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1.
    
A methodical design-of-experiments were performed by applying quality-by-design concepts to establish a design-space for simultaneous and rapid quantification of Carvedilol and Ivabradine by UPLC in the presence of degradation products. Response-surface, central-composite design, and quadratic model were employed for statistical assessment of experimental data using the Design-Expert software. Response variables such as resolution and retention time were analyzed statistically for chromatographic screening. During DoE study, various plots such as perturbation, contour, 3D and design-space plots were considered for method optimization. The method was developed using C8 [100?×?2.1?mm, 1.8?µ] UPLC column, mobile phase comprising 0.5% triethylamine buffer [pH 6.4] and acetonitrile in the ratio of 50:50 v/v, the flow rate of 0.4?mL minute?1 and UV detection at 285?nm for both Carvedilol and Ivabradine. The method was developed with a short run time of two minutes. The method was found to be linear in the range of 25.0–199.9?µg?mL?1 and 8.9–21.3?µg?mL?1 for Carvedilol and Ivabradine, respectively with a correlation coefficient of 0.9998 in each case. The recovery values were found in the range of 99.7–100.8% and 98.9–100.9% for Carvedilol and Ivabradine, respectively. The method was validated according to ICH Q2 (R1) guidelines.  相似文献   

2.
    
With the objective of developing an advanced method for rapid separations with shorter runtime, a simple, precise, accurate stability-indicating isocratic reverse phase ultra-performance liquid chromatographic (RP-UPLC) method coupled with a photodiode array detector was developed for the quantitative determination of Gemcitibine hydrochloride and its three impurities (GEM) in drug substance. The determination was completed for an active pharmaceutical ingredient in the presence of degradation products and its process-related impurities. The method was optimized by using the samples generated from forced degradation studies. Good resolution between the peaks for impurities formed during synthesis, degradation products, and the analyte was achieved on a Waters Acquity UPLC HSS T3 (2.1 × 100 mm, 1.8 µm) column using mobile phase containing a mixture of buffer and methanol in the ratio of 90:10. The eluted compounds were monitored at 210 nm. The runtime was only 5.0 min, within which Gemcitabine, its three impurities, and degradation products were well separated. The degradation samples were assayed against the qualified reference standard and the mass balance in each case was more than 99%. The newly developed method was validated as per ICH guidelines with respect to specificity, linearity, limit of detection, limit of quantification, accuracy, precision, and robustness. Forced degradation studies were also performed to demonstrate the stability indicating power of the developed UPLC method.  相似文献   

3.
    
Although a number of methods are available for evaluating Rivastigmine hydrogen tartrate (RIV) and its possible impurities, a common method for separation if its potential impurities and positional isomers with good efficiency remains unavailable. With the objective of developing an advanced method for rapid separations with shorter runtimes, a simple, precise, accurate stability-indicating gradient reverse phase ultra-performance liquid chromatographic (RP-UPLC) coupled with a photodiode array detector method was developed for the quantitative determination of RIV and its impurities in drug substance and drug product. The determination was done for an active pharmaceutical ingredient, its pharmaceutical dosage form in the presence of degradation products, and its process-related impurities. Chromatographic separation was achieved on Acquity UPLC BEH Phenyl (100 mm × 2.1 mm, 1.7 µm) column with a mobile phase containing a gradient mixture of solvents A and B. The compounds eluted within a short runtime of 10 min and were monitored at 210 nm with the flow rate and the column oven temperature of 0.4 mL/min and 40°C, respectively. The resolution of RIV and its eleven impurities (positional and potential) was greater than 2.0 for all pairs of components. The newly developed method was validated as per ICH guidelines with respect to specificity, linearity, limit of detection, limit of quantification, accuracy, precision, and robustness. Forced degradation studies were also performed to demonstrate the stability indicating power of the developed UPLC method.  相似文献   

4.
    
A novel stability-indicating mass compatible gradient reverse phase ultra-performance liquid chromatographic (RP-UPLC) method was developed for the quantitative determination of purity of Ramelteon drug substance samples in the presence of its impurities and degradation products. The method was developed using Waters Acquity UPLC BEH SHIELD RP18 (100 mm × 2.1 mm, 1.7 µm) column with mobile phase containing a gradient mixture of solvents A and B. The eluted compounds were monitored at 230 nm, the run time was 10 min within which Ramelteon and its four impurities were well separated. Ramelteon was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal, and photolytic degradation. Ramelteon was found to degrade significantly in acidic and slightly in oxidative stress conditions and stable in base, hydrolytic, and photolytic degradation conditions. The degradation products were well resolved from main peak and its impurities, proving the stability-indicating power of the method. The developed method was validated as per ICH guidelines with respect to specificity, linearity, limit of detection, limit of quantification, accuracy, precision, and robustness.  相似文献   

5.
    
