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Abstract

We investigated the inclusion process of Lamotrigine (LMN) in beta cyclodextrin (β-CD) with 1:1 stoichiometry using empirical, semi-empirical and quantum mechanical calculations models. We have found that the quantum and hybrid ONIOM2 methods gave the most favorable orientation in which the guest molecule is totally sequestered in the hydrophobic cavity of the cyclodextrin with the tiazine ring located near the primary hydroxyls of the β-CD and the dichloro phenyl moiety near the secondary hydroxyls with no hydrogen bonding formation. Moreover, the statistical thermodynamic calculations at 1 atm and 298.15 K demonstrate that 1:1 LMN/β-CD complexation is an exothermic process, enthalpically favorable in nature and that non bonded Van der Waals interactions represent the mainly driving forces leading to complex stability. While, HOMO and LUMO orbital investigations confirm on one hand the better stability of ‘A’ orientation and on the other hand prove that no significant change will be observed in the electronic structure of LMN after complexation.

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... The initial geometry of the drugs and a-CD, b-CD were constructed with Spartan 08 and then optimized by PM3 (Parametric method 3). Both a-CD, b-CD were fully optimized by PM3 without any symmetry constraint [8][9][10][11][12]. The glycosidic oxygen atoms of CD were placed onto the XY plane and their centre was defined as the centre of the coordination system. ...
... The inclusion process was simulated by putting the guest in one end of CD and then letting it pass through the CD cavity. Since density functional theory (DFT) calculations are expensive (cost and takes long time) in treating such large molecular systems, we used single point energy calculations to the PM3 optimized geometries using semiempirical method as implemented in Gaussian 03W [8][9][10][11][12]. ...
... Further (E HOMO -E LUMO ) gap is an important scale of stability [10][11][12] and guests with large (E HOMO -E LUMO ) values tend to have higher stability. So we investigated the electronic structure of the complexes in with these considerations using PM3 method. ...
Article
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The inclusion complexation between methylparaben, ethylparaben, propylparaben, butylparaben with α-CD, β-CD, hydroxypropyl α-cyclodextrin and hydroxypropyl β-cyclodextrin were carried out by UV–Vis, steady state and time-resolved fluorescence, FT-IR, 1H NMR techniques and semi-empirical method (PM3). The drug molecules are all given one emission maximum in water where as dual emission in all the CDs. CDs study revealed that the paraben molecules were formed 1:1 inclusion complex. The aliphatic side chain is present in the hydrophilic part whereas hydroxyl group is present in the hydrophobic part of the CD cavity. Nanosecond time-resolved studies indicated that paraben exhibited biexponential decay in water whereas triexponential decay in CDs solution. The complexation energy, thermodynamic parameters and HOMO–LUMO energy structure were calculated using quantum chemical calculation.
... 20 The phase solubility profile of LMN with b-cyclodextrin (b-CD) was reported and classified as AL-type, indicating the formation of a 1 : 1 stoichiometry inclusion complex with a stability constant of 369.96 ¡ 2.26 M 21 . 21 We have prepared the inclusion complex of LMN with p-sulfonatocalix [4]resorcinarene (PSC[4]R) and investigated the dissolution behavior of LMN in the complex. The solid inclusion complex was studied using different analytical techniques including FT-IR, PXRD and DSC. ...
... The simulation box was automatically defined by considering all atoms of the PSC[4]R inclusion complex and filled with water as explicit solvent. Energy minimization of the molecular system was initially executed using Amber03 force field with tolerance 1.00 e 24 kcal mol 21 and 100 steps of iterations. The MD simulations were performed with constant volume and shape ensemble in which the center of mass was fixed with 50 000 as number of steps and 7 as cut off radius. ...
... The FT-IR spectrum of LMN ( Fig. 4(C)) was characterized by the principal absorption peaks at 3448 cm 21 ...
