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1.
Anticancer Drugs ; 31(9): 942-949, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32187024

RESUMEN

Recent findings implied the significance of reactive oxygen species (ROS) as a part of tyrosine kinase inhibitors (TKIs) pharmacological activity. Evidences also suggested that toxic effects of TKIs were related to ROS production. The results regarding benefits of vitamin E usage alongside with prescribed TKIs therapy are ambiguous. We aimed to examine oxidative stress and antioxidative defense in human serum treated with four different TKIs and their possible interactions with hydrosoluble vitamin E analog (Trolox). An in-vitro experiment with serum pool as a substitute model was performed. Different parameters of oxidative stress and antioxidative defense were measured in serum pool with and without addition of TKIs (axitinib, crizotinib, nilotinib, and imatinib), before and after addition of Trolox. Z score statistic was used for calculation of Prooxidative and Antioxidative scores. The highest oxidative potential was recorded for samples incubated with imatinib and nilotinib, while the lowest damaging scores were observed for crizotinib and axitinib (nilotinib vs. imatinib, P < 0.05; axitinib vs. imatinib, P < 0.01; crizotinib vs. imatinib, P < 0.001). The best capability for antioxidative protection was seen in samples with nilotinib, then with imatinib, while the lowest level was obtained in samples with crizotinib and axitinib (imatinib and axitinib vs. nilotinib, P < 0.05 for both; crizotinib vs. nilotinib, P < 0.01; axitinib vs. imatinib, P < 0.05, crizotinib vs. imatinib, P < 0.01). Our results demonstrated the opposite effects of Trolox in combination with imatinib and nilotinib. Usage of antioxidant in combination with TKIs should be carefully evaluated in each specific case.


Asunto(s)
Estrés Oxidativo/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Suero/efectos de los fármacos , Suero/metabolismo , Antioxidantes/farmacología , Cromanos/farmacología , Humanos , Oxidación-Reducción/efectos de los fármacos , Inhibidores de Proteínas Quinasas/sangre , Especies Reactivas de Oxígeno/sangre
2.
Anal Bioanal Chem ; 406(17): 4217-32, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24752695

RESUMEN

Hydrophilic interaction liquid chromatography (HILIC) has emerged in recent years as a valuable alternative to reversed-phase liquid chromatography in the analysis of polar compounds. Research in HILIC is divided into two directions: the assessment of the retention mechanism and retention behavior, and the development of HILIC methods. In this work, four polar neutral analytes (iohexol and its related compounds A, B, and C) were analyzed on two silica and two diol columns in HILIC mode with the aim to investigate thoroughly the retention mechanisms and retention behavior of polar neutral compounds on these four columns. The adsorption and partition contribution to the overall HILIC retention mechanism was investigated by fitting the retention data to linear (adsorption and partition) and nonlinear (mixed-retention and quadratic) theoretical models. On the other hand, the establishment of empirical second-order polynomial retention models on the basis of D-optimal design made possible the estimation of the simultaneous influence of several mobile-phase-related factors. Furthermore, these models were also used as the basis for the application of indirect modeling of the selectivity factor and a grid point search approach in order to achieve the optimal separation of analytes. After the optimization goals had been set, the grids were searched and the optimal conditions were identified. Finally, the optimized method was subjected to validation.


Asunto(s)
Cromatografía Liquida/métodos , Yohexol/química , Adsorción , Cromatografía Liquida/instrumentación , Interacciones Hidrofóbicas e Hidrofílicas , Estructura Molecular , Dióxido de Silicio/química
3.
Acta Chim Slov ; 60(2): 411-5, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23878947

RESUMEN

This paper presents multiobjective optimization of complex mixtures separation in hydrophilic interaction liquid chromatography (HILIC). The selected model mixture consisted of five psychotropic drugs: clozapine, thioridazine, sulpiride, pheniramine and lamotrigine. Three factors related to the mobile phase composition (acetonitrile content, pH of the water phase and concentration of ammonium acetate) were optimized in order to achieve the following goals: maximal separation quality, minimal total analysis duration and robustness of an optimum. The consideration of robustness in early phases of the method development provides reliable methods with low risk for failure in validation phase. The simultaneous optimization of all goals was achieved by multiple threshold approach combined with grid point search. The identified optimal separation conditions (acetonitrile content 83%, pH of the water phase 3.5 and ammonium acetate content in water phase 14 mM) were experimentally verified.


