOAC Int ; 97(6): 1552-62, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25632433

RESUMEN

During the synthesis of Azilsartan (AZS), it was speculated that 15 potential impurities would arise. This study investigated the possible mechanism for the formation of 14 of them, and their structures were characterized and confirmed by IR, NMR, and MS techniques. In addition, an efficient chromatographic method was developed to separate and quantify these impurities, using an Inertsil ODS-3 column (250 x 4.6 mm, 5 pm) in gradient mode with a mixture of acetonitrile and the potassium dihydrogen orthophosphate buffer (10 mM, pH adjusted to 3.0 with phosphoric acid). The HPLC method was validated for specificity, precision, accuracy, and sensitivity. LOQ of impurities were in the range of 1.04-2.20 ng. Correlation coefficient values of linearity were >0.9996 for AZS and its impurities. The mean recoveries of all impurities in AZS were between 93.0 and 109.7%. Thus, the validated HPLC method is suitable for the separation and quantification of all potential impurities in AZS.


Asunto(s)
Bencimidazoles/análisis , Cromatografía Líquida de Alta Presión/métodos , Contaminación de Medicamentos , Oxadiazoles/análisis , Bencimidazoles/química , Tampones (Química) , Límite de Detección , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Oxadiazoles/química , Espectrofotometría Infrarroja
7.
Drug Res (Stuttg) ; 70(1): 12-22, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31539916

RESUMEN

Bepotastine besilate (here after referred to as BTST), chemically known as ({d(S)4[4[(4chlorophenyl) (2pyridyl) methoxy] piperidino} butyric acid monobenzene sulphonate), is a second-generation antihistamine drug. To the best of our knowledge, no studies concerning the isolation or identification of process-related impurities have been reported so far. The current study reports the development and validation of a stability-indicating RP-HPLC method for the separation and identification of 5 potential impurities in bepotastine besilate. In this experiment, the structures of 3 process-related impurities were found to be new compounds. They were characterized and confirmed by NMR and MS spectroscopy analyses. These 3 new compounds were proposed to be (S)-4-[(phenyl)-2-pyridinylmethoxy]-1-piperidinebutanoic acid,(Imp-A); 4-[(S)-(4-chlorophenyl)-2-pyridinylmethoxy]-1- piperidinebutyric acid, N-oxide (Imp-B) and (S)-4-[(4- chlorophenyl)-2-pyridinylmethoxy]-1-piperidylethane (Imp-C). In addition, an efficient optimized chromatographic method was performed on a Shimadzu Inertsil C8-3 column (150 mm×4.6 mm, 3 µm) to separate and quantify these 5 impurities. It was using 15 mmol ammonium formate buffer in water (pH adjusted to 3.8 with formic acid) and acetonitrile as the mobile phase in gradient mode. The method was developed to separate and quantify these 5 impurities obtained in the range of 0.05-0.75 µg/mL. It was validated and proven to be selective, accurate and precise and suitable. It is the first publication of identification and characterization data of the 3 new compounds. It is also the first effective HPLC method for separation and quantification of all of process-related impurities in bepotastine besilate.


Asunto(s)
Antialérgicos/análisis , Composición de Medicamentos/normas , Contaminación de Medicamentos/prevención & control , Piperidinas/análisis , Piridinas/análisis , Antialérgicos/normas , Cromatografía Líquida de Alta Presión/instrumentación , Cromatografía Líquida de Alta Presión/métodos , Límite de Detección , Espectroscopía de Resonancia Magnética , Piperidinas/normas , Piridinas/normas , Espectrometría de Masas en Tándem
8.
Biomed Chromatogr ; 23(1): 54-62, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18850581

RESUMEN

A highly sensitive and selective LC-ESI-MS was developed, validated for the simultaneous determination of 18alpha-glycyrrhetic acid (alpha-GA) and 18beta-glycyrrhetic acid (beta-GA) for pharmacokinetic studies in healthy subjects. Sample preparation was performed by liquid-liquid extraction with ethyl acetate and the separations were achieved using a C(18) column with the mobile phase composed of 10 mmol/L ammonium acetate solution-methanol-acetonitrile (40:36:24, v/v/v) at a flow rate of 1 mL/min. The internal standard was honokiol and the epimers were quantified using a single quadrupole mass spectrometer employing ESI in the negative ion mode. The separation factor, alpha, was 1.512 for alpha- and beta-GA. The standard curves were linear for both epimers with coefficients of determination (r >or= 0.9998) over the concentration range of 1-150 ng/mL. The precision and accuracy were