Article
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As a part of our research investigations to unfold the chemistry of calixresorcinarene, we studied the formation of inclusion complex with para-sulfonato calix[4]resorcinarene (PSC[4]R) of a poorly water soluble drug lamotrigine (LMN). The complete complexation of the drug was achieved after 48 h of stirring with PSC[4]R in water and evaporation of water to get solid complex. The inclusion complexes between PSC[4]R and LMN was studied by different analytical techniques including FT-IR, PXRD and UV-VIS spectroscopy. The complexation was determined by thermal analysis and phase solubility study. The prepared complexes exhibited improved in vitro dissolution profile and decreased in vivo acute oral toxicity compared to the pure drug. The results of the phase solubility experiments are in good conformity to signify the formation of 1:1 PSC[4]R:LMN complexes. Computational studies were performed to understand the intermolecular association of this inclusion complex using docking and short dynamic simulations. The purpose of this study was to enhance solubility resulting in high dissolution rate and bioavailability of this essentially poorly water soluble drug LMN.
... To model the molecular docking process, we followed the method described in references [27][28][29][30][31]. The coordinate system for the complexation process is shown in Fig. 2a. ...
... The structure generated at each step is optimized, in vacuum, using PM3 method without imposing any symmetrical restriction. As reported in our previous papers [28][29][30][31], our computing strategy is a compromise between computing cost and accuracy of the results. These tasks are computationally expensive at the ab-initio or DFT level for such large system, so we choose to use PM3 method, which has proven its efficiency for CD chemistry and was proved powerful in the conformational study of supramolecular systems as well as cyclodextrin inclusion complexes [27,32,33]. ...
... Evidently, the lowest negative value corresponds to the most stable complex. It is calculated according to the following equation [28][29][30][31]: ...
Article
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Using quantum chemistry, we modeled the docking process of flavanone Naringenin guest molecule (Narg) in the host β-Cyclodextrin (β-CD) and also in modified heptakis(2,6-di-O-methyl)-β-CD (DIMEB). The effect of host methylation on the complexation behavior was highlighted through structural, electronic and nuclear studies. All ONIOM2 combinations of PM3 with B3LYP, M06-2X and wB97X-D methods at 6-31G (d) basis set, agree on the inclusion mode and the optimum 3D structure. We found a deep insertion of the hydroxy phenyl ring in the hydrophobic cavity of both hosts. On the other hand, only a partial inclusion of the hydroxy chromanone moiety, located nearby the primary rim in Narg/DIMEB complex 1 and the secondary rim in Narg/DIMEB complex 2 was found. Ground state calculations show that complex 1 is more stable than complex 2, which corroborates well with experimental results. We investigated Frontier Molecular Orbitals and global reactivity descriptors and we identified the interaction sites, the nature and the strength of intermolecular interactions using ¹H NMR GIAO (Gauge-Including Atomic Orbital) method, Natural Bond Orbital (NBO) and Quantum Theory of Atom In Molecule (QTAIM) analysis. Particularly, the multifaceted nature of H-bonding interaction has been explained with QTAIM topological model which revealed the stabilization via the closed-shell interactions: C–H…H and O–H…O for both complexes, O–H…H and C–H…C for Narg/β-CD and Narg/DIMEB, respectively. QTAIM topological properties correlate well with the structural geometry and interactions predicted by both GIAO NMR and NBO analysis.
... Due to the amphiphilic molecular structure of CDs are easy to form inclusion complexes with several organic, inorganic and biological compounds without covalent bond and the resultant inclusion complexes can induce modification of the physicochemical properties of guest molecules (such as water solubility and solution stability) [4,5]. Therefore pharmaceutical application of CDs as additives and drug-complexing agents had attracted growing attention in many years [4][5][6][7]. In addition, CDs can mediate many organic reactions in which CDs represent a good model of mimicking enzymes [6,7] and have molecular recognition property to identify the small differences between compounds [8,9]. ...
