Stable Polymorph Research Articles

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.

High-temperature solid-state rutile-to-anatase phase transformation in TiO2

TiO2 has many polymorphs, among which rutile is the most thermodynamically stable. Bulk anatase TiO2 is usually a metastable phase at room temperature. Hence, phase transformation of bulk rutile TiO2 to anatase TiO2 by heat treatment is thermodynamically forbidden. However, the stability of TiO2 polymorphs is dependent on particle size and doping level. In this work, we harnessed this characteristic to develop a solid-state high-temperature route of sequential NH3 and O2 treatment that transforms rutile TiO2 to anatase phase via grain fracture and N-doping. As an additional advantage, this technique produces a mixture of anatase and rutile phases, with anatase being a major phase. Biphasic TiO2 is advantageous from a charge separation perspective for photocatalytic applications. Furthermore, the bandgap of anatase TiO2 can be manipulated by controlling the O2 treatment time to tune it for specific applications.

Dynamics and disorder: on the stability of pyrazinamide polymorphs

Dynamics and disorder: on the stability of pyrazinamide polymorphs

Phase diagram P/T of resorcinol and the stabilization of high-pressure polymorphs by rational doping

Phase diagram <i>P</i>/<i>T</i> of resorcinol and the stabilization of high-pressure polymorphs by rational doping

The formation of highly stable form of isotactic polybutene-1 electrospun membrane via self-seeding

The non-isothermal crystallization behavior from the incomplete melting of isotactic polybutene-1 (iPB-1) electrospun (e-spun) membranes is investigated. The standard sample of e-spun iPB-1 contains the concomitant form II and I′, which are less stable than form I. So, we adopted a pathway of treating a nucleation stage of concomitant polymorphs. Cross-nucleation was observed when a stable polymorph nucleates and grows on a formerly existing polymorph. The present outcomes revealed that upon non-isothermal crystallization of a partially molten state, an appropriate Domain of self-seeding temperature (Ts) 115 °C to 125 °C directed towards forming highly stable iPB-1 form I. Such phenomena might be typified to the memory effect of their pristine crystalline structure and the inter-lamella confinement effect in that particular and constrained environment of the partially molten state. In addition, the influence of variable applied voltage on the self-nucleation mechanism was also considered comparatively. Based on their morphology, spectral, and thermal analysis, samples spun at 11 kV were relatively preeminent to proceed with the self-seeding route.

Examining the Non-Covalent Interactions for Two Polymorphs of a 2,1,3-benzoxadiazole Derivative

Two polymorphs of a benzoxadiazole derivative were examined to determine the interactions leading to the formation of two distinct crystalline forms. Hirshfeld surface analysis was used to establish and contrast the interactions in the two samples. Fingerprints derived from the surface analysis were used to distinguish and lead the analysis in discovering the different interactions in the two crystals. π interactions, specifically, π-hole interactions with a nitro moiety, were found to play an important role in the formation of the crystal structure. Further, carbonyl interactions and π-stacking contribute to the overall relative stability of the different conformational polymorphs. Calculated energy frameworks were used to help visualize the interactions between molecules in the crystal structure, supported by an understanding of the individual interactions. The experimental data were supplemented with theoretical studies to establish a through understanding of these heterocyclic systems.

The ikaite to calcite transformation: Implications for palaeoclimate studies

Marine sedimentary ikaite is the parent mineral to glendonite, stellate pseudomorphs found throughout the geological record which are most usually composed of calcite. Ikaite is known to be metastable at earth surface temperatures and pressures, readily breaking down to more stable carbonate polymorphs when exposed to warm (ambient) conditions. Yet the process of transformation of ikaite to calcite is not well understood, and there is an ongoing debate as to the palaeoclimatic significance of glendonites in the geological record. This study uses a combination of techniques to examine the breakdown of ikaite to calcite, outside of the ikaite growth medium, and to assess the palaeoclimatic and palaeoenvironmental significance of stable and clumped isotope compositions of ikaite-derived calcite. Powder X-ray diffraction shows that ikaite undergoes a quasi- solid-state transformation to calcite during heating of samples in air, yet when ikaite transforms under a high temperature differential, minor dissolution-recrystallisation may also occur with the ikaite structural waters. No significant isotopic equilibration to transformation temperature is observed in the resulting calcite. Therefore, in cases of transformation of ikaite in air, clumped and stable isotope thermometry can be used to reconstruct ikaite growth temperatures. In the case of ancient glendonites, where transformation of the ikaite occurred in contact with the interstitial waters of the host sediments over unknown timescales, it is uncertain whether the reconstructed clumped isotope temperatures reflect ikaite crystallisation or its transformation temperatures. Yet clumped and stable isotope thermometry may still be used conservatively to estimate an upper limit for bottom water temperatures.Furthermore, stable isotope along with element/Ca ratios shed light on the chemical environment of ikaite growth. Our data indicate that a range of (bio)geochemical processes may act to promote ikaite formation at different marine sedimentary sites, including bacterial sulphate reduction and anaerobic oxidation of methane. The colours of the ikaites, from light brown to dark brown, indicate a high organic matter content, favouring high rates of bacterial sulphate reduction as the main driver of ikaite precipitation. Highest Mg/Ca ratios are found in the most unstable ikaites, indicating that Mg acts to destabilise ikaite structure.

