Real-time in situ X-ray micro-computed tomography study of the effect of impurities on the crystallization of amorphous nifedipine

Yuta Amano, Takashi Misawa, Tamaki Miyazaki, Daisuke Ando, Tatsuo Koide, Ken ichi Izutsu, Hideko Kanazawa, Kenjiro Hanaoka, Eiichi Yamamoto

Research output: Contribution to journalArticlepeer-review


Controlling the physical stability of noncrystalline active pharmaceutical ingredients remains a major challenge in the development of amorphous formulations such as amorphous solid-dispersion (ASD) formulations. To establish new evaluation and formulation strategies, the spatial distribution of the crystal phase in bulk amorphous nifedipine (NFD) was investigated as a model. The crystallization of amorphous NFD and the effect of a deliberately added impurity were investigated using powder X-ray diffraction (PXRD), differential scanning calorimetry and real-time in situ X-ray micro-computed tomography (X-ray CT). The stability data of amorphous samples, i.e., NFD and a mixture of NFD with an oxidative degradation product of NFD, impurity A (Imp A), at a weight ratio of 90:10, presented as percent amorphous remaining, suggests that Imp A accelerates the bulk crystal growth of NFD. Real-time in situ X-ray CT results showed surface-enhanced crystal growth and cavity formation in solid NFD samples. Moreover, the crystals were heterogeneous in density. These results suggest that Imp A affects the physical stability of the amorphous NFD. X-ray CT equipped with a heating unit can aid in-situ evaluation and assessment of physicochemical properties and physical stability of amorphous samples and formulations.

Original languageEnglish
Article number115248
JournalJournal of Pharmaceutical and Biomedical Analysis
Publication statusPublished - 2023 Mar 20


  • Crystal growth
  • Crystallization
  • Degradation product
  • Forced condition
  • Image analysis
  • Stability

ASJC Scopus subject areas

  • Analytical Chemistry
  • Pharmaceutical Science
  • Drug Discovery
  • Spectroscopy
  • Clinical Biochemistry


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