Polymorphic Forms Research Articles

Hydroxide-Source-Dependent Polymorphism and Phase Stability of Cobalt(II) Hydroxides in Diffusion-Driven Systems.

Hydroxides of cobalt(II) exist predominantly in two polymorphic forms, namely, the blue-green α-form [α-Co(OH)2] and reddish β-form [β-Co(OH)2]. These hydroxides have a layered structure with interlayer galleries of around 7 and 4 Å, respectively, for α- and β-Co(OH)2. In most of the previous studies, both the polymorphs were synthesized separately, and a few of them showed that the α-form gets converted to a thermodynamically more stable β-form via physical processes. In the present work, we have optimized the conditions for the simultaneous synthesis of both polymorphs under identical conditions in the same reactor using the 1D reaction-diffusion framework by employing different outer electrolytes. We found that the polymorph chemistry of Co(OH)2 depends on the source and concentration of OH- rather than other reaction conditions or later physical transformation. The products are characterized to confirm their morphology, structure, and chemical environment. We observed that the use of NaOH and NH4OH as the OH- precursor leads to α-Co(OH)2 only; however, with NaOH, a continuous precipitate is formed, and with NH4OH, periodic precipitation is formed. On the other hand, with hydrazine (HYZ) as the OH- source, Liesegang bands of α-Co(OH)2 and β-Co(OH)2 as granules are formed throughout the diffusion reactor. Another intriguing observation on the HYZ system is that at its high concentration, the bands of α-Co(OH)2 get converted to β-Co(OH)2. We articulate the reasons and mechanism of those observations.

Discovery of a novel marine bacterial AIEgen that lights up specific G-quadruplexes

The emergence of aggregation-induced emission (AIE) phenomenon two decades ago marked a significant advancement in chemical science. It has fostered the development of versatile AIE luminogens (AIEgens) applicable in bioimaging, optoelectronics, and biochemical sensing. However, the application potential of synthetic AIEgens is limited owing to their constrained chemical space, environmental concerns, and uncertain biocompatibility. Consequently, the pursuit of naturally derived AIEgens (BioAIEgens) is considered a promising solution to developing next-generation AIEgens. Here, we report the discovery of 2-(2-hydroxy-6-methoxy-3-propionylphenyl)quinazolin-4(3H)-one (HMPQ) from marine bacterial metabolite as AIEgen for the first time. HMPQ shows its unique fluorescence mechanism through excited-state intramolecular proton transfer. Comprehensive photophysical assessments unveiled that HMPQ varied emissions in diverse solvents and solid-state polymorphic forms. Notably, HMPQ exhibited specific binding affinity to G-quadruplexes (G4s), illuminating these non-canonical nucleic acid structures without altering their conformation. Its remarkable safety profile and precise cellular visualization of G4 structures imply HMPQ’s potential in biological applications, opening new avenues for utilizing BioAIEgens as G4 probes.

Genetic diversity, population structure, and phylogenetic relationships of a widespread East Asia herb, Cryptotaenia japonica Hassk. (Apiaceae) based on genomic SNP data generated by dd-RAD sequencing.

