(134g) Effects of Rotation Rate, Mixing Angle, and Cohesion In Two Continuous Powder Mixers – a Statistical Approach

Portillo, P. M., Rutgers University
Vanarase, A. U., Rutgers, The State University of New Jersey
Muzzio, F. J., Rutgers University

Among emerging technologies for improving the performance of blending operations, continuous mixing currently commands enormous interest for pharmaceutical companies. Continuous processing has numerous known advantages, including reduced cost, increased capacity, facilitated scale up, mitigated segregation, and easily applied controlled shear. However, development of a continuous powder blending process requires venturing into a process that has a large and unfamiliar parametric space.

The process is as follows: as material enters the mixer, the powder crosses the pathway of several impeller blades attached to a rotating shaft placed along the axial length of the horizontal cylinder. Convective flow is the primary source of cross-sectional mixing, driven by the impeller blades. The other function of the convective motion is to axially transport the powder along the vessel (from the entrance to the discharge). The effectiveness of the mixer is particularly affected by the design of the convective system (the impeller and blades). As shown in our previous work (Portillo et al. [1]), a design parameter that affects mixing performance is the blade angle relative to the shaft.

In terms of operating conditions, the effect of impeller rotation rate, mixing angle on the powder residence time and the content uniformity of the blend exiting from two continuous powder mixers is studied. The two mixing systems examined initially in this work are both continuous blenders manufactured by GEA Buck Systems. The blenders vary in diameter and length as well as the design of the blades within the vessel. The first blender has a diameter that is 3 fold that of the second blender. Moreover, the first blender has an axial vessel that is 2.4 times longer than the second blender. For both mixers, powder samples are retrieved from the mixers outflow and characterized using Near Infrared Spectroscopy (NIR) which is commonly used to assay the content of powder samples Sánchez et al. [2].

The model blends have been formulated using Milled Acetaminophen, Lactose 100M, and Lactose 125M. The supplier (DMV International) stated that Lactose 100 M has a Hausner 1.21 ratio and Lactose 125M reported to have a 1.28 ratio (De Melkindustrie Veghel product specifications Overview).

A detailed explanation of the results for the first mixer can be found in Portillo et al. [1]. In summary we found that although increasing shear rate increased the blade passes the powder experienced, interestingly in terms of content uniformity the homogeneity worsened. Vessel inclinations resulted in longer residence times, which have also been noticed in rotary calciners (Sudah et al. [3]). Mixing performance got worse at negatively sloped inclinations, which may be a result of shorter residence times. A broader set of conditions are considered for the second mixer, including 5 mixing angles and 9 rotation rates, which were up to 300 RPM. The effect of increasing the speed further for the second continuous mixer is in good agreement with the results obtained for the first mixer.

For both blenders, 2 different Lactose powders, Lactose 100M and Lactose 125 M, a slightly more cohesive powder, are examined. The results show that the effect of powder cohesion is scale-dependent, having a significant effect in the larger mixer. However no significant effects were observed which might be due to the fact that shear rates are typically higher in convective systems than in tumblers (in fact convective blenders are often used for cohesive materials because they impart more shear), and it is possible that for both materials considered here, cohesion is simply too small to affect the outcome of the convective mixing process to a large degree.

Analysis of variance (ANOVA) is used to determine significance of main effects and their interactions. We have applied this approach to the scale-up of batch mixing where the effects of tote-size, rotation rate, fill level, and cohesion were studied (Portillo et al [4]). In this work, a randomized experimental design was used to examine the four main variables (mixer type, mixing angle, rotation rate, and powder cohesion), as well as their interactions for continuous blending. For each mixer, we initially examine a three-way ANOVA considering mixing angle, speed, and type of powder. Initially, all factors and interactions are considered, followed by a reduction in factors to remove the non-significant effects.

For the first mixer, the levels examined for the factorial design include 3 mixing angles and 2 rotation rates (16 RPM and 76 RPM), reflecting the speed limitations of the device. The data was analyzed under the assumption of normality, which was validated using a qq-plot. In terms of mixing performance, the impeller rotation rate is found to be the most significant factor, followed by the powder cohesion. The least significant factor although still significant, was found to be the mixing angle. Residence time is significantly affected by both rotation rate and mixing angle.

