Development of In Vitro Dissolution Tests which Correlate Quantitatively with Dissolution Rate-Limited Drug Absorption in Man

Levy, Gerhard; Leonards, Jack R.; Procknal, Josephine A.

doi:10.1002/jps.2600541204

Cited by 98 publications

(22 citation statements)

References 16 publications

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“…However, when the dissolution data were obtained at 50 rpm, a satisfactory correlation was obtained, encompassing all 3 products. 9 Luminal hydrodynamics were also recently shown to be an important factor in the absorption rate of felodipine from course suspensions in dogs. 10 Thus, in establishing IVIVCs, the hydrodynamic conditions are critical.…”

Section: Introductionmentioning

confidence: 98%

Simulating the hydrodynamic conditions in the united states pharmacopeia paddle dissolution apparatus

et al. 2003

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KEYWORDS: computational fluid dynamics (CFD), USP paddle apparatus, dissolution, hydrodynamics, modeling The objective of this work was to examine the feasibility of developing a high-performance computing software system to simulate the United States Pharmacopeia (USP) dissolution apparatus 2 (paddle apparatus) and thus aid in characterizing the fluid hydrodynamics in the method. The USP apparatus was modeled using the hydrodynamic package Fluent. The Gambit program was used to create a "wireframe" of the apparatus and generate the 3-dimensional grids for the computational fluid dynamics solver. The Fluent solver was run on an IBM RS/6000 SP distributed memory parallel processor system, using 8 processors.Configurations with and without a tablet present were developed and examined. Simulations for a liquidfilled vessel at a paddle speed of 50 rpm were generated. Large variations in fluid velocity magnitudes with position in the vessel were evident. Fluid velocity predictions were in good agreement with those previously published, using laser Doppler velocity measurements. A low-velocity domain was evident directly below the center of the rotating paddle. The model was extended to simulate the impact of the presence of a cylindrical tablet in the base of the dissolution vessel. The presence of the tablet complicated the local fluid flow, and large fluid shear rates were evident at the base of the compact. Fluid shear rates varied depending on the tablet surface and the location on the surface and were consistent with the reported asymmetrical dissolution of model tablets. The approach has the potential to explain the variable dissolution results reported and to aid in the design/prediction of optimal dissolution conditions for in vitro-in vivo correlations.

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Section: Introductionmentioning

confidence: 98%

Simulating the hydrodynamic conditions in the united states pharmacopeia paddle dissolution apparatus

et al. 2003

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“…In a study of the dissolution of acetylsalicylic acid tablets using a paddle-type apparatus, the "beaker method," Levy 18 showed that in vitro/in vivo correlations could be achieved only at an agitation rate of 50 rpm and not when the paddle was rotated at 60 rpm. It should be noted that the beaker method setup is quite different from the hemispheric paddle method.…”

Section: Introductionmentioning

confidence: 99%

Computational fluid dynamics modeling of the paddle dissolution apparatus: Agitation rate, mixing patterns, and fluid velocities

et al. 2004

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The purpose of this research was to further investigate the hydrodynamics of the United States Pharmacopeia (USP) paddle dissolution apparatus using a previously generated computational fluid dynamics (CFD) model. The influence of paddle rotational speed on the hydrodynamics in the dissolution vessel was simulated. The maximum velocity magnitude for axial and tangential velocities at different locations in the vessel was found to increase linearly with the paddle rotational speed. Path-lines of fluid mixing, which were examined from a central region at the base of the vessel, did not reveal a region of poor mixing between the upper cylindrical and lower hemispherical volumes, as previously speculated. Considerable differences in the resulting flow patterns were observed for paddle rotational speeds between 25 and 150 rpm. The approximate time required to achieve complete mixing varied between 2 to 5 seconds at 150 rpm and 40 to 60 seconds at 25 rpm, although complete mixing was achievable for each speed examined. An analysis of CFDgenerated velocities above the top surface of a cylindrical compact positioned at the base of the vessel, below the center of the rotating paddle, revealed that the fluid in this region was undergoing solid body rotation. An examination of the velocity boundary layers adjacent to the curved surface of the compact revealed large peaks in the shear rates for a region within ~3 mm from the base of the compact, consistent with a 'grooving' effect, which had been previously seen on the surface of compacts following dissolution, associated with a higher dissolution rate in this region.

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“…We later conceived of an indirect way to determine the stirring rate equivalent in our in vitro system to the typical in vivo conditions (2). The result turned out to be very close to the stirring rate that I had selected initially.…”

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confidence: 70%

“…This becomes important for tablets containing two or more interacting components. We showed that aspirin in tablets containing an antacid dissolved much more rapidly than aspirin in tablets without antacid upon mild stirring and that these differences disappeared totally when the dissolution medium is stirred more rapidly so that all the particles are completely dispersed and individually separated in the dissolution medium (2). The pH of the microenvironment of the aggregate of an aspirin-antacid mixture as determined with microelectrodes was several units higher than that in the bulk dissolution medium.…”

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confidence: 91%

“…The result turned out to be very close to the stirring rate that I had selected initially. Moreover, we could demonstrate that stirring rates too fast or too slow could produce very misleading results in comparative dissolution studies (1,2). Our beaker dissolution test eventually evolved into the widely used Dissolution Method 2 of the United States Pharmacopeia (USP).…”

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confidence: 99%

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Development of In Vitro Dissolution Tests which Correlate Quantitatively with Dissolution Rate-Limited Drug Absorption in Man

Cited by 98 publications

References 16 publications

Simulating the hydrodynamic conditions in the united states pharmacopeia paddle dissolution apparatus

Simulating the hydrodynamic conditions in the united states pharmacopeia paddle dissolution apparatus

Computational fluid dynamics modeling of the paddle dissolution apparatus: Agitation rate, mixing patterns, and fluid velocities

Levy G, Hayes B, “Physiochemical Basis of the Buffered Acetylsalicylic Acid Controversy New Engl. J. Med. 262:1053–1058 (1960)”—The Backstory

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