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This manuscript demonstrates a Quality by Design approach using Design of Experiments to prove the robustness of a stability indicating HPLC method. The method determines the omeprazole in the presence of eight related substances and ketoprofen with six impurities developed for pellets filled capsule as a combined finished drug product. Based on the results, controllable factors that have influential effect on the resolution between peaks were identified and were examined while blocking the uncontrollable factors. The design employs a full factorial design of experiment for the interaction of controllable factors. A flowchart parades all steps of QbD approach by blocking and varying certain factors. Thus, the primary objective of this manuscript is to demonstrate the method's robustness by clarifying various steps systematically.

A novel gradient reversed-phase high-performance liquid chromatographic method has been developed for quantitative determination of Ropinirole hydrochloride and its six impurities in pharmaceutical dosage forms. Chromatographic separation has been achieved on an Inertsil ODS-3V (250 mm × 4.6 mm) 5 µm with buffered mobile phase consisting of solvent A (mixture of 0.1 molar (M) phosphate (pH 7.1) buffer and acetonitrile in the ratio 90:10 (v/v); respectively) and solvent B (mixture of 0.1 molar (M) phosphate (pH 7.1) buffer and acetonitrile in the ratio 60:40 (v/v); respectively) delivered at flow rate of 1.2 mL min−1 and the detection wavelength of 215 nm. Resolution of Ropinirole hydrochloride and all the six potential impurities has been achieved greater than 2.0 for all closely eluting impurities. This drug product was subjected to the stress conditions and stability studies were one degradant impurity was crossing reporting threshold those degradants were separated by preparative high performance liqui...

This paper describes a systematic design of experiments (DoE) approach by applying the principle of quality by design (QbD) to determine the design space for a stability-indicating HPLC method prior to validation. By employing DoE, a simultaneous multivariate approach was carried out for mobile phase pH, flow rate, percentage of organic content and column temperature. A two-level fractional factorial design (24−1 + 2 center points = 10 experiments) was employed and statistical analysis of the experimental data uncovered the significant influential chromatographic factors. The experimental data for USP tailing and resolution were analyzed statistically to screen the chromatographic factors. This approach determined the most influential chromatographic factors. During this process, inferences were evaluated from various data tables, for example, analysis of variance, summary of fit, lack of fit, and parameter estimates. The study also explained various plots such as actual vs. predicted plot, Pareto plot, and prediction profiler. The acceptable range of the chromatographic factors was displayed as a Contour plot defining the ‘design space’ of the method. The range of operating conditions that guarantee a satisfactory QbD was deduced to finalize the method prior to validation. The method is simple, rapid, and robust for the determination of montelukast in montelukast sodium oral granules dosage form. The method was validated according to ICH guidelines for accuracy, precision, linearity, range, specificity, ruggedness and robustness (one factor varied at a time). The method has been successfully transferred to the quality control department for quality analysis of manufactured batches and stability samples.

A new stability-indicating gradient reverse phase high-performance liquid chromatographic (RP-HPLC) method was developed for the quantitative determination of Eslicarbazepine acetate (antiepileptic drug) in bulk drugs and pharmaceutical dosage forms along with its impurities and degradation products. The method was developed using Zorbax SB C-18 (150 mm × 4.6 mm, 3.5 µm) column with mobile phase containing a gradient mixture of solvents A and B. The solvent A contains a mixture of 0.01 M KH2PO4 and Methanol in the ratio of 80:20, and the solvent B contains a mixture of Acetonitrile, Methanol, and Water in the ratio 75:5:20 (v/v). Eslicarbazepine acetate was subjected to the stress conditions of oxidative degradation, acid, base, neutral hydrolysis, and thermal and photolytic degradation. Eslicarbazepine acetate was found to degrade significantly in acid, base, neutral hydrolysis, and oxidative stress conditions. The degradation products were well resolved from main peak and its impurities within 20 min ru...