Single-nucleotide polymorphisms (SNPs) represent the most prevalent form of genomic polymorphism and are extensively used in population genetics research. Using dd-RAD sequencing, a high-throughput sequencing method, we investigated the genome-level diversity, population structure, and phylogenetic relationships among three morphological forms of the widely distributed taxon Cryptotaenia japonica Hassk., which is native to East Asia. Our study aimed to assess the species status of C. japonica according to its genetic structure and genetic diversity patterns among 66 naturally distributed populations, comprising 26C. japonica f. japonica, 36C. japonica f. dissecta (Y. Yabe) Hara and 4C. japonica f. pinnatisecta S. L. Liou accessions. Based on genomic SNP data generated by dd-RAD sequencing, we conducted genetic diversity, principal component, neighbor-joining (NJ) phylogenetic, admixture clustering, and population differentiation analyses. The findings revealed the following: (1) 5,39,946 unlinked, high-quality SNPs, with mean π, H O, H E and F IS values of 0.062, 0.066, 0.043 and -0.014, respectively, were generated; (2) population divergence was unaffected by isolation through distance; (3) six main distinct regions corresponding to geographic locations and exhibiting various levels of genetic diversity were identified; (4) pairwise F ST analysis showed significant (P < 0.05) population differentiation in 0%-14% of populations among the six regions after sequential Bonferroni correction; and (5) three migration events (historical gene flow) indicated east‒west directionality. Moreover, contemporary gene flow analysis using Jost's D, Nei's G ST, and Nm values highlighted the middle latitude area of East Asia as a significant contributor to genetic structuring in C. japonica. Overall, our study elucidates the relatively low genetic differentiation and population structure of C. japonica across East Asia, further enhancing our understanding of plant lineage diversification in the Sino-Japanese Floristic Region.

When less is more: The association between the expression of polymorphic CYPs and AFB1-induced HCC.

An individual's genetic fingerprint is emerging as a pivotal predictor of numerous disease- and treatment-related factors. Single nucleotide polymorphisms (SNPs) in drug-metabolizing enzymes play key roles in an individual's exposure to a malignancy-associated risk, such as Aflatoxin B1 (AFB1)-induced hepatocellular carcinoma (HCC). This study aimed at reviewing literature on the polymorphisms that exist in CYP enzymes and their possible link with susceptibility to AFB1-induced HCC. A set of keywords associated with the study subject of interest was used to search the Google Scholar and the PubMed database. The last ten years' worth of research projects were included in the results filter. The research involved HCC patients and any connection between polymorphic forms of CYP enzymes and their susceptibility to AFB1-induced HCC, including older but significant data. Variations in CYP1A2 and CYP3A4 were reported to impact the rate and magnitude of AFB1 bio-activation, thus influencing an individual's vulnerability to develop HCC. In HCC patients, the activity of CYP isoforms varies, where increased activity has been reported with CYP2C9, CYP2D6, and CYP2E1, while CYP1A2, CYP2C8, and CYP2C19 exhibit decreased activity. CYP2D6*10 frequency has been discovered to differ considerably in HCC patients. Rs2740574 (an upstream polymorphism in CYP3A4 as detected in CYP3A4*1B) and rs776746 (which affects CYP3A5 RNA splicing), both of which influence CYP3A expression, thus impacting the variability of AFB1-epoxide adducts in HCC patients. CYP1A2 is the primary enzyme accountable for the formation of harmful AFBO globally. CYP3A4, CYP3A5, CYP3A7, CYP2B7, and CYP3A3 are also implicated in the bio-activation of AFB1 to mutagenic metabolites. It is thought that CYP3A4 is the protein that interacts with AFB1 metabolism the most. Polymorphic variants of CYP enzymes have a functional impact on the susceptibility to AFB1-induced HCC. Outlining such variation and their implications may provide deeper insights into approaching HCC in a more personalized manner for guiding future risk-assessment, diagnosis, and treatment.

Single nucleotide polymorphisms: A paradigm in oral disease research

Background: A higher occurrence of oral cancer is observed in South Asian and Southeast Asian countries when compared with other countries in the world. Cancer, a disease with complex pathophysiology, has been linked to chronic inflammation. Inflammation has been considered an important component of tumor initiation and progression. This is supported by the fact that many cancers arise at the sites of chronic inflammation, but the exact mechanism by which inflammation influences cancer is unknown. Purpose: This review article correlates single nucleotide polymorphisms (SNPs), chronic inflammation, and oral cancer. The article emphasizes the critical role that SNPs play in oral cancer susceptibility, progression, and prognosis. This involves discussing the impact of specific SNPs on oral cancer risk and patient outcomes. Review: Gene polymorphism has been documented in the molecular pathogenesis of various cancers, including oral cancer, and SNPs are the most common form of gene polymorphism. Genetic variation has been documented in the molecular pathogenesis of various cancers, including oral cancer, and SNPs are the most common form of gene polymorphism. SNPs have been documented in inflammatory conditions as well as in various diseases. Conclusion: SNPs have phenotypic consequences and therefore can serve as genetic fingerprints. The upregulation or downregulation of genes is able to drive oral carcinogenesis.

