Abstract: A mathematical model based on an analytical solution for the axial dispersion plug flow model is used for simulating the dispersion in flow injection analysis. The dispersion coefficients for the leading and trailing components of the profile are modeled as a function of the physical parameters of the system (reactor length, internal diameter of the reactor) and experimental conditions (flow rate and sample volume). Modeling the dispersion coefficients using all these parameters renders the model with a generality that has not been previously observed when simulating the dispersion profiles. The internal radius of the coiled manifold was observed to have a significant influence on the axial dispersion coefficient; an variable that has not been taken into account in many previous approaches. The volume of the sample plug did not significantly influence the axial dispersion coefficient. The model was set based on a spectrophotometric determination of a colored compound, bromocresol green. The full dispersion profile can be estimated for a large range of experimental conditions and the information retrieved from the simulation can be used in a rapid yet less reagent consuming optimization of the flow conditions.
Abstract: In this study, we investigate how the effect of L-arginine (ARG) and cyclodextrins upon omeprazole (OME) stability and solubility. The effect of the presence of ARG on the apparent stability constants (K1:1) of the inclusion complexes formed between OME and each cyclodextrin, β-cyclodextrin (βCD), and methyl-β-cyclodextrin is studied by phase solubility diagrams and nuclear magnetic resonance (NMR) spectroscopy. The interaction of OME with those cyclodextrins, in the presence of ARG, is characterized using NMR spectroscopy and molecular dynamics simulations. ARG significantly increases the drug solubility and complex stability, in comparison to inclusion complexes formed in its absence. The effect is more pronounced for the OME:βCD complex. ARG also contributes to a larger stability of OME when free in aqueous solution. The combination of ARG with cyclodextrins can represent an important tool to develop stable drug formulations.
Abstract: Structural equilibrium properties of transient networks formed by microemulsion droplets and ABA triblock copolymers in solution have been studied by Monte Carlo simulation. The droplets were represented by soft spheres and the polymers by junctions connected by harmonic bonds with an angular potential regulating the intrinsic chain stiffness. The interaction parameters were selected such that the end A-blocks were localized inside the droplets and the middle B-block in the continuous phase. The influence of (i) the droplet volume fraction, (ii) the droplet radius, and (iii) the contour length of the middle B-block on the formation and the structure of the microemulsion–polymer network at three-fold excess of the polymers were investigated by using polymer end-to-end separation probability distribution functions, droplet radial distribution functions, and network connectivity indicators. A universal behavior of the properties investigated was found when examining the results versus the length ratio of the polymer end-to-end separation and the surface-to-surface separation between neighboring droplets for a hypothetical homogeneous droplet distribution. At a length ratio of 0.5, few polymer bridges between droplets were established and only clusters with a small number of droplets were found. However at a length ratio of ca. 1.5 a connected network was formed and most of the polymers formed bridges between two droplets.
Abstract: Compaction of negatively charged polyanions by polycations with different characteristics is investigated using Monte Carlo simulation in a coarse-grain model. Two different routes are tested and the results compared. In one, the polycation/polyanion charge ratio is varied by increasing the amount of polycations, keeping all the chain characteristics constant. In the other, the linear charge density of the polycations is altered but their number is kept constant. The set of systems in which the linear charge density changes is used as a model for a system comprising chains with different degrees of ionization under different pH conditions. In both cases, polycation/polyanion charge ratios ranging from 0.25 to 1.25 are addressed. The system with unitary charge ratio is common to both routes. It is seen that, although the overall trends followed by the two sets of systems are similar, marked differences can be discerned both for low charge ratios, and for the higher ones, where the systems are overcharged. Coexistence regimes are clearly detected in some of the systems. The results obtained computationally can be used to guide practical applications.
Abstract: Structural equilibrium properties of transient networks formed by microemulsion droplets and ABA triblock copolymers in solution have been studied by Monte Carlo simulation. The droplets were represented by soft spheres and the polymers by junctions connected by harmonic bonds with an angular potential regulating the intrinsic chain stiffness. The interaction parameters were selected such that the end A-blocks were localized inside the droplets and the middle B-block in the continuous phase. The influence of (i) the polymer concentration, (ii) the polymer stiffness, and (iii) the contour length of the middle B-block on the formation and the structure of the microemulsion–polymer network were investigated by using polymer end-to-end separation probability distribution functions, droplet radial distribution functions, droplet–droplet nearest-neighbor probability distribution functions, and network connectivity indicators. An increase of the polymer–droplet number ratio had a strong impact on the network formation. For typical conditions and at an intermediate polymer–droplet number ratio, (i) the fraction of telechelic chains forming bridges between droplets raised from essentially zero to unity and (ii) the fraction of polymers forming loops decreased as the ratio of the polymer end-to-end separation and the surface-to-surface separation between neighboring droplets for a hypothetical homogeneous droplet distribution was increased from 0.5 to 2. For long and flexible polymers a mesoscopic segregation triggered by a depletion attraction between droplets appeared, and, furthermore, for sufficiently stiff chains only bridge conformations occurred. The percolation probability could be represented as a function of the average droplet cluster size only, across all systems.
Abstract: We report results regarding the use of 1H-NMR spectroscopy in the study of the conformational behaviour and optical activity of omeprazole. Changes in the chemical shifts of chosen atoms reveal that the conformational behaviour of omeprazole is temperature and pH sensitive. Separation and identification of omeprazole enantiomers in the presence of natural and derivative cyclodextrins, such as b-cyclodextrin (bCD) and methyl-b-cyclodextrin (MbCD) are achieved using 1H-NMR spectroscopy, with information from molecular dynamics simulation. This work shows that bCD includes preferentially R-(–)-omeprazole, acting as a chiral selector. This discrimination of omeprazole enantiomers by cyclodextrins allows development of pharmaceutical formulations with a better bioavailability profile.
