RESUMEN
Metabolic Syndrome (MetS) is associated with the risk of developing chronic disease (atherosclerotic cardiovascular disease, type 2 diabetes, cancers and chronic kidney disease) and has an important role in early prevention. Previous research showed that an artificial neural network (ANN) is a suitable tool for algorithmic MetS diagnostics, that includes solely non-invasive, low-cost and easily-obtainabled (NI&LC&EO) diagnostic methods. This paper considers using four well-known machine learning methods (linear regression, artificial neural network, decision tree and random forest) for MetS predictions and provides their comparison, in order to induce and facilitate development of appropriate medical software by using these methods. Training, validation and testing are conducted on the large dataset that includes 3000 persons. Input vectors are very simple and contain the following parameters: gender, age, body mass index, waist-to-height ratio, systolic and diastolic blood pressures, while the output is MetS diagnosis in true/false form, made in accordance with International Diabetes Federation (IDF). Comparison leads to the conclusion that random forest achieves the highest specificity (SPC=0.9436), sensitivity (SNS=0.9154), positive (PPV=0.9379) and negative (NPV=0.9150) predictive values. Algorithmic diagnosis of MetS could be beneficial in everyday clinical practice since it can easily identify high risk patients.
Asunto(s)
Algoritmos , Síndrome Metabólico/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Redes Neurales de la Computación , Factores de RiesgoRESUMEN
The diagnosis of metabolic syndrome (MetS) has a leading role in the early prevention of chronic disease, such as cardiovascular disease, type 2 diabetes, cancers and chronic kidney disease. It would be very greatful that MetS diagnosis can be predicted in everyday clinical practice. This paper presents artificial neural network (ANN) prediction of the diagnosis of MetS that includes solely non-invasive, low-cost and easily-obtained diagnostic methods. This solution can extract the risky persons and suggests complete tests only on them by saving money and time. ANN input vectors are very simple and contain solely non-invasive, low-cost and easily-obtained parameters: gender, age, body mass index, waist-to-height ratio, systolic and diastolic blood pressures. ANN output is M e t S-coefficient in true/false form, obtained from MetS definition of International Diabetes Federation (IDF). ANN training, validation and testing are conducted on the large dataset that includes 2928 persons. Feed-forward ANNs with 1-100 hidden neurons were considered and an optimal architecture were determinated. Comparison with other authors leads to the conclusion that our solution achieves the highest positive predictive value P P V = 0.8579. Further, obtained negative predictive value N P V = 0.8319 is also high and close to PPV, which means that our ANN solution is suitable both for positive and negative MetS prediction.
Asunto(s)
Síndrome Metabólico/diagnóstico , Redes Neurales de la Computación , Adolescente , Adulto , Factores de Edad , Anciano , Glucemia , Presión Sanguínea , Índice de Masa Corporal , Diagnóstico Precoz , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lípidos/sangre , Masculino , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Reproducibilidad de los Resultados , Factores Sexuales , Relación Cintura-Estatura , Adulto JovenRESUMEN
In this paper, chromatographic analysis of active substance olopatadine hydrochloride, which is used in eye drops as antihistaminic agent, and its impurity E isomer by hydrophilic interaction liquid chromatography (HILIC) and application of design of experiments (DoE) methodology are presented. In addition, benzalkonium chloride is very often used as a preservative in eye drops. Therefore, the evaluation of its chromatographic behavior in HILIC was carried out as well. In order to estimate chromatographic behavior and set optimal chromatographic conditions, DoE methodology was applied. After the selection of important chromatographic factors, Box-Behnken design was utilized, and on the basis of the obtained models factor effects were examined. Then, multi-objective robust optimization is performed aiming to obtain chromatographic conditions that comply with several quality criteria simultaneously: adequate and robust separation of critical peak pair and maximum retention of the first eluting peak. The optimal conditions are identified by using grid point search methodology. The experimental verification confirmed the adequacy of the defined optimal conditions. Finally, under optimal chromatographic conditions, the method was validated and applicability of the proposed method was confirmed.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Dibenzoxepinas/química , Cromatografía Líquida de Alta Presión/instrumentación , Dibenzoxepinas/aislamiento & purificación , Interacciones Hidrofóbicas e Hidrofílicas , Isomerismo , Estructura Molecular , Clorhidrato de OlopatadinaRESUMEN
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/químicaRESUMEN
In this article, a step-by-step optimization procedure for improving analyte response with implementation of experimental design is described. Zwitterionic antiepileptics, namely vigabatrin, pregabalin and gabapentin, were chosen as model compounds to undergo chloroformate-mediated derivatization followed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis. Application of a planned stepwise optimization procedure allowed responses of analytes, expressed as areas and signal-to-noise ratios, to be improved, enabling achievement of lower limit of detection values. Results from the current study demonstrate that optimization of parameters such as scan time, geometry of ion source, sheath and auxiliary gas pressure, capillary temperature, collision pressure and mobile phase composition can have a positive impact on sensitivity of LC-MS/MS methods. Optimization of LC and MS parameters led to a total increment of 53.9%, 83.3% and 95.7% in areas of derivatized vigabatrin, pregabalin and gabapentin, respectively, while for signal-to-noise values, an improvement of 140.0%, 93.6% and 124.0% was achieved, compared to autotune settings. After defining the final optimal conditions, a time-segmented method was validated for the determination of mentioned drugs in plasma. The method proved to be accurate and precise with excellent linearity for the tested concentration range (40.0 ng ml(-1)-10.0 × 10(3) ng ml(-1)).
