(220a) Are Crosslinked Polystyrene Beads As Effective As Zirconia Beads to Produce Drug Nanoparticles Via Wet Stirred Media Milling?

Nearly 40% of approved drugs and 90% in the discovery phase show poor water solubility and as a result low bioavailability [1]. A promising way of overcoming these challenges is by reducing the particle size to nanoscale, which results in an increase in drug surface area and dissolution rate. Wet stirred media milling (WSMM) has proven itself to be a robust top-down method for producing nanoparticles. However, the WSMM process is energy intensive, costly, time-consuming, and can potentially cause product contamination from bead wear. Developing a fundamental understanding of the impact of milling process parameters on particle size, breakage kinetics, and cycle time is critical to resolving some of the aforementioned issues as well as developing a robust milling process. To this end, Afolabi et al. [2] elucidated the impact of stirrer speed, concentration of zirconia beads, and drug loading; Li et al. [3] studied the impact of zirconia bead size. Both studies used a microhydrodynamic model to interpret the impact using microscale parameters such as zirconia beads oscillation velocity and frequency. Crosslinked polystyrene (CPS) beads are also widely used in pharmaceutical WSMM; but, the WSMM process with such beads has not been subjected to the same rigorous and systematic analysis as for that with the zirconia beads. Moreover, the question as to whether CPS beads are as effective as zirconia beads has not been answered in a controlled, systematic study.

We aim to gain a fundamental understanding of the impact of stirrer speed and volumetric loading of CPS beads on breakage kinetics during WSMM and compare the performance of these beads to zirconia beads. Griseofulvin (GF), a Biopharmaceutical Classification System class II drug, was chosen as the model drug for this study. Suspensions of GF were prepared using two stabilizers, hydroxypropyl cellulose (HPC) SL grade and an anionic surfactant, sodium dodecyl sulfate (SDS). Previous studies [2-4] have shown that the combination of HPC and SDS creates a synergistic effect that ensures stability of the GF suspensions. This excellent stability of the GF nanosuspensions allowed us to solely isolate the impact of process parameters on the breakage kinetics, without much confounding from particle aggregation. CPS beads with a nominal size of 400 µm was used as the milling media and compared with Zirmil Y grade yttrium-stabilized zirconia (YSZ) beads with identical nominal size. Four different bead volume fractions/loadings (c), i.e., 0.198, 0.298, 0.397, and 0.594, with respect to the total volume (80 mL) of the mill chamber were used. About 230 g pre-suspensions were prepared by dispersing 10% GF particles in an aqueous solution of 5% HPC and 0.2% SDS, where all the percentages were w/w with respect to de-ionized water (200 g). The pre-suspensions were milled for 256 min in a Netzsch Microcer recirculation mill at the stirrer speeds of 2000, 3000, and 4000 rpm with the aforementioned bead loadings. Samples were taken during milling at fixed times, particles size measurement of the samples were then determined using laser diffraction (Coulter Beckman LS 13 320). Viscometry (Brookfield R/S plus cylinder-in-cylinder rheometer) was used to characterize the apparent shear viscosity.

To quantify the breakage kinetics, time for the 50 vol.% passing size (median, d₅₀) to reach 0.5 µm (t_d50) and time for 90 vol.% passing size (d₉₀) to reach 1 µm (t_d90) were calculated via the Hermite interpolation. Moreover, an exponential decay model was fitted to the time-wise evolution of the median size and a characteristic process time constant Ï„_p was determined. Average power consumption, apparent shear viscosity, and density were measured for each milled suspension. Using a microhydrodynamic model developed by Eskin et al. [5], various microhydrodynamic parameters were determined such as granular temperature, average bead oscillation velocity, frequency of single bead oscillation, maximum contact pressure, and average frequency of drug particle compression. The breakage data and kinetics were then further analyzed with the insight of these parameters.

GF nanosuspensions with d₅₀ < 200 nm were produced within 256 min using CPS beads for all stirrer speed–bead loadings (c) except for 2000 rpm and c < 0.4. Their sizes did not change after 7-day storage. This suggests that (i) aggregation was effectively suppressed by the stabilizers and (ii) CPS beads can be used to prepare GF nanosuspensions successfully. All three characteristic milling times t_d50, t_d90, and Ï„_p decreased with an increase in stirred speed and beads loading monotonically, indicating faster breakage. YSZ beads exhibited similar trends [2]; however, they appear to have caused faster breakage than CPS beads of “similar sizes” (results will not be shown for brevity). The major findings from the microhydrodynamic analysis can be summarized as follows: it was observed that as stirrer speed increased, all microhydrodynamic parameters increased monotonically. An increase in stirrer speed led to an increase in the mechanical energy that contributed to the bead–bead collisions. This resulted in more forceful bead–bead collision during drug compression and more frequent bead–bead collisions, which explains the observed faster breakage. When bead loading was varied, counteracting effects were observed. As volumetric bead loading increased, bead-bead oscillation and frequency of drug particle compressions increased, which favors faster breakage. However, less energetic/forceful collisions and compressions occurred. Apparently, the former effect was dominant, and the higher beads loading led to faster breakage overall. A systematic comparison of the performance of CPS beads and YSZ beads of the same nominal size was also performed. In this comparison, volumetric bead loading was kept constant and stirrer speed was varied. YSZ beads led to faster breakage and higher microhydrodynamic parameters than those of CPS beads under identical conditions. However, as stirrer speed increased, the process time constants associated with CPS beads and YSZ beads began to converge, and their impact on the breakage kinetics becomes similar. Overall, we conclude that while YSZ beads are more effective for breakage than CPS beads for most experimental conditions studied, at the highest stirrer speed (4000 rpm) and highly energetic conditions, both types of beads appear to perform well and similarly. From a process engineering perspective, both types of beads can be used effectively to produce drug nanoparticles; however, they may have different extent/types of product contamination, which could be a determining factor in the selection of bead type. This aspect has not been investigated in this study and warrants future investigation.

References:

1. Kalepu; V. Nekkanti, Insoluble drug delivery strategies: review of recent advances and business prospects, Acta Pharm. Sinica B, 5 (2015) 442–453.
2. 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.
3. 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.
4. 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.
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.