Multicomponent Crystals Research Articles

Managing negative linear compressibility and thermal expansion through steric hindrance: a case study of 1,2-bis(4'-pyridyl)ethane cocrystals.

Multicomponent crystals have great scientific potential because of their amenability to crystal engineering in terms of composition and structure, and hence their properties can be easily modified. More and more research areas are employing the design of multicomponent materials to improve the known or induce novel physicochemical properties of crystals, and recently they have been explored as materials with abnormal pressure behaviour. The cocrystal of 1,2-bis(4'-pyridyl)ethane and fumaric acid (ETYFUM) exhibits a negative linear compressibility behaviour comparable to that of framework and metal-containing materials, but overcomes many of their deficiencies restricting their use. Herein ETYFUM was investigated at low temperature to reveal negative thermal expansion behaviour. Additionally, a cocrystal isostructural with ETYFUM, based on 1,2-bis(4'-pyridyl)ethane and succinic acid (ETYSUC), was exposed to high pressure and low temperature, showing that its behaviour is similar in nature to that of ETYFUM, but significantly differs in the magnitude of both effects. It was revealed that the minor structural difference between the acid molecules does not significantly affect the packing under ambient conditions, but has far-reaching consequences when it comes to the deformation of the structure when exposed to external stimuli.

Characterization of Physicochemical Properties and Dissolution Studies of Multicomponent Crystals of Piperine and Glutamic Acid

Characterization of Physicochemical Properties and Dissolution Studies of Multicomponent Crystals of Piperine and Glutamic Acid

Mechanochemical synthesis and solid-state characterization of molecular salts of pyridoxine: Vibrational spectroscopic and thermal consideration

Crystal engineering of multicomponent crystals offers opportunities for both generic active pharmaceutical ingredients (APIs) and innovative APIs (under patent protection) to be noncovalently bound with a wide range of organic compounds, forming new solid phases such as salts or cocrystals. These multicomponent crystals can enhance the physicochemical properties, processibility, and bioavailability of the APIs. The purpose of this research is to correlate vibrational (FTIR and Raman) spectroscopy studies with the thermal behavior of new molecular salts of the drug model pyridoxine (PN), using salt formers from the group of hydroxybenzoic acid derivatives known for their potent antioxidant activity. The coformers include syringic acid (SA) and ferulic acid (FA), synthesized through eco-friendly mechanochemical methods by treating bulk powders of their stoichiometric mixture with PN. The assigned vibrational modes and thermal behaviors of the pyridoxonium syringate (PN/SA) and pyridoxonium ferulate (PN/FA∙H2O) reveal the protonation of the pyridoxine N-atom in both salts structures. This protonation results in structural alterations in the crystal packing of the counterions, which exhibit unique spectral fingerprints and thermal profiles compared to the starting compounds.

Investigating Elastic Deformation of Ordered Precipitates by Ab Initio-Informed Phase-Field Crystal Modeling

Ni-based superalloys, essential for high-temperature applications, derive strength from coherent second-order precipitates that impede dislocation motion through coherency misfit and elastic mismatch. This study employs multi-component phase-field crystal (PFC) simulations to explore the elastic deformation of such precipitates. Using a binary ordered square structure for the precipitate and a single species square structure for the matrix, elastic properties and lattice parameters are fitted to data from ab initio density functional theory calculations for Ni and Ni3Ti systems. Simulations reveal a smooth strain gradient across the matrix–precipitate interface with coherency misfit influenced by precipitate size and strain state. These findings highlight the utility of PFC simulations for understanding strain distribution and deformation in precipitate–matrix systems with the potential to offer insights for both experimental and computational studies.

Bonding Optimization Strategies for Flexibly Preparing Multi-Component Piezoelectric Crystals.