Applying the same procedure to study the mixing performance, the 3-way analysis was also applied to the second continuous blender. The three-way ANOVA was performed for the fractional factorial design, consisting of 9 rotation rates, 5 mixing inclinations, and 2 levels of cohesiveness. Both process parameters (rotation rate and inclination) were shown to be significant, where rotation rate is more influential than mixing angle. Cohesion on the other hand resulted in a high p-value, suggesting the insignificance of this factor. In terms of particle mobility, as expected lower shear rates and vessel inclinations resulted in longer residence times. One remaining question is whether a difference between the mixers is significant.

A 4-way ANOVA considers the results from both mixers, and reassesses the significance of other parameters when considering both datasets. The sources for the four-way statistical model are the mixer, processing inclination, rotation rate, and cohesion on the mixing performance. The ANOVA showed that cohesion was not a significant factor. Mixing angle and mixer, followed by rotation rate, are the most significant parameters. Further examining the effects of the three most significant factors, we neglect the main effect of cohesion and all interactions, the ANOVA illustrates that mixer, processing angle, and rotation rate are significant. This leads to the hypothesis that convective continuous mixers may not be significantly affected by material properties, whereas the convective design and blender geometry may be the most important operating parameters. 4-way ANOVA results from the two continuous blenders show that the blender geometry is a very significant factor.

We are expanding on the design of experiments, by examining a third continuous blender, manufactured by Gericke which is integrated with loss-in-weight feeders. The blender has diameter of 0.091 meter and length of 0.3 meter. This mixer is fixed at horizontal processing angle. The impeller has equally spaced triangular shaped 12 blades which can be arranged to propel powder forward or backward aswell as different blade angles (angle relative to the shaft). This mixer is facilitated by a weir, the weir, a semicircular disc, is fixed at the exit of the mixer. Rotating the weir angle essentially changes the powder fill level in the mixer.

The processing conditions examined in this mixer are impeller rotation rate (0-290 RPM), weir position (horizontal/rotated), and blade pattern (blade angle, forward/backward direction). The material parameters examined with respect to the powder are feed rate and concentration of API (Active Pharmaceutical Ingredient). The experimental design used is a split-split plot design. The set proposes two replications and two levels of: feed rate, API concentration, weir position, and blade configuration in addition to examining three levels of impeller rotation rate. and blade configuration form the whole plots. Weir position is randomized within each blade configuration to form a split plot, at each blade-weir replication, the remaining parameters are randomized to form a split ?split plot design.

So far we have found that the residence time in the mixer and the fill level are affected by the rotation rate, weir position, and the blade angle. Homogeneity of the powder at the exit of the mixer is found to be a strong function of residence time. Interesting results so far suggest that the mean residence time does not seem to be impacted by variation of the flow rate (30 kg/hr, 55 kg/hr). A detailed experimental study to examine statistical significance of all the parameters is in progress.


[1] Portillo P.M., Ierapetritou M.G., Muzzio F.J., 2008, Characterization of continuous convective powder mixing processes, Powder Technology, 182, 368-379.

[2] Sánchez F.C., Toft J., van den Bogaert B., Massart D. L., Dive S.S., Hailey P., 1995, Monitoring powder blending by NIR spectroscopy, Fresenius' Journal of Analytical Chemistry, Volume 352, Numbers 7-8 / January, 1995.

[3] Sudah O.S., Chester A.W., Kowalski J.A., Beeckman J.W., Muzzio F.J., 2002b, Quantitative characterization of mixing processes in rotary calciners, Powder Technology, 126, 166-173.

[4] Portillo P.M., Ierapetritou M.G., Tomassone S., McDade C., Clancy D., Avontuur P.C., Muzzio F.J., Quality by Design Methodology for Development and Scale-Up of Batch Mixing Processes, Submitted to Journal of Pharmaceutical Innovation Feb. 2008.