Marcela Tkadlecova

Interaction of ionic liquids ions with natural cyclodextrins.

The interaction of natural α-, β-, and γ-cyclodextrins (CDs) with 14 hydrophobic ionic moieties of ionic liquids (ILs) was systematically examined in dilute aqueous solutions using isothermal titration microcalorimetry (ITC) and NMR spectroscopy. The studied cationic and anionic moieties involved some recently developed heavily fluorinated structures, as well as some others of common use. To isolate the effect of a given ion, the measurements were performed on salts containing the hydrophobic IL ion in question and a complexation-inactive counterion. Additional ITC experiments on ILs whose both cation and anion can interact appreciably with the CD cavity demonstrated that to resolve the effect of individual ions from such data is generally a tricky task and confirmed the superiority of the isolation strategy adopted for the purpose throughout this work. The binding constant, enthalpy and entropy determined at 298.15 K for the 1:1 (ion:CD) inclusion complex formation range in broad limits, being 0 < K < 2 × 10(5), 0 < -Δ(r)H°/(kJ·mol(-1)) < 44, and -28 < TΔ(r)S°/(kJ·mol(-1)) < 14, respectively. The stabilities of complexes of perfluorohexyl bearing ions with β-CD belong to the highest ever observed with natural CDs in water. The established binding affinity scales were discussed in both thermodynamic and molecular terms. The concepts of hydrophobic interaction and guest-host size matching supported by simple molecular modeling proved useful to rationalize the observed widely different binding affinities and suggest possible binding modes. Enthalpy and entropy contributions to the stability of the ion-CD complexes were found to compensate each other considerably obeying more or less the linear compensation relationship marked by existing literature data on binding other guests to natural CDs. As outliers to this pattern, the most stable complexes of -C(6)F(13) bearing ions with β-CD were found to receive an enhanced inherent entropy stabilization due to extraordinarily high extent of desolvation occurring in the course of binding.

Systematic approach to new ligands for anion recognition based on ureido-calix[4]arenes

Mono, di-, tri- and tetraureido-calix[4]arenes in the cone, partial cone and 1,3-alternate conformations have been synthesised and their complexation ability towards selected anions has been studied. The structure–anion complexation ability relationship has been systematically monitored. A new type of very efficient ligands based on diureido-calix[4]arene in a 1,3-alternate conformation with pronounced bonding ability towards carboxylates was designed.

Synthesis of Novel Calixsugars: Calix[4]arene–Monosaccharide Conjugates Based on Amide Bonds

Abstract Novel calix[4]arenes containing two sugar moieties in the molecule have been prepared. Both components are connected through the amidic bonds on the lower rim of a calixarene unit preorganised in the cone conformation. This design leads to new chiral receptors with potential recognition ability towards suitable guest molecules.

1H NMR and thermodynamic study of self-association and complex formation equilibria by hydrogen bonding. Methanol with chloroform or halothane

Mixtures of methanol with two strong proton donors, chloroform and halothane (2-bromo-2-chloro-1,1,1-trifluoroethane), were studied. The behaviour of these systems is governed by aggregate formation through H-bonding, where methanol self-association and its complex formation with the proton donors compete. In order to obtain information about these aggregate formation equilibria, 1H NMR chemical shifts of the chloroform or halothane proton and of the hydroxy proton of methanol were measured as a function of concentration and temperature. The NMR data are expressed in the form of a new quantity, defined in this work, the relative change of the chemical shift. This quantity is convenient because it gives directly the extent of H-bonding without containing any NMR-specific parameter. The NMR data and the excess thermodynamic functions from the literature (GE or ln γi, HE and CPE) were analysed using simple models of athermal association, amended by physical or thermal terms estimated on the basis of coupled homomorph and solution-of-groups approaches. Three particular models were tested, two of continuous methanol association (from tetramers to infinite size species) and one model that considers only methanol tetramerization. For the three models, methanol self-association parameters were previously obtained from independent data. Using enthalpy of solvation values obtained from quantum mechanical calculations, the equilibrium constant for the formation of methanol–chloroform and methanol–halothane complexes was the only fitted parameter. The continuous association models failed to fit the present data even qualitatively, whereas the tetramerization model gave reasonable agreement with experiment both for NMR and the excess thermodynamic functions. In accordance with previously studied mixtures of chloroform and halothane with oxygenated compounds, the methanol–halothane complex is found to be stronger than the methanol–chloroform complex; this is due to a more acidic hydrogen atom in halothane than in chloroform.

