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In mining the CSD we identified a total of 95 families of polymorphs related by proton transfer which were classified into six different categories depending on the type of proton transfer observed and the ionisation of species involved.

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 {10

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.

This paper reviews the theoretical background of the ΔpKa rule and highlights the crucial role of solvation in determining the outcome of the potential proton transfer from acid to base.

Changes in molecular conformation and its relationship with crystal polymorphism have been well documented in previous work. To the best of our knowledge, however, the effect of solvate formation on molecular conformation has never been explored. Using the Cambridge Structural Database (CSD) in combination with molecular modelling, we provide insights on the impact of solvate formation on the conformation adopted by a compound and whether such conformation is different to those found in its neat form(s). Typically, the more flexible a molecule is, the higher the chances that conformational change occurs upon solvate formation. There are no trends as to the relative stability of conformers and their likelihood to be observed in either the solvates or the neat forms. Typically, conformer energy differences in solvate-neat form pairs are small (< 4 kJ/mol) and when larger energy differences are observed (> 15 kJ/mol), these can be reduced significantly when both solvent as well as thermal effects are considered in the simulations. This highlights of the importance of computing thermal contributions in conformer energies as well as accounting for environmental effects. Overall, we find that conformational change in solvate-neat form pairs mirrors the behaviour of conformational change in polymorphism.

A study on the hydration behavior of fluconazole demonstrates that both sample age and polymorphic form impact the drug’s kinetic stability to hydration. For two of the polymorphs, aged samples wer...

Single crystals of aspirin form I were cleaved and indented on their dominant face. Upon inspection, it was possible to observe strongly anisotropic shallow lateral cracks due to the extreme low surface roughness after cleavage. Atomic force microscopy (AFM) imaging showed spalling fractures nucleating from the indent corners, forming terraces with a height of one or two interplanar spacings d100. The formation of such spalling fractures in aspirin was rationalized using basic calculations of attachment energies, showing how (100) layers are poorly bonded when compared to their relatively higher intralayer bonding. An attempt at explaining the preferential propagation of these fractures along the [010] direction is discussed.

Nanoindentation measurements of the mechanical properties of the (020), (002) and (101) crystal faces in carbamazepine (CBZ) form III revealed that the (020) face had a greater elastic modulus and hardness than the (002) and (101) faces, which had similar modulus and hardness values. Atomic force microscopy (AFM) imaging of the indents showed that whilst no surface plastic displacement was observed around the residual indents on the (020) face, indents on both (002) and (101) faces nucleated cracks in multiple orientations and showed slip bands parallel to (020). The computed compliance matrix of CBZ form III was in good agreement with the experimental results and predicted anisotropic stiffness, with E(020) > E(002) > E(101). Modelling also revealed that the molecular flexibility of CBZ results in a less stiff material than that of an equivalent rigid compound. Indentation in one direction results in the opening of the CBZ-butterfly wings whilst in the other two results in their closing. Molecular dynamics simulations confirmed the primary (020) slip plane, consistent with the AFM images of the indents. It was also found that shear on the primary (020) slip plane, requires the breaking and forming of CBZ hydrogen bonded dimers. The slip plane, (020), was identified as having the lowest structural rugosity and hydrogen bonding density but not the lowest attachment energy.

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., Little is known about the relationship between the kinetic process of nucleation and the molecular and crystal structures of a crystallizing solute. Here we compare the behaviour of a series of benzoic acids with a focus on conformational effects.

We report on nanoindentation data for two pairs of polymorphic compounds of p-aminobenzoic acid (pABA) and p-nitrobenzoic acid (pNBA). Variations of 60% or higher are observed in both stiffness and hardness data between the two forms of each pair. We interpret these observations through variations of periodic bond chains (PBCs), i.e. variations in continuous intermolecular interactions strength and nature. Aided with hardness data of polymorphs from the literature, we then further assess how PBCs can be used to assess and compare mechanical properties of polymorphs. We define a new parameter, s-PBC, which quantifies the strongest PBC interaction that needs breaking so as to allow a switch of the PBC network from 3D to 2D/1D. We found that higher values of s-PBCs, normalised by the mean molecular volumes, usually led to higher values of mechanical properties. Although not infallible, this trend seemed to hold well when comparing polymorphs of a given compound, but not so much when comparing across different compounds.

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.

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., The link between structural surface rugosity and ease of crystallisation has been explored (see picture). Smooth polymorphs were found to crystallise more readily than rough polymorphs. A code was written to compute crystal rugosity and applied to crystal structure prediction calculations, thus affording a new way of linking landscapes to experimentation.

