Use of OrbiSIMS to identify impurities on drug crystal surfaces and characterise surface chemical structures on spray-dried pharmaceutical formulations

Small amounts of impurities on the surfaces of pharmaceutical crystals (used in tablets and inhalers) can significantly affect the performance of the crystals. During drug crystallisation, byproducts of synthesis steps are likely to be "pushed" to the surface. The levels of such surface impurities are far too low to be of concern regarding patient toxicity. But such low impurity levels when concentrated on the surface can lead to tablets which don't meet drug release rate specifications.This is especially problematic when the surface impurity profile changes when new production sites are added for medicines achieving high sales. To more efficiently deliver quality medicines to our patients, we need to understand the surface purity of drug crystals.Additionally, spray-dried inhalation powders have complex, amorphous surfaces which are difficult to characterize. Characterising nearest-neighbour interactions between molecules in the surface mixture will facilitate the design of stably-amorphous surfaces.By teaming up with the National Physical Laboratory, we will gain access to a new type of instrument, an OrbiSIMS, which permits surface mass spectrometry at accurate mass resolutions and with MSn capabilities. Surface mass spectrometry by time-of-flight secondary ion mass spectrometry (TOF-SIMS) can detect impurity peaks. But lacking accurate mass resolution or MS-MS, TOF-SIMS cannot identify the surface impurities. The combination of the front end of a TOF-SIMS (i.e. a primary ion beam for removing and ionizing surface molecules) with the accurate mass resolution and MSn of an Orbitrap permits identification of the surface impurities. Furthermore, an OrbiSIMS should be able to differentiate between different physical states, such as amorphous and crystalline, with greater facility than TOF-SIMS can due to the richness of the spectra (more peaks since less overlap). Perhaps even different amorphous states could be characterised based upon interactions of amorphous molecules with their nearest neighbours. This could aid in the development of stabilized amorphous surfaces.