Metastable Polymorph Research Articles

Thermodynamic stability of Li-B-C compounds from first principles.

Prediction of high-Tc superconductivity in hole-doped LixBC two decades ago has brought about an extensive effort to synthesize new materials with honeycomb B-C layers, but the thermodynamic stability of Li-B-C compounds remains largely unexplored. In this study, we use density functional theory to characterize well-established and recently reported Li-B-C phases. Our calculation of the Li chemical potential in LixBC helps estimate the (T,P) conditions required for delithiation of the LiBC parent material, while examination of B-C phases helps rationalize the observation of metastable BC3 polymorphs with honeycomb and diamond-like morphologies. At the same time, we demonstrate that recently reported BC3, LiBC3, and Li2B2C phases with new crystal structures are both dynamically and thermodynamically unstable. With a combination of evolutionary optimization and rational design, we identify considerably more natural and favorable Li2B2C configurations that, nevertheless, remain above the thermodynamic stability threshold.

Correction: Shaping particle size distribution of a metastable polymorph in additive-assisted reactive crystallization by the Taguchi method

Correction for ‘Shaping particle size distribution of a metastable polymorph in additive-assisted reactive crystallization by the Taguchi method’ by Hung Lin Lee et al., CrystEngComm, 2022, 24, 7176–7192, https://doi.org/10.1039/D2CE00355D.

Progress and challenges in the development of ultra-wide bandgap semiconductor α-Ga2O3 toward realizing power device applications

Ultra-wide-bandgap (UWBG) semiconductors, such as Ga2O3 and diamond, have been attracting increasing attention owing to their potential to realize high-performance power devices with high breakdown voltage and low on-resistance beyond those of SiC and GaN. Among numerous UWBG semiconductors, this work focuses on the corundum-structured α-Ga2O3, which is a metastable polymorph of Ga2O3. The large bandgap energy of 5.3 eV, a large degree of freedom in band engineering, and availability of isomorphic p-type oxides to form a hetero p–n junction make α-Ga2O3 an attractive candidate for power device applications. Promising preliminary prototype device structures have been demonstrated without advanced edge termination despite the high dislocation density in the epilayers owing to the absence of native substrates and lattice-matched foreign substrates. In this Perspective, we present an overview of the research and development of α-Ga2O3 for power device applications and discuss future research directions.

Adaptation of the Crystal Structure to the Confined Size of Mixed-oxide Nanoparticles.

Chemical composition and crystal structure are central to defining the functional properties of materials. But when a material is prepared in the form of nanoparticles, the structure and, as a consequence, the composition will also frequently change. Understanding these changes in the crystal structure at the nanoscale is therefore essential not only for expanding fundamental knowledge, but also for designing novel nanostructures for diverse technological and medical applications. The changes can originate from two thermodynamically driven phenomena: (i) a crystal structure will adapt to the restricted size of the nanoparticles, and (ii) metastable structural polymorphs that form during the synthesis due to a lower nucleation barrier (compared to the equilibrium phase) can be stabilized at the nanoscale. The changes to the crystal structure at the nanoscale are especially pronounced for inorganic materials with a complex structure and composition, such as mixed oxides with a structure built from alternating layers of several structural blocks. In this article the complex structure of nanoparticles will be presented based on two examples of well-known and technologically important materials with layered structures: magnetic hexaferrites (BaFe12O19 and SrFe12O19) and ferroelectric Aurivillius layered-perovskite bismuth titanate (Bi4Ti3O12).

Surfactant Provided Control of Crystallization Polymorphic Outcome and Stabilization of Metastable Polymorphs of 2,6-Dimethoxyphenylboronic Acid

2,6-Dimethoxyphenylboronic acid was used as a model substance to investigate the additive crystallization approach for polymorph control in phenylboronic acids. It was crystallized under different conditions by performing evaporation and cooling crystallization from different solvents. Most of the crystallizations from pure solvents produced the thermodynamically stable Form I, but in evaporation crystallization from alcohols, Form II or even a new polymorph, Form III, could be obtained. Structurally related substances, polymers, and surfactants with diverse intermolecular interaction possibilities were tested as additives. Surfactants were found to facilitate the crystallization of the metastable forms and therefore were investigated more extensively. The surfactants Span 20 and n–octyl-β-D-glucopyranoside provided crystallization of the metastable forms in the evaporation crystallization and notably stabilized Form II. The lattice energy, energy frameworks, Hirshfeld surface analysis, full interaction maps, and morphology prediction were used to identify the structural differences between Forms I and II and rationalize the ability of the additives to provide formation of Form II in the crystallization and to stabilize it.

