Multicomponent Crystals Research Articles

A new strategy to design isostructural salts: The case of the antitumor drug dimethylaminomicheliolide

Isostructural multicomponent crystals provide a promising way for fine-tuning physicochemical properties, whereas their design remains quite challenging. The purpose of this work was to provide a new strategy for obtaining isostructural multicomponent crystals by introducing coformers with functional group positional isomerism. Five isostructural salts of an antitumor drug dimethylaminomicheliolide (DMAMCL) were reported and designed with a series of dihydroxybenzoic acid regioisomers for the first time, which were identified by power and single-crystal X-ray diffractions. Similar lattice parameters suggested these obtained salts may have the same crystal packing mode. The quantitative similarity parameters via XPac, CrystalCMP and Mercury program further proved these crystal structures are 3D isostructural. Hirshfeld surface maps and 2D fingerprint plots show that the isostructural salts have similar intermolecular interactions. Compared with DMAMCL, obvious improvement was observed in the thermal stability, hygroscopicity, and solubility of these isostructural salts. Meanwhile, isostructural crystals may have different physicochemical properties, even though the shape and molecular size are similar and the packing of crystal structures is equally matched.

Accelerated identification of equilibrium structures of multicomponent inorganic crystals using machine learning potentials

The discovery of multicomponent inorganic compounds can provide direct solutions to scientific and engineering challenges, yet the vast uncharted material space dwarfs synthesis throughput. While the crystal structure prediction (CSP) may mitigate this frustration, the exponential complexity of CSP and expensive density functional theory (DFT) calculations prohibit material exploration at scale. Herein, we introduce SPINNER, a structure-prediction framework based on random and evolutionary searches. Harnessing speed and accuracy of neural network potentials (NNPs), the program navigates configurational spaces 102–103 times faster than DFT-based methods. Furthermore, SPINNER incorporates algorithms tuned for NNPs, achieving performances exceeding conventional algorithms. In blind tests on 60 ternary compositions, SPINNER identifies experimental (or theoretically more stable) phases for ~80% of materials. When benchmarked against data-mining or DFT-based evolutionary predictions, SPINNER identifies more stable phases in many cases. By developing a reliable and fast structure-prediction framework, this work paves the way to large-scale, open exploration of undiscovered inorganic crystals.

Effects of composition and growth parameters on phase formation in multicomponent aluminum garnet crystals.

The effects of composition on the phase formation of multicomponent garnet crystals grown via directional solidification by the micro-pulling-down method are studied. A relatively wide range of rare-earth (RE) average ionic radii (AIR) is explored by formulating ten compositions from the system (Lu,Y,Ho,Dy,Tb,Gd)3Al5O12. Crystals were grown at either 0.05 or 0.20 mm min-1. The hypothesis is that multicomponent compounds with large AIR will form secondary phases as the single-RE aluminum garnets formed by larger Tb3+ or Gd3+; this will result in crystals of poor optical quality. Crystals with large AIR have a central opaque region in optical microscopy images, which is responsible for their reduced transparency compared to crystals with small AIR. Slow pulling rates suppress the formation of the opaque region in crystals with intermediate AIR. Powder and single-crystal X-ray diffraction and electron probe microanalysis results indicate that the opaque region is a perovskite phase. Scanning electron microscopy and energy dispersive spectroscopy measurements reveal eutectic inclusions at the outer surface of the crystals. The concentration of the eutectic inclusions increases with increasing AIR.