Experimental and computational techniques have been used in combination, to monitor the dehydration process of fluconazole monohydrate (MH), this unveiling the dehydration mechanism at the molecular level. Experimentally, dehydration was observed to start at around 55 °C and complete around 100 °C, with metastable Pbca, Z’=1 polymorph (AH-C) as the sole product of dehydration (as determined by in-situ hot stage PXRD). Conformational and structural changes were identified as key in the initiation and progression of the dehydration process. Thermal expansion is most significant along the c-axis, with molecular dynamic (MD) simulations and experimental observations identifying that water migrates through the MH crystal lattice within the plane perpendicular to that direction. Water was found to migrate within the (001) plane along both the a and b-axis directions. The MD simulations revealed that water was not able to migrate within the lattice at room temperature. Migration at 70°C (342K) was plausible, but only after the hydroxyl group undergoes conformational change. The conformational change, around the hydroxyl group, is key to both the weakening of the fluconazole-water hydrogen bonding, found in the MH structure, and the promotion of the fluconazole-fluconazole hydrogen bonding, required for the formation of polymorph AH-C.

Conformational polymorphs of organic molecular crystals represent a challenging test for quantum chemistry because they require careful balancing of the intra- and intermolecular interactions. This study examines 54 molecular conformations from 20 sets of conformational polymorphs, along with the relative lattice energies and 173 dimer interactions taken from six of the polymorph sets. These systems are studied with a variety of van der Waals-inclusive density functionals theory models; dispersion-corrected spin-component-scaled second-order Møller–Plesset perturbation theory (SCS-MP2D); and domain local pair natural orbital coupled cluster singles, doubles, and perturbative triples [DLPNO-CCSD(T)]. We investigate how delocalization error in conventional density functionals impacts monomer conformational energies, systematic errors in the intermolecular interactions, and the nature of error cancellation that occurs in the overall crystal. The density functionals B86bPBE-XDM, PBE-D4, PBE-MBD, PBE0-D4, and PBE0-MBD are found to exhibit sizable one-body and two-body errors vs DLPNO-CCSD(T) benchmarks, and the level of success in predicting the relative polymorph energies relies heavily on error cancellation between different types of intermolecular interactions or between intra- and intermolecular interactions. The SCS-MP2D and, to a lesser extent, ωB97M-V models exhibit smaller errors and rely less on error cancellation. Implications for crystal structure prediction of flexible compounds are discussed. Finally, the one-body and two-body DLPNO-CCSD(T) energies taken from these conformational polymorphs establish the CP1b and CP2b benchmark datasets that could be useful for testing quantum chemistry models in challenging real-world systems with complex interplay between intra- and intermolecular interactions, a number of which are significantly impacted by delocalization error.

CrystEngComm 24(12), 2305 - 2313 (2022). doi:10.1039/D2CE00162D, We demonstrate the ability to controllably desolvate a crystal-solvate system in a step-wise fashion through polymer-assisted grinding by varying the type and proportion of polymer agent used. A plausible mechanistic explanation is proposed based on a combination of experimental evidence and computational analysis. Specifically, Raman spectroscopy, total scattering pair distribution function analysis and computed reaction energies suggest that the desolvation process is associated with preferred interactions between the solvent molecules and specific polymers. This approach could potentially be extended to any type of material, including heat-sensitive materials, where classical desolvation by thermal processes is not possible, and provides an additional route for formulation processing., Published by RSC, London

In this contribution the hydration kinetics of three anhydrous poly-morphs (AH-A, AH-B and AH-C) of fluconazole [2-(2,4-difluorophenyl)-1,3-bis (1H- 1,2,4-triazol-1-yl)-propan-2-ol] were studied. The conversion kinetics from the anhydrous forms to the monohydrate (MH) were monitored at various relative humidities above the critical water activity. The studies revealed very different kinetic stabilities for the three anhydrous forms, with AH-A and AH-C converting much more easily to the MH than AH-B. Various energetic factors, which may be influencing the kinetics of hydration, were explored together with crystal structure and molecular conformation similarities between the anhydrous forms and the MH. The level of conformational and packing similarity between the anhydrous and MH structures was found to be consistent with the ease of hydration. We believe that surface similarity may be required for the nucleation of the hydrate, whilst the level of crystal packing similarity impacts the ease of growth. In terms of conformational variations, AH-B was found to require a significantly more dramatic conformational change to convert to the MH con-formation than those in either AH-A or AH-C. Soft planes (low attachment energies) may allow for easier diffusion of solvent into the crystal structure to allow for solvation. The overall kinetic energy barrier of water diffusion into the lattice plus conformational change was found to correlate well with our observed hydration kinetics, indicating that both the crystal structure and the conformation play a role in the kinetic stability towards hydration of the various fluconazole polymorphs.

