Crystal Polymorphism Research Articles

Advanced Solid-State NMR Analysis of Two Crystal Forms of Ranitidine Hydrochloride: Detection of 1H-14N Intra-/Intermolecular Correlations.

Understanding the characteristics of crystal polymorphism of active pharmaceutical ingredients and analyzing them with high sensitivity is important for quality of drug products, appropriate characterization strategies, and appropriate screening and selection processes. However, there are few methods to measure intra- and intermolecular correlations in crystals other than X-ray crystallography, for which it is sometimes difficult to obtain suitable single crystals. Recently, solid-state NMR has been recognized as a straightforward method for measuring molecular correlations. In this study, we selected ranitidine hydrochloride, which is known to exist in two forms, 1 and 2, as the model drug and investigated each form using solid-state NMR. In conducting the analysis, rotating the sample tube, which had a 1-mm inner diameter, increased the solid-state NMR resolution at 70 kHz. The 1H-14N dipolar-based heteronuclear multiple quantum coherence (D-HMQC) analysis revealed the intermolecular correlation of Form 1 between the N atom of the nitro group and a proton of the furan moiety, which were closer than those of the intramolecular correlation reported using single X-ray crystal analysis. Thus, 1H-14N D-HMQC analysis could be useful for characterizing intermolecular interaction in ranitidine hydrochloride crystals. In addition, we reassigned the 13C solid-state NMR signals of ranitidine hydrochloride according to the liquid-state and multiple solid-state NMR experiments.

Do metastable polymorphs always grow faster? Measuring and comparing growth kinetics of three polymorphs of tolfenamic acid.

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.

Luminescent hexagonal microtubes prepared through water-induced self-assembly of a polymorphic organoboron compound: formation mechanism and waveguide behaviour.

Tetra-coordinated organoboron (TCOB) compounds are promising candidates for developing high-performance optical devices due to their excellent optoelectronic performance. Fabricating TCOB-based nanomaterials of controlled and defined morphology through rapid and easy-to-execute protocols can significantly accelerate their practical utility in the aforesaid applications. Herein, we report water-induced self-assembly (WISA) to convert a polymorphic TCOB complex (HNBI-B, derived from a 2-(2'-hydroxy-naphthyl)-benzimidazole precursor) into two unique nanomorphologies viz. nanodiscoids (NDs) and fluorescent microtubes with hexagonal cross-sections (HMTs). Detailed electron microscopic investigations revealed that oriented assembly and fusion of the initially formed NDs yield the blue emissive HMTs (SSQY = 26.7%) that exhibited highly promising photophysical behaviour. For example, the HMTs outperformed all the crystal polymorphs of HNBI-B obtained from CHCl3, EtOAc and MeOH in emissivity and also exhibited superior waveguide behaviour, with a much lower optical loss coefficient α' = 1.692 dB mm-1 compared to the rod-shaped microcrystals of HNBI-B obtained from MeOH (α' = 1.853 dB mm-1). Thus, this work reports rapid access to high performance optical nanomaterials through WISA, opening new avenues for creating useful nanomaterial morphologies with superior optical performance.

Multi-stimuli responsive organic polymorphic crystals: anisotropic elasticity and plasticity, mechanochromism and photomechanical motions

The development of organic crystals responsive to multiple external stimuli (mechanical force, light and heat) as potential smart materials is always compelling but challenging.

Discriminating and understanding molecular crystal polymorphism.