Minoxidil Multi-Component Crystals with Aromatic Carboxylic Acids: Theoretical Calculation and Structural Analysis

Minoxidil Multi-Component Crystals with Aromatic Carboxylic Acids: Theoretical Calculation and Structural Analysis

A potent anesthetic drug salt: experimental and computational studies

The title compound Ethyl 4-aminobenzoate – 3,5-dinitrosalicylate salt [ES] has been synthesized, crystallized and characterized using FTIR, 1H NMR, 13C NMR and confirmed by single crystal X-ray diffraction method. The molecular structure and crystal packing were carried out using theoretical optimization at the DFT level and the concept of atom in molecules (AIM) analysis was performed. Further, the molecular packing is visualized and quantified using Hirshfeld surfaces analysis. The crystal structure is stabilized via intermolecular hydrogen bonds of the type N – H …O and O – H …O. The hydrogen bonding acquires three-dimensional architecture and the molecules in the crystal are connected through C(8) hydrogen motif. The inter contact H...O (45.0%) contributes more to the Hirshfeld surfaces and the strength and stability of the multicomponent crystal have been estimated using the energy framework calculation. Further, the biological study of the title compound was studied through antibacterial and antifungal activities.

Co-crystal Phase Diagram Determination by the Solution Addition Method

Multicomponent crystals such as co-crystals, salts, and solid solutions can be used to modify physical properties of active pharmaceutical ingredients. Phase diagrams of such multicomponent crystals are essential for crystallization process development, especially in the case where multiple solid phases may coexist. However, additional components and solid phases make phase diagrams more complex and their determination more time consuming. We propose to accelerate this process by identifying the eutectic points and constructing the rest of the phase diagram using thermodynamic models, informed by further measurements, if necessary. In this work, a novel solution addition method is proposed for determining the eutectic points in a co-crystal system. This method implements gradual compositional changes to traverse various regions of the phase diagram. Phase boundaries are determined by monitoring changes in the liquid phase (UV–vis) and solid phase (Raman), and eutectic points are obtained from intersection of phase boundaries. The results from solution addition are compared to those of an equilibration method, which combines gravimetry, XRPD, and NMR to identify the eutectic solution composition starting from a composition in the three-phase region of a co-crystal phase diagram. Both methods were able to locate all eutectic points, allowing construction of the ternary phase diagrams of benzoic acid and isonicotinamide in ethanol.

Crystal structures and phase transitions in two new hybrid crystals: (Me3NCH2CH2X)4[Ni(NCS)6] (X = Cl and Br)

Understanding phase transitions in multi-component crystals is of importance for regulating specified functional materials. Herein, we present two new organic-inorganic hybrid crystals, (Me3NCH2CH2X)4[Ni(NCS)6] (X = Cl and Br), revealing distinct phase transitions. Specifically, the Cl-substituted cations weakly interact with discrete inorganic part hence reveal step-wise dynamic changes upon heating, which result in multi-step solid-solid phase transitions (P1¯–P21/n–A2/a–Cmce) including a ferroelastic one with a spontaneous strain of 0.0475. Whereas the Br-substituted cations with larger steric effect prevent the solid-solid phase transition but give a solid-liquid phase transition at above 419 K. The present instances well demonstrate the complicity for multi-component crystals arising from the delicate balance established by abundant weak intermolecular interactions, and inspire the design of novel phase-transition materials by judiciously assembling multi-component crystals.

Validation of UV spectrophotometric method for ketoprofen multicomponent crystals with malic acid and tartaric acid

These multicomponent crystals are formed by two chemical substances, between ketoprofen and their co-formers, which are malic acid and tartaric acid. Analysis of multicomponent crystals showed a possibility of interference between constituents. To determine interference between pure drugs and their co-formers, a validated, fast, easy, efficient, and adequate analysis method is required. This study aims to evaluate and develop an analytical method validation that is accurate, specific, and reproducible on ketoprofen multicomponent crystals using UV-Vis spectrophotometry. The study was conducted by the dissolving of phosphate buffer with 7.4 pH with the addition of ethanol co-solvent to obtain calibration curve solution. The calibration curve was analyzed for linearity, accuracy, and precision. Meanwhile, the placebo interference parameter was measured on an equimolar ratio of 1:1 between ketoprofen and co-former. Validation result on the wavelength of 260.5 nm with a range of 1-16.834 µg/mL showed the linearity of R2 = 0.999 and intercept P-value > 0.05, accuracy of Recovery = 100.652%, precision of RSD = 0.568%, and placebo interference of 0%. Based on the results of this study, the UV-Vis spectrophotometer method for ketoprofen multicomponent crystals fulfilled the validation standard.