Asunto(s)
Antiinflamatorios/sangre , Cromatografía Liquida/métodos , Ácido Glicirretínico/sangre , Espectrometría de Masa por Ionización de Electrospray/métodos , Antiinflamatorios/química , Antiinflamatorios/farmacocinética , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/farmacocinética , Humanos , Estructura Molecular , Reproducibilidad de los Resultados
9.
Se Pu ; 37(12): 1291-1296, 2019 Dec 08.
Artículo en Zh | MEDLINE | ID: mdl-34213130

RESUMEN

A sensitive and high throughput method by ultra high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was established for the determination of trihexyphenidyl in human plasma. The method was used to evaluate the bioequivalence of the test preparation and reference preparation, and to investigate the effect of food on the pharmacokinetic behavior of trihexyphenidyl. The trihexyphenidyl and internal standard trihexyphenidyl-d11 were extracted from human plasma by protein precipitation using methanol as the precipitant. Chromatographic separation was achieved on a Waters UPLC BEH C8 column (50 mm×2.1 mm, 1.7 µm) with 0.1% (v/v) formic acid aqueous solution containing 5 mmol/L ammonium acetate and acetonitrile-water (95:5, v/v) as the mobile phases. The analytes were detected by an electrospray ionization source in positive ion and multiple reaction monitoring modes. The linear range of trihexyphenidyl was 0.1-40 ng/mL. This test involved 30 healthy male and female subjects with a single oral administration of a 2-mg trihexyphenidyl hydrochloride tablet each. The 90% confidence intervals under fasting conditions of peak plasma concentration (Cmax), area under the plasma concentration-time curve (AUC0-t) and area under the plasma concentration-time curve from zero to infinity (AUC0-∞) were 82.2%-99.4%, 82.3%-97.3% and 83.4%-97.9%, and these pharmacokinetics parameters under postprandial conditions were 100.8%-122.8%, 96.8%-112.4% and 96.6%-112.1%, which were all in the range of 80.0%-125.0%, indicating that the test tablets and reference tablets were bioequivalent.

10.
Se Pu ; 37(6): 581-588, 2019 Jun 08.
Artículo en Zh | MEDLINE | ID: mdl-31152507

RESUMEN

A simple, sensitive, and stable high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and validated for the simultaneous determination of leucovorin and 5-methyltetrahydrofolate diastereomers in human plasma using methotrexate as the internal standard. The analytes and the internal standard were extracted from plasma samples by simple ultrafiltration centrifugation-based extraction. The separation was achieved on a chiral HSA column (150 mm×4 mm, 5 µm) using mobile phases containing 10 mmol pH 8.0 ammonium acetate and acetonitrile in gradient mode. The method showed good linearities in the ranges of 25-5000 µg/L and 12.5-3000 µg/L for leucovorin and 5-methyltetrahydrofolate diastereoisomers, respectively. The method was fully validated with respect to sensitivity, precision, accuracy, matrix effect, extraction recovery, and stability of analytes under various conditions. The method was successfully applied to a pharmacokinetic study of 125 mg/m2 6R,S-leucovorin and 62.5 mg/m2 6S-leucovorin. The results showed that the maximum observed concentrations (Cmax) of 6S-leucovorin and L-5-methyltetrahydrofolate were (3137.917±408.837) and (1679.633±244.132) µg/L, respectively, and the areas under the curve from the time of dosing to the last measurable concentration (AUC0-t) were (7504.883±1185.101) and (14001.214±2868.949) µg/L in the 125 mg/m2 6R,S-leucovorin dose group. The Cmax values of 6S-leucovorin and L-5-methyltetrahydrofolate were (3187.917±387.298) and (1739.204±224.755) µg/L, respectively, and AUC0-t values were (7426.664±854.825) and (14884.331±1843.353) µg/L in the 62.5 mg/m2 6S-leucovorin dose group. There were no significant diffe-rences in the main pharmacokinetic parameters between the two dose groups, and the pharmacokinetic characteristics as well as the rate and extent of absorption were consistent. This method can provide technical support for future bioequivalence studies of sodium leucovorin.


