The impact of paracetamol impurities on face-specific properties: investigating the surface of single crystals using TOF-SIMS

Understanding the mechanism of interaction between pharmaceutical molecules (API’s) and impurities on a crystal surfaces is key concept in understanding purification and designing pharmaceutical crystallization processes.
Different techniques may be used to study crystal surface properties, such as scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS) that provide detailed imaging or elemental surface characterization. However, for studying molecular mechanisms of interaction time of flight secondary ion mass spectrometry (TOF-SIMS) is valuable in determining molecular identification and distribution. A primary ion pulse is accelerated and focused on the sample surface under ultra-high vacuum to emit secondary particles from the crystal surface. The emitted particles comprise; molecules, fragments of molecules and atoms. Analyzing these secondary particles provides information about the molecular and elemental species present on the surface.
By combining TOF-SIMS, SEM and OM analysis we can determine the usefulness of TOF-SIMS as a surface characterization technique for pharmaceutical crystals. The added value of this surface characterization technique is to understand the interactions between different molecular species during purification. 4-nitrophenol has been selected as an impurity which can be incorporated during crystallization of acetaminophen (paracetamol). Our study explores the distribution of impurity concentration on the different crystal faces of samples obtained by cooling crystallization over a range of impurity loadings and supersaturation conditions.
HPLC, Raman spectroscopy and single crystal XRD are used to verify the overall impurity presence and concentration and to confirm the identity of the crystal faces investigated.