Study On Crystallization Process Of PCERG-1201

PCERG-1201is one of the effective anti-epileptic drugs approved by the World Health Organization, and it shows polymorphisms. Four crystalline forms of PCERG-1201, known as Ⅰ, Ⅱ, Ⅲ and Ⅳ, have been identified, of which form IE is the most stable at room temperature. There are some serious problems in the production process of PCERG-1201, such as relatively large crystal size and tendency of aggregation. In this thesis, an optimized process for the recrystallization of PCERG-1201was presented based on a systematic study of the crystallization processes.First, the crystal habit and polymorphism of PCERG-1201was studied. Recrystallization method and anti-solvent method were used for high-throughput polymorphism screening, where differential scanning calorimetry thermal, thermal gravimetric analysis analyzer, scanning electron microscopy, and optical microscope were used to study the crystal habit and crystal form. The obtained results showed that there was no definitive relationship between the crystal habit and the crystal form of PCERG-1201. The crystal habit of PCERG-1201was further studied in the scaleup experiments. It was found that products obtained using a cooling crystallization method with80%ethanol as the solvent showed a better crystal habit which was characteristic of plate shape and no aggregation. Thermal analysis method was used to study the process of crystal transformation, and irreversible solid-state melting transition from form I to form Ⅲ was observed.Dynamic method was used to study the thermodynamics of the crystallization of PCERG-1201by measuring its solubility in various single solvent and water-ethanol binary system with various proportions. The solubility data was then analyzed, and a good correlation was obtained. At the same time, the metastable zone of the crystallization process was determined. Specifically, the effect of the cooling rate and stirring rate on the metastable zone was evaluated; the results showed that the metastable zone with the cooling rate increases gradually widened, with the stirring rate increases narrowed. The nucleation induction period during the cooling crystallization process was determined, and the solid-liquid surface tension was calculated.Batch dynamic method was used to study the cooling crystallization dynamics profile of PCERG-1201. MJ2model, the commonly used model, was used to analyze the experimental data to obtain the nucleation rate equation and the growth rate equation. It turned out that the cooling crystallization kinetics, stirring speed and supersaturation ratio were the main factors which may affect the crystal growth process. The process of crystal growth was under the control of surface reaction.Aim to obtain the qualified product of PCERG-1201, two crystallization methods including anti-solvent crystallization and cooling crystallization were studied. The results showed that the optimized crystallization process was using80%ethanol as the solvent by the cooling crystallization method. The factors, such as crystallization concentration, plus without seed, stirring rate, cooling rate, crystallization end temperature, aging time, which could affect the particle size and yield of PCERG-1201were also studied. The optimized crystallization conditions were determined, and the products were characteristic of plate shape with uniform size to fulfill the demand of the client.