Crystals Of Small Organic Molecules Research Articles

The interplay between nucleation and patterning during shear-induced crystallization from solution in a parallel plate geometry.

Cooling crystallization of small organic molecules from solution is an important operation for the separation and purification of drug products. In this research, shear-induced nucleation from a supersaturated solution is studied in a parallel plate geometry. Under conditions of shear and small gap sizes, narrow mesoscale circular bands of small crystals appeared spontaneously and reproducibly on the plate's surface. We have investigated the connection between nucleation and the emergence of these circular patterns. Our results show that nucleation occurs preferably in zones with high local shear rate (located at the outer edges of the plates), compared to zones with low local shear rate (at the center of the plates). The time before nucleation occurs decreases significantly for increasing mean shear rate and time. The circular crystalline patterns appear at the plate's surface, where heterogeneous nucleation first occurs. Multiple hypotheses are explored to understand the pattern formation in crystallization. Since no satisfactory explanation is found, a new mechanism is proposed. This hypothesis involves crystals initially forming on the surface of the plates and undergoing stick-slip motion, which influences the local nucleation kinetics. This results in an interplay between (secondary) nucleation and stick-slip motion at the start of the crystallization process. By modifying the surface of the plates, their ability to act as a heterogeneous nucleation site can be altered, allowing control over the formation of patterns.

Range-dependence of two-body intermolecular interactions and their energy components in molecular crystals.

Routinely assessing the stability of molecular crystals with high accuracy remains an open challenge in the computational sciences. The many-body expansion decomposes computation of the crystal lattice energy into an embarrassingly parallel collection of computations over molecular dimers, trimers, and so forth, making quantum chemistry techniques tractable for many crystals of small organic molecules. By examining the range-dependence of different types of energetic contributions to the crystal lattice energy, we can glean qualitative understanding of solid-state intermolecular interactions as well as practical, exploitable reductions in the number of computations required for accurate energies. Here, we assess the range-dependent character of two-body interactions of 24 small organic molecular crystals by using the physically interpretable components from symmetry-adapted perturbation theory (electrostatics, exchange-repulsion, induction/polarization, and London dispersion). We also examine correlations between the convergence rates of electrostatics and London dispersion terms with molecular dipole moments and polarizabilities, to provide guidance for estimating convergence rates in other molecular crystals.

