The supramolecular synthon behavior within cocrystals of pyrazinamide and alkyl dicarboxylic acids: A perspective from terahertz spectroscopy and quantum chemical calculation.

Pyrazinamide (PZA) is a widely-used anti-tuberculosis pharmaceutical, but its poor solubility prompts us to optimize pharmaceutical performance. Cocrystallization is a promising technique to improve physiochemical properties of active pharmaceutical ingredient (API) by connecting it with cocrystal former (CCF) via intermolecular interactions. Even though a series of alkyl dicarboxylic acids are employed to form cocrystal structures, systematic understanding on the role of intermolecular interactions is still missing. Therefore, terahertz (THz) spectroscopy and quantum chemical calculation are combined to elucidate the behavior of ubiquitous supramolecular synthons, such as hetero-synthons of acid-pyrazine, acid-amide and homo-synthon of amide-amide, from energy's view. Potential energy is calculated to differentiate the stability within polymorphs of PZA-MA cocrystal and free energy is evaluated to compare the solubility of PZA-CCF cocrystals respectively. With regard to vibrational energy, THz spectral fingerprints are theoretically assigned to specific vibrations and attributed to the flexibility deformation of supramolecular synthons based on oscillation theory, where stretching and twisting modes dominate the collective vibrational behavior. It provides a promising tool to evaluate cocrystal performance from its driving force and insightful guidance to discover new pharmaceutical cocrystals.

Unprecedented Packing Polymorphism of Oxindole: An Exploration Inspired by Crystal Structure Prediction.

Crystal polymorphism, characterized by different packing arrangements of the same compound, strongly ties to the physical properties of a molecule. Determining the polymorphic landscape is complex and time-consuming, with the number of experimentally observed polymorphs varying widely from molecule to molecule. Furthermore, disappearing polymorphs, the phenomenon whereby experimentally observed forms cannot be reproduced, pose a significant challenge for the pharmaceutical industry. Herein, we focused on oxindole (OX), a small rigid molecule with four known polymorphs, including a reported disappearing form. Using crystal structure prediction (CSP), we assessed OX solid-state landscape and thermodynamic stability by comparing predicted structures with experimentally known forms. We then performed melt and solution crystallization in bulk and nanoconfinement to validate our predictions. These experiments successfully reproduced the known forms and led to the discovery of four novel polymorphs. Our approach provided insights into reconstructing disappearing polymorphs and building more comprehensive polymorph landscapes. These results also establish a new record of packing polymorphism for rigid molecules.

Synthesis of Metastable Calcium Carbonate Using Long-Chain Bisphosphonate Molecules.

Cementation in construction materials primarily relies on the aqueous precipitation of minerals such as carbonates and silicates. The kinetics of nucleation and growth play a critical role in the development of strength and durability, yet our understanding of the kinetic controls governing phase formation and porosity reduction in cements remains limited. In this study, we synthesized bisphosphonate molecules with varying alkyl chain lengths and functional groups to investigate their impact on calcium carbonate precipitation. Through conductivity measurements, infrared spectroscopy, and thermogravimetric analysis, we uncovered the selective formation of polymorphs and the specific incorporation of these molecules within the carbonate matrix. Further, in situ atomic force microscopy revealed that these molecules influenced the morphology of the precipitates, indicating a possible effect on the ionic organization through sorption mechanisms. Interestingly, amorphous calcium carbonate (ACC), when formed in the presence of bisphosphonates, showed metastability for at least seven months without inhibiting further calcium carbonate precipitation. Our research sheds light on the diverse mechanisms by which organic additives can modify mineral nucleation and growth, offering valuable insights for the control and enhancement of carbonate-based cementation processes.

4-(1H-2,3-Dihydronaphtho-[1,8-de][1,3,2]di-aza-borinin-2-yl)-1-ethylpyridin-1-ium iodide monohydrate.

