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To understand the role of analytics in drug development, regulatory bodies also started using the approach of Quality by Design (QbD) during analytical method developments. The present study deals with the development of the "Method Operable Design Region" for assay and purity determination of risperidone in risperidone drug substance and formulations usingy UHPLC. Five different column chemistries, five different pH buffers, oven temperatures from 25 to 45°C, and different organic modifier composition, column lengths and flow rates were studied and statistically evaluated using Fusion QbD software. The final method parameters were selected by performing multivariable changes in a single run and evaluated using the Monte Carlo simulation approach. The uniqueness of this method is that it is mass compatible, a total of 10 peaks are separated within a short run time of 12.0 min and it uses a "Platforming approach", which means the use of a single method for testing the drug substance, different strengths of a drug product and different formulations. The same method can be also used for the determination of the preservative (benzoic acid) in risperidone 1 mg/ml oral solution. The use of the QbD approach is aligned with the US Pharmacopeia <1220>, BP supplementary chapter 2022 and the International Conference on Harmonization Q14 guidelines for life cycle management of analytical methods. [ABSTRACT FROM AUTHOR]

A high-performance liquid chromatography-tandem mass spectrometric method for the determination of free and total dabigatran in human plasma has been developed and validated using a stable labeled internal standard (IS) as dabigatran D4. The extraction of analyte and IS was accomplished by the solid-phase extraction technique. Chromatographic separations were achieved using Peerless basic C8 (150 × 4.6) mm, 5 µ column eluted at a flow rate of 1 mL/min with mobile phase Acetonitrile: 5 mM ammonium formate: Methanol and 0.2% formic acid (30:20:50, v/v/v). The run time of the method was about 2.5 min with elution times of dabigatran and dabigatran D4 at around 1.2 min. The multiple reaction monitoring transitions (Q1/Q3) were set at 472/289, 172 (m/z) for dabigatran, and 476/293 (m/z) for dabigatran D4. The calibration curves were linear (r2 ≥0.99) over the range of 1.04–406.49 ng/mL. The presented method was successfully employed in the analysis of pharmacokinetic studies with the added advantage of demonstrating the effect of co-administration of dabigatran with the proton pump inhibitor pantoprazole on bioavailability and pharmacokinetic characteristics. Re-analysis of incurred sample resulted in >98% compliance indicating good assay precision of target analytes. [ABSTRACT FROM AUTHOR]

Background and Objectives: Gymnema sylvestre R. Br. is a well-known Indian medicinal herb. Gymnemic acids are pentacyclic triterpenes saponins and active phytoconstituents of Gymnema sylvestre. The study aimed at evaluation of the in vitro rat liver cytochrome P450 (CYP) inhibition potential of extracts and total gymnemic acid (TA)-enriched fractions from G. sylvestre.Methods: Standardization of G. sylvestre [ethanolic (EL), hydroethanolic (HE), total acid of ethanolic (TAE), total acid of hydroethanolic (TAHE) and total acid of aqueous (TAAQ) extract] was done with respect to deacyl gymnemic acid (DAGA), using reverse phase-high performance liquid chromatography (RP-HPLC). Total triterpenoid content was determined by vanillin perchloric acid assay.Results: Total triterpene content was found to be the highest in TAAQ (59.86 ± 0.005% w/w) and TAE (49.77 ± 0.009% w/w). TAAQ showed IC50 ≤ 50 µg/ml for all selected CYP activities. Testosterone 6β-hydroxylation was strongly inhibited by TAE (IC50: 15.48 ± 2.13 µg/ml) and was moderately by TAAQ and EL with IC50 ≥ 50 µg/ml. Flurbiprofen 4′-hydroxylation was subject to strong, weak and moderate inhibition by TAAQ (IC50: 34.67 ± 1.38 µg/ml), TAE (IC50: ≥ 50 µg/ml) and EL (IC50: > 50 µg/ml), respectively. Dextromethorphan O-demethylation was inhibited by TAHE and TAAQ.Conclusions: In vitro inhibition studies suggested that TA strongly inhibits activity of selected CYP. This inhibition may possibly be due to triterpenoids and gymnemic acids that have been reported to be present in it. Data also suggest a potential for possible in vivo herb-drug interactions involving G. sylvestre and other medications that are metabolized by the same CYP. [ABSTRACT FROM AUTHOR]