Simultaneous Chromatographic Estimation of Vildagliptin and Dapagliflozin Using Hybrid Principles of White Analytical Chemistry and Analytical Quality by Design.

BACKGROUND: The fixed-dose combination of vildagliptin (VDG) and dapagliflozin (DGZ) is used in the treatment of type 2 diabetes mellitus. According to the literature survey, RP-HPLC and HPTLC methods have been reported for routine analysis of VDG and DGZ. These chromatographic methods have been developed using potentially neurotoxic and teratogenic solvents, which are unsafe for human and aquatic animal life and hazardous to the environment. These types of organic solvents shall be replaced or reduced during chromatographic analysis of drugs for the safety of human and aquatic animal life and the protection of the environment. The novel white analytical chemistry (WAC) approach has been introduced, which emphasizes robust, green, user-friendly, economical, and rapid analysis of drug samples. OBJECTIVE: Hence, the WAC-based RP-HPLC method has been developed for the estimation of VDG and DGZ using lower toxic and economical solvents. METHOD: The development of the RP-HPLC method includes the implementation of the analytical quality by design approach using principles of design of experiments to reduce organic waste generation and regulatory compliance of analytical method. The central composite design was applied for response surface modeling (RSM) and optimization of the RP-HPLC method. The method validation was carried out according to ICH Q2 (R1) guidelines. RESULTS: The fixed-dose combinations of VDG and DGZ were assayed, and results were found in compliance with their labeled claim. The published and proposed RP-HPLC methods were assessed for chromatographic analysis of VDG and DGZ using the Red-Green-Blue (RGB) model, AGREE calculator, Eco-Scale Assessment tool, GAPI software, and NEMI standards. CONCLUSIONS: The proposed method was found to be robust, green, economical, and user-friendly for chromatographic analysis of VDG and DGZ. The proposed method can be an economical and eco-friendly analytical tool in the pharmaceutical industry for quality control and routine analysis of fixed-dose combinations of VDG and DGZ. HIGHLIGHTS: Hybrid principles of WAC and analytical quality by design to RP-HPLC method for simultaneous estimation of VDG and DGZ in their fixed-dose combinations.

Analytical Quality Risk Assessment and Design of Experiments to Green HPTLC Method for Simultaneous Estimation of Sildenafil Citrate and Dapoxetine Hydrochloride.

A green and robust high-performance thin-layer chromatographic method has been developed for the simultaneous estimation of sildenafil citrate and dapoxetine hydrochloride. A fractional factorial design was applied for analytical quality risk assessment of potential analytical risk factors. The identified critical analytical risk factors were optimized using the design of experiment-based response surface analysis by full factorial design. The analytical design space was navigated for the optimization of the method and the control strategy was framed for low-risk life-cycle management of the chromatographic method. The chromatographic analysis of sildenafil and dapoxetine was carried out on a TLC plate coated with silica gel G60 F254 using n-butanol:ethyl acetate:ethanol (8.0 + 2.0 + 0.5, v/v) as mobile phase. The chromatographic peaks of sildenafil and dapoxetine were found to be at Rf 0.29 and 0.69, respectively. The method was found to be accurate, precise, robust, specific and sensitive. The fixed-dose combinations of sildenafil and dapoxetine were assayed and results were found in compliance with their labeled claim. The present method was developed using safe and eco-friendly organic solvents for the safety of analysts and the protection of the environment. The greenness profiles of developed and reported methods were evaluated using the NEMI scale and AGREE software.

Implementation of White Analytical Chemistry-Assisted Analytical Quality by Design Approach to Green Liquid Chromatographic Method for Concomitant Analysis of Anti-Hypertensive Drugs in Human Plasma.

