The effect of disorder on the chemical reactivity of an organic solid, tetraglycine methyl ester: change of the reaction mechanism

Many drugs undergo chemical changes in the solid state, and understanding chemical reactivity of organic crystals is a critical factor in the drug development process. In this report, the impact of milling on the thermal chemical reactivity of an organic solid, tetraglycine methyl ester, was studied using DSC, isothermal calorimetry, chemical analysis (HPLC and insoluble residue determination), and powder X-ray diffraction. Significant changes in both X-ray diffraction patterns and DSC curves were detected after very brief milling (5 s). The changes were interpreted as the formation of a disordered phase. The disordered phase was tentatively identified as a crystal mesophase that combines properties of both crystalline (i.e., long-range order) and amorphous (i.e., glass transition) states. In the disordered material, the reaction mechanism changed from the methyl transfer reaction, which was observed in the intact crystal, to a polycondensation reaction when the reaction was performed at 165 degrees C. Such changes in the reaction mechanism occurred in materials milled for > 30 s.