Development of Continuous Additive-Controlled MSMPR Crystallization by DoE-Based Batch Experiments.

Additive-controlled crystallization is a promising method to improve crystal morphology and produce solid drug particles with the desired technological and pharmacological properties. However, its adaptation to continuous operation is a hardly researched area. Accordingly, in this work, we aimed to come up with a methodology that provides the systematic and fast development of a continuous three-stage MSMPR cascade crystallizer. For that, a cooling crystallization of famotidine (FMT) from water, in the presence of a formulation additive, poly(vinylpyrrolidone) (PVP-K12), was developed. Process parameters with a significant impact on product quality and quantity were examined in batch mode through a 24-1 fractional factorial design for the implementation of additive-controlled continuous crystallization. These batch experiments represented one residence time of the continuous system. Based on the statistical analysis, the residence time (RT) had the highest effect on yield, while the polymer amount was critical from the product polymorphism, crystal size, and flowability points of view. The values of critical process parameters in continuous operation were fixed according to the batch results. Two continuous cooling crystallization experiments were carried out, one with 1.25 w/wFMT% PVP-K12 and one with no additive. A mixture of FMT polymorphs (Form A and Form B) crystallized without the additive through five residence times (>6.5 h) with 70.8% overall yield. On the other hand, the additive-controlled continuous experiment resulted pure and homogeneous Form A product with excellent flowability. The system could be operated for >6.5 h without clogging with a 71.1% overall yield and a 4-fold improvement in productivity compared to its batch equivalent.

Cocoa Butter: Evolution from Natural Food Ingredient to Pharmaceutical Excipient and Drug Delivery System.

For decades, cocoa butter has been extensively used in food industries, particularly in the production of chocolate confectioneries. The composition of fats within cocoa butter, such as stearic acid, palmitic acid, and oleic acid, determines its properties. Studies have indicated the existence of at least six polymorphic forms of cocoa butter, each possessing distinct characteristics and melting points. Recently, cocoa butter has garnered attention for its potential as a delivery system for pharmaceutical products. This review thoroughly explores cocoa butter, encompassing its production process, composition, properties, and polymorphism. It delves into its diverse applications across various industries including food, cosmetics, and pharmaceuticals. Additionally, the review investigates cocoa butter alternatives aiming to substitute cocoa butter and their roles in different drug delivery systems. The unique properties of cocoa butter have sparked interest in pharmaceutical industries, particularly since its introduction as a drug delivery system and excipient. This has prompted researchers and industry stakeholders to explore novel formulations and delivery methods, thereby expanding the range of options available to consumers in the pharmaceutical market.

