Crystallization of Cephradine Polymorphs and Hydrates from Mixed Solvents of Methanol and Water

Cephradine monohydrate (CPH) crystallizes with a needle‐like shape which leads to severe agglomeration and slow filtration. Effects of different operating conditions on the particle size and shape as well as the filterability of the crystal products are described. The solubility and stability of one anhydrate of cephradine (CPA1) and CPH as a function of temperature and water activity was investigated in different methanol and water mixtures. A solvent‐mediated transformation from CPH to CPA1 was observed at water mole fractions below 0.2–0.35 depending on the temperature. The crystallization behavior of CPH was studied by linear cooling and antisolvent crystallization. Lowering the cooling rate and addition of seeds led to an increase in particle size and improvement of filterability. The solubility and relative stability of cephradine anhydrate and monohydrate in various water‐methanol mixtures were evaluated at different temperatures. Cephradine monohydrate was crystallized by cooling crystallization from aqueous solutions. It was found that using a slow cooling rate and seeding can improve the particulate properties as well as the filterability of the obtained products.