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

Tuomas Kilpeläinen; Tuomas Ervasti; Emilia Uurasjärvi; Arto Koistinen; Jarkko Ketolainen; Ossi Korhonen; Katja Pajula

doi:10.1016/j.ejpb.2022.09.011

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

Eur J Pharm Biopharm. 2022 Nov:180:161-169. doi: 10.1016/j.ejpb.2022.09.011. Epub 2022 Sep 17.

Authors

Tuomas Kilpeläinen¹, Tuomas Ervasti², Emilia Uurasjärvi³, Arto Koistinen³, Jarkko Ketolainen², Ossi Korhonen², Katja Pajula²

Affiliations

¹ School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland. Electronic address: tuomas.kilpelainen1@uef.fi.
² School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
³ SIB Labs, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.

PMID: 36122786
DOI: 10.1016/j.ejpb.2022.09.011

Abstract

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 (T_g) to monitor their phase separation. Thermodynamic properties (crystallization tendency, melting point (T_m) and T_g) 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.

Keywords: API co-amorphous; Amorphous; Drug; IR spectroscopy; Pharmaceutical; Phase separation.

MeSH terms

Calorimetry, Differential Scanning
Drug Stability
Reproducibility of Results
Solubility
Spectroscopy, Fourier Transform Infrared* / methods
Transition Temperature