Impact milling of pharmaceutical agglomerates in the wet and dry states.

This study focused on the milling of wet granulated agglomerates at points before and after drying in a typical high-shear pharmaceutical process train. These steps, referred to here as wet and dry milling, utilized a conical screen mill. Milling of granulation in the wet state eliminated 1-10mm size agglomerates without affecting granule porosity or inducing further agglomeration. These millimeter-size agglomerates broke down during wet milling into moderately sized fragments larger than 125microm. In contrast, when milled after drying, these same 1-10mm-size agglomerates broke down predominantly into fine particles less than 125microm. Data from screen-less milling trials suggest that the mill screen served only as a classifier and did not significantly contribute to the route of breakage for either wet or dry milling. However, in the case of dry milling, mill screens with grated surface textures did result in fewer fines than non-grated screens. This may be a result of reduced residence time in the mill. Experiments varying the size fraction of feed material and the rotational speed of the mill's impeller identified impact attrition as the primary mechanism governing dry granule breakage. The findings in this study shed light into the fundamental breakdown behavior of pharmaceutical agglomerates and demonstrate how breakdown of wet agglomerates via a de-lumping step prior to drying can lead to a reduced level of fine particle generation during dry milling.

Experimental and computational determination of blend time in USP Dissolution Testing Apparatus II.

Blend time, the time to achieve a predefined level of homogeneity of a tracer in a mixing vessel, is an important parameter to evaluate the mixing efficiency of mixing devices. In this work, the blend time required to homogenize the liquid content of a USP Dissolution Testing Apparatus II under a number of operating conditions was obtained using two different experimental methods (tracer detection via colorimetric and conductivity measurements), a computational approach (computational fluid dynamics (CFD)), and a semi-theoretical analysis of the phenomenon. Under the standard geometric and operating conditions in which the USP Apparatus II is typically used (N = 50 rpm) the experimental blend time to achieve a 92.74% uniformity level was found to be between 27.5 and 33.3 s, depending on the location of the injection point and monitoring point for the tracer. These values were in close agreement with those obtained from CFD simulations. Changing the impeller vertical position (+/-2 mm) had only a limited effect. The CFD predictions also indicated that blend time is inversely proportional to the agitation speed. This conclusion is in agreement with previous reports and equations for blend time in mixing vessels. The blend times obtained in this work appear to be some two orders of magnitude smaller than the time usually required for appreciable tablet dissolution during the typical dissolution test, implying that the liquid contents of the USP Apparatus II can be considered to be relatively well mixed during the typical dissolution test.

Hydrodynamic investigation of USP dissolution test apparatus II.

The USP Apparatus II is the device commonly used to conduct dissolution testing in the pharmaceutical industry. Despite its widespread use, dissolution testing remains susceptible to significant error and test failures, and limited information is available on the hydrodynamics of this apparatus. In this work, laser-Doppler velocimetry (LDV) and computational fluid dynamics (CFD) were used, respectively, to experimentally map and computationally predict the velocity distribution inside a standard USP Apparatus II under the typical operating conditions mandated by the dissolution test procedure. The flow in the apparatus is strongly dominated by the tangential component of the velocity. Secondary flows consist of an upper and lower recirculation loop in the vertical plane, above and below the impeller, respectively. A low recirculation zone was observed in the lower part of the hemispherical vessel bottom where the tablet dissolution process takes place. The radial and axial velocities in the region just below the impeller were found to be very small. This is the most critical region of the apparatus since the dissolving tablet will likely be at this location during the dissolution test. The velocities in this region change significantly over short distances along the vessel bottom. This implies that small variations in the location of the tablet on the vessel bottom caused by the randomness of the tablet descent through the liquid are likely to result in significantly different velocities and velocity gradients near the tablet. This is likely to introduce variability in the test.