Polymorph discrimination for a molecular crystal has long been a challenging task, which, nonetheless, is a major concern in the pharmaceutical industry. In this work, we have investigated polymorph discrimination on three different molecular crystals, tetrolic acid, oxalic acid, and oxalyl dihydrazide, covering both packing polymorphism and conformational polymorphism. To gain more understanding, we have performed energy decomposition analysis based on many-body expansion, and have compared the results from the XO-PBC method, that is, the eXtended ONIOM method (XO) with the periodic boundary condition (PBC), with those from some commonly used dispersion corrected density functional theory (DFT-D) methods. It is shown here that, with the XYG3 doubly hybrid functional chosen as the target high level to capture the intra- and short-range intermolecular interactions, and the periodic PBE as the basic low level to take long range interactions into account, the XO-PBC(XYG3:PBE) method not only obtains the correct experimental stability orderings, but also predicts reasonable polymorph energy ranges for all three cases. Our results have demonstrated the usefulness of the present theoretical methods, in particular XO-PBC, while highlighted the importance of a better treatment of different kinds of interactions to be beneficial to polymorph control.

Effect of tempering and cocoa butter equivalents on crystallization kinetics, polymorphism, melting, and physical properties of dark chocolates

The high price and scarcity of cocoa butter (CB) motivate the search for new cocoa butter equivalents (CBE) for manufacturing dark chocolates. Using CBEs in combination with tempering regimens is an option to produce fine chocolates. Thus, CBEs' thermal properties and crystallization kinetics were studied, and the effect of CBE, and tempering regimes on the crystallization kinetics, polymorphism, melting, and physical properties of dark chocolates were determined. The CBE consisted of CB mixtures with coconut oil (CB/CNO) and sacha inchi oil (CB/SIO) in concentrations of 55/45 and 65/35, respectively. CBEs combined with two tempering regimes (high and low) were used to produce Ch-CNO and Ch-SIO dark chocolates, whose thermal data were obtained by Differential Scanning Calorimetry. The adjustment of thermal data to the Avrami equation permitted us to determine that both factors accelerated the crystallization process up to 7.25 ± 0.18 min in Ch-CNO and 7.08 ± 0.15 min in Ch-SIO and produced spherical and plate-like geometries crystallized nuclei. Also, they generated 90.3 ± 1.18 of form β2 in Ch-CNO and 92.56 ± 1.49 in Ch-SIO. Moreover, the chocolates' texture, rheology, color, and melting properties were within acceptable limits. Therefore, using coconut oil and sacha inchi oil as an alternative to traditional CBEs in dark chocolates is feasible.

Surface engineering of zinc phthalocyanine organic thin-film transistors results in part-per-billion sensitivity towards cannabinoid vapor

Phthalocyanine-based organic thin-film transistors (OTFTs) have been demonstrated as sensors for a range of analytes, including cannabinoids, in both liquid and gas phases. Detection of the primary cannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), is necessary for quality control and regulation, however, current techniques are often not readily available for consumers, industry, and law-enforcement. The OTFT characteristics, X-ray diffraction (XRD) spectra, and grazing incident wide angle x-ray scattering (GIWAXS) spectra of two copper and three zinc phthalocyanines, with varying degrees of peripheral fluorination, were screened to determine sensitivity to THC vapor. Unsubstituted ZnPc was found to be the most sensitive material and, by tuning thin-film morphology, crystal polymorphs, and thickness through altered physical vapor deposition conditions, we increased the sensitivity to THC by 100x. Here we demonstrate that deposition conditions, and the resulting physical film characteristics, play a significant role in device sensitization.

Analysis of Cimetidine Crystal Polymorphs by X-ray Absorption Near-Edge Spectroscopy.

Sulfur K-edge X-ray absorption near-edge spectroscopy (XANES) measurements were performed to characterize the crystal polymorphs of the active pharmaceutical ingredients (APIs) containing sulfur atoms. Cimetidine (CIM) was used as a model API. Each crystal form of CIM has its own XANES spectrum, so we can discriminate the crystal form by its spectrum. The analysis of the crystal structure of CIM revealed that the difference in the shape of XANES spectra was ascribable to the difference in the C-S-C bond angle of CIM molecules and the intermolecular hydrogen bonds, such as C-H···S and N-H···S, and S-S interaction. It was found that the peak shape of the XANES spectrum is gentle when the C-S-C bond angle is large, while the peak shape can be steep when the C-S-C bond angle is small. Furthermore, it was found that the peak energy values varied depending on the hydrogen bonds and S-S interaction. By linear combination fitting using XANES spectra, it was possible to quantify the ratio of CIM form A crystal in mixed powders of form A and monohydrate crystals. These results indicate that XANES measurements can be a useful technique to evaluate the crystal polymorphism of APIs containing S atom in pharmaceutical formulation.

