(M1230-01-05) Mechanistic Analysis of Excessive Viscosity Increase of Drug Nanosuspension during Wet Milling

Purpose: Drug nanoparticle formulations have been widely utilized to improve the dissolution rate and oral bioavailability of poorly water-soluble drugs. Wet milling is one of the top-down approaches to preparing drug nanosuspension and enables to prepare the highly-concentrated drug nanosuspension. Drug nanoparticles obtained as a suspension are unstable, and aggregation occurs during storage or due to exposure to the gastrointestinal environment after oral administration. To inhibit drug nanoparticle aggregation, various dispersion stabilizers, such as polymers, are used. However, depending on combinations of drug and dispersion stabilizers, there is a risk of excessive viscosity increase of drug nanosuspensions during wet milling. Excessive viscosity increase can lead to manufacturing problems, such as yield loss. Therefore, mechanistic elucidation of the viscosity increment of drug nanosuspension is required for efficient drug nanoparticle preparation. In this study, we focused on the amount of polymer adsorption on the drug nanoparticle surface and the rheological properties of the drug nanosuspension to elucidate the viscosity-increasing mechanism of the drug nanosuspension.

Methods: Seven commercial drugs were used as model compounds, and a 2% hypromellose (HPMC) solution was used as a dispersant. A rotation/revolution pulverizer NP-100 (Thinky, Japan) and zirconia beads (0.1 mm diameter) were used for preparing nanosuspensions. The adsorption amount of HPMC on the drug nanoparticle surface was quantified by ¹H-NMR measurement. The rheological evaluation of each drug nanosuspension was performed with MCR102e (Anton Parr).

Results: The particle size analysis by laser diffraction revealed that all the model drugs used in the present study were successfully nanosized by wet milling. Among the processed compounds, nanosuspension of griseofulvin, ketoconazole, and nevirapine exhibited excessive viscosity increase (high-viscosity group). On the other hand, nanosuspensions of fenofibrate, glimepiride, phenytoin, and probucol did not exhibit an excess increase in the viscosity (low-viscosity group) (Figure 1). ¹H-NMR measurements demonstrated that the high-viscosity group had relatively small amounts of HPMC surface adsorption on the drug nanoparticles (Figure 2). In contrast, the HPMC adsorption on the drug nanoparticles of the low-viscosity group was relatively high, while fenofibrate nanoparticles exhibited exceptionally low HPMC adsorption. Flow-curve measurement using a rheometer showed that the nanosuspensions of the high-viscosity group exhibited shear-thinning behavior at low shear rates with thixotropic properties (Figure 3). Thus, it can be assumed that the excessive viscosity increase during wet milling in the high-viscosity group was due to the formation of a network structure between nanoparticles. Viscoelastic measurements in increasing temperature revealed that the storage modulus G’ of each drug nanosuspension increased rapidly at a certain temperature, and this inflection temperature was relatively low for the drug nanosuspension of the high-viscosity group. This implied that the energy required for increasing the viscosity of drug nanosuspension was lower for the high-viscosity group, resulting in the excessive viscosity increase during wet milling.

Conclusion: The rheological evaluation of drug nanosuspensions prepared in 2% HPMC solution revealed that the significant viscosity increase during nano-milling was attributed to the formation of the network structure of nanoparticles. The network structure formation seems to be caused by inter-particle attraction and cross-linking of HPMC adsorbed on the nanoparticle surface. Thus, when preparing the drug nanosuspension by wet milling techniques, the amount of HPMC adsorbed on the surface of the nanoparticles and the energy required to form the network structure of nanoparticles should be considered to avoid the risk of excessive viscous increase during wet milling of drug nanoparticles.

Figure 1 Appearance of nanosuspensions of (A) phenytoin (low-viscosity group) and (B) griseofulvin (High-viscosity group)

Figure 2. Amount of HPMC adsorbed on the drug nanoparticle surface

Figure 3. Flow curves for nanosuspensions of (A) low-viscosity group and (B) high-viscosity group drugs. Solid and dashed lines indicate the results of UP or DOWN measurements, respectively.