Asunto(s)
Leucovorina/sangre , Tetrahidrofolatos/sangre , Centrifugación , Cromatografía Líquida de Alta Presión , Humanos , Leucovorina/farmacocinética , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem , Tetrahidrofolatos/farmacocinética , Ultrafiltración
11.
J Chromatogr Sci ; 58(1): 31-36, 2019 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-31844877

RESUMEN

A simple and enantioselective method was developed and validated for the simultaneous determination of (R)- and (S)-trelagliptin in beagle dog plasma by chiral liquid chromatography tandem mass spectrometry. Trelagliptin enantiomers and (R)-rabeprazole (as internal standard, IS) were extracted from plasma samples by liquid-liquid extraction and separated on a CHIRALCEL OX-3R column using acetonitrile-5 ammonium bicarbonate as the mobile phase in gradient elution mode. The multiple reactions monitoring transitions of m/z 358.1→341.2 and 359.9→150.1 were used to quantify trelagliptin enantiomers and IS, respectively. This method was validated for sensitivity, specificity, linearity, precision, accuracy and stability of specific analytes under various conditions. And it was successfully applied to evaluating the pharmacokinetic profile of trelagliptin enantiomers in beagle dogs after single intravenous administration of (R)-trelagliptin injection (at 1 mg/kg) and oral administration (at 6.7 mg/kg). In this study, no chiral bioconversion of (R)-trelagliptin to (S)-trelagliptin in beagle dog plasma was observed. The absolute bioavailability of (R)-trelagliptin was identified to be 128.2%.


Asunto(s)
Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Uracilo/análogos & derivados , Animales , Perros , Femenino , Masculino , Reproducibilidad de los Resultados , Uracilo/sangre
12.
J Chromatogr Sci ; 56(8): 702-708, 2018 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-29800104

RESUMEN

A sensitive, efficient and stable bioanalytical method has been developed and validated for determination of brexpiprazole in dog plasma with UPLC-MS-MS for the first time. Brexpiprazole and internal standard were extracted from plasma samples by liquid-liquid extraction and separated on an Acquity UPLC BEH C18 column. A gradient elution program was developed employing methanol and 10 mM ammonium acetate aqueous solution as mobile phases. The method was validated for parameters of selectivity, LLOQ, linearity, accuracy, precision, matrix effects and stability in accordance with the regulatory guidance on bioanalytical method validation. The validated method was applied in evaluating the pharmacokinetic profiles of brexpiprazole in beagle dogs after a single-dose oral administration of a 4 mg tablet.


Asunto(s)
Perros/sangre , Agonistas de Dopamina/sangre , Quinolonas/sangre , Tiofenos/sangre , Administración Oral , Animales , Cromatografía Líquida de Alta Presión/métodos , Agonistas de Dopamina/administración & dosificación , Límite de Detección , Quinolonas/administración & dosificación , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodos , Tiofenos/administración & dosificación
13.
J AOAC Int ; 100(4): 1029-1037, 2017 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-28150570

RESUMEN

The characterization of process-related impurities and degradation products of safinamide mesilate (SAFM) in bulk drug and a stability-indicating HPLC method for the separation and quantification of all the impurities were investigated. Four process-related impurities (Imp-B, Imp-C, Imp-D, and Imp-E) were found in the SAFM bulk drug. Five degradation products (Imp-A, Imp-C, Imp-D, Imp-E, and Imp-F) were observed in SAFM under oxidative conditions. Imp-C, Imp-D, and Imp-E were also degradation products and process-related impurities. Remarkably, one new compound, identified as (S)-2-[4-(3-fluoro-benzyloxy) benzamido] propanamide (i.e., Imp-D), is being reported here as an impurity for the first time. Furthermore, the structures of the aforementioned impurities were characterized and confirmed via IR, NMR, and MS techniques, and the most probable formation mechanisms of all impurities proposed according to the synthesis route. Optimum separation was achieved on an Inertsil ODS-3 column (250 × 4.6 mm, 5 µm), using 0.1% formic acid in water (pH adjusted to 5.0) and acetonitrile as the mobile phase in gradient mode. The proposed method was found to be stability-indicating, precise, linear, accurate, sensitive, and robust for the quantitation of SAFM and its process-related substances, including its degradation products.