Tolfenamic acid (TFA) is a very well-studied polymorphic compound with eight polymorphs discovered to date. Here, we report on a new polymorph of TFA, form IX, which was unexpectedly crystallised from isopropanol at low temperatures. Crystals of form IX appeared concomitantly with the more common forms I and II, raising the question as to why this polymorph had never been reported before. With the aid of dispersion corrected DFT, paired with calculations of vibrational frequencies, we analysed the stability of this new polymorphic form of TFA. Thermal measurements, solubility measurements and solvent-mediated phase transformation experiments confirm that TFA form IX is a metastable polymorph, with a stability that is close to the well-known forms I and II.

Almost 200 years ago, benzamide was reported as polymorphic with two of its forms (II and III) found to be difficult to crystallise. In a recent study, it was shown that benzamide form I can easily convert into benzamide form III using mechanochemistry in the presence of nicotinamide. Here we show, experimentally and computationally, that this transformation is the result of a thermodynamic switch between these two polymorphic forms driven by the formation of solid solutions with small amounts of nicotinamide. The presence of nicotinamide in the crystallisation environment promotes the robust and exclusive crystallisation of the elusive form III. These results represent a promising route to the synthesis and utilisation of elusive polymorphs of pharmaceutical interest. The formation of solid solutions can result in changes of relative stabilities of crystal polymorphs. Here, the elusive form III of benzamide is stabilized through solid solution formation with nicotinamide. It is shown, experimentally and computationally, how such thermodynamic switching allows for consistent and facile crystallization of the otherwise elusive benzamide form III.

Single crystals of aspirin form I were cleaved and indented on their dominant face. Upon inspection, it was possible to observe strongly anisotropic shallow lateral cracks due to the extreme low surface roughness after cleavage. Atomic Force Microscopy (AFM) imaging showed spalling fractures nucleating from the indent corners, forming terraces with a height of one or two interplanar spacings d100. The formation of such spalling fractures in aspirin was rationalised using basic calculations of attachment energies, showing how (100) layers are poorly bonded when compared to their relatively higher intralayer bonding. An attempt at explaining the preferential propagation of these fractures along the [010] direction is discussed.

We investigate the polymorphic behavior of benzamide, the first compound known to exhibit polymorphism, in the presence of small amounts of nicotinamide in the crystallization environment. A previous study by Emmerling et al.1 showed that the presence of nicotinamide promotes the transformation of the thermodynamic polymorph I of benzamide into its metastable polymorph III via mechanochemistry. We show that this transformation is the result of a thermodynamic switch between these two polymorphic forms driven by the formation of solid solutions with a small amount of nicotinamide. The presence of nicotinamide in the crystallization environment promotes the robust and exclusive crystallization of the elusive form III. These results represent a promising route to the synthesis and utilization of elusive polymorphs of pharmaceutical interest.

We have measured mechanical properties in molecular crystals of a series of para-substituted benzoic acids using nanoindentation. Two linear correlations were found for these materials: first between the Young’s modulus and the melting point per unit of volume, and second between the hardness and the crystal cohesive energy density. These correlations, however, were found to only hold within isomechanical groups. These are groups of materials with similar interaction strengths and dimensionalities. A close analysis of the intermolecular interactions present in these crystals revealed that structures with aromatic rings interacting through t-type interactions may achieve higher interaction dimensionalities and thus result in harder crystals than those with rings interacting through aromatic stacking. In these systems, thus, the dimensionality of the aromatic interactions in the crystals appears to play the major role in their mechanical behavior.

Classical nucleation theory teaches the idea that molecular clusters form and grow in solution and that depending on prevailing conditions there is a chance for some to grow large enough to overcome the interfacial energy penalty and become mature crystals. However, from such a kinetic analysis, nothing is learnt of the nature of the composition or the molecular packing in such clusters. As a means of addressing this shortcoming consideration has, in the past, been given to the idea that in certain systems crystallography may offer additional, structural, insights. From this approach the notions of ‘nucleation pathway’ or ‘nucleation transition state’ have become useful concepts around which to formulate hypotheses as to how clusters may yield specific molecular packing, resulting for example, in the observation of crystal polymorphs. Here we offer an in-depth crystallographic analysis related to the nucleation of the α and β polymorphs of para-aminobenzoic acid in an attempt to reveal the pathways leading to the two forms. Using a combination of CSD analyses, crystal structure prediction and targeted crystallizations we explore plausible solution pathways to these polymorphs and discuss our results in the light of known kinetic data for the nucleation and growth of this material.