The cation of the title hydrated salt, C17H17BN3 +·I-·H2O, is a di-aza-borinane featuring substitution at the 1, 2, and 3 positions in the nitro-gen-boron six-membered heterocycle. The cation is approximately planar with a dihedral angle between the pyridyl ring and the di-aza-borinane ring system of 5.40 (5)°. In the crystal, the cations stack along [100] in an alternating head-to-tail manner, while the iodide ion and water mol-ecule form one-dimensional hydrogen-bonded chains beside the cation stack. The cation stacks and I--water chains are crosslinked by N-H⋯I and N-H⋯O hydrogen bonds.

Crystal structures of tri-chlorido-(4-methyl-piperidine)gold(III) and two polymorphs of tri-bromido(4-methyl-piperidine)-gold(III).

Tri-chlorido-(4-methyl-piperidine)-gold(III), [AuCl3(C6H13N)], 1, crystallizes in Pbca with Z = 8. Tri-bromido-(4-methyl-piperidine)-gold(III), [AuBr3(C6H13N)], 2, crystallizes as two polymorphs, 2a in Pnma with Z = 4 (imposed mirror symmetry) and 2b, which is isotypic to 1. The Au-N bonds trans to Cl are somewhat shorter than those trans to Br, and the Au-Cl bonds trans to N are longer than those cis to N, whereas the Au-Br bonds trans to N are slightly shorter than the cis bonds. The methyl and AuX 3 groups (X = halogen) occupy equatorial positions at the six-membered ring. The packing of all three structures involves chains of mol-ecules with offset stacking of the AuX 3 moieties associated with short Au⋯X contacts; for 1 and 2b these are reinforced by N-H⋯X hydrogen bonds, whereas for 2a there are no classical hydrogen bonds and the chains are inter-connected by Br⋯Br contacts.

Discovery of a New Polymorph of 5-Methoxy-1H-Indole-2-Carboxylic Acid: Characterization by X-ray Diffraction, Infrared Spectroscopy, and DFT Calculations.

This study presents a new 5-methoxy-1H-indole-2-carboxylic acid (MI2CA) polymorph investigated by single-crystal X-ray diffraction, infrared spectroscopy, and density functional theory (ωB97X-D) calculations employing two basis sets (6-31++G(d,p) and aug-cc-pVTZ). The compound crystallizes in the monoclinic system, space group P21/c (a = 4.0305(2) Å, b = 13.0346(6) Å, c = 17.2042(9) Å, ß = 91.871(5)°, Z = 4). In the crystalline structure, the formation of cyclic dimers via double hydrogen bonds O-H⋯O between MI2CA molecules was observed. Interactions between the NH groups of the indole rings and the adjacent methoxy groups, as well as C-H⋯O contacts, significantly influence the spatial arrangement of molecules. The results from DFT calculations, including dimeric and trimeric structures, agree well with the experimental structural and spectroscopic data. Analysis of the infrared spectra confirms the conclusions drawn from X-ray diffraction studies and reveals differences between the IR spectra of the newly obtained polymorph and that reported earlier in the literature. This comprehensive study sheds some light on the MI2CA polymorphism and is important for a potential pharmacological applications of this compound.

Relationship between synthesis method-crystal structure-melting properties in cocrystals: the case of caffeine-citric acid.

The influence of the crystal synthesis method on the crystallographic structure of caffeine-citric acid cocrystals was analyzed thanks to the synthesis of a new polymorphic form of the cocrystal. In order to compare the new form to the already known forms, the crystal structure of the new cocrystal (C8H10N4O2·C6H8O7) was solved by powder X-ray diffraction thanks to synchrotron experiments. The structure determination was performed using `GALLOP', a recently developed hybrid approach based on a local optimization with a particle swarm optimizer, particularly powerful when applied to the structure resolution of materials of pharmaceutical interest, compared to classical Monte-Carlo simulated annealing. The final structure was obtained through Rietveld refinement, and first-principles density functional theory (DFT) calculations were used to locate the H atoms. The symmetry is triclinic with the space group P-1 and contains one molecule of caffeine and one molecule of citric acid per asymmetric unit. The crystallographic structure of this cocrystal involves different hydrogen-bond associations compared to the already known structures. The analysis of these hydrogen bonds indicates that the cocrystal obtained here is less stable than the cocrystals already identified in the literature. This analysis is confirmed by the determination of the melting point of this cocrystal, which is lower than that of the previously known cocrystals.