Development and validation of analytical methods for multicomponent crystals of ibuprofen with malic and tartaric acid using spectrophotometry

Various chemical substances have been used as pharmaceutical active ingredients, such as ibuprofen, which is an analgesic. The validity of an analytical method of a pharmaceutical active ingredient combined with co-formers into one single phase should be confirmed so that the analysis can be well received. Therefore, this study aims to validate the analytical method of ibuprofen in multicomponent crystals using a UV spectrophotometer with the parameters of linearity, accuracy, precision, and placebo interference. Ibuprofen was dissolved in phosphate buffer with a pH of 7.2 using ethanol as co-solvent. The solution was diluted and analyzed to obtain the maximum wavelength. The calibration curve was analyzed to obtain the linear regression equation for ibuprofen to determine linearity. The accuracy and precision parameters were measured by the results of replications. Meanwhile, placebo interference was determined using an equimolar ratio of 1:1 between ibuprofen with malic acid and tartaric acid. The results of the analysis showed that ibuprofen had a maximum wavelength of 265 nm. The linearity, accuracy, precision, and placebo interference fulfilled the requirement. Based on the validation parameter performed, the analytical method used was valid for the analysis of ibuprofen multicomponent crystals with malic acid and tartaric acid as co-formers.

Synthesis of multicomponent crystals composed of 4-amino-1-methylpyridinium p-toluenesulfonate and phenol derivatives

Preparation of crystals containing three chemical species was investigated using two ionic components of 4-amino-1-methylpyridinium p-toluenesulfonate (AP-TS) and one more molecular component from phenol derivatives. Oxygen atoms at the sulfonate group of TS act as hydrogen-bonding acceptors while hydrogen atoms at the hydroxy group of phenol derivatives as well as at the amino group of AP act as hydrogen-bonding donors, and hydrogen bonding among these species helps to form three-component cocrystals. Among ten phenol derivatives investigated, 4,4’-biphenol and (±)-1,1’-bi-2-naphthol cocrystallized with AP-TS. From these crystal structure studies, we found a common structural feature based on the hydrogen-bonding patterns.

Improved Solubility and Dissolution Rate of Ketoprofen by the Formation of Multicomponent Crystals with Tromethamine

This study aims to improve the dissolution rate of ketoprofen by preparing multicomponent crystals with tromethamine. The multicomponent crystals (equimolar ratio) of ketoprofen and tromethamine were prepared by the solvent co-evaporation method. The solid-state properties of the resulting powder were characterized by powder X-ray diffraction, DSC thermal analysis, FT–IR spectroscopy, solubility, and in vitro dissolution rate. The crystal structure of the multicomponent crystal was determined by single-crystal X-ray diffraction analysis. The results showed that the powder X-ray diffraction pattern of the ketoprofen–tromethamine binary system was different from that of the starting materials. This difference indicates the formation of a new crystalline phase between ketoprofen and tromethamine (equimolar ratio). The DSC thermogram of the ketoprofen–tromethamine binary system exhibited a single and sharp endothermic peak at 128.67 °C, attributed to the melting point of a multicomponent crystal of ketoprofen–tromethamine. A single-crystal X-ray analysis revealed that ketoprofen–tromethamine formed a layered structure, salt-type multicomponent crystal. The solubility and dissolution rate of the multicomponent crystal were notably enhanced compared to the intact ketoprofen. The ketoprofen–tromethamine binary system forms salt-type multicomponent crystals, which can significantly increase the solubility and dissolution rate.

Structural Characterization of Multicomponent Crystals Formed from Diclofenac and Acridines.