Genetic aspects associated with increased risk of developing atrial fibrillation

Abstract Atrial Fibrillation (AF) is the most common sustained arrhythmia in clinical practice with increasing prevalence and association with increased morbidity and mortality. Studies have suggested a greater contribution of the genetic factor to the etiopathogenesis of arrhythmia, which could indicate up to 40% more risk for the individual who has a family member with the arrhythmia, and later in the form of single nucleotide polymorphisms (SNPs). Objective To verify the association of polymorphisms in the PITX2, HCN4, CAV1 and KCNN3 genes with the occurrence of AF. Method The study is cross-sectional with group comparison, prospective with a quantitative approach. 505 randomly selected subjects were included (357 cases and 148 controls). The real-time PCR methodology was used, using the TAQMAN® system (Thermo scientific, CA, USA). Result The sample was matched by sex and age. The most common type of AF was permanent (69%) followed by paroxysmal (23%). When comparing the groups selected for CAV1, statistical significance was found for AA vs AG genotypes (p 0.003; OR= 2.2; CI 1.29-3.7). For the HCN4 gene allele and genotypes A vs G (p 0.024; OR= 0.66; CI 0.47-0.9) and AA vs AG (p 0.014, OR= 0.57; CI 0.37-0.88), respectively. Regarding the comparison of the dominant and recessive genetic model of each gene, the following models/genes presented statistical significance: in the genotypic model of the CAV1 gene (AA vs AG vs GG) p 0.013, as well as the same model applied to the HCN4 gene (AA vs AG vs GG) (p 0.03); when comparing the dominant models, the HCN4 gene (AA vs AG/GG) presented (p 0.01; OR=0.58; 95% CI 0.38 – 0.88), with the recessive model of the CAV1 gene (AA vs AG/GG) with (p 0.008; OR=2.0; 95% CI: 1.19 – 3.34). Regarding allelic associations between the two groups, a greater chance of susceptibility to developing AF was observed in patients who had the "G" allele (25.6%; p 0.024; OR= 0.66, CI 0.47-0.9) in the HCN4 gene polymorphism. Polymorphisms in the CAV1 (rs3807989) and HCN4 (rs7164883) genes were also included in the multivariate analysis with maintenance of the risk factor for AF. However, only HCN4 rs7164883 showed statistical significan, thus showing it to be an independent variable regarding the probability of the patient with this polymorphism presenting AF. The present study showed a significant association with a greater chance of susceptibility to developing atrial fibrillation in patients with a polymorphism in the CAV1 gene (rs3807989) in a univariate and multivariate model and for patients with the HCN4 gene SNP (rs7164883). Conclusion Therefore, the results revealed an association between the HCN4 gene polymorphism rs7164883 and susceptibility to the development of AF, suggesting that the presence of the G allele may be one of the genetic factors related to the arrhythmia. The CAV1 rs3807989 gene polymorphism also seemed to suggest a risk for the development of AF, also relating the G allele.

Topological constraints-induced radiation shielding efficiency of SiO2 α-cristobalite polymorphism: Signatures from Hirshfeld pseudo-surfaces

The paper presents a synergetic and comprehensive investigation into γ-radiation shields properties on SiO2 α-cristobalite subject varying external pressures (0<p < 9.1 GPa). Utilizing crystallographic methods involving γ-rays and Hirshfeld pseudo-surface (HPSs) analyses, we explore the structural responses of SiO2 α-cristobalite to external pressure and its consequent impact on MAC and LAC. The study encompasses a broad energy range (0.015<E < 15.0 MeV), employing online tool for analysis. Our findings reveal that the fundamental shielding characteristics of SiO2 α-cristobalite, including (5.809<MAC<0.021 cm2/g), (3.10 × 1023<Neff< 3.74 × 1023 e/g), (10.32<Zeff<12.43), and (10.79<Zeq<11.56), remain reliable across different polymorphic forms within the energy domain and varying pressures. The LAC values exhibit a clear dependency on both incident photon energies where it's LAC ∈ [0.042 to 11.776] cm−1 as pressure elevated on the crystal. This relationship underscores the influence of pressure-induced changes in crystal density on LAC values. Additionally, changes in lattice parameters (4.975<a<4.599 Å) and bond lengths under pressure contribute to this observed variation in the LAC values. Further analysis of the topological constraints (TCs) (i.e., 1.603<Si⋯O < 1.610 Å, 111.42°<O⋯Si⋯O < 112.00°, and 146.49°<Si⋯O⋯Si < 127.80° bending and twisting angles respectively) reveals defined correlations with LAC values.HPS topological analyses were also employed shed light on valuable insights into the mutual forces of interaction between atoms in the crystal unit cell. Changes in external stress lead to transformations in the HPSs, reflecting the impact of pressure on topological constraints. The evolution of HPS volume (i.e., 179.59-35.24 Å3) and area (i.e., 205.73-161.51 Å2) as well as void's volume (i.e., 10.20-0.17 Å3) and surface area (i.e., 46.10-3.12 Å2) within the crystal lattice is also observed, indicating a direct relationship between HPSs, crystal compactness, electron density and radiation effectiveness. These signatures have been correlated with TCs and thus on the γ-rays shield effectiveness.

