Orientation of planes

As discussed in Chapter 1, there is sustained interest in sub-100 nm particles of poorly water-soluble drugs as such small particles offer improved permeation through various biological barriers and result in rapid onset of therapeutic action. Chapter 3 rationalized the selection of bead size at different stirrer speeds for the efficient production of drug nanosuspensions via the wet stirred media milling (WSMM) process. Not only the bead size, but also the other process parameters, such as stirrer speed, bead loading, and suspension flow rate, can affect the drug breakage. Chapter 4 aims to develop an intensified WSMM process to produce sub-100 nm BCS Class II drug particles. To this end, the impact of bead size on the drug particle size, breakage kinetics, energy consumption, and bead wear were investigated for griseofulvin, a poorly water-soluble drug, under highly energetic milling conditions in the turbulent flow regime. Laser diffraction, dynamic light scattering, scanning electron microscopy, and XRD were used to characterize the milled suspensions. Yttrium-stabilized zirconia beads with a nominal size ranging from 50 µm to 800 µm were used in the baseline process, which was subsequently intensified with the optimal bead size by increasing rotor tip speed, bead loading, and suspension flow rate stepwise, as guided by a microhydrodynamic model. After examining the breakage kinetics under the intensified conditions, shorter milling experiments, which targeted approximately 100 nm particle size, were performed to examine the energy consumption and bead wear along with the microhydrodynamics. The novel

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intensification method, i.e., the use of optimal (50 m) beads with the intensified process conditions as guided by the microhydrodynamic model, was also applied to wet-milling of indomethacin, another poorly water-soluble drug, confirming the generality of the novel model-guided process intensification method. In pursuit of the goal of preparing sub-100 nm drug particles fast, this study contributes to a fundamental understanding of the impact of bead size and process intensification while addressing all major issues associated with the WSMM process, i.e., excessively long processing time, high energy consumption, and potentially high media contamination in a holistic, model-guided approach.

4.1 Materials and Methods

4.1.1 Materials

EP/BP grade griseofulvin (GF) and USP grade indomethacin (IND) were purchased from Letco Medical (Decatur, AL, USA). GF and IND are two BCS Class II drugs with an aqueous solubility of 7.7 and 16 g/ml, respectively (Merisko-Liversidge and Liversidge, 2011). Methocel E3 grade hydroxypropyl methyl cellulose (HPMC), which is commonly used as a neutral polymeric stabilizer, was a donation from Dow Chemical (Midland, MI, USA). Sodium dodecyl sulfate (SDS), which is an anionic surfactant, was purchased from Sigma Aldrich (Bellefonte, PA, USA), and nitric acid (65 wt%) was purchased from Fisher Scientific Inc. (Pittsburgh, PA, USA). Zirmil Y grade yttrium-stabilized zirconia (YSZ) beads with nominal sizes of 800, 400, 200, 100, and 50 µm were purchased from Saint Gobain ZirPro (Mountainside, NJ, USA) and used as the milling media. Throughout the dissertation, the beads were labeled

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with their nominal sizes, while their actual median sizes, i.e., 802, 396, 214, 107, and 54 µm, respectively, measured in dry dispersion mode via a laser diffraction particle size analyzer (Helos/Rodos, Sympatec, NJ, USA) were used in the microhydrodynamic model. De-ionized water was used in all milling and particle sizing experiments. Fresh beads were rinsed with de-ionized water and sonicated for 40 min followed by a final rinse.

4.1.2 Preparation of Suspensions via Wet Media Milling

The stabilizer concentrations, milling procedure, and baseline process conditions were selected based on our recent investigations (Afolabi et al., 2014; Knieke et al., 2013). First, about 225 g pre-suspensions were prepared by dispersing 10% drug particles in an aqueous solution of 2.5% HPMC-E3 and 0.2% SDS under constant stirring at 300 rpm (Cat#. 14-503, Fisher Scientific, Pittsburgh, PA, USA) for a total of 90 min. Here, all percentages are w/w with respect to de-ionized water (200 g).

The pre-suspensions were then milled at the conditions presented in Table 4.1. The impact of bead size db was studied through Runs 1–5, followed by process intensification experiments (Runs 6–8) guided by the microhydrodynamic model.

Runs 9 and 10 were performed to establish the applicability of the intensification method to IND.

