Plasma cholic, chenodeoxycholic, deoxycholic, lithocholic or ursodeoxycholic acids, free and as their glycine or taurine conjugates, did not correlate with Child-Pugh or MELD score when corrected for multiple comparisons. The presence of HCC did not influence these correlations. Highly statistically significant correlations (P < 0.0001) were found between severity of liver cirrhosis, determined by the Child-Pugh and MELD scores, with plasma 1 and 2 concentrations, both alone and combined. Plasma concentrations of 1 and 2 were investigated in 25 adult patients with varying degrees of liver cirrhosis with and without hepatocellular carcinoma (HCC). The chemical synthesis of 1 and 2 is therefore described and their quantitation in plasma by ultrarapid chromatography-triple quadrupole mass spectrometry. Relatively little is known about 1 and 2 in adult patients with liver disease. All rights reserved.Two 3-oxo-Δ 4 fetal bile acids, 3-oxachola-4,6-dien-24-oic acid (1) and 7α-hydroxy-3-oxochol-4-en-24-oic acid (2), occur normally in the human fetus but remain elevated in neonates and children with severe cholestatic liver disease due to an autosomal recessive inborn error of metabolism affecting Δ 4-3-oxo-steroid 5β-reductase (AKR1D1). Although the FODS method was developed and evaluated using CPM in 500 mL dissolution volume, the dissolution method using a more common pharmacopoeial dissolution volume, i.e., 900 mL, was used to demonstrate the troubleshooting experiments for the drug products requiring 900 mL dissolution media.Ĭhlorpheniramine maleate Fiber optic dissolution system (FODS) Metformin hydrochloride Method development Validation Warfarin sodium.Ĭopyright © 2020 Elsevier B.V. The instrument-specific artifacts and data analysis problems are addressed and troubleshooting with possible solutions to eliminate or mitigate the errors. Additionally, the current work discusses problems related to media preparation, probe sensitivity, and excipient effects on data collected using FODS. Therefore, the FODS is a suitable alternative to traditional dissolution for CPM immediate-release tablets (many other drug products have been tested in the laboratory, and reports are in preparation). No significant difference in the amount dissolved at Q-timepoint was observed between FODS and traditional testing. Robustness testing demonstrates that small changes in operating conditions did not significantly change the result. Based on the statistics generated using the dissolution tests, the results are linear, accurate, precise, and specific. Method equivalence was established by comparing the dissolution results from FODS and the traditional dissolution method using UV spectrophotometry. Probe sampling depth, orientation, analytical wavelength, and paddle speed were varied to evaluate the robustness of the system tested. The linearity determination method was developed using five concentration levels between 25-125 % of the expected concentration, while for accuracy, 80 %, 100 %, and 120 % levels were used, and precision was determined using six runs at the 100 % level. The dissolution system was validated for linearity, accuracy, precision, specificity, and robustness analogously to an HPLC method validation. Dissolution runs were conducted at 37 ± 0.2 ☌ using a USP apparatus II, at 50 rpm in 500 mL of 0.01 N hydrochloric acid. In this report, a dissolution protocol was developed and validated for a model product, chlorpheniramine maleate (CPM) 4 mg IR tablets. Currently, there is no systematic approach available for the validation, quantitative assessment, and troubleshooting for the in-situ fiber optic/bathless dissolution system (FODS).
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