The Study On The Mechanism And Regulation Of Induced-crystallization Of Small Organic Molecules

Solution crystallization is a typical unit operation of separation and purification,which plays a key role in regulating the quality of crystal products.Nowadays,the requirements for the production of crystal products maintain a trend of diversification,refinement and large-scale,which puts forward the higher quality requirements of crystal products,i.e.,crystal morphology,solubility,dissolution rate,compressibility and bioavailability.To conduct an efficient and reliable regulation strategy,researchers have explored and studied the method and mechanism of solution crystallization in depth.In this paper,experiments,online-offline characterization and molecular simulation were used to investigate the induction mechanism and regulation of solution crystallization.The effects of different methods and systems on the habit and polymorph of crystalline products,and the induction mechanism of solution crystallization were investigated.The characteristics of organic molecules and clusters matter in solution,i.e.,molecular and cluster behavior,molecular conformational distribution,interaction energy etc,were discussed emphatically.The main results are listed as follows:(1)The mechanism of crystal transformation from amorphous to polymorph I during the anti-solvent crystallization of GMP was studied.For the antisolvent crystallization experiments in different solution environments(p H and additives),the on-line Raman spectra and the liquid~1H-NMR characterization at low temperature were collected.While for the solid samples,the off-line Raman,infrared spectra and PXRD measurements were carried out.Combining with the molecular dynamics simulation,the microscopic characteristics of clusters and hydrogen bonds were analyzed,and the mechanism of crystal transformation induced by p H value and additives was discussed.The results show that the existence of sodium hydroxide and sodium formate greatly weakens the hydrogen bond of the long-chain helix,but has little effect on the related hydrogen bond of the dimer or tetramer,which leads to the disappearance of flocs,the recombination of GMP molecules and the transformation from amorphous to crystal.(2)To regulate the crystal habit and polymorph of API,the crystallization process and mechanism of typical drug active ingredients(APIs)induced by templates were studied by adding polymer films to the cooling system or solvent evaporation system.For different systems,the habits and polymorphs of API crystals were measured by PXRD,and the API solution properties were analyzed by a series of spectral characterizations.The adsorption energy of crystal facet and the behavior of molecules or clusters,were analyzed by the molecular simulation.The mechanisms of template-induced crystallization were discussed based on the experimental and simulation results,which show that:1)For the paracetamol system,different polymer films have different surface chemical groups,resulting in different strength of hydrogen bonds at the interface,thus resulting in different prefered orientation effects,which was verified by the experiment of modified film.2)For the pyrazinamide system,template and solvent induce ? or ? polymorph and weaken the 27.6°PXRD peak in the volatile crystallization,the main reason is that the templates affect the adsorption energy of each polymorph and each crystal facet.3)For the carbamazepine system,it is found that template and supersaturation affect the distribution of carbamazepine molecular conformation.(3)The induced crystallizations of paracetamol or pyrazinamide in agarose hydrogel were studied.Combined with the PXRD and the solution ~1H-NMR characterization at low temperature,the factors affecting the habit or polymorph of API crystal during cooling crystallization were explored for the different concentrations of agarose hydrogel.The results show that:1)For the paracetamol system,high concentration of agarose hydrogel has prefered orientation effect on paracetamol(002)facet.2)For the pyrazinamide system,high concentration agarose hydrogel has prefered selectivity forgpolymorph.Furthermore,combining with the molecular dynamics simulation,the RDFs and the cluster analysis indicate that the gel molecules hinder the gathering of API molecules,which makes the nucleation difficult.At the same time,gel molecules interact with API molecules,resulting in different molecular behavior,and finally affects the habit or polymorph of crystal.In this paper,the method combined with the experiment,characterization and molecular simulation were employed to conduct the beneficial attempt for the polymorph or habit regulation of solution crystallization.We provide new ideas for the in-depth study of the regulation method and the mechanism for the solution crystallization.It is valuable for the theoretical exploration of the solution crystallization process.