Abstract The control of crystallization processes in polymorphic systems remains a long-term goal at both laboratory and industrial scales. The rational design of processes that yield specific, desired crystal structures with suitable physical properties requires not only phase equilibrium data but also insights into the relative nucleation and growth rates of available crystal forms. For polymorphic systems that crystallize concomitantly, not only is such data largely unavailable, but also it is difficult to measure. This study determines the nucleation and growth kinetics of tolfenamic acid forms I and II from induction time distributions obtained from their crystallization in isopropanol in small volumes. The significant influence of crystal growth on both the form and analysis of induction time distributions has been examined, and methods to appropriately account for this effect are discussed. An analytical solution is developed, describing the induction time distribution in a dimorphic system in terms of the nucleation and growth kinetics of both forms. Despite the relevance of such data, this appears to be the first occasion in which such kinetic data have been obtained in a concomitantly crystallizing system.

Professor Angelo Gavezzotti’s scientific works have shaped the field of structural chemistry and inspired crystallographers and molecular modellers alike. To honour his legacy in this contribution, the Durham Molecular Crystals and Crystallisation (DuMoC2) group (and friends) have reviewed his work with a touch of humour and enormous gratitude. After presenting a concise review of his scientific contributions to crystallography and molecular modelling, the Gavezzotti Structural Database (GSD) was compiled and compared to the Cambridge Structural Database (CSD). We then used Angelo’s PIXEL method to analyse some of the GSD crystal structures. Together, through the writing of this paper, we celebrate Angelo’s career.

The presence of trace amounts of additives during crystal growth can have a significant impact on the physical properties of the crystallizing substrate (e.g., crystal morphology, purity, polymorphic phase, or growth kinetics). In this work, we report the growth of α-glycine crystals (α-gly) in the presence of a variety of diverse additives: two l-amino acids, two organic acids, α-iminodiacetic acid, and two chloride salts. Growth rate data from imaging, together with analytical techniques such as X-ray photoelectron spectroscopy (XPS) and fluorescence microscopy, are used to observe which facet growth is impacted by the additive and to what extent. Relating these findings to the α-gly crystal structure provides explanations for the observed effects. Specifically, the growth inhibition of the (02̅0) facet α-gly in the presence of l-tryptophan and l-methionine shows how the prochirality of glycine results in two symmetrically equivalent facets growing at different rates. In the presence of malonic acid and salicylic acid, growth of the {011} facets is inhibited as a result of the interaction of deprotonated acids at the {011} surfaces. We find α-iminodiacetic acid to be an extremely effective inhibitor of α-gly, stopping the growth of both the {011} and {020} facets. We correlate the effectiveness of α-iminodiacetic acid to its structural similarity to gly, allowing it to easily block the growth of two α-gly facets. Finally, we observe the incorporation of the metal ions Fe(II), Cu(II), and Zn(II) into the {011} facets of α-gly. Interestingly, in the cases of Cu(II) and Zn(II), the incorporation of the metals into the α-gly lattice does not cause a noticeable change in the growth rates. The formation of coordination complexes containing the metal ions and glycine ligands allows for the observed incorporation of the metals into the α-gly lattice with limited disturbance to its crystal growth.

With the ever-increasing complexity of new drug compounds, their crystallization is becoming more challenging than ever. Controlling the crystallization of present and future drugs will remain a chimera unless we gain an improved understanding of the effects of molecular flexibility on crystal nucleation and growth at the molecular level. As a contribution to this understanding, we report here the growth kinetics of a series of diacids with chain lengths from 4 to 10 carbon atoms. These compounds are ideal for such a study since (a) they all crystallize as linear conformers, (b) their crystal structures are very similar across the series, and (c) their molecular flexibility increases with increasing chain length. Upon analysis of their crystal growth behavior, we stumbled upon a surprising finding: the growth of these crystals along the length increases linearly for the series up to the diacid containing seven carbon atoms, beyond which the rates drop dramatically. Such a dramatic decrease in growth rates at longer chain lengths cannot be explained by the crystal structure differences of the diacids. To gain further insights, we explored the conformational landscapes of two diacids in solution using well-tempered metadynamics simulations. With increasing chain length, the conformational landscape becomes more complex, with folded conformations becoming more important for long chain acids. Our simulations show that some of the minor conformers present in the solution act as potent crystal growth inhibitors (a phenomenon we refer to as conformational self-poisoning). To the best of our knowledge, this work represents the first report of conformational self-poisoning in crystal growth, with experimental evidence supported by a molecular-level mechanism. While this effect is bad news for crystallization scientists, who must work with complex flexible compounds, for these diacids, we show that selected solvents are able to disfavor the problematic conformers in the solution, turning off the self-poisoning effect.