Exploratory phase stabilization in heteroepitaxial gallium oxide films by pulsed laser deposition

Gallium oxide (Ga2O3) is featured by various types of polymorphs that exhibit distinct properties for a broad range of applications. Selective stabilization of distinct Ga2O3 polymorphs is highly desired, but is usually limited by impurity phase formation. Here we report the controlled growth of metastable gallium oxide films by pulsed laser deposition (PLD), and explore a comprehensive phase evolution picture tuned by key synthesis parameters, substrate orientations, and extrinsic tin (Sn) dopants. We demonstrate the stabilization of both undoped and Sn-doped α-Ga2O3 films by selecting a-plane sapphire substrates, and find that Sn dopants can largely broaden the growth window of α-Ga2O3. Besides, Sn-doped ε-Ga2O3 is more favored than β-Ga2O3 to be stabilized on c-plane substrates, and the oxygen pressure is the critical factor to dictate the ε-Ga2O3 formation. The structural impact on the thermal transport among these metastable Ga2O3 films is investigated, which shows a maximum value of 5.66 Wm−1K−1 in α-Ga2O3 and a minimum value of 1.04 Wm−1K−1 in amorphous Ga2O3. The native defects of these phases are sensitive to the Sn doping, which exhibits distinct response for deep ultraviolet photodetection. This study establishes a synthesis guideline of metastable Ga2O3 polymorphs by PLD and provides insights into selective phase stabilization of transition metal oxides with various crystal phases.

Ge136 type-II clathrate as precursor for the synthesis of metastable germanium polymorphs: A computational study

The response to compression of the clathrate type-II structure Ge(cF136) is investigated by means of \textit{ab initio} small-cell metadynamics at different temperatures and pressures. At lower pressure $p$=2.5 GPa the metastable metallic bct-5 phase competes against $\beta$-Sn Ge(tI4), which forms at higher pressures. On lowering temperature, the presence of amorphous intermediates obtained from Ge$_{136}$ is more pronounced and is instrumental to the formation of denser structural motifs, from which metallic bct-5 can form. Therein, anisotropic box fluctuations promote phase formation. The metadynamics runs are analysed in depth using a set of topological descriptors, including coordination sequence and ring statistics. Differences in the structural landscape history and amorphous intermediates are critical for the selective formation of particular metastable polymorphs, towards turning crystal structure predictions into actual materials.

Controlled crystallization of metastable polymorphic pharmaceutical: Comparative study of batchwise and continuous tubular crystallizers

The deliberate and reproducible crystallization of metastable polymorphs of active pharmaceutical ingredients (APIs) from solution remains difficult and is still far from trivial. The main challenge is to prevent cross nucleation of the stable form. The traditional cooling experiments in a batch crystallizer cannot repeatably produce aripiprazole (APZ) metastable Form III within selected initial concentrations and cooling rates. The computational fluid dynamics simulations confirmed that fluctuations in temperature and solution concentration in the batch crystallizer would induce the nucleation of stable crystal forms and accelerate solvent-mediated phase transformation. This work presents, for the first time, ultrasonic- and slug-assisted tubular crystallizers for the continuous and controllable preparation of pure metastable crystal Form III of APZ. The ultrasound-assisted air segmented plug flow tubular crystallizer provides an efficient configuration to produce high purity metastable polymorphism pharmaceuticals, which also offers a facile approach for the continuous manufacturing of drug substances.

Formation of delta-mannitol by co-spray drying: enhancing the tabletability of paracetamol/mannitol formulations

δ-mannitol is a metastable polymorph of mannitol, known for its superior tableting properties. However, there is no easy, reproducible and scalable production method for δ-mannitol. It was evaluated whether δ-mannitol could be formed via co-spray drying with an API exhibiting tabletability issues, to improve the API tabletability in a one-step process prior to compaction. Aqueous suspensions with paracetamol and β-mannitol were co-spray dried. Raman spectroscopy was used to identify the mannitol polymorphs. In these formulations, paracetamol was the key factor to allow the formation of δ-mannitol since no traces of the δ-polymorph could be detected after spray drying a pure mannitol feed. The presence of δ-mannitol after co-spray drying was confirmed even for low paracetamol/mannitol ratios (1:99). The δ-mannitol content varied depending on the process drying parameters, predominantly by the airflow. A lower airflow promoted the formation of δ-mannitol, while more α-mannitol was formed when applying a higher airflow. The starting material, β-mannitol, was often no longer detectable by Raman spectroscopy. The tabletability of the spray dried powders clearly improved in association with the δ-mannitol concentration. The co-processed powders showed superior tabletability in comparison with physical mixtures of the starting materials. Harder tablets with a maximal tensile strength of 2.9 MPa at a main compression pressure of 247 MPa were achieved.