Controlling orientation, polymorphism, and crystallinity in thin films of poly(lactic‐acid) homopolymer and stereocomplex aligned by high temperature rubbing

AbstractHigh temperature rubbing is a fast and low‐cost method that can align semi‐crystalline polymers such as poly(lactic acid) (PLA) by application of a shear‐force via a rotating cylinder covered with a microfiber cloth on a thin film maintained at high temperature. A multi technique approach uncovers the role of rubbing temperature and film thickness on the PLA thin film structure. Both poly(l‐lactic acid) (PLLA) and the stereo‐complex (SC‐PLA) can be readily aligned by high temperature rubbing. The rubbing temperature TR and the film thickness are the key parameters that control polymorphism, in‐plane orientation, crystallinity and contact plane of the polymer crystals. Rubbing PLLA films in the range 80–140°C affords different aligned polymorphs (mesophase, α′, α′ + α mixtures and pure α phase) depending on the rubbing temperature. Pure α form of PLLA with 53% crystallinity is obtained at TR = 140°C whereas pure oriented crystalline SC‐PLA films are obtained by rubbing at 200°C.

A rod- and tessellation-based comparative analysis of polymorphic and structurally-invariant molecular crystals: application to sulfathiazole and 2-benzyl-5-benzylidenecyclopentanones.

A rationalization of the alternative crystal structures adopted by a given molecular compound or by a set of substitutionally related molecular compounds is provided by reference to the five known polymorphs of sulfathiazole and 16 substituted 2-benzyl-5-benzylidene cyclopentanones (BBCPs), respectively. Two-dimensional (2D) packing fractions (ϕ2D) take space-group symmetry into account, with a clear demarcation of closed-packed zones (CPZ) and molecular junction zones (JZ) in all Z' = 1 structures. Representation of the molecules as two linked rods allows a concise treatment of conformation and rapid visualization of crystal packing. Combined with calculations of intermolecular potential energies, the rod method provides insight into the stabilization mechanisms of alternative polymorphs. In sulfathiazole, the primary factor is to obtain satisfactory hydrogen bonding, with close packing a secondary consideration. In BBCP derivatives, by comparison, close packing is the primary mechanism of stabilization. Whereas the 2D structures arising in CPZ can be analysed as tessellations of molecular-based cells, a method based on 2D Dirichlet cells is required for the JZ. These are calculated from the centroids of the molecular envelopes in high-symmetry planes. It is shown that these centroid coordinates, when combined with space-group symmetry and unit cell coordinates, provide a concise parameterization of all structures containing JZ. It is anticipated that this parameterization may be exploited to predict such crystal structures from powder diffraction data.

Hydrated polymorphs of 2,3,4,5,6-pentachlorobenzoic acid: Crystallographical and computational analyses of disordered hydrogen-bonding networks

The title compound, 2,3,4,5,6-pentachlorobenzoic acid (PCBAH), was found to have two crystal polymorphs, I and II. In this work, novel two hydrated polymorphs, polymorph III and IV, were reported. An asymmetric unit of the polymorph III is comprised of one PCBAH and a water molecule. They align alternatively along the a axis, forming C22(6) hydrogen-bonding. The water molecule makes another hydrogen bond with a water molecule in an inversion symmetry to give two-legged ladder hydrogen-bonding network. In polymorph IV, there are two PCBAHs, 2,3,4,5,6-pentachlorobenzate (PCBA) and H3O+ in an asymmetric unit. H3O+ molecule makes hydrogen-bonding with two PCBA anions, forming C22(6) hydrogen-bonding along the 21 axis. Two PCBAH molecule make hydrogen bonds with both H3O+ and PCBA. In both hydrated polymorphs, hydrogen atoms of water molecules are disordered. The positions of hydrogen atoms of the water molecules were determined with assistance of computational calculations under the crystalline environment.