Asunto(s)
Alanina/análogos & derivados , Bencilaminas/análisis , Cromatografía Líquida de Alta Presión , Contaminación de Medicamentos , Mesilatos/análisis , Alanina/análisis , Estabilidad de Medicamentos
14.
J Chromatogr Sci ; 54(9): 1489-1494, 2016 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-26966270

RESUMEN

A liquid chromatographic separation method of ezetimibe optical isomers on the immobilised-type Chiralpak IC chiral stationary phase, onto which cellulose tris-(3,5-dichlorophenylcarbamate) was covalently grafted as a chiral selector, was developed under normal-phase conditions. The optimized chromatographic conditions were as follows: n-hexane-isopropanol-diethylamine (90:10:0.1, v/v) as mobile phase, 1.0 mL min-1 as flow rate, 256 nm as UV detection wavelength and 25°C as column temperature. Several factors concerning the enantioseparation were studied, including quality and quantity of different polar organic modifiers, additives, and flow rate and column temperature. Separation and resolution in the temperature range of 15-35°C was investigated. Apparent thermodynamic parameters were calculated from the Van't Hoff plots and used to explain the strength of interactions between the optical isomers and chiral selector. The validated method is simple, rapid and robust. Four ezetimibe optical isomers can be effectively separated from each other and the resolutions are 3.5, 2.7 and 2.5 successively. The method has been demonstrated to be applicable in routine quality control of Ezetimibe.

15.
J Pharm Biomed Anal ; 131: 436-443, 2016 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-27664386

RESUMEN

As the first approved androgen receptor(AR) signalling inhibitor, Enzalutamide was approved by the US Food and Drug Administration as an anticancer drug used to treat castration-resistant prostate cancer in 2012. In this manuscript, six potential impurities of Enzalutamide including process impurities and degradation products were studied. The structures of six impurities obtained by synthesis were characterized and confirmed by IR, NMR and MS techniques. In addition, an efficient chromatographic method to separate and quantify these impurities was developed, which achieved on Inertsil ODS-3 column (250mm×4.6mm,5µm) in gradient mode with a mixture of acetonitrile and the ammonium acetate buffer (10mM, pH adjusted to 4.0 with glacial acetic acid). The method was validated with respect to specificity, precision, accuracy, and sensitivity and satisfactory result was achieved. The method was demonstrated to be applicable in routine quality control and stability evaluation of Enzalutamide.


Asunto(s)
Contaminación de Medicamentos , Feniltiohidantoína/análogos & derivados , Espectrometría de Masas en Tándem/métodos , Espectrometría de Masas en Tándem/normas , Antineoplásicos/análisis , Antineoplásicos/química , Benzamidas , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Líquida de Alta Presión/normas , Cromatografía Liquida/métodos , Cromatografía Liquida/normas , Nitrilos , Feniltiohidantoína/análisis , Feniltiohidantoína/química , Reproducibilidad de los Resultados , Relación Estructura-Actividad
16.
J Chromatogr Sci ; 54(3): 353-60, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26489435

RESUMEN

Eleven potential impurities, including process-related compounds and degradation products, have been analyzed by comprehensive studies on the manufacturing process of clevidipine butyrate. Possible formation mechanisms could also be devised. MS and NMR techniques have been used for the structural characterization of three previously unreported impurities (Imp-3, Imp-5 and Imp-11). To separate and quantify the potential impurities in a simultaneous fashion, an efficient and advanced RP-HPLC method has been developed. In doing so, four major degradation products (Imp-2, Imp-4, Imp-8 and Imp-10) can be observed under varying stress conditions. This analytical method has been validated according to ICH guidelines with respect to specificity, accuracy, linearity, robustness and stability. The method described has been demonstrated to be applicable in routine quality control processes and stability evaluation studies of clevidipine butyrate.


Asunto(s)
Butiratos/análisis , Cromatografía Líquida de Alta Presión/métodos , Cromatografía de Fase Inversa/métodos , Piridinas/análisis , Contaminación de Medicamentos/prevención & control , Industria Farmacéutica , Estabilidad de Medicamentos , Humanos , Control de Calidad , Reproducibilidad de los Resultados
17.
J Pharm Biomed Anal ; 117: 325-32, 2016 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-26412721

RESUMEN

The current study reports the development and validation of a stability-indicating reversed phase HPLC method for the separation and identification of potential impurities in vortioxetine, a recently developed antidepressant. The structures of a new compound and four process-related impurities formed during the synthesis were characterized and confirmed by NMR, MS, and IR spectroscopy analyses. The most probable formation mechanisms of the impurities identified were proposed. Based on the characterization data, the new compound was proposed to be 1-[4-[(2,4-dimethylphenyl)thio]phenyl]-piperazine. In addition, an efficient chromatographic method was optimized to separate and quantify the impurities, which were obtained in the 0.05-0.75 µg/mL range. The developed HPLC method was validated with respect to accuracy, precision, linearity, robustness, and limits of detection and quantitation.


