Search

Pharmaceutical cocrystals have emerged over the past several decades as an alternative path for synthesizing stable and/or improved crystalline forms of active pharmaceutical ingredients. In this contribution, we developed a reproducible cocrystallization path for the supramolecular synthesis of four new pharmaceutical cocrystal forms of fluconazole (FLZ), an antifungal multifunctional drug: fluconazole–fumaric acid monohydrate (1:1:1), fluconazole–malic acid (1:1), fluconazole–dipicolinic acid (1:1), and fluconazole–adipic acid (1:1). All the new cocrystals were characterized by powder/single-crystal X-ray diffraction, Raman, Fourier transform infrared spectroscopy, differential scanning calorimetry/thermogravimetric analysis, and hot-stage polarized optical microscopy, and their water solubility was determined. Structurally, although the coformers were different, the same strong O–H···N hydrogen bond between the FLZ molecule and the coformers was observed. The aqueous solubility studies revealed that al...

Fluconazole (FLZ) is one of the most used antifungal drugs worldwide and has been the focus of various investigations with the aim of enhancing its biomedical application. Most of the new solid forms achieved for this drug were determined by powder X-ray diffraction, and a few reports on polymorphs, solvates, cocrystals, and one salt–cocrystal by single-crystal X-ray diffraction (SCXRD) are available. By considering that FLZ is a very weak base (pKa = 1.76, when protonated), salt formation with this drug is expected with the use of very strong organic acids, in order to dislocate the proton from the acid to the FLZ. To the best of our knowledge, only one organic salt of FLZ with picric acid (pKa = 0.38) and one salt–cocrystal (maleate–maleic, pKa1 = 1.92) were reported by SCXRD until now. Having in mind all the advantages that pharmaceutical salts have in drug delivery, in this work we depict the methodology and techniques employed to synthesize a new salt of FLZ using oxalic acid (pKa1 = 1.23). The screening process was initially monitored using Raman spectroscopy, while further characterization by X-ray diffraction (powder and single crystal) and thermal analysis (DSC and TG) was performed to confirm the new salt fluconazolium oxalate (1 : 1). Finally, salt equilibrium solubility studies confirmed an improvement, about 7-fold, when compared to the commercialized active pharmaceutical ingredient (polymorph II). In addition, this is the first reported GRAS (generally regarded as safe) salt of the antifungal drug fluconazole.

Aqueous biphasic systems (ABS) are biocompatible systems applied in the extraction of biomolecules. Despite the biocompatibility of polymers and, particularly polyethylene glycol (PEG), to form ABS, their limitation in terms of phase separation is recognized. A new approach was recently proposed based on the use of ionic liquids (ILs) as adjuvants in ABS, enlarging the polarity range of these systems. Up to now, the effects of ILs in PEG-salt ABS have been poorly described. To overcome this limitation, the phase diagrams of imidazolium-based ILs acting as adjuvants in ABS based in PEG with potassium salt buffers (pH = 7), that is potassium citrate (C6H5K3O7/C6H8O7) and potassium phosphate (K2HPO4/KH2PO4) buffers, are herein addressed. Imidazolium-based ILs were focused in this work, since they have been applied on the purification of several biomolecules with success, even as adjuvants or electrolytes. The phase diagrams were mapped out for PEG/salt ABS without adjuvants. In this work, systems composed of PEG (1000, 1500, 2000, 3350, 4000, 6000, and 8000) with potassium phosphate buffer and PEG (2000, 6000, 10 000, and 20 000) with potassium citrate buffer were tested. Moreover, the presence of 5 wt % of imidazolium-based ILs (varying the anion moiety) for the system PEG 1500 with potassium phosphate buffer was also investigated. Imidazolium-based ILs with different anions were tested to investigate a large range of polarities attributed to the adjuvant. Moreover, the effect of the adjuvant content (5, 10, and 20 wt %) in the PEG 2000 with potassium citrate buffer system was studied for two distinct ILs, namely [C4mim][CF3SO3] and [C4mim][(CH3O)2PO2], with lower and higher energy of intramolecular hydrogen bond, EHB, respectively, a parameter representing the ions' hydration. A correlation between the anion moiety of imidazolium-based IL and the ability to form two phases was observed, being this related to the ILs' anion EHB value. The concentration of the adjuvant confirmed the effects of enhancing or decreasing the ability to form two phases for ILs with lower and higher EHB value, respectively. published