Abstract: Purpose. Cyclodextrins are known to be good solubility enhancers for several drugs, improving bioavailability when incorporated in pharmaceutical formulations. In this work we intend to assess and characterize the formation of inclusion complexes between omeprazole (OME) and a methylated derivative of beta-cyclodextrin, methyl-beta-cyclodextrin (MbetaCD). A comparison with results obtained from
the most commonly used natural cyclodextrin, beta-cyclodextrin (betaCD) is also presented in most cases.
Materials and Methods. The interaction of OME with the mentioned cyclodextrins in aqueous solutions was studied by phase solubility studies, 1D 1H and 2D rotating frame nuclear overhauser effect NMR spectroscopy (ROESY) and Molecular Dynamics.
Results. The solubility of OME was significantly increased by formation of inclusion complexes with each cyclodextrin. Phase solubility studies and continuous variation plots revealed that OME forms an inclusion complex in a stoichiometry of 1:1 with both cyclodextrins. 1H NMR and ROESY spectra of the inclusion complexes indicated that the benzimidazole moiety is included within the cyclodextrins cavities. Molecular dynamics showed that OME is more deeply included in the MbetaCD than in betaCD cavity, in agreement with a larger apparent stability constant (KS) obtained for the inclusion complex with MbetaCD.
Conclusions. MbetaCD proved to be an efficient enhancer of OME solubility, thus possessing characteristics for being an useful excipient in pharmaceutical formulations of this drug.
Abstract: In this work we discuss different factors governing coil-globule coexistence in the compaction process of DNA. We initially analyse the role played by fluctuations in the degree of binding of an external compacting agent in the conformational behavior of the chain backbone. The analysis relies both on Monte Carlo simulation results and simple statistical approaches. Compacting agents of various binding characteristics are taken into consideration and the degree of charge neutralization upon the chain is related to conformational indicators. Selected model systems comprising stiff chains in the presence of multivalent ions are employed to assess intrinsic single chain conformational fluctuation, in the presence of external agents but not resulting from differences in binding. It is shown that trends found for a variety of compacting agents, including the extension of the coil-globule coexistence regions, can be rationalised on the basis of this analysis.
Abstract: It has been experimentally observed that trivalent ions are capable of promoting compaction of semi-flexible polyelectrolyte chains. In this work we perform Monte Carlo simulations on single chain model systems with varying chain size and stiffness and evaluate the action of multivalent salt on the chain conformation. It is observed that longer chains tend to achieve relatively more compact conformations than shorter ones, and the dimensions of the collapsed structures do not significantly vary with contour length. The influence of contour length and intrinsic stiffness in the process of ion condensation is studied by analysis of the ion–ion nearest-neighbor distribution. The general trend is an increase of the degree of ion condensation as the chain length increases, in accordance with experimental evidence. A decreased importance of end-effects and, especially, larger volume charge densities are responsible for such behavior. The influence of chain stiffness is nontrivial, and depends on salt concentration. The results emphasize the complex nature of ion correlation phenomena in flexible or semi-flexible chains and call for the development of more sophisticated analytical theories.
Abstract: We discuss a simple approach to describe the ion density around a polyelectrolyte chain, quantifying bound and bulk counterions, and allowing for the renormalization of the charge in the polyion. This approach is both physically motivated and readily extensible to systems containing other types of highly charged ions. The method addresses the problem in simulation experiments and allows to correlate ion condensation and compaction.
Abstract: Polyion conformation and the distribution of small ions near the polyion have been investigated using Monte Carlo simulations. The systems of interest contained one polyion and its monovalent counterions, and variable amount of a 3:1 salt. With monovalent counterions only, the polyion is strongly extended. As salt is added, the polyion folds, and the most compact and spherical-like structure appears at a three-fold excess of the trivalent counterions. The polyion exerts a strong influence on the nearest-neighbor distance among the trivalent ions, an effect being relevant for energy transfer reactions.
Abstract: The interaction of trivalent lanthanides with sodium dodecyl sulfate micelles (SDS) in aqueous solution has been studied by a variety of experimental techniques. Potentiometric measurements with a sodium selective electrode, steady-state fluorescence spectra of Ce(III), emission lifetime measurements of Ce(III), Tb(III),
and Eu(III), and electronic paramagnetic resonance spectra (EPR) of Gd(III) all show that the lanthanide ions bind to the micellar surface. From analysis of the Tb(III) lifetime measurements in water and D2O solutions, it is found that the lanthanide ions lose one hydration water on binding to SDS. However, the EPR measurements suggest that the lanthanide ions still have considerable freedom of movement. Energy transfer
between Ce(III) and Tb(III) has been used to obtain further information on multiple lanthanide ion binding. From steady-state fluorescence measurements in aqueous solution in the absence of SDS no energy transfer is observed, although there is quenching of Tb(III) emission by Ce(III), which is found to follow good Stern-
Volmer kinetics. In the presence of SDS micelles, very different behavior is observed and energy transfer occurs from excited Ce(III) to Tb(III). This is only possible when the two ions are on the same micelle. The energy transfer phenomena is highly dependent on micelle concentration and has been analyzed theoretically via a Monte Carlo simulation. This shows that the lanthanide ions bind close to the micelle surface, and are consistent with the loss of a water molecule. Also, assuming a Dexter-type model in which the energy transfer intensity is proportional to the inverse of the square root of the average distance between cerium and the closest terbium it is possible to reproduce qualitatively the experimental cerium(III)-sensitized Tb(III) luminescence intensity data.
