Editorial Feature

Analyzing Crystallite Contamination in Drug Formulation Using ToF Secondary Ion Mass Spectrometry

Contemporary techniques for surface chemical characterization have a crucial role to play in the analysis and development of pharmaceutical products. X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) are two of the most significant surface analysis methods, and possess the following features:

X-Ray Photoelectron Spectroscopy (XPS)

  • Quantitative analysis
  • Elemental and chemical state information

Time-of-Flight Secondary Ion Mass Spectroscopy (ToF-SIMS)

  • Comprehensive and very specific chemical information (elements, polymer structures, chemical groups, molecules)
  • Imaging with a high spatial resolution (<200 nm)
  • Extremely sensitive (trace detection limits)

Case Study: Crystalline Contamination in a Drug Formulation

ToF-SIMS was used to recognize a foreign crystalline material, which was detected in a drug solution after storage. There existed just a microscopic amount of crystallite, inadequate for bulk analytical methods.

The material was collected using a fine filter and a small clump of crystallites on the filter surface was examined. The measurements required the state-of-the-art technology whereby RAW data were obtained from an area having a few of the crystallites of interest. Retrospectively, mass spectra were formed for blank filter and crystallite areas offering, by comparison, the mass spectral fingerprint for the crystallite.


The information was improved by retrospective chemical mapping, which evidently revealed the crystallites (red—using a peak from the mass spectral fingerprint) on top of the filter (green—using a signal that is filter-specific). This analysis showed that a polymer additive had leached out of a bottle stopper and into the drug solution, and then crystallized.


RAW data: A designated area on a sample is scanned and a mass spectrum is obtained and stored at each pixel point. In retrospect, the following operations can be carried out:

  • Region-of-Interest (ROI) analysis: For demarcated regions (any size and shape) within the chosen area of analysis, it is possible to add the mass spectra at all of the pixel points within each specified region, thereby producing area-specific mass spectra.
  • Imaging analysis: For the chosen area of analysis, it is possible to produce chemical maps (images) for any of the spectral peaks. In the case of very weak signals, where the individual peak intensity is not enough to create meaningful images, it is also possible to incorporate peak intensities, thereby enhancing image statistics.

Pharmaceutical White Paper—Surface Analysis Exposes Counterfeit Drugs

Since counterfeit drugs are becoming available more and more (the U.S.-based Centre for Medicines in the Public Interest has estimated that in 2010, counterfeit drug sales is worth US$75 billion worldwide), the technology that is used to make these fake medicines is becoming more advanced.

CERAM Surface and Materials Analysis, along with GlaxoSmithKline, has formulated a technique for detecting fake tablets, when compared to real drugs, by making use of approaches such as ToF-SIMS and XPS.

Besides standard approaches of examining the composition, this technique focuses on process and the manufacturing route of the drugs, the end result being that formerly undetectable chemical copies of pharmaceuticals can be detected.

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