In order to seek for new compounds with antitumor activity, our research group is focused on copper complexes with mixed ligands. This work presents the synthesis and characterization of eight compounds with general formula [Cu(iminodiacetate)(diimine)(H2O)x], with x = 0 or 1, and their cytotoxic activities against tumor cells. The chosen diimine ligands were: 2,2-dipyridil-amine (bam), 2,2-bipyridine (bipy), 4,4-dimethyl-2,2-bipyridine (dmb), 1,10-phenanthroline (phen), 4-methyl-1,10-phenanthroline (4met-phen), 5-nitro-1,10-phenanthroline (5nitro-phen), neocuproine (neo) and bathophenanthroline (batho). Compounds were characterized in solid state using FT-IR, TGA, DSC and single crystal X-ray diffraction analyses by which five new crystal structures were determined. Common features of the coordination scheme include fac-NO + O isomerism of the iminodiacetate (ida) ligand, except for the complex with neo where the ida presents mer-NO2 isomerism. The diimine ligand completes the equatorial plane for the facial isomers, with different degrees of distortion in the octahedral or square-based pyramid geometry depending on the diimine ligand, whereas the neo is perpendicular to the equatorial plane in the latter. Studies in solution, using EPR, UV–Vis spectroscopy and conductimetry, showed that the copper coordination observed in solid state is retained except for the batho complex. DNA interaction studies evidenced that the complexes bind to this biomolecule, inducing different conformational changes. Biological experiments evidenced that all complexes induce cell death in the cell line MDA-MD-231 (metastasic breast cancer line). [Cu(ida)(neo)] and [Cu(ida)(batho)] presented the highest activity. Taken all these data together we propose that [Cu(ida)(neo)] and [Cu(ida)(batho)] are good candidates for further studies in vitro and in vivo.

Mechanochemistry synthesis was applied to the supramolecular synthesis and green scale-up production of a 1:1 drug–drug cocrystal involving the antimetabolite prodrug 5-Fluorocytosine (5-FC) and the tuberculostatic drug Isoniazid (INH), namely, 5FC-INH. Crystalline material, also obtained by traditional slow evaporation methods, was analyzed by single-crystal X-ray diffraction (XRD). The crystal packing is stabilized by a classical N–H···N hydrogen-bond interaction between the amine moiety of 5-FC and the INH pyridine nitrogen. IR and Raman data provided spectroscopic evidence about the hydrogen atom positions, thereby confirming the neutral nature of the cocrystal. Furthermore, 5FC-INH codrug was also evaluated by a range of analytical techniques such as powder XRD and thermal (thermogravimetric analysis, differential scanning calorimetry, hot stage microscopy) analyses. A physical stability study was performed in high relative humidity conditions to verify possible 5-FC solid-state hydration and/or INH ...

Hexafluorosilicate salts of the antidepressant drugs Paroxetine (PRX) and Fluoxetine (FLX), [PRX]2SiF6 and [FLX]2SiF6⋅H2O, are investigated herein by SCXRD, Hirshfeld surface analysis, and Infrared spectroscopy. By their crystal structures, it is possible to observe, for the first time, at least at the best of our knowledge, the formation of a supramolecular architecture of the [SiF6]2− anion with protonated secondary amine groups. The [PRX]2SiF6 crystallizes in the P21 space group and the [FLX]2SiF6⋅H2O in the P21/c, as a hydrate racemate. While two conformers are present in the asymmetric unit of [PRX]2SiF6, two enantiomers enclose the one of [FLX]2SiF6⋅H2O. Analysis of the crystal packing show that N HF Si (1.94–2.42 Ǻ), C HF Si (2.36–2.62 A), and C Hπ interactions are the main contributors toward the supramolecular architectures in these salts.

Solid solutions could represent a viable alternative to better understand and control structure–property relationships of drugs, in order to optimize their properties for practical applications. Lamivudine (3TC) and emtricitabine (FTC) are nucleoside analogue reverse transcriptase inhibitor antiretroviral drugs, which have similar molecular structures, differing by a single fluorine atom, which is only present in the FTC molecule. Due to these similarities in structure and molecular resemblances, lamivudine and emtricitabine are good candidates for producing a solid solution with physicochemical properties controlled by the stoichiometry. Following this hypothesis, the formation of a nonconventional solid solution was verified, whose crystalline structure is not defined by any of the individual constituents but by the one of the lamivudine hydrate with emtricitabine as a solute. The crystalline structures of two members of the solid solution were determined showing a nonuniform distribution of the solute ...