A simple, sensitive, and reproducible ultra-performance liquid chromatography (UPLC) coupled with a photodiode array detector method was developed for the quantitative determination of olmesartan medoxomil (OLM) in active pharmaceutical ingredient (API) and pharmaceutical dosage forms. Chromatographic separation was achieved on Acquity UPLC BEH phenyl 100 mm, 2.1 mm, and 1.7 µm phenyl columns and the gradient eluted within a short run time, that is, within 10.0 min. The eluted compounds were monitored at 210 nm, the flow rate was 0.3 mL/min and the column oven temperature was maintained at 27°C. The resolution of OLM and seventeen (potential, bi-products, and degradation products) impurities was greater than 2.0 for all pairs of components. The high correlation coefficient (R2 > 0.9991) values indicated clear correlations between the investigated compound concentrations and their peak areas within the LOQ (limit of quantification) to 150% level. The drug was subjected to the International Conference on Harmonization (ICH)-prescribed hydrolytic, oxidative, photolytic, and thermal stress conditions. The performance of the method was validated according to the present ICH guide lines for specificity, limit of detection, limit of quantification, linearity, accuracy, precision, ruggedness, and robustness.  相似文献   

6.
    
A stability indicating UPLC method was developed for the quantitative determination of Zolpidem Tartrate (ZT) and its product related variants present in drug substance and drug products. The liquid chromatographic separation was achieved on Acquity UPLC HSS T3-C18 column. All the eight potential variants and the drug were eluted within 8 minutes. A narrow range pH gradient, in combination with organic modifier was used to obtain separation (Rs > 1.5) between critical pairs. There was no placebo interference during the determination of analytes. The method had shown a good and consistent recoveries [98.91 ± 0.55 (mean ± RSD)] with a high degree of intra- and inter-day precision (ANOVA: FCalculated = 0.6498 < FCritical = 3.6823) for the drug. Linear regression analysis data revealed the best R2 values (0.9980–0.9998) and F Siginificance values (p < α = 0.05) for the drug and impurities. The stability-indicating capability of the method was verified by subjecting the drug to hydrolytic, oxidative, photolytic, and thermal stress conditions. LC-MS was used to identify the mass numbers of the degradation products. The m/z values 281 and 227 were matched with zolpidem acid and zolpyridine, respectively. Possible degradation pathways were discussed for the product related variants formed during stress studies.  相似文献   

7.
    
A simple, sensitive, and reproducible ultra-performance liquid chromatography (UPLC) coupled with a photodiode array detector method was developed for the quantitative determination of Ziprasidone Hydrochloride (ZIP) in API and pharmaceutical dosage forms. Chromatographic separation was achieved on an Acquity UPLC BEH 100-mm, 2.1-mm, and 1.7-µm Shield RP-18 columns, and within a short runtime, that is, within 8.0 min. The eluted compounds were monitored at 230 nm, the flow rate was 0.3 mL/min, and the column oven temperature was maintained at 27°C. The resolution of ZIP and seven (potential, bi-products, and degradation) impurities were greater than 2.0 for all pairs of components. The high correlation coefficient (r2 > 0.9992) values indicated clear correlations between the investigated compound concentrations and their peak areas within the test ranges. The repeatability and intermediate precision, expressed by the RSD, were less than 2.0%. The accuracy and validity of the method were further ascertained by performing recovery studies via a spike method. The accuracy of the method expressed as relative error was satisfactory. The drug was subjected to the International Conference on Harmonization (ICH)-prescribed hydrolytic, oxidative, photolytic, and thermal stress conditions. The performance of the method was validated according to the present ICH guidelines.  相似文献   

8.
    
This study validates a stability-indicating LC method for detecting organic impurities in the chlorzoxazone dosage form. Using a Waters X-Select R HSS T3 analytical column, mobile phase of it was made by mixing of water, methanol, and glacial acetic acid in the ratio of 700:300:10 (v/v/v). The drug product and drug substance were subjected to the stress conditions such as acid, base, oxidation, heat, and photolysis as per the recommendations of the International Conference on Harmonization (Q2) methodology. The study revealed the susceptibility of 4-chloro-2-aminophenol to alkaline environments, emphasizing peak homogeneity and stability. The method verification, per ICH guidelines and USP<1225>, established precision, specificity, linearity, accuracy, and robustness for quality control. The mean impurity recovery ranged from 95.5% to 105.2%, the correlation coefficient (r) was greater than 1.000, and the RSD values (n = 6) ranged from 0.6% to 5.1% across the LOQ–150% ranges. Full-factorial design tested final method conditions, evaluating multiple parameters concurrently. Graphical optimization within the design space defined strong method requirements, ensuring consistent and reliable outcomes. The study develops and validates chlorzoxazone stability-indicating methods, employing advanced statistical approaches like design of experiments and factorial design, with resilient conditions established through graphical optimization of the design space.  相似文献   

9.
    