Asunto(s)
Espectroscopía de Resonancia Magnética/métodos , Piperazinas/análisis , Sulfuros/análisis , Espectrometría de Masas en Tándem/métodos , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida/métodos , Contaminación de Medicamentos , Estabilidad de Medicamentos , Piperazinas/química , Espectrofotometría Infrarroja/métodos , Sulfuros/química , Vortioxetina
18.
J Pharm Biomed Anal ; 128: 18-27, 2016 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-27209451

RESUMEN

A sensitive, selective and stability indicating reversed-phase LC method was developed for the determination of process related impurities of Trelagliptin succinate in bulk drug. Six impurities were identified by LC-MS. Further, their structures were characterized and confirmed utilizing LC-MS/MS, IR and NMR spectral data. The most probable mechanisms for the formation of these impurities were also discussed. To the best of our knowledge, six structures among these impurities are new compounds and have not been reported previously. The superior separation was achieved on an InertSustain C18 (250mm×4.6mm, 5µm) column in a gradient mixture of acetonitrile and 20mmol potassium dihydrogen phosphate with 0.25% triethylamine (pH adjusted to 3.5 with phosphate acid). The method was validated as per regulatory guidelines to demonstrate system suitability, specificity, sensitivity, linearity, robustness, and stability.


Asunto(s)
Uracilo/análogos & derivados , Cromatografía Líquida de Alta Presión/métodos , Contaminación de Medicamentos , Estabilidad de Medicamentos , Espectroscopía de Resonancia Magnética/métodos , Sensibilidad y Especificidad , Espectrofotometría Infrarroja/métodos , Espectrometría de Masas en Tándem/métodos , Uracilo/química
19.
J Chromatogr Sci ; 53(8): 1361-5, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25824570

RESUMEN

Liquid chromatographic separation of mirabegron enantiomers on Chiralpak AY-H, a column coated with amylose tris-(5-chloro-2-methylphenylcarbamate) as a chiral stationary phase, was studied under normal phase conditions. The influence of ethanol content (30-45%) and column temperature (20-40°C) on retention, resolution and separation were evaluated. Apparent thermodynamic parameters deduced from Van't Hoff plots were used to understand chiral separation mechanisms, and the chiral separation was enthalpy driven. The optimized chromatographic conditions were using a mixture solution of n-hexane, ethanol and diethyl amine (55 : 45 : 0.1, v/v/v) as a mobile phase at a flow rate of 1.0 mL/min. The column temperature and UV detector were set at 35°C and 254 nm, respectively. The method was validated to be simple, accuracy, sensitive and robust according to the ICH guidelines, and it was suitable for the routine quality control of mirabegron enantiomers for pharmaceutical industries.


Asunto(s)
Acetanilidas/química , Acetanilidas/aislamiento & purificación , Amilosa/análogos & derivados , Carbamatos/química , Cromatografía Líquida de Alta Presión/métodos , Tiazoles/química , Tiazoles/aislamiento & purificación , Acetanilidas/análisis , Amilosa/química , Etanol , Límite de Detección , Modelos Lineales , Reproducibilidad de los Resultados , Estereoisomerismo , Termodinámica , Tiazoles/análisis
20.
J Chromatogr Sci ; 53(5): 830-5, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25480456

RESUMEN

Dispersive liquid-liquid microextraction based on the solidification of a floating organic droplet combined with high-performance liquid chromatography with ultraviolet detection (HPLC-UV) was developed for the determination of clevidipine and its primary metabolite in Sprague-Dawley rat plasma samples. During the extraction procedure, to facilitate an efficient procedure, the plasma protein was precipitated first by using a mixture of a zinc sulfate solution and acetonitrile. Several extraction parameters were carefully evaluated and optimized, including the type and volume of the extraction solvent, salt effect, pH and extraction time. Under the optimum conditions, the limits for quantification were 2.5 and 5.0 ng mL(-1) for clevidipine and its primary metabolite, respectively. Sufficient linearity of clevidipine or its primary metabolite was observed with the coefficient of correlation (r) above 0.9979. The method showed good precision and accuracy, with intra- and inter-assay coefficients of variation <6.1% at all concentrations. The proposed pretreatment technique with HPLC was successfully applied to the determinate of clevidipine and its primary metabolite in rat plasma samples. Furthermore, the method, which requires less time than conventional techniques, is environmentally friendly and requires only a small amount of low-toxicity extraction solvent.


Asunto(s)
Microextracción en Fase Líquida/métodos , Piridinas/sangre , Piridinas/aislamiento & purificación , Animales , Cromatografía Líquida de Alta Presión , Piridinas/metabolismo , Ratas , Ratas Sprague-Dawley
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