Asunto(s)
Anticonvulsivantes/análisis , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Ácido gamma-Aminobutírico/análisis , Anticonvulsivantes/sangre , Anticonvulsivantes/química , Humanos , Límite de Detección , Reproducibilidad de los Resultados , Proyectos de Investigación , Ácido gamma-Aminobutírico/sangre , Ácido gamma-Aminobutírico/químicaRESUMEN
This paper presents the chemometrically assisted optimization and validation of the RP-HPLC method intended for the quantitative analysis of itraconazole and its impurities in pharmaceutical dosage forms. To reach the desired chromatographic resolution with a limited number of experiments in a minimum amount of time, Box- -Behnken design was used to simultaneously optimize some important chromatographic parameters, such as the acetonitrile content in the mobile phase, pH of the aqueous phase and the column temperature. Separation between itraconazole and impurity F was identified as critical and selected as a response during the optimization. The set optimal mobile phase composition was acetonitrile/ water pH 2.5 adjusted with o-phosphoric acid (50:50, V/V). Separations were performed on a Zorbax Eclipse XDB-C18, 4.6 × 150 mm, 5 µm particle size column with the flow rate 1 mL min-1, column temperature set at 30 °C and UV detection at 256 nm. The established method was then subjected to method validation and the required validation parameters were tested. For the robustness evaluation, fractional factorial 24-1 design was utilized and factors that might significantly affect the system performance were defined. As other validation parameters were also found to be suitable, the possibility to apply the proposed method for the determination of itraconazole, its impurities B and F in any laboratory under different circumstances has been proven.
Asunto(s)
Acetonitrilos/análisis , Cromatografía Líquida de Alta Presión/métodos , Cromatografía de Fase Inversa/métodos , Contaminación de Medicamentos , Itraconazol , Antifúngicos/química , Antifúngicos/farmacología , Fraccionamiento Químico , Itraconazol/química , Itraconazol/farmacología , Límite de Detección , Reproducibilidad de los ResultadosRESUMEN
This paper presents exploration of chromatographic behavior in HILIC system by experimental design and improved chromatographic response function denoted as N(CRF)*. As a model mixture six antidepressants were chosen: selegiline, mianserine, sertraline, moclobemide, fluoxetine and maprotiline. Due to complexity of retention mechanisms in HILIC system, detailed examination of experimental space assessing the influence of important factors (acetonitrile content in the mobile phase, buffer concentration and pH of the mobile phase) and their interactions was done by applying 3(3) experimental design. N(CRF)* is developed and designed to be the only output of the system which simultaneously measures the separation of all the examined substances, the chromatographic run duration and the quality of the obtained peaks shape. It allowed objective estimation of overall chromatogram quality and excluded the arbitrary judgment in ambiguous situations. The applied function highlighted the influence of investigated factors on entire mixture and enabled identification of experimental regions where the chromatographic behavior was satisfactory. Applied experimental design strategy combined with N(CRF)* proved to be valuable assistance in HILIC separation of complex mixtures.
