Crystal Engineering of Stable Temozolomide Cocrystals

摘要

The antitumor prodrug temozolomide (TMZ) decomposes in aqueous medium of pH ≥ 7 but is relatively stable under acidic conditions. Pure TMZ is obtained as a white powder but turns pink and then brown, which is indicative of chemical degradation. Pharmaceutical cocrystals of TMZ were engineered with safe coformers such as oxalic acid, succinic acid, salicylic acid, D,L-malic acid, and D,L-tartaric acid, to stabilize the drug as a cocrystal. All cocrystals were characterized by powder X-ray diffraction (PXRD), single crystal X-ray diffraction, and FT-IR as well as FT-Raman spectroscopy. Temozolomide cocrystals with organic acids (pK_a 2-6) were found to be more stable than the reference drug under physiological conditions. The half-life (T_(1/2)) of TMZ-oxalic and TMZ-salicylic acid measured by UV/Vis spectroscopy in pH 7 buffer is two times longer than that of TMZ (3.5 h and 3.6 h vs. 1.7 h); TMZ-succinic acid, TMZ-tartaric acid, and TMZ-malic acid also exhibited a longer half-life (2.3, 2.5, and 2.8 h, respectively). Stability studies at 40℃ and 75% relative humidity (ICH conditions) showed that hydrolytic degradation of temozolomide in the solid state started after one week, as determined by PXRD, whereas its cocrystals with succinic acid and oxalic acid were intact at 28 weeks, thus confirming the greater stability of cocrystals compared to the reference drug. The intrinsic dissolution rate (IDR) profile of TMZ-oxalic acid and TMZ-succinic acid cocrystals in buffer of pH 7 is comparable to that of temozolomide. Among the temozolomide cocrystals examined, those with succinic acid and oxalic acid exhibited both an improved stability and a comparable dissolution rate to the reference drug.