Investigations On Crystal Nucleation And Crystal Morphology Manipulation Under Microfluidic Conditions

The control of the nucleation process and crystal morphology is crucial to the quality of crystal products.Generally,the primary nucleation rate is faster in the nucleation process of inorganic salts,and the accuracy of studies on the nucleation rate using traditional methods is limitied by techniques and methods.In the aspect of polycrystalline control,The traditional method has the disadvantages of high consumption of raw materials and heavy workload.In addition,as for drug nanocrystals,there are some problems in the preparation of nanocrystals by traditional methods,such as limited particle size reduction and wide particle size distribution.Under the above background,several structures of microfluidic devices were developed in this paper combined with the special fluid characteristics provided by microfluidics,aluminum potassium sulfate dodecahydrate,L-glutamic acid and azlocillin acid were selected as model compounds to systematically investigate nucleation kinetics,polymorph control and nanoparticle regulation under microfluidic conditions,respectively.Firstly,different microfluidic devices for crystallization process were designed and developed in this paper,and the performances of microfluidic devices were tested and discussed.The developed COC material chip has better transparency,and the self-made PTFE microtube system has better leakage resistance.Meanwhile,preliminary experiments verified the system's regulation on fluid flow patterns and droplet size.Secondly,the effects of various parameters on droplet formation and size were systematically studied,and the influence of droplet size on crystal nucleation probability was further investigated.After optimizing conditions,the droplet size was 1.11 mm and the droplet spacing was 837 nm.With the aid of monodisperse and mutually independent droplets,the primary homogeneous nucleation and heterogeneous nucleation of aluminum potassium sulfate dodecahydrate were studied.The corresponding kinetic models of primary homogeneous and heterogeneous nucleation were established.The nucleation rates of primary homogeneous and heterogeneous were calculated.The kinetic parameters of nucleation were also determined.The average amount of heterogeneous nucleation active center in the droplets during heterogeneous nucleation was estimated,and the influence of active center on the nucleation process was discussed.Then,two kinds of microchannel structures were designed to explore the polymorphism selectivity of L-glutamic acid.The effects of channel structure,flow rate,temperature and solution concentration on the polymorphs were investigated.In the T-type microchannel,the polymorph was greatly affected by the flow rates,while at the lower solution flow rate,the polymorph was greatly affected by the solution concentrations.In the Y-type microchannel,the content of ? form increased with the broadening of the focusing flow width and the decrease of the temperature,and decreased with the increase of the total flow rate.Compared with the traditional experimental results,it was confirmed that the mixing mode between the solution and the antisolvent changed the supersaturation in the system,which significantly affected the composition of the product polymorph.Finally,three kinds of microfluidic devices were designed and developed to prepare azlocillin acid nanoparticles by antisolvent precipitation method.The effects of surfactant,flow rate,temperature and solution concentration on quality of nanoparticles were evaluated and discussed.In cross-type microchannel,the particle size increased with the increase of the solution flow rate,the decrease of the total flow rate and the concentration of the solution.The particle size firstly decreased and then increased with the increase of antisolvent flow rates and concentrations of surfactant.In the Y-type microchannel,the particle size increased with the increase of the solution flow rate,but decreased firstly and then increased with the increase of the antisolvent flow rate and solution concentration.In the T-shaped microchannel,the particle size first decreased and then increased with the increase of total flow rate and flow rate ratio,and increased with the increase of temperature.The nanoparticles with average diameter of 130-200 nm were obtained by optimizing the conditions.