According to current concepts of white analytical chemistry (WAC), the use of organic solvents those are teratogenic and carcinogenic must be avoided for the protection of the environment and of the analysts. This led to the development and validation of the WAC-assisted green liquid chromatographic technique (reverse-phase high-pressure liquid chromatography (RP-HPLC)) for the simultaneous analysis of anti-hypertensive drugs (azilsartan medoxomil, chlorthalidone and cilnidipine) in human plasma and their fixed-dose combinations. The analytical quality by design approach was used in conjunction with the design of experiments and chemometrics concepts to develop the method. To develop the green RP-HPLC method, critical method variables (CMVs) and critical analytical attributes were identified using the multivariate analytical tools principal component analysis and partial least square regression. Using the Box-Behnken design, the design of experiments was used for CMV optimization and response surface analysis. It was possible to explore the analytical design space for the life cycle management of the RP-HPLC method. The developed method was found to be validated following International Council for Harmonization Q2 (R1) and M10 requirements. Using the red, green and blue paradigm, the existing and proposed chromatographic methods were evaluated for their validation efficacy, greenness profile and cost-effectiveness.

Green analytical chemistry-driven response surface modeling to stability-indicating chromatographic method for estimation of cilnidipine and application of high-performance thin-layer chromatography-mass spectrometry for characterization of degradation products.

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.

Principles of White Analytical Chemistry and Design of Experiments to Development of Stability-Indicating Chromatographic Method for the Simultaneous Estimation of Thiocolchicoside and Lornoxicam.

BACKGROUND: A variety of chromatographic methods have been published for the stability evaluation of thiocolchicoside (THC) and lornoxicam (LNX). Nevertheless, the development of chromatographic methods requires the use of neurotoxic and teratogenic organic solvents that are detrimental to the environment and harmful to human life. OBJECTIVES: Using the principles of design of experiments (DoE), a novel white analytical chemistry-driven stability-indicating high-performance thin-layer chromatographic (SI-HPTLC) method has been developed for the concurrent stability study of THC and LNX. To protect the environment and human life, the stability-indicating HPTLC method was developed using safe organic solvents. METHOD: Potential analytical method risk parameters (AMRPs) and analytical method performance attributes (AMPAs) were screened using the fractional factorial design. The response surface analysis and optimization of critical AMRPs and AMPAs was carried out using full factorial design. Navigation of the method operable design region (MODR) was used to develop the SI-HPTLC technique. The developed method was validated in accordance with the International Council for Harmonization (ICH) Q2 (R1) guideline. RESULTS: The developed method's greenness was evaluated using the AGREE (Analytical Procedure Greenness) tool and ESA (Eco-Scale Assessment). The Blue (B) model was used to assess the proposed method's cost and time efficiency and user-friendliness. For the stability studies of THC and LNX, the 12 principles of WAC (white analytical chemistry) were used to evaluate the published and proposed chromatographic techniques. CONCLUSIONS: Compared to previously published chromatographic techniques for studying the stability of THC and LNX, the suggested approach was found to be more affordable, environmentally friendly, and user-friendly. HIGHLIGHTS: The development of a stability-indicating HPTLC method using a novel white analytical chemistry approach and organic solvents with low toxicity potential. Application of the developed method for analysis of the forced degraded sample and fixed-dose combinations of THC and LNX.

Glycerol Monooleate (GMO): A Valuable Biobased Lubricity and Pour Point Enhancer Blend Component for the ULSD Fuel.

Novel value-added usage of glycerol (biodiesel coproduct) derivatives has been indispensable due to the extensive production of biodiesel. The physical properties of ultralow-sulfur diesel (ULSD) improved with the addition of technical-grade glycerol monooleate (TGGMO) with increasing concentration from 0.01 to 5 wt %. The influence of increasing concentration of TGGMO was studied on the acid value, cloud point, pour point, cold filter plugging point, kinematic viscosity, and lubricity of its blend with ULSD. The results showed improved lubricity for the blended ULSD with TGGMO as shown by the reduced wear scar diameter from 493 to 90 µm. The low-temperature flow properties were also improved as shown by lower pour points of -36 °C for the 1% TGGMO/ULSD blend compared to -25 °C for ULSDTGGMO blends in ULSD of up to 1 wt %, which met the ASTM standard D975 specifications. We also investigated the blending effect of the pure-grade monooleate (PGMO, purity level >99.98%) on the physical properties of ULSD at a blend concentration of 0.5 and 1.0%. Compared to PGMO, TGGMO significantly improved the physical properties of ULSD with increasing concentration from 0.01 to 1 wt %. Nevertheless, PGMO/TGGMO did not significantly affect the acid value, cloud point, or cold filter plugging point of ULSD. A comparison between TGGMO and PGMO showed that TGGMO improves the ULSD fuel lubricity and pour point more effectively than PGMO. PDSC data indicated that although addition of TGGMO will lower the oxidation stability slightly, it is still better than the addition of PGMO. Thermogravimetric analysis (TGA) data showed higher thermal stability and lesser volatility for TGGMO blends compared to those for PGMO blends. The cost effectiveness of TGGMO makes it a better ULSD fuel lubricity enhancer than PGMO.