Asunto(s)
Cromatografía Liquida/métodos , Psicotrópicos/aislamiento & purificación , Concentración de Iones de Hidrógeno
4.
Drug Test Anal ; 15(11-12): 1488-1502, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37525530

RESUMEN

Higenamine is prohibited in sports as a ß2 -agonist by the World Anti-Doping Agency. As a key component of a great variety of plants, including the Annonaceae family, one aim of this research project was to evaluate whether the ingestion of Annona fruit could lead to higenamine adverse analytical findings. Single-dose administration studies including three Annona species (i.e., Annona muricata, Annona cherimola, and Annona squamosa) were conducted, leading to higenamine findings below the established minimum reporting level (MRL) of 10 ng/mL in urine. In consideration of cmax values (7.8 ng/mL) observed for higenamine up to 24 h, a multidose administration study was also conducted, indicating cumulative effects, which can increase the risk of exceeding the applicable MRL doping after Annona fruit ingestion. In this study, however, the MRL was not exceeded at any time point. Further, the major urinary excretion of higenamine in its sulfo-conjugated form was corroborated, its stability in urine was assessed, and in the absence of reference material, higenamine sulfo-conjugates were synthesized and comprehensively characterized, suggesting the predominant presence of higenamine 7-sulfate. In addition, the option to include complementary biomarkers of diet-related higenamine intake into routine doping controls was investigated. A characteristic urinary pattern attributed to isococlaurine, reticuline, and a yet not fully characterized bismethylated higenamine glucuronide was observed after Annona ingestion but not after supplement use, providing a promising dataset of urinary biomarkers, which supports the discrimination between different sources of urinary higenamine detected in sports drug testing programs.


Asunto(s)
Annona , Frutas , Detección de Abuso de Sustancias , Biomarcadores
5.
J Sep Sci ; 35(12): 1424-31, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22740252

RESUMEN

In this paper, the retention prediction models for mixture of ß-lactam antibiotics analyzed by hydrophilic interaction chromatography (HILIC) are presented. The aim of the study was to investigate the retention behavior of some organic acids and amphoteric compounds including cephalosporins (cefotaxime, cefalexin, cefaclor, cefuroxime, and cefuroxime axetil) and penicillins (ampicillin and amoxicillin). Retention of substances with acidic functional group in HILIC is considered to be interesting since the majority of publications in literature are related to basic compounds. In the beginning of the study, classical silica columns were chosen for the retention analysis. Then, preliminary study was done and factors with the most significant influence on the retention factors were selected. These factors with the impact on the retention factors were investigated employing Box-Behnken design as a tool. On the basis of the obtained results the mathematical models were created and tested using ANOVA test and finally verified. This approach enables the presentation of chromatographic retention in many ways (three-dimensional (3-D) graphs and simple two-dimensional graphical presentations). All of these gave the possibility to predict the chromatographic retention under different conditions. Furthermore, regarding the structure of the analyzed compounds, the potential retention mechanisms in HILIC were suggested.


Asunto(s)
Antibacterianos/química , Cromatografía Liquida/métodos , beta-Lactamas/química , Antibacterianos/aislamiento & purificación , Cromatografía Liquida/instrumentación , Interacciones Hidrofóbicas e Hidrofílicas , beta-Lactamas/aislamiento & purificación
6.
J AOAC Int ; 94(3): 723-34, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21796999

RESUMEN

This paper describes the development and validation of a microemulsion liquid chromatography (MELC) method for simultaneous determination of perindopril tert-butylamine and its impurities in bulk active substances and the pharmaceutical dosage form of tablets. An appropriate resolution with reasonable retention times was obtained for a microemulsion containing 0.24% (w/v) butyl acetate, 0.30% (w/v) ethyl acetate, 2% (w/v) sodium dodecyl sulfate, 7.75% (w/v) n-butanol, and 20.0 mM potassium dihydrogen phosphate, the pH of which was adjusted to 3.70 with 85% orthophosphoric acid. Separations were performed on a Nucleosil 120-5 butyl modified (C4), 250 x 4 mm, 5 microm particle size silica column at 40 degrees C, with a mobile phase flow rate of 1.25 mL/min. UV detection was performed at 254 nm. The established method was subjected to method validation, and required validation parameters were defined. Robustness testing, an important part of method validation, was performed as well. Since robustness validation can be conducted using different experimental designs, the Plackett-Burman design was applied due to its possibility of testing many factors at the same time. The validated MELC method was found to be suitable for the simultaneous determination of perindopril tert-butylamine and its impurities in pharmaceuticals.


Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/química , Cromatografía Liquida/métodos , Emulsiones/química , Perindopril/química , Estructura Molecular , Reproducibilidad de los Resultados , Comprimidos/química
7.
J AOAC Int ; 93(4): 1102-12, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20922940

RESUMEN

In this paper, a previously optimized method for HPLC analysis of pramipexole and its impurities was subjected to method validation in accordance with official regulations. The optimized chromatographic conditions were as follows: mobile phase acetonitrile-water phase [15 + 85, v/v, water phase contained 1% triethylamine (TEA), pH adjusted to 7.0 with orthophosphoric acid]; detection at 262 nm for pramipexole, BI-II 751 xx, BI-I 786 BS, BI-II 820 BS, and 2-aminobenzothiazole and at 326 nm for BI-II 546 CL; column temperature, 25 degrees C; and flow rate, 1 ml/min. Acetonitrile and TEA content, pH of the water phase, flow rate, column temperature, and column type were factors studied in robustness testing. According to the experimental plan defined by a Plackett-Burman design, five dummy variables were added in order to have 12 factors. As output, resolution factor was chosen. Robustness was assessed by graphical (half-normal probability plots and Pareto charts) and statistical (t-test) methods. Also, nonsignificance intervals for significant factors were estimated, and limits for the system suitability test were determined. Finally, linearity, accuracy, and precision of the proposed HPLC method were defined. LOD and LOQ values for analyzed impurities were determined. The method was completely defined by these experiments.


Asunto(s)
Benzotiazoles/análisis , Cromatografía Líquida de Alta Presión/métodos , Contaminación de Medicamentos , Calibración , Límite de Detección , Pramipexol
8.
J AOAC Int ; 93(1): 102-7, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20334171

RESUMEN

An RP-HPLC method has been optimized and validated for the simultaneous determination of hydrocortisone acetate and of lidocaine in suppositories. For the method optimization, response surface methodology was applied, and the obtained model was tested using analysis of variance. The optimal separations were conducted on a Beckman-Coulter 150 x 4.6 mm, 5 microm particle-size column at 20 degrees C. The mobile phase was methanol-water (65 + 35, v/v), pH adjusted to 2.5 with 85% orthophosphoric acid, with a flow rate of 1.0 ml/min. UV detection was performed at 250 nm. Phenobarbital was used as an internal standard. The method was validated for selectivity, linearity, precision, and robustness.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Cromatografía de Fase Inversa/métodos , Hidrocortisona/análogos & derivados , Lidocaína/administración & dosificación , Lidocaína/análisis , Análisis de Varianza , Anestésicos Locales/administración & dosificación , Anestésicos Locales/análisis , Antiinflamatorios/administración & dosificación , Antiinflamatorios/análisis , Hemorroides/tratamiento farmacológico , Humanos , Hidrocortisona/administración & dosificación , Hidrocortisona/análisis , Concentración de Iones de Hidrógeno , Metanol , Supositorios/análisis
9.
J Pharm Biomed Anal ; 173: 86-95, 2019 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-31125948

RESUMEN

This paper presents integration of Quality by Design concept in the development of hydrophilic interactions liquid chromatographic methods for analysis of amitriptyline and its impurities (A, B, C, and F). This is the first time that HILIC method for amitriptyline and its impurities is developed. Using QbD concept, it is possible to design a robust method and incorporate quality directly into its development. QbD concept in combination of Design of Experiments methodology (DoE) enables creation of well-defined design space. In this study, for method optimization a Box-Behnken design was used to test the effect of acetonitrile content, buffer concentration and pH of water phase on critical system responses such as retention factor of impurity A, resolution between impurity B and impurity C, amitriptyline peak asymmetry factor and retention time of last eluted impurity F. The defined mathematical models and Monte Carlo simulations were used to identify the design space. For robustness testing, fractional factorial design was applied. Optimal chromatographic conditions were the analytical column ZORBAX NH2 (250 mm x 4.6 mm, 5 µm particle size); mobile phase consisted of acetonitrile-water phase (60 mM ammonium acetate, pH adjusted to 4.5 with glacial acetic acid) (92.5:7.5 v/v); column temperature 30 °C, mobile phase flow rate 1 mL min-1, wavelength of detection 254 nm. Finally, method was fully validated and applicability of the method in tablet analysis was confirmed.


