Date of Award

Summer 2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Chemical Engineering - (Ph.D.)

Department

Chemical, Biological and Pharmaceutical Engineering

First Advisor

Piero M. Armenante

Second Advisor

Norman W. Loney

Third Advisor

Laurent Simon

Fourth Advisor

Ecevit Atalay Bilgili

Fifth Advisor

Zongming Gao

Sixth Advisor

Vivian Gray

Abstract

Dissolution testing is routinely conducted in the pharmaceutical industry to provide critical in vitro drug release information for quality control purposes, and especially to assess batch-to-batch consistency of solid oral dosage forms such as tablets. Among the different types of apparatuses listed in the United States Pharmacopoeia (USP), the most commonly used dissolution system for solid dosage forms is the USP Dissolution Testing Apparatus 2, consisting of an unbaffled, hemispherical-bottomed vessel equipped with a 2-blade radial impeller.

Despite its extensive use in industry and a large body of work, some key aspects of the hydrodynamics of Apparatus 2 have received very little attention, such as the determination of its power dissipation requirements (which controls solid-liquid mass transfer processes) and the velocity distribution under the different agitation conditions at which this system is routinely operated. In addition, the tablet dissolution performance of Apparatus 2 has been shown to be highly sensitive to a number of small geometric factors, such as the exact locations of the impeller and the dissolving tablet.

Therefore, in this study, computation and experimental work was conducted to (a) quantify the roles of some key hydrodynamic variables of importance for the standard Apparatus 2 system and determine their impact on the dissolution profiles of solid dosage forms, and (b) design and test a modified Apparatus 2 that can overcome the major limitations of the standard system, and especially those related to the sensitivity of the current apparatus to tablet location.

Accordingly, the hydrodynamics in the standard USP Apparatus 2 vessel was experimentally quantified using Laser-Doppler Velocimetry (LDV) and Particle Image Velocimetry (PIV). Complete experimental mapping of the velocity distribution inside the standard Apparatus 2 was obtained at three agitation intensities, i.e., 50 rpm (NRe=4939), 75 rpm (NRe= 7409) and 100 rpm (NRe= 9878). The velocity distributions from both LDV and PIV were typically found to be very similar. It was found that the overall flow pattern throughout the whole vessel was dominated by the tangential component of the velocity at all agitation speeds, whereas the magnitudes of the axial and radial velocity components were typically much smaller. In the bottom zone of the vessel, two regions were observed, i.e., a central, low-velocity inner core region, and an outer recirculation loop below the impeller, rotating around the central inner core region. This core region typically persisted, irrespective of the impeller agitation speed. Computation Fluid Dynamics (CFD) was additionally used to predict velocity profiles. Typically, the CFD predictions matched well the experimental results.

The power dissipated by the impeller in Apparatus 2 was experimentally measured using a frictionless system coupled with torque measurement. CFD was additionally used to predict the power consumption, using two different approaches, one based on the integration of the local value of the energy dissipation rate, and the other based on the prediction of the pressure distribution on the impeller blade, from which the torque and the power required to rotate the impeller were predicted. The agreement between the experimental data and both types of numerical predictions was found to be quite satisfactory in most cases. The results were expressed in terms of the non- dimensional Power number, Po, which was typically found to be on the order of ~0.3. The power number was observed to decrease very gradually with increasing agitation speeds.

The results of this work and of previous work with the standard USP Apparatus 2 confirm that this apparatus is very sensitive to the location of the tablet, which is typically not controlled in a typical test since the tablet is dropped into the vessel at the beginning of the test and it may rest at random locations on the vessel bottom. Therefore, in this work a modified USP Dissolution Testing Apparatus 2, in which the impeller was placed 8-mm off-center in the vessel, was designed and tested. This design eliminates the poorly mixed inner core region below the impeller observed in the standard Apparatus 2 vessel. Dissolution tests were conducted with the Modified Apparatus for different tablet locations using both disintegrating calibrator tablets (Prednisone) and non-disintegrating calibrator tablets (Salicylic Acid). The experimental data clearly showed that all dissolution profiles in the Modified Apparatus were not affected by the tablet location at the bottom of the vessel. This design can effectively eliminate artifacts generated by having the tablet settle randomly at different locations on the vessel bottom after dropping it at the beginning of a dissolution testing experiment.

The hydrodynamic and mixing characteristics of the modified Apparatus 2 were studied in some detail by experimentally measuring and computationally predicting the velocity distribution, power dissipation, and mixing time in the modified system. The velocity profiles near the bottom of the vessel were found to be significantly more uniform than in the standard Apparatus 2, because of the elimination of the poorly mixed zone below the impeller. The power dissipation in the modified Apparatus 2 was typically higher than in the standard system, as expected for an non-symmetrical system, and the corresponding Power number, Po, was less dependent on Reynolds number than Po in the standard system. Finally, the mixing time in the modified system, as experimentally measured by using a decolorization method and computationally predicted through CFD simulation, was found to be shorter in the modified Apparatus 2 by 7.7 %-12.9 % as compared to Apparatus 2.

It can be concluded that the modified Apparatus 2 is a more robust testing apparatus, which is capable of producing dissolution profiles that are less sensitive to small geometric factors that play a major role in the standard USP Apparatus 2.

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