A reproducible gradient reversed-phase ultra-performance liquid chromatographic method is developed for quantitative determination of duloxetine hydrochloride in pharmaceutical dosage forms. The method is also applicable for analysis of related substances and for study of in vitro dissolution profiles. Chromatographic separation is achieved on a 50 mm × 4.6 mm, 1.8 μm C-18 column. Mobile phase A contains a mixture of 0.01 M KH(2)PO(4) (pH 4.0) buffer, tetrahydro furan, and methanol in the ratio 67:23:10 (v/v/v), respectively, and mobile phase B contains a mixture of 0.01 M KH(2)PO(4), (pH 4.0) buffer, and acetonitrile in the ratio 60:40 (v/v), respectively. The flow rate is 0.6 mL/min, and the detection wavelength is monitored at 236 nm. Resolution of duloxetine hydrochloride and three potential impurities is greater than 2.0 for all pairs of components. The drug was subjected to ICH prescribed hydrolytic, oxidative, photolytic, and thermal stress conditions. Method is validated for linearity, specificity, accuracy, precision, ruggedness, and robustness.

A stability-indicating UPLC method was developed for the simultaneous quantitative determination of losartan potassium, atenolol, and hydrochlorothiazide in pharmaceutical dosage forms in the presence of degradation products. The separation was achieved on a simple isocratic method (water: acetonitrile: triethyl amine: ortho phosphoric acid (60:40:0.1:0.1, v/v) at 0.7 mL min−1, a detection wavelength of 225 nm). The retention times of losartan potassium, atenolol, and hydrochlorothiazide were 2.3, 0.6 and 0.9 min. The total runtime was 3 min. Losartan potassium, atenolol, and hydrochlorothiazide were subjected to different ICH prescribed stress conditions. The method was validated with respect to linearity, accuracy, precision, robustness and ruggedness.

A stability-indicating LC method was developed for the simultaneous determination of ibuprofen and diphenhydramine citrate in pharmaceutical dosage forms. The chromatographic separation was achieved on an Inertsil ODS 3V, 150 × 4.6 mm, 5 μm, column. The mobile phase contained a mixture of 50 mM potassium dihydrogen phosphate buffer:acetonitrile:triethylamine:glacial acetic acid (55:45:0.2:0.2, v/v/v/v). This method allowed the determination of 2.85–9.14 mg mL−1 of ibuprofen and 0.54–1.73 mg mL−1 of diphenhydramine citrate, in a diluent consisting of pH 7.2, 50 mM potassium dihydrogen phosphate buffer:acetonitrile (40:60, v/v). The flow rate was 1.2 mL min−1 and the detection wavelength was 260 nm. The limit of detection for ibuprofen and diphenhydramine citrate was 1.72 and 0.54 μg mL−1 and the limit of quantification was 5.73 and 1.64 μg mL−1, respectively. This method was validated for accuracy, precision and linearity. The method was also found to be stability indicating.

A novel, specific and stability-indicating reversed-phase (RP) ultra-high-performance liquid chromatography (UHPLC) method, which is mass compatible, was developed and validated for the quantitative determination of silodosin and its related substances. Silodosin was subjected to stress conditions like hydrolysis (acid and basic), oxidation, photolysis and thermal degradation, as per the guidelines of the International Conference Harmonization, to show that the method is stability-indicating. The proposed UHPLC method has a resolution of greater than 2.0 between silodosin and its process-related impurities. The chromatographic separation was achieved on an Agilent Poroshell 120 EC-C18 column (50 × 4.6mm i.d.; particle size, 2.7 µm). The method employed a linear gradient elution using a mobile phase consisting of acetonitrile and 10 mM ammonium acetate buffer with 0.1% triethyl amine, with pH adjusted to 6.0, monitored at 273 nm. The developed RP-LC method was validated with respect to linearity, accuracy, precision and robustness. The known process impurities were separated and their structure was confirmed by using liquid chromatography-mass spectrometry and direct mass analysis.