Green and Sustainable Analytical Chemistry-Driven Chromatographic Method Development for Stability Study of Apixaban Using Box-Behnken Design and Principal Component Analysis.

Apixaban (APX) is a novel anti-coagulant drug approved by USFDA. According to referred literature, numerous chromatographic methods such as RP-HPLC and high-performance thin-layer chromatography have been published for the stability study of APX. But these chromatographic methods have been developed using toxic organic solvents that are hazardous to the environment and unsafe for analysts. Hence, green and sustainable analytical chemistry-driven chromatographic method has been developed for the stability study of APX using safe organic solvents for the safety of analysts and the protection of the environment. APX was subjected to forced degradation for the development of a stability-indicating assay method. The method development was carried out by the implementation of chemometric and DoE approaches for minimizing solvent wastage. Principal component analysis was applied for the identification of critical method risk variables (MRVs) and method performance attributes. DoE-based response surface modelling was applied for the optimisation of critical MRVs. The greenness profile scales of published and developed chromatographic methods have been assessed by NEMI and AGREE methods for the estimation of APX. The developed method was found to be more eco-friendly and robust than the published chromatographic methods for the estimation of APX.

Red, Green, and Blue Model-Based Assessment and Principles of White Analytical Chemistry to Robust Stability-Indicating Chromatographic Estimation of Thiocolchicoside and Diclofenac Sodium.

BACKGROUND: White analytical chemistry (WAC) is a recent approach for evaluating analytical procedures based on their effectiveness in validating results, capacity to be environmentally friendly, and economic effectiveness. OBJECTIVE: The detection of diclofenac sodium (DCF) and thiocolchicoside (THC) simultaneously has been established using a WAC-driven stability-indicating chromatographic method (SICM). METHODS: For the concurrent stability study of THC and DCF, the suggested chromatographic technique was developed employing safe and environmentally acceptable organic solvents. To identify critical analytical method parameters (AMPs) and analytical quality attributes (AQAs), a design of experiments (DoE)-based screening design was applied. For the DoE-based response surface modelling (RSM) of critical AMPs and AQAs, the Box-Behnken design (BBD) was employed. RESULTS: A robust SICM was developed by navigating the analytical design space for simultaneous estimation of THC and DCF. IR, NMR, and mass spectral data were used to characterize the degradation products. Red, green, and blue (RGB) models were used to evaluate the suggested method's validation effectiveness, greenness power, and economic efficiency and compared to published chromatographic techniques. The effectiveness of the chromatographic method's validation concerning the International Council for Harmonization (ICH) Q2 (R1) guideline was evaluated using the red model. The analytical greenness (AGREE) evaluation tool and eco-scale assessment (ESA) approach were used to evaluate the green model's methodology. The blue model-based assessment was carried out for comparison of simplicity of instruments handling, cost, and time during sample analysis. The red, blue, and green scores of the techniques were averaged to arrive at the white score of the suggested and reported methods. CONCLUSION: For the concurrent stability study of THC and DCF, the suggested technique was shown to be validated, environmentally friendly, and cost effective. The suggested approach could be a cost-effective and environmentally friendly analytical technique for determining the stability and monitoring the quality of fixed-dose combinations (FDC) of THC and DCF. HIGHLIGHTS: Stability-indicating HPTLC method was developed for concomitant analysis of THC and DCF using concepts of DoE and WAC.