Designer Gelators for the Crystallization of a Salt Active Pharmaceutical Ingredient-Mexiletine Hydrochloride.

We report an approach to obtain drug-mimetic supramolecular gelators, which are capable of stabilizing metastable polymorphs of the pharmaceutical salt mexiletine hydrochloride, a highly polymorphic antiarrhythmic drug. Solution-phase screening led to the discovery of two new solvated solid forms of mexiletine, a type C 1,2,4-trichlorobenzene tetarto-solvate and a type D nitrobenzene solvate. Various metastable forms were crystallized within the gels under conditions which would not have been possible in solution. Despite typically crystallizing concomitantly with form 1, a pure sample of form 3 was crystallized within a gel of ethyl methyl ketone. Various type A channel solvates were crystallized from gels of toluene and ethyl acetate, in which the contents of the channels varied from those of solution-phase forms. Most strikingly, the high-temperature-stable form 2 was crystallized from a gel in 1,2-dibromoethane: the only known route to access this form at room temperature. These results exemplify the powerful stabilizing effect of drug-mimetic supramolecular gels, which can be exploited in pharmaceutical polymorph screens to access highly metastable or difficult-to-nucleate solid forms.

Application of functionalized magnetic silica nanoparticles for selective induction of three coumarin metastable polymorphs

The precise control of active pharmaceutical ingredient (API) crystal nucleation and polymorphism is a key consideration in pharmaceutical manufacturing. In this study, tunable nanoparticles were developed to regulate the nucleation process of coumarin. Magnetic silica nanoparticles with four different functional groups (–NH 2 , –COOH, –SH, –NCO) were prepared and coated on the substrate for inducing the crystallization of coumarin. Confined melt crystallization and microspacing sublimation crystallization methods were used to investigate the regulation mechanism. The results indicated that three metastable forms of coumarin can be obtained as pure components based on the combined influence of crystallization methods and functionalized nanoparticles. Form II could be selectively obtained by microspacing sublimation crystallization on Fe 3 O 4 @SiO 2 –SH substrates, and Form IV could be obtained by confined melt crystallization on Fe 3 O 4 @SiO 2 –NCO substrates. Form III could be obtained by further heating Form IV crystals to 52 °C on Fe 3 O 4 @SiO 2 –NCO substrates. Moreover, the polarized light microscopy results also indicated that the introduction of nanoparticles could also increase the stability of the metastable crystalline forms of coumarin. Finally, the diffusion and surface dynamics during nanoparticle induced crystallization were comparatively investigated and the corresponding polymorphic selectivity mechanism was proposed.

Quantitative Monitoring of Cocrystal Polymorphisms in Model Tablets Using Transmission Low-Frequency Raman Spectroscopy

Cocrystallization is a technique for improving the physical properties of active pharmaceutical ingredients. However, cocrystals can transform into more stable polymorphs as well as dissociate to original materials. Therefore, an analytical technique is required to determine the polymorphic transformation quickly and accurately in tablets. The purpose of this study is to develop a method to monitor cocrystal polymorphs in model tablets using transmission low-frequency Raman spectroscopy. The tablets, consisting of only metastable polymorphs of caffeine-glutaric acid cocrystals, were stored under various relative humidity levels. The composition of the cocrystal polymorphs were calculated from a calibration curve relating the actual composition to the predicted values calculated by partial least squares regression processing of low-frequency Raman spectra. The metastable form gradually converted to a stable form, and polymorphic phase transformation occurred with increasing relative humidity. Ninety-six percent of the metastable form converted into a stable form stored at 25 °C after 3 h at 95% RH. In conclusion, transmission low-frequency Raman spectroscopy can be used to quantitatively monitor cocrystal polymorphs. This technique is one of the candidate techniques to quantifiably evaluate the physico-chemical stability of cocrystal polymorphs in tablets.

First evidence of dmisteinbergite (CaAl2Si2O8 polymorph) in high-grade metamorphic rocks

Abstract We identified dmisteinbergite, the rare trigonal polymorph of CaAl2Si2O8, for the first time in high-grade metamorphic rocks. Dmisteinbergite occurs as a crystallization product of silicate melt inclusions (nanogranitoids) in garnet from three host rocks with different protoliths and re-equilibration conditions, i.e., from 1.0 to 4.5 GPa. Raman spectra and compositions of the dmisteinbergite here investigated are overall identical to those of previously characterized artificial and natural dmisteinbergite. In nanogranitoids, this phase coexists with other metastable polymorphs of feldspar (kumdykolite, kokchetavite) and SiO2 (quartz, cristobalite), recently interpreted as the result of undercooling, supersaturation and rapid crystallization of a silicate melt confined in a micrometric pore. Dmisteinbergite formation likely results from a similar process, and thus it should be regarded as a kinetically controlled phase. Moreover, the investigation of dmisteinbergite as well as of other metastable feldspar polymorphs offers new insights into the behavior of natural materials under non-equilibrium conditions.