Bioinspired superwettability: From interfacial materials to chemistry

<p indent="0mm">Interfacial wettability is one of the fundamental problems in material science. The research on wettability regulation is of great significance in exploring new knowledge and creating new applications. Learning from nature, Prof. Jiang has summarized three basic principles of superwettability: (1) The static wetting is determined by the cooperative effect of nanostructure and surface energy; (2) the transition point of the superlyophilicity and superlyophobicity on the nanostructure is the lyophilicity-lyophobicity limitation; (3) the direction of liquid transport is regulated by chemical composition gradient, rough gradient, curvature gradient, etc. Based on these principles, he further extended the superwettability interfacial material systems to interfacial chemistry. He established a superwetting interfacial material system including 64 combinations, and expanded to various liquid systems with different pressure and temperature ranges, leading and promoting the global development of this field. In this paper, we will introduce the design of superwetting interface and the new law of liquid/gas/solid three-phase interfacial wettability. Based upon the new law of three-phase interfacial wettability, we state the application of water-oil separation, pesticide spraying, electrochemical sensors, and photoelectric material patterning. And the recent research and application prospect in the field of quantum-confined superfluid are discussed. In the part of water-oil separation, focusing on the key issue of constructing membrane materials with both fine pore structure and super-wetting properties, without changing the traditional separation membrane preparation process, the micro-nano multi-level structure of the membrane surface is constructed through structure-induced tuning, and the surface is chemically modified. Synergistic action is used to realize the regulation of membrane transport behavior of water droplets or oil droplets, and a series of novel structural membrane separation materials have been successfully prepared, realizing high-precision and high-throughput separation of oil-water emulsions under low driving pressure. In-depth research on the relationship between the molecular structure of surfactants and the kinetic behavior and thermodynamic state of droplets on specially wetted surfaces has led to the discovery of a very cheap anionic surfactant (sulfosuccinic acid) capable of forming vesicles. Sodium dioctyl ester (AOT) can inhibit the ejection and sputtering of pesticide droplets on the surface of superhydrophobic plants at a very low concentration (3/1000 mass concentration). Aiming at the historical problem of “deficient oxygen” during the use of electrochemical enzyme sensors, we proposed and constructed an oxygen-enriched enzyme electrode with solid/liquid/gas three-phase coexistence. The three-phase electrode will greatly improve the detection performance of existing sensors, has extremely broad application prospects in future disease monitoring, and provides a new design idea for the development of high-efficiency enzyme sensors. We exploit the principle of “liquid bridge confinement assembly” by inducing site-specific condensation and crystallization of small organic molecules by exploiting asymmetric wettability interfaces, fabricating one-dimensional arrays of organic polymer semiconductors by exploiting highly adhesive three-phase interfaces, and exploiting superwetting The micro-nano interface controls the three-dimensional dewetting process and realizes the preparation of highly oriented one-dimensional single-crystal nanowires. These three methods are the key issues to realize one-dimensional micro-nano materials from material preparation to device application. Since 2008, we have successfully achieved the fabrication of smart nanopores that mimic ion channels in biomembranes. This channel has properties similar to biological ion channel switching, selection and rectification. Furthermore, by imitating the mechanism of energy conversion in living systems, the design of energy conversion systems driven by chemical potential gradients based on biomimetic nanopores and the design of nanopore-based sensing devices are realized. Since 2018, we focused on dynamic superwetting. The concept of ionic/molecular superfluid is proposed, which promotes the understanding of the realization of ultra-low energy conversion and information transmission in biological systems and provides new ideas for the study of ultra-low energy chemical synthesis in biological systems. It is believed that future research on ionic/molecular superfluidity will promote the development of neuroscience and brain science, develop quantum ion technology, develop future chemical and chemical reactors with high flux, high selectivity and low energy consumption, and will produce a series of disruptive technologies.

A Comparison of Structure Determination of Small Organic Molecules by 3D Electron Diffraction at Cryogenic and Room Temperature

3D electron diffraction (3D ED), also known as micro-crystal electron diffraction (MicroED), is a rapid, accurate, and robust method for structure determination of submicron-sized crystals. 3D ED has mainly been applied in material science until 2013, when MicroED was developed for studying macromolecular crystals. MicroED was considered as a cryo-electron microscopy method, as MicroED data collection is usually carried out in cryogenic conditions. As a result, some researchers may consider that 3D ED/MicroED data collection on crystals of small organic molecules can only be performed in cryogenic conditions. In this work, we determined the structure for sucrose and azobenzene tetracarboxylic acid (H4ABTC). The structure of H4ABTC is the first crystal structure ever reported for this molecule. We compared data quality and structure accuracy among datasets collected under cryogenic conditions and room temperature. With the improvement in data quality by data merging, it is possible to reveal hydrogen atom positions in small organic molecule structures under both temperature conditions. The experimental results showed that, if the sample is stable in the vacuum environment of a transmission electron microscope (TEM), the data quality of datasets collected under room temperature is at least as good as data collected under cryogenic conditions according to various indicators (resolution, I/σ(I), CC1/2 (%), R1, Rint, ADRA).

Functional Molecular Crystals in Biology

AbstractHighly reflective crystals of small organic molecules are the functional materials in a wide variety of optical systems in animals. We present a perspective on this field of organic biomineralization and review evidence for the widespread distribution of organic crystals in animals. These materials were, until recently, largely overlooked principally because the crystals are lost during conventional electron microscopy preparation procedures. We document the discovery of the crystalline pteridines as a new class of biological crystals and explain why many more organic biocrystals will likely be discovered and where they may be found. We examine the chemical basis for the extraordinary optical properties of the crystals and review some of their newly discovered biological functions. The study of biogenic molecular crystals promises to yield fascinating insights into photonic systems in animals and will inspire the development of artificial optical materials.

Polyaniline Hybrid Nanofibers via Green Interfacial Polymerization for All-Solid-State Symmetric Supercapacitors.

