A Novel, Sustainable, and Eco-Friendly Spectrophotometric and Chemometric Approach for Determination of Severely Overlapped Spectrum via Unified Regression Equation: Greenness and Whiteness Assessment.

BACKGROUND: Nebivolol and valsartan (VAL) in combination with each other successfully control blood pressure and improve hypertension patient outcomes. OBJECTIVE: To develop and validate innovative, simple, and sustainable spectrophotometric methods for the simultaneous analysis of nebivolol and valsartan. METHOD: The new modified difference amplitude modulation (MD-AM) method uses only unified regression equation and does not require any resolution techniques. Other different approaches were also applied for the determination of the same mixture including univariate and multivariate spectrophotometric methods. The multivariate methods were PLS and PCR, whereas the univariate methods were derivative ratio (DD1), ratio difference (RD), constant center (CC), constant center spectrum subtraction (CC-SS), constant value coupled with amplitude difference (CV-AD), advanced concentration value (ACV), and amplitude difference (AD). The proposed methods use a green solvent; thus, the environmental impact of the presented procedures was evaluated qualitatively and quantitatively using six well-known evaluation tools. RESULTS: All methods were applied successfully for the analysis of the studied drugs in their bulk powder, pharmaceutical dosage form Byvalson®, and in vitro release at intestinal pH (7.4) using a USP dissolution tester. Results obtained were compared statistically with the reported method and with each other using a one-way ANOVA statistical test, and no significant differences were found. CONCLUSIONS: All green and white analytical chemistry evaluation tools results confirm the safety, sustainability, and cost-effectiveness of the approaches, indicating that the methods are regarded green and sustainable. Results were agreeable, encouraging their applicability in quality control laboratories for dosage form and making these methods an eco-friendly substitute for the analysis of this combined dosage form and for evaluating the dissolution profile. HIGHLIGHTS: For the first time, a severely overlapped spectrum was determined using a unified regression equation without the need of extended part or zero contribution regions by the novel method MD-AM. The proposed methods are the first study of in vitro dissolution profiling of nebivolol hydrochloride (NEB) and VAL and the first sustainable and green methods applied without compromising the analytical criteria.

In Vitro Dissolution Profile of Antihypertensive Mixture: Comparison Between Multivariate Methods and Statistical and Graphical Representation of Different Univariate Spectrophotometric Data.

BACKGROUND: Triplixam® is a new antihypertensive drug combination consisting of perindopril, amlodipine, and indapamide, which have a synergistic mechanism of action in combination with each other. OBJECTIVE: Comparative study of different spectrophotometric approaches used for the simultaneous determination of perindopril, indapamide, and amlodipine in bulk powder and in dosage form Triplixam. METHOD: The methods include univariate and multivariate spectrophotometric methods depending on either mathematical calculation or graphical representation of data. For the univariate methods: perindopril was resolved from other components using constant multiplication followed by spectrum subtraction resolution technique, and then two base point, AUC, constant value, and concentration value (CNV) methods were applied. For both amlodipine and indapamide: constant multiplication resolution technique was used, and then constant value and CNV methods were applied. CNV depends on graphical representation of data rather than statistical data. PLS and PCR chemometric assisted spectrophotometric techniques were also applied. The proposed methods are considered a green alternative to the reported methods as the greenness of the proposed methods was evaluated qualitatively and quantitatively by four green analytical evaluation tools. RESULTS: The methods were applied for the analysis of the mixture in the pharmaceutical dosage form Triplixam and in vitro release at intestinal pH (7.4) using a USP dissolution tester. CONCLUSIONS: The proposed green analytical methods are considered to be greener than the reported methods and simpler, so they could be used as an alternative for routine analysis of the mixture in quality control laboratories for the reason of their accurate results beside minimum manipulation steps that reduced the error and time required of the analysis with no harmful effect on analyst health as well as the environment. HIGHLIGHTS: The study was the first in vitro dissolution profiling of perindopril, amlodipine, and indapamide. The developed methods were excellent green methods without compromising the analytical criteria.

Univariate calibrations with or without chemometric assistance for determination of drugs lacking peak maxima in their zero-order profiles.