Multicomponent crystals containing diclofenac and acridine (1) and diclofenac and 6,9-diamino-2-ethoxyacridine (2) were synthesized and structurally characterized. The single-crystal XRD measurements showed that compound 1 crystallizes in the triclinic P-1 space group as a salt cocrystal with one acridinium cation, one diclofenac anion, and one diclofenac molecule in the asymmetric unit, whereas compound 2 crystallizes in the triclinic P-1 space group as an ethanol solvate monohydrate salt with one 6,9-diamino-2-ethoxyacridinium cation, one diclofenac anion, one ethanol molecule, and one water molecule in the asymmetric unit. In the crystals of the title compounds, diclofenac and acridines ions and solvent molecules interact via N–H⋯O, O–H⋯O, and C–H⋯O hydrogen bonds, as well as C–H⋯π and π–π interactions, and form heterotetramer bis[⋯cation⋯anion⋯] (1) or heterohexamer bis[⋯cation⋯ethanol⋯anion⋯] (2). Moreover, in the crystal of compound 1, acridine cations and diclofenac anions interact via N–H⋯O hydrogen bond, C–H⋯π and π–π interactions to produce blocks, while diclofenac molecules interact via C–Cl⋯π interactions to form columns. In the crystal of compound 2, the ethacridine cations interact via C–H⋯π and π–π interactions building blocks, while diclofenac anions interact via π–π interactions to form columns.

Ciprofloxacin salt and salt co-crystal with di-hydroxy-benzoic acids.

The crystal structure of two multi-component crystals of ciprofloxacin [systematic name: 1-cyclo-propyl-6-fluoro-4-oxo-7-(piperazin-1-yl)quinoline-3-carb--oxy-lic acid], a fluoro-quinolone anti-biotic, namely, ciprofloxacin 2,6-di-hydroxy-benzoate salt, C17H19FN3O3 +·C7H5O4 -, (I), and ciprofloxacin hydro-chloride-3,5-di-hydroxy-benzoic-water (1/1/1), C17H19FN3O3 +·Cl-·C7H6O4·H2O, (II), were determined. In (I) and (II), the ciprofloxacin cations are connected via head-to-tail N-H⋯O hydrogen bonding. Both structures show an alternating layered arrangement between ciprofloxacin and di-hydroxy-benzoic acid.

Theoretical and Structural Understanding of the Different Factors Influencing the Formation of Multicomponent Crystals of 2,4-Dichlorophenoxyacetic Acid with N-heterocyclic Compounds

Theoretical and Structural Understanding of the Different Factors Influencing the Formation of Multicomponent Crystals of 2,4-Dichlorophenoxyacetic Acid with N-heterocyclic Compounds

Above-Room-Temperature Ferroelastic Phase Transitions in Two Tetrafluoroborate-Based Hexagonal Molecular Perovskites.

ABX3-type molecular perovskites provide an important platform to tune phase transitions, via judiciously choosing A-, B-, and X-site components, to approach advanced functional materials for applications. Although tetrafluoroborate can act as X-site component to assemble ten instances of ABX3 molecular perovskites, only two of them possess hexagonal perovskite structures. Herein, we report two tetrafluoroborate-based hexagonal molecular perovskites, A[Na(BF4)3], by judiciously choosing two different A-site cations: 1-methyl-1,4-diazabicyclo[2.2.2]octane-1,4-diium (Hmdabco2+) for 1 and 1-methylpiperazine-1,4-diium (H2mpz2+) for 2. They have high-temperature phases in the same space group (P63/mmc) revealing highly disordered A-site cations. Upon cooling, 1 undergoes two-step P63/mmc ↔ P3̅c1 ↔ P21/n transitions at 344 and 338 K, respectively, including a ferroelastic one (3̅mF2/m) accompanied by a spontaneous strain of 0.013. In contrast, the smaller H2mpz2+ cation with more adoptable conformations induces a one-step sharp P63/mmc ↔ P21/c ferroelastic transition (6/mmmF2/m(s)) at 418 K in 2, leading to more significant symmetry breaking and a considerable spontaneous strain of 0.129. This study provides important clues to modulate structural phase transitions by tuning diverse components for the multicomponent dense hybrid crystals.

