Study On Molecular Mechanism Of Nucleation Of Organic Crystal

Crystallization from solution is an important solid-liquid separation method,widely used in chemical,pharmaceutical and material fields.The understanding and effective control of crystal nucleation and growth determine crystals' properties.As a key step,nucleation controls crystal structure,chirality,and size distribution,etc.;however,the underlying molecular mechanism is poorly understood.The solute aggregate in solution has been recognized to play a critical role in nucleation,but its characterization was difficult in the past.The development of ATR technique in various vibrational spectroscopies and advent in powerful computation techniques make it possible now to investigate solution aggregates.The main goal of the thesis is to achieve the fundamental understandings of nucleation mechanism of organic molecules at the molecular level,specifically,to investigate the self-association and assembly process,structures of aggregates,and nucleation mechanism.A widespread array of techniques,including attenuated total reflectance fourier-transform infrared spectroscopy(ATR-FTIR),Raman,and nuclear magnetic resonance(NMR)spectroscopies,in combination with density functional theory(DFT)calculations,were utilized to study solid-liquid equilibrium thermodynamics,effects of crystallization conditions(solvent,pH,and concentration etc.)on solution aggregates and polymorphic nucleation,leading to the following results:The first principle-based conductor-like screening model for real solvents(COSMO-RS)along with Jouyban-Acree and nonrandom two-liquid segment activity coefficient(NRTL-SAC)models were applied to predict two different types of solubility data in binary solvents,and their prediction capacity was evaluated.The COSMO-RS model shows the best performance.Two distinct self-association pathways of tolfenamic acid(TFA),mediated respectively by carboxylic acid and aromatic stacking,were found.The association process was suggested to be the first step in the early stage of nucleation,and govern TFA polymorphic formation.The competition and cooperativity of solute-solvent and solute-solute interactions were found determine the structural correlation between solution aggregates and the resultant crystals.The method to identify the concomitant crystallization of TFA polymorphs ? and ? was developed for the first time by using mathematical simulation and experimental verification approaches.It was found there is a minimum in the composition of crystal form I in crystalline phase.Benzoic acid(BA)molecules form dimer by the primary hydrogen-bonding interactions between carboxylic acids,and tetramer at higher concentrations by the secondary force ?…? stacking.It was unveiled that the hierarchy in non-covalent intermolecular interactions plays a critical role in governing the molecular recognition and assembly process.Glycine(Gly)molecules indeed self-associate in H2O?and the configuration of the hydrogen-bonded dimer was determined to be open.The pH-dependence of Gly self-association correlates well with its polymorphic formation.The underlying nucleation mechanisms of ? and y forms were discussed.The concomitant crystallization of DL-methionine(DL-Met)? and ? forms in water was found in a wide range of conditions.Solution chemistry studies reveal the molecules self-associate into the micelle-like aggregates.Given the above results,a novel,'non-classical' molecular pathway of nucleation mechanism was postulated.The solution aggregates' structures were found determine the molecular pathways of nucleation kinetics.4400 induction time data of mefenamic acid(MFA)were collected,from which the stochastic nature of nucleation was probed.The correlation between MFA aggregates in solution and nucleation kinetics was found,and the desolvation in cluster-based molecule pathway of nucleation was proposed.