A Research On Crystal Morphology Control And Synthon Behaviors During Drug Crystallization Processes

During the solution crystallization process,morphological indicators such as crystal form,habit and particle size distribution of the crystal product will have an important impact on the downstream processes such as filtration,washing,drying and tabletting.At the same time,due to their different microstructures and macroscopic morphologies,crystal products which have the same chemical composition and different crystal morphology will have very different physical and chemical properties and bioavailability.Therefore,it has important theoretical value and practical significance to conduct the research on crystal morphology,molecular dynamics,nucleation kinetics,as well as crystal morphology control of the crystal products that have different habits in organic systems.At present,the mechanism of control the crystal form and crystal habit of solid products has not been fully understood,and the design and preparation of target crystal products still largely depend on high-throughput experimental screening.Therefore,in order to effectively control the solution crystallization process and the crystal form of the product,it is necessary to understand the effects of the internal structure properties of the crystal and the external growth environment on the crystal form and habit at a molecular level.This paper uses molecular dynamics simulation and “synthonic” engineering methods to systematically study the effects of the arrangement of solvents and supramolecular synthons on the crystal habit and form of crystal products during solution crystallization from the perspective of nucleation and growth.A single crystal of cefaclor ethanol-water solvate was obtained by using cooling crystallization method,and its crystal structure was refined using an X-ray single crystal diffractometer.Using online process analysis technology,the solution-mediated phase transition process of cefaclor dihydrate in the supersaturated solution was monitored,and the nucleation of cefaclor ethanol-water solvent compounds on the surface of cefaclor dihydrate crystals was found.A solvent box model with different solvent mixing ratios was established,and the ratio of the mixed solvent at the transition point was calculated.Through molecular dynamics calculation analysis,it was revealed that the controlling factor of the surface nucleation rate is the surface adsorption energy of the dihydrate crystal,that is,the larger the adsorption energy is,the easier the surface nucleation phenomenon to occur.Employing the modified AE model and combining with crystal habit control experiments under different supersaturation,the solvent correction factor was introduced.Through molecular dynamics calculation and analysis,the growth habit of cefaclor crystals as well as the trend of the aspect ratio of the crystals in water and different supersaturation were reasonably predicted.The growth promotion/inhibition mechanism of different crystal faces by solvent and solute modelcue during solution crystallization were explained at a molecular perspective.According to the solubility data of ritonavir in different solvents,the recrystallization of it's "disappearing polymorphism" was achieved in acetone,acetonitrile,ethyl acetate and toluene by quenching crystallization.And the range of supersaturation of crystal forms I and II was determined.The nucleation induction time of form I in four solvents were measured.Through the calculations,it was found that the difficulty of nucleation of form I increased with the increasing of the boiling point of the solvents.The analysis of intermolecular interactions showed that the controlling factor of the nucleation of form I in different solvents is the intermolecular ?-? stacking interactions.The conformational analysis of the molecular structures of ritonavir crystal forms ? and ? was carried out,and the lattice energy of crystal forms I and II was calculated.Based on the calculation of the strength and properties of the "supramolecular synthon",The reasons for the appearance of form I at high saturation and form II at low supersaturation were explained.The crystal morphology and surface energy of crystal forms I and II are predicted,and the solid crystals of forms I and II were obtained from the recrystallization experiment.The growth mechanism of each crystal face of different forms in solution was explained by using the nature of the synthons.Based on the analysis of "synthons" behavior,using the knowledge of hydrogen bond propensity to predict the potentially exists of ritonavir crystal form.Through evaporation and cooling crystallization experiments,the new form of ritonavir was obtained and the results are in accordance with the predicted results.Further,using X-Ray single crystal diffractometer refined this new crystal structure.