Organic compounds can crystallize in different forms known as polymorphs. Discovery and control of polymorphism is crucial to the pharmaceutical industry since different polymorphs can have significantly different physical properties which impacts their utilization in drug delivery. Certain polymorphs have been reported to ‘disappear’ from the physical world, irreversibly converting to new ones. These unwanted polymorph conversions, initially prevented by slow nucleation kinetics, are eventually observed driven by significant gains in thermodynamic stabilities. The most infamous of these cases is that of the HIV drug ritonavir (RVR): Once its reluctant form was unwillingly nucleated for the first time, its desired form could no longer be produced with the same manufacturing process. Here we show that RVR’s extraordinary disappearing polymorph as well as its reluctant form can be consistently produced by ball-milling under different environmental conditions. We demonstrate that the significant difference in stability between its polymorphs can be changed and reversed in the mill—a process we show is driven by crystal size as well as crystal shape and conformational effects. We also show that those effects can be controlled through careful design of milling conditions since they dictate the kinetics of crystal breakage, dissolution, and growth processes that eventually lead to steady-state crystal sizes and shapes in the mill. This work highlights the huge potential of mechanochemistry in polymorph discovery of forms initially difficult to nucleate, recovery of disappearing polymorphs, and polymorph control of complex flexible drug compounds such as RVR.

The phenomenon of molecular crystal polymorphism is of central importance for all those industries that rely on crystallisation for the manufacturing of their products. Computational methods for the evaluation of thermodynamic properties of polymorphs have become incredibly accurate and a priori prediction of crystal structures is becoming routine. The computational study and prediction of the kinetics of crystallisation impacting polymorphism, however, have received considerably less attention despite their crucial role in directing crystallisation outcomes. This is mainly due to the lack of available experimental data, as nucleation and growth kinetics of polymorphs are generally difficult to measure. On the one hand, the determination of overall nucleation and growth kinetics through batch experiments suffers from unwanted polymorphic transformations or the absence of experimental conditions under which several polymorphs can be nucleated. On the other hand, growth rates of polymorphs obtained from measurements of single crystals are often only recorded along a few specific crystal dimensions, thus lacking information about overall growth and rendering an incomplete picture of the problem. In this work, we measure the crystal growth kinetics of three polymorphs (I, II and IX) of tolfenamic acid (TFA) in isopropanol solutions, with the intention of providing a meaningful comparison of their growth rates. First, we analyse the relation between the measured growth rates and the crystal structures of the TFA polymorphs. We then explore ways to compare their relative growth rates and discuss their significance when trying to determine which polymorph grows faster. Using approximations for describing the volume of TFA crystals, we show that while crystals of the metastable TFA-II grow the fastest at all solution concentrations, crystals of the metastable TFA-IX become kinetically competitive as the driving force for crystallisation increases. Overall, both metastable forms TFA-II and TFA-IX grow faster than the stable TFA-I.

Organic compounds can crystallise in different forms known as polymorphs. Some polymorphs have disappeared from the physical world, never to be recrystallised again under the same conditions. The most infamous of these cases is that of the HIV drug ritonavir: once its reluctant stable form II was unwillingly nucleated for the first time, its desired but metastable form I could never be produced again with the same manufacturing process. The disappearance of metastable polymorphs remains a mysterious phenomenon, and the lack of control over it can be frustrating and costly for drug development. Here we show that Ritonavir’s extraordinary disappearing polymorph can be consistently produced by ball-mill grinding. Our work shows that not only crystal size, but also crystal shape and molecular conformation dictate polymorph stability switches in the mill. Through population balance modelling simulations, we also demonstrate how the size and shape of crystals at the steady state are determined by crystal breakage, dissolution and growth kinetics in the mill, which in turn can be controlled by the milling conditions. This work highlights the huge potential of mechanochemistry in polymorph discovery, and the manufacturing and control of complex flexible drug compounds such as Ritonavir.