Wet milling was carried out in a Microcer stirred media mill (Netzsch Fine Particle Size Technology, LLC, Exton, PA, USA) with an 80 ml (Vm) milling chamber lined with zirconia and a zirconia shaft with a diameter D of 7 cm (Figure 2.1). The pre-suspension was added to the holding tank (500 ml) and recirculated

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between the holding tank and the milling chamber at a controlled flow rate Q by a peristaltic pump (Cole-Parmer, Master Flex^®, USA). Stainless steel screens with different opening sizes, which are approximately half of the nominal size of the beads, were used to keep the beads inside the milling chamber. The Netzsch Microcer mill is limited to ~50 µm beads in the recirculation mode by its design, which requires the use of a screen with an opening size of 25 µm. When 50 µm beads were used as the smallest beads, the presence of large GF particles and IND particles initially resulted in clogging of the screen and the pressure rose. This practical issue was resolved by using a higher rotor tip speed (14.7 m/s) and lower suspension flow rate (80 ml/min) shortly in Run 5, which were then restored back to the set values in Table 4.1. Similarly, in Runs 6–8 and 10, the milling with a lower flow rate (80 ml/min) was carried out; then the flow rate was restored back to the target value and milling continued up to the long duration presented in Table 4.1. A chiller (Model M1-.25A-11HFX, Advantage Engineering, Greenwood, IN, USA) provided cooling for both the milling chamber and the holding tank, which allowed for keeping the suspension temperature in the holding tank below 34 ^oC, as a maximum. Due to the low cooling capacity of this specific chiller, a cooling strategy similar to that in Afolabi et al. (2014) was adopted here: the mill was stopped for few minutes of additional, intermittent cooling after 3 h during Runs 1–5 and Run 9 and about every 8 min during Runs 6–8 and Run 10. The suspensions at several milling time points were collected from the outlet of milling chamber and used for particle size and morphology analysis. The final milled suspensions were also characterized and remaining suspensions were stored in a refrigerator at 8 ^oC for 7 days.

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To study the impact of bead size on wear, additional 6 h milling experiments were performed under the same conditions of Runs 1–5 mentioned above using 800, 400, 200, 100, and 50 m beads, respectively. These beads had already been used in the previous milling experiments as described above; hence, they are regarded as conditioned or pre-treated for the purpose of the wear study. Additional experiments were also performed with pre-treated 50 m beads under Runs 6–10 conditions, including shorter milling times that allow for preparation of 100 nm drug particles.

Bead wear was characterized on suspension samples following the procedure detailed in Section 4.1.3. The wet beads were oven-dried overnight at 40 °C following 40 min sonication–rinsing in de-ionized water before a new milling experiment.

The total energy consumption E was directly recorded from the mill control panel. Using this information, the average stirrer power applied per unit volume of the slurry (beads, drug, stabilizers, and water) P_w was calculated using





w E V t

P  (4.1)

where tT is the total milling time. The specific energy consumption E*, which is the energy spent per unit mass of drug suspension, was also calculated as follows:

sus

* E m

E  (4.2)

where msus is the total mass of the drug suspension.

Table 4.1 Parameters Varied in the Wet Milling Experiments. Fixed Parameters: Drug Loading of 10%, 200 gDe-ionized Water, and HPMC/SDS Concentration of 2.5%/0.2% (Weight Percent with Respect to De-ionized Water)

Run No. Drug Nominal Bead Size

db (µm)

Rotor Tip Speed u (rpm, m/s)

Bead Mass, Volume Fraction c

(g), (–)

Suspension Flow Rate Q

(ml/min)

Milling Time t

(min)

1 GF 800 3200, 11.7 196, 0.408 126 360

2 GF 400 3200, 11.7 196, 0.408 126 360

3 GF 200 3200, 11.7 196, 0.408 126 360

4 GF 100 3200, 11.7 196, 0.408 126 360

5 GF 50 3200, 11.7 196, 0.408 126 360

6 GF 50 4000, 14.7 196, 0.408 126 120

7 GF 50 4000, 14.7 261, 0.543 126 120

8 GF 50 4000, 14.7 261, 0.543 343 120

9 IND 50 3200, 11.7 196, 0.408 126 360

10 IND 50 4000, 14.7 261, 0.543 343 120

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