HPLC determination of rubber septum contaminants in the iodinated intravenous contrast agent (sodium iothalamate).
A simple and rapid method is described for the determination of 2-mercaptobenzothiazole and mercaptobenzothiazole disulfide leached from rubber closures into the iodinated contrast medium (sodium iothalamate). The contaminants were extracted with methylene chloride and analyzed by high-performance liquid chromatography using ultraviolet detection at wavelengths of 272 and 328 nm. The structures of the impurities were confirmed unequivocally by mass spectrometry. The minimum detectable level was 1 microgram/100 mL (0.01 ppm). The quantitation of contaminants leached from rubber stoppers provides a means for evaluating possible health risks of the extractables.
Development and validation of HPLC methods for the determination of potential extractables from elastomeric stoppers in the presence of a complex surfactant vehicle used in the preparation of parenteral drug products.
HPLC methods were developed and validated for potential extractables [zinc dithiocarbamate, 2,6-di-tert-butyl-para-cresol (BHT), octylated diphenylamine antioxidant, sulfur, pentylphenol, and tetrakis(methylene(3,5-di-tert-butyl-4-hydroxyhydro cinnamate))methane] from commercial elastomeric stoppers in a complex surfactant matrix. These stoppers were proposed to be part of the container-closure system for experimental formulations containing the surfactant, polyoxyethylated Castor oil (USP/NF) (POE Castor oil) and ethanol. The presence of POE Castor oil in the formulation posed unique challenges to the development and validation of the HPLC methods. POE Castor oil, also known as Cremophor, is a viscous and complex solubilizing agent with a number of uncharacterized fractions. Hence the goal was to identify HPLC conditions that would be suitable for the separation, detection, and quantitation of the potential stopper extractables in the presence of such a complex drug product matrix. A number of experiments were performed to evaluate the effects of different columns, mobile phase composition, injection volume, and gradient profile on the separation and detection of the potential stopper extractables. The quantitation limits of these stopper extractables are between 1 and 10 ppm. The methods demonstrate good linearity, acceptable accuracy, and precision.
Pharmacokinetics and Metabolism of 14C-Brivaracetam, a Novel SV2A Ligand, in Healthy Subjects
This study was designed to investigate the human absorption, disposition, and mass balance of 14C-brivaracetam, a novel high affinity SV2A ligand with potent anticonvulsant activity. Six healthy male subjects received a single p.o. dose of 14C-brivaracetam (150 mg, 82 μCi, or 3.03 MBq). Serial blood and complete urine and feces were collected until 144 h postdose. Expired air samples were obtained until 24 h. Brivaracetam was rapidly absorbed, with Cmax of 4 μg/ml occurring within 1.5 h of dosing. Unchanged brivaracetam amounted to 90% of the total plasma radioactivity, suggesting a modest first-pass effect. Plasma protein binding of radioactivity was low (17.5%). Urinary excretion exceeded 90% after 2 days, and the final mass balance reached 96.8% of the radioactivity in urine and 0.7% in feces. Only 8.6% of the radioactive dose was recovered in urine as unchanged brivaracetam, the remainder being identified as non–cytochrome P450 (P450)- and P450-dependent biotransformation products resulting from hydrolysis of the amide moiety (M9, 34.2%), hydroxylation of the n-propyl side chain (M1b, 15.9%), and a combination of these two pathways leading to the hydroxy acid (M4b, 15.2%). Minor amounts of taurine and glucuronic acid conjugates and other oxidized derivatives were also identified. Brivaracetam is completely absorbed, is weakly bound to plasma proteins, extensively biotransformed through several metabolic pathways, and eliminated renally.