White analytical chemistry-driven stability-indicating concomitant chromatographic estimation of thiocolchicoside and aceclofenac using response surface analysis and red, green, and blue model.

White analytical chemistry is a novel concept for the assessment of analytical methods on basis of its validation efficiency, greenness power, and economical efficiency. White analytical chemistry-driven stability indicating chromatographic method has been developed for the concomitant analysis of thiocolchicoside and aceclofenac. The proposed chromatographic method has been developed using a safe and environmental-friendly organic solvents for the concomitant stability study of thiocolchicoside and aceclofenac. The analytical risk assessment was carried out for the identification of high-risk analytical risk factors and analytical method performance attributes. The mixture design was applied for the design of experiments-based response surface modeling of high-risk analytical risk factors and analytical method performance attributes. The degradation products were isolated and characterized using infrared, nuclear magnetic resonance, and mass spectral data. The proposed method was compared for its validation efficiency, greenness power, and cost-efficiency with published chromatographic methods using the red, green, and blue models. The white score of the proposed and reported method was calculated by averaging the red, green, and blue scores of the methods. The proposed method was found to be robust, green, and economical for the concomitant stability study of thiocolchicoside and aceclofenac.

In the Quest for Potent and Selective Malic Enzyme 3 Inhibitors for the Treatment of Pancreatic Ductal Adenocarcinoma.

The genome of pancreatic ductal adenocarcinoma (PDAC) is associated with frequent deletion of the tumor suppressor gene SMAD family member 4 (SMAD4) with collateral deletion of its chromosomal neighbor malic enzyme 2 (ME2). In SMAD4 -/- /ME2 -/- PDAC cells, ME3 takes over the function of the ME2 enzyme, and hence therapeutic targeting of ME3 is expected to arrest tumor growth. Hitherto no selective small molecule inhibitor of ME3 has been reported in the context of PDAC. Based on the molecular docking studies and structure-activity relationships with the reported ME1 inhibitor, several analogues of 6-piperazin-1-ylpyridin-3-ol amides have been synthesized and screened for their ME inhibition activity. Among them, compound 16b is identified as the most potent and selective ME3 inhibitor with an IC50 of 0.15 µM on ME3, and with 15- and 9-fold selectivity over ME1 and ME2, respectively. In the cell viability assay, compound 16b exhibited an IC50 of 3.5 µM on ME2-null PDAC cells, viz., BxPC-3.

Application of Principal Component Analysis and DoE-Driven Green Analytical Chemistry Concept to Liquid Chromatographic Method for Estimation of Co-formulated Anti-Hypertensive Drugs.

BACKGROUND: The fixed-dose combination (FDC) of metoprolol succinate (MTS), cilnidipine (CDN), and telmisartan (TST) is used for the management of hypertension. Numerous reversed phase (RP)-HPLC methods have been reported in the literature for chromatographic analysis of MTS, CDN, and TST. According to the concept of green analytical chemistry (GAC), toxic organic solvents should be avoided or minimized during chromatographic method development for the safety of analysts and the protection of the environment. The reported RP-HPLC methods have been developed using acetonitrile (ACN) or methanol as an organic component of the mobile phase and diluent for sample preparation. These organic solvents are considered toxic solvents as per the International Council for Harmonization (ICH) Q3C (R6) guideline and Pfizer medicinal chemistry solvent selection (PMCSS) guide. OBJECTIVE: We aimed to develop an environment-friendly and economical RP-HPLC-photo-diode array (PDA) method for the analysis of MTS, CDN, and TST using less toxic organic solvents to support the concept of GAC. METHODS: The method development was carried out by the implementation of chemometrics and design of experiments (DoE) to avoid wastage of organic solvent. Principal component analysis (PCA) was applied as a chemometric tool for the identification of critical method risk variables (MRVs) and method performance attributes (MPAs). The identified critical MRVs and MPAs were further studied by DoE-based response surface modelling for optimization of the method. RESULTS: The chromatographic analysis of MTS, CDN, and TST was carried out using a Shim-pack ODS column as a stationary phase and ethanol as an organic modifier in the mobile phase. The developed method was applied to the assay of FDCs and results were found to be in compliance with the label claim. The greenness profiles of reported and present RP-HPLC methods were evaluated by national environmental method index (NEMI) and analytical greenness (AGREE) methods. CONCLUSION: The developed method was found to be green, robust, and economical as compared to published methods for the analysis. HIGHLIGHTS: Development and validation of an RP-HPLC method for simultaneous estimation of MTS, CDN, and TST using safe organic solvents. Implementation of a analytical quality by design (AQbD) approach in method development using PCA and DoE. Application of the method for assay of FDCs of MTS, CDN, and TST.

