ＴＳＰ質量分析法による開発医薬品の熱安定性評価の試み

Abstract

An application of thermospray ionization mass spectrometry to a rapid on-line characterization of thermal decomposition of new chemical entities was investigated, which is beneficial in the early stage of pharmaceutical development. Relative abundance of product protonated molecular ions was measured as a function of the probe temperature at a thermospray tip. Thermal decomposition curves for PNU-52047 and PNU-100766 were constructed from which decomposition pathways were elucidated. It was found that PNU-52047 decomposes via an elimination of water and/or methanol and a methyl group whereas PNU-100766 does via an opening of the oxazolidinone ring resulting from an elimination of CO2 or CO. Activation energies were elucidated from the Arrhenius plots for relative abundance of the non-decomposing drug parent ion. The activation energy for thermal decomposition of PNU-52047 was ca. 9.4 kcal mol-1 which indicates that this drug is quite unstable in solution state. Regarding to PNU-100766, a comparison of the Arrhenius plots obtained from this on-line thermospray method and those in terms of the regulatory thermal stress-study for the sterile solution for injection in the tightly sealed vials led that decomposition in both experiments occurs with the same activation energy of ca. 26 kcal mol-1 but with considerably different frequency factors.