DEVELOPMENT AND CHARACTERIZATION OF LAURIC ACID OLEOGELS

Bu çalışmada laurik asit (LA) oleojelatörü Span 60 ve Pluronic F68 (%10 poloksamer 188) emülgatörleriyle birlikte kullanılarak ayçiçek yağı oleojelleri geliştirilmiştir. Geliştirilen oleojellerin fizikokimyasal, termal, yapısal ve reolojik özellikleri belirlenmiştir. Sadece LA içeren (%20) oleojellerin jel oluşum zamanının %15 LA ve %5 emülgatör içeren oleojellerden daha kısa olduğu, LA konsantrasyonundaki artışın jel yapı oluşum zamanını kısalttığı gözlenmiştir. LA konsantrasyonu ve emülgatör çeşidine bağlı olarak oleojellerin renk değerlerinde farklılıklar görülürken tüm oleojel örneklerinin yağ bağlama kapasitelerinin yüksek olduğu belirlenmiştir. Polarize ışık mikroskobu görüntülerinde oleojellerin ince kristal yapılar oluşturduğu gözlenirken, X-ışını kırınım deseni β ve β՛ polimorf kristallerinin varlığını kanıtlamıştır. Reolojik analizlerle geliştirilen oleojellerinin yapısal geri dönüşüm yeteneğinin olduğu belirlenmiştir. Emülgatör ilavesinin daha düşük konsantrasyonlarda LA ile oleojel oluşumuna olanak sunduğu, aynı zamanda daha dayanıklı jel yapı oluşturabildiği reolojik testlerle tespit edilmiştir.

Crystal polymorphism in fragment-based lead discovery of ligands of the catalytic domain of UGGT, the glycoprotein folding quality control checkpoint.

None of the current data processing pipelines for X-ray crystallography fragment-based lead discovery (FBLD) consults all the information available when deciding on the lattice and symmetry (i.e., the polymorph) of each soaked crystal. Often, X-ray crystallography FBLD pipelines either choose the polymorph based on cell volume and point-group symmetry of the X-ray diffraction data or leave polymorph attribution to manual intervention on the part of the user. Thus, when the FBLD crystals belong to more than one crystal polymorph, the discovery pipeline can be plagued by space group ambiguity, especially if the polymorphs at hand are variations of the same lattice and, therefore, difficult to tell apart from their morphology and/or their apparent crystal lattices and point groups. In the course of a fragment-based lead discovery effort aimed at finding ligands of the catalytic domain of UDP-glucose glycoprotein glucosyltransferase (UGGT), we encountered a mixture of trigonal crystals and pseudotrigonal triclinic crystals-with the two lattices closely related. In order to resolve that polymorphism ambiguity, we have written and described here a series of Unix shell scripts called CoALLA (crystal polymorph and ligand likelihood-based assignment). The CoALLA scripts are written in Unix shell and use autoPROC for data processing, CCP4-Dimple/REFMAC5 and BUSTER for refinement, and RHOFIT for ligand docking. The choice of the polymorph is effected by carrying out (in each of the known polymorphs) the tasks of diffraction data indexing, integration, scaling, and structural refinement. The most likely polymorph is then chosen as the one with the best structure refinement Rfree statistic. The CoALLA scripts further implement a likelihood-based ligand assignment strategy, starting with macromolecular refinement and automated water addition, followed by removal of the water molecules that appear to be fitting ligand density, and a final round of refinement after random perturbation of the refined macromolecular model, in order to obtain unbiased difference density maps for automated ligand placement. We illustrate the use of CoALLA to discriminate between H3 and P1 crystals used for an FBLD effort to find fragments binding to the catalytic domain of Chaetomium thermophilum UGGT.

