Crystallization products of risedronate with carbohydrates and their substituted derivatives

The gastrointestinal absorption of bisphosphonates is in general only about 1%. To address this problem mixtures of risedronate monosodium salt with twelve varied sugar alcohols, furanoses, pyranoses and eight gluco-, manno- and galactopyranoside derivatives as counterions were designed in an effort to prepare co-crystals/new entities with improved intestinal absorption. Crystalline forms were generated by means of kinetically and/or thermodynamically controlled crystallization processes. One hundred and fifty-two prepared samples were screened by means of FT-NIR and FT-Raman spectroscopy. No co-crystal was prepared, but noteworthy results were obtained. A new solid phase of risedronate monosodium salt generated in the presence of phenyl-β-d-galactopyranoside under thermodynamically controlled crystallization conditions was found and also characterized using solid state NMR spectroscopy, X-ray powder diffraction and differential scanning calorimetry. This new polymorph was named as form P. Interactions between risedronate monosodium salt and both carbohydrates were confirmed by means of molecular dynamics simulation. In the present study the relationships between the chemical structures of the studied compounds required for crystalline form change are discussed.     

Crystal engineering of photochromic diarylethene single crystals

Photochromic performance of diarylethene single crystals was controlled by crystal engineering using non-covalent aromatic-aromatic interactions as the directional intermolecular force. A diarylethene derivative with two pentafluorophenyl groups, 1,2-bis(2-methyl-5-pentafluorophenyl-3-thienyl)perfluorocyclopentene (1a), formed stoichiometric co-crystals with benzene (Bz) and naphthalene (Np) by aryl-perfluoroaryl interactions. Face-to-face pi-stacking interactions between the pentafluorophenyl groups of 1a and the aromatic molecules are responsible for 2:1 and 1:1 stoichiometric compositions in 1a/Bz and 1a/Np co-crystals, respectively. The diarylethene underwent thermally stable and photoreversible photochromic reactions in a homo-crystal of 1a and co-crystals 1a/Bz and 1a/Np. The absorption spectra of the photogenerated closed-ring isomers varied depending on the conformation of the diarylethene molecules packed in the crystals. The diarylethene 1a also formed 1:1 stoichiometric co-crystals with different kinds of diarylethenes, 1,2-bis(2-ethyl-5-phenyl-3-thienyl)perfluorocyclopentene (2a) and 1,2-bis[2-methyl-5-(1-naphthyl)-3-thienyl]perfluorocyclopentene (3a). Both co-crystals 1a/2a and 1a/3a showed photochromism. Although 1a, 2a, and 3a underwent efficient photocyclization reactions in their homo-crystals, highly selective photocyclization reactions of 2a or 3a were observed in the co-crystals. The selective reactions were confirmed by HPLC and X-ray crystallography. Excited energy transfers from 1a to 2a and from 1a to 3a are considered to occur and cause the selective reactions.     

The use of co-crystals for the determination of absolute stereochemistry: an alternative to salt formation

Absolute stereochemistry of oils and viscous liquids can be difficult to determine. Co-crystallization involves generating a crystalline material consisting of more than one neutral compound. The combination of co-crystallization with both X-ray diffraction and chiral HPLC was particularly powerful in overcoming these difficulties for a series of chiral 3-arylbutanoic acids. Co-crystallization offers advantages over salt formation because co-crystals dissociate in solution, meaning identical HPLC conditions can be used for both the materials of interest and their co-crystals.     

热磁双重响应性载药微囊的制备及其性能研究

采用LbL模板技术,将天然聚电解质壳聚糖CS和海藻酸钠ALG、磁性纳米颗粒Fe3O4或带负电荷或双亲性磷脂在单分散胶体表面进行组装,制备了一种具有热磁双重响应性的新型载药微囊.通过透射电镜、激光共聚焦显微镜、zeta-电位分析仪、紫外分光光度计等对微囊结构及载药、释药性能进行了表征.实验结果表明:微囊的载药量最高可达到22.40%,且具有磁导向作用.微囊外层组装具有热敏性质的磷脂层能有效地克服壳聚糖/海藻酸钠微囊通透性大而导致在较低温(正常生理环境)的输送过程中药物泄漏问题,而在较高温条件下又可使药物迅速释放,从而实现药物的可控释放.     