Handedness-Inverted and Stimuli-Responsive Circularly Polarized Luminescent Nano/Micromaterials Through Pathway-Dependent Chiral Supramolecular Polymorphism.

The precise manipulation of supramolecular polymorphs has been widely applied to control the morphologies and functions of self-assemblies, but is rarely utilized for the fabrication of circularly polarized luminescence (CPL) materials with tailored properties. Here, this work reports that an amphiphilic naphthalene-histidine compound (NIHis) readily self-assembled into distinct chiral nanostructures through pathway-dependent supramolecular polymorphism, which shows opposite and multistimuli responsive CPL signals. Specifically, NIHis display assembly-induced CPL from the polymorphic keto tautomer, which become predominant during enol-keto tautomerization shifting controlled by a bulk solvent effect. Interestingly, chiral polymorphs of nanofiber and microbelt with inverted CPL signals can be prepared from the same NIHis monomer in exactly the same solvent compositions and concentrations by only changing the temperature. The tunable CPL performance of the solid microbelts is realized under multi external physical or chemical stimuli including grinding, acid fuming, and heating. In particular, an emission color and CPL on-off switch based on the microbelt polymorph by reversible heating-cooling protocol is developed. This work brings a new approach for developing smart CPL materials via supramolecular polymorphism engineering.

Milligram-scale assembly and NMR fingerprint of tau fibrils adopting the Alzheimer's disease fold.

In the Alzheimer's disease (AD) brain, the microtubule-associated protein tau aggregates into paired helical filaments in which each protofilament has a C-shaped conformation. In vitro assembly of tau fibrils adopting this fold is highly valuable for both fundamental and applied studies of AD without requiring patient-brain extracted fibrils. To date, reported methods for forming AD-fold tau fibrils have been irreproducible and sensitive to subtle variations in fibrillization conditions. Here, we describe a route to reproducibly assemble tau fibrils adopting the AD fold on the multi-milligram scale. We investigated the fibrillization conditions of two constructs and found that a tau (297-407) construct that contains four AD phospho-mimetic glutamate mutations robustly formed the C-shaped conformation. 2D and 3D correlation solid-state NMR spectra show a single predominant set of chemical shifts, indicating a single molecular conformation. Negative-stain electron microscopy and cryo-EM data confirm that the protofilament formed by 4E-tau (297-407) adopts the C-shaped conformation, which associates into paired, triple, and quadruple helical filaments. In comparison, NMR spectra indicate that a previously reported construct, tau (297-391), forms a mixture of a four-layered dimer structure and the C-shaped structure, whose populations are sensitive to the environmental conditions. The determination of the NMR chemical shifts of the AD-fold tau opens the possibility for future studies of tau fibril conformations and ligand binding by NMR. The quantitative assembly of tau fibrils adopting the AD fold should facilitate the development of diagnostic and therapeutic compounds that target AD tau.

Determination of the process effect on cocoa butter crystallization by rheometer: Kinetic modeling by Gompertz equation.

In this study, the effects of temperature (22, 24, 26, 28, and 30°C) and strain (0.1%, 1%, and 5%) on cocoa butter (CB) crystallization were investigated by oscillatory test, and the four-parameter Gompertz model was used to interpret the effect of parameters on pre-crystallization, nucleation, and crystal growth stages of CB. Lag time and growth rate were calculated using the Gompertz model using time-dependent storage modulus (G') data. According to the results, CB crystallization at 26°C with a 1% strain value had the highest growth rate value, the shortest lag time, and the formation of ßv polymorph type. Followingly, polymorphic types of the CB crystals were determined based on the melting points of polymorphs via the temperature ramp step, and the results obtained were correlated with a polarized light microscope. In conclusion, using a rheometer in both the observation of the pre-crystallization process and the determination of polymorph types is very important for research and development studies in the chocolate industry for process and formulation optimization. PRACTICAL APPLICATION: This study demonstrates the feasibility of a novel approach for investigating crystallization and oscillatory shear of CB using a rheometer, both for observing crystallization kinetics and determining polymorph type, accompanied by the Gompertz equation to model the crystallization kinetics. According to the results, the effect of process parameters (temperature and shear) on the crystallization behavior of CB can be observed by rheometer, which can provide a detailed perspective for chocolate manufacturers and researchers in research and development studies.