Flexible films with optimal piezoelectric performance and water-triggered dissolution behavior are fabricated using the co-dissolution-evaporation method by mixing trimethylchloromethyl ammonium chloride (TMCM-Cl), CdCl2, and polyethylene oxide (PEO, a water-soluble polymer). The resultant TMCM trichlorocadmium (TMCM-CdCl3) crystal/PEO film exhibited the highest piezoelectric coefficient (d33) compared to the films employing other polymers because PEO lacks electrophilic or nucleophilic side-chain groups and therefore exhibits relatively weaker and fewer bonding interactions with the crystal components. Furthermore, upon slightly increasing the amount of one precursor of TMCM-CdCl3 during co-dissolution, this component gained an advantage in the competition against PEO for bonding with the other precursor. This in turn improved the co-crystallization yield of TMCM-CdCl3 and further enhanced d33 to ≈71 pC/N, exceeding that of polyvinylidene fluoride (a commercial flexible piezoelectric) and most other molecular ferroelectric crystal-based flexible films. This study presents an important innovation and progress in the methodology and theory for maintaining a high piezoelectric performance during the preparation of flexible multi-component piezoelectric crystal films.

Study on the formation mechanism and effective manipulation of polymorphs and solvates in Osimertinib-Caffeic acid multi-component crystal with distinct properties.

Investigating the formation mechanism and effective manipulation of multi-component crystal polymorphs is crucial for facilitating industrial drug development. Herein, five novel Osimertinib-caffeic acid forms were first strategically tailored by varying solvent selection. Theoretical analysis demonstrated this polymorphism is correlated with multiple hydrogen bond donors-acceptors within multi-component system, which provides manipulation space for reconfiguration of intermolecular interactions and structural competition, while solvent further induced or involved in hydrogen-bonded rearrangements. Molecular dynamics simulation and solvent characterization revealed strong solute-solvent interaction and hydrogen bond donor propensity promoted the generation of hydrate. Small molecular size or large cavity of crystal facilitated solvent entry, resulting in the generation of channel-type solvates. Higher solvation free energy implied faster reaction rate and poorer solvent removal ability for solvates. Thermal analysis confirmed removal of the solvent occupying crystal channels for precursor solvates led to polymorph formation while maintaining the structure. Properties assessments revealed multi-component crystals significantly enhanced the physicochemical properties of Osimertinib. Polymorphs and hydrate exhibited remarkable distinctions in solubility, dissolution rate and physical stability. Nanoindentation and tableting tests confirmed distinct mechanical properties of different forms. Overall, this exploration has the potential to reshape the landscape of multi-component crystal polymorph development, paving the way for manipulating intermolecular interactions.

An Overlooked Supramolecular Synthon in Multicomponent Trimethylglycine Crystals: Moderate Hydrogen Bonding Between Carboxylate and H-N Groups of Guanidine Species

Three novel multicomponent crystals of trimethylglycine with 2-cyanoguanidine, guanidinium and aminoguanidinium chlorides are synthesized and structurally characterized. All three crystal packings are based on the supramolecular synthon formed by two N–H groups of the guanidine species and carboxylate group of trimethylglycine (graph set notation R22(8)). Its enthalpy is about 50 kJ•moL−1. The three-dimensional structure of crystals is stabilized by intermolecular interactions of various types. The energy of C–H∙∙∙X− interactions, where X = O, Cl, reaches 16 kJ•moL−1 due to the acidic nature of methyl hydrogens. The possible structure of the trimethylglycine–urea–2H2O complex is discussed. Its theoretical metric and spectroscopic parameters are in reasonable agreement with the available literature data on the deep eutectic solvent trimethylglycine–urea.

Temperature dependence of photoluminescence kinetics, scintillation properties, and coincidence time resolution of Mo co-doped Y1.5Gd1.5Al2Ga3O12:Ce (Mo = 0, 300, 600 ppm) multicomponent garnet crystals

Temperature dependence of photoluminescence kinetics, scintillation properties, and coincidence time resolution of Mo co-doped Y1.5Gd1.5Al2Ga3O12:Ce (Mo = 0, 300, 600 ppm) multicomponent garnet crystals

Cocrystallization Enables Ensitrelvir to Overcome Anomalous Low Solubility Caused by Strong Intermolecular Interactions between Triazine-Triazole Groups in Stable Crystal Form.

