Salt or co-crystal? determination of protonation state by X-ray photoelectron spectroscopy (XPS)

Combined 15N ssNMR and X-ray photoelectron spectroscopy (XPS) investigations for theophylline, a theophylline co-crystal, and a theophyllinium salt demonstrate that XPS allows direct observation of the degree of proton transfer, and thus identification of whether a salt or a co-crystal has been formed. The presence of a strongly binding-energy-shifted N 1s XPS peak with protonation indicates a salt (C=NH+), while this peak is unmistakably absent in the co-crystal. XPS should be considered as an alternative and complementary technique to single crystal X-ray diffraction and solid-state nuclear magnetic resonance spectroscopy (ssNMR). © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4453-4457, 2010.