Enabling Control over Mechanical Conformity and Luminescence in Molecular Crystals: Interaction Engineering in Action

Molecular crystals of π-conjugated molecules are of great interest as the highly ordered dense packing offers superior charge and exciton transport compared with its amorphous counterparts. However, integration into optoelectronic devices remains a major challenge owing to its inherently brittle nature. Herein, control over the mechanical conformity in single crystals of pyridine-appended thiazolothiazole derivatives is reported by modulating the molecular packing through interaction engineering. Two polymorphs were prepared by achieving control over the thermodynamic/kinetic factors of crystallization; one of the polymorphs exhibits elastic bending whereas the other is brittle. The control over the bending ability was achieved by forming co-crystals with hydrogen/halogen bond donors. A seamless extended crisscross pattern with respect to the bend plane through a ditopic hydrogen-bonding motif showed the highest compliance towards mechanical bending, whereas the co-crystals with a layered crisscross arrangement with segregated layers of co-formers exhibit slightly lower bending conformity. These results update the rationale behind the plastic/elastic bending in molecular crystals. The co-crystals of ditopic halogen bond co-assemblies are particularly appealing for waveguiding applications as the co-crystals blend high mechanical flexibility and luminescence properties. The hydrogen bonded co-crystals are non-emissive in nature owing to excited state proton transfer dynamics. The rationale behind the fluorescence properties of these materials was also established from DFT calculations in a quantum mechanics/molecular mechanics (QM/MM) framework.     

Anticancer potential of novel 5-Fluorouracil co-crystals against MCF7 breast and SW480 colon cancer cell lines along with docking studies

In the present investigation, 5-Fluorouracil co-crystals with four cyclic dimers of amino acids (Glycine, Tryptophane, Leucine and Alanine conformers are prepared via co-crystallization route, with an aim to improve its anticancer effectiveness and to minimize its associated drawbacks. The prepared co-crystals were characterized by FTIR and PXRD techniques. FTIR revealed the presence of respective functional groups in the prepared co-crystals. Frequencies (v) of NH (3416 cm^?1) and carbonyl group (1671 cm^?1) in the 5-Fu (FTIR) spectrum were considerably moved in all co-crystal’s spectra exhibiting the development of new interactions. 5-Fu peak at 2θ = 28.48° was visibly transformed in the co-crystal’s graphs of PXRD. MTT assays was studied on MCF7 breast and SW480 colon cancer cell lines using 0.78 to 200 μg mL^?1 dose concentration. Co-crystals with Tryptophane and Leucine cyclic dimers revealed highest potential (99 % and 100 %) respectively, against colon cancer cell line Likewise Alanine and Tryptophane dimers furnished promising efficiency (100 %) against MCF7 cell line Genetic Optimization for Ligand Docking/GOLD was applied to evaluate the latent anti-tumor behaviors against the proteins [C-myc. (PDB ID: 6G6K, Thymidylate synthase (PDB ID:1HVY) and protein kinase (PDB ID: 2X18). Results revealed that the developed 5-Fluorouracil co-crystals have promising antitumor efficacy as compared to already reported 5-Fu co-crystals and 5-Fu alone.     

Amino Acids as the Potential Co-Former for Co-Crystal Development: A Review

Co-crystals are one of the most popular ways to modify the physicochemical properties of active pharmaceutical ingredients (API) without changing pharmacological activity through non-covalent interactions with one or more co-formers. A “green method” has recently prompted many researchers to develop solvent-free techniques or minimize solvents for arranging the eco-friendlier process of co-crystallization. Researchers have also been looking for less-risk co-formers that produce the desired API’s physicochemical properties. This review purposed to collect the report studies of amino acids as the safe co-former and explored their advantages. Structurally, amino acids are promising co-former candidates as they have functional groups that can form hydrogen bonds and increase stability through zwitterionic moieties, which support strong interactions. The co-crystals and deep eutectic solvent yielded from this natural compound have been proven to improve pharmaceutical performance. For example, l-glutamine could reduce the side effects of mesalamine through an acid-base stabilizing effect in the gastrointestinal fluid. In addition, some amino acids, especially l-proline, enhances API’s solubility and absorption in its natural deep eutectic solvent and co-crystals systems. Moreover, some ionic co-crystals of amino acids have also been designed to increase chiral resolution. Therefore, amino acids are safe potential co-formers, which are suitable for improving the physicochemical properties of API and prospective to be developed further in the dosage formula and solid-state syntheses.     