Ensitrelvir is a nonpeptide 3CL protease inhibitor used for coronavirus disease 2019 treatment. Four crystalline forms of ensitrelvir, metastable (Form I), acetonate (Form II), stable (Form III), and hydrate (Form IV), have been analyzed as pharmaceutical crystals. Their rank order of solubility is Form I > IV > III. Form III is the stable crystal with a significantly lower solubility than that predicted from its log P value of 2.7. Here, single-crystal structural analysis revealed strong intermolecular interactions between the triazine (acidic) and triazole (basic) groups of Form III not Forms I and IV. Multicomponent crystals were also designed to improve the solubility by altering the intermolecular interactions in Form III. Slurry conversion with equal molar ratios of ensitrelvir and fumaric acid successfully induced the formation of a novel cocrystal (Form V). Fumaric acid inhibited the triazine-triazole interactions, and dissolution of Form V was approximately 8- and 13-fold higher than that of Form III in pH 1.2 and 6.8 media, respectively. Furthermore, Form V exhibited an approximately 16-fold higher flux value than that of Form III. Therefore, alterations in intermolecular interactions via cocrystallization significantly enhance the dissolution and permeation of ensitrelvir.

Multicomponent crystals: Solubility enhancement of simvastatin using arginine and glycine coformers

Context: Simvastatin can be modified by the formation of multicomponent crystals to increase its solubility. Aims: To compare the solubility of multicomponent simvastatin crystals to pure simvastatin. Methods: The in silico study of simvastatin and the coformers arginine and glycine revealed non-covalent interactions, so multicomponent preparations of simvastatin crystals were prepared by solvent evaporation using a mole ratio of 1:1; 1:2 and 2:1. Results: Each simvastatin-arginine and simvastatin-glycine ratio increased the solubility, with the highest increase observed for the 1:2 ratio compared to pure simvastatin. Conclusions: Simvastatin-arginine multicomponent crystals (1:2) showed the best dissolution profile in phosphate buffer medium pH 7.0 with 67.69% dissolution, while simvastatin-glycine multicomponent crystals (1:2) exhibited the best dissolution profile in buffer media pH 1.2 with 16.19% dissolution. Characterization of the multicomponent crystals revealed a shift in the peaks, a decreased melting point, and enthalpy, indicating decreased % crystallinity and the formation of a new solid phase.

Virtual Screening, Polymorphism, and Formation Thermodynamics Study of Riluzole Multicomponent Crystals with Dihydroxybenzoic Acids

Virtual Screening, Polymorphism, and Formation Thermodynamics Study of Riluzole Multicomponent Crystals with Dihydroxybenzoic Acids

Structural multiplicity in a solvated hydrate of the anti-retroviral protease inhibitor Lopinavir.

Lopinavir is a potent protease inhibitor that is used as a first-line pharmaceutical drug for the treatment of HIV. The multi-component solvated Lopinavir crystal, systematic name (2S)-N-[(2S,4S,5S)-5-[2-(2,6-di-methyl-phen-oxy)acetamido]-4-hy-droxy-1,6-di-phenyl-hexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide-ethane-1,2-diol-water (8/3/7) 8C37H48N4O5·3C2H6O2·7H2O, was prepared using evaporative methods. The crystalline material obtained from this experimental synthesis was characterized and elucidated by single-crystal X-ray diffraction (SC-XRD). The crystal structure is unusual in that the unit cell contains 18 mol-ecules. The stoichiometric ratio of this crystal is eight Lopinavir mol-ecules [8(C37H48N4O5)], three ethane-1,2-diol mol-ecules [3(C2H6O2)] and seven water mol-ecules [7(H2O)]. The crystal packing features both bi- and trifurcated hydrogen bonds between atoms.