Correction to “Roles of Chain Architecture and Polymorphic Form in Tailoring the Properties of Surface‐Roughened Biaxially Oriented Polypropylene Films for Capacitors”

Correction to “Roles of Chain Architecture and Polymorphic Form in Tailoring the Properties of Surface‐Roughened Biaxially Oriented Polypropylene Films for Capacitors”

Pea protein isolate-kappa-carrageenan complex coacervate as a lecithin substitute and their effect on physical properties, polymorphism, and melting behaviour of dark chocolates

This study used pea protein isolate (4% w/w) and kappa-carrageenan (4% w/w) to prepare complex coacervate through electrostatic interactions by optimizing the pH and ratio of protein-to-polysaccharide. The maximum coacervate yield of 81% was achieved at the optimized pH of 3.0 and the protein-to-polysaccharide ratio of 4:1. The optimized coacervate at various concentrations (1, 1.5, 2, 2.5, and 3% w/v) was assessed to emulsify cocoa butter to water fractions. The 2% w/v of complex coacervate successfully emulsified up to 40% aqueous phase in cocoa butter to water fractions whereas complex coacervates at 1%, 1.5%, 2.5%, and 3% w/v were found to stabilize only 20% aqueous phase. The storage and temperature stability of emulsions were higher upon usage of 2% w/v complex coacervate as the serum layer separation was minimal. Based on the emulsion stability observations, complex coacervate (2% w/v) was used to partially and completely substitute lecithin in dark chocolates. The results showed that irrespective of the emulsifiers utilized, the polymorphism and melting behaviour of all chocolates remained the same and retained the desired polymorphic form V. The moisture content and particle size distribution of chocolates did not exceed the acceptable limit. The Casson plastic viscosity (ηca), Casson yield stress (τ0c), and hardness (N) of chocolates significantly (p < 0.05) increased upon increasing the complex coacervate. The present findings revealed that partial substitution (50%) of lecithin with complex coacervate is highly promising for the production of dark chocolates while retaining the desirable flow properties and polymorphism.

Comparative structural analysis of anhydrous and monohydrated polymorphs of diclofenac diethylammonium: Implications for stability, dissolution, and bioavailability

Diclofenac diethylammonium belongs to the class of non-steroidal anti-inflammatory drugs, and it is widely used to relieve pain and reduce systemic inflammation. This drug exists in polymorphic forms, which can directly affect the ability to process the drug, as well as drug product dissolution, stability, and bioavailability. Considering the worldwide regulatory guidance for polymorphs in drug substances, a detailed structural analysis of two polymorphs exhibiting the anhydrous and monohydrated structures of diclofenac diethylammonium is presented here, using the supramolecular arrangement and its relationship with structural-physicochemical properties. The polymorph’s structures show conformational differences in the carboxylic group caused by coordinated water molecules presented in the monohydrated polymorphic structure. Both polymorphs have the supramolecular arrangement stabilized by NH···O and CH···Cl intermolecular interactions, but the monohydrated molecule presents a strong OH···O intermolecular interaction due to the presence of a water molecule. Hirshfeld surface analysis showed CH···π and π···π contacts in the anhydrous and monohydrated polymorphs, respectively. Theoretical results, including solvent effect with explicit and implicit approaches for water, indicated the kinetic stability of the diclofenac diethylammonium drug and showed susceptible electrophilic attacks occurring in the region close to the carbonyl oxygen atom.

