(431b) Micro-Mixing Characterization of Continuous Mixing Processes Using Near Infrared Chemical Imaging

Continuous powder mixing has been a subject of much interest in the past few years. The mixing efficiency of these processes is commonly characterized by estimating the blend homogeneity from relevant samples. The concentration of the critical component (i.e. active pharmaceutical ingredient, API) is measured from these samples and the blend homogeneity is quantified by estimating the relative standard deviation (RSD). This bulk homogeneity (macro-mixing) does not yield much information on the dispersion or degree of agglomeration (micro-mixing) of the API in the blend.  In this study, powder blends obtained from a continuous mixing process are characterized using near infrared chemical imaging (NIR-CI). This allows the micro-mixing quantification of the critical ingredient in the final blends. An experimental design was used to vary the concentration of API in the blend, the total flow rate through the system, and the impeller rotation rate of a continuous mixer (GCM 250, Gericke). These led to changes in cohesion of the blend, mean residence time and hold-up [1]. The blend used was composed of semi-fine acetaminophen (APAP, ~45 μm) and Avicel PH 200 (~220 μm). Samples were taken at the outlet of the mixer for analysis and a Spectral Dimension SyNIRgy chemical imaging spectrometer (Malvern) was used to analyze the powder blend samples.

The chemical images showed the areas in which APAP could be in aggregates. The chemical images were treated and converted to binary images by choosing a specific threshold using the distribution of pixels of each image. Binary images were used to quantify aggregate size statistics. The statistical analysis from the binary images yielded several qualitative and quantitative results. For example, the aggregate equivalent area measured was correlated to the rotation rate for several APAP concentrations. These correlations were comparable to the previous results obtained in the bulk characterization of this continuous mixer [1]. Previous results showed a maximum number of blade passes and minimum RSDs at intermediate rotation rates in which the powder experiences the most shear and total strain. Both of these results are in accordance with blends having a minimum aggregate equivalent area at intermediate impeller rotation rates. More correlations between the micro-mixing state of the final blends as a function of the mixing parameters and concentration of the API will be presented. The use of this technique can help in the development of pharmaceutical blend formulations and the optimization of continuous powder mixing processes.   

[1] A.U. Vanarase, F.J. Muzzio, Effect of operating conditions and design parameters in a continuous powder mixer, Powder Technol 208 (2011) 26-36.