Utilizing Polymorphism To Improve The Purity Of Pharmaceuticals

Crystallization is an important separation and purification process which is widely used in pharmaceuticals, food, and fine chemicals. Generally high purities can be obtained in this single operation. However, when the raw materials contain impurities that have quite similar structures with the products, partial or complete solid solutions may be formed leading to a poor purification. In such cases, the most effective method to improve the purity is to change the crystal structure.In this thesis, the effects of polymorphs and polymorphic transformation rate on the final product purities of lincomycin hydrochloride and glutamic acid were investigated.1) The influence of operation conditions of anti-solvent crystallization of lincomycin hydrochloride, such as temperature, stirring speed, aging time and the rate of feeding anti-solvent on the polymorphic transformation rate and product purities was studied. It was found that the purity of the final product is related not only to the polymorph, but also to the polymorphic transformation rate. PolymorphⅠof lincomycin hydrochloride can accommodate more impurity than polymorphⅡ. At the conditions of higher temperature, faster stirring speed, longer aging time and slower feeding rate of anti-solvent, the final product has a lower content of impurity.2) The influence of operation conditions on the polymorphic compositions and the purities of the final product of glutamic acid was also studied. The result shows thatα-glutamic acid contains lower content of the impurity (aspartic acid). When glutamic acid is crystallized at the conditions of longer aging time, lower supersaturation and lower temperature, the impurity can be hardly removed. The adsorption of aspartic acid on the crystal surface of different polymorphs of glutamic acid was investigated using molecular modeling.. The result shows that binding energies of aspartic acid on the surface ofβ-glutamic acid are higher than that on the surfaces of a-glutamic acid. Thus, the molecule of asparatic acid is preferable to incorporate intoβ-glutamic acid.