| Compared with the conventional pharmaceutical formulation, nanomedicine possesses some potential advantages, such as smaller particle size and higher bioavailability. In pharmaceutics, nanoparticles can be divided into nanodrug and nanocarrier. The technology for obtaining drug nanoparticles has an important application potential and academic value in medicine, which is a hot research topic in the present government, academic and industry worlds. Microreactor has excellent micromixing, mass-transfer and heat-transfer properties. It has been widely applied in the preparation of various inorganic nanoparticles, but relatively little has been done for the synthesis of organic nanoparticles, especially drug nanoparticles. Therefore, in this doctoral dissertation, typical Y-type microchannel and line-type microchannel were selected for the preparation of silybin (water-insoluble liver-protection drug for oral formulation) nanoparticles, beclomethasone dipropionate (BDP) (glucocorticosteroids for inhalation formulation) micro-structured particles, and PLGA (drug carrier) nanoparticles. Based on these results, high-throughput metal microporous tube-in-tube microchannel reactor was further adopted for large-scale preparation of cefuroxime axetil (CFA) nanoparticles. The main contents and research results are summarized as follows.1. Based on the study on micromixing performance in Y-type and line-type microchannels, silybin nanocomposite powder and the corresponding aqueous nanodispersion were prepared by using antisolvent precipitation in Y-type and line-type microchannels, combined with spray drying technology. The effects of drug concentration, solvent flow rate, antsolvent flow rate, total flow rate, the selection of the injection phase and precipitation temperature on the particle size and distribution were investigated. The results showed that in the experimental range, the selection of the injection phase, liquid flow rate, and drug concentration have significant effects on the particle preparation. The particle size rapidly decreased by decreasing temperature and drug solution flow rate; while firstly decreased and then increased with the increase of antisolvent flow rate, overall flow rate and drug concentration. In a line-type microchannel, the obtained particles had a smaller size when solvent was used as the injection phase. The silybin with an average size of 30 nm could be achieved at an optimized preparation condition, Further dissolution study indicated that the as-prepared silybin nanoparticles had a fast dissolution process, reaching more than 97% in 10 min, much better than 22% and 5% of physical mixture with a same ratio and raw silybin, respectively.2. BDP microstructured particles by combining microfluidic antisolvent precipitation, high-pressure homogenization (HPH) and spray drying. The effects of surfactant, solvent and antisolvent flow rates, drug concentration, HPH and spray drying conditions on particle size and morphology were explored. The results indicated that BDP appeared rodlike without surfactant HPMC while spherical with the addition of HPMC. Besides, the particle size decreased by decreasing BDP solution flow rate and precipitation temperature and increasing antisolvent flow rate. As the increase of BDP concentration, the particle size first decreased and then increased. BDP nanoparticles with an average size of 200-260 nm could be achieved. In addition, BDP porous spherical agglomerates (PSA) were prepared by combining high-pressure homogeneous method and spray drying technology with no addition of surfactant. BDP PSA with an average size of 1-3 μm and uniform size distribution could be obtained by increasing feeding speed and drying temperature, as well as decreasing particle size in slurry. The aerosol performance investigation indicated that the as-prepared PSA had a high FPFcmitted of 68.39%, while the vacuum-dried BDP and raw BDP particles had only 47.25% and 24.76, respectively.3. Drug carrier PLGA and drug loaded PLGA nanoparticles were prepared by microfluidics. In this study, PLGA nanoparticles were prepared by utilizing acetone and water as the solvent and antisolvent, and poloxamer 188 as surfactant. The effects of solution concentration, the amount of surfactant, flow rate, the selection of injection phase and temperature on particle size and distribution. The results indicated that PLGA particle size decreased by decreasing temperature and PLGA solution flow rate; while firstly decreased and then increased with the increase of PLGA concentration, antisolvent flow rate, and overall flow rate. In a line-type microchannel, particle size was smaller when the injection phase was antisolvent. In addition, the particle size decreased with the decrease of solvent flow rate, the increase of antisolvent flow rate and the overall flow rate. PLGA nanoparticles with an average size of 60-70 nm could be achieved at an optimized condition. In a Y-type microchannel, drug loaded PLGA nanoparticles were prepared by selecting voriconazole as model drug. The product had a good sustained release property.4. On the basis of the investigation results in typical Y-type and line-type microchannels, the novel metal microporous tube-in-tube microchannel reactor (MTMCR) with a high-throughput of two orders of magnitude higher than T-type or line-type microchannel was used for the preparation of amorphous CFA nanoparticles. The effects of solvent/anti-solvent volume ratio, CFA concentration, over all flow rate, micropore size, annular channel width and temperature on CFA particle size was investigated. The results indicated that CFA particle size decreased with the increase of the flow rate, the decrease of micropore size and annular channel width. At an optimized condition, CFA nanoparticles with an average size of 300 nm could be prepared, which is almost consistent with the results of Y-type and line-type microchannles. MTMCR would meet the requirements for practical production application.The above-mentioned investigation indicated the microchannels had a great potential in the preparation of various organic drug nano/micro structured particles. |
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