... Therefore pharmaceutical application of CDs as additives and drug-complexing agents had attracted growing attention in many years [4][5][6][7]. In addition, CDs can mediate many organic reactions in which CDs represent a good model of mimicking enzymes [6,7] and have molecular recognition property to identify the small differences between compounds [8,9]. Due to the limitations of the experimental methods, in recent times molecular modeling has become very popular in CD chemistry [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. ...
... The initial geometry of the drugs and b-CD were constructed with Spartan 08 and then optimized by PM3 (Parametric method 3). b-CD was fully optimized by PM3 without any symmetry constraint [14][15][16][17][18]. The glycosidic oxygen atoms of CD were placed onto the XY plane and their center was defined as the center of the coordination system. ...
... The inclusion process was simulated by putting the guest in one end of b-CD and then letting it pass through the b-CD cavity. Since Density Functional Theory (DFT) calculations are expensive (cost and takes long time) in treating such large molecular systems, we used single point energy calculations to the PM3 optimized geometries using Hartree-Fock (HF) method as implemented in Gaussian 03W [14][15][16][17][18]. ...
Article
The inclusion complexation behavior of salbutamol, sotalol and atenolol drugs with β-cyclodextrin (β-CD) were investigated by UV-visible, fluorometry, time resolved fluorescence, FT-IR, (1)H NMR, SEM and PM3 methods. The above drugs gave a single emission maximum in water where as dual emission in β-CD. In β-CD solutions the shorter wavelength fluorescence intensity was regularly decreased and longer wavelength fluorescence intensity increased. Addition of β-CD to aqueous solutions of drugs resulted into excimer emission. The excimer emission is concluded to be due to a 1:2 inclusion complex between β-CD and drug. Nanosecond time-resolved studies indicated that all drugs exhibited biexponential decay in solvents and triexponential decay in CD. Investigations of thermodynamic and electronic properties confirmed the stability of the inclusion complex.
... To this effect, two different orientations ('A' and 'B') are investigated: in 'A' orientation, the butanone group is oriented towards the wider rim of the β-CD, and in 'B' orientation, the methoxy group pointed towards the secondary hydroxyls (Fig. 2). To locate the lowest energy structure, the method reported in references [3,[16][17][18]] is adopted. The bond C(3)-C(18) of NAB coincides with X-axis and the relative position of the guest and the host molecules is determined by X coordinate of carbon atom C (18) corresponding to the reference atom (Fig. 2). ...
... Therefore, the obtained ∆G 0 could not have an absolute meaning (especially in this case), and should be considered only as a comparative assessment. Similar situations are presented in previous works [17,51]. Also, it is shown that the smallest standard free energy change ∆G 0 corresponds to the complex 'B', which proves that the complex B is more stable than the complex A, thus promoting the methoxy group to enter the cavity of the β-CD from its wide side rather than the butanone group. ...
Article
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The aim of the present work is the investigation of the inclusion complex of nabumetone (NAB) and β-cyclodextrin (β-CD) using PM3, DFT, DFT-D and ONIOM2 methods. The results indicate that the most energetically favorable structure predicts a preference of the methoxy group to enter the cavity of β-CD from its wide rim. Consequently, the butanone moiety is positioned outside the cavity on the side of the secondary hydroxyls, with a total insertion of naphthalene group. The semi-empirical PM3 results are in good agreement with those obtained by the DFT optimization (with and without dispersion correction). The donor–acceptor interactions between drug and the cavity wall of the host, studied on the basis of natural bonding orbital (NBO) analysis, show the presence of weak intermolecular hydrogen bonds in addition to the most important van der Waals interactions. Furthermore, it is revealed that among the DFT and DFT-D techniques selected to quantify these interactions, WB97X-D functional provides the greatest values of stabilization energies E⁽²⁾. Finally, a detailed topological charge density analysis based on the quantum theory of atoms in molecules (QTAIM), developed by Bader and co-workers, has been accomplished using the WB97X-D and B3LYP methods on the most favorable complexes. A good correlation between the structural parameters and the electronic density is found.