Multivariate Analysis and Response Surface Modeling to Green Analytical Chemistry-Based RP-HPLC-PDA Method for Chromatographic Analysis of Vildagliptin and Remogliflozin Etabonate.

BACKGROUND: The fixed-dose combination (FDC) of vildagliptin (VDG) and remogliflozin etabonate (RGE) is used as antidiabetic medicine. Numerous reverse phase high-pressure liquid chromatographic (RP-HPLC) methods have been reported for the estimation of VDG and RGE using toxic organic solvents such as acetonitrile and methanol. These organic solvents are also hazardous to the environment. OBJECTIVE: Hence, the robust and green analytical chemistry-based RP-HPLC-PDA method has been developed for chromatographic analysis of VDG and RGE for the safety of analysts and protection of the environment. METHOD: The multivariate analysis has been carried out for the identification of critical method risk parameters (CMRPs) and critical method performance attributes (CMPAs) using principal component analysis (PCA). The identified CMRPs and CMPAs were linked with each other for optimization of the RP-HPLC-PDA method using DoE-based response surface modeling. The analytical design space (ADS) has been explored for robust chromatographic analysis of VDG and RGE. RESULTS: The chromatographic analysis of VDG and RGE has been carried out using Shim-Pack C18 column (250 mm L, 4.6 mm ID, 5.0 µm PS) and isopropyl alcohol-0.1% (v/v) formic acid (FA) in water (45 + 55, v/v, pH -3.5). The developed method has been validated in accordance with ICH Q2 (R1) guidelines. The method has been applied for the assay of VDG and RGE in their FDCs. The results of the assay were found in compliance with the labeled claims. CONCLUSIONS: The developed RP-HPLC-PDA method did not include any toxic or carcinogenic solvents. Hence, it is safe for analysts and the environment. The greenness profiles of the published and proposed RP-HPLC methods were evaluated by the national environmental method index (NEMI) scale, and the analytical greenness scores were calculated using the AGREE software. The developed method can be used as an eco-friendly tool in the pharmaceutical industry for routine analysis and quality control of FDCs of VDG and RGE. HIGHLIGHTS: Development of a green and robust RP-HPLC method for the estimation of VDG and RGE using safe organic solvents. The analytical quality by design (AQbD) approach has been implemented in the development of a method to minimize solvent wastage. The method was applied for the assay of FDCs of VDG and RGE.

Chemometric and DoE-Based Analytical Quality Risk Management to HPTLC Method for Simultaneous Estimation of Metronidazole and Norfloxacin.

According to the upcoming ICH Q14 guideline, the development of an analytical method by the implementation of the AQbD approach based on analytical quality risk management and design of experiments will become a regulatory requirement for the registration of new drug substances and products. In literature, the HPTLC method has not been reported yet for simultaneous estimation of metronidazole and norfloxacin. Hence, the robust HPTLC method has been developed and validated for simultaneous estimation of metronidazole and norfloxacin using QRM and the DoE-based enhanced AQbD approach. The principal component analysis was applied for chemometric-based risk assessment of method risk parameters. The high-risk method parameters were optimized by a DoE-based full-factorial design. The MODR and control strategy was estimated for quality risk management throughout the lifecycle of the HPTLC method. The HPTLC method was developed using silica gel 60 F254 as stationary phase and acetonitrile-methanol-formic acid-ammonia (9.5 + 0.5 + 0.5 + 0.3, v/v) as mobile phase. The developed method was validated as per ICH Q2 (R1) guideline. The developed method was applied for the assay of combined pharmaceutical dosage forms of metronidazole and norfloxacin and results were found in compliance with their respective labeled claim.

