3D-printed microfluidics under ultrasonic cooling crystallization for nano-precipitation of Ezetimibe: Effect of process parameters and PBD approach

Abstract

The current research focuses on the antisolvent precipitation of Ezetimibe (EZB) via microfluidics under continuous ultrasonic cooling crystallization. One factor at a time was applied to study the effect of parameters: organic-aqueous flow rate ratio (1:2 - 1:5), EZB concentration (2.5 – 12.5, mg/mL), polymer concentration (0.025 - 0.3, % w/v), ultrasonic frequency (22 – 42, kHz), ultrasonic bath temperature (10 – 25, ⁰C), ultrasonic amplitude (20 – 100, %), confluence angle of micromixer inlet (90⁰- 180⁰) on the particle size (PS, nm), % yield, % encapsulation efficiency (% EE), and % dissolution rate (% DR). A PBD (Plackett-Burman design) was also employed for the screening studies of influencing factors for aforementioned responses. PS, Zeta potential (ZP, mv), Field Emission Gun Transmission Electron microscope (FEG-TEM), and X-ray diffraction (XRD) were analyzed for raw EZB and nano-precipitated EZB. An average EZB PS of 101 ± 1.1 nm, PDI of 0.027 ± 0.01, 80 ± 1.7 % yield, 78.83 ± 0.5 % DR, 90.67 ± 0.1 % EE, and -20 mV ZP were obtained under best parametric condition. FEG-TEM revealed the the final nano EZB morphology was likely to be elongated cuboidal or rod-shaped. An approximately 5-fold increase in %DR was observed for the confluence angle of 90⁰ (├- shaped) micromixer as compared to raw EZB. However, 94.14% decreament in avg EZB PS was achieved for the confluence angle of 90⁰ (├- shaped) micromixer and utilizing ultrasonic microfluidics under cooling crystallization as a process intesification approach.