Characterizing the Carbamazepine Polymorphs, Solubility and Metastable Zone Measurement

Introduction Polymorphism is a phenomenon related to the crystallized solid state which is problematic for many industries. A successful industrial crystallization typically requires the development of a robust process in the laboratory including the knowledge of the solubility curve and the stability of the solution in the vicinity of the equilibrium point, as indicated by the metastable zone width, which are essential to the successful development, optimization, and scale-up of a crystallization process. Carbamazepine(CBZ) is used in the treatment of epilepsy and trigeminal neuralgia and has used for over 20 years. Four polymorphs and a hydrate as well as other solvates of CBZ have been reported in the literature. Form III is the form used in the market tablets and the most stable form at room temperature. However, Form II has been observed and decreased the purity of CBZ Form III during laboratorial recrystallization. Therefore, characterizing the Form II and Form III and their thermodynamic relationship are important to enhance the purity of Form III. The objective of this work is to obtain pure CBZ metastable Form II and stable Form III, and then determine their relationship according to the thermodynamic laws developed by Burger and Ramberger 1-propanol was chosen as the single solvent and the metastable Form II was crystallized by rapid cooling of high degree of supersaturated solution and then characterized by differential scanning calorimeter (DSC) and X-ray powder diffraction (XRPD). The solubility and meta-stable zone were of the two forms were measured by insitu attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) and focused beam reflectance measurement (FBRM).