A Comparison of USP Paddle With CrescentShaped Spindle Dissolution Profiles

Abstract

Introduction In the pharmaceutical industry,dissolution testing is widely used as a quality control tool to ensure performance of production lots and as a tool in the selection of formulations in development. In addition,evaluation of dissolution profiles as a surrogate for in vivo performance allows for the determination of bioequivalence of all formulations. The ability of dissolution to fulfill all of these roles is dependent on the reliability of the dissolution procedure. It has been well documented in the literature that the hydrodynamics of USP Apparatus 2 (paddle) may result in poor reproducibility and also poor variability in profiles not related to the formulation or in vivo characteristics (1,2). Attempts to fully understand and prevent poor hydrodynamics at low paddle rotation speed has allowed for the advent of new dissolution techniques such as flat-bottom vessels or PeakTM vessels (3) to reduce cone formation,and only limited comparative data has been obtained on a new paddle design,the crescent-shaped spindle. The rationale for the development of a crescent-shaped spindle is extensively documented in a report from the product designer and inventor,Dr. Saeed Qureshi (4). The crescent-shaped spindle design allows for intimate contact with the dosage form therefore eliminating coning and reducing vibration effects. Several evaluations of calibrator tablets, fast dissolving and extended-release tablets,and capsules have been performed (4,5),and results have shown improved drug release with better product characterization. When presented with the published data and asked to evaluate the crescent-shaped spindle,our focus and intent was to investigate in vitro–in vivo relationships as well as to evaluate the crescent-shaped spindle application as a batchto-batch quality control indicator. As an early phase development laboratory,our interest was in comparing animal or human bioavailability data with the dissolution profiles obtained with the crescent-shaped spindle and in comparing that data with previously obtained USP 2 paddle data. Evaluation of two cases was performed. In the first case,a formulation change was compared in vivo,and the results compared with USP 2 (paddle) dissolution profiles as well as crescentshaped spindle profiles. In the second case,the particle size effect on dissolution profiles was evaluated and compared to animal bioavailability data. As a quality control discriminator, several mis-manufactured batches were compared,along with a dual active batch.Throughout the evaluation,if sample was available,the dissolution profiles were also performed at low paddle rotation speed of 25 rpm in order to compare and evaluate the potential for a single paddle rotation speed (6). Abstract Dissolution profiles are used in making decisions on the quality of the product,the effect of critical processing parameters, the selection of the optimum formulation,and the determination of stability. The literature has demonstrated several initiatives to eliminate system artifacts not related to the drug product in dissolution testing. A proposed new spindle design was evaluated using various formulation challenges encountered in a pharmaceutical development group. The crescent-shaped spindle is in contact with the vessel bottom and the dosage unit,changing the hydrodynamics of the dissolution. Dissolution profiles using the crescent spindles were compared to those obtained using USP 2 paddles and related to in vivo behavior or quality control indicators. The practical use of the spindle for a GLP laboratory was also evaluated. This paper presents the results of these evaluations. In two cases studied,pharmacokinetic data were related to the dissolution behavior. In both cases,the differences in the dissolution profiles for the variation in formulation or API properties obtained using the crescent spindles reflected the pharmacokinetic data,whereas this was true for only one case when using the USP 2 paddles. An evaluation of batch-to-batch reproducibility as a means of quality control resulted in a comparison of profiles using the USP 2 paddle versus the crescentshaped spindle. The crescent-shaped spindle provided data indicating that the dissolution profiles could discriminate differences in the manufactured product. The design of the crescent-shaped spindle addressed the issue of poor hydrodynamics seen at low rotation for the paddles and allowed for easy installation into existing VanKel dissolution baths. Consistent positioning in the dissolution vessel was not easily achieved and resulted in higher variability. Consequently,the curvature of the crescent spindle should be fixed to ensure consistent contact with the vessel and the product. In order to be more widely accepted,calibration of the crescent-shaped spindle would require conformance to USP standards.