Itraconazole Nanosuspensions via Dual Centrifugation Media Milling: Impact of Formulation and Process Parameters on Particle Size and Solid-State Conversion as Well as Storage Stability

Abstract

Nanocrystal suspensions proved to be a potent enabling principle for biopharmaceutics classification system class II drugs with dissolution limited bioavailability. In the example of itraconazole (ITZ) as a model drug combined with electrosteric stabilization using hydroxypropyl cellulose (HPC-SL), sodium dodecyl sulfate (SDS) and polysorbate 80 (PS80), the impacts of formulation and process parameters of a dual centrifugal mill on material attributes such as particle size, zeta potential, particle morphology, storage stability and especially solid-state characteristics were evaluated. A minimal concentration of 0.9% (w/w) HPC-SL, 0.14% (w/w) SDS and 0.07% (w/w) PS80 was necessary for sufficient nanoparticle stabilization. Despite the minor effect of PS80, its presence was beneficial for electrosteric stabilization. Choosing lower stabilizer concentrations resulted in a pronounced increase in particle size due to agglomeration, which was confirmed by SEM imaging and a decrease in zeta potential in combination with an amorphization of the particles. Milling temperature had no significant impact on the particle size, whereas milling speed and the size of the milling beads used were found to have a strong impact on the critical material attributes such as particle size and polydispersity index. The smallest particle sizes could be obtained by using the smallest milling bead size. However, the smallest obtainable particle size could only be achieved by using two-fold stabilizer concentrations, as smaller particles exhibit a larger specific surface area.

Keywords: agglomeration; amorphization; dual centrifugation; itraconazole; media milling; nanocrystals; nanosuspension.

Figure 1

Z-average after 8 h of milling with different stabilizer solutions. Composition is given in % (w/w) and HPC-SL concentration was kept constant at 0.9%. Milling was carried out at 4 °C with 1500 rpm and milling beads sized 0.3–0.4 mm. Hatched area: No stable nanosuspension was obtained. Values are given as mean of three measurements.

Figure 2

Effect of milling bead size on the ITZ particle size. Values are expressed as mean ± SD, n = 3. Milling was carried out at 4 °C with 1500 rpm. * Bead size was 0.1–0.2 mm; stabilizer concentration had to be changed to 0.9% (w/w) HPC-SL, 0.28% (w/w) PS80 and 0.28% (w/w) SDS (see Section 4).

Figure 3

Z-Average (A), PDI (B) and zeta potential (C) of F2 (black squares) and F6 (grey dots) in relation to the milling time. Milling was carried out at 4 °C with 1500 rpm and milling beads sized 0.3–0.4 mm. Values expressed as mean ± SD, n = 3.

Figure 4

XRPD pattern of F2 in relation to grinding time. Milling was carried out at 4 °C with 1500 rpm and milling beads sized 0.3–0.4 mm. Plots are shifted for a better illustration.

Figure 5

XRPD pattern of F6 in relation to grinding time. Milling was carried out at 4 °C with 1500 rpm and milling beads sized 0.3–0.4 mm. Plots are shifted for a better illustration.

Figure 6

DSC-thermograms of F2 ITZ nanosuspension. Milling was carried out at 4 °C with 1500 rpm and milling beads sized 0.3–0.4 mm. Plots are shifted for a better illustration. Arrow 1 marks an endothermic event, arrow 2 marks an exothermic event.

Figure 7

DSC-thermograms of F6 ITZ nanosuspension. Milling was carried out at 4 °C with 1500 rpm and milling beads sized 0.3–0.4 mm. Plots are shifted for a better illustration.

Figure 8

SEM images of F2 ITZ nanosuspension after different milling periods (indicated in the left upper corner of each image). Milling was carried out at 4 °C with 1500 rpm and milling beads sized 0.3–0.4 mm.

Figure 9

SEM images of F6 ITZ nanosuspension after different milling periods (indicated in the left upper corner of each image). Milling was carried out at 4 °C with 1500 rpm and milling beads sized 0.3–0.4 mm.