(170a) Insights from Microhydrodynamic Modeling of Nanomilling in a Wet Stirred Media Mill

Owing to their large surface area and unique physico-chemical and mechanical properties, materials with nanoscale features have found use in a multitude of products. Wet stirred media milling (WSMM) has been used for the production of nanoparticles of various active agents such as poorly water-soluble drugs, agrochemicals, nutraceuticals, etc. in suspension form as it is a scalable, solvent-free, environmentally benign process. However, the process is energy intensive, costly, time-consuming, and can cause contamination of the product due to bead wear if the process is not developed properly. The development of a cost-effective, robust wet media milling process that also avoids significant product contamination entails a good understanding of the underlying particle change mechanisms such as breakage and aggregation, and their relation to process and formulation parameters. Unfortunately, a great majority of the previous investigations especially in various high-value product industries, where WSMM has been used to manufacture active nanoparticles, the development approaches are usually very empirical, which is devoid of any fundamental understanding. In fact, majority of the effort has been directed toward formulation development to ensure that the nanosuspensions are physically stable over time. It is no surprise that in many product-value industries such as pharmaceuticals, WSMM has not become a platform technology due to the aforementioned engineering challenges.

In this presentation, insights from recent microhydrodynamic modeling studies [1–3] will be presented to explain the impact of various process parameters such as rotor speed, bead loading/size, and drug loading on the breakage kinetics in a unified framework. We used griseofulvin (GF), a poorly water-soluble hydrophobic drug, as a model active agent and prepared its aqueous nanosuspension with hydroxypropyl cellulose (HPC) and sodium dodecyl sulfate (SDS). The combined HPC–SDS provided excellent electrosteric stabilization and prevented particle aggregation [4], thus allowing us to solely discern the breakage kinetics and the impact of process parameters on the kinetics. Milling experiments were performed using a Netzsch Microcer wet stirred media mill. For various processing conditions, time-wise evolution of GF particle size was measured during milling using laser diffraction offline, and the process time constant for each set of processing conditions was calculated via an exponential decay model. Additionally, average power consumption as well as density–apparent shear viscosity of the milled suspensions were measured. Using a modified version of the microhydrodynamic model developed earlier by Eskin et al. [5], we calculated various microhydrodynamic parameters such as the granular temperature, the average bead oscillation velocity, the frequency of single-bead oscillations, the maximum contact pressure at the center of the contact circle of the colliding beads, the average frequency of drug particle compressions, and a milling intensity factor. The experimental data and calculated characteristic process time constants were analyzed in view of the calculated microhydrodynamic parameters. Most significant findings can be summarized as follows: upon an increase in rotor speed, more mechanical energy was imparted and all microhydrodynamic parameters increased monotonically. Higher rotor speed led to more frequent and energetic/forceful bead–bead collisions and more frequent drug particle compressions, which explains the experimentally observed faster breakage. An increase in volumetric bead concentration led to counteracting effects; higher bead loading led to more bead–bead collisions and drug particle compressions, but less energetic/forceful collisions/compressions. Overall, the experimentally observed positive impact of the bead loading, i.e., faster breakage of the drug particles, was explained by an increase in the milling intensity factor. An increase in drug loading led to a slight, almost linear decrease in all microhydrodynamic parameters, except the milling intensity factor, which exhibited a sharper decrease, thus explaining the reduced breakage rate at higher drug loading in the experiments. The process time constants from all different sets of processing conditions were uniquely predicted by a single exponential decay-type correlation of a single microhydrodynamic parameter, i.e., the milling intensity factor. Finally, in the experiments, there was an optimal bead size that achieved the fastest breakage at each rotor speed and that it shifted to a smaller size at higher speeds. Calculated microhydrodynamic parameters reveal two counteracting effects of bead size: more bead–bead collisions with less energy/force upon a decrease in bead size. The optimal bead size exhibited a negative power-law correlation with the specific energy consumption and each microhydrodynamic parameter. Hence, the microhydrodynamic model rationalizes the use of smaller beads for more energetic wet media milling. Overall, this presentation reveals significant insights from recent microhydrodynamic studies in a unified framework, which will guide streamlined development of more robust WSMM processes.

References:

1. Li, P. Alvarez, E. Bilgili, A microhydrodynamic rationale for selection of bead size in preparation of drug nanosuspensions via wet stirred media milling, International Journal of Pharmaceutics, 524 (2017) 178–192.
2. Li, N. Yaragudi, A. Afolabi, R. Dave, E. Bilgili, Sub-100 nm drug particle suspensions prepared via wet milling with low bead contamination through novel process intensification, Chemical Engineering Sciences, 130 (2015) 207–220.
3. Afolabi, O. Akinlabi, E. Bilgili, Impact of process parameters on the breakage kinetics of poorly water-soluble drugs during wet media milling: A microhydrodynamic view, European Journal of Pharmaceutical Sciences, 51 (2014) 75–86.
4. Bilgili, A. Afolabi, A combined microhydrodynamics–polymer adsorption analysis for elucidation of the roles of stabilizers in wet stirred media milling, International Journal of Pharmaceutics, 439 (2012) 193–206.
5. Eskin, O. Zhupanska, R. Hamey, B. Moudgil, B. Scarlett, 2005b. Microhydrodynamic analysis of nanogrinding in stirred media mills. AlChE Journal. 51 (2005) 1346–1358.