Asunto(s)
Amitriptilina/análisis , Contaminación de Medicamentos/prevención & control , Acetonitrilos/química , Amitriptilina/química , Cromatografía Liquida/métodos , Interacciones Hidrofóbicas e Hidrofílicas , Método de Montecarlo , Proyectos de Investigación , Comprimidos
10.
Steroids ; 150: 108430, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31229510

RESUMEN

A long-term metabolite of the doping agent oxymetholone (OXM-M2, 17ß-hydroxymethyl-2,17α-methyl-18-norandrost-13-en-3-one) which has been identified by GC-MS/MS was synthesized from commercially available materials. Two efficient synthetic routes to access both C-17 epimers of tentative metabolites were developed. The identity and molecular configuration of the in vivo metabolite: 17ß-hydroxymethyl-2α,17α-methyl-18-norandrost-13-en-3-one was confirmed by single crystal X-ray diffraction.


Asunto(s)
Oximetolona/síntesis química , Oximetolona/metabolismo , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Conformación Molecular , Oximetolona/química
11.
Indian J Pediatr ; 86(5): 427-432, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30637682

RESUMEN

OBJECTIVES: To evaluate the level of health-related quality of life (QoL) and presence of anxiety and depressive symptoms in Serbian children with celiac disease from the perspective of patients and their parents. METHODS: This cross-sectional study investigated the group of children and adolescents with celiac disease aged 5-18 y, and at least one parent of each patient with celiac disease. The patients and their parents were recruited at the Institute of Mother and Child Health of Serbia and the University Children's Hospital in Belgrade. The instruments used in this study were child-self and parent-proxy versions of the Pediatric Quality of Life Inventory (PedsQL), Screen for Child Anxiety Related Emotional Disorder (SCARED) and Short Mood and Feelings Questionnaire (MFQ). Additional information was collected from the medical records of each patient. RESULTS: According to the PedsQL questionnaire, the quality of life was similarly assessed by both parents and their children (p > 0.05), as well as the presence of depressive symptoms according to MFQ questionnaire. However, a statistically significant difference was observed in the total score of the SCARED questionnaire for children and parents [total score (p < 0.05), panic-somatic disturbance (p < 0.01) and social anxiety (p < 0.01)]. CONCLUSIONS: The patients and their parents in Serbia have similarly assessed the quality of life of children with celiac disease, but the differences in the scores of SCARED questionnaire indicate that it is necessary to include both children and parents in the assessment of QOL.


Asunto(s)
Trastornos de Ansiedad/psicología , Ansiedad/psicología , Enfermedad Celíaca/psicología , Depresión/psicología , Padres/psicología , Calidad de Vida/psicología , Adolescente , Niño , Salud Infantil , Preescolar , Estudios Transversales , Emociones , Femenino , Hospitales Pediátricos , Humanos , Masculino , Serbia , Encuestas y Cuestionarios
12.
J Chromatogr A ; 1202(2): 155-62, 2008 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-18644604

