Quantitative evaluation of crystallinity of active pharmaceutical ingredients in amorphous solid dispersion using T₂...

The aim of this study is to propose a novel method for quantifying the crystallinity of active pharmaceutical ingredients (APIs) in solid dispersion (SD)-based pharmaceuticals. The key technology employed for this quantitative method is time-domain NMR (TD-NMR) T₂ relaxometry. Model SDs were prepared using indomethacin (IMC) and polyvinylpyrrolidone (PVP). The T₁ relaxation behaviors were substantially different between the SD and a physical mixture (PM) of amorphous IMC and PVP, while their T₂ relaxation behaviors remained comparable. Subsequently, this study analyzed the changes in the T₂ relaxation characteristics of PMs as a function of crystalline-to-amorphous IMC ratios. A sharp linear relationship between the T₂ relaxation rate and the crystalline-to-amorphous IMC ratio was confirmed. In the latter part of the study, the crystallinity of IMC in SDs was quantified. After storage at 40 °C and 60 °C for 2 weeks, the crystallinity of IMC in the SD samples was evaluated by performing TD-NMR measurements and using a conventional method (powder X-ray diffraction, PXRD). The crystallinity values obtained from the T₂ relaxation-based measurements closely aligned with the PXRD results, confirming the accuracy of the proposed method. In conclusion, TD-NMR T₂ relaxometry emerges as a valuable alternative for assessing API crystallinity in SDs.