Trandolapril has no sharp peak in its zero-order spectrum and therefore, it is difficult to be measured by direct spectrophotometry. In this manuscript, several univariate and multivariate spectrophotometric methods were developed and validated for determination of Trandolapril (TR) and Verapamil (VR) combination. The first method for measuring Trandolapril is Constant Multiplication-Spectrum Subtraction (CM-SS), where Trandolapril was measured at 210 nm in its zero-order curve after elimination of Verapamil spectrum. Second and third methods are two Base Points (2BP) and area under the curve (AUC) to measure Trandolapril concentration without depending on the shoulder peak. The fourth method for Trandolapril is Derivative Subtraction (DS) that utilizes the sharp peak appeared in the first order spectrum of Trandolapril. Verapamil was determined by two methods, Constant Multiplication (CM) and Derivative Subtraction-Constant Multiplication (DS-CM). Also, two multivariate methods were developed for measurement of the mixture, Partial Least Squares (PLS) and Principal Component Regression (PCR). All the developed methods were validated as per ICH guidelines and the results proved that the developed methods are accurate and selective. Moreover, a statistical comparison between the developed methods and a reference method was done. Also, One-way ANOVA statistical test was done between all the proposed univariate and multivariate spectrophotometric methods.

Determination of amlodipine and atorvastatin mixture by different spectrophotometric methods with or without regression equations.

Four new, simple, and reproducible spectrophotometric methods were developed and validated for the simultaneous determination of Amlodipine (AML) and Atorvastatin (AT) in bulk powder and pharmaceutical dosage form. The four methods include two progressive and two successive resolution techniques. The two progressive methods are Absorbance Subtraction (AS) and Amplitude Modulation (AM), while the two successive methods are Constant Value (CV) and Concentration Value. In the Concentration Value method, the concentration of the drugs is determined from the graphical representation without the use of regression equations. Linearity range for the two progressive methods was from 5 µg/mL-35 µg/mL while for the two successive methods was from 5 µg/mL-55 µg/mL. The four methods were validated according to the ICH guidelines and were found to be accurate, precise, and selective. The methods were also applied for determination of the mixture in the marketed pharmaceutical dosage form. Results obtained were compared with reported methods. Also, One-way ANOVA statistical test was done between all the proposed spectrophotometric methods where no significant differences were found.

Response surface design as a powerful tool for the development of environmentally benign HPLC methods for the determination of two antihypertensive combinations: Greenness assessment by two green analytical chemistry evaluation tools.

Interest in implementing green chemistry principles in analytical chemistry has grown dramatically in the past few years. The solvents used have the major influence on the greenness of the method. Most conventional high-performance liquid chromatography methods employed utilize solvents that are "hazardous for the environment". In the present study, two-factor three-level response surface design was exploited to develop eco-friendly chromatographic methods for two different mixtures. The first one was atorvastatin and amlodipine and the second one was amlodipine, perindopril, and indapamide. As it is nontoxic to the environment, ethanol was used as the organic modifier in the mobile phase. The separation of the first mixture was attained using phosphate buffer (pH 7)/ethanol (42:58 v/v), and the second mixture was fully resolved using phosphate buffer (pH 5)/ethanol (40:60 v/v). The use of high-performance liquid chromatography allows excellent resolution in a short run time, hence, less waste was produced. The greenness of the developed methods was assessed by two evaluation tools, namely, National Environmental Methods Index and analytical eco-scale, and found to be excellent green analytical methods. Moreover, the developed methods were compared with other reported methods regarding accuracy and greenness and were found to be perfect alternatives to reported methods for separation and quantification of the mixtures.

Comparative pharmacokinetics of trandolapril, its active metabolite, and verapamil in human plasma of Egyptian population using HPLC-MS/MS.

Trandolapril and verapamil are commonly used antihypertensive drugs. However, there is a lack of available data on the change of their pharmacokinetics in patients with liver or kidney impairment and hence the need for dose adjustment. In this article, a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and validated for the monitoring of trandolapril, its active metabolite trandolaprilat, and verapamil in human plasma of patients with renal impairment and/or liver insufficiency. The chromatographic separation was achieved on a Gemini C18 reversed phase column using a gradient elution mode with a run time of 10 minutes. The mobile phase consisted of a mixture of methanol and 2% acetic acid. The electrospray ionization MS/MS analysis was performed in multiple reaction monitoring (MRM) mode. The assay was validated as per Food and Drug Administration (FDA) guidelines for bioanalytical method validation and proved to be suitable for the determination of therapeutic drug levels in plasma. The inter-group changes in pharmacokinetic data were compared to that of healthy volunteers. The comparison showed a significant difference in the pharmacokinetic parameters between the studied groups. The presented results exhibit the benefits of the proposed assay as a validated analytical tool for the continuous drug monitoring.