Formation Of Solid Lipid Nanoparticles In Microchannels And The Related Mass Transfer Mechanisms

Solid lipid nanoparticles (SLN) is a new drug delivery system developed in 1990s. It has attracted increasing attention for its advantages of excellent biocompatibility, controlled release, targeted therapy and suitability for different kinds of medication routes comparing to the traditional delivery systems, such as emulsions, liposomes and polymeric nanoparticles. In the traditional preparing methods of SLN, the preparing processes are generally conducted complexly under overcritical operation conditions like high speed, high temperature or pressure, and toxicological solvents were always employed. Furthermore the size and distribution of SLN are important factors for the property of SLN. Therefore, it is important to develop a novel method for preparing SLN with small size and narrow size distribution.Microchannels are applied to prepare SLN based on the anti-solvent precipitation in this thesis. The SLN samples were prepared by using a co-flowing microchannel and were compared with the samples prepared by ordinary batch method. The results show that the SLN prepared by co-flowing microchannels had smaller diameter, and that microchannels are suitable for SLN preparation. Compared with the traditional prepartion methods, the prepartion process by using microchannals is a very simple one, with moderate condition and easy to control. Therefore, it could be expected to be an efficient method for SLN preparation.The influences of lipid phase velocity, liquid phase velocity, the concentration of surfactant in liquid phase, the concentration of lipid, the solvent kinds and the dimension of microchannels on the formation of SLN were investigated in co-flowing microchannels, T junction microchannels and microchannels with cross-junction, respectively. It was found that the diameter of SLN increases with the increase of the lipid phase velocity at a certain aqueous phase velocity. For co-flowing microchannels and microchannels with cross-junction, the diameter of SLN decreases with the increase of the aqueous phase velocity at a certain lipid phase velocity, on the contrary, the diameter of SLN increases with the increase of the aqueous phase velocity for T junction microchannels. Moreover, the diameter of SLN increases with the increase of surfacent concentration in the aqueous phase, smaller SLN can be prepared when ethanol is used as lipid phase solvent instead of acetone, and the diameter of SLN decreased as the microchannel dimension decreased. Therefore, SLN with expected properties like small diameter and narrow size distribution can be prepared by controlling these operation conditions.The effect of slug flow on the formation of SLN was studied by inputing gas flow in microchannels. No blockage is observed in the mirochannels when slug flow is employed. The experiments also display that the slug flow has no negative influence on the size of SLN and its distribution, but smaller diameter SLN could be prepared for co-flowing microchannels and microchannels with cross-junction. This may indicate that slug flow can eliminate blockage and is good to the continueous production of SLN in microchannels.The flow patterns in the microchannels were inspected by digital inversion microscope and electron eyepiece or CCD. The mechanisms of mass transfer and the formation of SLN were analysed, and mathematical models were established. For the cross-junction microchannels, the process of SLN formation under slug flow was divided into three zones, such as convectional zone before bubble formation, liquid film zone and slug zone after bubble formation. The corresponding mathematical models for these zones were developed respectively. The solution of the models indicated that the velocity of mass transfer in the film is higher than that in the slug, which is similar to the reports in references, indicating that the model established is credible. On the other hand, the solution of the models also indicated that the increase of gas velocity resulted in the increase of slug turbulence, the film flow velocity and the mass transfer, so SLN was precipited faster. The mechanisms of mass transfer provide a reference for the the preparation of SLN and the design of microchannel apparatus.