Tailoring raloxifene into single-component molecular crystals possessing multilevel stimuli-responsive room-temperature phosphorescence.

Simultaneously achieving room-temperature phosphorescence (RTP) and multiple-stimuli responsiveness in a single-component system is of significance but remains challenging. Crystallization has been recognized to be a workable strategy to fulfill the above task. However, how the molecular packing mode affects the intersystem crossing and RTP lifetime concurrently remains unclear so far. Herein, four economic small-molecular compounds, analogues of the famous drug raloxifene (RALO), are facilely synthesized and further explored as neat single-component and stimuli-responsive RTP emitters via crystallization engineering. Thanks to their simple structures and high ease to crystallize, these raloxifene analogues function as models to clarify the important role of molecular packing in the RTP and stimuli-responsiveness properties. Thorough combination of the single-crystal structure analysis and theoretical calculations clearly manifests that the tight antiparallel molecular packing mode is the key point to their RTP behaviors. Interestingly, harnessing the controllable and reversible phase transitions of the two polymorphs of RALO-OAc driven by mechanical force, solvent vapor, and heat, a single-component multilevel stimuli-responsive platform with tunable emission color is established and further exploited for optical information encryption. This work would shed light on the rational design of multi-stimuli responsive RTP systems based on single-component organics.

Revisiting Dimorphs of 4-n-octyloxybenzoic Acid: Contrasting Mechanical Property and Surface Wettability.

4-n-octyloxy benzoic acid is known to exhibit liquid crystalline properties, and under normal pressure and temperature conditions, it exists as at least two crystalline polymorphs. We revisited the system and discovered that single crystals of one of the polymorphs display plastic deformation, whereas the other is brittle. n-octyl chains are arranged in an end-to-end fashion, forming slip planes in the plastically deformable polymorph, whereas they are interdigitated in the crystal structure of the brittle polymorph. Due to the difference in the arrangement of the -COOH group and alkyl chains, the major faces of the crystals of both polymorphs possess significant differences in the wettability towards moisture.

On rheological properties of disc-shaped cellulose nanocrystals.

The rheological properties of a substance depend greatly on its morphology, and rod-shaped cellulose nanocrystals (RCNCs) and cellulose nanofibrils (CNFs) have been extensively studied for their rheological properties. Nevertheless, the rheological properties of disc-shaped cellulose nanocrystals (DCNCs) with crystalline allomorph II derived from mercerized cellulose remain unknown yet. This work investigated the DCNCs' rheological properties in depth using steady-shear and oscillation measurements. At the same concentration, DCNC's suspension viscosity is lower than that of RCNC; RCNC has an instinct viscosity of 258.2, while DCNC has 187.9. Comparing RCNC suspensions with cellulose nanorods, DCNC has a lower aspect ratio and exhibits a distinct steady shear behavior. Under polarized film, DCNC suspension cannot self-assemble into chiral or liquid crystal phases, and with increasing concentrations, the system transitions from an isotropic phase to a gel phase. Oscillation sweeps demonstrate that the gel transition occurs at 7 %-8 %. Based on thixotropic recovery sweep outcomes, the high-stress oscillations enhance the network structure of DCNC suspensions, which is significantly different from that of RCNC suspensions. Results demonstrate the unique properties of DCNC, highlighting its application as a rheological modifier.

Prediction and Discovery of Cannabidiol Crystal Polymorph Form 2.

