Detecting different amorphous – Amorphous phase separation patterns in co-amorphous mixtures with high resolution imaging FTIR spectroscopy

• Published in: European journal of pharmaceutics and biopharmaceutics 2022-11, Vol.180, p.161-169
• Main Authors: Kilpeläinen, Tuomas, Ervasti, Tuomas, Uurasjärvi, Emilia, Koistinen, Arto, Ketolainen, Jarkko, Korhonen, Ossi, Pajula, Katja
• Format: Article
• Language: English
• Subjects: Amorphous; API co-amorphous; Drug; IR spectroscopy; Pharmaceutical; Phase separation
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/j.ejpb.2022.09.011

[Display omitted] Many active pharmaceutical ingredients (API) in development suffer from low aqueous solubilities. Instead of the crystal form, the amorphous state can be used to improve the API’s apparent solubility. However, the amorphous state has a higher Gibb’s free energy and is inherently unstable and tends to transform back to the more stable crystal form. In co-amorphous mixtures, phase separation needs to occur before there can be crystallization. The aim of this study was to devise a method to study amorphous-amorphous phase separation with high resolution imaging Fourier transform infrared (FTIR) spectroscopy with seven 1:1 M ratio API-API binary mixtures being examined. The binary mixtures were amorphized by melt-quenching and stored above their glass transition temperature (Tg) to monitor their phase separation. Thermodynamic properties (crystallization tendency, melting point (Tm) and Tg) of these mixtures were measured with differential scanning calorimetry (DSC) to verify the amorphization method and to assess the optimal storage temperature. The phase separation was examined with FTIR imaging in the transmission mode. Furthermore, measurements with two pure APIs were performed to ensure that the alterations occurring in the spectra were caused by phase separation not storage stress. In addition, the reproducibility of the imaging FTIR spectrometer was verified. The spectra were analyzed with principal component analysis (PCA) and a characteristic peak comparison method. Scatter-plots were produced from the amount of phase separated pixels in the measurement area as a way of visualizing the progress of phase separation. The results indicated that imaging with FTIR spectroscopy can produce reproducible results and the progress of phase separation can be detected as either a sigmoidal or as a start-to-finish linear pattern depending on the substances.