... The theoretical calculations were performed with Gaussian 03W package. The initial geometry of ISOP, MDOP, a-CD and b-CD were constructed with Spartan 08 and then optimized by PM3 (Parameter method 3) without any symmetry constraint [18,19]. CD was fully optimized by PM3 without any symmetry constraint. ...
... The inclusion process was simulated by putting the guest in one end of CD and then letting it pass through the CD cavity. Since Density Functional Theory (DFT) calculations are expensive (cost and takes long time) in treating such large molecular systems, we used single point energy calculations to the PM3 optimized geometries using semiempirical method as implemented in Gaussian 03 W [25][26][27][28]. ...
Article
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The inclusion complexation of 2-hydroxy-3-methoxybenzaldehyde (2HMB), 4-hydroxy-3-methoxybenzaldehyde (4HMB), 3,4-dimethoxybenzaldehyde (DMB) and 4-hydroxy-3,5-dimethoxybenzaldehyde (HDMB) with α-CD, β-CD, HP-α-CD and HP-β-CD were carried out by UV-Visible, steady-state and time-resolved fluorescence and PM3 methods. All the benzaldehydes shows dual fluorescence in aqueous and CD mediums and 1:1 inclusion complexes were formed with CDs. PM3 geometry optimizations results indicate that the HDMB/CD complex is significantly more favorable than the other complexes. The negative enthalpy changes suggest that the inclusion complexation processes are spontaneous. The geometry of the most stable complex shows that methoxy/OH group of HMBs is entrapped in the less polar CD cavities, while the aldehyde group present in the upper part of the CDs cavities.
... Currently, computational methods used in molecular modeling have became an important tool to study such supramolecular systems. Among the most widely used of these methods, we can mention: molecular mechanics (MM), molecular dynamics (MD), semiempirical methods such as Austin Model 1 (AM1), Parametrization Model 3 (PM3), Parametrization Model 6 (PM6), Own N-layered Integrated molecular Orbital and molecular Mechanics (ONIOM) method, Natural Bond Orbital (NBO) analysis, Hartree-Fock (HF) and Density Functional Theory (DFT) [42]. ...
Article
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Spectroscopic investigation supported by molecular modeling methods has been used to describe the inclusion complex of β-cyclodextrin (β-CD) with N-[(4-sulfonamidophenyl) ethyl]-5-(1,2-dithiolan-3-yl) pentanamide in solution and in solid state. By using UV–Vis absorption, the stoichiometric ratio of the complex was found to be 1:1 and the stability constant was evaluated as 1.3415.104 (mol/L)−1. Solid state characterization by FT-IR spectroscopy provided remarkable evidences of the formation of inclusion system. Moreover, semi-empirical calculations using PM3 level of theory and hybrid method ONIOM2 clearly indicate that the formed complexes are energetically favored in vacuum and in solution. From NBO analysis, the mutual interactions between β-CD and SULPA were analyzed and discussed.
... Molecular modeling studies have gained strong emphasis in the investigation of complexation with CDs. This allows the construction of three-dimensional models of drug-CD complexes, visualization of structural integrity, and intra-and intermolecular interactions (Seridi, Boufelfel, 2011;Leila et al., 2011;Eid et al., 2011;Ge et al., 2011;Mishur et al., 2011). ...
Article
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Cyclodextrins (CDs) are cyclic oligosaccharides composed of D-glucopyranoside units linked by glycosidic bonds. Their main property is the ability to modify the physicochemical and biological characteristics of low-soluble drugs through the formation of drug:CD inclusion complexes. Inclusion complexation requires that host molecules fit completely or partially within the CD cavity. This adjustment is directly related to the physicochemical properties of the guest and host molecules, easy accommodation of guest molecules within the CD cavity, stoichiometry, therapeutic dose, and toxicity. However, dosage forms may achieve a high volume, depending on the amount of CD required. Thus, it is necessary to increase solubilization efficiency in order to use smaller amounts of CD. This can be achieved by adding small amounts of water-soluble polymers to the system. This review addresses aspects related to drug complexation with CDs using water-soluble polymers to optimize the amount of CD used in the formulation in order to increase drug solubility and reduce dosage form volume.
