AN IN-VIVO BASED, FEEDBACK CONTROLLED DISSOLUTION TEST
Abstract
An in vitro drug product dissolution apparatus which is based upon limited in vivo data from a reference dosage form was developed. It was shown to satisfactorily predict the in vivo plasma concentrations of test (eg: generic) drug products. This represents the ultimate accomplishment of in vitro drug product bioavailability testing. The dissolution rate was first controlled by altering the solubility volume of the sink which exists around the dosage form. Feedback control theory manipulated this process variable by altering the rate of effluent which was recycled through the dissolution cell. A more successful approach was to control the dissolution rate by altering the pH of the dissolution fluid and thereby its total solubility, again by negative feedback control. The pH manipulated dissolution concentrations were continuously compared to the scaled in vivo plasma concentrations for the reference dosage form to generate the error signal which was operated on by the controller and used to affect changes in the pH of the dissolution media. This procedure gave an in vitro dissolution to in vivo plasma concentration correlation with a correlation coefficient of 0.98. The control signal which created the dissolution conditions resulting in this correlation was recorded on magnetic tape and used later for in vitro bioequivalency tests on different dosage forms of the same drug. All predicted points fell within one standard deviation of the in vivo data. A comparison of this correlation procedure was made to the Transfer Function Analysis procedure and they were found to yield nearly identical results. The standard flow through dissolution cell proved to be unsuitable for feedback control due to its cumbersome procedure to introduce a dosage form. In its place the Injector Dissolution Cell was developed to immediately introduce a dosage form into a flowing stream of dissolution fluid. This novel dissolution cell was shown to overcome several problems inherent in the standard flow through dissolution cell.
Degree
Ph.D.
Subject Area
Pharmaceuticals
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