Enhanced biopharmaceutical performance of brick dust molecule nilotinib via stabilized amorphous nanosuspension using...

"Brick dust" compounds have high lattice energy as manifested by the poor aqueous solubility and suboptimal bioavailability. Nilotinib being a weakly basic brick dust molecule exhibits erratic and limited absorption during gastrointestinal transit, attributed to pre-absorptive factors like pH-dependent solubility, poor dissolution kinetics, and post-absorptive factors including P-gp-mediated drug efflux. In our study, these problems are addressed holistically by the successful fabrication of amorphous nanosuspension by an acid-base neutralization approach. The nanosuspension was obtained via rapid precipitation of nilotinib in an amorphous form and the generated in situ sodium chloride salt assisted in stabilizing the drug-loaded nanosuspension in a cage of salt and micellar stabilizer. Soluplus^® and hypromellose acetate succinate (HPMCAS) were employed as a novel combination of stabilizers. Systematic optimization was carried out by employing the I-optimal method using Design Expert^® software with a concentration of HPMCAS and Soluplus^® as independent variables and evaluating them for responses viz particle size, polydispersity index (PDI), and zeta potential. The resultant nanosuspension showed a mean particle size of 130.5 ± 1.22 nm with a PDI value of 0.27 ± 0.01, and a zeta potential of - 5.21 ± 0.91 mV. The nanosuspension was further characterized for morphology, dissolution, and in vivo pharmacokinetics study. X-ray powder diffraction study of the nano-formulation displayed a halo pattern revealing the amorphous form. Stability studies showed that the nanosuspension remained stable at 40 °C ± 2 °C and 75% RH ± 5% RH for a period of three months. In vitro drug release and solubility study showed threefold and 36-fold enhancement in dissolution and solubility of the nanosuspension. Furthermore, an in vivo pharmacokinetic study in Sprague-Dawley rats following oral administration displayed a 1.46-fold enhancement in the relative bioavailability of the nanosuspension in contrast to neat nilotinib.