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.

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.

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.

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.

DoE-Based Analytical Quality Risk Management for Enhanced AQbD Approach to Economical and Eco-Friendly RP-HPLC Method for Synchronous Estimation of Multiple FDC Products of Antihypertensive Drugs.

According to the literature review, numerous chromatographic methods have been published for estimation of fixed-dose combination products of telmisartan but no reverse-phase high-pressure liquid chromatographic (RP-HPLC) method has been published yet for synchronous estimation of fixed-dose combination (FDC) products of telmisartan to save time, cost and solvent for analysis. Hence, an economical and eco-friendly RP-HPLC method has been developed for synchronous estimation of multiple FDC products of antihypertensive drugs using the quality risk management (QRM) and DoE-based enhanced analytical quality by design approach. The analytical-QRM was started with the identification of potential method risk parameters followed by their risk assessment by risk priority number ranking and filtering. The identified critical method parameters were optimized using the DoE-based central composite design. The method operable design range was navigated and the control strategy was framed for control and mitigation of risk throughout the life-cycle of the developed method. The method was developed using Shimpack Octadecyl silane (ODS) C18 column and acetonitrile-1.0%v/v triethylamine in water (pH 6.0; 45 + 55, %v/v). The developed method was validated as per the International Council for Harmonization Q2 (R1) guideline. The developed method was applied for the analysis of seven different antihypertensive dosage forms. The developed RP-HPLC method can be used as an eco-friendly, robust and economical alternative analytical tool to several published methods for estimation of FDC products of antihypertensive drugs in the pharmaceutical industry.

Application of Quality Risk Assessment and DoE-Based Enhanced Analytical Quality by Design Approach to Development of Chromatography Method for Estimation of Combined Pharmaceutical Dosage Form of Five Drugs.

The high-performance liquid chromatography method was only reported for simultaneous estimation of aspirin, simvastatin, ramipril, atenolol and hydrochlorothiazide in polycap capsule. High-performance thin-layer chromatography (HPTLC) method is now accepted as a method of analysis by many pharmaceutical industries and included as an official method in monographs of pharmacopeias of many countries. Hence, HPTLC method was developed and validated for the estimation of polycap capsule using enhanced analytical quality by design based on principles of quality risk management and design of experiment (DOE). Quality risk management was performed by the identification and assessment of risky method parameters. DoE was carried out by Placket-Burman screening design and Box-Behnken response surface methodology using resolution and tailing factor as critical method attributes. Method operable design region was navigated for optimization and development of the method. The developed method was validated as per ICH Q2 (R1) guideline. The method was found accurate, specific, precise and sensitive for the said estimation. The developed method was applied for the assay of polycap capsule and results were found in good agreement with the labeled claim. The developed method can be used as an alternative to reported HPLC methods for quality control of polycap capsule.

Quality Risk Management-Based AQbD Approach to Development of VEER Chromatography Method for the Estimation of Multiple Combined Formulations of Anti-Hypertensive Drugs.

BACKGROUND: A number of chromatography methods for estimating combined dosage forms of telmisartan have been published in the literature, but each combined dosage form needs separate chromatography conditions for analysis. OBJECTIVE: The versatile, economical, eco-friendly, and robust chromatographic method has been developed for simultaneous estimation of multiple combined pharmaceutical dosage forms of anti-hypertensive drugs using the analytical quality by design approach based on principles of quality risk management (QRM) and design of experiment (DoE). METHOD: Analytical QRM was performed by identifying probable method risk parameters and risk assessment for the development of the method. DoE was performed by Taguchi Orthogonal Array (OA)  screening design and Box-Behnken response surface design using Design-Expert software (trial version). Chromatographic separation was performed using silica gel 60 GF254 as stationary phase and toluene-ethyl acetate-methanol-glacial acetic acid (5.5 + 2 + 1 + 0.2, v/v/v/v) as a mobile phase keeping saturation time of 15 min. The developed method was applied for the assay of six combined pharmaceutical dosage forms of anti-hypertensive drugs. RESULTS: The developed method was found to be validated for accuracy, precision, specificity, linearity, LOD, LOQ, and robustness as per ICH guideline. The results of the assay were found in good agreement with the labelled claim. CONCLUSIONS: The developed method can be applied for analysis and quality control of multiple combined dosage forms of telmisartan. HIGHLIGHTS: A QRM and DoE-based AQbD approach was applied for development of chromatography method for simultaneous estimation of multiple combined dosage forms of telmisartan. The developed method was successfully applied for simultaneous estimation of six different multiple combined dosage forms of temisrtan.