THE PREDICTION OF THE TIME COURSE OF IN-VIVO BIOAVAILABILITY FROM IN-VITRO DISSOLUTION TESTING
Abstract
Two methods of transforming in-vitro dissolution data into in-vivo bioavailability profiles are discussed. The first is a mathematical approach utilizing a transfer function relationship between in-vitro dissolution and in-vivo blood levels of acetazolamide and oxprenolol. The second is an apparatus-based methodology which predicts bioavailability profiles for acetazolamide in the form of dissolution rate profiles. Dissolution testing with acetazolamide is performed in the Sartorius absorption and solubility simulators in pH 10 and pH 1.2 (--->) 6.5. A weighted average weighting function is determined for both pH treatments and plasma levels of acetazolamide are computed. The resulting profiles show a good correlation with average observed blood levels of acetazolamide in a panel of human subjects. The results of a bioavailability study with oxprenolol in a panel of human subjects are reported. The average plasma level profile resulting from capsule dosing is used as the weighting function between dissolution of the drug product in the gastrointestinal tract and blood levels of oxprenolol. This information, along with the ideal plasma level profile for oxprenolol, can be used to determine the ideal release rate from a dosage form which will give good blood levels with once-daily dosing. The computed release profile for an elementary osmotic pump drug delivery system is shown. A microprocessor-based digitally controlled biopredictor apparatus was developed. This apparatus, when run in the closed-loop mode with a reference dosage form, determines the time-varying dissolution test process variables required to produce a dissolution rate versus time profile which simulates the average blood levels for acetazolamide. When a test dosage form of acetazolamide is exposed to the same time-varying process variables, the resulting dissollution rate profile is the predicted plasma level profile for that dosage form. Results are shown for three sets of predictions. In one set the time-varying process variables are produced by controlling only pH of the medium. Another set was produced by controlling only the primary flow rate in the flow-through dissolution cell. The third set resulted from controlling both primary flow rate and pH.
Degree
Ph.D.
Subject Area
Pharmaceuticals
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