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

Understanding the mechanism of interaction between pharmaceutical molecules (APIs) and impurities on crystal surfaces is a key concept in understanding purification and for the design of pharmaceutical crystallization processes. Several techniques may be used to study crystal surface properties, such as scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS), which provide detailed imaging and elemental surface characterization. Time of flight secondary ion mass spectrometry (TOF-SIMS) is valuable in determining molecular identity and distribution. By combining TOF-SIMS, SEM, and optical (OM) and Raman microscopies, we can evaluate the usefulness of TOF-SIMS as a surface characterization technique for pharmaceutical crystals. 4-Nitrophenol has been selected as an impurity that can be incorporated during crystallization of acetaminophen (paracetamol). This study explores the distribution of impurity and its concentration on the different crystal faces of samples obtained by crystallization over a range of impurity loadings and supersaturation conditions. Raman maps of paracetamol single crystal faces were analyzed using the characteristic Raman peak intensity of 4-nitrophenol to identify regions where it accumulated; Raman maps of three single crystals produced in the presence of 4-nitrophenol using different crystallization procedures highlight how it can be difficult to detect very low concentrations of similar chemical species. In contrast, the 4-nitrophenol monoisotopic mass obtained via TOF-SIMS was shown to be detectable in all the three single crystals produced. This indicates that TOF-SIMS can be a valuable technique for single crystal impurity distribution mapping even when the impurity concentration is very low

The impact of solvent systems, process conditions and structurally related impurities on the growth rate and morphologies of paracetamol crystals

Single crystal growth (S.C.G) experiments were conducted to investigate face specific growth rates of paracetamol (acetaminophen) crystals. There are a few examples in literature where S.C.G of paracetamol crystals and different process conditions are analysed [1] but no examples of the addition of structurally related impurities (Metacetamol and Acetanilide) can be found. Carefully selected conditions of supersaturation and temperature were also analysed. The resulting growth rates were then determined in two solvents, ethanol and 3-Methyl-1-butanol. The impact of the structurally related impurities on the solubility of paracetamol was determined in each of solvents investigated. The relative growth rates of pairs of faces and the associated habit change of monoclinic paracetamol was observed using in-situ optical microscopy. The respective growth rates increased with an increase of supersaturation and temperature, as the impurity concentration increased the relative growth rate of the faces decrease

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