Detection of free base surface enrichment of a pharmaceutical salt by X-ray photoelectron spectroscopy (XPS)

Yellow discoloration was observed at the surface of normally white crystals of a development pharmaceutical fumarate salt, tentatively ascribed to the presence of trace amounts of free base. The impact of impurities on sample properties and behavior can be significant, especially if localized at the surface. No conventional bulk analytical technique could readily provide an explanation for the yellow color, so a surface-sensitive technique, X-ray photoelectron spectroscopy (XPS), was employed to characterize the salt. XPS reveals the presence of free base at the surface through the HN+/N ratio. A free radical decarboxylation mechanism is proposed to account for the alterations observed with extended irradiation. The lower intensity carboxyl signal and significantly lower HN+/N ratio for the yellow surface samples reveal a higher level of free base at the surface than the white samples. The samples with yellow surfaces could not be successfully milled, which was an important part of the production process for providing material of the required physical quality for product formulation. Identification of residual free base at the surface of the crystalline material, by XPS, was significant for optimization of the crystallization process to yield material of required quality for successful milling at plant scale. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association.