Inclusion abilities towards hexyne isomers by co-crystallization with extended V-shaped host molecule

Disubstituted adamantane derivative possessing chloropyrazine (1) was synthesized and used as an extended V-shaped host molecule for the preparation of inclusion crystals containing hexyne isomers. The crystallization of 1 with 3-hexyne or 2-hexyne in chloroform provided co-crystals (1a, 1b) with 1:2 host:guest complexation stoichiometry, whereas guest-free crystals (1c) were produced in the case of 1-hexyne. In the co-crystals, the dimers built from 1 through CH···O interaction were arranged into a molecular network through multiple intermolecular interactions, and the guest molecules were accommodated within the cavity built from four molecules of 1. From the crystallization of equimolar binary mixtures of 3-hexyne or 2-hexyne and 1-hexyne in the presence of 1, co-crystals 1a and 1b were supplied, respectively. Competition experiments revealed that the selectivity order of 1 for the hexyne isomers was 3-hexyne and 2-hexyne ≫ 1-hexyne.     

多重氢键自组装联萘酚和含氮化合物

作为相互识别的结果,(±)-2,2′-二羟基-1,1′-联萘酚可与4,4′,6,6′-四甲基-2,2′-联嘧啶、1,2-双(4-吡啶)乙烷、反式-1,2-双(4-吡啶)乙烯、4,4′-联吡啶-N,N′-双氧化物及双-2-吡啶基甲酮等多种含氮化合物分别形成外形良好的共晶化合物1,2,3,4及5.本文对5个共晶化合物的晶体...     

Preparation of fluorine-containing polyethers

Polyethers were prepared from 3,3,3-trifluoro-1,2-epoxypropane by using both cationic and anionic initiators. Aluminum chloride and boron trifluoride were the two cationic initiators investigated. The polymer obtained with the use of aluminum chloride contained no functional endgroups other than hydroxyl, while the polymer prepared with boron trifluoride contained some terminal unsaturation. Potassium hydroxide and the monosodium salt of hexafluoropentanediol were investigated as anionic initiators. The polymer obtained by using potassium hydroxide also contained terminal unsaturation, while the polymer prepared with the monosodium salt of hexafluoropentanediol was terminated with primary hydroxyl groups capable of being used in polyurethanes. All polymers had molecular weights in the range from 970 to 4300. A fluorine-containing polyformal was prepared in high yield by the reaction of hexafluoropentanediol with trioxane. The same polymer was obtained in poor yield by the reaction of hexafluoropentanediol with dibutyl formal. Ring-opening polymerizations were attempted on two fluorinated cyclic ethers, 2,2,3,3,4,4-hexafluoropentamethylene oxide and 3,3,4,4-tetrafluorotetramethylene oxide. There was no reaction with anionic initiators. With most of the cationic initiators, there was no reaction. Boron trifluoride and phosphorus pentafluoride formed complexes with the ether, but would not cause ring opening.     

Halogen Bonds of Halotetrafluoropyridines in Crystals and Co-crystals with Benzene and Pyridine

The structures of the three para-substituted halotetrafluoropyridines with chlorine, bromine, and iodine have been determined in the solid state (X-ray diffraction). The structures of these compounds and that of pentafluoropyridine were also determined in the gas phase (electron diffraction). Structures in the solid state of the bromine and iodine derivatives exhibit halogen bonding as a structure-determining motif. On the way to an investigation of halogen bond formation of halotetrafluoropyridines in the solid state with the stronger Lewis base pyridine, co-crystals of benzene adducts were investigated to gain an understanding of the influence of aryl–aryl interactions. These co-crystals showed halogen bonding only for the two heavier halotetrafluoropyridines. In the pyridine co-crystals halogen bonding was observed for all three para-halotetrafluoropyridines. The formation of homodimers and heterodimers with pyridine is also supported by quantum-chemical calculations of electron density topologies and natural bond orbitals.     

