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

药物晶体（用于片剂和吸入器）表面的少量杂质会显著影响晶体的性能。在药物结晶过程中，合成步骤的副产物很可能被“推”到表面。这种表面杂质的水平太低，不足以引起患者毒性的关注。但是，如此低的杂质水平在表面浓缩时，可能会导致片剂不符合药物释放速率规格。当增加新的生产地点以获得高销售额的药物时，表面杂质分布发生变化时，这尤其是个问题。为了更有效地为患者提供优质药物，我们需要了解药物晶体的表面纯度。此外，喷雾干燥吸入粉末具有复杂的无定形表面，难以表征。表征表面混合物中分子之间的最近邻相互作用将有助于设计稳定的无定形表面。通过与国家物理实验室合作，我们将获得一种新型仪器，OrbiSIMS，它可以在精确的质量分辨率和MSn能力下进行表面质谱分析。飞行时间二次离子质谱（TOF-SIMS）的表面质谱可以检测杂质峰。但由于缺乏精确的质量分辨率或MS-MS，TOF-SIMS无法识别表面杂质。TOF-SIMS的前端（即用于去除和电离表面分子的初级离子束）与精确的质量分辨率和Orbitrap的MSn相结合，可以识别表面杂质。此外，OrbiSIMS应该能够区分不同的物理状态，如非晶和结晶，由于光谱的丰富性（更多的峰，因为更少的重叠），比TOF-SIMS更容易区分。也许甚至可以根据无定形分子与其最近邻分子的相互作用来表征不同的无定形状态。这可以帮助稳定的无定形表面的发展。

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.