Primary Nucleation And Secondary Nucleation Metastable Zone Widths Of Roy And Their Applications

Polycrystalline control and identification has become an important content in drug consistency evaluation,while nucleation is the key in the process of crystal type regulation,which will directly affect the crystallization results.Metastable zone width(MSZW)of nucleation is an operational region that regulates nucleation behavior and crystallization process.By determining the nucleation MSZWs under a certain condition,the industrial crystallization can inhibit the primary nucleation by adding seeds in the suitable region,and improve the controllability of the crystallization process by using secondary nucleation.However,the nucleation mechanism is complex and depends on such factors as saturation temperature,cooling rate,solvent and seed number,etc.,and the primary and secondary nucleation modes and their kinetic effects need to be further studied.In this paper,the polycrystalline ROY was used as a model substance.The solubility of ROY in different solvents and the metastable regions of primary nucleation and secondary nucleation were measured and the two nucleation mechanisms were analyzed.In addition,the secondary nucleation and crystal transformation under different operating conditions were investigated by changing the conditions of adding crystal seeds in the metastable zone.The results can provide guidance for the crystal type regulation during crystallization process.Firstly,the solubility of ROY in six organic solvents with different proton-giving abilities was measured.The solubility data were correlated by Alpelbat model,polynomial empirical method and van’t Hoff model.All three models can describe the solubility law of ROY well.Based on van’t Hoff equation,the corresponding thermodynamic parameters such as dissolution enthalpy,dissolution entropy and dissolution Gibbs free energy are calculated to be positive,and ζH and ζS contributions are introduced to evaluate the relative contribution of enthalpy and entropy to the dissolution Gibbs free energy.The results show that the dissolution of ROY is a spontaneous entropy-driven endothermic process,and the enthalpy change contributes greatly to the dissolution of Gibbs free energy.Secondly,ethanol,acetonitrile and ethyl acetate were selected as solvents based on the solubility data,and the focused beam reflection measurement technology(FBRM)was used to measure the MSZW of ROY’s cooling crystals with or without seed crystals.Combined with the modified Sangwal model,The dynamic parameters of nucleation,such as solid-liquid interfacial tension,critical nucleus size and critical Gibbs free energy,were calculated,and the dynamics of primary and secondary nucleation processes were investigated.It is shown that ROY’s nuclear dynamics in different solvent systems mainly depends on supersaturation and the interaction between solute and solvent molecules.Compared with primary nucleation,nucleation sites are provided on the surface of seed crystals,which significantly reduces the nucleation barrier and promotes nucleation.In the primary nucleation process,the nucleation rate depends on the competition of crystallization driving force and nucleation temperature,while in the secondary nucleation process,the amount of seed addition and nucleation driving force are the main factors affecting the nucleation dynamics.Then,the effect of seed crystal type on polycrystalline regulation in the MSZW of secondary nucleation was investigated.In this paper,the preparation process of OP form product was designed,and the crystallization kinetics and law of OP in ethanol and ethyl acetate were determined by Differential scanning calorimeter(DSC).The results show that the conversion rate of OP form in ethyl acetate is very fast,followed by ethanol.It is concluded that the dissolution of OP form is the controlling step of crystallization transformation,and solubility and solvation are the main reasons affecting crystallization transformation.The dynamic parameters of solvent mediated crystallization,were obtained by fitting the Avrami-Erofeev model,and the conversion amount of crystal type at different time was calculated.Finally,by changing cooling rate,saturation temperature,seed crystal type and quality,ROY cooling crystallization process in ethanol was designed and developed to achieve polycrystalline control.The Y form was used as the seed to obtain the OP form.The appearance of the OP form indicated that the source of secondary nucleation came from the solute layer on the crystal surface rather than the microwear of the parent crystal.The variation of solution concentration and driving force affects the way of secondary nucleation and leads to different polymorphisms,thus revealing the source and mechanism of secondary nucleation.