RESUMEN

HPLC stability-indicating method has been developed for the simultaneous determination of some water-soluble vitamins (ascorbic acid, thiamine hydrochloride, riboflavin-5'-phosphate sodium, pyridoxine hydrochloride, nicotinamide, D(+)-panthenol) and two preservatives (methylparaben and sodium benzoate) in multivitamin syrup preparation. Water-soluble vitamins, preservatives and their degradants were separated on Zorbax SB-Aq (C(18)) (250 mm x 4.6 mm, 5 microm) column at an ambient temperature. Combined isocratic and gradient elution was performed with a mobile phase consisting of 0.0125 M hexane-1-sulfonic acid sodium salt in 0.1% (m/v) o-phosphoric acid, pH 2.4-2.5 (solvent A) and acetonitrile (solvent B) at the flow-rate 1 ml min(-1). Starting with solvent A an isocratic elution was performed for 15 min, then the composition was changed to 85% of A and 15% of B during the next 20 min and it was constant for 5 min, then the composition was changed to 70% of A and 30% of B during next 15 min and it was constant for 5 min and finally was changed to 100% of A as at the beginning of the elution. Detection was performed with diode array detector at 210, 230 and 254 nm. Multivitamin syrup preparation was subjected to stress testing (forced degradation) in order to demonstrate that degradants from the vitamins, preservatives and/or product excipients do not interfere with the quantification of vitamins and preservatives. Typical validation characteristics: selectivity, accuracy, precision, linearity, range, limit of quantification and limit of detection were evaluated for vitamins and preservatives.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Vitaminas/análisis , Ácido Ascórbico/análisis , Niacinamida/análisis , Ácido Pantoténico/análogos & derivados , Ácido Pantoténico/análisis , Parabenos/análisis , Piridoxina/análisis , Reproducibilidad de los Resultados , Benzoato de Sodio/análisis , Solubilidad , Tiamina/análisis , Vitaminas/química , Agua/química
13.
Bioanalysis ; 10(22): 1861-1876, 2018 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-30412677

RESUMEN

AIM: An ultra pressure liquid chromatography (UPLC)/MS/MS method for vancomycin and teicoplanin determination in human plasma was developed in accordance with analytical quality by design (AQbD) concept and fully validated. MATERIALS & METHODS: Chromatographic separation was performed on ACQUITY UPLC C18 charge surface hybrid (CSH) column (2.1 mm × 50 mm, 1.7 µm particle size) in gradient mode and the mobile phase consisted of 0.1% formic acid in water and pure acetonitrile. The experimental design methodology was used for the definition of optimal chromatographic and protein precipitation conditions. RESULTS: The linearity ranges were 0.05-10 µg ml-1 for vancomycin and 0.5-200 µg ml-1 for total teicoplanin. The relative standard deviations for precision estimation were below 15% and the accuracy was within 85-115% for all quality control levels. CONCLUSION: The method was utilized for glycopeptide antibiotics bioanalysis.


Asunto(s)
Antibacterianos/sangre , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas/métodos , Teicoplanina/sangre , Vancomicina/sangre , Humanos
14.
J Pharm Biomed Anal ; 161: 289-295, 2018 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-30189410

RESUMEN

Meldonium is a drug exhibiting cardioprotective and anti-ischemic effects. Due to its potential performance-enhancing benefit in sports, meldonium was added to the World Anti-Doping Agency list of prohibited substances in 2016. Since then, a high number of adverse analytical findings reported on meldonium has questioned meldonium`s detection time in urine. Hence, the objective of the current study was to characterize the pharmacokinetic urinary excretion pattern of meldonium when administered as multiple intravenous injections. Three injections of 250 mg meldonium were given over a time period of five days to six healthy volunteers and urine samples were collected for eight months after the last injection of the drug. For the quantification of meldonium in urine, a liquid chromatography-tandem mass spectrometry method was fully validated according to the World Anti-Doping Agency guidelines in terms of specificity, matrix interferences, intra- and inter-day precision, accuracy, carry-over, robustness, linearity, limit of detection, and limit of quantification. The assay was successfully applied to the pharmacokinetic study. A three-compartment model was found to best describe the pharmacokinetics of meldonium with average alpha, beta, and gamma half-lives of 1.4 h, 9.4 h, and 655 h, respectively. The detection time in urine varied between 94 and 162 days.


Asunto(s)
Metilhidrazinas/administración & dosificación , Metilhidrazinas/orina , Detección de Abuso de Sustancias/métodos , Adulto , Cromatografía Liquida/métodos , Femenino , Semivida , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Modelos Biológicos , Espectrometría de Masas en Tándem/métodos
15.
J Pharm Biomed Anal ; 134: 18-26, 2017 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-27871053

RESUMEN

This paper deals with the development of hydrophilic interaction liquid chromatography (HILIC) method with gradient elution, in accordance with Analytical Quality by Design (AQbD) methodology, for the first time. The method is developed for olanzapine and its seven related substances. Following step by step AQbD methodology, firstly as critical process parameters (CPPs) temperature, starting content of aqueous phase and duration of linear gradient are recognized, and as critical quality attributes (CQAs) separation criterion S of critical pairs of substances are investigated. Rechtschaffen design is used for the creation of models that describe the dependence between CPPs and CQAs. The design space that is obtained at the end is used for choosing the optimal conditions (set point). The method is fully validated at the end to verify the adequacy of the chosen optimal conditions and applied to real samples.


