(308b) Use of Bead Mixtures As an Enabling Approach for Optimal Production of Drug Nanosuspensions

Preparation of drug nanoparticles is one of the most popular approaches in dissolution enhancement of poorly water-soluble drugs [1,2]. Due to their higher surface area and mass transfer coefficient, drug nanoparticles dissolve faster than their micron-sized counterparts [3]. In addition, sub-100 nm particles have higher saturation solubility owing to their high curvature [3]. Wet stirred media milling (WSMM) has been the most preferred method for the manufacture and preparation of marketed drug nanocrystal-based products and nanocrystal suspensions in scientific studies according to a recent literature review [2]. The reason for this high demand in WSMM is that it has the potential of producing high drug-loaded, stable nanosuspensions while being a reproducible, scalable, solvent-free, and environmentally benign process [4–6]. Most of the WSMM studies in the literature focuses on the formulation aspects such as stabilization of the milled suspensions against aggregation. In contrast, there have been fewer studies focusing on the processing–operational challenges such as cost due to high energy consumption, long operating hours, high cooling demand due to heat dissipation, and contamination of drug particles by the beads [2,4,7,8]. In order to address the operational challenges, a mechanistic understanding of the impact of process parameters such as bead concentration, bead material, and stirrer speed should be developed.

Unlike any study in the WSMM literature including non-pharmaceutical fields, as a major novelty, this study aims to explore the feasibility of cross-linked polystyrene (CPS)–yttrium-stabilized zirconia (YSZ) bead mixtures as a novel optimization approach for fast, efficient production of drug nanosuspensions via WSMM. While both CPS and YSZ beads were utilized in prior WSMM studies [9,10], they have not been used in a bead mixture before. We hypothesize that bead mixtures allow for optimal milling of drug suspensions from a combined energy–cycle time–heat dissipation perspective. In this study, fenofibrate (FNB) was selected as a poorly water-soluble model drug. A total of 20 experiments were conducted at two stirrer speeds (ω = 3000 and ω = 4000 rpm) and two volumetric fractional bead loadings (c = 0.35 and c= 0.50) with five CPS–YSZ bead mixtures including CPS alone and YSZ alone (CPS:YSZ 0:1‒1:0 v/v). About 235 g pre-suspensions that have 10% FNB, 7.5% HPC-L (L grade of hydroxypropylcellulose), and 0.05% SDS (sodium dodecyl sulfate) with respect to 200 g deionized (DI) water were prepared, wherein HPC-L and SDS served as the stabilizers based on our prior work [11,12]. XRPD was used to assess the crystallinity of the drug, while viscometry was used to determine the dynamic viscosity and examine the shear-thinning behavior of the milled suspensions. The timewise evolution of the FNB particle size was investigated via laser diffraction by taking suspension samples at various milling times. To characterize the breakage kinetics, three different kinetic measures were defined and analyzed including the apparent breakage rate constant of an n^th-order kinetic model. A microhydrodynamic model was used to elucidate the different microhydrodynamic behavior of the CPS vs. YSZ beads and their pros/cons [13,14]. Various optimization criteria based on industrial considerations were adopted and relevant merit scores were calculated. Kinetic parameters and specific power–energy consumption were used together to assess the impact of bead mixtures.

Fig. 1 (left panel) presents the average power per unit volume P_w and time required for the median particle size to reach 0.25 µm t_d50 as a function of the YSZ bead concentration in the mixture c_YSZ for four different operating conditions. As a general trend, higher c_YSZ led to higher lower t_d50 at higher P_w. In other words, CPS beads were found to be efficient in terms of power consumption but YSZ beads provide faster breakage, which results in shorter cycle time to achieve the desired particle size. The microhydrodynamic model attributed the faster breakage with the YSZ beads compared to the CPS beads to their more frequent, energetic/forceful collisions than those of CPS beads owing to the higher density–elastic modulus of the YSZ beads.

An ideal WSMM process should produce a targeted drug particle size at the shortest cycle time with the lowest energy expenditure without serious heat dissipation (temperature control) issues. Hence, we defined a merit score, as shown at the top right panel of Fig.1, to guide our optimal process selection. We considered three major factors: energy expenditure (cost), cycle time, and heat dissipation related issues, and created four different scenarios with different values of the weighting coefficients w_i in the merit score definition. A higher merit score indicates that the operating parameters and bead mixtures selected are more desirable within the context of specific process optimization criteria considered. There are four scenarios: one wherein all three factors contribute to the merit score equally (w₁ = w₂ = w₃ = 1), a scenario wherein energy expenditure is considered less significant compared to cycle time and temperature related process shutdowns (most likely scenario in pharmaceutical industry as compared with other industries, reduced w₂: w₂ = 0.1), a scenario wherein heat dissipation related process shutdowns as related to P_w are partly mitigated by a high-capacity chiller (reduced w₁, w₁ = 0.1), and a scenario wherein milling cycle time is considered less important than other two factors (reduced w₃, w₃ = 0.1). In all scenarios (not shown here for brevity), 3000 rpm and 50% loading were optimal (highest merit scores). Moreover, in 9 out of 16 total cases examined (4 different processes with various ω–c in 4 different scenarios), a bead mixture had the highest merit score as opposed to CPS or YSZ beads alone. Fig. 1 illustrates that in the most likely scenario relevant to the pharmaceutical industry (w₁ = w₃ = 1, w₂ = 0.1), the highest merit score corresponded to the following milling conditions: 3000 rpm and 50% loading of 0.5:0.5 v/v CPS:YSZ.

Overall, this study has demonstrated that mixtures of two different bead types, YSZ and CPS, have achieved optimal wet stirred media milling (WSMM) when specific energy consumption (cost), milling cycle time (breakage kinetics), and heat dissipation related process shutdowns are simultaneously considered. This comprehensive, combined experimental–modeling study has revealed various insights as to why bead mixtures vs. YSZ or CPS beads alone offer much needed flexibility for WSMM optimization. Future work will focus on heat transfer analysis of the milling process, examination of the impact of bead mixtures on media wear and contamination and development of a new microhydrodynamic theory for bead mixtures.

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