Tuning the topological band gap of bismuthene with silicon-based substrates

Some metastable polymorphs of bismuth monolayers (bismuthene) can host non-trivial topological phases. However, it remains unclear whether these polymorphs can become stable through interaction with a substrate, whether their topological properties are preserved, and how to design an optimal substrate to make the topological phase more robust. Using first-principles techniques, we demonstrate that bismuthene polymorphs can become stable over silicon carbide (SiC), silicon (Si), and silicon dioxide (SiO2) and that proximity interaction in these heterostructures has a significant effect on the electronic structure of the monolayer, even when bonding is weak. We show that van der Waals interactions and the breaking of the sublattice symmetry are the main factors driving changes in the electronic structure in non-covalently binding heterostructures. Our work demonstrates that substrate interaction can strengthen the topological properties of bismuthene polymorphs and make them accessible for experimental investigations and technological applications.

Experimental and Theoretical Study of Stable and Metastable Phases in Sputtered CuInS2.

The chalcopyrite Cu(In,Ga)S2 has gained renewed interest in recent years due to the potential application in tandem solar cells. In this contribution, a combined theoretical and experimental approach is applied to investigate stable and metastable phases forming in CuInS2 (CIS) thin films. Ab initio calculations are performed to obtain formation energies, X‐ray diffraction (XRD) patterns, and Raman spectra of CIS polytypes and related compounds. Multiple CIS structures with zinc‐blende and wurtzite‐derived lattices are identified and their XRD/Raman patterns are shown to contain overlapping features, which could lead to misidentification. Thin films with compositions from Cu‐rich to Cu‐poor are synthesized via a two‐step approach based on sputtering from binary targets followed by high‐temperature sulfurization. It is discovered that several CIS polymorphs are formed when growing the material with this approach. In the Cu‐poor material, wurtzite CIS is observed for the first time in sputtered thin films along with chalcopyrite CIS and CuAu‐ordered CIS. Once the wurtzite CIS phase has formed, it is difficult to convert into the stable chalcopyrite polymorph. CuIn5S8 and NaInS2 accommodating In‐excess are found alongside the CIS polymorphs. It is argued that the metastable polymorphs are stabilized by off‐stoichiometry of the precursors, hence tight composition control is required.

Comparison of calcite and vaterite as precursors for CO3Ap artificial bone fabrication through a dissolution–precipitation reaction

Carbonate apatite (CO3Ap) artificial bone is fabricated in an aqueous solution using calcium carbonate as a precursor. CO3Ap has attracted attention because it demonstrates high osteoconductivity and can replace a damaged bone based on the bone remodeling process. This study aims to compare vaterite and calcite, which are metastable and stable polymorphs of calcium carbonate, respectively, as precursors. When the vaterite granules, which have higher solubility and consist of smaller crystals than calcite, prepared from calcium oxide granules were immersed in disodium hydrogen phosphate solution, the compositional transformation to CO3Ap was quicker than that of calcite. Based on the investigations on rabbit femurs, it was observed that the remodeling of CO3Ap to a new bone was faster when vaterite was used as a precursor compared to when calcite was used as a precursor. It is concluded that vaterite can be a better precursor than calcite for CO3Ap artificial bone fabrication.

Crystal Structure and Twisted Aggregates of Oxcarbazepine Form III.

Polymorphism and crystal habit play vital roles in dictating the properties of crystalline materials. Here, the structure and properties of oxcarbazepine (OXCBZ) form III are reported along with the occurrence of twisted crystalline aggregates of this metastable polymorph. OXCBZ III can be produced by crystallization from the vapor phase and by recrystallization from solution. The crystallization process used to obtain OXCBZ III is found to affect the pitch, with the most prominent effect observed from the sublimation-grown OXCBZ III material where the pitch increases as the length of aggregates increases. Sublimation-grown OXCBZ III follows an unconventional mechanism of formation with condensed droplet formation and coalescence preceding nucleation and growth of aggregates. A crystal structure determination of OXCBZ III from powder X-ray diffraction methods, assisted by crystal structure prediction (CSP), reveals that OXCBZ III, similar to carbamazepine form II, contains void channels in its structure with the channels, aligned along the c crystallographic axis, oriented parallel to the twist axis of the aggregates. The likely role of structural misalignment at the lattice or nanoscale is explored by considering the role of molecular and closely related structural impurities informed by crystal structure prediction.

