The crystallisation of ibuprofen under diffusion-limited conditions measured as a function of supersaturation, solvent (95% ethanol/water, ethyl acetate, acetonitrile and toluene) and reactor scale is examined. Measurement of solubility as a function of temperature reveals less than ideal behaviour, consistent with strong solute–solute interactions, particularly in the case of acetonitrile. The crystal growth rates of the {001} and {011} faces of spontaneously nucleated crystals are precisely measured in situ using optical microscopy revealing that their respective growth rates increase with increasing supersaturation to different extents, depending on the solvent type, with concomitant impact on the crystal habit. The measured growth rates, as a function of supersaturation, are generally higher at the 15 mL than the 0.5 mL scale size. Analysis of the growth rates versus supersaturation is consistent with a 2-D surface nucleation (Birth and Spread) model for both faces and at both scale sizes. The growth rates of the {001} and {011} faces exhibit much less growth rate dispersion when compared to literature data for a stirred batch crystallizer. The data are rationalised by examining the surface chemistry of the growing faces revealing, e.g. that polar protic solvents inhibit the growth rate of faces containing available binding sites for hydrogen bond formation, such as carboxylic acid groups.

Carrier-based dry powder inhaler (DPI) formulations need to be accurately characterised for their particle size distributions, surface roughnesses, fines contents and flow properties. Understanding the micro-structure of the powder formulation is crucial, yet current characterisation methods give incomplete information. Commonly used techniques like laser diffraction (LD) and optical microscopy (OM) are limited due to the assumption of sphericity and can give variable results depending on particle orientation and dispersion. The aim of this work was to develop new powder analytical techniques using X-ray computed tomography (XCT) that could be employed for non-destructive metrology of inhaled formulations. α-lactose monohydrate powders with different characteristics have been analysed, and their size and shape (sphericity/aspect ratio) distributions compared with results from LD and OM. The three techniques were shown to produce comparable size distributions, while the different shape distributions from XCT and OM highlight the difference between 2D and 3D imaging. The effect of micro-structure on flowability was also analysed through 3D measurements of void volume and tap density. This study has demonstrated for the first time that XCT provides an invaluable, non-destructive and analytical approach to obtain number- and volume-based particle size distributions of DPI formulations in 3D space, and for unique 3D characterisation of powder micro-structure.

Sono-crystallisation has been used to enhance crystalline product quality particularly in terms of purity, particle size and size distribution. In this work, the effect of impurities and ultrasound on crystallisation processes (nucleation temperature, yield) and crystal properties (crystal size distribution determined by Focused Beam Reflectance Measurement (FBRM), crystal habit, filtration rate and impurity content in the crystal product by Liquid Chromatography-Mass Spectroscopy (LC-MS)) were investigated in bulk suspension crystallisation experiments with and without the use of ultrasound. The results demonstrate that ultrasonic intervention has a significant effect on both crystallisation and product crystal properties. It increases the nucleation rate resulting in smaller particles and a narrower Particle Size Distribution (PSD), the yield has been shown to be increase as has the product purity. The effect of ultrasound is to reduce the level acetanilide impurity incorporated during growth from a 2 mol% solution of the selected impurity from 0.85 mol% to 0.35 mol% and likewise ultrasound reduces the uptake of metacetamol from 1.88 mol% to 1.52 mol%.

Understanding the mechanism of interaction between pharmaceutical molecules (API’s) and impurities on crystal surfaces is key concept in understanding purification and designing 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 microscopy (OM) and Raman microscopy we can evaluate the usefulness of TOF-SIMS as a surface characterization technique for pharmaceutical crystals. One benefit of this technique is to build understanding of 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). This study explores the distribution of impurity concentration on the different crystal faces of samples obtained by crystallization over a range of impurity loadings and supersaturation conditions. HPLC, Raman microscopy and single crystal XRD are used to verify the presence and concentration of the impurity and to confirm the identity of the crystal faces investigated. TOF-SIMS is a valuable technique for single crystal impurity distribution mapping even when the impurity concentration is very low.