Study On The Polymorphism Of Carbamazepine

As a very common phenomenon in pharmaceuticals, polymorphism is defined as the ability of a compound to crystallize in more than one crystal forms with different unit cell parameters. It can have a major impact on the physical and chemical properties, bioavailability and formulation of drugs, which will further affect their treatment. The study of polymorphism plays an important role in the development of new drugs, the optimization of crystallization processes and the patent protection of drugs. It has become a key research area for pharmaceutical researchers in recent years. In this research, carbamazepine(CBZ), a mood stabilizing drug, was chosen to study the crystallization process and polymorphism in depth. The details are as follows.The solubility of CBZ in methanol, ethanol and ethyl acetate was measured by gravimetric method, and the solubility data was correlated with the Apelblat equation. The metastable zone width(MSZW) of CBZ in ethanol was measured by turbidimetric method, and the calibrated model for prediction of MSZW was developed. It is found that the solubility of CBZ in these three solvents increased as the temperature went up. The MSZW of CBZ in ethanol tended to broaden with the increase of the cooling rate and with the decrease of the stirring rate and saturation temperature. The experimental data of solubility and MSZW showed good agreement with the calculated values, respectively.The model for prediction of solute(CBZ) concentration in ethanol was developed using attenuated total reflection fourier transform infrared spectroscopy(ATR-FTIR), with which the CBZ concentration was measured online in the process of cooling crystallization in the CBZ- ethanol system. The result shows that the model was highly accurate and could give a reliable on-line concentration measurement.Cooling crystallization of CBZ was investigated experimentally to study the effect of operating conditions on polymorphism. Powder X-ray diffraction(PXRD), optical microscope and scanning electron microscope(SEM) were performed to identify the crystal form. Two crystal polymorphic forms: the needle-like form Ⅱ and the prism-like form Ⅲ were observed. The result reveals that the effect of solvent on the polymorphism of CBZ was related to the hydrogen bonding interaction. In ethanol the low initial concentration and fast cooling rate were more likely to produce metastable form Ⅱ. The stirring rate could accelerate the transformation of CBZ from form Ⅱ to form Ⅲ. Seeding had little influence on the polymorphism of CBZ.The theoretical crystal habits of CBZ form Ⅱ and Ⅲ were predicted based on BFDH model and AE model with Materials Studio. It is found that the theoretical crystal habit of CBZ form Ⅱ predicted based on AE model was more like the actual one, while the prediction results of CBZ form Ⅲ based on both models showed a great difference compared to the actual one.