Hydrodynamic Complexity Induced by the Pulsing Flow Field in USP Dissolution Apparatus 4

USP dissolution Apparatus 4 can have a pulsing or non-pulsing flow, with most commercial apparatus employing a pulsing flow. Overall, a low velocity flow field is present, particularly in the larger 22.6-mm diameter cell. Dissolution data, computational fluid dynamics (CFD), and imaging methods are used and discussed to investigate the effects of low velocity pulsing flow on dissolution. Local velocity patterns, density gradients, and the effect of flow rate on particulate dispersion can all contribute to the observed dissolution rate. In silico simulation tools and imaging techniques have proved useful in determining local hydrodynamics and, in some cases, their effect on observed dissolution rates. Methods to investigate concentration gradients at the dissolving surface are required to investigate further the effect of hydrodynamics on the dissolution process. In conclusion, it is necessary to take local flow patterns and velocities into account, rather than overall flow rate alone, when interpreting dissolution rate data in the flow-through apparatus. INTRODUCTION Hydrodynamics in USP dissolution Apparatus 4 have been analyzed theoretically using computational fluid dynamics (CFD) and imaging techniques such as magnetic resonance imaging (MRI) (1–4). An important point to recognize when considering hydrodynamics in the flow-through apparatus is the low-velocity operating conditions. Although low-velocity regions are present at the center of the vessel base in both paddle and basket apparatus, in general, fluid velocities in the flow-through cell are lower than those present in the paddle and basket apparatus at typical operating conditions. For example, previous CFD simulations have predicted that the maximum velocity at 1 mm from a compact positioned at the center of the base of the paddle apparatus at 50 rpm ranged from almost zero to maximum values of 4.9 × 10 to 6.7 × 10 ms, with the velocity increasing radially from this location. Maximum simulated velocities relative to the location of a rotating compact in the basket of the basket apparatus at 50 rpm were approximately 2.6 × 10 ms (5). On the other hand, in the smaller 12-mm cell of USP 4 flow-through apparatus at 17 mL/min, the predicted maximum velocity was approximately 1.4 × 10 ms in a simulation of a cell containing a vertical compact (3). In contrast to simulated velocity data from the paddle and basket apparatus, this maximum value only occurs during the peak flow velocity generated by the pulsing flow field. As pharmacopeial recommended flow rates range from 4 to 16 mL/min (6, 7) and velocities are faster in the 12-mm cell than in the 22.6-mm cell due to the reduced cross-sectional area, this value of 1.4 × 10 ms can be considered a representative maximum velocity present in the flow-through apparatus at typical operating conditions. The size, shape, and orientation of a dosage form in the cell will naturally also affect the cross-sectional area available for fluid to traverse the cell, with a horizontally orientated compact likely to generate a slightly higher velocity than the model with a vertically orientated compact. In the 22.6-mm diameter cell operated at 8 mL/min, the average fluid velocity through the cell is 0.033 × 10 ms in a cell containing no dosage form. For a pulsing flow, in a cell containing a compact, the maximum simulated fluid velocity at 1 mm from the compact surface was 0.13 × 10 ms (3). In addition to the typical flow rates outlined in the pharmacopeias, it is also stated that flow may be constant or pulsing. A pulsing flow must consist of 120 (±10) pulses per minute and follow a sinusoidal flow profile (6, 7). The flow profile from a typical piston pump is detailed in Figure 1, with the outflow following a half-sine-wave profile during the pump discharge phase (0–0.25 s) and zero outflow during the pump suction phase (during suction from the reservoir into the pump). Figure 1 also depicts vectors of velocity magnitude from a simulation of flow around the curved side of a compact in the 12-mm diameter cell at 17 mL/min, illustrating the simulated velocities present near the maximum inflow velocity in a pulsing flow and during the zero inflow velocity period. The situation of flow past the planar surface of the compact simulated under the same flow conditions was previously presented (3). The variation in fluid velocity distribution in the cell of USP Apparatus 4 arise from both (1) variation of input flow rates and (2) variation of velocity in the cell over each pulse at a specific flow rate. The magnitude and nature of * Corresponding author. diss-18-04-12.indd 6 12/5/2011 7:14:49 AM dx.doi.org/10.14227/DT180411P6