Simultaneous Estimation of Telmisartan, Chlorthalidone, Amlodipine Besylate and Atorvastatin by RP-HPLC Method for Synchronous Assay of Multiple FDC Products Using Analytical FMCEA-Based AQbD Approach.

Numerous reversed-phase high-pressure liquid chromatography (RP-HPLC) and high-performance thin-layer chromatography (HPTLC) techniques have been published for the estimation of fixed-dose combinations (FDCs) of telmisartan (TEL). No published literature has been reported to date which described the synchronous estimation of FDCs of TEL using a single chromatography condition. Hence, the RP-HPLC method has been developed and validated for synchronous analysis of FDCs of TEL using an enhanced analytical quality by design (AQbD) approach to save time, cost and solvent for analysis. The implementation of AQbD was initiated with the identification of failure modes (FMs) using the Ishikawa diagram, and their critical effect analysis was carried out by risk priority number ranking and filtering method. The identified critical FMs were optimized by design of experiments-based response surface modeling using the Box-Behnken design. The method operable design region was navigated and control strategy was framed to mitigate the risk of critical FM. The RP-HPLC method was developed using Shim-Pack octadecyl silane C18 column and acetonitrile: 1.0%v/v triethylamine (pH 6.5 adjusted using perchloric acid; 42:58, %v/v). The developed method was found to be validated as per the International Council For Harmonization Q2 (R1) guideline. The method was applied for the synchronous assay of seven different FDCs of TEL and assay results were found in good compliance with the respective labeled claim.

Application of Taguchi OA and Box-Behnken Design for the Implementation of DoE-based AQbD Approach to HPTLC Method for Simultaneous Estimation of Azilsartan and Cilnidipine.

Hypertension is the most prominent disease found in people due to stressful routines and the working environment. The fixed-dose combination (FDC) of azilsartan medoxomil (AZL) and cilnidipine (CLN) is used for the treatment of hypertension. According to the green chemistry approach, organic solvents should be minimized in the development of the analytical method for the safety of the environment. The high-performance thin-layer chromatographic (HPTLC) method required less amount of organic solvent for the analysis of the drug. Hence, it was thought of interest to develop an accurate and robust HPTLC method for the estimation of AZL and CLN in their FDC. The development of the method was carried out by the implementation of the analytical quality by design approach using the Taguchi orthogonal array and BBD for regulatory compliance as per the upcoming ICH Q14 guideline. The analytical design space and control strategy was framed for the lifecycle management of the method. The chromatographic separation was performed using silica gel GF254 and toluene ethylacetate-methanol (6.5 + 1.5 + 2.0, v/v). The method was applied for the assay of FDC and results were found in compliance with the labeled claim. The developed method was also applied for the estimation of spiked human plasma and the recovered amount of drugs was found in the range of 80-85%.

Method Greenness Profile Assessment to AQbD-Driven Stability Indicating HPTLC Method for Estimation of Aripiprazole Using Screening Design and Response Surface Modeling.