Transition state of matter in the fluctuation model of crystal growth

Two mechanisms of the effect of the transition state of building particles (activated complexes according to S. Arrhenius) on the crystal growth rate within the framework of the fluctuation model of dislocation crystal growth are discussed. Transition state clusters adsorbed on the surface of the growing face perform the function of an impurity that lowers the surface energy of the crystal at the time moments between free energy fluctuations. Thus, the transition state of the crystallizing substance by the first mechanism affects the relaxation rate of the secondary adsorption of impurities and shortens the time period of attachment of building particles to the crystal face. Other clusters formed in solution reduce the number of free particles and under conditions of low concentration of the building substance are able to decrease the crystallization rate. Nevertheless, in a natural multicomponent crystallization environment, at low concentrations of building material, significant thermal effect of crystallization and small deviations from equilibrium, the role of the transition state in crystal growth is generally insignificant.

Eutectic mixtures of nevirapine: Phase diagrams, solid-state characterization, and dissolution studies

Solid-state modifications can improve drug performance. Studies have shown that multicomponent crystals, such as cocrystals and eutectic compositions, have successfully improved the performance of certain drugs, including their solubility. Nevirapine (NEV) is an antiretroviral drug with low aqueous solubility, impacting its bioavailability. This work aimed to study different nevirapine/co-former solid eutectic systems, define their phase diagrams and evaluate their dissolution properties. Caffeine (CAF), Theobromine (TEOB), and Theophylline (THEO) were chosen as co-formers due to their functional groups that can interact with NEV. Aiming to determine both temperature and eutectic composition, phase and Tamman diagrams were obtained using the differential scanning calorimetry (DSC) analysis of the mixtures indifferent NEV-co-former compositions (%w/w). Powder X-ray diffraction (PXRD) and DSC were used to characterize the eutectic materials. To assess the influence of eutectic systems on dissolution properties, we determined the powder dissolution profiles and intrinsic dissolution rates of anhydrous NEV and eutectic systems NEV-CAF and NEV-THEO using different dissolution media (pH 1.2 and pH 6.8). The eutectic compositions were calculated through the phase diagrams, interpolating the curves obtained by linear regression. Thus, the eutectic composition of the NEV-CAF system was determined to be 36.55 % NEV and eutectic temperature at 201.1 °C, while in the NEV-THEO system, the eutectic was obtained in a composition of 71.04 % NEV and eutectic temperature at 217.8 °C. Tamman diagrams were generated using the enthalpy values obtained from the DSC curves, and eutectic compositions were calculated using linear regression. The analysis revealed a eutectic composition of 36.51 % of NEV for the NEV-CAF system, and a eutectic composition of 70.94 % of NEV for the NEV-THEO system. It was not possible to determine the eutectic mass fraction of NEV-TEOB. A comparison of dissolution profiles and intrinsic dissolution rates in different dissolution media showed a significant improvement in the NEV dissolution rate in both eutectic systems. In an acidic medium, NEV dissolved 16 times faster in the NEV-CAF sample and 4 times faster in the NEV-THEO sample compared to pure anhydrous NEV. In a neutral medium, the dissolution profile of NEV was even more favorable in the same eutectic systems, showing that the increase in dissolution is relevant in a wide range of pH. In addition, the intrinsic dissolution rate in the two eutectic systems was higher than that of anhydrous NEV in all employed dissolution mediums. These eutectic systems improve the dissolution rate compared to pure NEV, offering the potential for enhancing the dissolution of poorly water-soluble drugs in the future.

Crystal structures of two different multi-component crystals consisting of 1-(3,4-di-meth-oxy-benz-yl)-6,7-di-meth-oxy-iso-quinoline and fumaric acid.

