Mohammad B. Zughul

Novel inclusion complex of ibuprofen tromethamine with cyclodextrins: Physico-chemical characterization

Guest-host interactions of ibuprofen tromethamine salt (Ibu.T) with native and modified cyclodextrins (CyDs) have been investigated using several techniques, namely phase solubility diagrams (PSDs), proton nuclear magnetic resonance ((1)H NMR), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffractometry (XRPD), scanning-electron microscopy (SEM) and molecular mechanics (MM). From the analysis of PSD data (A(L)-type) it is concluded that the anionic tromethamine salt of ibuprofen (pK(a)=4.55) forms 1:1 soluble complexes with all CyDs investigated in buffered water at pH 7.0, while the neutral form of Ibu forms an insoluble complex with beta-CyD (B(S)-type) in buffered water at pH 2.0. Ibu.T has a lower tendency to complex with beta-CyD (K(11)=58 M(-1) at pH 7.0) compared with the neutral Ibu (K(11)=4200 M(-1)) in water. Complex formation of Ibu.T with beta-CyD (DeltaG(o)=-20.4 kJ/mol) is enthalpy driven (DeltaH(o)=-22.9 kJ/mol) and is accompanied by a small unfavorable entropy (DeltaS(o)=-8.4 J/mol K) change. (1)H NMR studies and MM computations revealed that, on complexation, the hydrophobic central benzene ring of Ibu.T and part of the isobutyl group reside within the beta-CyD cavity leaving the peripheral groups (carboxylate, tromethamine and methyl groups) located near the hydroxyl group networks at either rim of beta-CyD. PSD, (1)H NMR, DSC, FT-IR, XRPD, SEM and MM studies confirmed the formation of Ibu.T/beta-CyD inclusion complex in solution and the solid state.

SL2 TYPE PHASE SOLUBILITY DIAGRAMS, COMPLEX FORMATION AND CHEMICAL SPECIATION OF SOLUBLE SPECIES

A method is presented for the analysis of SL2-typephase solubility diagrams. Themethod allows the determination of individualcomplex formation and solubilityproduct constants through rigorous fitting of allsegments of the diagram: the risingportion, the plateau and the descending portion.Rigorous analysis of the descendingportion offers the means of discerning the typeof complex precipitate (SL or SL2).The method has been tested by computer simulation ofexperimental datafor both SL and SL2 complex precipitates. The limitsof precision of experimental datarequired to obtain reasonable estimates of equilibriumconstants have been exploredthrough superimposition of statistical random noise.The method has also beensuccessfully applied to the analysis of someexperimentally measured phase solubilitydiagrams that have been reported in the literature.These include the measuredsolubilities of 1,3-dimethylbenzoylurea (DMBU) againstcatechol concentration incarbon tetrachloride, tolbutamide (Tolb) against aqueousβ-cyclodextrin concentration,spironolactone (SP) against aqueous γ-cyclodextrinconcentration, in addition tomethylparaben, ethylparaben and propylparaben againstaqueous α-cyclodextrinconcentration at 25 °C.

Thermodynamics of Propylparaben/β-Cyclodextrin Inclusion Complexes

ABSTRACTThe aim of this study was to develop models for rigorous analysis of phase solubility diagrams, particularly the descending portion, in order to obtain individual thermodynamic complex formation and solubility product constants. Additionally, the effect of varying the initial solute concentration St in excess of the optimal solubility Sm, on the general shape of the plateau and descending portions of the solubility diagram was investigated. The solubilities of propylpapraben (Seq) were measured against initial β-cyclodextrin concentrations (Lt) at different temperatures and different St Equilibrium concentrations (Leq) were also measured. The only effect observed was a broadening of the plateau region with increase in St with no discernible effect on Sm. Simultaneous rigorous analysis of the rising as well as the descending portions of the phase diagram could only be interpreted in terms of formation of two soluble complexes: SL and S2L. Rigorous analysis of the descending portion allowed the dete...

