THE OPTIMIZATION OF THE DOSE UNIFORMITY OF PHARMACEUTICAL SUSPENSIONS AS AFFECTED BY THE RHEOLOGICAL AND FLOCCULATION CHARACTERISTICS OF A MODEL SUSPENSION (SULFISOXAZOLE)

Optimization of the dose uniformity of a model suspension, containing the drug sulfisoxazole, was studied. The basic physical properties, including rheological behavior, sedimentation behavior and flocculation-deflocculation character, were examined to gain an insight into their relative effects upon the dose uniformity of suspended drug, sulfisoxazole. The suspensions were prepared containing an ionic flocculating agent, aluminum chloride, AlCl(,3), and a viscosity inducing agent, carboxymethylhydroxyethylcellulose type 37 medium viscosity (CMHEC-37M), and the concentrations and combinations of each were based upon a completely randomized block design. Accurate dosing from suspensions is a complex phenomenon based upon the physico-chemical makeup of the dispersions, the history of the dispersion, and extent and duration of agitation prior to the dosage measurement. The purpose of this research was to isolate the major factors influencing dose uniformity in a model suspension and then apply optimization as a means of systematically designing this class of drug delivery system. The electrophoretic mobility, as determined by the Electrophoretic Mass-Transport Analyzer (EMTA), together with drug sedimentation properties, were used to determine the flocculation-deflocculation state of the various suspensions, and the subsequent effect of this parameter on the dose uniformity. The rheological behavior of each suspension was measured from the standpoint of thixotropy and pseudoplasticity, and the effects of these parameters on the pourability of the suspensions and dose uniformity were determined. Optimization provided a systematic method for the analysis of the extreme nonlinearity typically found with each of the aforementioned suspension parameters, employing sound statistical design and precise evaluation to provide a new, unique, and objective approach to suspension formulation. Interrelationships between each factor were studied and identified to provide an increased understanding of the mechanisms involved in particle-particle interactions and to contribute to the overall understanding of suspension theory. Dose uniformity was expressed as dose variation which was defined as the theoretical amount per dosage unit minus the actual analytically assayed amount so established to provide the zero point corresponding to a theoretically, absolutely accurate dose. A type of univariate search technique was used to obtain contours of zero dose variation. The values providing the zero dose variation allowed the calculation of the other measured physical properties, i.e., pseudoplastic behavior, pourability, sediment height, and electrophoretic velocity. The calculations, based upon sound, rigourous statistical analysis, showed the extreme dependence of each physical phenomenon upon the other. . . . (Author\u27s abstract exceeds stipulated maximum length. Discontinued here with permission of school.) UM