X-Ray Powder Diffraction Study on the Grinding Effect of the Polymorphs of a Novel and Orally Effective Uricosuric Agent: FR76505

Abstract

The polymorphism of a novel and orally effective uricosuric agent, [3-(4-bromo-2-fluorobenzyl)-7-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-1-yl] acetic acid, designated as FR76505, was characterized by X-ray powder diffractometry and thermal analysis. In the crystalline state, FR76505 exists in at least three polymorphic forms, Forms A, B and C. Among them, Form B is a stable form, and Forms A and C which are transformed to Form B are metastable forms. Form C was not stable enough to keep its state even at room temperature. Therefore, it was not suitable to be used for the pharmaceutical preparation, and further investigation for Form C was not carried out. The mechanochemical effect of grinding makes the crystallite size smaller and the lattice strain larger for both the Forms A and B crystals. After grinding for 60 minutes, both forms changed into noncrystalline powders. Thermal behavior of the ground sample was investigated by the X-ray powder diffractometry under the heating condition, as well as the thermal analysis. It is concluded that the mechanochemical effect of grinding made Form A change into Form B easily, and the increase of a grinding time led the transformation temperature lower.