In this study, we report an enormously simple green approach for the synthesis of polyaniline hybrid (PANI-SO) nanofibers in emeraldine salt form. We have carried out the synthesis via an interfacial polymerization method using vegetable oil as an organic phase instead of the commonly used solvents like CHCl3, CCl4, etc. Characterization techniques such as Fourier transform infrared (FTIR), UV–visible, powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) have been used for studying the synthesized polyaniline hybrid nanofibers. An interesting observation is the crystallization of small organic molecules in the PANI matrix. PANI-SO shows a pseudocapacitance behavior with a capacitance value of 302 F g–1 at a current density of 1 A g–1. In addition, the material shows an energy density of 26.8 W h kg–1 and a maximum power density of 402.6 W kg–1. Furthermore, the PANI-SO electrode maintains about 84% of the initial capacitance after 1000 cycles. Similarly, the PANI-SO symmetric solid-state supercapacitor shows an areal capacitance of 118.7 mF cm–2 and retains a stability of 80% even after 1000 cycles. Thus, the PANI-SO electrode shows a good cyclic performance, which implies the structural stability of PANI-SO nanofibers. The electrochemical properties of PANI-SO are compared with those of PANI nanofibers synthesized by taking CHCl3 as the organic phase and keeping all other parameters identical. PANI-SO is observed to be a superior material compared to the latter one. All electrochemical analyses show that the PANI synthesized using cooking soyabean oil (PANI-SO) is an effective supercapacitor material.

Liquid Metastable Precursors of Ibuprofen as Aqueous Nucleation Intermediates.

The nucleation mechanism of crystals of small organic molecules, postulated based on computer simulations, still lacks experimental evidence. In this study we designed an experimental approach to monitor the early stages of the crystallization of ibuprofen as a model system for small organic molecules. Ibuprofen undergoes liquid–liquid phase separation prior to nucleation. The binodal and spinodal limits of the corresponding liquid–liquid miscibility gap were analyzed and confirmed. An increase in viscosity sustains the kinetic stability of the dense liquid intermediate. Since the distances between ibuprofen molecules within the dense liquid phase are similar to those in the crystal forms, this dense liquid phase is identified as a precursor phase in the nucleation of ibuprofen, in which densification is followed by generation of structural order. This discovery may make it possible to enrich poorly soluble pharmaceuticals beyond classical solubility limitations in aqueous environments.

Spatiotemporal Control of Enzyme‐Induced Crystallization Under Lyotropic Liquid Crystal Nanoconfinement

AbstractWater nanoconfinement has important effects on the properties of biomolecules and ultimately on their specific functions. By performing experiments and molecular dynamic simulations, we show how intrinsic nanoconfinement controls the crystallization of small organic molecules converted by enzymatic reactions within the water nanochannels of lipid cubic phases (LCPs). By controlling the nanochannel size, enzymatic reactions in LCPs can be engineered to turn the same converted substrate into its soluble, microcrystal, or needle‐like crystal form due to the large variability in water dynamics. Differential scanning calorimetry studies, supported by molecular dynamics simulations, show that most of water within the mesophase nanochannels behaves differently due to interactions with the LCP interface, and that this mechanism has a larger impact for smaller channels. These findings suggest that the amount of free water in the core of the nanochannels is the key factor determining local substrate diffusion and self‐assembly within LCPs.

Spatiotemporal Control of Enzyme-Induced Crystallization Under Lyotropic Liquid Crystal Nanoconfinement.

Water nanoconfinement has important effects on the properties of biomolecules and ultimately on their specific functions. By performing experiments and molecular dynamic simulations, we show how intrinsic nanoconfinement controls the crystallization of small organic molecules converted by enzymatic reactions within the water nanochannels of lipid cubic phases (LCPs). By controlling the nanochannel size, enzymatic reactions in LCPs can be engineered to turn the same converted substrate into its soluble, microcrystal, or needle-like crystal form due to the large variability in water dynamics. Differential scanning calorimetry studies, supported by molecular dynamics simulations, show that most of water within the mesophase nanochannels behaves differently due to interactions with the LCP interface, and that this mechanism has a larger impact for smaller channels. These findings suggest that the amount of free water in the core of the nanochannels is the key factor determining local substrate diffusion and self-assembly within LCPs.

