38 × 10−23 J/K), η is the solvent viscosity (kg/ms; for blood = 0.035 kg/ms), T is the

temperature (K; 37°C), and r is the solute molecule radius (cm). This equation can be extended to relate the diffusion coefficient to the molecular weight and density of the molecule of interest: where N is Avogadro’s number, V is the molar volume of the solute, r is the hydrodynamic radius, which 4SC-202 molecular weight considers the solvent bound to the solute, and ρ is the density of the solute. The resulting equation is as follows: Using the MW for paclitaxel (MW = 853.9), the diffusion coefficient (D) was calculated to be 9.5 × 10−7 cm2/s. An estimate of the particle radius needed to achieve a dissolution time of <10 s under non-stirred sink condition was determined using the Hixson-Crowell cube root law [33, 34]: where Γ is the estimate time for complete dissolution, ρ is the density of the solution, r o is the radius of the particle, D is the diffusion coefficient, Cs is the solubility in plasma at 37°C (40 μg/mL). Based on the relationship described above, the calculated target mean radius for the paclitaxel

nanoparticles was calculated to be 0.6 μm under sink conditions. The paclitaxel nanosuspension was characterized in order to ensure its proper preparation. D 50 and D 90 of paclitaxel particles in the IV formulation were determined to be 0.4 and 0.7 μm, respectively (Figure 1). A D 50 of 0.4 μm was within HDAC inhibitor the mean target radius of 0.6 μm. PXRD characterization of the solid form of the nanomaterial indicated no significant change in crystal form from the milling process (Figure 2). The paclitaxel crystalline nanosuspension formulation was stable at room temperature with no significant changes in

PXRD, particle size, and chemical stability over a period of 3 weeks. Figure 1 Particle size characterization of paclitaxel nanosuspension. Figure 2 PXRD of paclitaxel post-milling (top) and API (bottom). Using a previously published theoretical calculation [30, 33, 34], measured paclitaxel solubility in plasma (40 ± 2 μg/mL at 37°C), and the D 50 listed above, the estimated dissolution time of an average paclitaxel particle in the nanosuspension was estimated to be less than 5 s. The actual in vivo dissolution time should theoretically be much more rapid since turbulent blood flow Baricitinib in the vein should serve to both reduce the diffusion boundary thickness and rapidly disperse the injection formulation minimizing local concentration effects [33, 34]. Plasma and tissue pharmacokinetics in tumor-bearing xenograft mice Paclitaxel plasma, tumor, spleen, and liver concentration-time profiles following intravenous administration at 20 mg/kg using the Cremophor EL:ethanol and nanosuspension Blebbistatin purchase formulations are presented in Figures 3 and 4, respectively. The plasma clearance of paclitaxel after intravenous dosing was substantially higher with nanosuspension (158.