Search

Four crystalline polymorphs of the proinsecticide chlorfenapyr [4-bromo-2-(4-chlorophenyl)-1-ethoxymethyl-5-trifluoromethyl-1H-pyrrole-3-carbonitrile] have been identified and characterized by polarized light optical microscopy, differential scanning calorimetry, Raman spectroscopy, X-ray diffraction, and electron diffraction. Three of the four structures were considered polytypic. Chlorfenapyr polymorphs show similar lethality against fruit flies (Drosophila melanogaster) and mosquitoes (Anopheles quadrimaculatus) with the least stable polymorph showing slightly higher lethality. Similar activities may be expected to be consistent with structural similarities. Knockdown kinetics, however, depend on an internal metabolic activating step, which further complicates polymorph-dependent bioavailability.

The performance of crystalline organic semiconductors depends on the solid-state structure, especially the orientation of the conjugated components with respect to device platforms. Often, crystals can be engineered by modifying chromophore substituents through synthesis. Meanwhile, dissymetry is necessary for high-tech applications like chiral sensing, optical telecommunications, and data storage. The synthesis of dissymmetric molecules is a labor-intensive exercise that might be undermined because common processing methods offer little control over orientation. Crystal twisting has emerged as a generalizable method for processing organic semiconductors and offers unique advantages, such as patterning of physical and chemical properties and chirality that arises from mesoscale twisting. The precession of crystal orientations can enrich performance because achiral molecules in achiral space groups suddenly become candidates for the aforementioned technologies that require dissymetry.

Crystallization from the melt can allow the achievement of high driving force for crystallization accompanied by relatively slow growth, nucleation, and transformation rates, features that favor its use as an efficient polymorph screening method. Surprisingly, even though melt crystallization has a long history, it has been employed less often in the search for new polymorphs than solution crystallization. Applications of melt crystallization to 21 highly polymorphic, well-characterized compounds with at least five ambient polymorphs revealed that melt crystallization afforded more than half of the known polymorphs and in many cases revealed new polymorphs not detected by other screening methods. A statistical analysis revealed that polymorphs grown from the melt have a greater propensity for high Z′ values, which are not easily accessible by other crystallization protocols and are often not detectable by crystal structure prediction methods. Melt crystallization within nanopores (8–100 nm) performed for 19 of the 21 compounds mostly resulted in polymorphs that dominated crystallization from the bulk melt at similar temperatures. The total number of polymorphs observed in nanopores was less than that observed during crystallization from the bulk melt, however, and melt crystallization under confinement revealed new polymorphs not detected by other crystallization methods.

The crystallization of nicotinamide (NA) and its constitutional isomer, isonicotinamide (INA), is compared. NA formed eight polymorphs from the melt and two from solution, whereas INA formed two polymorphs from the melt and six from solution. This analysis was provoked by the observation that NA is highly polymorphic from the melt, while the closely related INA is highly polymorphous from solution. A combination of hot stage polarized light microscopy, powder X-ray diffraction, and Raman spectroscopy revealed that the polymorph selectivities are not related to supramolecular self-association in the growth media. The larger estimated free energy gap separating NA polymorphs, compared with that of the INA polymorphs, is consistent with the smaller number of NA polymorphs generated from solution. Phenomenological analyses of crystallization kinetics suggest that cross nucleation is the most likely reason more polymorphs of NA than INA crystallize from the melt.

Ripening (also called recrystallization) is a process that occurs commonly in nature and industry that shifts the size distribution of an ensemble of crystals toward a smaller number of larger crystals. Ostwald ripening is by far the best known recrystallization mechanism and sometimes is mistakenly considered as the only mechanism for shifting the crystal size distribution. Ostwald ripening accounts for recrystallization under thermodynamic control and is driven only by the well-known size dependence of solubility. There are, however, other recrystallization mechanisms that can be observed on laboratory timescales for crystals of any size under certain conditions. Internal stress dispersion is a thermodynamic ripening mechanism that depends not on surface energies but rather on crystal defects. In addition, there are two other mechanisms that are kinetic in nature. The most efficient is driven by the size dependence of growth and dissolution rates at low supersaturation. Finally, a mechanism proposed by Punin is driven by the difference between growth and dissolution rates due to crystal defects. All the four mechanisms can be at work simultaneously. The efficiency of ripening can be enhanced by temperature oscillations, but only the thermodynamic mechanisms can work at constant temperature. In this paper, we discuss the fundamentals of these four ripening mechanisms and revisit in detail Punin’s mechanism because it is the least well articulated in the literature.