... In the past few years, computational methods in combination with experimental techniques have been mainly focused on the conformational study of inclusion complex of natural CDs or their derivatives. There are several computational methods used in molecular modeling studies for the complexes of CDs or their derivatives with guest molecules (host-guest systems) such as molecular mechanics (MM), molecular dynamics (MD), semiempirical method, hybrid ONIOM method (our Own N-layer Integrated Orbital Molecular mechanics), Hartree Fock (HF) and density functional theory (DFT) [11][12][13][14][15][16]. Among these methods, semi-empirical calculations using PM3 level of theory is generally acceptable and frequently used for the structural assignment of CD inclusion complexes, which coincide with the experimental results [17]. ...
... Exchange of the water molecules (with high enthalpy) by proper guest molecules is primary motive for this complex formation. As a consequence, CDs can form host-guest inclusion complexes with diverse hydrophobic molecules [30,31]. Table 1 details several characteristics of natural CDs [3,32,33]. ...
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Pollution monitoring in a contaminated environmental water samples is a big challenge. In this article, immobilization of β-cyclodextrin molecules onto the magnetic core-shell silica nanoparticles was conducted by using adhesive properties of polydopamine. The synthesis path was included of three steps: producing Fe3O4 nanoparticles as a core, coating the cores with a silica layer, and further coating with β-cyclodextrin molecules. The structural characteristics of the synthesized nanocomposite were investigated by using attenuated total reflection-Fourier transform infrared spectroscopy, x-ray diffraction analysis, field emission scanning microscopy, transmission electron microscopy, dynamic light scattering, vibrating-sample magnetometer and energy-dispersive X-ray spectroscopy. Afterwards, obtained nanocomposite was used to extract eight polycyclic aromatic hydrocarbons from environmental water samples. Results were demonstrated that analyts with different chemical structures had different extraction manners during the process. Important effective parameters on the extraction efficiency; such as sorbent type and mass, desorption solvent (type and volume), salt concentration and the time of extraction & desorption; were investigated. Under the optimum operating conditions, good linearity within the range of 1-1000 ng/mL was obtained while coefficient of determination (r2) was in the range of 0.990-0.998. The limits of detection were between 0.04 and 0.57 ng/mL, and the enrichment factor was found to be 21-90. This nanocomposite was also applied for the extraction and enrichment of aromatic analytes from the canal and rain water samples prior to gas chromatography analysis.
... Exchange of the water molecules (with high enthalpy) by proper guest molecules is primary motive for this complex formation. As a consequence, CDs can form host-guest inclusion complexes with diverse hydrophobic molecules [30,31]. Table 1 details several characteristics of natural CDs [3,32,33]. ...
... If all parameters are compatible, the water molecules will impose to expel from the CD cavity, and the guest molecule would replace. This molecule exchange in the CD cavity is counted as the main motive force for the creation of host-guest interaction between CDs and analytes [29]. ...
Article
Determination of organic pollutants in environmental water samples is known as the challenging field. In this study, we have reported an extraction methodology based on the β-cyclodextrin-starch composite (β-CD-Starch) as a sorbent for the extraction of polycyclic aromatic hydrocarbons (PAHs) from water samples. The synthesis procedure of sorbent was straightforward and convenient. A hard gel of wheat starch in combination with different kinds of CDs/maltodextrin (MD) was prepared. It then was applied as a sorbent in dispersive micro solid-phase extraction (d-µ-SPE) of target analytes (i.e., naphthalene, acenaphthene, fluorene, phenanthrene, anthracene, fluoranthene, pyrene, and benzo[a]pyrene) from aqueous solutions. Optimization of the extraction process was followed by the investigation of the effective parameters on the extraction efficiency; like sorbent type (based on the type of used CD/MD) and its mass amount, type and volume of desorbing solvent, the salt concentration of sample solution and, the extraction/desorption times. Under the optimal extraction conditions, good linear ranges between 0.1-1000 ng/mL with r² > 0.991 were obtained. The detection limit was from 0.01 to 0.07 ng/mL, and the limit of quantification was varied over the range 0.04 to 0.24 ng/mL. As well, the enrichment factor of the extraction method was calculated between 84.1- 94.8 (with a maximum value of 100). The efficient and sensitive proposed method was then applied for extraction and determination of PAHs from agricultural and rainwater samples along with the GC-FID system and, acceptable results were received.
