title: Screening for differences in the amorphous state of indomethacin using multivariate visualization.
abstract: The aim of this study was to examine molecular-level differences in the amorphous state of indomethacin prepared from both alpha- and gamma-polymorphs using various preparative techniques: milling, quench cooling of a melt, slow cooling of a melt and spray drying. X-ray powder diffraction (XRPD), polarizing light microscopy (PLM), differential scanning calorimetry, as well as mid-infrared (MIR), near infrared (NIR) and Raman spectroscopy were used to analyze the samples after preparation. Principal component analysis (PCA) was used to visualize the differences in the spectroscopic data. According to the XRPD and PLM measurements, all samples except the spray dried indomethacin were amorphous after preparation. Spray dried indomethacin had some remaining residual crystallinity. Differences in the amorphous samples could be found on molecular level: the milled samples clustered separately from the other amorphous samples in the PCA of MIR, NIR and Raman spectra. This could be due to either small degrees of undetected crystallinity remaining in the samples after milling or differences in the hydrogen bonding in the different amorphous samples of indomethacin. The spectroscopic techniques revealed different information about the samples. Raman spectroscopy was most sensitive to differences caused by the preparation techniques and degradation products. Multivariate methods, such as PCA, offer an efficient tool to screen for these differences in the amorphous state.
authors.affiliation: Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland. marja.savolainen@helsinki.fi <marja.savolainen@helsinki.fi>
authors.forename: Marja
authors.initials: M
authors.lastname: Savolainen
authors.forename: Andrea
authors.initials: A
authors.lastname: Heinz
authors.forename: Clare
authors.initials: C
authors.lastname: Strachan
authors.forename: Keith C
authors.initials: KC
authors.lastname: Gordon
authors.forename: Jouko
authors.initials: J
authors.lastname: Yliruusi
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
authors.forename: Niklas
authors.initials: N
authors.lastname: Sandler
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization / Q000379:methods; D004055:Differential Thermal Analysis; D004355:Drug Stability; D007213:Indomethacin / Q000737:chemistry*; D015394:Molecular Structure; D025341:Principal Component Analysis; D017550:Spectroscopy, Fourier Transform Infrared; D019265:Spectroscopy, Near-Infrared; D013059:Spectrum Analysis, Raman
chemical_list: D007213:Indomethacin