Fabrication And Application Of Small-molecular Organic Nanomaterials By High-gravity Technology

Organic nanomaterials exhibit excellent optical,electrical,magnetic and biological properties on basis of their structural diversity,easy tailoring and modification.The research hotspots of organic nanomaterial mostly focus on the biopharmaceutical field centered on drugs and optoelectronics industry relied on the organic photoelectric materials.However,the current theory of nanomaterials based on inorganic nanomaterials could not be completely applied to the organic nanomaterial due to the differences in the structure and physicochemical properties of organic nanomaterials and inorganic nanomaterials.In particular,organic nanomaterials exhibit low boiling point,easy sublimation and poorly stability because of molecular arrangement and mode of action,which makes the preparation methods of inorganic nanomaterials are not suitable for preparation of organic nanomaterials.At present,the preparation methods of organic nanomaterials have many problems,such as complex preparation process,difficult scale production and so on.Therefore,researchers have been working on development of the technological route of controllable preparation of organic nanomaterials,which is easy to industrialize.In this paper,small molecular drugs and small molecular organic optoelectronic materials was taken as study objects,and high-gravity technology was applied to fabricate organic small molecular nanomaterials owing to the advantage of no negative scale-up effects.Furthermore the properties of organic small molecular nanomaterials and the mechanism of fabrication of organic small molecular nanomaterials by high-gravity have been deeply studied.The main contents and innovations are summarized as follows.1.Based on the model drug:sorafenib,small molecule drug for treatment of liver cancer,the nucleation mechanism of drug nanoparticles in high-gravity rotating packed bed was studied,which provides theoretical guidance for the fabrication of organic small molecular nanomaterials by high-gravity technology.The effect of high-gravity level,polymer stabilizer and solvent/antisolvent flow rate ratio on the nucleation process of drug particles were investigated.It was found that the nucleation rate of the particles in the rotating packed bed was 100?200 times that of stirred tank reactor and the polymer stabilizer effectively increased nucleation rate by reducing the interfacial tension in the system.The solvent/antisolvent flow rate ratio affected the nucleation process of drug particles by the regulation of the supersaturation level of the system.2.The sorafenib nanosuspensions with average particle size of 80 nm and 170 nm were successfully prepared through the control of nucleation process of sorafenib in the high-gravity rotating packed bed.After freeze-drying,the nanocomposite powder had good water re-dispersivity and the residue of organic solvents conformed to standard.Through physicochemical characterization,sorafenib nanoparticles were found to be amorphous.After 160 days of storage,nanoparticles did not appear crystal transformation and particle agglomeration.3.The regorafenib nanocomposite particles were prepared by high-gravity technology.The effects of the solvent/antisolvent system,kind of stabilizer,concentration of stabilizer,rotating speed,solvent/antisolvent flow rate ratio and drying condition on the morphology and particle size of regorafenib particle were studied.Finally,regorafenib nanocomposite nanoparticle with average particle size of 140 nm have been successfully prepared.XRD analysis showed that the drug changed from crystalline to amorphous after particle reduction by high-gravity technology.In vitro dissolution experiment showed that the dissolution rate of the raw drug was greatly increased by the particle reduction,and the total dissolution rate reached 98%in 5 min.4.The influences of drug particle size on drug performance were studied through the investigation of the effects of sorafenib nanoparticles with different particle sizes on the dissolution rate,in vitro anti-tumor performance and pharmacokinetics in vivo.It was found that the dissolution rate and anti-tumor properties of the sorafenib raw drug were significantly increased with the reduction of particle.In the pharmacokinetics,with the decrease of the size of nanoparticles,the maximum peak concentration of the drug time curve increased,the half-life and the average residence time of the drug increased.And the value of AUC of sorafenib nanoparticles with average size of 80 nm was 2.24 times that of the raw drug.5.The nano tablet of regorafenib was developed,and the quality of nano tablet was evaluated.The optimal formulation of the nano tablet of regorafenib was determined by the investigation of the effect of the type of filling agent,the type and concentration of disintegrating agent,the type and concentration of lubricant,the size of particle and the harness of the tablet on the performance of nano tablet.The dissolution test in vitro showed that the dissolution of prepared nano tablet achieved balance in 30 min,and the cumulative dissolution rate is 99.48%,which is superior to the dissolution rate of commercially available tablets.The tablets conformed to the provisions of thet"China Pharmacopoeia"(2015 edition).Moreover it had no effect on the appearance and dissolution of the tablets under the conditions of strong light irradiation and high temperature storage,but the nano tablet was more sensitive to high humidity,and the tablet should be preserved under dry condition.6.A new routine for the fabrication of organic small molecular photoelectric material,Y-type oxotitanium phthalocyanine nanocrystal(Y-TiOPc),was proposed by combining external circulation rotating packed bed(EX-RPB)and internal circulation rotating packed bed(IN-RPB),which was applied to the precipitation process and crystal transformation process of TiOPc,respectively.The influence of the stabilizer and solvent/antisolvent flow rate ratio on the precipitation process,as well as the effect of crystal transformation temperature and the crystal transformation time on the crystal transformation process were investigated.Compared to stirring tank reactor,it was found that EX-RPB helped to reduce the size of TiOPc particle in the precipitation process,and IN-RPB helped to shorten the crystal transformation time and inhibited the increase of the particle size after crystal transformation process.Finally,the Y-TiOPc nanocrystal with an average diameter of 6 nm was successfully prepared,and the multilayer photoconductor assembled by it had good photoconductivity.