BACKGROUND: According to the literature review, organic solvents such as methanol, acetonitrile, toluene, and carbon tetrachloride have been used for the chromatographic analysis of aripiprazole (APZ). The green chemistry approach recommends these organic solvents are unsafe for analysts and the environment and should be avoided or minimized in chromatographic analysis. OBJECTIVE: Hence, the stability-indicating assay method (SIAM) has been developed for the estimation of aripiprazole using safe organic solvents. METHODS: The quality risk management was started with risk identification, which was followed by risk assessment. By the risk assessment process, seven analytical risk factors (ARFs) were found to be potentially risky for method development. Further risk analysis was done by Taguchi OA design for the study of the main effect of ARF on resolution between the peaks. Design of experiments (DoE)-based response surface modeling (RSM) was performed by central composite design. Method operable design region (MODR) was navigated for resolution between peaks more than 1.0 for risk control. After navigation of the MODR, a risk review was done by validation of the design model for SIAM. RESULTS: Control strategy was set for ARFs and separation was carried out on the precoated aluminum plate with silica gel 60 F254 using ethyl acetate-ethanol (8.0 + 2.0, v/v) as the mobile phase keeping 15 min saturation time. The developed method was validated as per the International Council for Harmonisation (ICH) Q2 (R1) guideline. The developed SIAM was applied for the assay of aripiprazole in its tablet, and results were found in agreement with the labeled claim. CONCLUSIONS: The organic solvents ethyl acetate and ethanol used in chromatographic analysis of APZ are recommended as safe organic solvents by the ICH Q3C guidelines. The method greenness profiles of developed and published methods were evaluated by national environmental method index (NEMI) and analytical greenness (AGREE) methods. The developed method was found to be safe and green for chromatographic analysis of APZ. HIGHLIGHTS: Development of a green, robust, accurate, and precise stability-indicating HPTLC method for estimation of APZ. The quality risk management (QRM) and DoE-based analytical quality by design (AQbD) approach was implemented in support of the green analytical chemistry concept. Estimation of greenness profile of method by NEMI and AGREE methods.

Advances on nanoformulation approaches for delivering plant-derived antioxidants: A case of quercetin.

Oxidative stress has been implicated in tumorigenic, cardiovascular, neuro-, and age-related degenerative changes. Antioxidants minimize the oxidative damage through neutralization of reactive oxygen species (ROS) and other causative agents. Ever since the emergence of COVID-19, plant-derived antioxidants have received enormous attention, particularly in the Indian subcontinent. Quercetin (QCT), a bio-flavonoid, exists in the glycosylated form in fruits, berries and vegetables. The antioxidant potential of QCT analogs relates to the number of free hydroxyl groups in their structure. Despite presence of these groups, QCT exhibits substantial hydrophobicity. Formulation scientists have tested nanotechnology-based approaches for its improved solubilization and delivery to the intended site of action. By the virtue of its hydrophobicity, QCT gets encapsulated in nanocarriers carrying hydrophobic domains. Apart from passive accumulation, active uptake of such formulations into the target cells can be facilitated through well-studied functionalization strategies. In this review, we have discussed the approaches of improving solubilization and bioavailability of QCT with the use of nanoformulations.

Chemometry and Green Chemistry-Based Chromatographic Analysis of Azilsartan Medoxomil, Cilnidipine and Chlorthalidone in Human Plasma Using Analytical Quality by Design Approach.

According to the green chemistry approach, the usage of carcinogenic and teratogenic organic solvents should be minimized in the development of the analytical method for the safety of the environment and analysts. According to the literature review, no high-performance thin-layer chromatographic (HPTLC) method has been reported yet for concomitant analysis of azilsartan medoxomil (AZM), chlorthalidone (CTD) and cilnidipine (CDP) in human plasma. Hence, a robust and accurate HPTLC method has been developed using safe and non-toxic organic solvents for the concomitant analysis of AZM, CTD and CDP in human plasma, fixed-dose combinations (FDCs) and laboratory mixtures. The HPTLC method was developed by the implementation of the analytical quality by design approach using principles of quality risk management and design of experiments (DoE) for regulatory compliance. The principal component analysis was applied for the risk assessment and analysis of potential method variables in the method development. The principle of DoE was used for the response surface modeling to link identified critical method risk parameters with critical method performance attributes using full factorial design (FFD). The method operable design region and analytical control space were navigated for the optimization of the method as per quality target analytical profile. The developed method was also applied for concomitant analysis of AZM, CTD and CDP in their FDCs and laboratory mixture and results were found in good agreement with the labeled amount of the respective drug.

