Acidity of several polyprotic acids, amiodarone and quetiapine hemifumarate in pure methanol

Methanol is the organic solvent closest to water and able to dissolve a huge amount of organic compounds. Therefore, it is a good candidate for pK_a determination of drugs sparingly soluble in water or a basic drug presented as a salt which pK_a is close to that of its counter-acid. In this work, the acidic dissociation constants in pure methanol of the most common acids used in pharmaceutical preparations (lactic, tartaric, fumaric, maleic and citric) were determined. In addition, the pK_a values of the antipsychotic quetiapine presented as hemifumarate (Seroquel) and the very insoluble antiarrhythmic amiodarone were also determined by potentiometry. From these values, the aqueous pK_a of these drugs were estimated by means of previously established equations. Estimated values are consistent with those from literature and show the interest of methanol for drug discovery pK_a measurements.     

Inclusion complexation of diclofenac with natural and modified cyclodextrins explored through phase solubility, 1H-NMR and molecular modeling studies

Guest–host interactions were examined for neutral diclofenac (Diclo) and Diclofenac sodium (Diclo sodium) with each of the cyclodextrin (CD) derivatives: α-CD, β-CD, γ-CD and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), all in 0.05 M aqueous phosphate buffer solution adjusted to 0.2 M ionic strength with NaCl at 20 °C, and with β-CD at different pHs and temperatures. The pH solubility profiles were measured to obtain the acid–base ionization constants (pK _as) for Diclo in the presence and absence of β-CD. Phase solubility diagrams (PSDs) were also measured and analyzed through rigorous procedures to obtain estimates of the complex formation constants for Diclo/CD and Diclo sodium/CD complexation in aqueous solutions. The results indicate that both Diclo and Diclo sodium form soluble 1:1 complexes with α-, β-, and HP-β-CD. In contrast, Diclo forms soluble 1:1 Diclo/γ-CD complexes, while Diclo sodium forms 1:1 and 2:1 Diclo/γ-CD, but the 1:1 complex saturates at 5.8 mM γ-CD with a solubility product constant (pK _sp = 5.5). Therefore, though overall complex stabilities were found to follow the decreasing order: γ-CD > HP-β-CD > β-CD > α-CD, some complex precipitation problems may be faced with aqueous formulations of Diclo sodium with γ-CD, where the overall concentration of the latter exceeds 5.8 mM γ-CD. Both ¹H-NMR spectroscopic and molecular mechanical modeling (MM⁺) studies of Diclo/β-CD indicate the possible formation of soluble isomeric 1:1 complexes in water.     

Benchmarking and validating algorithms that estimate p<Emphasis Type="Italic">K</Emphasis><Subscript>a</Subscript> values of drugs based on their molecular structures

The REGDIA regression diagnostics algorithm in S-Plus is introduced in order to examine the accuracy of pK _a predictions made with four updated programs: PALLAS, MARVIN, ACD/pKa and SPARC. This report reviews the current status of computational tools for predicting the pK _a values of organic drug-like compounds. Outlier predicted pK _a values correspond to molecules that are poorly characterized by the pK _a prediction program concerned. The statistical detection of outliers can fail because of masking and swamping effects. The Williams graph was selected to give the most reliable detection of outliers. Six statistical characteristics (F _exp, R ², , MEP, AIC, and s(e) in pK _a units) of the results obtained when four selected pK _a prediction algorithms were applied to three datasets were examined. The highest values of F _exp, R ², , the lowest values of MEP and s(e), and the most negative AIC were found using the ACD/pK _a algorithm for pK _a prediction, so this algorithm achieves the best predictive power and the most accurate results. The proposed accuracy test performed by the REGDIA program can also be applied to test the accuracy of other predicted values, such as log P, log D, aqueous solubility or certain physicochemical properties of drug molecules.     

Crystalline inclusion compounds of tetrabenzo-18-crown-6 with uncharged organic molecules. Solid-state structure of the nitroethane complex

Diethylaminoethyl (DEAE) groups were introduced into -cyclodextrin (-CD) and -CD. The products, DEAE-CDs with various numbers of substituents, trappedp-nitrophenoxide and 3,4-dinitrophenoxide preferentially over their respective conjugate acids. This caused a decreased pK _a of the guest nitrophenol. Some signals of the proton-NMR of both guest nitrophenol and host DEAE-CD changed upon host-guest interaction. The relation between the number of DEAE groups and the extent of the pK _a decrease, as well as association constants, is discussed.     

