A novel salt, amantadinium hydrogen squarate hydrate (1), has been synthesized and characterized by single-crystal X-ray diffraction (SXRD) and Fourier-transform infrared (FTIR) spectroscopy. The crystals of 1 crystallize in the centrosymmetric triclinic space group P1, with the asymmetric unit comprising two independent amantadinium cations, two hydrogen squarate anions, and two water molecules. The hydrogen squarate anions form an infinite zigzag alpha-chain via short O-H center dot center dot center dot O hydrogen bonds of 2.521(2) & Aring; and 2.520(2) & Aring;. The FTIR spectrum exhibits a band at 3035 cm-1, corresponding to the stretching vibration of the N+-H center dot center dot center dot O-interactions, and a broad absorption centered at 1316 cm-1, attributed to O-H stretching vibrations associated with the short hydrogen bonds between hydrogen squarate anions. The structural features in the solid state were further investigated using density functional theory (DFT) calculations at the APF-D/6-311++G(d,p) level, complemented by the Quantum Theory of Atoms in Molecules (QTAIM) approach. A comparison was made between the experimental and computed infrared spectra. Additionally, the thermal stability of 1 was assessed using thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The biological activity of 1, as well as its components-amantadine (AMD) and squaric acid (H2SQ)-was evaluated through their interactions with selected strains of bacteria and mold fungi.

Vitamin B6 (pyridoxine, 3-hydroxy-4,5-bis(hydroxymethyl)-2-methylpyridine) forms ionic complexes with oxalic, malonic, succinic acids in a 1:1 stoichiometry and with adipic acid in a 2:1 stoichiometry. Whereas as a result of the reaction of glutaric acid with pyridoxine, a salt co-crystal was obtained containing pyridoxine cations, glutaric acid dianions and glutaric acid molecules in a stoichiometric ratio of 2:1:1. The structure of the obtained salts was characterized by single-crystal X-ray diffraction and FTIR spectroscopy. Molecular geometry optimizations were carried out at the APF-D/6-311++G(d,p) level of theory, employing a conductor-like screening model. In the crystal structures, the molecules are linked by hydrogen bonds involving the nitrogen atom of pyridoxine and the corresponding dicarboxylic acid, with N- H & sdot;& sdot;& sdot;O distances ranging from 2.6309(10) to 2.7836(6) & Aring;. The hydroxyl groups of pyridoxine participate in hydrogen bonding with either carboxylate or carboxylic acid groups, thereby stabilizing the crystal structure. In the optimized structures, proton transfer was observed in the complexes with oxalic, malonic, and glutaric acids. The N- H & sdot;& sdot;& sdot;O and O- H & sdot;& sdot;& sdot;N hydrogen bond distances in these cases range from 2.586 to 2.624 & Aring;. The study includes analysis of molecular geometries, hydrogen bond parameters, infrared spectra, molecular electrostatic potential (MEP) surface, natural atomic charges and frontier molecular orbitals (HOMO and LUMO). Simultaneous thermal analysis was employed to assess the thermal stability of the investigated salts. Additionally, the antibacterial activity of the pyridoxine - dicarboxylic acid ionic complexes and their components was evaluated against both pathogenic and probiotic bacterial strains.

Miconazole is a commonly used imidazole antifungal drug with a broad spectrum of activity against Candida strains and other microorganisms. However, its poor solubility and low bioavailability have limited its use to topical infections. To overcome this limitation through the use of cocrystalization techniques, the present work focuses on the relatively less explored class of heterocyclic carboxylic acid coformers, containing two nitrogen atoms in the ring, aimed at developing alternative multicomponent forms of miconazole. Five new forms of miconazole were subjected to in-depth structural analysis, including an evaluation of the effect of hydrate formation. Furthermore, layered motifs in the supramolecular crystal architectures were subjected to qualitative and quantitative surface analysis using CSD-Particle. All new forms of miconazole were also characterized by FT-IR spectroscopy and thermogravimetric analysis. Water solubility was identified as the most important physicochemical property, and significant improvements were obtained for four of the five salts studied. Notably, the newly synthesized miconazole salts with heterocyclic (di)carboxylic acids exhibited high antifungal activity. The tested compounds effectively inhibited the growth of C. albicans and C. parapsilosis at concentrations several times lower than the parent drug and also showed activity against the important C. auris strain. Therefore, the obtained salts may constitute attractive alternatives to currently used antifungal therapies.

