| Cefuroxime axetil (CFA) is a poorly-water-soluble drug with a high activity against Gram-positive and Gram-negative microorganisms. CFA exists as crystalline and amorphous forms, of which the latter shows higher bioavailability and is more desirable. After oral administration, CFA is absorbed and rapidly hydrolyzed by esterases in the intestinal mucosa and portal blood to produce cefuroxime. The 1-acetoxyethyl ester group at the position 4 of CFA ensures its lipophilicity and compromises on solubility. Accordingly CFA presents a low solubility and dissolution rate in gastrointestinal tract, which limits its absorption and bioavailability. Micronization or size reduction is regarded as an effective method to address this problem.The traditional micronization methods, such as jet-milling, media milling and high-pressure homogenization, have been attempted to produce drug microparticles. However, these methods need high-energy input and usually result in pharmaceutical contamination, broad particle size distribution and difficulty to control surface properties. Compared to the above methods, liquid antisolvent precipitation (LASP) process, which is based on the decrease of the solute saturation caused by mixing the solution with an antisolvent, offers an attractive alternative for drug nanoparticle formation at mild temperature and pressure with no requirement of expensive equipment.Microtechnology has been attracting attention as a method for the production of fine particles in recent years because of their highly efficient micromixing performance and short transport time, leading to a better control of nucleation and particle growth. However, due to the structure limitation, the production capacities of most reported microdevice are at uL or mL/min, which are much lower than those of conventional devices. We have designed and fabricated a high-throughput microporous tube-in-tube microchannnel reactor (MTMCR) to offer a continuous process to produce nanoparticles. The MTMCR demonstrated the excellent micromixing performance and the throughput capacities at L/min level.In this study, the MTMCR was employed for the micronization of drugs for the first time. Ultrafine CFA was prepared in the MTMCR by LASP. CFA was prepared in the acetone-water system with or without the surfactant. The results showed that a suitable surfactant can mitigate CFA particle agglomeration and coalescence. The as-prepared CFA exhibited a smooth, spherical morphology, good dispersion, uniform particle size and an average diameter of about 1μm. In the acetone-isopropyl ether system, the influence of experimental parameters such as solvent/anti-solvent volume ratio, CFA concentration, overall volumetric flow rate, micropore size, annular channel width, mixing distance, temperature and surfactant on CFA particle formation in the MTMCR was studied. CFA with a mean particle size of 290 nm was obtained. The experimental results indicated that CFA particle with a tunable size of 290-1400 nm could be achieved with a throughput in the range of 1.5～6 L/min. The average particle size decreased with increasing overall volumetric flow rate and decreasing CFA concentration, micropore size, and annular channel width.The produced CFA particles were characterized by SEM, XRD, FT-IR, DSC and dissolution test, which indicated that the nanosized CFA was amorphous and exhibited higher dissolution rate compared to the raw CFA. The MTMCR might offer a general and facile pathway for mass production of the ultrafine particles of hydrophobic pharmaceuticals thanks to its high throughput capacity and excellent micromixing performance. |
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