Estimation of the pK a of the amine groups of benzhydrylamine resin and its lysyl derivative by measurement of swelling

Summary For better evaluation of the potential of benzhydrylamine resin (BHAR), used as a solid support for peptide synthesis, as a novel anion-exchange resin, the pK _a of its amine group was estimated by microscopic measurement of the sizes of the dry and swollen beads. Using the volume of the bead occupied by the solvent (as a percentage) as the swelling parameter, a plot of the degree of swelling of BHAR loaded with 2.4 mmol g^–1 amine groups against the pH of the medium produced a decreasing sigmoidal-type curve with increasing pH. By considering the point of inflection of the curve, a pK _a value of approximately 7.5 was estimated for the amine group of the BHAR. The same approach was also applied to the lysyl derivative of the BHAR (Lys-BHAR) and pK _a values around 6.5 and 10.0 were obtained for the and amine groups, respectively.     

A fluorine scan of non-peptidic inhibitors of neprilysin: Fluorophobic and fluorophilic regions in an enzyme active site

This article describes the synthesis and in vitro biological affinities of (poly)fluorinated neprilysin inhibitors. Two series of inhibitors with F-substitution of the central benzimidazole platform of the ligands and the benzylic vector to fill the S1’ pocket of NEP were investigated. The S1’ pocket was found to be highly fluorophobic, and F-substitution led to significantly decreased binding affinities of inhibitors. This result is explained by electrostatically unfavorable close contacts of organic fluorine with the negatively polarized π-surfaces of surrounding aromatic amino acid side chains. In contrast, the protein environment around the benzimidazole platform, with three electropositive guanidinium side chains of Arg residues, was found to provide a fluorophilic environment. Overall, the data support that organic fluorine, with its high negative charge density prefers to orient into electropositive regions of receptor sites. pK_a measurements of fluorinated ligands provided several simple patterns for the prediction of pK_a values of benzimidazoles, important building blocks in medicinal chemistry.     

Determination of pKa values of some antihypertensive drugs by liquid chromatography and simultaneous assay of lercanidipine and enalapril in their binary mixtures

In this study, pK_a values were determined using the dependence of the retention factor on the pH of the mobile phase for three ionizable substances, namely, enalapril, lercanidipine and ramipril (IS). The effect of the mobile phase composition on the ionization constant was studied by measuring the pK_a at different methanol-water mixtures, ranging between 50 and 65% (v/v), using LC-DAD method. Two simple, accurate, precise and fully validated analytical methods for the simultaneous determination of enalapril and lercanidipine in combined dosage forms have been developed. Separation was performed on an X-Terra RP-18 column (250 mm × 4.60 mm ID × 5 μm) at 40 °C with the mobile phase of methanol-water 55:45 (v/v) adjusted to pH 2.7 with 15 mM orthophosphoric acid. Isocratic elution was performed in less than 12 min with a flow rate of 1.2 mL min⁻¹. Good sensitivity for the analytes was observed with DAD detection. The LC method allowed quantitation over the 0.50-20.00 μg mL⁻¹ range for enalapril and lercanidipine. The second method depends on first derivative of the ratio-spectra by measurements of the amplitudes at 219.7 nm for enalapril and 233.0 nm for lercanidipine. Calibration graphs were established for 1-20 μg mL⁻¹ for enalapril and 1-16 μg mL⁻¹ lercanidipine, using first derivative of the ratio spectrophotometric method. Both methods have been extensively validated. These methods allow a number of cost and time saving benefits. The described methods can be readily utilized for analysis of pharmaceutical formulations. The methods have been applied, without any interference from excipients, for the simultaneous determination of these compounds in tablets. There was no significant difference between the performance of the proposed methods regarding the mean values and standard deviations.     

Charge equilibria and pK values of 5-carboxypyranomalvidin-3-glucoside (vitisin A) by electrophoresis and absorption spectroscopy

Apparent pK values of the wine pigment, 5-carboxypyranomalvidin-3-glucoside (vitisin A), were determined using UV-vis spectroscopy, viz. pK_a1=0.98 (±0.10), pK_H1=4.51 (±0.03) and pK_H2=7.57 (±0.02). An additional ionisation constant at high pH (pK_a4=8.84±0.06) was established by high-voltage paper electrophoresis. These data in conjunction with previously published pK_a values determined by high-voltage electrophoresis suggest that in wine (pH 3.2-3.8), 5-carboxypyranomalvidin-3-glucoside exists as a complex mixture of hydrated and non-hydrated, partially ionised species with the predominant species being the quinonoidal base (λ_max 498 nm).     