Obtaining new pharmaceutical salts or cocrystals is a popular way to get compounds with better properties than their components. We report the synthesis of four different multi-component systems (I-IV) containing pyridoxine with gentisic acid (2,5-dihydroxybenzoic acid). Their crystal structures were studied by X-ray diffraction and FT-IR spectroscopy. Dihydrate form (IV), the easiest to obtain, was tested for antioxidant activity and preservation effects on boar sperm. Crystallization with gentisic acid significantly improved the free radicals scavenging ability of pyridoxine, increasing it more than three times. In vitro tests suggest that the supplementation of 2 or 4 mM solution of IV may support the quality of sperm cells, the observed effect is, however, breed-specific.

Cocrystallization provides an efficient approach to modifying a wide range of physicochemical properties of active pharmaceutical ingredients (APIs), including solubility, dissolution rate, melting point, and hygroscopicity. Therefore, the development of effective and fast cocrystallization techniques is crucial for selectively obtaining a specific crystalline form. This study explores the potential of green chemical methods for synthesizing multicomponent cocrystals of theobromine (TBR) and theophylline (TPH) using pyromellitic acid (PMLA) as a coformer. Solution-based screening experiments with TBR resulted in the identification of a new TBR·PMLA 2:1 cocrystal. In the case of TPH, four new multicomponent forms were discovered, including two polymorphic TPH·PMLA 2:1 cocrystals (forms I and II) and two cocrystal solvates: TPH·PMLA·MeOH 2:1:2 and TPH·PMLA·H2O 1:1:2. Cocrystallization via grinding enabled the formation of cocrystals within 30 min to 2 h, while microwave-assisted cocrystallization significantly reduced the process time to just 5 min. Powder X-ray diffraction (PXRD) confirmed the formation of the obtained cocrystals, and single-crystal X-ray diffraction (SXRD) facilitated X-ray structural analysis for the characteristic supramolecular synthons formation in the crystal. Simultaneous thermal analysis (STA) demonstrated the high thermal stability of the studied systems. Additionally, a variable-temperature SXRD experiment, performed for the TPH·PMLA·MeOH 2:1:2 single crystal in the 300-415 K range, revealed negative volumetric thermal expansion of this cocrystal solvate and a gradual solvent release, ultimately leading to a phase transition into the TPH·PMLA 2:1 II cocrystal. UV-vis spectroscopy confirmed an enhancement in TBR solubility and a decrease in TPH solubility in water following cocrystallization using PMLA. Furthermore, biological studies demonstrated the influence of the cocrystallization on the inhibition of specific bacterial and fungal strains.

Three gemini hydroxypyridine salts: 1,3-bis(3-hydroxypyridinium)propane dibromide dihydrate (1), 1,3-bis(3-hydroxypyridinium)propane tetrabromozincate hydrate (2), and 1,3-bis(3-hydroxypyridinium)propane tetrabromocuprate (3) were synthesized and characterized by X-ray diffraction, FTIR, Raman, NMR, and DFT methods. The dibromide salt (1) crystallizes with two water molecules. One of the two bromide anions is connected to the hydroxyl group of one pyridinium cation moiety through the O(10)−H(10)···Br(2)− hydrogen bond of 3.146(2) Å, while the other bromide anion, Br(1)− is surrounded by three water molecules. In 1,3-bis(3-hydroxypyridinium)propane tetrabromozincate (2) the water molecule acts as a bridge between the hydroxypyridinium cation and the tetrabromozincate anion, while the tetrabromocuprate anion interacts directly with the hydroxypyridinium cation. The molecular structures of the studied 1,3-bis(3-hydroxypyridinium)propane derivatives 1a, 2a, and 3a were optimized using the APF-D/6-311++G(d,p) method. The optimized structure of salt 1a resembles the crystal structure, while in salts 2a and 3a the structure of 1,3-bis(3-hydroxypirydinium)propane dication is bent to the U-form and the tetrabromomethallate anion is located in a niche. The significant role of the intermolecular interactions and hydrogen bonds was revealed based on IR spectra. The interpretation of 1H and 13C NMR spectra in DMSO-d6 was based on 2D experiments. The quantum theory of atoms in molecules (QTAIM) was employed to classify the strength of hydrogen bonds in salts 1, 2, and 3. Based on the σ-hole concept, intermolecular interactions in 2 and 3 were described.