A stability-indicating reversed-phase liquid chromatography method was developed for the determination of nifedipine in raw material. The analyses were performed on a reversed-phase Phenomenex Luna® C18 column (250 mm × 4.6 mm), maintained at 40 ± 1°C. The mobile phase was composed of methanol:water (70:30; v/v) and was eluted isocratically at a 1.2 mL min−1 flow rate. The method was validated in terms of specificity, linearity, quantification limit, detection limit, accuracy, precision, and robustness. The response was linear in the range of 0.2–1.0 mg mL−1 (r2 = 0.9992). The relative standard deviation values for inter- and intra-day precision were 0.70% and 0.73%, respectively. Recoveries ranged between 97.5% to 101.6%. The method was successfully applied for the determination of nifedipine in raw material.  相似文献   

10.
    
Stress testing studies were carried out on Valsartan (VAL) under hydrolytic (acidic, basic, and neutral), photolytic, oxidative, and thermal (in the solid state) conditions. Relevant degradation was observed when the drug was exposed to photolytic conditions, where two degradants (DP-1 and DP-2) were produced and when submitted to acid hydrolysis, which yielded one degradation product (DP-3). A high performance liquid chromatography method for the simultaneous determination of VAL and its degradation products was developed, optimized employing experimental design strategies, and validated, employing fully characterized standards of the degradation products. The results proved the stability-indicating property of the method.  相似文献   

11.
    
A simple, rapid, accurate, precise, selective, and reproducible stability‐indicating HPLC method has been developed for simultaneous estimation of metoprolol succinate and telmisartan using a mobile phase consisting mixture of Methanol: 10 mM potassium dihydrogen phosphate buffer: 10 mM hexane sulphonic acid (80:10:10,v/v/v) at the flow rate of 1 mL/min and detection wavelength at 223.0 nm. HiQ Sil C18 (250 × 4.6 mm, 5 µm) column was used as stationary phase. The retention time for metoprolol succinate and telmisartan were 3.067 min and 5.653 min, respectively. Linearity was observed in the concentration range of 5–80 µg/mL for metoprolol succinate and 5–60 µg/mL for telmisartan. The coefficient of correlation for metoprolol succinate and telmisartan was found to be 0.9990 and 0.9980, respectively. The results of analysis have been validated statistically and by recovery studies. Both the drugs were subjected to acid, alkali and neutral hydrolysis, oxidation, dry heat, and photolytic degradation. The degradation products of telmisartan and metoprolol succinate were well resolved from the pure drugs with significant differences in the retention time values. This method can be successfully employed for simultaneous quantitative analysis of metoprolol succinate and telmisartan in bulk drugs and formulations.  相似文献   

12.
Cilnidipine is a calcium channel blocker that is used to treat cardiac diseases such as angina and high blood pressure. Several column and planar chromatographic methods for estimating cilnidipine in pharmaceutical dosage forms have been documented. However, these method developments have been carried out employing organic solvents such as acetonitrile, methanol, toluene, chloroform, and others as mobile phase components or as sample pretreatment diluents. These organic solvents are neurotoxic and teratogenic to humans and aquatic animals, according to International Council for Harmonization Q3C (R8) recommendations. According to the green analytical chemistry approach, such organic solvents should be reduced or removed during the development of chromatographic methods for environmental protection and the safety of human and aquatic animal life. As a result, the stability-indicating chromatographic estimation of cilnidipine was performed utilizing less toxic organic solvents. To prevent organic solvent waste during method development, mobile-phase optimization was performed using the design of experiment-based response surface modeling. Cilnidipine has been subjected to hydrolysis, oxidation, photolysis, and dry-heat decomposition to determine its stability. The greenness profiles of the suggested and published chromatographic methods were examined using the national environment method index, analytical greenness calculator, green analytical procedure index software, and eco-scale assessment tool.  相似文献   

13.
    