A study of amino-protecting groups using the polarizable continuum model (PCM)

In order to better understand the performance of 1,2-dimethyl-5-acetyl barbituric acid (DMB) as an amino protecting group relative to 5,5-dimethylcyclohexane-1,3-dione (DMD), ab initio calculations were performed. pK_a calculations using the PCM model indicated that both molecules are more acidic in the enol form. Therefore, the protecting reaction of these molecules should involve the anions formed from the loss of a proton from the enol compounds. Contrary to what would be expected, the larger efficiency exhibited by the DMB molecule cannot be attributed to an extension of the electronic conjugation effect. In the absence of any other noticeable effect that could be responsible for the greater efficiency of the DMB molecule, we are inclined to believe that the difference could be accounted for by the presence of two independent centers of conjugation.This paper is dedicated to Jacopo Tomasi in recognition of his outstanding contribution to the field of computational chemistry in solution. The authors are honored to contribute to this volume; especially so for two of them (COS and MACN) who have the privilege of his friendship.Acknowledgements The authors would like to thank the Brazilian research agencies CNPq, CAPES and FAPERJ for the financial support. C. O. da Silva thanks the Dipartimento di Chimica e Chimica Industriale, University of Pisa, where the MCSCF calculations were performed.     

Investigation of the Role of Ionic Liquids in Tuning the p<Emphasis Type="Italic">K</Emphasis><Subscript>a</Subscript> Values of Some Anionic Indicators

The effect of imidazolium-based ionic liquids, ([C₁₂mim][Cl] and [C₈mim][Cl]), on the acid-base equilibria of two sulfonated indicators has been studied. The presence of ILs leads to decreased pK _a values because of the stronger electrostatic interaction of cationic ILs with the basic forms of the indicators with more negative charge. The longer alkyl side chain of [C₁₂mim][Cl] compared to [C₈mim][Cl] results in stronger hydrophobic interaction of this IL with the basic forms of the dyes leading to a more effective decrease in the pK _a values. Also, the transition points and transition intervals of the acid-base titration curves of the indicators were affected by the presence of ILs. It was found that the IL interaction with acid-base indicators also results in sharpening the acid-base titration curves of the indicators. From these observations, it is concluded that the presence of ILs can tune the pK _a values of indicators. All the experiments were performed spectrophotometrically and the results were obtained using curve fitting methods.     

Effect of salts on the excited state of pyranine as determined by steady-state fluorescence

Pyranine is a pH-sensitive fluorescent probe useful in the pH range of 4.5–8, and it has been extensively employed to determine pH inside cells, membranes and membrane models. The fluorescent properties of pyranine are a consequence of the excited states ROH^* and RO^−*. The prototropic equilibrium of these excited species has a much lower than that of the ground state. In this paper we determined the (1.42 ± 0.06) and the relative quantum yield of pyranine in the pH range of 1–8 by analyzing the component peaks of the steady-state of the dye's emission spectrum. As pyranine is very sensitive to the medium we studied the influence of salts formed by mono-, di-, and trivalent ions on the apparent . In all cases, the presence of salts reduced the apparent to varying degrees depending on the valence of the cations. The strategy used to obtain this information was a dual emission ratiometric method at 441 and 511 nm after excitation at 350 nm. The results obtained demonstrate that pyranine is suitable to determine the pH of aqueous solutions in the range of 1–3.5.     

Thermal behaviour of high surface area V2O5/TiO2 catalysts

Thermal analysis (TG and DTA) was employed for the characterization of V₂O₅/TiO₂ catalysts supported on high surface area TiO₂. The results obtained are consistent with a uniform spreading of vanadium oxide on TiO₂ surface for V₂O₅ content less than 15% by weight.The presence of V₂O₅ on the surface of TiO₂ affects the anatase-rutile phase transition lowering the temperature at which it occurs.DTA measurements, performed on catalysts after many months from the preparation, show the appearance of an exothermic peak in the range 280°–340°C. This signal has been related to the oxidation of V(IV) to V(V) on the catalyst surface.Catalysts characterization, performed by chemical analysis and FT-IR spectroscopy, has confirmed this interpretation.It has been suggested that a slow modification of the catalyst occurs, leading to an increase of the V(IV) content during the time.