Asunto(s)
Benzodiazepinas/análisis , Química Farmacéutica/métodos , Interacciones Hidrofóbicas e Hidrofílicas , Benzodiazepinas/metabolismo , Cromatografía Liquida/métodos , Olanzapina
16.
Bioanalysis ; 9(24): 1943-1954, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29205055

RESUMEN

AIM: The objective of the study was development of hydrophilic interaction liquid chromatography-ESI/MS/MS method for the determination of olopatadine in tear matrix. MATERIALS & METHODS: Separation was performed on Acquity BEH amide column (2.1 × 100 mm, 1.7 µm). The mobile phase was consisted of 0.1% formic acid in water and acetonitrile. Mianserin hydrochloride was implemented as an internal standard. The artificial tear fluid was used as matrix. The tear samples were collected using Schirmer test strips. For the optimization of ultra pressure liquid chromatography conditions, Box-Benhken design was utilized. RESULTS: The optimal values of the ion source and collision cell parameters were found. Quantification was performed in multiple reaction monitoring mode. The optimized method was fully validated. CONCLUSION: The proposed method was utilized for monitoring of olopatadine in human tear.


Asunto(s)
Cromatografía Líquida de Alta Presión , Clorhidrato de Olopatadina/análisis , Espectrometría de Masas en Tándem , Lágrimas/química , Calibración , Cromatografía Líquida de Alta Presión/normas , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Límite de Detección , Mianserina/análisis , Clorhidrato de Olopatadina/normas , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/normas , Lágrimas/metabolismo
17.
J Pharm Biomed Anal ; 125: 385-93, 2016 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-27131148

RESUMEN

This paper deals with the development of hydrophilic interaction liquid chromatographic (HILIC) method for the analysis of bilastine and its degradation impurities following Analytical Quality by Design approach. It is the first time that the method for bilastine and its impurities is proposed. The main objective was to identify the conditions where an adequate separation in minimal analysis duration could be achieved within a robust region. Critical process parameters which have the most influence on method performance were defined as acetonitrile content in the mobile phase, pH of the aqueous phase and ammonium acetate concentration in the aqueous phase. Box-Behnken design was applied for establishing a relationship between critical process parameters and critical quality attributes. The defined mathematical models and Monte Carlo simulations were used to identify the design space. Fractional factorial design was applied for experimental robustness testing and the method is validated to verify the adequacy of selected optimal conditions: the analytical column Luna(®) HILIC (100mm×4.6mm, 5µm particle size); mobile phase consisted of acetonitrile-aqueous phase (50mM ammonium acetate, pH adjusted to 5.3 with glacial acetic acid) (90.5:9.5, v/v); column temperature 30°C, mobile phase flow rate 1mLmin(-1), wavelength of detection 275nm.


Asunto(s)
Bencimidazoles/química , Cromatografía Liquida/métodos , Piperidinas/química , Interacciones Hidrofóbicas e Hidrofílicas
18.
J Pharm Biomed Anal ; 123: 93-103, 2016 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-26895494

RESUMEN

In this paper separation of granisetron and its two related substances in HILIC mode is presented. Separation was done on silica column derivatized with sulfoalkylbetaine groups (ZIC-HILIC). Firstly, retention mechanisms were assessed whereby retention factors of substances were followed in wide range of acetonitrile content (80-97%), at constant concentration of aqueous buffer (10mM) as well as at constant pH value of 3.0. Further, in order to developed optimal HILIC method, Design of Experiments (DoE) methodology was applied. For optimization full factorial design 3(2) was employed. Influence of acetonitrile content and ammonium acetate concentration were investigated while pH of the water phase was kept at 3.3. Adequacy of obtained mathematical models was confirmed by ANOVA. Optimization goals (α>1.15 and minimal run time) were accomplished with 94.7% of acetonitrile in mobile phase and 70 mM of ammonium acetate in water phase. Optimal point was in the middle of defined Design Space. In the next phase, robustness was experimetally tested by Rechtschaffen design. The investigated factors and their levels were: acetonitrile content (±1%), ammonium acetate molarity in water phase (±2 mM), pH value of water phase (±0.2) and column temperature (±4 °C). The validation scope included selectivity, linearity, accuracy and precision as well as determination of limit of detection (LOD) and limit of quantification (LOQ) for the related substances. Additionally, the validation acceptance criteria were met in all cases. Finally, the proposed method could be successfully utilized for estimation of granisetron HCl and its related substances in tablets and parenteral dosage forms, as well as for monitoring degradation under various stress conditions.


