An evaluation of rheological parameters for a model shear-thinning system with application to the diffusion of hydrocortisone

Many pharmaceutical systems exhibit shear-thinning flow properties but the expression of these properties in terms of meaningful rheological parameters remains a problem. To be useful, the parameters must be rheometer-independent and either describe the fluid under application, processing and storage conditions, or specify the fluid structure and disposition of the molecules at negligible shear rates. Interlinked with this problem is the correct selection of rheological parameters and systems for applied studies, i.e. the determination of rheological effects on drug diffusion. The components of the model shear-thinning system, the nonionic cellulose polymer, hydroxyethylcellulose (HEC, Natrosol 250G), and the nonionic surfactant, polyoxyethylene (4) dodecyl ether (Brij 30), were characterized, physicochemically. The addition of Brij 30 to HEC dispersions provided a reliable means of obtaining a series of systems showing predictable increments in shear-thinning behaviour at each HEC concentration. Over a 5 year period, the rheological reproducibility and stability of aqueous HEC dispersions were determined and compared with corresponding data for 2% methylcellulose (MC, 1500 cP) dispersions. For similar consistencies, HEC and MC dispersions showed comparable reproducibility and stability. The power-law consistency index was observed to be related to both storage time and polymer concentration. Two methods of shear stress calibration were examined for the Rotovisko. The determination of a shear stress calibration constant for each shear rate provided a significant improvement for non-Newtonian shear-thinning fluids over the manufacturer's calibration method when both methods were compared with corresponding data generated with the cone-plate Weissenberg rheogoniometer. The limitations of shear rate equations and two Couette rheometers, Haake Rotovisko and Brookfield Synchro-lectric (with SC-4 spindles), to accurately represent shear stress-shear rate parameters were examined. The Krieger-Maron and the Mooney shear rate equations were found to yield the widest range of rheometer-independent results for the Rotovisko and Brookfield rheometers, respectively, when separately compared with similar data obtained with the rheogoniometer. Viscometric properties of polyoxyethylene (4) dodecyl ether in HEC dispersions were evaluated over a concentration range of 2.0 -3.5% HEC and 0 - 16% Brij 30. Three rheological models: the modified Shangraw structure equation, the Steiger-Trippi-Ory equation and the power-law model were fitted to the data and found to describe accurately the flow behaviour of the dispersions at 30.0°C between shear rates of 8.5 - 685 s⁻¹. Variation of model parameters with surfactant concentration was computed for each HEC dispersion. A shear-sensitive interaction between the surfactant and the cellulose polymer was noted. To determine the disposition of HEC in solution and the nature of the viscous interaction noted for the HEC - Brij 30 systems, low shear rate and dynamic measurements were made. From storage and loss moduli, dynamic viscosities and loss tangents, HEC was determined to be a molecule with intermediate flexibility and the HEC - Brij 30 systems were composed of a loose three dimensional network. The effect of increased limiting viscosity at low shear rates was measured on the diffusion of hydrocortisone through nylon membrane and human autopsy epidermis. The absence of drug-vehicle interactions was demonstrated and the similarity in the results for the two membranes indicated that the observed decrease in steady state flux was due to the alteration of vehicle viscosity. The solubility, partition coefficient and diffusion coefficients were measured for hydrocortisone.Pharmaceutical Sciences, Faculty ofGraduat