Role of an intramolecular H-bond in lidocaine conformer distribution and polymorph stability

• Solubility of lidocaine in scCO 2 in wide range of phase diagram was measured. • Analysis of the conformations of lidocaine in scCO 2 was performed. • Stability of intramolecular hydrogen bond in lidocaine molecule was found. In this work, we study conformational equilibria of lidocaine molecules in a saturated lidocaine solution in scCO 2 under heating conditions in the temperature range of 35–80 °C along three isochores corresponding to the scCO 2 density of 1.1, 1.3, and 1.5 of its critical value. It is established that among of 68 conformers obtained by quantum chemical calculations, it is only conformers with an intramolecular hydrogen bond that are realized within the studied range of parameters of state. The IR spectroscopy data show that the lidocaine solubility in scCO 2 increases significantly with the fluid phase temperature and density growth, reaching the concentration about 10 −1 mol·L −1 . However, this does not lead to the formation of intermolecular hydrogen bonds between the lidocaine molecules in the solution. Moreover, the heating changes the conformational equilibrium of lidocaine molecules in the scCO 2 phase, but this change is not related to the destruction of the intramolecular hydrogen bond. Higher scCO 2 phase density is found to reduce the temperature effect on the conformational equilibrium. Finally, we establish that the temperature-induced conformational changes in the lidocaine molecules in the scCO 2 phase are completely reversible. It allows us to assume that, regardless of the SCF solution parameters of state in the considered phase diagram region, lidocaine crystallization from this solution will lead to the formation of the same stable polymorph.

Polymorphic and microstructural behaviors of palm oil/lecithin blends crystallized under shear

AbstractThere has been much work on polymorphism and crystal habit of quiescently crystallized palm oil. However, researchers have found it difficult to probe the process of sheared crystallization. The effect of surface‐active molecules as nucleation agents or habit modifiers was demonstrated in quiescent systems. The aim of this work is to explore the effects of shear and specific lecithins (soy and sunflower) on palm oil crystallization by monitoring crystallization under shear using a synchrotron radiation source, as well as microscopy and DSC. It was found that increasing shear led to increasing β′ stabilization in all situations. Soybean lecithin had little effect on behavior. Sunflower lecithin led to even greater β′ stabilization. The different lecithins interact with the crystallizing fat changing rates of nucleation and crystal growth. Thus, the structure of the overall system can be dramatically altered. Microscopy revealed very different structures even if the polymorphism of the different systems was similar. Consequently, specific interactions can be manipulated in order to control the system. In particular, control of lecithin composition affects the stability of the different polymorphs. Palm oil crystallization under realistic processing conditions has been characterized. Under these conditions, increasing shear rates give higher β′ stability. Specific lecithins have different effects. In particular, soybean lecithin is β′ stabilizing, whereas sunflower lecithin has limited effects. Thus the overall structure of lecithin is important in determining the efficacy. This can be applied to control the structure and properties of different systems such as shortenings or spreads where crystalline interactions create the macro‐structure that determines product properties.

Directed Dehydration as Synthetic Tool for Generation of a New Na4 SnS4 Polymorph: Crystal Structure, Na+ Conductivity, and Influence of Sb-Substitution.

We present the convenient synthesis and characterization of the new ternary thiostannate Na4SnS4 (space group I41/acd ) by directed removal of crystal water molecules from Na4SnS4⋅14 H2O. The compound represents a new kinetically stable polymorph of Na4SnS4, which is transformed into the known, thermodynamically stable form (space group P4‾21c ) at elevated temperatures. Thermal co‐decomposition of mixtures with Na3SbS4⋅9 H2O generates solid solution products Na4−x Sn1−x Sb x S4 (x=0.01, 0.10) isostructural to the new polymorph (x=0). Incorporation of Sb5+ affects the bonding and local structural situation noticeably evidenced by X‐ray diffraction, 119Sn and 23Na NMR, and 119Sn Mössbauer spectroscopy. Electrochemical impedance spectroscopy demonstrates an enormous improvement of the ionic conductivity with increasing Sb content for the solid solution (σ 25°C=2×10−3, 2×10−2, and 0.1 mS cm−1 for x=0, 0.01, and 0.10), being several orders of magnitude higher than for the known Na4SnS4 polymorph.