Microfluidic Continuous Seeded Crystallization: Extraction of Growth Kinetics and Impact of Impurity on Morphology

We describe a continuous microfluidic system for seeded crystallization of small organic molecules, such as active pharmaceuticals, and demonstrate integration with in situ detection tools for determining the size and polymorphic form of the crystals. This integrated device is used to extract growth kinetics, as a screening platform for process parameter effects and optimization, and to gain insight into the fundamentals of the crystallization process. In addition, the microfluidic system also allows studies of additive effects on the crystal habit. The method is demonstrated with growth kinetics for α-, β-, and γ-forms of glycine along with the effects upon the morphology of adding glutamic acid and methionine.

An automated platform for parallel crystallization of small organic molecules

An automated platform for parallel crystallization of small organic molecules from solution is described. The principal gain over manual crystallization lies in the automated sequencing of crystallization steps, including computer-controlled dosing of liquids and solids. The platform is designed to conduct 32 crystallizations per day, from solution volumes up to 10 ml, allowing a search for physical forms to be conducted over a finer grid than might be accessible manually and thereby increasing the probability of success.

Structural insights into substrate traffic and inhibition in acetylcholinesterase

Acetylcholinesterase (AChE) terminates nerve-impulse transmission at cholinergic synapses by rapid hydrolysis of the neurotransmitter, acetylcholine. Substrate traffic in AChE involves at least two binding sites, the catalytic and peripheral anionic sites, which have been suggested to be allosterically related and involved in substrate inhibition. Here, we present the crystal structures of Torpedo californica AChE complexed with the substrate acetylthiocholine, the product thiocholine and a nonhydrolysable substrate analogue. These structures provide a series of static snapshots of the substrate en route to the active site and identify, for the first time, binding of substrate and product at both the peripheral and active sites. Furthermore, they provide structural insight into substrate inhibition in AChE at two different substrate concentrations. Our structural data indicate that substrate inhibition at moderate substrate concentration is due to choline exit being hindered by a substrate molecule bound at the peripheral site. At the higher concentration, substrate inhibition arises from prevention of exit of acetate due to binding of two substrate molecules within the active-site gorge.

4-Aminophenylacetic acid

This thesis deals with the controlled crystallization of small organic molecules and is focused on solubility and polymorphism. The solubility was determined for phenylacetic acid, p-hydroxyphenylacetic acid, p-aminophenylacetic acid, p-hydroxybenzoic acid and ibuprofen in both water and in a range of organic solvents. Data is discussed from the standpoint of molecular aspects of solute – solvent interactions and by estimated solid phase activity. It was shown that better understanding could be acquired by making a qualitative analysis of the molecular interactions in the solution and the crystal structure of the compounds in question. Solubility predictions that are carried out by the UNIFAC method are not sufficiently accurate to serve as a basis for a reliable design of a crystallization process or selection of a suitable solvent since they deviate more than 15% from experimental values. The reason for the discrepancies are related to uncertainties in the prediction of activity coefficients by UNIFAC, as well as, difficulties in the estimation of the activity of the solid state. p-Aminobenzoic acid (PABA) has been crystallized from thirteen different solvents either by slow cooling, after which the product is allowed to mature in suspension, or by rapid cooling followed by immediate isolation. Two different polymorphs have been crystallized. The system is found to be enantiotropic with the transition temperature of 25 °C, below which the β-form is the stable polymorph. The α-form was obtained from all solvents by both methods. The β-form is obtained only in carefully controlled conditions from water and ethyl acetate, well below the transition temperature. Often the α-form appears concomitantly. It is shown in this work that sonication significantly reduces the induction time for nucleation. The β-form crystallizes more reproducibly and at higher cooling rates when controlled sonication is used. In addition sonication is found to selectively favor the appearance of one of the polymorphs. Producing the pure β-form was possible even above the transition temperature where other crystallization techniques were only capable of producing the stable α-form. The α-form structure is based on centro symmetric dimers formed by association of carboxylic acid groups. It is suggested that the preference for nucleation of the α-polymorph is related to the formation of dimers in the supersaturated solution. Only at the condition where the formation of dimers is reduced sufficiently, (i.e. in the polar solvents or when sonication is applied) the nucleation of the β-form is favored.

