Crystal Nucleation Parameters Of Propyzamide

Nucleation,beginning of the crystallization process,plays a decisive role in the crystal product qualities,including the crystal purity,morphology,size,and so on.These qualities will further affect the subsequent unit operations such as filtering and drying.Qualities of the crystal drug products will affect the solubility,dissolution rate and bioavailability.As one of the emerging amide herbicides,propyzamide has been widely used worldwide due to its high efficiency and low toxicity.However,domestic propyzamide can not enter the high-end market due to its poor crystal product qualities which is urgent to be improved.In this work,the nucleation process of propyzamide was systemically investigated,and the nucleation parameters were measured and estimated under the framework of classical nucleation theory through the induction time experiments and molecular simulations,aiming to accurately control the nucleation process and improve the product qualities.Specific contents are as follows:The induction time data of propyzamide in three solvents was measured under different conditions.The obtained induction time distribution under the same experimental condition indicates that nucleation process of propyzamide has essential feature of randomness and therefore the Poisson distribution model was introduced to process and analyze the induction time data,estimating the nucleation rate.Then the pre-exponential factor and interfacial tension was derived from the relationship between nucleation rate and supersaturation.According to the classical nucleation theory,the nucleation parameters of propyzamide such as the critical nucleation free energy,critical nucleation radius and the number of molecules within the nuclear were all calculated.The results from parallel orthogonal experiments shows that increasing the supersaturation and the temperature and decreasing the volume of solution will enhance the nucleation process.The nucleation difficulty in the three solvents was determined as follows: ethanol > toluene > acetone.The reason could be attributed to interaction between solvent and solute molecules,with the aid of infrared spectroscopic analysis,it was demonstrated that the stronger interaction made the nucleation process more difficult.Meanwhile,the width of metastable zone was estimated according to the relationship between induction time and metastable zone.The electrostatic potential map(EPM)of propyzamide was obtianed to identify the binding sites for solvent molecules.The binding energies of solute and solvent(1:1,and for solvent layer)were calculated,and the binding energy in solvents was ranked as ethanol > toluene > acetone,which also gave the explanation for the influence of solvent on nucleation that the large binding energy makes the solvent and solute interact closer and the nucleation more difficult.The interfacial tension between solute and solvent was estimated from two methods,the empirical formula calculation based on solubility data and the definition formula calculation based on crystal surface attachment energy.The specific values of interfacial tension of propyzamide in different solvents were calculated respectively,to further determine the corresponding nucleation parameters.The results showed that the nucleation parameters obtained from the estimated interfacial tension are basically the same as those obtained from the induction time experiments,which proved the accuracy of the theoretical calculation of the nucleation parameters,and it greatly reduced the workload.