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.

Understanding the Anisotropic Mechanical Behavior of Single‐Crystalline Alpha Quartz From the Insight of Molecular Dynamics

AbstractQuartz is among Earth's most abundant minerals, which has several stable polymorphs in nature. In this study, molecular dynamics simulations are used to investigate the mechanical properties of crystalline alpha quartz. The obtained results specify that tensile stress under uniaxial tension is greater in z (c‐axis) than in other directions (290 vs. 115 GPa and 190 GPa). This outcome confirms that crystalline quartz has an anisotropic behavior under applied load, and as a result, Young's modulus varies in different directions. Furthermore, the effect of existing central cracks with different lengths are considered and the results analyzed. According to the results, central cracks decrease average stress and strain, and this reduction is higher in the z‐direction([0 0 0 1]). Additionally, it was found that the strain rate affects the stress‐strain behavior of the models; however, the strain rate plays a negligible role when the central crack length extends. In terms of potential energy, simulation results indicate that potential energy is the highest in the model without any crack and reduces by growing the central crack size.

Dynamics and disorder: on the stability of pyrazinamide polymorphs.

This article focuses on the structure and relative stability of four pyrazinamide polymorphs. New single crystal X-ray diffraction data collected for all forms at 10 K and 122 K are presented. By combining periodic ab initio DFT calculations with normal-mode refinement against X-ray diffraction data, both enthalpic and entropic contributions to the free energy of all polymorphs are calculated. On the basis of the estimated free energies, the stability order of the polymorphs as a function of temperature and the corresponding solid state phase transition temperatures are anticipated. It can be concluded that the α and γ forms have higher vibrational entropy than that of the β and δ forms and therefore they are significantly more stabilized at higher temperatures. Due to the entropy which arises from the disorder in γ form, it overcomes form α and is the most stable form at temperatures above ∼500 K. Our findings are in qualitative agreement with the experimental calorimetry results.

Prediction of a model crystal structure for Ni2F5 by first-principles calculations

Abstract Electrochemical fluorination in anhydrous HF, also known as the Simons process, is a widely used industrial method for fluorination of organic compounds. Its mechanism, being not so well understood, has long been debated and is believed to involve higher valent nickel fluorides formed on the nickel-plated anode during the process. One of these is speculated to be Ni2F5, which was previously reported in the literature and assigned via infrared spectroscopy, but its crystal structure is not yet known. We have identified known crystal structures of compounds with similar stoichiometries as Ni2F5 and utilized them as a starting point for our periodic DFT investigations, applying the PBE+U method. Ni2F5 as the most stable polymorph was found to be of the same crystal structure as another mixed valent fluoride, Cr2F5. The calculated lattice parameters are a = 7.24 Å, b = 7.40 Å, c = 7.08 Å and β = 118.9° with an antiferromagnetic ordering of the nickel magnetic moments.

Comparative study of the fundamental properties of Ga2O3 polymorphs

Full potential linearized augmented plane wave method plus local orbitals (FP-LAPW ​+ ​lo) on the basis of Density Functional Theory (DFT) is called to study the structural, electronic, elastic, optical, thermodynamic and transport properties of four different phases of Ga2O3 denoted by α, β, δ, and ε. The calculated gap energy Eg for the stable polymorph β-Ga2O3 using the modified Becke-Johnson (mBJ) exchange potential is 4.6 ​eV which lies in the deep ultraviolet range making Ga2O3 promising for optoelectronics. Thermal effects on some macroscopic properties such as heat capacity, thermal expansion coefficient, Grüneisen parameter and Debye temperature are predicted using the quasi-harmonic Debye model. The analysis of transport properties for β-Ga2O3 using semi-classical Boltzmann transport theory in temperature range between 300 and 1000 ​K showed high Seebeck coefficient S ​= ​−348.4 μVK−1 at room temperature with huge power factor PF ​= ​39.5 ​× ​1010 WK−2m−1 ​s−1 ​at T ​= ​1000 ​K. This suggests that Ga2O3 is a potential thermoelectric material.