Abstract

The present work aims at developing a liquid chromatographic method for the determination of drugs in the artemisinin combination therapy. The method development utilised the principles of QbD (Quality by Design) and design space in order to provide a specific, accurate and precise method. The drugs used in the study were Amodiaquine (AMD), Mefloquine(MFQ),Lumefantrine (LFN), Artesunate (ART) and Artemether (AMR). Separations of the analytes were achieved on a UPLC system using a HSS Cyano column (100 x 2.1) mm, x 1.8 µm and mobile phase consisting of20mM Ammonium formate buffer (pH 6.5) as mobile phase A, 0.04% formic acid and methanol as mobile phase B in gradient elution program. The method development was based on the systematic trials suggested by the software using QbD. The design space of the experimental conditions was proposed to indicate the ruggedness of the analytical method using DoE. The proposed method was successfully applied to various formulations and thus was approved as good analytical method based on its applications. The method was thoroughly validated as per ICH guidelines. The developed method finds its application in bulk drug and formulations with its extension to quality control and also in investigation of counterfeit drugs.  相似文献   

14.
    
A state-of-the-art ultra-performance liquid chromatographic (UPLC) method has been developed for purity testing of carbamazepine.

Successful chromatographic separation of the active pharmaceutical ingredient (API) from its impurities was achieved on a WATERS ACQUITY UPLC CSH C18 column with the dimensions 2.1 mm × 100 mm and 1.7 µm particle size with gradient elution of 0.2% phosphoric acid and acetonitrile in only 5 min.

Incorporating Quality by Design (QbD) principles to the method development approach by using the statistical software package Fusion AE allows the study of the relationship between chromatographic parameters (factors) and the resolution (response) between the peaks of interest. In a screening phase, the factors known to have a major effect on column selectivity (stationary phase, pH of the aqueous eluent, organic eluent type, gradient time, and slope) were studied. In the second phase, the chromatographic parameters that were identified as affecting the resolution were studied with additional instrument settings. In both phases, statistical concepts with experimental design plans (Design-of-Experiments) are used as an efficient and fast tool to simultaneously gain knowledge regarding the influencing factors and interactions. An operating space within the design space was established and a verification study confirmed the robustness of the final method.

Total analysis time was only 5 min, which is an impressive 22-fold increase in productivity in comparison to the method published in the European Pharmacopeia.  相似文献   

15.
    
Simple, precise, and stability-indicating reversed-phase liquid chromatography (RP-LC) method was developed and validated for simultaneous determination of delapril (DEL) and manidipine (MAN) in pharmaceutical dosage form, using the Plackett-Burman experimental design for robustness evaluation. The LC method was carried out on a C8 column (250 mm × 4.6 mm i.d., 5 µm), maintained at 35°C. The mobile-phase consisted of acetonitrile and a solution of triethylamine 0.3% pH 3.0 (adjusted with phosphoric acid) (55:45; v/v), run at a flow rate of 1.2 mL · min−1 and using photodiode array (PDA) detection at 220 nm. The chromatographic separation was obtained within 7 min and was linear in the range of 3–120 µg · mL−1 (r2 = 0.9997) for DEL and 1–40 µg · mL−1 (r2 = 0.9998) for MAN. Validation parameters such as the specificity, linearity, precision, accuracy, and robustness were evaluated, giving results within the acceptable range. Stress studies were carried out and no interference of the degradation products was detected. The proposed method was successfully applied for the simultaneous quantitative analysis of DEL and MAN in the tablet dosage form, contributing to improve the quality control and to assure the therapeutic efficacy.  相似文献   

16.
    
A simple, sensitive, and reproducible gradient reverse-phase ultra-performance liquid chromatographic (UPLC) method was developed for the quantitative determination of Prasugrel and all possible process-related impurities (positional isomers, degradants and byproducts) at the level of 0.5–2.0 µg mL−1. The main objective of this study is to control the impurities at crude and final stages of prasugrel hydrochloride. This method is applicable to drug substance and pharmaceutical dosage forms. Six potential impurities were formed during the process development, including the degradation products, and the desacetyl impurity existing in its keto and enol form was stabilized by using acidic pH. All these impurities were well separated primarily with a gradient HPLC method, based on their selectivity differences by using a polar embedded C8 column, monobasic potassium buffer, a basic organic modifier, and acetonitrile in the mobile phase. Initially, structures of all these impurities formed were identified by liquid chromatography equipped with mass spectrometer and further confirmed by spiking with the characterized impurities. The drug was subjected to International Conference on Harmonization (ICH) prescribed hydrolytic, oxidative, photolytic, and thermal stress conditions. The performance of the method was validated according to the present ICH guidelines.  相似文献   

17.
    