Polymorphic transition due to grinding: the case of 3-[1-(tert-butoxycarbonyl)azetidin-3-yl]-1,2-oxazole-4-carboxylic acid.

A polymorphic transition as a result of grinding was found for 3-[1-(tert-butoxycarbonyl)azetidin-3-yl]-1,2-oxazole-4-carboxylic acid. The thorough study of polymorphic structures before and after crystal structure transformation has revealed some pre-conditions for a polymorphic transition and regularities of changes in molecular and crystal structure. In metastable polymorph 1a, the conformationally flexible molecule adopts a conformation with the higher energy and forms a less preferable linear supramolecular synthon. Additional energy imparted to a crystal structure during the grinding process proved to be enough to overcome low energy barriers for the nitrogen inversion and rotation of the oxazole ring around the sp3-sp2 single bond. As a result, polymorph 1b with a molecule adopting conformation with lower energy and forming a more preferable centrosymmetric supramolecular synthon was obtained. The study of pairwise interaction energies in the two polymorphs has shown that metastable polymorph 1a is organized by molecular building units and has a columnar-layered structure. A centrosymmetric dimer should be recognized as a complex building unit in more stable polymorph 1b, which has a layered structure.

Characterization and Crystal Nucleation Kinetics of a New Metastable Polymorph of Piracetam in Alcoholic Solvents.

A new polymorph of the drug active pharmaceutical ingredient piracetam (Form VI) has been discovered and characterized by X-ray powder diffraction (PXRD), solid-state Raman, attenuated total reflectance infrared spectroscopy, and differential scanning calorimetry. The PXRD diffractogram of Form VI shows a distinct peak at 24.2° (2θ) that distinguishes it from the previously known polymorphs and solvates. Form VI is metastable with respect to the previously known polymorphs Form II and Form III; in ethanol solution at 288 K, Form VI transforms into Form II within 15 min, while in isopropanol solution Form VI is kinetically stable for at least 6 h. A total of 1200 crystal nucleation induction time experiments of piracetam in ethanol and isopropanol solutions have been conducted, in sets of 40–80 repeat experiments carried out at different temperatures and solute concentrations. Each solution nucleated as a single polymorph, and each set of repeat experiments resulted in different proportions of Form II, Form III, and Form VI, with Form VI dominating at low nucleation temperatures and Form II at higher nucleation temperatures. The induction time data for Form VI at 288 K have been evaluated within the framework of the classical nucleation theory. At equal driving force, nucleation of Form VI is less obstructed in ethanol than in isopropanol, as captured by a lower interfacial energy and higher pre-exponential factor in ethanol. The proportion of Form VI obtained at a comparable driving force increases in the order ethanol < isopropanol.

Role of disorder in the synthesis of metastable zinc zirconium nitrides

In materials science, it is often assumed that ground-state crystal structures predicted by density functional theory are the easiest polymorphs to synthesize. Ternary nitride materials, with many possible metastable polymorphs, provide a rich materials space to study what influences thermodynamic stability and polymorph synthesizability. For example, ${\mathrm{ZnZrN}}_{2}$ is theoretically predicted at zero Kelvin to have an unusual layered ``wurtsalt'' ground-state crystal structure with compelling optoelectronic properties, but it is unknown whether this structure can be realized experimentally under practical synthesis conditions. Here, we use combinatorial sputtering to synthesize hundreds of ${\mathrm{Zn}}_{x}{\mathrm{Zr}}_{1\ensuremath{-}x}{\mathrm{N}}_{y}$ thin-film samples, and find metastable rocksalt-derived or boron-nitride-derived structures rather than the predicted wurtsalt structure. Using a statistical polymorph sampler approach, it is demonstrated that although rocksalt is the least stable polymorph at zero Kelvin, it becomes the most stable polymorph at high effective temperatures similar to those achieved using this sputter deposition method, and thus corroborates experimental results. Additional calculations show that this destabilization of the wurtsalt polymorph is due to configurational entropic and enthalpic effects, and that vibrational contributions are negligible. Specifically, rocksalt- and boron-nitride-derived structures become the most stable polymorphs in the presence of disorder because of higher tolerances to cation cross substitution and off stoichiometry than the wurtsalt structure. This understanding of the role of disorder tolerance in the synthesis of competing polymorphs can enable more accurate predictions of synthesizable crystal structures and their achievable material properties.