Application of direct crystallization for racemic compound propranolol hydrochloride

作者：Wang Xiujuan^*; Lu Jie; Ching Chi Bun

来源：Journal of Pharmaceutical Sciences, 2007, 96(10): 2735-2745.

DOI：10.1002/jps.20911

• direct crystallization
• racemic compound
• solubility
• metastable zone width
• HPLC
• optical purity
• DSC
• FBRM

The application of direct crystallization integrating with chromatography to the resolution of a racemic compound propranolol hydrochloride was studied and the crystallization progression was clearly illustrated in terms of the diagram of solubility and metastable zone widths with different enantiomeric compositions. The solubility and metastable zone widths of propranolol hydrochloride in the mixture of methanol and isopropanol were determined using an in situ Lasentec Focused Beam Reflectance Measurement (FBRM) probe. The direct crystallizations were carried out in an automatic lab reactor (Mettler Toledo LabMax) system. The optical purity of final product crystals was examined using differential scanning calorimetry (DSC), HPLC and PXRD. The crystal size distribution and morphology were analyzed using Malvern Mastersizer and Jeol SEM. It was found that optically pure crystal product could be obtained within certain safe supersaturation limit and there was no evidence of polymorph or solvate/ hydrate transformation during the crystallization process. There was no selectivity of crystal growth or nucleation between the pure enantiomer and its racemate when the solution reaches the temperature lower than saturation temperature of the racemate. Hence, the critical supersaturation control of a solution was essential to obtain pure enantiomers from a partially resolved racemate.

• 出版日期2007-10
• 单位南阳理工学院