Specific ion effects in zwitterionic micelles, especially for anions, are evident in reaction kinetics, zeta potential, and critical micelle concentration measurements. However, anion adsorption to zwitterionic micelles does not produce significant changes in shape, aggregation number, or interfacial hydration. Here we used molecular dynamics simulation of systems containing sulfobetaine zwitterionic micelles of

Two novel multicomponent crystal forms of the prodrug 5-fluorocytosine (5-FC), an ionic cocrystal and a monohydrate salt, with 2,4,6-trinitrophenol (picric acid, PA) and 3,5-dinitrosalicylic acid (DNSA), respectively, were rationally designed and synthesized. Nitro compounds are used to treat many diseases, such as cancer, one of the 5-FC targets via gene-directed prodrug therapy. In addition, within the wide range of applications for nitro compounds is the formation of charge-transfer complexes with organic molecules. Among all 5-FC crystalline structures depicted, only two contain nitro compounds: a salt with PA and a dihydrate cocrystal with 5-nitrouracil. Therefore, the two new single translucent pale gold prism crystals of 5FC-PA and 5FC-DNSA were successfully obtained by slow evaporation from aqueous solution and characterized by X-ray diffraction (single crystal and powder), Fourier Transform Infrared (FT-IR), and Raman (FT-Raman) spectroscopies. In both crystal structures, the 5-FC pyrimidine ring is protonated at the N3 atom and the respective packings are mainly stabilized by N–H⋯O H-bonds. For the 5FC-PA ionic cocrystal, the formation of triple H-bonds (two N–H⋯O and one charge assisted N–H+⋯N H-bonds) among the 5-FC molecules was observed. This is consistent with the expected stability of the duplex structure, which is considered the strongest association between two species. In addition to the structural study, Hirshfeld surface analysis was carried out based on the single crystal X-ray diffraction data. Thermal stability was assessed through thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and hot-stage microscopy (HSM), indicating that these compounds are stable up to approximately 200 °C. The results contribute to the diversity of new 5-FC solid forms and introduce two novel compounds, with possible application in fungal/cancer medicine formulations or to better understand the behavior of cytosine in DNA/RNA base pairing.

Paroxetine hydrochloride, PRX HCl, is an important and widely prescribed antidepressant drug for anxiety and depression treatment. Since hydrochloride salts can cause problems in their manufacture, we have designed organic salts with oxalic, fumaric, maleic and L-tartaric acids based on the NH2+⋯COO− synthon. All the salts were obtained from an innovative anion exchange method: selective crystallization from a mixture of PRX HCl and an acid in a certain ratio. The crystal structures of paroxetine (PRX) salts with dicarboxylic acids were determined by the single-crystal X-ray diffraction (SCXRD) method and were also analysed by thermogravimetric analysis, differential scanning calorimetry and FT-IR spectroscopy. Except for FUM and MAL acids, all the carboxylic acids form hydrate salts. Oxalate and tartrate salts are formed through the complete protonation of the anion and exhibit a 1 : 2 stoichiometry. All structures have a Z′ > 1 and different conformations are found for the PRX molecules. In general, the ionic units in the salts extend into chains that pack cohesively, via CH⋯O and CH⋯π interactions, into layers. The oxalate salt forms a channel structure where H2O molecules are hosted. On the other hand, the presence of water molecules in the tartrate salt allows the packing of ionic layers. The organic salts are thermally more stable than the commercial PRX form, m.p. > 143 °C. They exhibit lower solubility compared to the hydrochloride form. The scientific contributions of this study show the diversity of the PRX solid forms and identify candidates for use in new antidepressant API solid formulations.

Molecular salts of terephthalic acid (TA) with 2-amino-4-chloropyridine (ACP), 2-amino-6-methylpyridine (AMP), 2-aminothiazole (AT) and 2-amino-5-methylthiazole (AMT), were prepared with an intent to get new crystalline materials with improved physical properties. Crystals of the desired compounds were obtained through slow evaporation technique. The solid state structures reveal that proton transfer from acid to aromatic nitrogen of the base occurs, thus affording molecular salts of general representation AT-TA-AT (1), AMT-TA-AMT (2), AMP-TA-AMP (3) and ACP-TA-ACP (4). The NH2 group at position 2 of each amino base is still available to interact with C O to afford planar fragment. The COOH functional groups in TA at para position with respect to each other accommodated the respective base in a 1:2 M ratio (acid:base, respectively) to give almost planar Base-Acid-Base (BAB) fragments. The resultant molecular salts were structurally characterized with the help of FT-IR and X-ray diffraction. The antimicrobial (selected strains), antioxidant (2,2-DiPheny-1-Picry-l-Hydrazyl, DPPH and 2,2′-Azino-Bis(3-ethylbenzoThiazoline-6-Sulphonic acid, ABTS) and enzyme inhibition (AChE, BChE and AGS) potencies of the synthesized Base-Acid-Base type, molecular salts were explored. In addition to improved physical properties, all molecular salts showed promising biological activities. The optimization, natural bonding orbitals (NBOs) and FT-IR analysis of the molecular salts were carried out by DFT/B3LYP/6-311G (d,p) level in PCM model with ethanol solvent. However, frontier molecular orbitals (FMOs) analysis was performed utilizing TD-DFT/B3LYP/6-311G (d,p) level. A comparative analysis reveals that consistency is found between the experimental and theoretical findings of geometric parameters and vibrational frequencies. The inter-molecular hydrogen bond (IHB) and hyper conjugative interactions are characterized by NBO analysis. The chemical stability of molecules is evaluated by FMOs. The energies of FMOs are also used to calculate the global reactivity descriptor parameters. The obtained high softness values indicated that entitled compounds might be biologically active.