Study of the identity of the polymorphic form of API – dapagliflosin derivative and of its permanency structure under the influence of the tableting process

The aim. To investigate the polymorphic structure of the API – Dapagliflozin propanediol monohydrate and to reveal the absence of an effect of the tabletting process on the polymorphic structure of the API in model compositions of tablets. Materials and methods. Model mixtures of API - dapagliflozin propanediol monohydrate and excipients were studied. The research used the method of designing pharmaco-technological parameters of solid dosage forms, the method of quantum-chemical modelling of the mechanical properties of polymorphic modifications of APIs, the modelling of shear deformation, the nanoindentation method, the Rietveld method for calculating X-ray patterns, X-ray structural analysis of API and selected model compositions of tablets. Results. The polymorphic structure of API - dapagliflozin propanediol monohydrate and its polymorphic structure in selected model compositions of tablets produced by the pressing method were studied and analyzed. An X-ray structural study was carried out, and the qualitative and phase composition of samples and polymorphic modifications of API and model series of tablets were determined. According to the results of the X-ray structural analysis, it was established that there is no polymorphic transition and that the polymorphic structure of API is invariant under the influence of pressing pressure, which ensures the quality of the tablet form. Conclusions. The design of an experimental study was determined based on the application of the QbD concept, design of experiments – DoE, for designing and ensuring a high-quality technological process – tabletting of API - Dapagliflozin propanediol monohydrate and excipients. To manage a critical technological parameter - the stability of the polymorphic structure of the API, which guarantees the quality of the tablet form, its bioavailability and bioequivalence, it is necessary to use a set of methods for studying structural changes and polymorphic modifications of the API during the tableting process. According to the results of the X-ray structural study of API and selected model compositions of tablets, it was established that during the process of tabletting under pressure, the structure of the polymorphic modification of dapagliflozin propanediol monohydrate does not change, and no polymorphic transition is observed

X-ray computed tomography for 3D crystallization monitoring: A use case with paracetamol

This work highlights the capabilities and limits of X-ray computed tomography in crystallization monitoring through a use case involving paracetamol as the solute, recrystallized from ethanol, methanol, or a mixture of both. The cooling crystallization operation was set up in two different containers, prepared with cotton yarns stretched vertically, acting as linear nucleation sites that immobilize the grown crystals in the recording area. The largest container (10 mL test tubes) allowed the acquisition of a larger number of crystals (up to 300 particles) for a more appropriate bulk analysis. The smallest container (5 mL pipette tips) allowed for a finer resolution of the recorded solid phase at the expense of a reduced recording volume. Crystallization was monitored in terms of the number of individual crystals, their size, and the overall volume, thus leading to the nucleation and growth rates, and solid-phase production rate. The main benefit of X-ray computed tomography is in the 3D analysis of the reconstructed solid phase. The crystal habit of paracetamol form I was predicted using force-field modeling. The predicted habit was in great accordance with the reconstructed solids, confirming the polymorphic form. Furthermore, face-specific growth rates of reconstructed crystals were measured, paving the way for a novel approach to the investigation of crystal-solvent interactions.

Utilization of Eggshell Waste Calcite as a Sorbent for Rare Earth Element Recovery.