A simple, sensitive, and reproducible stability-indicating high-performance liquid chromatography method was developed for the analysis of glyoxal content in ondansetron HCl by derivatization technique. Chromatographic separation was achieved on symmetry shield RP18 (250 mm length, 4.6 mm inner diameter with 5 µm with a mobile phase consisting of a mixture of monobasic potassium phosphate and acetonitrile and pH adjusted to 3.0 with orthophosphoric acid (95:5 v/v) as mobile phase A, and acetonitrile, methanol, and water (85:5:10 v/v/v) as mobile phase B. UV detection was performed at 385 nm, the flow rate was 1.0 mL/min, and the column oven temperature was maintained at 30 °C. The high correlation coefficient (r 2  > 0.999) values indicated clear correlations between the investigated compound concentrations and their peak areas within the test ranges. The repeatability and intermediate precision, expressed by the RSD, were less than 2.0%. The accuracy of the method was further ascertained by performing recovery studies via a spike method. The high recovery and low relative standard deviation confirm the suitability of the method for routine quantification of glyoxal content in ondansetron HCl. The method was validated according to the present ICH guidelines for, limit of detection, limit of quantification, linearity, accuracy, precision, ruggedness, and robustness.  相似文献   

18.
Primary objective of this study was to develop a stability-indicating reverse-phase high-performance liquid chromatography (HPLC) method for simultaneous quantitation of tramadol and aceclofenac in presence of their degradation products. The drugs were subjected to various International Conference on Harmonization recommended stress conditions, such as acid hydrolysis, alkaline hydrolysis, peroxide oxidation, thermolysis, and photolysis. The major degradation products got well resoluted from the analytes in HPLC analysis with a mobile phase composed of a mixture of 0.01?M ammonium acetate buffer (pH 6.5) and acetonitrile (65:35, v/v) through a Phenomenex Gemini C18 (250?mm?×?4.6?mm, 5?µm particle size) column. The method was linear over a range of 15–60?µg/mL for tramadol and 40–160?µg/mL for aceclofenac concentration. The analytes were detected at a wavelength of 270?nm. The method was validated and found to be specific, accurate, precise, stable, and robust for its intended use. The method can be recommended for its future use in routine quality control, accelerated and real-time stability analysis of the formulations containing tramadol and aceclofenac combination.  相似文献   

19.
    
A new ion exchange high performance liquid chromatographic (IEC) method has been developed and validated for quantitative determination of Zoledronic acid in pharmaceutical injection dosage form. Complete separation was achieved for the parent compound Zoledronic acid, the impurities and excipients in an overall analytical run time of approximately 20 minutes. The proposed chromatographic conditions employed an isocratic elution of mobile phase at constant eluent flow rate of 0.7 mL min−1 and by using a new generation Allsep® anion exchange column. A UV-Vis detector set at 215 nm was used to monitor the eluate. The 100% aqueous mobile phase consisted of only diluted formic acid without any ion-pair substance. The drug product was subjected to oxidation, hydrolysis, photo-stability, and heat to apply the stress conditions. The method was found to be linear over the concentrations range from 0.200 to 1.200 mg mL−1(25% to 150% of Zoledronic acid concentration). The newly developed method has the requisite accuracy, selectivity and precision to assay Zoledronic acid in commercial pharmaceutical injection dosage form.  相似文献   

20.
    
A new simple, rapid, and sensitive stability-indicating high-performance liquid chromatography method has been developed and validated for the simultaneous determination of pizotifen, methylparaben, propylparaben, and synthesis impurities A and B of pizotifen in syrup. The separation of these compounds was achieved within 14 min on a Waters X-terra RP18 column using an isocratic mobile phase consisting of acetonitrile/tetrahydrofuran/potassium dihydrogenophosphate 0.1 M at pH 3.5 containing 4.59 mM heptane sulfonate (38:1.5:62, v/v/v). The analysis was performed at a flow rate of 1 mL min−1 and a detection wavelength of 220 nm. The selectivity, linearity, and calibration range, accuracy, within and between-days precision, limit of detection and quantification, and recovery were examined as part of method validation. Forced degradation showed that pizo does not undergo degradation under heat, acidic, and basic conditions, but that it was susceptible to oxidation with first-order kinetic degradation. Liquid chromatography coupled with mass spectrometry was used to analyze the degraded samples and tentative structural identification were assigned based upon known reactivity of the drug and molecular weight measurements.  相似文献   

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