Symmetry-forming closest approaches of aromatic rings; 'Symthons', are usually the strongest interactions in halobenzene crystal structures. Where they combine to create pi-pi stacking, they are as strong as hydrogen bonds. This pi-pi stacking is disrupted when fluorine is present, as revealed in this analysis of all 290 closest aromatic approaches in the crystal structures of halobenzenes. Closest aromatic approaches involving fluorine show fewer examples of 'Symthon I' pi-pi stacking, and more examples of offset translations with larger displacements. Edge & ctdot;face approaches are also more common in the presence of fluorine, frequently accommodating fluorine atoms in the 'edges'. Some edge & ctdot;face approaches do not embody any symmetry. These findings are consistent with lower melting points and favourable connections between fluorine and positively charged carbon atoms. Halobenzenes containing fluorine are clumsy, floppy or slippy (as shown) when crystallising.

In this contribution the single crystal growth rates of four para substituted benzoic acids measured in toluene and isopropyl alcohol solutions are reported. Major objectives of the work have been to consider how such data might be correctly compared and how such comparisons may be related to underlying packing arrangements in the respective crystal structures. Morphological determinations formed an important part of the overall study. Consideration has been given to various practical issues arising from the varying solubility of the materials and growth rate dispersion among the measured crystal seeds. This provides suggestions as how best to measure growth rates for this purpose. The ultimate aims of such work have been to explore connections between growth and nucleation kinetics as well as to consider what such a data set might predict about the kinetics of other related molecules.

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.

ADVERTISEMENT RETURN TO ISSUEEditorialNEXTJohn Neil Sherwood: Pioneer in Organic and Molecular CrystalsRoger J. DaveyRoger J. DaveyMore by Roger J. Daveyhttps://orcid.org/0000-0002-4690-1774, Radoljub I. RisticRadoljub I. RisticMore by Radoljub I. Ristic, and Kevin J. Roberts*Kevin J. Roberts*Email: [email protected]More by Kevin J. Robertshttps://orcid.org/0000-0002-1070-7435Cite this: Cryst. Growth Des. 2023, 23, 10, 6989–6992Publication Date (Web):August 28, 2023Publication History Received24 May 2023Published online28 August 2023Published inissue 4 October 2023https://pubs.acs.org/doi/10.1021/acs.cgd.3c00628https://doi.org/10.1021/acs.cgd.3c00628editorialACS PublicationsCopyright © Published 2023 by American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views792Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (2 MB) Get e-AlertscloseSUBJECTS:Crystal structure,Crystallization,Crystals,Defects,Materials Get e-Alerts

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.

ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTA Personal Reflection: From Sgt. Pepper to COVID-19Roger J. Davey*Roger J. Davey*Email: [email protected]More by Roger J. Daveyhttps://orcid.org/0000-0002-4690-1774Cite this: Cryst. Growth Des. 2022, 22, 6, 3579–3580Publication Date (Web):May 9, 2022Publication History Published online9 May 2022Published inissue 1 June 2022https://pubs.acs.org/doi/10.1021/acs.cgd.1c01304https://doi.org/10.1021/acs.cgd.1c01304editorialACS PublicationsCopyright © Published 2022 by American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views707Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (471 KB) Get e-AlertscloseSUBJECTS:Chemical engineering and industrial chemistry,Crystallization,Crystallography,Crystals,Kinetics Get e-Alerts

We present an automated method for measuring facet specific growth rates by combining a crystal growth flow cell with image processing. This paper details the design of the growth cell and its advantages over previous models. The method of image processing utilizes a Hough transform to identify crystal facets, ultimately leading to facet specific growth rate measurements. Finally, experimental results are presented for facet specific growth rates of alpha-glycine crystals and compared to previous data.

A design strategy for the selection of crystal growth modifiers for non-polar crystals is proposed and its application demonstrated for the case of benzophenone.

The glycine polymorphs have provided a rich and challenging tapestry for crystal growth and polymorphism studies. In this new contribution we report some preliminary studies of the impact of two ionic surfactants on the morphologies and the competitive crystallisation of the α and γ polymorphs. We find both selective growth inhibition and acceleration combined with fascinating crystal aggregates. The role of both monomeric and micellar forms of the surfactants are explored and discussed in terms of nucleation and crystal growth processes.