We demonstrate, for four different systems of pharmaceutical relevance, that ball mill grinding leads to different polymorphic transformations dependending on the milling conditions. In all four cases, the commercial polymorph converts to a different polymorph upon ball-mill neat grinding (NG). This transformation can be reversed by grinding the so obtained polymorph in the presence of small amounts of solvent (LAG), leading back to the commercial polymorph. Scherrer particle size determinations reveal that NG conditions almost always lead to smaller particle sizes in the nanometer length scales. Computational studies confirm that polymorphs obtained by the specific ball mill LAG conditions reported correspond to the the lowest lattice energy forms. Our study further confirms our earlier conclusions that, at the nanoscale, polymorphs with higher lattice energies can become the thermodynamically stable forms if their surfaces are more stable than those of the polymorphs obtained by LAG. We found, however, one exception to this trend in D-sorbitol. We observe that polymorphs with smoother surfaces (low roughness) are usually the ones observed by NG. This observation points to a link between surface roughness and surface stability.

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. Theophylline:2-pyrrolidone mono (1:1) and sesqui (2:3) solvates have been discovered through variable-amount liquid-assisted grinding (VALAG). The structures and stability of the solvates and the kinetics involved in their formation are investigated both experimentally and theoretically. Ex-situ studies reveal a delayed appearance of the sesquisolvate, and show that sesquisolvate formation occurs via the monosolvate rather than directly from pure theophylline. Theoretical calculations show that the obtained solvates are the thermodynamic products corresponding to the reactant ratio. The kinetics of the transformations were found to be related to the energy required to cleavage the crystals through the softest planes. This was quantified by means of attachment energy calculations

We review the polymorphism of p-aminobenzoic acid (pABA), a model drugcompound whose crystallisation and polymorphic behaviour has been extensively studied in recent years. Beyond the well-known and characterised α and β forms, pABA also crystallises as a γ polymorph, which is structurally similar to the α form. In addition we also compare the newly reported δ form, obtained by high pressure crystallisation and through compression of the α-form. A structural analysis and comparison of all of the forms is presented, the conditions by which each of them is obtained summarised. Crystal structure prediction calculations have also been carried out in order to probe the solid form energy landscape of this compound. The overall picture of the polymorphism of pABA, reveals, surprisingly, the rarity of the β form.

We present a simple way of estimating the entropy cost of solvate formation in crystals. The entropy penalty of making solvates can be as low as 9 kJ mol−1 and is entirely dependent on the nature of the liquid component and the temperature of solvate formation. A link is found between a low entropy cost and a higher likelihood for a solvent to make solvates.

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.

peer-reviewed Crystalline solid solutions have the potential to afford tunable materials for pharmaceutical and technological applications. Unfortunately, these poorly understood phases are difficult to obtain and, hence, to study. In fact, commonly accepted empirical rules prescribe that only molecules of similar size and electron distribution are mutually soluble in the solid state. Here, despite the evident structural and electronic differences, the enantiomers of malic acid and tartaric acid are crystallized together in a variable stoichiometric ratio to produce both cocrystals and solid solutions. In some cases, physical mixtures are observed. The composition and polymorphism of the crystalline products are explained by DFT-d molecular substitution calculations for the cocrystallized molecules in different (known) structures. At the same time, from a crystal engineering perspective, the behavior of this complex system is rationalized thanks to the existence of intermediate cocrystal forms that merge the structural features of the pure molecular components.Crystalline solid solutions have the potential to afford tunable materials for pharmaceutical and technological applications. Unfortunately, these poorly understood phases are difficult to obtain and, hence, to study. In fact, commonly accepted empirical rules prescribe that only molecules of similar size and electron distribution are mutually soluble in the solid state. Here, despite the evident structural and electronic differences, the enantiomers of malic acid and tartaric acid are crystallized together in a variable stoichiometric ratio to produce both cocrystals and solid solutions. In some cases, physical mixtures are observed. The composition and polymorphism of the crystalline products are explained by DFT-d molecular substitution calculations for the cocrystallized molecules in different (known) structures. At the same time, from a crystal engineering perspective, the behavior of this complex system is rationalized thanks to the existence of intermediate cocrystal forms that merge the structural features of the pure molecular components. ACCEPTED peer-reviewed

Welcome to this CrystEngComm themed issue entitled “The solid state of pharmaceuticals.”