Fexofenadine/Cyclodextrin Inclusion Complexation: Phase Solubility, Thermodynamic, Physicochemical, and Computational Analysis

Interactions of fexofenadine (Fexo) with cyclodextrins (CDs: α- β-, γ-, and HP-β-CD) were investigated by several techniques including phase solubility, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), 1H-nuclear magnetic resonance (1H-NMR) and molecular mechanical modeling (MM+). The effects of CD type, pH, ionic strength, and temperature on complex stability were also explored. Fexo/CD complex formation follows the decreasing order: β-CD > HP-β-CD > γ-CD > α-CD (i.e., at pH 7.0 and 30°C, K11 = 1139, 406, 130, and 104 M−1, respectively). The linear correlation of the free energy of Fexo/β-CD complex formation (ΔG11) with the free energy of inherent Fexo solubility (ΔGSo), obtained from the variation of K11 with inherent Fexo solubility (So) at different pHs and ionic strengths, was used to measure the contribution of the hydrophobic character of Fexo to escape from water by including into the hydrophobic CD cavity. The hydrophobic effect (desolvation) contributes about 76% of the total driving force towards inclusion complex formation, while specific interactions contribute −7.7 kJ/mol. Moreover, Zwitterionic Fexo/β-CD complex formation appears to be driven both by favorable enthalpy (ΔH° = −23.2 kJ/mol) and entropy (ΔS° = 15.2 J/mol.K) changes at pH 7.0. 1H-NMR and MM+ studies indicate multimodal inclusion of the piperidine, carboxypropylphenyl, and phenyl moieties into the β-CD cavity. MM+ computations indicate that the dominant driving force for complexation is Van der Waals force with very little electrostatic contribution. 1H-NMR, DSC, and XRPD studies indicate the formation of inclusion complex in aqueous solution and the solid state.

Temporal distribution of chlorophyll a, suspended matter, and the vertical flux of particles in Aqaba (Jordan)

The temporal distribution of chlorophyll a (chl a), suspended matter (SM), and vertical flux of chl a and organic carbon (OC) has been investigated at three sites along the north-eastern coast of the Gulf of Aqaba during the period from January 1991 through December 1992. Highly significant temporal and interannual variations were found in chl a, and in the vertical flux of chl a and OC. The SM and its OC content did not show any significant temporal or interannual variations. The recorded levels of the forementioned variables were generally low. The temporal distribution of chl a in the water column was polymodal in 1991 with peaks in March, June, August and December, and bimodal in 1992 with peaks in May–June, and October. Maximum values of SM and its OC content occurred in July of 1991 and September of 1992. The temporal variations in the vertical flux of total particles, chl a, and OC followed those of chl a in the water column. The bulk of the sediment material was of inorganic nature, derived from desert sand carried from Wadi Araba by the prevailing northerly winds, and dust of exported raw phosphate. The temporal changes described appear to be related to the temporal variations in water stability, horizontal advection, and winds.

Free energy perturbation and MM/PBSA studies on inclusion complexes of some structurally related compounds with β-cyclodextrin

Molecular dynamics (MD) simulations have been conducted to explore time-resolved guest–host interactions involving inclusion complex formation between β-cyclodextrin and organic molecules bearing two peripheral benzene rings in aqueous solution. Moreover, free energy perturbation (FEP) and thermodynamic integration (TI) methods at different simulation times have been employed to estimate the relative free energy of complexation. Also, the less computer-time demanding molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) method was used to estimate the free energy of complexation based on only 1-ns MD simulation. Results showed that both FEP and TI methods were able to reasonably reproduce the experimental thermodynamic quantities. However, long simulation times (e.g. 15 ns) were needed for benzoin mutating to benzanilide (BAN), while moderately shorter times were sufficient for BAN mutating to phenyl benzoate and for benzilic acid mutating to diphenylacetic acid. The results have been discussed in the light of the differences in the chemical structural and conformational features of the guest molecules. In general, it was apparent that the TI method requires less time for convergence of results than the FEP method. However, the less expensive MM/PBSA method proved capable of producing results that are in agreement with those of the more expensive TI and FEP methods.

