Primary Nucleation Kinetics Of Small Organic Molecule Crystals

The study on crystal nucleation kinetics provides a way to find out the key influencing factors,unravel the molecular assembly process,determine nucleation mechanism and could help to control the nucleation process.However,the work published usually focused on the determination of induction time and interface energy data of single component crystals,rather than the inherent properties of crystal nucleation.Meanwhile,most of the publications worked on one solute / one solvent system and the nucleation kinetics and mechanism of multicomponent cystals have not been paid much attention to.To solve these questions,with aromatic carboxylic acids and chiral molecules as the model systems,the primary nucleation kinetics of small organic molecules were investigated systematically in this work.Thermodynamic data is the basis of crystal nucleation and crystallization process study.In this work,the solubility data of benzoic acid in toluene,acetonitrile,ethyl acetate,isopropanol + water mixture and para-nitrobenzoic acid(Form I and Form II)in ethanol were measured experimentally using static method and correlated using modified Apelblat equation,?h equation,van't Hoff equation as well as NRTL model.The phase equilibrium data between RS-ibuprofen and liquid phase for R-ibuprofen / S-ibuprofen / Heptane ternary system at 293.15 K and 313.15 K were also determined using static method and its dissolution model was established using ternary NRTL model.Based on the thermodynamic data,solute / solvent systems with appropriate solubility were chosen to conduct induction time measurements by using deterministic method with an online turbidimeter.According to the Classical Nucleation Theory,the relationships between induction time and superstauration for benzoic acid(in toluene,acetonitrile,isopropanol + water)and para-nitrobenzoic acid form II(in ethanol and isopropanol)were analyzed and their corresponding nucleation kinetic models were built to help determine the key factors influencing nucleation rates.To exclude the external influence factors of deterministic method,a stochastic statistical modelling method was developed to estimate the inherent uncertainty of nucleation rates obtained from stochastic induction time data in small volumes of solution.Both the key influence factors for nucleation rate reliability as well as reasonable experimental and data processing protocals were determined from the modelling experiments.The results could help to direct the design of nucleation experiments and analyze the nucleation rate uncertainty obtained from real experiments.Furthermore,nucleation rates of benzoic acid in toluene were determined using the stochastic induction time method and its nucleation rate model was established by taking their uncertainty into consideration.Applying the same procedure to nucleation rates of benzoic acid,para-toluic acid,para-aminobenzoic acid and para-nitrobenzoic acid in different solvens measured by other group members,and with molecular energy calculation,a systematic analysis of nucleation kinetics was conducted from solution chemistry and molecular assembly perspectives.And the key interaction driving nucleation process was found.Finally,nucleation rates and its kinetic and thermodynamic parameters of RS-ibuprofen in n-heptane with different S-enantiomer excess at different supersaturations were determined using the stochastic induction time method.The effect of enantiomer excess on nucleation kinetics was investigated and a modified nucleation kinetic equation was proposed for racemic compound.