Structural rationalisation of co-crystals formed between trithiocyanuric acid and molecules containing hydrogen bonding functionality

Crystallisation of trithiocyanuric acid (TTCA) from various organic solvents that have hydrogen bonding capability (acetone, 2-butanone, dimethylformamide, dimethyl sulfoxide, methanol and acetonitrile) leads to the formation of co-crystals in which the solvent molecules are incorporated together with TTCA in the crystal structure. Structure determination by single-crystal X-ray diffraction reveals that these co-crystals can be classified into different groups depending upon the topological arrangement of the TTCA molecules in the crystal structure. Thus, three different types of single-tape arrangements of TTCA molecules and one type of double-tape arrangement of TTCA molecules are identified. In all co-crystals, hydrogen-bonding interactions are formed through the involvement of N-H bonds of TTCA molecules in these tapes and the other molecule in the co-crystal. Detailed rationalisation of the structural properties of these co-crystals is presented.     

Co-crystals of Isonicotinamide and p-Cyanobenzoic Acid

Isonicotinamide(INA) and p-Cyanobenzoic acid (CNBA) interact in alcohol solutions to give co-crystals INA-CNBA and INA(CNBA)₂. These co-crystals have been characterized by single crystal X-ray crystallography and were further studied by infrared spectroscopy and differential scanning calorimetry. The crystallography provides a structural basis for thermal reactivity in INA(CNBA)₂ and relevant intermolecular contacts in the co-crystals are discussed.     

Azine Steric Hindrances Switch Halogen Bonding to N-Arylation upon Interplay with σ-Hole Donating Haloarenenitriles

An interplay between 4-bromo- and 4-iodo-5-nitrophthalonitriles (XNPN, X=Br or I) and any one of the azines (pyridine 1 , 4-dimethylaminopyridine 2 , isoquinoline 3 , 4-cyanopyridine 4 , 2-methylpyridine 5 , 2-aminopyridine 6 , quinoline 7 , 1-methylisoquinoline 8 , and 2,2’-bipyridine 9 ) proceeds differently depending on steric and electronic effects of the heterocycles. Sterically unhindered azines 1–3 underwent N-arylation to give the corresponding azinium salts (characterized by ¹H and ¹³C{H} NMR and high-resolution ESI-MS). In contrast, azines 4 – 9 with sterically hindered N atoms or bearing an electron-withdrawing substituent, form stable co-crystals with XNPN, where two interacting molecules are bound by halogen bonding. In all obtained co-crystals, X⋅⋅⋅N structure-directed halogen bonds were recognized and theoretically evaluated including DFT calculations (PBE0-D3/def2-TZVP level of theory), QTAIM analysis, molecular electrostatic potential surfaces, and noncovalent interaction plot index. Estimated energies of halogen bonding vary from −7.6 kcal/mol (for 6 ⋅ INPN) to −11.4 kcal/mol ( 5 ⋅ INPN).     

Unexpected formation of novel two-component gels comprising of glycoluril carboxylic acid amides and imidazole: Synthesis and morphology

New gelling agents have been discovered: glycoluril carboxylic acid amides, giving two-component gels with imidazole. First, the one-pot, two step reaction of glycoluril carboxylic acids, CDI and various amines was investigated for the preparation of gels and it was found that the reaction mixtures were gelled in dry DMF during the preparation of some amides. The conditions of the gel-sol-gel transitions were found. The morphology of the xerogels was studied by SEM. The structure of the xerogels is constructed from interlocked rods or from interlaced curved fibres. Self-organization in the co-crystals of amides with H₂O or imidazole was detected. The molecules of the co-crystals of amides with H₂O are self-assembled into homochiral tapes.     

Preparation and studies of the co-crystals of meloxicam with carboxylic acids

Mechanical treatment with addition of some liquid, crystallization from solutions, and heating of the mixture components preliminary subjected to mechanical treatment were the methods used for the preparation of the co-crystals of 4-hydroxy-2-methyl-N-(5-methylthiazol-2-yl)-2H-1,2-benzothiazin-3-carboxamide 1,1-dioxide (meloxicam) with carboxylic acids. It was shown that preliminary mechanical treatment plays significant role for the synthesis, whereas the addition of small amounts of solvents accelerates the process. The co-crystals were obtained for 17 mixtures of meloxicam—carboxylic acid. The use of the co-crystals of meloxicam in the compositions of improved pharmaceutical forms was found promising, which was attributable to the fact that the dissolution rate and the solubility of the co-crystals of meloxicam with the carboxylic acids under study are higher than those for meloxicam itself.     