Infrared Spectroscopic Study of the Role of Water in Crown Ethers and Their Molecular Complexes with 3- and 4-Nitrophenol

The IR spectra of the crystalline complexes of 3-and 4-nitrophenol with crown ethers were studied, viz.,18-crown-6 (18C6), benzo-18-crown-6 (B18C6),dibenzo-18-crown-6 (DB18C6), dicyclohexano-18-crown-6 (DC18C6) and dibenzo-24-crown-8 (DB24C8). The spectra of uncomplexed crown ethers showed water absorption bands which indicate the presence of two types of bound water molecules, viz., cavitant water enclosed by the strong ether-cavity field and outer-layer hydrogen-bonded water molecules. Upon complexation with 3- and 4-nitrophenol, the bands attributed to cavitant water disappeared, leaving the outer layer water to act as a bridge between the host crown ether and the guest phenols. The results further showed that of the crown ethers and of the phenols, B18C6 and DC18C6 and 3-nitrophenol, have the strongest interaction. The behaviour of the phenols was explained by the increased contribution of the inductiveσ-moment over the resonance π-moment in thecomplexes.

Solubilization of Terfenadine, Riboflavin, and Sudan III by Aqueous Multi-basic Organic Acids

ABSTRACT The aqueous solubility of terfenadine, riboflavin, and Sudan III (water-insoluble compounds) was enhanced by the addition of multi-basic organic acids, including citric, glutaric, malic, malonic, and tartaric acids. The variations of physical properties (density, viscosity, electrical conductivity, pH, and surface tension) against acid concentration (0–3.6 M at 25°C) were measured in order to explore possible mechanisms of solubility enhancement. Apart from the partial molar volumes, the measured physical properties varied nonlinearly with acid concentration. Glutaric acid contributes to solubility enhancement of terfenadine and Sudan III more than citric acid, with the latter slightly more effective towards riboflavin. Tartaric acid is the least effective, while malic and malonic acids occupy an intermediate position. Among the organic acids examined, only glutaric acid solutions exhibit significant surface activity, which lends itself to solubility enhancement of the three hydrophobic drugs (interfacial packing of 55 ± 3 Å2 at the air–water interface, critical aggregate concentrations (CAC) at 1.8 ± 0.4 M). In contrast, all five organic acid solutions of terfenadine demonstrate more effective lowering of the surface tension of water, with the terfenadinium acid salts exhibiting interfacial packing of 108 ± 9 Å2 at the air–water interface. On the other hand, organic acid solutions of riboflavin and Sudan III exhibited essentially no surface activity, aside from the intrinsic contribution of the organic acids themselves. Thus, self-association of glutaric acid contributes to the solubility enhancement of the three hydrophobic drugs. This combined with the surface activity of terfenadinium acid salts explains the higher tendency of glutaric acid to solubilize terfenadine. Mixed micellization of terfenadinium glutarate and glutaric acid occurs with an interfacial packing of 166 ± 18 Å2 at the air–water interface. The corresponding CAC were estimated at 3.1 ± 0.2 mM for terfenadinium glutarate and 8.0 ± 0.4 mM for glutaric acid. Intermolecular hydrogen bonding with the extensive hydroxyl group network of riboflavin reflects the higher affinity of citric acid than glutaric acid towards riboflavin. The variability in solubility enhancement exhibited by tartaric, malic, and malonic acids appears to be a result of the interplay between several factors including intra- vs. inter-molecular hydrogen bonding, slight organic acid surface activity, and acid hydration.

ASSOCIATION OF KETOROLAC TROMETHAMINE IN AQUEOUS SOLUTIONS AND ITS RELATIONSHIP TO SOLUBILIZATION

Abstract Some physico-chemical properties of aqueous racemic Ketorolac Tromethamine (KT) solutions were measured as a function of concentration (0-1.0 M). These included surface tension, osmolality, partition coefficients and electrical conductivity at different temperatures (10, IS, 20, 25, 30, 40 and 50° C). These measurements indicate that KT undergoes nonmicelar self-association in water. Comparison of thesolubilitiesof spironolactone and diazepam in aqueous KT with the corresponding solubilities in known aqueous hydrotropic agents (sodium benzoate and salicylate) nonmicellar chlorpheniramine maleate (BP grade of  99 % purity) and miceilar chlorpromazine hydrochloride (BP grade of  99 % purity) indicates KT to undergo nonmicellar association, with a capacity for solubilization intermediate between hydrotropic agents and miceilar solubilizers. The solubilities of normal alkanols (C4-C10 ) were also measured against aqueous KT concentration. Compared with their solubilities in miceilar surfactants (so...