The green energy transition requires rare earth elements (REE) for the permanent magnets used in electric cars and wind turbines. REE extraction and beneficiation are chemically intensive and highly damaging to the environment. We investigated the use of eggshell waste as a sustainable alternative sorbent for the capture and separation of REE from aqueous solutions. Hen eggshell calcite was placed in multi-REE (La, Nd, Dy) solutions at 25 to 205 °C for up to 3 months. A pervasive diffusion of the REE inside the eggshell calcite was observed along pathways formed by the intracrystalline organic matrix and calcite crystal boundaries. At 90 °C, kozoite (REECO3OH, orthorhombic) spherulites precipitate on the surface of the dissolving calcite. At 165 and 205 °C, an interface-coupled dissolution-precipitation mechanism is observed, resulting in the complete dissolution of the calcite shell and its pseudomorphic replacement by polycrystalline kozoite. At 205 °C, kozoite is slowly replaced by hydroxylbastnäsite (REECO3OH, hexagonal), the stable form of the rare earth hydroxycarbonate polymorphs. Our results demonstrate two potential applications of eggshell waste for the uptake of rare earth elements in solution: at low temperatures, as a mixed organic-inorganic adsorbent and absorbent, given sufficient sorption time; and at higher temperatures, as an efficient sacrificial template for the precipitation of rare earth hydroxycarbonates.

Insights into the population dynamics of phytophthora species associated with arecanut fruit rot disease

Phytophthora, a ubiquitous filamentous oomycete, causes huge yield losses and is fatal to arecanut palms in case of severe infection. From 2014 onwards, a severe fruit rot epidemic has been recorded during the South-West monsoon season in major arecanut-growing states of South India. We have assessed the diversity and delineated the population structure of Phytophthora isolates infecting arecanut in India using a combination of morphological traits, multi-gene profiling, haplotype analysis, and pathogenicity. Ninety-eight Phytophthora isolates were obtained from infected samples collected from disease-endemic regions of Karnataka, Kerala, and Goa states in southern India from 2014 to 2019. Morphological traits coupled with phylogenetic analysis using the loci ITS, β-tub, TEF-1α, and Cox-II identified the A2 mating type of P. meadii as the predominant species together with two isolates of homothallic P. heveae. Linkage disequilibrium analysis revealed significant diversity in the form of single nucleotide polymorphisms (SNPs) from the concatenated sequence dataset. Population structure analysis using 590 SNPs demonstrated the existence of four population groups (sub-populations at K = 4 and K = 2) and significant diversity in the geo-distant Phytophthora populations. In summary, 22 haplotypes were identified from the representative 40 isolates with higher haplotype diversity of 1.23 and relatively varying haplotype frequency. Pathogenicity assays confirmed that both the species of Phytophthora were pathogenic to arecanut, while P. meadii coastal region isolates exhibited more virulence compared to others.

A New polymorphic forms of Lenvatinib mesylate and process for their preparation

A New polymorphic forms of Lenvatinib mesylate and process for their preparation

A comprehensive study on the intermolecular interactions and energy frameworks exist in crystal structures of Form-I, Form-II and Form-III polymorphs of Ethyl maltol

The present study serves as a comprehensive investigation into the molecular crystal structures of three polymorphic forms of ethyl maltol. Crystal structures of the polymorphs grown via slow evaporation and quench cooling crystallization processes were determined through single crystal X-ray diffraction (SCXRD) analysis. Through the utilization of SCXRD data CIF file as an input, we explored the nature and strength of intermolecular interactions, atom pair close contacts, interaction types, 2D fingerprint plots, surface characteristics and percentage of voids present within each polymorph of ethyl maltol. The comparative analysis involves the application of advanced methods, such as Hirshfeld surface analysis and 3D-energy frameworks using Crystal Explorer 17.5. In a supramolecular organization, intermolecular interaction between the carbonyl and hydroxyl groups is a collective structural motif employed among the three polymorphs. However the three polymorphs share common structural features, but the conformations within the crystal packing of each form are different from each other. Shape Index and Curvedness surfaces reveal π stacking interactions with varying properties on differing sides of the molecular moieties between the polymorph. Fingerprint analysis emphasizes that (H…H) is the predominant interaction whereas (O…H) and (H…O) interactions contribute more towards the generation of H-bond interactions in the structure of ethyl maltol polymorphs. The crystal structures of all the three ethyl maltol polymorphs stabilized by various intermolecular contacts within the Hirshfeld surface area was comparable. The interaction energy and the 3D-energy frameworks offer a visualization of the crystal packing topology, enhancing our understanding of the three-dimensional arrangement of molecules and their structural stability. The resulting overall average total energy values for Form-I, Form-II and Form-III polymorphs of ethyl maltol are -56.3 kJ /mol, -74 kJ /mol and -80.45 kJ /mol respectively which reveals that all the three polymorphs show a significant difference in their total energies and reveals further that Form-III polymorph of ethyl maltol is the most stable one while Form-I is the least stable and Form-II is metastable relatively. Moreover, the dispersion energy framework is predominant over the electrostatic energy framework. The void analysis reveals the percentage of volume occupied by the voids present in the unit cell of Form-I, Form-II, and Form-III polymorphs of ethyl maltol are found to be 7.20%, 6.55 %, and 9.43% respectively.