Ultrafast magic angle spinning NMR characterization of pharmaceutical solid polymorphism: A posaconazole example

Protons represent the most NMR-sensitive nucleus in pharmaceutical compounds. Therefore, proton-detected solid-state NMR techniques under fast magic angle spinning are among the few solutions to overcome the challenge of low sensitivity to analyze natural abundant drug substances and products. In this study, we report the structural characterization of crystal polymorphs of a commercial drug molecule, posaconazole, with a relatively large molecular weight of 700.8 g·mol−1 and at the natural abundance. The enhanced sensitivity and resolution at 100 kHz MAS enables the exploration of the distinct intermolecular packing in posaconazole forms I, III, and γ. These results demonstrate that proton-detected homo- and heteronuclear correlation methods can probe the structural details of pharmaceutical polymorphism.

Crystal Polymorphism Induced by Surface Tension.

We use classical density functional theory (cDFT) to calculate fluid-solid surface tensions for fcc and bcc crystals formed by hard spheres and Lennard-Jones (LJ) particles. For hard spheres, our results show that the recently introduced "explicitly stable" functionals perform as well as the state of the art, and for both interaction potentials, our results compare well to simulation. We use the resulting bulk and interfacial energies for LJ to parametrize a capillary model for the free energy of small solid clusters and thereby determine the relative stability of bcc and fcc LJ clusters. We show a crossover from bcc to fcc stability as cluster size increases, thus providing insight into long-standing tension between simulation results and theoretical expectations. We also confirm that the bcc phase in contact with a vapor is unstable, thus extending earlier zero-temperature results. Our Letter demonstrates the potential of cDFT as an important tool in understanding crystallization and polymorphism.

Flow-induced crystallization effect on polypropylene with respect to nucleating agents

To study FIC on the laboratory scale, we used a parallel plate rheometer (PPR), which imparts shear rates of some order of magnitude. Applying shear in undercooling temperature (151 °C) conditions to induced crystallization, which was monitored by the increase in viscosity in the PPR following an established protocol that was stetted up to assess the conditions of the experiments. After annealing samples at 230 °C for 10 min to remove the melt memory effect, it was cooled to crystallization temperature (1510C) at the rate of -1.5 °C/min to undertake FIC and finally the sample was quenched by a cryo-freezer aerosol below 0 °C before being removed for characterization study. FIC involves the formation of the time and temperature-dependent relative crystallinity of a series of isotactic polypropylene (iPP) homopolymers. In this study, I selected iPP as a typical sample due to its simple formation conditions of polymorphic crystals and its unique properties of melting curves and crystalline morphology. In this research, the influence of some nucleating agents on the crystallization behavior of (iPP) Homopolymer has been investigated by OM (Optical Microscopy) and Transmission Electron Microscope (TEM) after undergoing FIC crystallization. The study of crystallization kinetics of iPP Homopolymer nucleated with (Talc, Na-Benzoate) and neat melt (Not nucleated-used as control) helped us to control the final morphologies and mechanical properties of semi-crystalline polymers. From the measured onset time of crystallization, it was possible to conclude that iPP containing Na- Benzoate as the nucleating agent was faster in crystallization.

Phase control of two-dimensional tin sulfide compounds deposited via atomic layer deposition

Two-dimensional (2D) semiconductor materials are emerging as potential candidates for emerging electronic device applications due to their excellent electrical properties and unique properties such as flexibility and transparency. Among the various potential 2D semiconductor materials, tin sulfide compounds can form polymorphs of different 2D crystals: 2D layered-SnS2 with hexagonal symmetry and 2D layered SnS with orthorhombic symmetry. In addition, since they each have different electrical and optical properties, their controlled growth is important for appropriate target applications. Therefore, we investigated the phase control of tin sulfide compounds deposited via atomic layer deposition according to their deposition temperature and post-annealing conditions. A strategy for controlling the growth of SnS2 or SnS was proposed by investigating phase transition tendencies according to deposition temperature and annealing conditions (temperature, pressure, atmosphere). As a result, it was possible to selectively deposit SnS2 and SnS thin films based on a phase transition study; it was confirmed that SnS2 and SnS thin films exhibited n-type and p-type semiconductor characteristics, respectively.