Two books that describe the forms of thin films of many molecular crystals grown from the melt in polarized light, “Gedrillte” Kristalle(1929) by Ferdinand Bernauer and Thermomicroscopy in the Analysis of Pharmaceuticals(1971) by Maria Kuhnert-Brandstätter, are analyzed. Their descriptions, especially of curious morphologies consistent with helicoidal twisting of crystalline fibrils or narrow lamellae, are compared in the aggregate with observations from our laboratory collected during the past 10 years. According to Bernauer, 27% of molecular crystals from the melt adopt helicoidal crystal forms under some growth conditions even though helicoids are not compatible with long-range translational symmetry, a feature that is commonly thought to be an a priori condition for crystallinity. Bernauer’s figure of 27% is often met with surprise if not outright skepticism. Kuhnert-Brandstätter was aware of the tell-tale polarimetric signature of twisting (rhythmic interference colors) but observed this characteristic morphology in less than 0.5% of the crystals described. Here, the experience of the authors with 101 arbitrarily selected compounds—many of which are polymorphous—representing 155 total crystal structures, shows an even higher percentage (ca. 31%) of twisted crystals than the value reported by Bernauer. These observations, both positive (twisting) and negative (no twisting), are tabulated. It is concluded that twisting is not associated with molecular structure or crystal structure/symmetry. Rather, these nonclassical morphologies are associated with certain habits with exaggerated aspect ratios, and their appearance is strongly controlled by the growth conditions. Comments are offered in an attempt to reconcile the observations here, and those of Bernauer, the work of seekers of twisted crystals, with those of Kuhnert-Brandstätter, whose foremost consideration was the characterization of polymorphs of compounds of medicinal interest.

Benzamide, a simple derivative of benzoic acid and a common intermediate of pharmaceutical compounds, was reported to form two polymorphs in 1832, but the single crystal structure of the more stable form was not solved until 1959. Nearly 50 years later, the second form was characterized by powder diffraction, followed shortly thereafter by characterization of a third form, a polytype of the most thermodynamically stable Form I. These two new forms, Forms IIand III, are metastable. Herein, we describe a fourth polymorph, Form IV, discovered by melt crystallization concurrently with its crystallization under confinement at small length scales (<10 nm), where it is stable indefinitely. Form IIIexists under confinement in larger pores, and melting point data for different pore sizes corroborate the existence of Form IVbelow 10 nm. Form IVis highly disordered, precluding indexing of powder diffraction data other than hk0 reflections. Nonetheless, a combination of powder X-ray diffraction and computational crystal structure prediction reveals that Form IVcontains a 2D motif resembling that of Form II, but with long-range order in the third dimension masked by ubiquitous stacking faults. This approach relies on distilling a large number of candidate structures to a few possible disorder models based on benzamide tetrads that organize in 2D parquet-like tiles, with organization along the third dimension, that can be modeled with various stacking fault configurations having distinct intermolecular interactions and translations in the dimension orthogonal to the tiling planes. These observations reveal a bewildering crystallographic complexity for such a simple molecule. Nonetheless, the approach described herein demonstrates that challenging structures that may be abandoned prematurely because of poor crystallinity, twinning, or disorder can be solved.

Dislocations in crystals affect material properties and are essential for crystal growth near equilibrium, yet their genesis in the absence of external or internal stresses is unresolved. X-ray topography has revealed microscopic inclusions as dislocation sources, but the real-time creation of a dislocation by a particulate inclusion has not been reported. In situ atomic force microscopy (AFM) was used herein to visualize dislocation generation in an l-cystine crystal by a cube-like hematite particle embedded in, and slightly inclined with respect to, the l-cystine {0001} surface. The particle produced two pairs of heterochiral screw dislocations with opposing Burgers vectors. After overgrowth of the particle, dissolution in undersaturated solutions revealed the dislocations once again until the detachment of the particle exposed a flat basal plane devoid of dislocations, thereby corroborating the essential role of the particle. Hematite particles with their flat faces parallel or at high angle to the surface, as well as spherical poly(styrene) particles, did not produce dislocations, suggesting that shape and orientation of the particle with respect to the step train advancing across the growing crystal surface are critical features for dislocation generation.

Various researchers recently reported that they had first controlled the mesoscale helicity of achiral crystals with the use of chiral additives. In fact, Wallerant showed in 1907 that resorcinol crystals, among others, grew from the melt as helical fibers whose sense of twist was determined by resolved additives. Wallerant’s demonstration is reproduced herein and his observations are given interpretation via computation of adsorption energetics through simulated annealing.

Disorder is a common feature of molecular crystals that complicates determination of structures and can potentially affect electric and mechanical properties. Suppression of disorder is observed in otherwise severely disordered benzamide and thiobenzamide crystals by substituting hydrogen with fluorine in the ortho-position of the phenyl ring. Fluorine occupancies of 20–30% are sufficient to suppress disorder without changing the packing motif. Crystal structure prediction calculations reveal a much denser lattice energy landscape for benzamide compared to 2-fluorobenzamide, suggesting that fluorine substitution makes disorder less likely.

