Box Behnken Design Optimization for Synthesis of Dexibuprofen Nanocrystals Using Anti-solvent Precipitation Method and Oral Bioavailability Testing

Abstract

Dexibuprofen (DXI) is the S(+) enantiomer of Ibuprofen [(±)-a-methyl-4–(2-methylpropyl) benzeneacetic acid. It has poor physical solubility of less than 1mg/mL. Due to its solubility, it causes low bioavailability in the gastrointestinal tract. One way to improve its solubility is to reduce its size to form nanocrystals. The objective of this study is to synthesize stable nanocrystals of dexibuprofen (DXI) through the use of the anti-solvent precipitation method. Furthermore, the study aims to optimize the synthesis process using the Box-Behnken method and evaluate the oral bioavailability of the nanocrystals. DXI nanocrystals were synthesized using an antisolvent precipitation method. Optimization formula using an experimental design by Box Behnken to determine the formula for DXI nanocrystals with three-factor variations in magnetic stirring speed (400-800 RPM), the concentration of PVP K90 (1-3%), and Tween 80 (1-3%), as stabilizers for DXI nanocrystal synthesis. The optimum DXI nanocrystal was dried by Freeze-drier and further characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The nanocrystals were evaluated by solubility and in vitro dissolution tests. The oral bioavailability test of DXI nanocrystal was conducted on Wistar male rats and compared to raw DXI. The optimized DXI nanocrystal was produced from manufacturing under conditions of magnetic stirrer speed at 400 RPM, 3% of PVP K90, and 3% of Tween 80. The resulting DXI nanocrystal has a size of 118.83nm, with polydispersity index and zeta potential values of 0.422 and -186.6 mV, respectively. The DSC characterization found DXI nanocrystal powder to peak at 45.41°C. Furthermore, the results of the diffractogram in the PXRD test of the DXI nanocrystal powder showed a sharp intensity indicating that the DXI nanocrystals did not change into other physical forms. Finally, the solubility, dissolution, and oral bioavailability of DXI nanocrystals were higher than raw DXI. The optimized DXI nanocrystal was successfully manufactured using the anti-solvent precipitation method with conditions optimization results from Box-Behnken Design. The resulting optimal formula shows better solubility and oral bioavailability than raw DXI.