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The purpose of this research was to investigate inclusion complex formation between poorly soluble drug amisulpride (AMI) and γ-cyclodextrin (γ-CD). The solubility of AMI was enhanced by formation of inclusion complex of AMI with nano-hydrophobic cavity of γ-CD. The stoichiometry of inclusion complex was studied by continuous variation Job's plot method and found 1:1. The binding constant was found 1166.65M(-1) by Benesi-Hildebrand plot. The molecular docking of AMI and γ-CD was done to investigate complexation. The inclusion complex formation was further confirmed by (1)H NMR and FT-IR, DSC and XRD analysis. The solubility of AMI was increased 3.74 times after inclusion complex formation with γ-CD.
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The inclusion complex of N-nitroso, N-(2-chloroethyl), N′, N′-dibenzylsulfamid with β-Cyclodextrin have been investigated using the spectrofluorescence technique 1H NMR spectroscopy. The stoichiometric ratio of the complex was found to be 1:1 and the stability constant was evaluated using the Benesi-Hildebrand equation. In order to find the most favorable structure, molecular mechanics calculations were employed to study the inclusion of CENS-Dibenz in β-CD in vacuum and in the presence of water as a solvent. The driving forces for complexation are dominated by non-bonded van der Waals host-guest interactions with very little electrostatic contribution in both environments. After this stage of calculation, both the most stable complexes obtained by MM+ were re-optimized using semi-empirical and quantum mechanical calculations. It was found that the PM3 and the hybrid method ONIOM2 calculations predict the same mode of inclusion of the drug molecule in the host cavity. In the most stable conformation (i.e. Complex A), one of the two aromatic cycles is dipped within the relatively less polar cavity of β-cyclodextrin, while the other aromatic cycle as well as the active groupings (alkylating agent and nitroso group) are directed towards the exterior through the narrow rim of β-CD. This orientation is preferred because it is the most energetically favorable structure. Moreover, statistical thermodynamic calculations demonstrate that the formation of the inclusion complex is an enthalpy-driven process. A comparison between the experimental and theoretical values of ΔG0 proves that simulation of the complexes without an explicit treatment of the solvent leads to dubious results.
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Inclusion complex MM+, Amber 99 Monte Carlo simulation We simulated the docking of the fullerene C 60 in β-Cyclodextrin using two models. We considered in this study complexes formed by 1:1 and 1:2 guest–host stoichiometries in vacuum and aqueous phase. We investigated three orientations for β-CDs in 1:2 complexes, Head to Head (HH), Head to Tail (HT) and Tail to Tail (TT). Both models agree on energetic of the inclusion process, optimum 3D structure complex, inclusion mode and stoichiometry of most stable structure. In both media, we predicted the possibility of formation of 1:1 complexes, where the most stable structure corresponds to the location of C 60 at the wider rim of β-CD with a partial inclusion. In vacuum, for 1:2 stoichiometry, the most stable complex was in HH orientation with a "V" shaped structure which favored some intermolecular hydrogen bonds, but in water both TT and HH orientations were equally stable within the calculations errors. Over all, we found that the complex with 1:2 stoichiometry is more stable than that with 1:1 stoichiometry. Our results are in agreement with the experimental spectroscopic data. We found that the driving forces for complexation in both environments were non bonded Van der Waals interaction between the host and the guest molecule for both stoichiometries. Also, we noticed that the presence of water molecules caused a relative destabilization of all complexes in both stoichiometries except for TT orientation.