Prediction of Solvents Suitable for Crystallization of Small Organic Molecules

Selection of suitable solvent is essential for crystallization of pharmaceuticals. Based on chemical structures of 6397 compounds and 15 single solvents that were used to obtain their single crystals, correlations between the molecular characteristics and the solvents have been investigated by cheminformatics methods. Decision-tree and Bayesian-probability methods have been applied to make classification models. These two models are complementary in character in the present case. It has been proven that the prediction of the solvent rankings for particular compounds by use of the classification models is satisfactory from the practical point of view. The present study has demonstrated that cheminformatics methods could greatly help rational crystallization of small organic molecules such as pharmaceuticals.

Effect of High Pressure on Crystalline Glycine: A New High-Pressure Polymorph

Study of the effect of pressure on organic molecularcrystals is of considerable interest for predicting theresponse of drugs, materials, and devices based onmolecular crystals to high pressures and to othermechanical actions, as well as for upgrading theoreticalmodels used for predicting crystal structures andmolecular conformations as a function of conditions.Information obtained for crystals of small organic mol-ecules can be used for studying biological macromole-cules, in particular, for predicting the secondary struc-ture of polypeptide chains [1].Prominent among organic molecular crystals arecrystals of amino acids. They can serve as biomimet-ics, as well as medicines and materials for molecularelectronics. Studies of the effect of pressure on aminoacids are also of importance for geo- and cosmochem-istry [2]. The search for new high-pressure polymor-phs is believed to be one of the most central problems;however, reliable data on pressure-induced polymor-phous transformations in amino acid crystals have nothitherto been reported. The conclusion based onRaman spectra that pressure induces polymorphoustransformations in L -asparagine [3] and alanine [4]was not supported by later diffraction studies ofthese structures (J.A. Beukes and S. Parsons, privatecommunications). The existence of a high-pressurephase was suggested for glycine [Dawson, A.,Parsons, S., Allan, D., Loveday, J., and Guthrie, M.,http://www.isis.rl.ac.uk/BCA2001/Abstract%20files/bca1…];however, neither the data supporting this suggestion northe data describing the crystal structure of such a phaseare currently available. α -Glycine was not found toundergo pressure-induced phase transitions, at least upto pressures of about 4 GPa (X-ray diffraction) [5] or23 GPa (Raman spectroscopy) [6]. The X-ray diffrac-tion study of α -glycine containing an impurity of γ -glycine at pressures up to 4 GPa [5] showed that, at apressure of about 3.5 GPa, all reflections of the γ phaseabruptly disappeared and no new lines were observed.It was suggested that the γ phase thereby undergoes aphase transition at this pressure and the lines of a newphase are masked by the lines of the α modification [5].To verify this assumption, we prepared a pure phase of γ -glycine by the ad hoc procedure in [7]. This samplewas studied by X-ray diffraction at hydrostatic pres-sures of up to 8 GPa.The high-pressure experiments were carried out insitu in diamond anvil cells of the Merrill–Bassett type[8]. A methanol–ethanol mixture was used as the pres-sure-transmitting medium; this mixture was speciallydried in order to rule out the possible influence of watertraces on the polymorphous transformations of glycine.The X-ray powder diffraction experiment was carriedout with synchrotron radiation ( λ = 0.7195 A) at theEuropean Synchrotron Radiation Facility, Grenoble.X-ray diffraction patterns were recorded with anMAR345 image plate detector. Primary diffraction datawere processed and integrated using the Fit2D software[Hammersley, A., v. V11.012, hammersley@esrf.fr].Diffraction spectra were indexed with the TREOR pro-gram [10]. The subtraction of the background andstructure solution and refinement by the Rietveld tech-nique were performed with the MRIA program pack-age [11]. The PowderCell program package [Kraus, W.and Nolze, G., PowderCell for Windows, v. 2.3,http://www.bam.de/a_v/v_1/powder/e_cell.html] wasused for graphic representation and crystal-chemicalanalysis.The use of a pure sample allowed us, for the firsttime, to reliably detect a pressure-induced phase transi-tion resulting in the formation of a new polymorph andto solve and refine its structure. The initial γ modifica-tion and the new high-pressure phase coexisted in awide range of pressures. The first indications of a new