Chemometric and Design of Experiments-Based Analytical Quality by Design and Green Chemistry Approaches to Multipurpose High-Pressure Liquid Chromatographic Method for Synchronous Estimation of Multiple Fixed-Dose Combinations of Azilsartan Medoxomil.

BACKGROUND: Azilsartan medoxomil (AZL) is an anti-hypertensive drug, and its numerous FDCs are used for the treatment of hypertension. Numerous chromatographic methods have been reported for the estimation of FDCs of AZL, but analysts have to establish a separate chromatographic condition for the analysis of each FDC of AZL. No reverse-phase high-pressure liquid chromatography (RP-HPLC) method has been reported yet that can be used for synchronous estimation of multiple FDCs of AZL. OBJECTIVE: Hence, the RP-HPLC-PDA method has been developed for synchronous estimation of multiple FDCs of AZL to save time, cost, and solvent for the analysis. METHOD: The RP-HPLC-PDA method has been developed by the implementation of the analytical quality by design (AQbD) approach based on chemometric and DoE as per the upcoming International Council for Harmonization (ICH) Q14 guideline. RESULTS: The method was applied for synchronous estimation of multiple FDCs of AZL, and the assay results were found in compliance with the labeled claim of the FDCs. CONCLUSIONS: The developed method requires less time, cost, and organic solvent for analysis of the said pharmaceutical dosage forms compared to published chromatographic methods. Hence, the developed method is green and multipurpose for the estimation of multiple FDCs of AZL. HIGHLIGHTS: Development and validation of RP-HPLC method for synchronous estimation of multiple FDCs of AZL using chemometric (principal component analysis and PLS) and design of experiments (DoE). Applications of the method for synchronous estimation of multiple FDCs of AZL.

Chemometric-Based AQbD and Green Chemistry Approaches to Chromatographic Analysis of Remogliflozin Etabonate and Vildagliptin.

BACKGROUND: According to the green chemistry approach, during method development, the usage of toxic and carcinogenic organic solvents should be avoided or minimized for the safety of the environment and analysts. The chromatographic methods such as reverse-phase high-pressure liquid chromatography (RP-HPLC) and high-performance thin-layer chromatography (HPTLC) include the usage of class 2 organic solvents as per the International Council for Harmonization (ICH) Q3C (R6) guideline. The chromatographic analysis by HPTLC requires less organic solvent compared to the RP-HPLC method. OBJECTIVE: Hence, HPTLC-based chromatographic analysis of vildagliptin (VIL) and remogliflozin etabonate (RMG) has been carried out using green chemistry and analytical quality by design (AQbD) approaches. METHOD: The principal component analysis (PCA)-based chemometric analysis was applied for the identification of critical method variables (CMV) for the development of the method. The design of experiments (DoE)-based Box-Behnken design (BBD) was applied for response surface modeling (RSM) and optimization of CMV. The analytical design space (ADS) and analytical control point were navigated for the development of the HPTLC method as per the quality target analytical profile. RESULTS: The chromatographic analysis of VIL and RMG was carried out using silica gel G60 F254 as the stationary phase and acetone-ethyl acetate-water-triethylamine (7.0 + 2.5 + 0.3 + 0.2, v/v) as the mobile phase. The HPTLC method was validated as per the ICH Q2 (R1) guideline. The HPTLC method was applied for the assay of fixed-dose combinations (FDCs) of VIL and RMG, and the results were found to comply with their labeled claim. CONCLUSIONS: The developed method included the usage of organic solvents that belong to the class 3 category as per the ICH Q3C (R6) guideline. Hence, the developed method can be used as an eco-friendly alternative to published chromatographic methods for quality control and routine analysis of FDCs of VIL and RMG in the pharmaceutical industry. HIGHLIGHTS: Chromatographic analysis of VIL and RMG using green chemistry and AQbD approaches. Application of the method for assay of drugs in their combined pharmaceutical dosage forms.