Asunto(s)
Antidepresivos/análisis , Cromatografía Liquida/métodos , Acetonitrilos/química , Algoritmos , Antidepresivos/química , Fraccionamiento Químico , Concentración de Iones de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Proyectos de Investigación , SolucionesRESUMEN
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 & purificaciónRESUMEN
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/químicaRESUMEN
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 , PramipexolRESUMEN
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/análisisRESUMEN
Trimetazidine dihydrochloride is an anti-anginal drug, which possesses protective properties against ischemia inducing heart damage. In this paper, a new procedure for liquid chromatographic analysis was successfully developed, optimized, and applied in assessment of trimetazidine dihydrochloride content and its impurities, Y-145, Y-235, and Y-234 at most 1.0%, 0.2%, and 0.2%, respectively, in commercially available pharmaceutical preparation containing 35 mg of trimetazidine dihydrochloride. The retention behavior of trimetazidine dihydrochloride and its impurities is investigated by using several stationary and mobile phases to settle a simple, sensitive, and precise RP-HPLC method. The separation conditions are optimized by DryLab 2000 Plus Chromatography Optimization Software version 3.5.00. Separations are performed on PurospherSTAR RP18 endcapped (150 x 4.6 mm, 5 microm particle size) column at 20 degrees C with UV detection at 210 nm. The mobile phase composition is acetonitrile-aqueous phase (10 mmol/L disodium hydrogenphosphate and 2 mmol/L sodium dihydrogen phosphate, pH 7.6) (30:70 v/v). Afterwards, the method is validated; the important statistical parameters for selectivity/specificity, linearity, precision, limit of detection, and quantitation are defined. The recovery value of the trimetazidine dihydrochloride is 98.06%, and the content of impurities is 0.23% for Y-145, less than 0.02% for Y-235, and less than 0.01% for Y-234. In addition, this method is used for analyzing trimetazidine dihydrochloride and its impurities in pharmaceuticals and bulk drug.
Asunto(s)
Cromatografía Liquida/métodos , Computadores , Trimetazidina/análisis , Vasodilatadores/análisis , Estándares de Referencia , Espectrofotometría UltravioletaRESUMEN
The properties of the eluent are the essential factors governing the efficiency in the high-performance liquid chromatography (HPLC) method. A novel approach in retention modelling in the liquid chromatographic separation of fosinopril sodium and its degradation product, fosinoprilat, applying a microemulsion as the mobile phase, was used. The modifications of the mobile phase included the changes to the type of the lipophilic phase, the type and concentration of co-surfactant and surfactant, as well as the pH of the mobile phase. In this study, a full factorial 2(3) design, as the optimal method for screening of the experiment, was applied for selecting factors which had an influence on separation. Optimisation was done by a central composite design. An appropriate resolution with reasonable retention times was obtained with a microemulsion containing 0.9% w/w of cyclohexane, 2.2% w/w of sodium dodecyl sulphate (SDS), 8.0% w/w of n-butanol and 88.9% of aqueous 25 mM disodium phosphate, the pH of which was adjusted to 2.8 with 85% orthophosphoric acid. Separations were performed on an X-Terra 50-mmx4.6-mm, 3.5-mum particle size column at 30 degrees C. UV detection was performed at 220 nm and with a flow rate of 0.3 mL min(-1). The established method was validated and applied for analysis of appropriate tablets. The proposed chromatographic procedure for the separation of fosinopril sodium and its degradation product is less expensive compared with the conventional reversed-phase HPLC method, as well as being simple and rapid. The optimised and validated method can be used for separation, identification and simultaneous determination of fosinopril sodium and fosinoprilat in bulk drug and in pharmaceutical dose forms.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Fosinopril/análogos & derivados , Fosinopril/análisis , Emulsiones/química , Fosinopril/química , Fosinopril/aislamiento & purificación , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
A novel and unique approach was used for retention modelling in the separation of simvastatin and six impurities by liquid chromatographic using a microemulsion as mobile phase. A microemulsion is a modification of a micellar system where a lipophilic organic solvent is dissolved in the micelles; for that reason, microemulsions are usually treated as solvent-modified micellar solutions. When microemulsions are used as eluents in HPLC separations, solutes partition between the charged oil droplets and the aqueous buffer phase. The complexity of the composition of the microemulsion permits extensive manipulations to be made during method development in order to achieve acceptable resolution of such a complex mixture of substances. In order to avoid a laborious "trial and error" procedure, a 2(3) full factorial design was applied for choosing an optimal microemulsion composition to obtain good separation in a reasonable run time. Organic solvent, sodium dodecyl sulphate, and n-butanol content were varied within defined experimental domain. Optimal conditions for the separation of simvastatin and its six impurities were obtained using an X Terra 50 x 4.6 mm, 3.5 microm particle size column at 30 degrees C. The mobile phase consisted of 0.9% w/w of diisopropyl ether, 2.2% w/w of sodium dodecylsulphate (SDS), 7.0% w/w of co-surfactant such as n-butanol, and 89.9% w/w of aqueous 25 mM disodium phosphate pH 7.0.