Asunto(s)
Cromatografía Liquida/métodos , Granisetrón/química , Acetatos/química , Acetonitrilos/química , Formas de Dosificación , Interacciones Hidrofóbicas e Hidrofílicas , Límite de Detección , Reproducibilidad de los Resultados , Dióxido de Silicio/química , Comprimidos/química , Temperatura , Agua/química
19.
J Chromatogr Sci ; 54(3): 436-44, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26590237

RESUMEN

In this article, retention modeling of eight aminopyridines (synthesized and characterized at the Faculty of Pharmacy) in reversed-phase high performance liquid chromatography (RP-HPLC) was performed. No data related to their retention in the RP-HPLC system were found. Knowing that, it was recognized as very important to describe their retention behavior. The influences of pH of the mobile phase and the organic modifier content on the retention factors were investigated. Two theoretical models for the dependence of retention factor of organic modifier content were tested. Then, the most reliable and accurate prediction of log k was created, testing multiple linear regression model-quantitative structure-retention relationships (MLR-QSRR) and support vector regression machine-quantitative structure-retention relationships (SVM-QSRR). Initially, 400 descriptors were calculated, but four of them (POM, log D, M-SZX/RZX and m-RPCG) were included in the models. SVM-QSRR performed significantly better than the MLR model. Apart from aminopyridines, four structurally similar substances (indapamide, gliclazide, sulfamethoxazole and furosemide) were followed in the same chromatographic system. They were used as external validation set for the QSRR model (it performed well within its applicability domain, which was defined using a bounding box approach). After having described retention of eight aminopyridines with both theoretical and QSRR models, further investigations in this field can be conducted.


Asunto(s)
Aminopiridinas/aislamiento & purificación , Cromatografía Líquida de Alta Presión/métodos , Cromatografía de Fase Inversa/métodos , Modelos Estadísticos , Agua , Acetonitrilos , Aminopiridinas/síntesis química , Cromatografía Líquida de Alta Presión/estadística & datos numéricos , Cromatografía de Fase Inversa/estadística & datos numéricos , Concentración de Iones de Hidrógeno , Soluciones , Solventes
20.
J Pharm Biomed Anal ; 110: 42-8, 2015 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-25796982

RESUMEN

This study presents the development of hydrophilic interaction liquid chromatographic method for the analysis of iohexol, its endo-isomer and three impurities following Quality by Design (QbD) approach. The main objective of the method was to identify the conditions where adequate separation quality in minimal analysis duration could be achieved within a robust region that guarantees the stability of method performance. The relationship between critical process parameters (acetonitrile content in the mobile phase, pH of the water phase and ammonium acetate concentration in the water phase) and critical quality attributes is created applying design of experiments methodology. The defined mathematical models and Monte Carlo simulation are used to evaluate the risk of uncertainty in models prediction and incertitude in adjusting the process parameters and to identify the design space. The borders of the design space are experimentally verified and confirmed that the quality of the method is preserved in this region. Moreover, Plackett-Burman design is applied for experimental robustness testing and method is fully validated to verify the adequacy of selected optimal conditions: the analytical column ZIC HILIC (100 mm × 4.6 mm, 5 µm particle size); mobile phase consisted of acetonitrile-water phase (72 mM ammonium acetate, pH adjusted to 6.5 with glacial acetic acid) (86.7:13.3) v/v; column temperature 25 °C, mobile phase flow rate 1 mL min(-1), wavelength of detection 254 nm.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Contaminación de Medicamentos , Yohexol/análisis , Tecnología Farmacéutica/métodos , Tampones (Química) , Cromatografía Líquida de Alta Presión/normas , Simulación por Computador , Concentración de Iones de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Yohexol/normas , Isomerismo , Modelos Químicos , Modelos Estadísticos , Método de Montecarlo , Análisis Multivariante , Control de Calidad , Reproducibilidad de los Resultados , Tecnología Farmacéutica/normas
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