We exploit the possible link between structural surface roughness and difficulty of crystallisation. Polymorphs with smooth surfaces may nucleate and crystallise more readily than polymorphs with rough surfaces. The concept is applied to crystal structure prediction landscapes and reveals a promising complementary way of ranking putative crystal structures.

Despite the technological importance of crystallization from solutions almost nothing is known about the relationship between the kinetic process of nucleation and the molecular and crystal structures of a crystallizing solute. Nowhere is this more apparent than in our attempts to understand the behavior of increasingly large, flexible molecules developed as active components in the pharmaceutical arena. In our current contribution we develop a general protocol involving a combination of computation (conformation analysis, lattice energy), and experiment (measurement of nucleation rates), and show how significant advances can be made. We present the first systematic study aimed at quantifying the impact of molecular flexibility on nucleation kinetics. The nucleation rates of 4 para substituted benzoic acids are compared, two of which have substituents with flexible chains. In making this comparison, the importance of normalizing data to account for differing solubilities is highlighted. These data have allowed us to go beyond popular qualitative descriptors such ‘crystallizability’ or ‘crystallization propensity’ in favour of more precise nucleation rate data. Overall, this leads to definite conclusions as to the relative importance of solution chemistry, solid-state interactions and conformational flexibility in the crystallization of these molecules and confirms the key role of intermolecular stacking interactions in determining relative nucleation rates. In a more general sense, conclusions are drawn as to conditions under which conformational change may become rate determining during a crystallization process.

Polymorphs, crystals with different structure and properties but the same molecular composition, arise from the subtle interplay between thermodynamics and kinetics during crystallisation. In this opinion piece, the authors review the latest developments in the field of polymorphism and discuss standing open questions.

Using crystallography to search for nucleation pathways: α and β polymorphs of p-aminobenzoic acid.

Increasing commercial application of state of the art crystal structure prediction to aid solid form discovery of new molecular entities allows the experimentalist to target the polymorphs with desired properties. Here we remind ourselves that in this field the gap between such prediction and experimentation can be vast, the latter depending strongly on kinetic processes not accounted for in the computations. Nowhere is this gap more evident than in examples of so-called "elusive" polymorphs, forms that have been found difficult to crystallize, sometimes taking years to appear or sometimes disappearing altogether. In attempting to probe the origins of such phenomena this work targets a well-known, relatively simple molecule, paracetamol (PCM), and explores the structural and kinetic origins of its elusive nature. It is noted that in general comparisons of the kinetic factors (nucleation and crystal growth) between polymorphs have rarely been reported and of course in cases where one or more forms is "elusive" this will, by definition, be essentially impossible. PCM however offers a unique opportunity and we show how the recent discovery of the impact of metacetamol (MCM) in stabilizing PCM form II can be used to advantage, enabling otherwise impossible comparative kinetic experiments to be made. Resulting from this study we now appreciate that MCM has a selective impact in blocking the growth of the thickness and width of PCM form I while it has no impact on form II. This is interpreted in terms of strong adsorption of MCM on the {011} faces (width and thickness) of form I in orientations that inhibit crystal growth ("wrong" orientations). Of more significance here is the use of the additive in allowing an otherwise impossible comparison of linear growth rates of forms I and II. This leads to the appreciation that only through calculation of growth volumes can we finally appreciate how the relative growth kinetics lead inevitably to the elusive nature of Form II.

From a general formulation of batch crystallization in a polymorphic system, it is shown that the concept of an Ostwald ratio provides a fundamental parameter with which to understand and compute the variation in polymorph composition with time, temperature, and supersaturation. In particular, it defines the conditions under which a system will exhibit sequential development of polymorphs, as per the widely known Ostwald's Rule of Stages and conversely when either only the stable polymorph will result or when forms appear simultaneously resulting in concomitant polymorphism. The Ostwald ratio is not a constant but varies with temperature, the initial supersaturation, crystal shape, and density. It is shown that its evaluation can lead to a kinetically based phase diagram enabling the construction of polymorph maps in compositional and temperature space. A review of relevant existing kinetic data reveals a lack of information concerning both the relative nucleation and growth rates of polymorphic phases. The specific case of gestodene is used as a means of demonstrating the significance and potential of this approach to the robust design of batch crystallization processes in polymorphic systems.