Effects of Scale-Up and Impeller Types on Spherical Agglomeration of Dimethyl Fumarate

Abstract

Spherical agglomeration (SA) allows for intensifying a crystallization process through simultaneous particle size enlargement and process efficiency enhancement, without a compromise between bioavailability and processability of active pharmaceutical ingredients (APIs). Inefficient collision intensity may encounter during scale-up of an SA process, while mixing intensity and flow patterns do play critical roles especially in a batchwise stirred tank. In the present study, the scalability of an SA process by operating at all the same configurations of different scales, 0.5, 2, and 10 L, using a common one-layered impeller with four pitched blades was examined through the use of dimethyl fumarate as a model API. Insights into the guidelines for scaling up of the SA process are also given. Furthermore, the effects of impeller types, including the one-layered impeller, the two-layered impeller with four pitched blades, and the maxblend impeller, on the size, size distribution, and roundness of dimethyl fumarate agglomerates were investigated carefully.

Particle Design of Drugs via Spherical Crystallization: A Review from Fundamental Aspects to Technology Development

“…26 Therefore, in the industrialization of SA, mixing intensity and flow patterns do play critical roles. 142 The core principle for the scale-up of SA is to design the appropriate impeller type, location of the impeller in the crystallizer, and stirring speed, to ensure efficient collision, i.e., momentum transfer. QESD is performed by the rapid diffusion between the good solvent and poor solvent, 6 which means efficient mass transfer is prerequisite.…”

“…SA is carried out based on the collisions among wetted particles which leads to coalescence of the wetted particles, squeezing of the bridging liquid, and the formation of spherical agglomerates . Therefore, in the industrialization of SA, mixing intensity and flow patterns do play critical roles . The core principle for the scale-up of SA is to design the appropriate impeller type, location of the impeller in the crystallizer, and stirring speed, to ensure efficient collision, i.e., momentum transfer.…”

Large blade impeller application for turbulent liquid–liquid and solid–liquid mixing

“…Moving beyond impeller classifications, different impeller types, including both conventional turbines, whose total diameter typically does not exceed half of the tank diameter and the blade axial extension is limited, and large blade impellers, which are characterized by much higher height and diameter, have been recently compared for evaluating the performances in important applications, such as spherical agglomeration of active pharmaceutical ingredients (APIs), recovery of rare earth minerals by emulsification, and CO 2 hydrate formation for carbon capture. In particular, interesting results were obtained from Chen et al [2] in the case of APIs production using a Maxblend (MB) impeller, which gave the least requirement of agitation speed with respect to single and double pitched blade turbines (PBT), both for the solid-liquid and the liquid-liquid operations taking place for accomplishing the agglomeration. Also, higher selectivity in the recovery of minerals by emulsification, most likely associated with higher shear rate uniformity that gives rise to more uniform droplets in the vessel volume, was obtained with an MB impeller with respect to a PBT by Avazpour et al [3] Extremely efficient formation of CO 2 hydrates in a tank stirred with an MB impeller with the best energy performance compared with other impeller types, probably due to the combination of high pumping capacity, uniform shear field, and good gas-liquid contact, was found by Douïeb et al [4] Besides the above-mentioned examples showing that, depending on the specific design, large blade impellers can provide appropriate flow circulation and good performances in two-phase operations, the hydrodynamics characteristics of these impellers have been investigated in a significantly lower number of cases with respect to traditional fast impellers.…”