Two different multi-component crystals consisting of papaverine [1-(3,4-di-meth-oxy-benz-yl)-6,7-di-meth-oxy-iso-quinoline, C20H21NO4] and fumaric acid [C4H4O4] were obtained. Single-crystal X-ray structure analysis revealed that one, C20H21NO4·1.5C4H4O4 (I), is a salt co-crystal composed of salt-forming and non-salt-forming mol-ecules, and the other, C20H21NO4·0.5C4H4O4 (II), is a salt-co-crystal inter-mediate (i.e., in an inter-mediate state between a salt and a co-crystal). In this study, one state (crystal structure at 100 K) within the salt-co-crystal continuum is defined as the 'inter-mediate'.

Hydrogen-Bonded Ionic Co-Crystals for Fast Solid-State Zinc Ion Storage.

The development of new ionic conductors meeting the requirements of current solid-state devices is imminent but still challenging. Hydrogen-bonded ionic co-crystals (HICs) are multi-component crystals based on hydrogen bonding and Coulombic interactions. Due to the hydrogen bond network and unique features of ionic crystals, HICs have flexible skeletons. More importantly, anion vacancies on their surface can potentially help dissociate and adsorb excess anions, forming cation transport channels at grain boundaries. Here, it is demonstrated that a HIC optimized by adjusting the ratio of zinc salt and imidazole can construct grain boundary-based fast Zn2+ transport channels. The as-obtained HIC solid electrolyte possesses an unprecedentedly high ionic conductivity at room and low temperatures (≈11.2 mScm-1 at 25°C and ≈2.78mScm-1 at -40°C) with ultra-low activation energy (≈0.12eV), while restraining dendrite growth and exhibiting low overpotential even at a high current density (<200mV at 5.0mAcm-2) during Zn symmetric cell cycling. This HIC also allows solid-state Zn||covalent organic framework full cells to work at low temperatures, providing superior stability. More importantly, the HIC can even support zinc-ion hybrid supercapacitors to work, achieving extraordinary rate capability and a power density comparable to aqueous solution-based supercapacitors. This work provides a path for designing facilely prepared, low-cost, and environmentally friendly ionic conductors with extremely high ionic conductivity and excellent interface compatibility.

Thermodynamic characteristics of multi-component crystals: Experimental evaluation, prediction and relationship with crystal parameters

In this study, we have analyzed the thermodynamic formation functions for four multi-component crystals based on the solubility data in the range of 293.15–313.15 K. The investigation was performed for the cocrystals of fluconazole (FLZ) with 4-hydroxybenzoic (4OHBA) and vanillic (VA) acids, and salts of fenbendazole (FNB) with maleic (Mal) and oxalic (Ox) acids. A database on the thermodynamic parameters of the multi-component molecular crystals (Gibbs free energy, enthalpy, and entropy) obtained in this study and borrowed from the literature was created. These parameters were determined using the experimental data on the solubility of the individual components and the product of the solubilities of the multi-component crystals at 298.15 K. A regression model was proposed to estimate the solubility product of the two-component crystals using the intrinsic solubility of the individual components as an independent variable. A detailed analysis of the database disclosed the relationship between the entropy term and the molecular volume of the multi-component crystal formation.

Component design and stable SESAM mode-locking of the disorder middle entropy Yb:CaSrBaF6 single crystal.