The article puts into perspective the recent discovery of cannabidiol crystal polymorph Form 2.

Study on triphase of polymorphs TiO2 (anatase/rutile/brookite) for boosting photocatalytic activity of metformin degradation.

The elution of pharmaceutical products such as metformin at higher concentrations than the safe level in aquatic systems is a serious threat to human health and the ecosystem. Photocatalytic technology using TiO2 semiconductors potentially fixes this problem. This study aims to synthesize triphasic anatase-rutile-brookite TiO2 using ultrasound assisted sol-gel technique in the presence of acid and its application to photodegradation of metformin under UV light irradiation. Based on X-ray diffraction analysis, a TiO2 sample consisted of anatase (76%), rutile (7%), and brookite (17%) polymorph (A76R7B17) that was fully crystallized. Scanning electron microscopy (EM)-energy dispersive X-ray spectra results showed agglomerated triphasic A76R7B17 with irregular spherical clusters. Transmission EM results revealed that the crystal size of A76R7B17 was 4-14 nm. The Brunauer-Emmett-Teller analysis showed the sample's specific surface area of 149 m2 g-1. The degradation test of metformin demonstrated that the A76R7B17 exhibited a 75.4% degradation efficiency after 120 min under UV light irradiation, significantly higher than using biphasic and single-phase TiO2 photocatalysts. This difference could be attributed to the heterojunction effect of triphasic materials that effectively reduced electron-hole recombination rate as well as the combination of effective electron transfer from conduction band of brookite and anatase and the utilization of wider range of UV-visible light using rutile.

Cryo-EM structures of the D290V mutant of the hnRNPA2 low-complexity domain suggests how D290V affects phase separation and aggregation.

Heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2) is a human ribonucleoprotein that transports RNA to designated locations for translation via its ability to phase separate. Its mutated form, D290V, is implicated in multisystem proteinopathy known to afflict two families, mainly with myopathy and Paget's disease of bone. Here, we investigate this mutant form of hnRNPA2 by determining cryo-EM structures of the recombinant D290V low complexity domain. We find that the mutant form of hnRNPA2 differs from the WT fibrils in four ways. In contrast to the WT fibrils, the PY-nuclear localization signals in the fibril cores of all three mutant polymorphs are less accessible to chaperones. Also, the mutant fibrils are more stable than WT fibrils as judged by phase separation, thermal stability, and energetic calculations. Similar to other pathogenic amyloids, the mutant fibrils are polymorphic. Thus, these structures offer evidence to explain how a D-to-V missense mutation diverts the assembly of reversible, functional amyloid-like fibrils into the assembly of pathogenic amyloid, and may shed light on analogous conversions occurring in other ribonucleoproteins that lead to neurological diseases such as amyotrophic lateral sclerosis and frontotemporal dementia.

Polymorphism-driven Distinct Nanomechanical, Optical, Photophysical, and Conducting Properties in a Benzothiophene-quinoline.

Polymorphic forms of organic conjugated small molecules, with their unique molecular shapes, packing arrangements, and interaction patterns, provide an excellent opportunity to uncover how their microstructures influence their observable properties. Ethyl-2-(1-benzothiophene-2-yl)quinoline-4-carboxylate (BZQ) exists as dimorphs with distinct crystal habits - blocks (BZB) and needles (BZN). The crystal forms differ in their molecular arrangements - BZB has a slip-stacked column-like structure in contrast to a zig-zag crystal packing with limited π-overlap in BZN. The BZB crystals characterized by extended π-stacking along [100] demonstrated semiconductor behavior, whereas the BZN, with its zig-zag crystal packing and limited stacking characteristics, was reckoned as an insulator. Monotropically related crystal forms also differ in their nanomechanical properties, with BZB crystals being considerably softer than BZN crystals. This discrepancy in mechanical behavior can be attributed to the distinct molecular arrangements adopted by each crystal form, resulting in unique mechanisms to relieve the strain generated during nanoindentation experiments. Waveguiding experiments on the acicular crystals of BZN revealed the passive waveguiding properties. Excitation of these crystals using a 532 nm laser confirmed the propagation of elastically scattered photons (green) and the subsequent generation of inelastically scattered (orange) photons by the crystals. Further, the dimorphs display dissimilar photoluminescence properties; they are both blue-emissive, but BZN displays twice the quantum yield of BZB. The study underscores the integral role of polymorphism in modulating the mechanical, photophysical, and conducting properties of functional molecular materials. Importantly, our findings reveal the existence of light-emitting crystal polymorphs with varying electric conductivity, a relatively scarce phenomenon in the literature.