Polymorphism of molecular crystals was Joel Bernstein’s (1941–2019) scientific focus. Polymorphism also has been the subject of lore: (1) McCrone made popular the belief that the longer you study a substance the more polymorphs you are likely to find, and (2) Bernstein made popular so-called disappearing polymorphs, forms that no matter how long you look you can no longer find (in the absence of extraordinary measures). Here, we add the following lore: (3) Molecular crystals with helicoidal morphologies are as common as those that are polymorphic. The aforementioned observations of McCrone, Bernstein, and the present authors do not rise to the level of scientific principles. They are nevertheless guides grounded in laboratory experience. The experiences out of which the third statement emerges is the work of overlooked researchers, as well as a long list of substances with helicoidal morphologies assembled during the past decade in our laboratories. Here, the claim of the ubiquity of twisted crystals is supported with a particular demonstration with polymorphs of active pharmaceutical ingredients, favorites of Bernstein because of their intersection with the law. It was previously shown that crystallites of particular polymorphs of aspirin and acetaminophen (paracetamol) twist as they grow. No such observations have been made for the other two popular over-the-counter pain relief medicines, ibuprofen and naproxen. They are given here. Twisting among all four common pain medicine crystals seems improbable, to us, and supports a fact about molecular crystal morphology that is not widely appreciated but hiding in plain view.

Microscopic inclusions are common sources of dislocations in solution-grown crystals, but the correspondence between the size and shape of inclusions and the probability of dislocation generation has not been established quantitatively. This correspondence is obtained herein through the use of spherical poly(styrene) particles with well-defined diameters, ranging from 1 to 90 μm, which were incorporated within potassium hydrogen phthalate crystals during growth from solution. The probability of generating dislocations by particle overgrowth increased with increasing supersaturation and particle size. The largest particles generate so many dislocations that daughter crystals emerge that are no longer in single-crystal register with the host. The results are consistent with a model that depends on surmounting the elastic energy of crystal layers associated with bending. Dislocation generation during the last stages of overgrowth is favored when the height difference between the growing layer and the particle protruding from the crystal surface is larger than a dislocation Burgers vector and the angle between the crystal surface and the particle surface is small enough that the growth layer can bend as it climbs onto the particle.

Trimorphic paracetamol, one of the most commonly used analgesic and antipyretic drugs, has been a model system for studying transformations among phases of molecular crystalline materials. During crystallization from the melt and the glass above 0 °C, three new polymorphs of paracetamol (N-acetyl-para-aminophenol or acetaminophen) were discovered, doubling the number of known ambient forms. The crystal structure of one new form was solved using a combination of powder X-ray diffraction and computational techniques. Growth kinetics became anomalous near the glass transition: as temperature decreased, growth rate increased; this rare and poorly understood phenomenon is commonly identified as the glass-to-crystal (GC) growth mode. In addition, two polymorphs displayed optical evidence of helicoidal morphologies, a characteristic of at least 25% of molecular crystals, that has been resistant to a universal explanation.

Contact insecticides often involve the interaction of whole organisms and toxicant crystal surfaces. The crystalline phase of these compounds has not, however, been considered for the optimization of insecticide performance. Lindane (1R,2r,3S,4R,5r,6S-hexachlorocyclohexane) has been one of the most widely used insecticides, but other (inactive) stereoisomers accompanying its manufacture have led to massive chemical waste remediation problems. Crystalline polymorphs are also isomers in the broadest sense, yet only one crystal structure of lindane has been reported. Herein, we report the discovery and characterization of two new polymorphs, Forms II and III. The efficacy of Forms I, II, and III against Drosophila melanogasterrevealed an inverse correlation between lethality and thermodynamic stability; the least stable kills fastest. This understanding provides a crystal engineering opportunity wherein formulations containing the most active contact insecticide polymorph can achieve infectious disease prophylaxis while reducing environmental exposure and associated chemical waste.

Organic additives play key roles in controlling the precipitation of calcium carbonate in the environment, industry, and biology, where they can direct polymorphism, alter crystal morphologies, and sometimes even become occluded, modifying bulk properties. However, significant questions remain regarding the pathway from adsorption on crystal surfaces to occlusion. Here, the optical properties of calcite crystals grown in the presence of the dye Congo red are used to characterize the organization of the additives within the crystal. Complemented by the analysis of surface adsorption through in situ atomic force microscopy (AFM), molecular simulations, and changes in crystal morphologies, we show that the occluded dye molecules are randomly oriented under fast growth conditions, but that slow growth engenders ordering of the dye within islands, whose orientation is determined by the dye/terrace interaction free energy. The islands are subsequently overgrown such that their internal structure is preserved. These results reveal that the occlusion of organic macromolecules into calcite can be understood by thermodynamics operating at the adsorption stage. This new insight will ultimately enable the design of additives to give specific material properties.

Theoretical crystal structure prediction (CSP) calculations of molecular crystals often generate structures representative of the components associated with disorder, stacking faults, and polytypism. The powder X-ray diffraction (PXRD) pattern of benzamide II contains diffuse scattering consistent with a disordered structure. Previous attempts to elucidate its ordered structure by PXRD and CSP were incomplete because the average structure is actually a complex superposition of multiple polytypes, thus making structure determination particularly challenging. To address this problem, an approach to modeling such complex structures from PXRD data and CSP in combination with molecular dynamics simulations is proposed. Using this approach, the potential building blocks for polytypes possessing a two-dimensional stacking fault structure are identified. For benzamide II polytypes, centric H-bonded amide dimers are found to be the preferred H-bonding motif. The stacking faults are also associated with conformational changes of phenyl rings, in agreement with observed diffraction intensities. A characteristic average structure containing the pertinent one-dimensional motifs is derived.