Novel Drug–Drug Multicomponent Crystals of Epalrestat–Metformin: Improved Solubility and Photostability of Epalrestat and Reduced Hygroscopicity of Metformin

Novel Drug–Drug Multicomponent Crystals of Epalrestat–Metformin: Improved Solubility and Photostability of Epalrestat and Reduced Hygroscopicity of Metformin

Multicomponent Crystal of Trimethoprim and Citric Acid: Solid State Characterization and Dissolution Rate Studies

BACKGROUND: Trimethoprim is a broad spectrum antimicrobial agent with low solubility in water which causes low bioavailability in systemic circulation.
 AIM: The purpose of this study was to prepare multicomponent crystals of trimethoprim and citric acid to increase the solubility and dissolution rate of trimethoprim.
 MATERIALS AND METHODS: Multicomponent crystals were prepared by solvent evaporation method. Characterizations of multicomponent crystalline solid phase properties were carried out by powder X-ray diffraction (PXRD) analysis, differential scanning calorimetry (DSC), FT-IR spectroscopy, scanning electron microscopy (SEM). Solubility and dissolution rate tests were carried out in aqueous medium.
 RESULTS: The PXRD characterization results showed a new X-ray diffraction pattern in the multicomponent crystal phase. DSC analysis showed the formation of a new endothermic peak. This indicates the formation of a multicomponent crystal phase between trimethoprim and citric acid. The results of the SEM analysis indicate the formation of a new crystal habit. Solubility of multi-component crystal phase of trimethoprim increased 7 times compared to intact trimethoprim. The dissolution of trimethoprim and multicomponent crystals in 0.1 N HCl medium at 60 minutes was 56.36% and 95.57% and CO2-free distilled water medium was 43.03% and 88.26%, respectively.
 CONCLUSIONS: From the results of the study, it can be concluded that the multicomponent phase of trimethoprim crystals with citric acid successfully increase the solubility and dissolution rate of trimethoprim significantly.

Programming "Atomic Substitution" in Alloy Colloidal Crystals Using DNA.

Although examples of colloidal crystal analogues to metal alloys have been reported, general routes for preparing 3D analogues to random substitutional alloys do not exist. Here, we use the programmability of DNA (length and sequence) to match nanoparticle component sizes, define parent lattice symmetry and substitutional order, and achieve faceted crystal habits. We synthesized substitutional alloy colloidal crystals with either ordered or random arrangements of two components (Au and Fe3O4 nanoparticles) within an otherwise identical parent lattice and crystal habit, confirmed via scanning electron microscopy and small-angle X-ray scattering. Energy dispersive X-ray spectroscopy reveals information regarding composition and local order, while the magnetic properties of Fe3O4 nanoparticles can direct different structural outcomes for different alloys in an applied magnetic field. This work constitutes a platform for independently defining substitution within multicomponent colloidal crystals, a capability that will expand the scope of functional materials that can be realized through programmable assembly.

Thermal method usage features for multicomponent crystal screening

In this work, the effectiveness of thermal methods, liquid-assisted grinding, and crystallization by a slow evaporation technique for the screening of multicomponent crystals of five quinolones with tyramine was investigated.

Multicomponent crystal compromising dasatinib and selected co-crystals formers: a patent evaluation of EP2861589B1.

Cocrystallization has gained significant prominence in pharmaceutical product development because of the enhancement of physical, chemical and pharmacological properties of active pharmaceutical ingredients, such as stability, solubility, dissolution rate, taste, hygroscopicity, mechanical property, bioavailability, permeability and therapeutic activity. Traditionally, co-crystals can be prepared by a grinding, solvent evaporation and slurry method. However, sophisticated methods such as spa drying, hot-melt extrusion, supercritical fluid and laser irradiation are also reported to be used for producing co-crystals. The selected patent describes the development of multicomponent crystals of dasatinib, with an aim to enhance the aqueous solubility of a selected drug. However issues surrounding the toxicity, stability, large scale manufacture, in vivo performance in human beings and regulations require adequate addressal prior to exploring the commercial viability of pharmaceutical co-crystals.