Bernard E. Cabana

Bioavailability of imipramine tablets relative to a stable isotope-labeled internal standard: Increasing the power of bioavailability tests

A new methodology for comparative bioavailability testing is described in which each drug formulation is compared with a stable isotope-labeled variant of the drug that is consumed orally in solution at the same time the tested formulation is ingested. The methodology is used to determine the comparative bioavailabilities of two commercially available brands of imipramine hydrochloride. The power of the new methodology to detect differences between drug formulations, when, in fact, such differences exist, is shown to be superior to that of conventional bioavailability tests.

Dissolution medium—a critical parameter to identify bioavailability problems of furosemide tablets

The pH-solubility profiles of furosemide bulk drug and the dissolution profiles of two brands of furosemide tablets as a function of pH have been determined. The dissolution rate increased as the pH of the medium increased. Even though dissolution rate differences were noted around the pKa (3.60) of furosemide, such differences were negligible in the phosphate buffer region. One of these brands was alleged to cause therapeutic failures. The brand that dissolved poorly at pH 4.6 also exhibited inferior bioavariability. The data suggests the need for careful selection of pH and buffers composing dissolution media to make in vitro results meaningful and consistent with in vivo data.

Improved method for the analysis of furosemide in plasma by high-performance liquid chromatography.

Modifications of existing rapid high-performance liquid chromatographic procedures for the determination of furosemide in plasma were made in order to achieve greater sensitivity. To a small volume of plasma was added in internal standard structurally related to furosemide. Then, following previously described procedures, acetonitrile was added to precipitate the proteins and the clear supernatant was separated. However prior to injection of the supernatant the pH and composition of the sample were adjusted. This modification of the sample enabled an injection volume of up to 300 microliters of the supernatant to be injected onto the chromatographic column. The effluent was monitored spectrofluorimetrically. A standard linear calibration curve with a mean precision of +/- 4.4% was obtained for plasma samples containing 20--900 ng/ml of furosemide. Two structurally related compounds were used as internal standards in the furosemide assay.

Importance of media selection in establishment of in vitro-in vivo relationships for quinidine gluconate

Abstract The dissolution profiles of two different commercial formulations of controlled release 324 mg quinidine gluconate tablets were investigated and their bioavailability differences were associated with in vitro results. One of the marketed brands which was not approved by the Food and Drug Administration was alleged by some patients to have no therapeutic effect when taken orally. Dissolution profiles using the paddle method at 100 rpm in different dissolution media revealed wide differences between these two products. The dissolution rates of the two products were significantly different in water, acetate buffer pH 5.4 and phosphate buffer pH 5.4. However, the dissolution profiles were similar for the two products with respect to rate and extent in simulated gastric fluid (no enzymes) and pH 7.4 phosphate buffer. Bioavailability data for these two products showed significant differences among various in vivo parameters. A reformulated product with comparable bioavailability to the FDA-approved product also had similar dissolution profiles in the systems studied earlier. These findings confirmed the importance of the screening and judicious selection of dissolution medium as well as the predictive usefulness of a dissolution test in the quality control of sustained (or controlled) released quinidine gluconate formulations.

Thiazides I. Limitations of Bratton-Marshall Colorimetric Assay Method and Its Modifications in the Determination of Chlorothiazide in Bioequivalency Studies

Abstract The bioavailability of a commercially available 250 mg and a 500 mg chlorothiazide tablet was determined in human volunteers using cumulative urinary drug excretion. Urine specimens were analyzed for concentrations of chlorothiazide by four different modifications of the Bratton-Marshail assay procedure. Study results demonstrated that the estimation of this drugs bioavailability could vary with the particular modification used for urinary drug analysis.