Acyclovir (ACV) cocrystallization experiments using 2,6-dihydroxybenzoic acid (26DHBA) as a coformer were performed, and two novel forms of acyclovirium 2,6-dihydroxybenzoate (ACV26DHBA) were prepared. These molecular salts were obtained by different techniques. In addition to the most commonly used methods, such as solution cocrystallization, slurry cocrystallization, and neat or liquid-assisted grinding, microwave-assisted slurry cocrystallization was applied. The use of different solvents allowed for the selective preparation of I and II forms of the ACV26DHBA salt. Novel adducts were characterized using single-crystal and powder X-ray diffraction. Moreover, the purity of the resulting phases was defined by profile fitting using Rietveld refinement. Fourier transform IR spectroscopy and theoretical studies confirmed the results obtained with X-ray methods. Solubility tests in water and phosphate buffer were performed using UV-vis spectroscopy. Moreover, the thermal stability of ionic complexes was examined using simultaneous thermal analysis (STA). Powder diffraction studies revealed two new salt phases. Forms I and II of ACV26DHBA salts can be obtained selectively by cocrystallization using appropriate solvents. The use of microwave radiation led to the formation of II, regardless of the liquid medium used. The salt of ACV with 26DHBA showed better solubility than that of pure ACV. In addition, the ionic complexes were found to be stable up to 176 degrees C for form II and 183 degrees C for form I, respectively. Two stable forms of ACV salts with 26DHBA, which are more soluble than the pure drug, were described. In addition, not only the possibility of selective cocrystallization using several techniques was shown but also the potential of microwave-assisted cocrystallization as a fast technique that does not require the use of a large amount of solvent was emphasized.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Squaric acid was used as a coformer to pyridine carboxylic acid cocrystallization. Adducts were obtained by evaporation from solution. Spectroscopic and theoretical studies were also performed. Thermal analysis reveals the high thermal stability of the obtained complexes.

Pyridoxine (Vitamin B 6, 3-hydroxy-4,5-bis(hydroxymethyl)-2-methylpyridine) forms a hydrate adduct with squaric acid (3,4-dihydroxy-3-cyclobuten-1,2-dione). The proton from squaric acid is transferred to the pyridoxine nitrogen atom. Two hydrogen squarate anions form a centrosymmetric alpha-dimer, which interacts symmetrically with two pyridoxinium cations and two water molecules, through several hydrogen bonds of the lengths from 2.498(3) to 2.843(3) angstrom. The molecular structure of the 2:2:2 adduct (dimer) was studied by a single-crystal X-ray diffraction, DFT calculations, FTIR and NMR spectroscopies. Structures of three models of the monomer of pyridoxinium hydrogen squarate monohydrate (1:1:1) were optimized at the APF-D/6-311++G(d,p) level of theory. Their molecular geometries, hydrogen bond distances, IR spectra, natural atomic charges, frontier molecular orbitals (HOMO and LUMO) were analyzed. The quantum theory of atoms in molecule (QTAIM) was used to classify the strength of the hydrogen bonds in the dimer and monomers of the optimized adducts. The studied compound was screened for antifungal activities and showed inhibiting properties against A. niger and P. placenta. (C) 2021 Elsevier B.V. All rights reserved.

Herein, we report the synthesis of analogues of amino acids with a monofluorovinyl moiety. Interestingly, we have found that cyclization of the obtained products proceeds easily in all cases. The cyclization process has not previously been observed at this reaction stage, and such fluorinated lactams derived from phenylalanine, valine, alanine have not been described before.

The study of various forms of pharmaceutical substances with specific physicochemical properties suitable for putting them on the market is one of the elements of research in the pharmaceutical industry. A large proportion of active pharmaceutical ingredients (APIs) occur in the salt form. The use of an acidic coformer with a given structure and a suitable pKa value towards purine alkaloids containing a basic imidazole N atom can lead to salt formation. In this work, 2,6-dihydroxybenzoic acid (26DHBA) was used for cocrystallization of theobromine (TBR) and caffeine (CAF). Two novel salts, namely, theobrominium 2,6-dihydroxybenzoate, C7H9N4O2+·C7H5O4- (I), and caffeinium 2,6-dihydroxybenzoate, C8H11N4O2+·C7H5O4- (II), were synthesized. Both salts were obtained independently by slow evaporation from solution, by neat grinding and also by microwave-assisted slurry cocrystallization. Powder X-ray diffraction measurements proved the formation of the new substances. Single-crystal X-ray diffraction studies confirmed proton transfer between the given alkaloid and 26DHBA, and the formation of N-H...O hydrogen bonds in both I and II. Unlike the caffeine cations in II, the theobromine cations in I are paired by noncovalent N-H...O=C interactions and a cyclic array is observed. As expected, the two hydroxy groups in the 26DHBA anion in both salts are involved in two intramolecular O-H...O hydrogen bonds. C-H...O and π-π interactions further stabilize the crystal structures of both compounds. Steady-state UV-Vis spectroscopy showed changes in the water solubility of xanthines after ionizable complex formation. The obtained salts I and II were also characterized by theoretical calculations, Fourier-transform IR spectroscopy (FT-IR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and elemental analysis.