To the best of our knowledge, this is the first report on continuous and passively mode-locked operation of the multi-component fluoride CaSrBaF6 crystal. A novel disorder laser material, Yb:CaSrBaF6 (Ca0.33Sr0.33Ba0.33F2) of multi-component middle entropy crystal was designed and grown by temperature gradient technique (TGT) for the first time. X-ray diffraction (XRD) and X-ray fluorescence (XRF) analysis of Yb:CaSrBaF6 crystal reveals that Ca2+, Sr2+, and Ba2+ of near equal atomic ratio (1:1:1) have formed a homogeneous single-phased fluorite solid solution. The first principle calculation further shows that Ca2+, Sr2+, Ba2+ ions tend to be evenly distributed in the matrix crystal. The total formation energy is the lowest -547.17 ev and the structure is also the most stable at this time. The spectral properties of the crystal are systematically characterized. The emission cross section of 2F5/2→2F7/2 transition at 1040 nm is 0.62 × 10-20 cm2 with the larger full width at half maximum (FWHM) of 60.5 nm. The evenly disordered distribution of various cations and lattice distortion effect leads to the more diverse local structure and the diversity of luminescence, which can cause non-uniform broadening of the spectrum. Meanwhile, the Yb:CaSrBaF6 crystal generated a continuous wave (CW) output power of 1.128 W, corresponding to a slope efficiency of 32% and an optical-to-optical conversion efficiency of 28.7% at 1055.4 nm. By implementing a semiconductor saturable absorber mirror (SESAM) for stable mode-locked laser operation, when the absorbed pump power reached 3.79 W, the laser ran into continuous wave mode-locking (CWML) regime, the maximum average output power of 123 mW was generated and the pulse duration of 89 ps was achieved at a pulse repetition rate of 54.6 MHz, with a pulse energy of 2.25 nJ and a pulse peak power of 25 W. Better laser performance could be expected after optimizing pump core diameter and elimination of dispersion. All results show that Yb:CaSrBaF6 crystal is regarded as a what we believe to be novel laser materials, which also provide a reference for the development of disordered material and other rare earth ions doping.

Multi-component Crystal Strategy for Improving Water Solubility and Antifungal Activity of Climbazole.

The primary problem with climbazole (CLB), a broad-spectrum imidazole antifungal drug, is its low water solubility. In order to increase its water solubility and antifungal activity, three new multi-component crystals were synthesized in this work, and the intermolecular interactions were systematically studied. This work helps to optimize the CLB product formulation and extend its application prospects. In this work, three novel multi-component crystals, CLB-malonic acid (CLB-MA) salt, CLB-succinic acid (CLB-SA) cocrystal and CLB-adipic acid (CLB-AA) cocrystal, were successfully synthesized. And the crystal structure, thermodynamic properties, solubility, dissolution, hygroscopicity, and antifungal activity of the three multi-component crystals were fully characterized by single-crystal X-ray diffraction (SCXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic water vapor adsorption (DVS) and powder dissolution tests, etc. The molecular interactions and molecular stacking in multi-component crystals were studied by Hirshfeld surface (HS), molecular surface electrostatic potential (MEP), interaction region indication (IRI) and atom and molecule (AIM) techniques. The results show that the three multi-component crystals have good moisture resistance stability, and their water solubility is 6-22 times that of pure CLB. Meanwhile, the measurement of the minimum inhibitory concentration (MIC) proves that the cocrystal/salt has a stronger antifungal activity than climbazole. Quantum chemistry calculations of crystal structure visualized and quantified the interactions that exist in multi-component crystals, and explored the microscopic mechanisms underlying the different performance of multi-component crystals.

Supramolecular self-assembly strategy for the enhanced solubility/dissolution rate and anti-cancer efficacy of osimertinib: Insights from multi-component crystals to drug chemistry

Multi-component crystal based on supramolecular self-assembly is an effective strategy to modify the physicochemical properties of poorly water-soluble drugs. In this study, eight novel multi-component crystals of Osimertinib (AZD) were firstly synthesized under the guidance of theoretical analysis. Five single crystals were successfully obtained, and the AZD-FMS cocrystal shows a distinctive structure wherein free FMS filled in the skeleton, which may be crucial for maintaining morphology. Analysis of crystal structures and Hirshfeld surfaces indicated the involvement of N−H···O and N···H−O hydrogen bonds in the multi-component crystals. Owing to robust intermolecular interactions, multi-component crystals exhibited improved solubility/dissolution rate compared to pure AZD. Multivariate analysis revealed coformers and strong solute–solvent interactions determined the solubility/dissolution rate. Multi-component crystals showed superior stability in solution and low humidity. Moreover, AZD-FSM increased 5.2-fold anti-tumor activity over AZD, which is anticipated to enhance efficacy, reduce drug toxicity, combat drug resistance, and transform from laboratory to clinical application.