Microwave-Responsive Flexible Room-Temperature Phosphorescence Materials Based on Poly(vinylidene fluoride) Polymer.

The development of flexible, room-temperature phosphorescence (RTP) materials remains challenging owing to the quenching of their unstable triplet excitons via molecular motion. Therefore, a polymer matrix with Tg higher than room temperature is required to prevent polymer segment movement. In this study, a RTP material was developed by incorporating a 4-biphenylboronic acid (BPBA) phosphor into a poly(vinylidene fluoride) (PVDF) matrix (Tg =-27.1 °C), which exhibits a remarkable UV-light-dependent oxygen consumption phosphorescence with a lifetime of 1275.7 ms. The adjustable RTP performance is influenced by the crystallinity and polymorph (α, ß, and γ phases) fraction of PVDF, therefore, the low Tg of the PVDF matrix enables the polymeric segmental motion upon microwave irradiation. Consequently, a reduction in the crystallinity and an increase in the α phase fraction in PVDF film induces RTP after 2.45 GHz microwave irradiation. These findings open up new avenues for constructing crystalline and phase-dependent RTP materials while demonstrating a promising approach toward microwave detection.

Effect of organic acids on the solid-state polymorphic phase transformation of piracetam.

Metastable polymorphs are frequently used in oral solid dosage forms to enhance the absorption of poorly water-soluble drug compounds. However, the solid phase transformation from the metastable polymorph to the thermodynamically stable polymorph during manufacturing or storage poses a major challenge for product development and quality control. Here, we report that low-content organic acids can exhibit distinct effects on the solid-state polymorphic phase transformation of piracetam (PCM), a nootropic drug used for memory enhancement. The addition of 1 mol% citric acid (CA) and tricarballylic acid (TA) can significantly inhibit the phase transformation of PCM Form I to Form II, while glutaric acid (GA) and adipic acid (AA) produce a minor effect. A molecular simulation shows that organic acid molecules can adsorb on the crystal surface of PCM Form I, thus slowing the movement of molecules from the metastable form to the stable form. Our study provides deeper insights into the mechanisms of solid-state polymorphic phase transformation of drugs in the presence of additives and facilitates opportunities for controlling the stability of metastable pharmaceuticals.

Impact of ocean acidification on shells of the abalone species Haliotis diversicolor and Haliotis discus hannai.

Ocean acidification (OA) results from the absorption of anthropogenic CO2 emissions by the ocean and threatens the survival of many marine calcareous organisms including molluscs. We studied OA effects on adult shells of the abalone species Haliotis diversicolor and Haliotis discus hannai that were exposed to three pCO2 conditions (ambient, ∼880, and ∼1600 µatm) for 1 year. Shell periostracum corrosion under OA was observed for both species. OA reduced shell hardness and altered the nacre ultrastructure in H. diversicolor, making its shells more vulnerable to crushing force. OA exposure did not reduce the shell hardness of H. discus hannai and did not alter nacre ultrastructure. However, the reduced calcification also decreased its resistance to crushing force. Sr/Ca in the shell increased with rising calcification rate. Mg/Ca increased upon OA exposure could be due to a complimentary mechanism of preventing shell hardness further reduced. The Na/Ca distribution between the aragonite and calcite of abalone shells was also changed by OA. In general, both abalone species are at a greater risk in a more acidified ocean. Their shells may not provide sufficient protection from predators or to transportation stress in aquaculture.