(421z) Experimental & Numerical Optimization of Mixing Conditions Towards Formation of Adhesive Mixtures for DPI Formulations

Authors: 
Sarkar, S., University of Connecticut
Thalberg, K., Astra Zeneca
Chaudhuri, B., University of Connecticut
Mukherjee, R., UConn

Adhesive mixtures, in which fine powders (API) are attached to a coarse carrier are commonly used for DPI formulations. The formation and segregation of these adhesive mixtures depends on the balance of strength of cohesive and adhesive forces between the particles. The purpose of the current study is to improve the understanding of mixing and handling  operations for formulating  robust  and  high performing  adhesive  mixtures. Systematic investigation of mixing patterns of a binary system (model API and carrier lactose) in low shear (double cone) and high shear (KG5, Key Intl) mixers is performed using experiments and Discrete Element Method (DEM) based numerical modeling. Micronized lactose (d50 = 3µm) and LactoHale100 (d50 = 125µm) from DFE Pharma are used as a model API and coarse carrier respectively. After loading the blenders in a given configuration and operating at specified speed, 6 samples are taken from different spatial locations at specified time points within the blenders .These were analysed to monitor the fines fraction (<=10µm) through laser diffraction based dry particle sizing in Malvern Mastersizer 2000 E unit fitted with a dry Scirocco dispersion unit operated at an air pressure of 4 bars. Progress of mixing within the blenders is done by plotting the Residual Standard Deviation (RSD) as a function of time. The estimated cohesive and adhesive forces between particles from Inverse Gas Chromatography measurements are used in the numerical model to simulate powder flow. The cohesive and adhesive forces are included through dimensionless Bond numbers, which represent the ratio of cohesive force to particle weight. Variables of study include material properties (cohesion, size), process and design parameters (rotational speed(s), fill levels and initial loading configurations).The parametric studies are used to identify optimal mixing conditions for a given set of powders.

Inefficient mixing, towards forming the desired adhesive mixtures, was observed within the low shear double cone blender. The DEM based numerical studies revealed insufficient shear is imparted in the double cone blender to break the cohesive API aggregates. On the contrary, high shear mixing was successful in generating desired adhesive mixtures. This was confirmed through SEM images. Impeller speed was found to be the most significant factor affecting the blending performance. Increasing the impeller speed from 100 to 500 rpm decreased the mixing time, but also resulted in greater impaction of fines to the vessel walls.