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Trinity College Dublin

Dissolution Solution

Using Computational Fluid Dynamics (CFD) to investigate variable dissolution of tablets

Deirdre D'Arcy, School of Pharmacy, Trinity College Dublin

In order for a drug to be absorbed from the gastrointestinal tract it must be in solution. As a result, knowledge of the rate at which a drug dissolves and is released from a dosage form is crucial for purposes of dosage form development and subsequent quality control. The paddle dissolution apparatus is widely used in the pharmaceutical industry to determine dissolution rates of tablets and other dosage forms. It consists of a stirrer rotating on a central vertical shaft, within a glass vessel with a cylindrical upper portion and a hemispherical base. The dosage form is dropped into the vessel, which contains the dissolution medium. The paddle is rotated at a specified speed, and the medium is regularly sampled and assayed to determine the rate of drug release. Despite its widespread use and strict manufacturing and operating specifications, it is recognised that reproducibility in dissolution studies can be a problem1. This variability has been partly attributed to variations in fluid flow patterns, or hydrodynamics, within the vessel. A location-dependent variation in dissolution rate has previously been demonstrated2,3,4. In order to further elucidate the effect of hydrodynamic variability on dissolution rate, CFD was used to simulate fluid flow around tablets in three different positions in the vessel. Dissolution rates from these three positions within the vessel were determined, and variability in dissolution from these positions was compared in terms of Relative Standard Deviation (RSD) %. The RSD is the standard deviation as % of the mean. The positions investigated are detailed in a schematic diagram of the paddle apparatus in Figure 1. The dissolution rates and associated variability are presented in Table 1. The “control” tablets referred to in Table 1 are those not affixed to a position, as standard dissolution testing procedure would not involve affixing the dosage form to a particular position.

Figure 1. Schematic diagram depicting the locations of dissolution of the tablets in the paddle dissolution apparatus.

 

Compact Position Average Dissolution Rate (mg/hour) Standard Deviation (mg/hour) RSD%
Centre81.33.64.5
Position 1104.25.04.8
Position 2100.62.82.8
Control91.17.07.7

Table 1: Dissolution rates from tablets of benzoic acid in 0.1M HCl in the paddle dissolution apparatus affixed to the central position, position 1 and position 2, and not affixed to a position – “control” tablets {5}.

 

The increased variability from the “control” tablets and the lower dissolution from the tablet in the central position compared to positions 1 and 2 are typical of the variability of dissolution results from the apparatus. The CFD package ‘Fluent’® was used to simulate the hydrodynamics around the dosage forms in these positions at 50 rpm. A vertical plane through the solution flow field within the vessel is presented in Figure 2. The lower velocity region surrounding the tablet in the central position is evident, which would support the lower dissolution rate from the central position. The fact that the control tablets would be exposed to a range of velocities, evident at the base of the vessel in Figure 2, helps to explain the variability found with the control tablets.

Figure 2. Contours of velocity magnitude on the y=0 vertical plane through the solution of the apparatus at 50 rpm, with a tablet located in the central position.

 

In addition to the off-centre tablets showing a higher dissolution rate, a slope was shown to have formed on the curved side surface after undergoing one hour of dissolution. This side was facing into the direction of fluid flow. This slope can be seen on the right hand side of the photograph in Figure 3. The solution of the hydrodynamics around the tablet in position 2 reveals an area of lower velocity at the base of this part of the tablet, corresponding to a lower dissolution rate from this region and hence the development of the sloped edge. This is illustrated in Figure 4 by CFD-generated vectors of velocity magnitude around the tablet in position 2.

Figure 3. Photograph of a compact after 1 hour of dissolution in Position 2. The front of the compact was facing the centre of the vessel base {5}.

Figure 4. Velocity vectors surrounding the compact in Position 2. The front of the compact was facing the centre of the vessel base.

The knowledge gained from CFD on hydrodynamic variability around tablets in different locations, and around different regions of the same tablet, has potential benefit therefore in interpreting dissolution rate data from pharmaceutical dosage forms.

 

References:

  1. Siewert, M., Weinandy, I., Whiteman, D., judkins, C. (2002) Eur. J. Pharm. Biopharm. 53: 9-14.
  2. Qureshi, S. A., McGilveray, I. J. (1999) Eur. J. Pharm. Sci. 7: 249-258.
  3. Healy, A. M., McCarthy, L.G., Gallagher, K. M., Corrigan, O. I. (2002) J. Pharm. Pharmacol. 54: 441-444.
  4. Kamba, M., Seta, Y., Takeda, N., Hamaura, T., Kusai, A., Nakane, H., Nishimura, K. (2003) Int. J. Pharm. 250: 99-109.
  5. D’Arcy, D. M., Corrigan, O. I., Healy, A. M. (2005) J. Pharm. Pharmacol. 57: 1243-1250.

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