Category: Formulation and Quality
Purpose: Toxicological formulation development for pre-clinical studies is very challenging due to the limited exposure of the poorly water-soluble compounds, poor dose-proportionality of the formulation, and higher variability. A discovery compound A has low water solubility and in-vivo exposure plateaued at 100 mg/kg in rat toxicological study without showing any side effects. To overcome the exposure challenge, multiple approaches such as micronized formulation, nano formulation and spray-dried dispersion formulation were tested. Nano formulation was selected due to high exposure, good dose-proportionality, and lower variability. A new large scale rotation revolution mixer (NP-500) was evaluated and showed robustness of scaling up nano formulation manufacture from small scale instrument (NP-100).
Methods: A small-scale rotation revolution mixer (Thinky NP-100) was used to prepare nano formulation of compound A with zirconium dioxide beads with a diameter of 0.1 mm. Micronized formulations with particle size of 3 mm and 1 mm were prepared using high pressure homogenizer. Spray-dried dispersions with polymer of HPMCAS-MG and Eudragit L100 with a drug loading of 25% compound A were prepared using Procept Spray dryer. SDD formulation of compound A with HPMCAS-MG polymer was prepared in corn oil at a dose level of 300 mg/kg and 600 mg/kg. SDD formulation of compound A with Eudragit L100 polymer was prepared in 0.5%MC at the same dose levels. Crystallinity of the formulations were analyzed by XRPD. Particle size distribution was measured by laser diffraction. The in-vivo study was conducted in rat tox studies. A large-scale rotation revolution mixer (Thinky NP-500) was used to prepare nano formulation with zirconium dioxide beads with a diameter of 0.1 mm.
Results: As shown in Table 1, SDD formulation of compound A with HPMCAS-MG polymer in corn oil showed the highest exposure. However, the corn-oil is not preferred in long-term tox study. The variability of the SDD formulation was also very high. Nano formulation showed second highest exposure with small variability and good dose-proportionality which was suitable for the tox studies. Table 2 showed the comparison of two scales of the nano rotation revolution mixer. NP-500 provided nano formulation with a batch size of 160 g API with using 480 g of zirconium dioxide beads within 1 hour. It is very efficient and cost effective for manufacturing nano formulation. As shown in Figure 1, the particle size of nano formulations manufactured by NP-100 and NP-500 were 89 nm and 106 nm which suggested the robustness of the NP-500 for scaling-up.
Conclusion: A novel large scale rotation revolution mixer (NP-500) showed robustness of scaling up nano formulation manufacture from small scale instrument (NP-100). NP-500 is very efficient and cost effective for nano formulation manufacturing.