Complex Additive‐Assisted Crystal Growth and Phase Stabilization of α‐FAPbI3 Film for Highly Efficient, Air‐Stable Perovskite Photovoltaics

AbstractSolution‐processed formamidinium lead iodide (FAPbI3) perovskite is entropically metastable, and it exhibits condition‐induced crystal polymorphism. Under an ambient atmosphere, the photoactive black α‐FAPbI3 converts easily to photoinactive yellow δ‐FAPbI3. This α → δ phase degradation is further accelerated upon exposure to high temperature/humidity, directly threatening the performance and stability of perovskite solar cells (PSCs). Herein, cesium iodide‐lead iodide:dimethyl sulfoxide (CsI‐PbI2:DMSO) complex is introduced as a phase stabilizer to modulate the crystallization of α‐FAPbI3 perovskite from δ‐FAPbI3 precursor and simultaneously, serve as a defect passivator to suppress trap states formation. Theoretical simulations and experimental results reveal the pivotal role of complex additive in optimizing the energy band alignment and optoelectronic properties of α‐FAPbI3 perovskite and most importantly, hindering the α → δ phase transition. The best PSC device based on the additive‐engineered perovskite film achieves an efficiency of ≈21.9%, which is ≈11% higher than that of its pristine counterpart (≈19.8%). In addition, the incorporation of CsI‐PbI2:DMSO complex remarkably enhances the long‐term stability and photostability of the PSCs by inhibiting ion migrations and preserving the α‐phase in FAPbI3 perovskite. The additive engineering presented herein offers a route to produce FAPbI3‐based PSCs with improved performance, stability, and reproducibility.

Surface-enhanced crystal nucleation and polymorph selection in amorphous posaconazole.

Molecules at a liquid/vapor interface have different organizations and mobilities from those in the bulk. These differences potentially influence the rate of crystal nucleation, but the effect remains imperfectly understood. We have measured the crystal nucleation rates at the surface and in the bulk of amorphous poscaconazole, a rod-like molecule known to have a preferred interfacial orientation. We find that surface nucleation is vastly enhanced over bulk nucleation, by ∼9 orders of magnitude, and selects a different polymorph (II) from bulk nucleation (I). This phenomenon mirrors the recently reported case of D-arabitol and stems from the similarity of anisotropic surface molecular packing to the structure of the surface-nucleating polymorph. In contrast to these two systems, the surface enhancement of nucleation is weaker (though still significant) in acetaminophen and in water and does not select a different polymorph. Together, the systems investigated to date all feature surface enhancement, not suppression, of crystal nucleation, and those showing a polymorphic change feature (1) structural reconstruction at the surface relative to the bulk and (2) existence of a different polymorph that can take advantage of the surface environment to nucleate. These results help predict the effect of a liquid/vapor interface on crystal nucleation and polymorph selection, especially in systems with a large surface/volume ratio, such as atmospheric water and amorphous particles.

Solution-mediated phase transition of pharmaceutical compounds: Case studies of acetaminophen and aspirin

Polymorphism is crucial in organic solid-state chemistry because different polymorphs exhibit different physical properties. Thus, the control of crystal polymorphism is a long-standing issue. We have been engaged in crystal polymorph control research, mainly targeting pharmaceutical compounds. Three processes to control the polymorphism must be considered: nucleation, crystal growth, and phase transition. Finding a metastable phase by nucleation control techniques is the first step. The next crucial step is controlling phase transition and keeping the metastable phase as long as possible. Understanding the phase transition from metastable to stable phase is essential, especially to realize the high stability metastable phase. Herein we will show the phase transition processes of acetaminophen and aspirin as model materials.