Octahydro-1H-indole-2-carboxylic acid is a key starting material for the synthesis of Perindopril and Trandolapril. A rapid, economical, simple, sensitive and reliable stability-indicating reverse phase HPLC method developed and validated for the quantitative determination of all isomers related to Octahydro-1H-indole-2-carboxylic acid and its related substances. The compound is non chromophoric, it has three chiral centers and there is a possibility of four pairs of enantiomers. Refractive index detector was used for the quantification of all its isomers. Optimized mobile phase is 10 mM potassium phosphate buffer with pH-3.0. The C18 column (Inertsil ODS-4, 250 mm×4.6 mm×5 μm) is used as the stationary phase with a mobile phase flow rate of 1.5 mLmin–1 and column temperature maintained at 35°C. The developed method was validated as per ICH guidelines for Accuracy, linearity, range, precision, ruggedness, robustness, solution stability, limit of quantification, and limit of detection. A linear range from LOQ to 150% performed for the analyte and its three isomers. The correlation coefficient obtained for all the isomers was more than 0.999. The recoveries obtained for all isomers were found in between 93.9% and 107.9%. The detection limit for all the isomers were about 0.006 mg/mL and the quantification limits were in between 0.022 mg/mL to 0.024 mg/mL respectively. The proposed method can be successfully applied for the quantification of the three isomers in Octahydro-1H-indole-2-carboxylic acid and provides a simple and cost effective quality control tool for routine analysis.

A novel, stability-indicating gradient reverse-phase ultra-performance liquid chromatographic method was developed for the simultaneous determination of ibuprofen and diphenhydramine citrate in the presence of degradation products and process related impurities in combined dosage form. The method was developed using C18 column with mobile phase containing a gradient mixture of solvent A and B. The eluted compounds were monitored at 220 nm. Ibuprofen and diphenhydramine citrate were subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal, and photolytic degradation. Major unknown impurity formed under oxidative degradation was identified using LC-MS-MS study. The developed method was validated as per ICH guidelines with respect to specificity, linearity, limit of detection, limit of quantitation, accuracy, precision and robustness. The described method was linear over the range of 0.20-6.00 μg/mL (r>0.998) for Ibuprofen and 0.084-1.14 μg/mL for diphenhydramine citrate (r>0.998). The limit of detection results were ranged from 0.200-0.320 μg/mL for ibuprofen impurities and 0.084-0.099 μg/mL for diphenhydramine citrate impurities. The limit of quantitation results were ranged from 0.440 to 0.880 μg/mL for ibuprofen impurities and 0.258 to 0.372 μg/mL for diphenhydramine citrate impurities. The recovery of ibuprofen impurities were ranged from 98.1% to 100.5% and the recovery of diphenhydramine citrate impurities were ranged from 97.5% to 102.1%. This method is also suitable for the simultaneous assay determination of ibuprofen and diphenhydramine citrate in pharmaceutical dosage forms.

A novel stability-indicating normal phase liquid chromatographic (NP-LC) method was developed for the determination of purity of clopidogrel drug substance and drug products in bulk samples and pharmaceutical dosage forms in the presence of its impurities and degradation products. This method is capable of separating all the related substances of clopidogrel along with the chiral impurities. This method can be also be used for the estimation of assay of clopidogrel in drug substance as well as in drug product. The method was developed using Chiralcel OJ-H (250mmx4.6mm, 5microm) column. n-Hexane, ethanol and diethyl amine in 95:5:0.05 (v/v/v) ratio was used as a mobile phase. The eluted compounds were monitored at 240nm. Clopidogrel bisulfate was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal and photolytic degradation. 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 International Conference on Harmonization (ICH) guidelines with respect to specificity, limit of detection, limit of quantification, precision, linearity, accuracy, robustness and system suitability.

A novel stability-indicating gradient reverse phase ultra-performance liquid chromatographic (RP-UPLC) method was developed for the determination of purity of desloratadine in presence of its impurities and forced degradation products. The method was developed using Waters Aquity BEH C18 column with mobile phase containing a gradient mixture of solvents A and B. The eluted compounds were monitored at 280 nm. The run time was 8 min within which desloratadine and its five impurities were well separated. Desloratadine was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal and photolytic degradation. Desloratadine was found to degrade significantly in oxidative and thermal stress conditions and stable in acid, base, hydrolytic and photolytic degradation conditions. The degradation products were well resolved from main peak and its impurities, thus proved 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. This method was also suitable for the assay determination of desloratadine in pharmaceutical dosage forms.