On the stability of MOPO4 structure types with M: V, Mo, Nb, W, Ta, Sb

Transition metal oxide phosphates MOPO4 have recently attracted interest due to their catalytic and electronic properties, and as electrode material. In order to predict possible polymorphs that have hitherto not been prepared, we present a systematic theoretical study on the stability of four known MOPO4 structure types, β-VOSO4, α-MoOPO4, SbOPO4 and monophosphate tungsten bronzes (MPTB) with six transition and main group metals that are interesting due to their catalytic activity (M: V, Mo, Nb, W, Ta, Sb). Harmonic frequencies and Crystal Orbital Hamilton Populations (COHP) were computed to verify and predict the stability and interpret the bond strengths, respectively, of the optimized structure models. The M-O bond strength has only a minor influence of the polymorph formation, but its vibrational contribution to the thermodynamic functions has a substantial effect. Based on the electronic energy calculated with the hybrid density functional PW1PW, every thermodynamical stable polymorph could be identified. The predictions of polymorph formation are in agreement with the experimental observations of VOPO4, NbOPO4 and TaOPO4, while the theoretical results for MoOPO4 and SbOPO4 show some deviations from the experimentally observed stability order.

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.

Rare Alleles and Signatures of Selection on the Immunodominant Domains of Pfs230 and Pfs48/45 in Malaria Parasites From Western Kenya.

Background: Malaria elimination and eradication efforts can be advanced by including transmission-blocking or reducing vaccines (TBVs) alongside existing interventions. Key transmission-blocking vaccine candidates, such as Pfs230 domain one and Pfs48/45 domain 3, should be genetically stable to avoid developing ineffective vaccines due to antigenic polymorphisms. We evaluated genetic polymorphism and temporal stability of Pfs230 domain one and Pfs48/45 domain three in Plasmodium falciparum parasites from western Kenya. Methods: Dry blood spots on filter paper were collected from febrile malaria patients reporting to community health facilities in endemic areas of Homa Bay and Kisumu Counties and an epidemic-prone area of Kisii County in 2018 and 2019. Plasmodium speciation was performed using eluted DNA and real-time PCR. Amplification of the target domains of the two Pfs genes was performed on P. falciparum positive samples. We sequenced Pfs230 domain one on 156 clinical isolates and Pfs48/45 domain three on 118 clinical isolates to infer the levels of genetic variability, signatures of selection, genetic diversity indices and perform other evolutionary analyses. Results: Pfs230 domain one had low nucleotide diversity (π = 0.15 × 10–2) with slight variation per study site. Six polymorphic sites with nonsynonymous mutations and eight haplotypes were discovered. I539T was a novel variant, whereas G605S was nearing fixation. Pfs48/45 domain three had a low π (0.063 × 10–2), high conservation index, and three segregating sites, resulting in nonsynonymous mutation and four haplotypes. Some loci of Pfs230 D1 were in positive or negative linkage disequilibrium, had negative or positive selection signatures, and others (1813, 1955) and (1813, 1983) had a history of recombination. Mutated loci pairs in Pfs48/45 domain three had negative linkage disequilibrium, and some had negative and positive Tajima’s D values with no history of recombination events. Conclusion: The two transmission blocking vaccine candidates have low nucleotide diversity, a small number of zone-specific variants, high nucleotide conservation index, and high frequency of rare alleles. With the near fixation a polymorphic site and the proximity of mutated codons to antibody binding epitopes, it will be necessary to continue monitoring sequence modifications of these domains when designing TBVs that include Pfs230 and Pfs48/45 antigens.

Discovery of Stishovite in the Prismatine-Bearing Granulite from Waldheim, Germany: A Possible Role of Supercritical Fluids of Ultrahigh-Pressure Origin

For the first time in the sixty years since the synthesis of stishovite, we report unambiguous evidence of stishovite formed in the deep Earth. A minimum pressure of about 7.5 GPa at 1000 °C is necessary for the formation of stishovite, corresponding to a depth of about 230 km. In this manuscript we report the identification of stishovite along with coesite as inclusions in mineral grains from the Waldheim granulite. This implies that the stishovite was transported upwards, probably very rapidly to a depth of about 130 km, corresponding to the highest pressure indicated by newly identified coesite in the prismatine of the Waldheim granulite, and continuing up to the depth of emplacement of the Waldheim prismatine granulite. The analysis of the Raman spectra obtained from a metastable trapped stishovite micro-crystal show that all the diagnostic Raman bands are present. However, given the metastability of the stishovite at room temperatures and pressures, this mineral breaks down step-by-step into stable polymorphs, first coesite and then quartz and cristobalite, during the Raman stimulation. The rare coesite crystals in prismatine have also resulted from the irreversible transformation from stishovite. Although the Waldheim occurrence may be unique, we suggest that Raman analysis of co-trapped crystals in similar deep-seated rocks, an area of limited previous research, may prove an important innovation in the study of mantle processes.