Spreadability Measurements to Assess Structural Equivalence (Q3) of Topical Formulations—A Technical Note

Abstract

Due to the disadvantages associated with comparative clinical trials (e.g., extensive time and cost involved), in vitro methods are of high interest for evaluating the bioequivalence of topical formulations (1,2). The analysis of spreadability is one such method that can help assess bioequivalence of formulations that are qualitatively (Q1) and quantitatively (Q2) equivalent. The FDA will usually not request additional bioequivalence testing for solution formulations that are Q1 and Q2 equivalent. However, semi-solid formulations that are Q1 and Q2 equivalent may have differences in the physical attributes and state of the product (arrangement of matter, aggregation) that reflect changes in the manufacturing method or the physical state of starting materials. Thus, structural similarity (Q3) can be defined as a third aspect of equivalence (3). The rheology of semi-solids is sensitive to changes in the microstructure and is potentially able to detect Q3 differences. In addition, the viscosity of a topical formulation will affect its application and delivery of the active agent to and across the skin, resulting in variance in its therapeutic performance. Subjective spreadability has been shown to be related to rheology through a material’s yield stress, the minimum shear stress required to initiate flow (σο). Specifically, the spreadability is inversely proportional to σο. (4,5) Extensive studies have been completed for the yield stress analysis of semi-solid foods that can be extended to semi-solid pharmaceutical formulations (4,6–8). In this study, the vane method has been employed to determine the yield stress of Q1/Q2 topical formulations in an attempt to determine if they were Q3 equivalent. The vane method (Fig. 1) involves the immersion of the blades of a vane into a sample followed by slow rotation at a constant RPM until the torque exerted on the vane reaches a maximum value and the sample begins to flow. Torque vs. time curves are used to determine yield stress where Mo is the maximum torque exerted on the vane by the fluid. Fig. 1 A vane, used in the vane method, with blade height of H and blade diameter of d with the height (h) of vane immersed in a fluid. This geometry is used along with the maximum torque value obtained with the vane method to obtain the yield stress of the ... MATERIALS AND METHODS The materials used in these studies were four topical formulations containing the active ingredient Econazole Nitrate 1%, and these were obtained from the Food and Drug Administration. All three of the generic formulations were previously determined to be equivalent to the innovator product in clinical bioequivalence studies. In these studies, the creams were referred to as formulations A, B, C and D, where formulation C is the innovator and formulations A, B, and D are generic brands. These rheological flow tests were carried out on a Brookfield RV DV III + Digital Rheometer using a Brookfield cone (CPE 52) and plate apparatus. The rheological vane method experiments were carried out on a Brookfield RV DV III + Digital Rheometer using a vane spindle attachment. Flow Curves Procedure Flow curves for these formulations were constructed by discharging 0.5 mL of each formulation onto the center of the plate. The gap was then set for the cone and plate apparatus so that the cone was at an appropriate and consistent distance from the plate for each trial. The rheometer was then programmed with increasing RPM (shear rate) over a range of 1 to 24 s−1 at constant temperature (25°C).