The Impact of Halogen Substituents on the Synthesis and Structure of Co-Crystals of Pyridine Amides

Strategies for co-crystal synthesis tend to employ either hydrogen- or halogen-bonds between different molecules. However, when both interactions are present, the structural influence that they may exert on the resulting assembly is difficult to predict a priori. To shed some light on this supramolecular challenge, we attempted to co-crystallize ten aliphatic dicarboxylic acids (co-formers) with three groups of target molecules; N-(pyridin-2-yl)picolinamides (2Pyr-X), N-(pyridin-2-yl)nicotinamides (3Pyr-X), N-(pyridin-2-yl)isonicotinamides (4Pyr-X); X=Cl/ Br/ I. The structural outcomes were compared with co-crystals prepared from the non-halogenated targets. As expected, none of the reactions with 2Pyr-X produced co-crystals due to the presence of a very stable intramolecular N-H···N hydrogen bond. In the 3Pyr series, all six structures obtained showed the same synthons, –COOH···N(py) and –COOH···N(py)-NH, that were found in the non-halogenated parent 3Pyr and were additionally accompanied by structure directing X···O(OH) interactions (X=Br/I). The co-crystals of the unhalogenated parent 4Pyr co-crystals assembled via intermolecular –COOH···N(py) and –COOH···N(py)-NH synthons. Three of the analogues 4Pyr-X co-crystals displayed only COOH···N(py) and –COOH···N(py)-NH interactions. The three co-crystals of 4Pyr-X with fumaric acid (for which no analogues structures with 4Pyr are known) formed –COOH···N(py)-NH and –NH···O=C hydrogen bonds and showed no structure-directing halogen bonds. In three co-crystals of 4Pyr-I in which –COOH···N(py)-NH hydrogen bond was present, a halogen-bond based –I···N(py) synthon replaced the –COOH···N(py) motif observed in the parent structures. The structural influence of the halogen atoms increased in the order of Cl < Br < I, as the size of σ-holes increased. Finally, it is noteworthy that isostructurality among structures of the homomeric targets was not translated to structural similarities between their respective co-crystals.     

耐高温含氟磺化聚苯并咪唑的合成及表征

采用5-磺酸钠间苯二甲酸、双(苯甲酸)六氟丙烷与3,3',4,4'-四氨基联苯在多聚磷酸中通过共缩聚反应, 合成了一系列磺化度(定义为100个重复单元中所含的磺酸基个数, SD)可控的含氟磺化聚苯并咪唑(sPBI), 并利用红外光谱、核磁共振、凝胶色谱和热失重分析等手段对其结构、分子量与热稳定性进行了表征, 还考察了其溶解性和成膜性. 结果表明, sPBI的数均分子量(M_n)为61300～86000, 多分散指数介于1.96～2.34之间, 并且sPBI具有良好的成膜性和优异的热稳定性能, 其5%和10%热失重对应温度均随着SD的增加而有所提高, 在SD为70%时分别为549和576 ℃. 此类聚合物在质子交换膜材料方面具有一定的应用前景.     

Experimentation and modelling of pharmaceutic lyophilization using a pilot plant

Freeze-drying is the process whereby a solvent (usually water) is removed from a frozen solution or a frozen foodstuff by sublimation. Since freeze-dryIn this study, the lyophilization process was carried out on a frozen solution of cloxacillin monosodium salt using a pilot plant. Experimental dryingA physical model is proposed for heat transfer between the heating plate and the tray containing the product, based on Knudsen conduction in a thin lay     

7-Ethyl-2,3,5,6,8-pentahydroxy-1,4-naphthoquinone (echinochrome A): a DFT study of the mechanism of the antioxidant action. 4. Migration of protons and the Na<Superscript>+</Superscript> cation in echinochrome a monosodium salts

According to B3LYP/6-31G(d,p) and B3LYP/6-31G(d) calculations, intramolecular migrations of H⁺ and Na⁺ cations in the molecule of 7-ethyl-2,3,5,6,8-pentahydroxy-1,4-naphthoquinone (echinochrome A) monosodium salt in the gas phase and in clusters containing five water molecules can proceed asynchronously through the chain of O-H...O hydrogen bonds by the jump-over mechanism.