The presence of needle-and plate-like particles has detrimental consequences on their downstream processing in the fine chemicals sector. Therefore, the ability to accurately characterize the particle size and shape is essential to quantify and predict their impact on the product processability. Nonetheless, tools to characterize both the size and shape of ensembles of cuboidal particles are seldom available. The overarching goal of this work is to provide a fast and accurate offline size and shape characterization tool. To this aim, we have designed and experimentally validated a combined imaging and chromatic confocal microscopy technique. We propose two modes of operation: one that facilitates the accurate 3D reconstruction of particles; and the other that facilitates their rapid characterization. We validate the performance of our technique using a commercial technique. We show that our technique can accurately characterize thousands of particles, making it a valuable addition to existing process analytical technology.

Understanding crystal growth kinetics is of great importance for the development and manufacturing of crystalline molecular materials. In this work, the impact of additives on the growth kinetics of benzamide form I (BZM-I) crystals has been studied. Using our newly developed crystal growth setup for the measurement of facet-specific crystal growth rates under flow, BZM-I growth rates were measured in the presence of various additives previously reported to induce morphological changes. The additives did not have a significant impact on the growth rates of BZM-I at low concentrations. By comparison to other systems, these additives could not be described as "effective" since BZM-I showed a high tolerance of the additives' presence during growth, which may be a consequence of the type of growth mechanisms at play. Growth of pure BZM-I was found to be extremely defected, and perhaps those defects allow the accommodation of impurities. An alternative explanation is that at low additive concentrations, solid solutions are formed, which was indeed confirmed for a few of the additives. Additionally, the growth of BZM-I was found to be significantly affected by solution dynamics. Changes in some facet growth rates were observed with changes in the orientation of the BZM-I single crystals relative to the solution flow. Of the two sets of facets involved in the growth of the width and length of the crystal, the {10l̅} facets were found to be greatly affected by the solution flow while the {011} facets were not affected at all. Computational fluid dynamics simulations showed that solute concentration has higher gradients at the edges of the leading edge {10l̅} facets, which can explain the appearance of satellite crystals. {10l̅} facets were found to show significant structural rugosity at the molecular level, which may play a role in their mechanism of growth. The work highlights the complexities of measuring crystal growth data of even simple systems such as BZM-I, specifically addressing the effect of additives and fluid dynamics.

The drying kinetics of single droplets of crystallizing and skin-forming species were investigated via acoustic levitation to provide a well-controlled environment mimicking spray drying operations. Particles manufactured by drying aqueous solution droplets containing varying ratios of D-mannitol and polyvinylpyrrolidone (PVP) were analysed using a range of techniques to elucidate their morphology and microstructure. Size, porosity and surface roughness of the manufactured particles increased with Dmannitol concentration in water, while the sphericity decreased, a consequence of the unique morphologies. The change in particle shell thickness was found to be minimal. Considering varying proportions of PVP led to a variety of fascinating structures, contrasting to those manufactured from pure D-mannitol. Temperature effects were further considered, and the results were matched by that from a lab and pilot scale spray dryer. Analysis of the solid form further demonstrates the opportunity to prepare different polymorphic forms of D-mannitol. (C) 2021 Elsevier Ltd. All rights reserved.

Particle size and shape significantly affect powder processing and their end-product quality in a variety of industries. Imaging methods can successfully characterize populations of needle-like particles. Prior to off-line imaging, adjusting the particle density can reduce particle overlaps but increase measurement/processing times. Discarding data of overlapping particles, as most image processing algorithms do, biases particle size and shape distributions. Building on previous efforts, we here provide an image processing technique that accurately separates and sizes overlapping needle-like particles. Our algorithm combines edge detection, layer-stripping watershed segmentation and length approximation. To test the algorithm, a large number of real particle projections were randomly overlapped with various overlap intensities. Approximately 92–72% of the particles were detected and the particles’ dimensions were characterized with an accuracy of 87–75%, with these ranges corresponding to low and high overlap intensities. Overall, the algorithm removes biases to considerably improve characterization accuracy of powders containing needle-like particles.