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Zusammenfassung Zur Charakterisierung von V₂O₅/TiO₂-Katalysatoren auf hochoberflächigem TiO₂ Trägermaterial wurde die Thermoanalyse (TG und DTA) angewendet. Für einen V₂O₅-Gehalt von weniger als 15 Gew.% entsprechen die erhaltenen Ergebnisse einer gleichmäßigen Verteilung des Vanadiumoxides an der TiO₂-Oberfläche.Die Gegenwart von V₂O₅ an der Oberfläche von TiO₂ beeinflußt die Anatas-Rutil-Phasenumwandlung, indem sie die zugehörige Temperatur verringert.DTA-Messungen an Katalysatoren mehrere Monate nach ihrer Herstellung zeigten das Auftreten eines exothermen Peaks im Bereich 280°–340°C. Dieses Signal wurde der Oxidation von V(IV) zu V(V) an der Katalysatoroberfläche zugeschrieben.Diese Interpretation konnte durch eine Charakterisierung des Katalysatoren durch chemische Analyse und FT-IR-Spektroskopie bestätigt werden.Es wurde angedeutet, daß der Katalysator mit der Zeit einer langsamen Modifikation unterliegt, die zu einem Ansteigen des V(IV)-Gehaltes führt.

     

Chromatography in silico,basic concept in reversed-phase liquid chromatography

Basic phenomena in reversed-phase liquid chromatography have been quantitatively analyzed using a computational chemical calculation. Pyridine interacted with an ionized silica surface under neutral conditions. Alkyl-chain length affected the contact surface area with an analyte. Steric hindrance was demonstrated using a model graphitic carbon phase and unsaturated alkenes. Quantitative structure–retention relationships in reversed-phase liquid chromatography were demonstrated for phenolic compounds and acidic and basic drugs. The correlations between predicted and measured retention factors were satisfactory. Dissociation constants were derived from the atom partial charge and used to predict retention factors of partially ionized compounds.     

Recent developments in the preparation of high surface area metal fluorides

An overview of the main procedures for the preparation of fluorides with very high surface areas is given. Three processes are outlined: (i) plasma fluorination, (ii) sol–gel route and (iii) oxidative decomposition of inorganic precursors. From all three processes nanostructured metal fluorides with 100–400 m² g⁻¹ can be obtained. Prevention of the local overheating during fluorination seems to be the key factor to obtain the high surface area fluorides. TEM investigations of AlF₃ and CrF₃ obtained by oxidative decomposition revealed considerable differences in their morphologies and crystallinity. CrF₃ is completely amorphous and unstable under beam. AlF₃ contains an amorphous phase and nanocrystalline phases of α-AlF₃ and β-AlF₃. Nanocrystals are uniformly distributed within the amorphous phase. Also present are the rod-like nanostructures that consist of β-AlF₃ and are 5–10 nm wide.     

Hydrogen bond interactions at the TiO2 surface: Their contribution to the pH dependent photo-catalytic degradation of p-nitrophenol

We have obtained pK_a values of p-nitrophenol–TiO₂ by measuring the adsorption equilibrium constants of p-nitrophenol (PNP) on the TiO₂ surface at different pH values. These values have been obtained from Langmuir isotherms and from a plot of 1/rate vs. 1/[PNP]_o obtained during TiO₂ catalyzed solar light photo-degradation of PNP. Two limit equilibrium constants are readily obtained depending on the solution pH: at pH 5 at which the TiO₂ surface is mainly positively charged and at pH 8 when it is negatively charged. With these and other adsorption equilibrium constants and the PNP pK_a value in solution, thermodynamic cycles are established in order to obtain the PNP pK_a when it is adsorbed on positively charged, neutral and negatively charged TiO₂ surfaces. From these pK_a values useful information on the PNP–TiO₂ interaction is readily obtained. For instance, the PNP nitro group interacts with the TiO₂ surface via a hydrogen bond, arising from the complex of water molecules with the Ti⁴⁺ ions on its surface. The weaker the hydrogen bond donor, the stronger the oxygen nitro group basicity. Therefore, pK_a changes on the phenolic hydroxyl group result from these interactions. Linear free energy correlations, maximum PNP adsorption capacity values (Q_L) and FTIR ATR, spectrum support this proposal. A k_obs vs. pH degradation profile of p-nitrophenol is also provided.     