Development of a Knowledge-Based Potential for Crystals of Small Organic Molecules:  Calculation of Energy Surfaces for C=0···H−N Hydrogen Bonds

This paper describes the derivation of a Knowledge-Based Potential for intermolecular interactions from the statistical information stored in the Cambridge Structural Database. We develop a statistical mechanical method that relates the occurrences of intermolecular contacts in the database to their energies. Our approach allows us to quantify (in the form of energy) the geometrical preferences of interactions. We use our method to construct energy maps for a hydrogen bond between carbonyl oxygen and amino hydrogen. Our results demonstrate high orientational selectivity of this type of hydrogen bonding.

Segmented anisotropic refinement of bovine ribonuclease A by the application of the rigid-body TLS model.

The anisotropic displacements of selected rigid groups in bovine ribonuclease A have been refined from X-ray diffraction data by the application of the rigid-body TLS model. The rigid groups chosen were the side chains of tyrosine, histidine and phenylalanine and the planar side chains of aspartic acid, glutamic acid, glutamine, asparagine and arginine. The method has also been applied to the co-crystallizing active-site sulfate anion. This has enabled the description of the motion of the above-mentioned side-chain atoms by anisotropic displacement ellipsoids from a 1.45 A refinement. The hydrophobic side groups in the protein core show mainly translational motion, with mean-square librations of 20 deg2 which are similar to those found in some close-packed crystals of small organic molecules. Librational displacements are much more significant in the hydrophilic side groups where their magnitudes can be correlated with solvent accessibility. Large librations of some solvent exposed side chains correspond with the breakdown of a simple TLS model and the existence of multiple orientations of the side groups. The TLS model has also been applied to the whole protein molecule and shows that the average motion is approximately isotropic with little librational character.

Highly ordered crystals of the plant seed protein crambin

Crystals of crambin, a plant seed protein of molecular weight 5000, diffract X-rays strongly to the interplanar spacing limit of 0.88 Å. These diffraction data should allow a definition of atomic structure that is on a par with that typically obtained from crystals of small organic molecules. The crystals are in space group P2 1 and have unit cell dimensions a = 41.1 A ̊ , b = 18.7 A ̊ , c = 22·7 A ̊ , and β = 90.6 ° . The asymmetric unit contains one protein molecule.

Short-range order, thermal vibration and expansion, and other properties of pseudosymmetric and mixed crystals of small organic molecules - Short-Range order in n- oxyphenazine and in mixed crystals of phenazine- n -oxyphenazine

Disorder diffuse scattering has been observed for N -oxyphenazine which indicates the existence of domains of short-range order in (100) planes, of average size 13 A (along b) by 50 A (along c). Along a the alternation of centrosymmetrically arranged molecules is random. Mixed crystals with phenazine show diffuse scattering which indicates that up to about 60 mole % of phenazine can occur in the structure without disrupting these short-range-order domains. Mixed crystals of low N -oxyphenazine content have these molecules arranged randomly in the phenazine matrix. Between these two phases there appears to be a miscibility gap. It is probable that two components, one of which is ordered and the other showing only short-range order cannot form a continuous mixed-crystal series.

Short-range order, thermal vibration and expansion, and other properties of pseudosymmetric and mixed crystals of small organic molecules - Calculation of dimensions of ordered regions in triclinic and monoclinic pseudosymmetic crystals from the intensity of diffuse scattering

Mathematical relations are obtained giving the X-ray scattering for a crystal the unit cell of which contains one or two asymmetric molecules, each of which can adopt either of two centrosymmetrically-related orientations, giving pseudocentrosymmetry. It is shown that measurements of the integral breadth of maxima of the diffuse ‘disorder’ scattering can give the dimensions of the short-range order regions. The temperature variation of intensity of such diffuse scattering is different from that of thermal diffuse scattering.