Structural characterization and comparative analysis of polymorphic forms of psilocin (4-hydroxy-N,N-dimethyltryptamine)

The title compound, C12H16N2O, is a hydroxy-substituted monoamine alkaloid, and the primary metabolite of the naturally occurring psychedelic compound psilocybin. Crystalline forms of psilocin are known, but their characterization by single-crystal structure analysis is limited. Herein, two anhydrous polymorphic forms (I and II) of psilocin are described. The crystal structure of polymorphic Form I, in space group P21/c, was first reported in 1974. Along with the redetermination to modern standards and unambiguous location of the acidic H atom and variable-temperature single-crystal unit-cell determinations for Form I, the Form II polymorph of the title compound, which crystallizes in the monoclinic space group P21/n, is described for the first time. The psilocin molecules are present in both forms in their phenol–amine tautomeric forms (not resolved in the 1974 report). The molecules in Forms I and II, however, feature different conformations of their N,N-dimethyl ethylene substituent, with the N—C—C—C link in Form I being trans and in Form II being gauche, allowing the latter to bend back to the hydroxyl group of the same molecule, leading to the formation of a strong intramolecular O—H...N hydrogen bond between the hydroxyl moiety and ethylamino-nitrogen group. In the extended structure of Form II, the molecules form one-dimensional strands through N—H...O hydrogen bonds from the indole group to the oxygen atom of the hydroxyl moiety of an adjacent molecule. Form II exhibits whole-molecule disorder due to a pseudo-mirror operation, with an occupancy ratio of 0.689 (5):0.311 (5) for the two components. In contrast, Form I does not feature intramolecular hydrogen bonds but forms a layered structure through intermolecular N—H...O and O—H...N hydrogen bonds.

NMR Longitudinal Rotating Frame Relaxation Time (T1ρ) with a Weak Spin Locking Field as an Approach to Characterize Solid-State Active Pharmaceutical Ingredients: Proof of Concept.

Nuclear magnetic resonance (NMR) longitudinal rotating frame relaxation time (T1ρ), rarely used in low-field NMR, can be more effective than conventional T1 and T2 relaxation times to differentiate polymorphic forms of solid pharmaceuticals. This could be attributed to T1ρ sensibility to structural and molecular dynamics that can be enhanced by changing the strength of the oscillating magnetic field (B1) of spinlock pulses. Here, we compared the capacity of T1, T2, and T1ρ to differentiate inactive (A) and active (C) crystalline forms of the World Health Organization essential drug Mebendazole. The results showed that T1 and T2 values of both forms were statistically identical at 0.47 T. Conversely, T1ρ of both forms measured with weak spinlock B1 fields, ranging from 0.08 to 0.80 mT were statistically different in the same spectrometer. The T1ρ also has the limit of detection to detect the presence of at least 10% of inactive A form in the active C form. Therefore, T1ρ, measured with weak spinlock B1 fields can be an effective, streamlined, and complementary approach for characterizing not only solid active pharmaceutical ingredients but other solid-state materials as well.