The importance of valencep functions in the bonding of Na2, K2, and Cu2 and their positive and negative ions

Summary The relative importance of the valencep functions for describing the bonding in the valence isoelectronic Na₂, K₂, and Cu₂ molecules and their positive and negative ions is investigated. In absolute magnitude the contribution of thep functions to the dissociation energy follows the trend Cu>Na>K while by percentage of the dissociation energy the importance of thep functions follows the polarizabilities, i.e. K>Na>Cu. The bonding in K₂, K ₂ ⁺ , and K ₂ ^– is analyzed to explain the observed trends.Dedicated to Prof. Klaus Ruedenberg     

Acidity constants in different media (I=0 and I=0.1 M KCl) from the uncertainty perspective

Procedures for estimating the measurement uncertainty for the acidity constant Ka (or the pKa value) in different media (I=0 and I=0.1 mol L(-1) KCl), as determined by potentiometric titration, are presented. The uncertainty budgets (the relative contributions of the different input quantities to the uncertainty in the result) of the pKa (I=0) and pKa (I=0.1 mol L(-1) KCl) values are compared. Unlike the values themselves, the uncertainties and uncertainty budgets of the values are comparable. The uncertainty estimation procedures are based on mathematical models of pKa measurement and involve the identification and quantification of individual uncertainty sources according to the ISO GUM approach. The mathematical model involves 52 and 48 input parameters for pKa (I=0) and pKa (I=0.1 mol L(-1) KCl), respectively. The relative importance of each source of uncertainty is discussed. In both cases, the main contributors to the uncertainty budget are the uncertainty components due to the hydrogen ion concentration/activity measurement, which provide 63.7% (for pKa (I=0)) and 89.3% (for pKa (I=0.1 mol L(-1) KCl)) of the uncertainty. The remaining uncertainty contributions arise mostly from the limited purity of the acid. From this work, it is clear that the uncertainties of the pKa (I=0.1 mol L(-1) KCl) values tend to be lower than those of the pKa (I=0) values. The main reasons for this are that: (1) the uncertainty due to the residual liquid junction potential is nominally absent in the case of pKa (I=0.1 mol L(-1) KCl) due to the similarly high concentrations of background electrolyte in the calibration solutions and measured solution; (2) the electrode system is more stable in solutions containing the 0.1 mol L(-1) KCl background electrolyte and so the readings obtained in these solutions are more stable.     

Structural properties and potential reactivity of substituted 3- aroyldithiocarbazates

A series of substituted 3-aroyldithiocarbazates has been synthesized and studied. The corresponding acid dissociation constants have been determined potentiometrically. Semiempirical PM3 molecular orbital calculations suggest the existence of several tautomeric forms of the compounds. Geometrical parameters, proton affinities, and static reactivity indices have been examined. Structural properties and protonation sites are well described by calculations. The strong correlations between the pK _a values and the Hammett constants as well as the N(3) calculated proton affinities indicate that the N(3) atom is the most probable protonation site. The thermodynamics of the protonation process are mainly controlled by HOMO-LUMO rather than electrostatic interactions. According to PM3 results, 3-aroyldithiocarbazic acid should be quite stable in the gas phase, while a mechanism for its decomposition in solution is proposed.     

What are the pKa values of organophosphorus compounds?

A first-principle theoretical protocol was developed, which could successfully predict the pK_a values of a number of amines and thiols in DMSO with a precision of about 1.1 pK_a unit. Using this protocol we calculated the pK_a values of diverse types of organophosphorus compounds in DMSO. The accuracy of these predicted values was estimated to be about 1.1 pK_a because phosphorus is in the same group as nitrogen and in the same period as sulfur. The theoretical predictions were also consistent with all the available experimental data. Thus, a scale of reliable pK_a values was constructed for the first time for organophosphorus. These pK_a values would be helpful to synthetic chemists who need to design the experimental conditions for handling deprotonated organophosphorus. On the basis of these pK_a values we also studied, for the first time, some interesting topics such as the substituent effects on the pK_a values of various types of organophosphorus, and the differences between the pK_a values of organophosphorus and organic amines.