EVALUATION OF INJECTABLE GENERIC DRUGS USING THERMOGRAVIMETRY AND THE INFLUENCE OF d-MANNOTOL ON THE STABLITLY OF GABEXATE MESILATE

Gabexate mesilate has been mainly used in the treatment of disseminated intravascular coagration (DIC) in Japan since 1983. Recently, several generic versions of injectable gabexate mesilate with or without d-mannitol as an additive have been put on the Japanese market. In our study, thermo gravimetry (TG) did not show any differences between gabexate mesilate products with or without d-mannitol as an additive. However, differential thermal analysis (DTA) showed a significant change in absorption derived from endothermic reactions. Differential thermal analysis for M1, M2 and M3, with 100 mg of d-mannitol produced two endothermic peaks during the first rise in temperature from 30◦C to 170◦C, followed by an exothermic peak derived from the 170◦C to 30◦C cooling period. During the second rise in temperature from 30◦C to 170◦C another endothermic peak was produced. On the other hand, N1, N2, N3, and FOY without d-mannitol derived from gabexate mesilate produced only one endothermic peak, and were followed by no exothermic peaks during the cooling period. Interestingly, a glass transition was found at the second rise in temperature. In addition, we confirmed that gabexate mesilate undergoes hydrolysis in the presence of water due to the ester bonds in its chemical structure. The addition of d-mannitol seems to cause moisture absorption in the lyophilized processing of gabexate mesilate products, resulting in a higher content of hydrolyzed ethyl 4-Hydrobenzoate for M1, M2, and M3 by HPLC analysis. We propose that the addition of d-mannitol should be avoided in the production of gabexate mesilate formulation.