New allylsulfonamide is prepared in a four-step synthetic route: the Morita-Baylis-Hillman adduct prepared from benzaldehyde and acrylonitrile is acetylated using acetic anhydride and DMAP. The acetylated product reacts with DABCO displaced by the addition of 4-methylbenzenesulfonamide. The final product is characterized by high-resolution mass spectrometry, infrared, and NMR spectroscopic techniques. The X-ray crystallographic method is used to determine the crystal structure and features of the molecular structure of the compound.

To obtain the complete operational picture of the maritime situation in the Exclusive Economic Zone (EEZ) which lies over the horizon (OTH) requires the integration of data obtained from various sensors. These sensors include: high frequency surface-wave-radar (HFSWR), satellite automatic identification system (SAIS) and land automatic identification system (LAIS). The algorithm proposed in this paper utilizes radar tracks obtained from the network of HFSWRs, which are already processed by a multi-target tracking algorithm and associates SAIS and LAIS data to the corresponding radar tracks, thus forming an integrated data pair. During the integration process, all HFSWR targets in the vicinity of AIS data are evaluated and the one which has the highest matching factor is used for data association. On the other hand, if there is multiple AIS data in the vicinity of a single HFSWR track, the algorithm still makes only one data pair which consists of AIS and HFSWR data with the highest mutual matching factor. During the design and testing, special attention is given to the latency of AIS data, which could be very high in the EEZs of developing countries. The algorithm is designed, implemented and tested in a real working environment. The testing environment is located in the Gulf of Guinea and includes a network of HFSWRs consisting of two HFSWRs, several coastal sites with LAIS receivers and SAIS data provided by provider of SAIS data.

The present investigation describes the synthesis and structural study of a metal-zinc ligand [ZnL.H 2 O], which was used to generate three dimensional supramolecular complex formulated as [Y{Zn(L)(SCN)}(SCN) 2 ].[Y{Zn(L)(SCN)} 2 (DMF) 2 ].(NO 3 ). The title compound crystallizes in the triclinic space group P-1 with the following unit cell parameters: a = 14.8987(7) A, b = 15.6725(8) A, c = 19.2339(10) A, a = 94.610(4)°, β = 103.857(4)°, γ = 101.473(4)°, V = 4234.4(4) A 3 , Z = 2, R 1 = 0.063 and w R 2 = 0.96. For this compound, the structure reveals that one heterodinuclear unit [Y{Zn(L)(SCN)}(SCN) 2 ] is co-crystallized with a heterotrinuclear unit [Y{Zn(L)(SCN)} 2 (DMF) 2 ].(NO 3 ). In the dinuclear moiety, the organic molecule acts as a hexadentate ligand and in the trinuclear unit, it acts as a pentadentate ligand with one of the oxygen methoxy group remaining uncoordinated. In both units the coordination environment of the zinc metal can be described as distorted square pyramidal. In the dinuclear unit the Y(III) is hexacoordinated while it is octacoordinated in the trinuclear unit. The environment of the Y(III) can be described as a distorted octahedral geometry in the dinuclear and as a distorted square antiprism in the trinuclear units respectively.

In multiple-drug therapy, isoniazid (INH) is considered one of the most important antibiotics for the treatment of tuberculosis. Beyond its pharmacological importance, INH is also a versatile compound that can be combined with several other molecules to produce salts and co-crystals. In this study, novel salts of INH, obtained from the reaction with pharmaceutically accepted inorganic acids (HBr, HNO3 and H2SO4), were investigated. The reaction of INH with H2SO4, gives rise to two forms: an INH sulfate and an INH sulfate hemihydrate salt. The four salts feature a supramolecular assembly quite different from the one described for INH hydrochloride. INH hydrobromide and INH nitrate adopt a head-to-tail assembly, where the cations (INH+) are directly connected to each other. However, this is not the case for the sulfate forms, where the cations appear surrounded by the anions, being connected to them through their pyridinium and hydrazide groups. Interestingly, an unexpected homodimer is observed in the INH sulfate salt. Hirshfeld surface analysis was used to highlight and quantify the contributions of the main interactions. The relative thermal stability of these salts was studied by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and hot-stage microscopy (HSM). Although the melting points of both sulfate forms are practically the same, the four INH salts have distinct thermal profiles.