Drug-excipient compatibility testing—Identification and characterization of degradation products of phenylephrine in several pharmaceutical formulations against the common cold

Different pharmaceutical preparations against the common cold containing phenylephrine (PHE) and saccharose were studied. New impurities were discovered in these preparations after exposure using isocratic ion-pair chromatography separation on a C18 column. LC-MS and NMR techniques were employed to identify and to fully characterize these new compounds. The products were identified as 1-[5-(hydroxymethyl)-2-furyl]-2-methyl-1,2,3,4-tetrahydroisochinolin-4,8-diol and 1-[5-(hydroxymethyl)-2-furyl]-2-methyl-1,2,3,4-tetrahydroisochinolin-4,6-diol. Identification of these degradation products allowed to understand and to confirm their formation mechanism. The developed HPLC method separates of all known impurities and impurities originated from PHE as well.

On the Interaction of Ionic Liquid 1-Butyl-3-Methylimidazolium Hexafluorophosphate with β-Cyclodextrin in Aqueous Solutions

Abstract The formation of inclusion complex of β-cyclodextrin (β-CD) with the hydrophobic room temperature ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate (bmimPF6) in aqueous solutions was studied at 298.15 K using 1H, 13C, 19F and 31P NMR spectroscopy and isothermal titration calorimetry (ITC). Currently, there is a disagreement in the literature concerning the structure of the complex formed. In contrast to some results published recently in the literature, we found no reasonable support for β-CD to form an inclusion complex with 1-butyl-3-methyl-imidazolium cation of bmimPF6 in water. Our measurements on bmimPF6, the ionic liquid 1-butyl-3-methylimidazolium chloride (bmimCl), and the inorganic salt potassium hexafluorophosphate (KPF6) consistently support the formation of a weak 1:1 inclusion complex of β-CD with hexafluorophosphate anion instead of the bmim+ cation. The thermodynamic parameters of the respective complexation were calculated. The binding constant was evaluated from ITC and proton, fluorine and phosphorus NMR measurements, and the complex formation enthalpy and entropy were obtained from ITC.

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.

Iodine salts of the pharmaceutical compound agomelatine: the effect of the symmetric H-bond on amide protonation

The search for new solid forms of an active pharmaceutical ingredient (API) is an important step in drug development. Often, an API has low water solubility, which then leads to low oral bioavailability. The problem can be solved by salt formation. One such API is agomelatine (AG), a melatonergic antidepressant. The aim of this work is to prepare iodide(s) of this compound. Three structurally different iodides of agomelatine were synthesized: agomelatine hydriodide trihydrate (AGI), agomelatine hemitriiodide (AG2I3) and agomelatine hemitriiodide iodine (AGI2). Their structures were solved from single-crystal X-ray diffraction data. In all of the structures, the agomelatine molecule was positively charged. Specifically, the amide oxygen was protonated, and in two of the structures (AG2I3 and AGI2), a symmetric hydrogen bond was formed. However, agomelatine is an amidic compound, and since amides are generally considered as neutral, in addition to SXRD, we present data from solid state NMR and the ΔpKa calculation to support the proton transfer and the salt formation.

SYNTHETIC STUDIES CONNECTED WITH THE PREPARATION OF N-[3-(3-CYANOPYRAZOLO[1,5-a] PYRIMIDIN-5-YL)PHENYL]-N-ETHYLACETAMIDE, A ZALEPLON REGIOISOMER

N-[3-(3-Cyanopyrazolo[1,5-a]pyrimidin-5-yl)phenyl]-N-ethylacetamide, a principal impurity of zaleplon, is prepared by Suzuki-Miyaura cross coupling reaction of the corresponding boronic acid and/or boronates with 5-chloropyrazolo[1,5-a]pyrimidin-3-carbonitrile (7). Various methods of preparation of both components are described, as well as approaches based on the final modification of the 5-(3-aminophenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile moiety prepared by Suzuki-Miyaura cross coupling. All the prepared compounds were unambiguouesly identified by NMR techniques. Spectral characteristics (IR, UV, MS) of these compounds are also given.

Preparation and properties of new co-crystals of ibandronate with gluco- or galactopyranoside derivatives.

Mixtures of ibandronate monosodium salt with eleven gluco- and/or galacto-pyranoside derivatives as counterions were designed to prepare co-crystals with improved intestinal absorption. In general, gastrointestinal absorption of bisphosphonates after oral administration is approximately 1%. Co-crystals were generated by means of thermodynamically and/or kinetically controlled crystallization processes. Seventy-seven prepared samples were analyzed by means of FT-NIR, FT-Raman spectrometry and solid state NMR spectroscopy. New entities of ibandronate monosodium salt with phenyl-β-d-galactopyranoside were found and characterized. The absorption of these potential new co-crystals was investigated by means of PAMPA experiments. In the present study the relationships between the chemical structures of the studied compounds required for co-crystal generation are discussed.