CHARACTERIZATION OF THERMAL-BEHAVIOR OF ETOPOSIDE

Etoposide is a potent cytotoxic agent useful in the treatment of various malignancies. Earlier work in our laboratory with this drug as obtained from the source (etoposide I) revealed that it undergoes thermal transitions during the course of heating to 300 degrees C. In this study these thermal events were characterized by subjecting etoposide I to differential thermal analyses, powder X-ray diffractometry, mass spectrometry, infrared analysis and HPLC. Etoposide I, a monohydrate, was found to undergo a dehydration reaction in the range of 85-115 degrees C to yield etoposide Ia, which upon further heating melted at 198 degrees C and crystallized to a new polymorph, etoposide IIa at 206 degrees C. Etoposide IIa was found to melt at 269 degrees C and converted to its hydrated form, etoposide II, when exposed to the atmosphere at room temperature. This hydrate was also found to undergo a dehydration reaction at 90-120 degrees C to yield etoposide IIa. The X-ray diffraction studies confirmed the existence of etoposide I, Ia and II, IIa as two different crystal arrangements. Nearly identical infrared spectra and retention times with the HPLC indicated that the two forms were not chemically different. The polymorphic transition was found to be irreversible and a monotropic type of transition. TGA and mass spectral analyses of etoposide I and II suggested that the water was present in their crystal lattices. Etoposide II was found to have greater aqueous solubility than that of etoposide I at 0, 22, and 37 degrees C.