The experimental observation that certain crystal faces do not grow, despite being in contact with supersaturated solution, is a widely reported phenomenon. This concept of a growth ‘dead zone’ has been known for many years but its origin remains an unresolved problem in crystal growth. Sometimes it seems to be an inherent feature of the solution growth process while at others it appears that an impurity is an essential element for its appearance. Here we review existing data and provide new experimental evidence to confirm the widespread existence of the dead zone across a range of molecular materials. Available crystal growth kinetics are confronted with mechanistic models. Examination of the packing arrangements of appropriate crystal faces suggests that this behavior is linked to molecular scale surface roughness.

We explore the polymorphism of p-aminobenzoic acid (pABA) under high-pressure conditions. We have been able to isolate a new high-pressure form (δ-pABA) at pressures exceeding 0.3 GPa from three different pressure-transmitting media, water, water : ethanol and pure ethanol. We explore the compression behaviour of α-pABA in each of these media using neutron powder diffraction and observe that the transition is kinetically hindered using the aqueous ethanol and ethanol solutions compared with the pure aqueous medium. δ-pABA is sufficiently stable to be recovered to ambient pressure to enable its characterisation via X-ray powder diffraction and differential scanning calorimetry. At ambient pressure we have observed that δ-pABA converts into α-pABA on heating beyond 70 °C.

Crystal nucleation from solution is of central importance in the chemical and biological sciences. Linking nucleation kinetics to the properties of solutes and solvents remains a grand-challenge in physical chemistry. Through a unique dataset of compounds able to self-assemble via both hydrogen-bonds and aromatic stacking, we are able to compare the importance of these two types of interaction in driving the nucleation process. Contrary to previous reports in which solution chemistry and hydrogen bonding have been seen as controlling factors, we are now able to show that cluster growth via aromatic stacking holds the key.

Reported here are the isolation and direct observation of extremely reactive S2 and its conversion into bent-S3 via a cyclo-S3 2+ intermediate on interactive sites in porous coordination networks., The isolation and characterization of small sulfur allotropes have long remained unachievable because of their extreme lability. This study reports the first direct observation of disulfur (S2) with X-ray crystallography. Sulfur gas was kinetically trapped and frozen into the pores of two Cu-based porous coordination networks containing interactive iodide sites. Stabilization of S2 was achieved either through physisorption or chemisorption on iodide anions. One of the networks displayed shape selectivity for linear molecules only, therefore S2 was trapped and remained stable within the material at room temperature and higher. In the second network, however, the S2 molecules reacted further to produce bent-S3 species as the temperature was increased. Following the thermal evolution of the S2 species in this network using X-ray diffraction and Raman spectroscopy unveiled the generation of a new reaction intermediate never observed before, the cyclo-tri­sulfur dication (cyclo-S3 2+). It is envisaged that kinetic guest trapping in interactive crystalline porous networks will be a promising method to investigate transient chemical species.

We report on the nucleation and growth kinetics of the α and β polymorphs of p-amino benzoic acid (pABA) in the presence of two additives: 3-nitro-4-amino benzoic acid (ANBA) and 3-methoxy-4-amino benzoic acid (AMBA). Whilst the presence of additives slowed down the nucleation kinetics of both forms, they had a much larger impact on the growth kinetics of the α-form than the β-form. This allowed the nucleation and growth, for the first time, of the β-form (a form much harder to crystallise) in conditions which would normally afford the α-form. Given our previous findings that the nucleation and growth of α pABA is primarily controlled by aromatic stacking, our additive design strategy was based primarily on the idea that additives could be selected to attach strongly to pABA stacks whilst at the same time disrupting adjacent molecules. Such a strategy was successful in selective polymorph inhibition of α; this was possible because the growth of β-form is controlled by interactions other than aromatic stacks. More generally, our study also confirms that additives designed to modify the growth of macroscopic crystals also inhibit their nucleation.

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Living organisms display a spectrum of wondrous colors, which can be produced by pigmentation, structural coloration, or a combination of the two. A relatively well-studied system, which produces colors via an array of alternating anhydrous guanine crystals and cytoplasm, is responsible for the metallic luster of many fish. The structure of biogenic anhydrous guanine was so far believed to be the same as that of the synthetic one, a monoclinic polymorph (denoted as α). Here we re-examine the structure of biogenic guanine, using detailed experimental X-ray and electron diffraction data, exposing troublesome inconsistencies, namely, a “guanigma”. To address this, we sought alternative candidate polymorphs using symmetry and packing considerations and then utilized first-principles calculations to determine whether the selected candidates could be energetically stable. We identified theoretically a different monoclinic polymorph (denoted as β), were able to synthesize it, and confirmed using X-ray diffractio...