(444g) Effects of Material Properties in Continuous Mixing of Pharmaceutical Powders

Continuous manufacturing for solid dose pharmaceutical products has been an area of high interest in recent years. In converting the current batch based manufacturing into continuous, increased process understanding of continuous mixing is highly critical. Parametric space of continuous mixing includes a set of design parameters (mixer size, impeller design, and outlet design), process parameters (impeller rotation rate and flow rate) and material properties (particle size distribution, cohesion). It is often challenging to select an optimal set of operating parameters based on raw material properties of the ingredients in the mixture. In this work, effects of the material properties of pharmaceutical powder blends on the bulk flow behavior and mixing performance in a continuous mixer were investigated. Bulk flow behavior of the powder decides the sensitivity of the system with respect to input parameters. Microscopic blend homogeneity however is dependent on the total shear, segregation tendency and inter-particle cohesion.

In our previous work [1, 2], for a fixed formulation, residence time distributions (RTDs) were measured for a range of process and design parameters pertaining to the specific mixer. Also, a reduced ordered model was developed using Fokker Planck Equations [3] which related mixing performance with the input variables. In the present work, different pharmaceutical blends were selected based on their flow properties. Flow properties were measured by Gravitational Displacement Rheometer (GDR) [4] and FT4 powder rheometer [5]. A continuous powder mixer, Gericke GCM 250 was used to prepare these blends. Using an appropriate tracer, RTDs were measured at different impeller rotation rates and flow rates. RTDs were fitted using the Taylor dispersion model to find the optimal model parameters (axial velocity and axial dispersion coefficient).

Mixing performance of different types of APIs including semi-fine APAP, granulated Acetaminophen and Caffeine was also examined. API concentration in the powder samples was determined using UV spectroscopy as well as NIR spectroscopy. NIR spectroscopy is often used as an in-line blend uniformity monitoring technique. The error associated with NIR measurement in the determination of API concentration was quantified through such multiple measurement systems. In this work, predictive selection of process parameters based on the material properties of pharmaceutical mixtures was achieved. In addition to this, role of the measurement system in the blend uniformity measurement was studied systematically.

References:

[1] P.M. Portillo, M.G. Ierapetritou, F.J. Muzzio, Characterization of continuous convective powder mixing processes, Powder Technol 182 (2008) 368-378.

[2] A.U. Vanarase, F.J. Muzzio, Effect of operating conditions and design parameters in a continuous powder mixer, Submitted to Powder Technology

[3] Y. Gao, A.U. Vanarase, F.J. Muzzio, Marianthi Ierapetritou, Characterization of continuous mixing process using residence time distribution, Submitted to Chemical Engineering Science

[4] A.W. Alexander, B. Chaudhuri, A. Faqih, F.J. Muzzio, C. Davies, M.S. Tomassone, Avalanching flow of cohesive powders, Powder Technol 164 (2006) 13-21.

[5] R. Freeman, Measuring the flow properties of consolidated, conditioned and aerated powders ? A comparative study using a powder rheometer and a rotational shear cell, Powder Technol 174 (2007) 25-33.