CHARACTERIZATION OF THERMAL-BEHAVIOR OF ETOPOSIDE

Etoposide is a potent cytotoxic agent useful in the treatment of vario us malignancies. Earlier work in our laboratory with this drug as obta ined from the source (etoposide I) revealed that it undergoes thermal transitions during the course of heating to 300 degrees C. In this stu dy these thermal events were characterized by subjecting etoposide I t o differential thermal analyses, powder X-ray diffractometry, mass spe ctrometry, infrared analysis and HPLC. Etoposide I, a monohydrate, was found to undergo a dehydration reaction in the range of 85-115 degree s C to yield etoposide Ia, which upon further heating melted at 198 de grees C and crystallized to a new polymorph, etoposide IIa at 206 degr ees 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 diffra ction studies confirmed the existence of etoposide I, Ia and II, IIa a s two different crystal arrangements. Nearly identical infrared spectr a and retention times with the HPLC indicated that the two forms were not chemically different. The polymorphic transition was found to be i rreversible and a monotropic type of transition. TGA and mass spectral analyses of etoposide I and II suggested that the water was present i n their crystal lattices. Etoposide II was found to have greater aqueo us solubility than that of etoposide I at 0, 22, and 37 degrees C.