Cocrystallization is becoming a more and more popular method to obtain new forms of drugs in the pharmaceutical industry. In this way, their physicochemical properties, like solubility, bioavailability, permeability through biological membranes, stability can be modified without affecting their pharmacological properties [1]. Cocrystals are homogeneous solids consisting of components in a neutral or ionic form, which are solids under ambient conditions, in a specific stoichiometric ratio. Such combinations of APIs (active pharmaceutical ingredients) with appropriately selected coformers are defined as pharmaceutical cocrystals [2]. The main goal of the study was to use purine alkaloids, such as theobromine, theophylline, and caffeine for cocrystallization with trimesic (TMSA) and hemimellitic acid (HMLA) [3]. Theobromine forms cocrystals TBR·TMSA and TBR·HMLA. Caffeine forms the cocrystal CAF·TMSA and the cocrystal hydrate CAF·HMLA·H 2 O. Theophylline forms TPH·TMSA and TPH·HMLA cocrystals, the cocrystal hydrate TPH·TMSA·2H 2 O and the salt hydrate (TPH) + ·(HMLA) - ·2H 2 O. The reactions were carried out in solution and by neat or liquid-assisted grinding in a ball mill. Powder analysis showed that 7 out of 8 solids were obtained by mechanochemical synthesis. All obtained multicomponent complexes were structurally characterized by the single-crystal X-ray diffraction method. The use of compounds with slight structural differences allowed the investigation of the complexity

N-(2-Hydroxyethyl)morpholine and chloroacetone form a new spirane compound, (R/S)-di-(N-morpholinyl-spiro-beta-hydroxy-beta-methylmorpholinyl chloride) hydrate (1). The molecular structure and spectroscopic properties of this salt were characterized by the single-crystal X-ray diffraction, DFT calculations, FTIR and NMR spectroscopies. The crystals of compound 1 are monoclinic, P2(1)/c space group. Compound 1 consists of two non-equivalent spiro units (R and S). Each unit is built of two morpholine rings joined at the N(1) spiro center. The spiro units are linked by a water molecule through the O(W)-H(WA)...Cl(1) hydrogen bond of 3.141(7) angstrom with R-isomer and by an unusual interaction of water with the electron pair of morpholine oxygen atom of the other S-isomer. The total energy, geometry and natural atomic charges, calculated at the B3LYP/6-311++G(d,p) level of theory, for studied compound and for R and S isomers were analyzed. The C-H...Cl contacts were confirmed by calculations based on the quantum theory of atoms in molecule (QTAIM). The H-1 and C-13 chemical shifts were assigned by two-dimensional techniques, COSY, HSQC and HMBC. The experimental and computed infrared spectra were compared. The potential energy distribution (PED) was used to assign the vibrational spectra. Diagrams of HOMO and LUMO are presented and discussed. (C) 2021 Elsevier B.V. All rights reserved.

In this work, benzene-1,3,5-tricarboxylic (trimesic acid, TMSA) and benzene-1,2,3-tricarboxylic acid (hemimellitic acid, HMLA) were used as coformers for cocrystal synthesis with chosen purine alkaloids. Theobromine (TBR) forms cocrystals TBR·TMSA and TBR·HMLA with these acids. Theophylline (TPH) forms cocrystals TPH·TMSA and TPH·HMLA, the cocrystal hydrate TPH·TMSA·2H2O and the salt hydrate (TPH)+·(HMLA)-·2H2O. Caffeine (CAF) forms the cocrystal CAF·TMSA and the cocrystal hydrate CAF·HMLA·H2O. The purine alkaloid derivatives were obtained by solution crystallization and by neat or liquid-assisted grinding. The powder X-ray diffraction method was used to confirm the synthesis of the novel substances. All of these solids were structurally characterized, and all synthons formed by purine alkaloids and carboxylic acids were recognized using a single-crystal X-ray diffraction method. The Cambridge Structural Database was used to determine the frequency of occurrence of analyzed supramolecular synthons, which is essential at the crystal structure design stage. Determining the influence of structural causes on the various synthon formations and molecular arrangements in the crystal lattice was possible using structurally similar purine alkaloids and two isomers of benzenetricarboxylic acid. Additionally, UV-vis measurements were made to determine the effect of cocrystallization on purine alkaloid solubility.