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The inclusion process of four tricyclic antidepressant drugs (carbamazepine, imipramine, dothiepin and doxepin) with β-cyclodextrin (β-CD), as well as their possible interaction types have been investigated theoretically. The data suggest that these drugs are partially encapsulated into the β-CD cavity. The formation of the inclusion complex is predicted to be an enthalpy-driven process in gas phase. Different interactions between these drugs and β-CD should be also possible due to their negative binding energy though their distributions differ greatly. Comparative study of the interactions of these drugs with β-CD has been investigated and their obvious differences in binding energy and enthalpy change suggest that the β-CD can identify the stability of the complex.
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The energies, geometries, and NMR chemical shifts have been calculated at the B3LYP/6-311++G(d,p) level for 17 structures of the anticonvulsant drug Lamotrigine and 29 structures of protonated Lamotrigine, including tautomers and E/Z isomers of the imino groups. The calculations were compared with solid state (X-ray and CPMAS NMR) and solution experimental results both reported in the literature and determined in this work. The conclusion is that Lamotrigine exists as the diamino tautomer and that its protonation takes place on the N2 atom. Using ABTE and/or deuterated ABTE as chiral solvating agent, it has been demonstrated for the first time by NMR in solution that Lamotrigine is a racemate of rapidly interconverting enantiomers. The crystal structure of two new solvated salts of Lamotrigine, both saccharinates, has been determined. Both salts present the same arrangement in chains of Lamotrigine and saccharinate joined by hydrogen bonds and stacking interactions. No isostructurality is present because of the different arrangement of the chains in both crystal structures.
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The theoretical investigation of five 3,3'-(phenylmethylene)bis(1H-indole) derivatives (BIM1, BIM2, BIM3, BIM4 and BIM5) with β-cyclodextrin (β-CD) were studied using density functional theory B3LYP 3-21G method as basis set. Substituents (–OCH2COOH and -OCH3) at the ortho-, para- and meta- positions in the phenyl ring of BIMs (BIM 1–5) has changed the stability of inclusion complexes BIMs:β-CD with forming 1:1 stoichiometric ratio. To access the chemistry behind this orientation and composition, we have studied the geometrical parameters, complexation energy, HOMO-LUMO energy gap, chemical reactivity, thermodynamic parameters, Mulliken charges and molecular electrostatic potential (MEP) map for all inclusion complexes (BIMs:β-CD) with stable orientation. Natural bond orbital (NBO), NCI-RDG and QTAIM analysis revealed the prospects of hydrogen bonds (=N–H–O and –O–H–O) between BIMs and β-CD.
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The host–guest interaction of hydroxypropyl-β-cyclodextrin (HP-β-CD) with ofloxacin (OFL) has been investigated by ultraviolet spectroscopy (UV), Fourier transform infrared spectroscopy (FT-IR) and molecular docking method. The influence of different factors affecting the inclusion interaction was discussed. The obtained results revealed that the inclusion complex of HP-β-CD with OFL was formed by non-bond interaction. The stoichiometry and inclusion constant (K) of OFL–HP-β-CD complex are 1:1 and 1300 M− 1, respectively. The low aqueous solubility of ofloxacin limited its efficacy. By the inclusion process solubility of OFL was significantly enhanced. Several experimental conditions were optimized in order to obtain the maximum spectroscopy signal. Due to remarkable enhancement of absorbance in the presence of HP-β-CD, a sensitive spectrophotometric method for the OFL determination was developed. The linear range was 1.8–16 μg mL− 1 with a correlation coefficient of 0.9996 and the detection limit 0.08 μg mL− 1. The proposed method was applied for the determination of OFL in pharmaceutical preparations with RSD of 0.98% and the results were satisfactory in comparison to the official method.
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The inclusion complexation behavior of norepinephrine (NORE) and epinephrine (EPIN) with native cyclodextrins (α-CD and β-CD) were investigated by UV-visible, fluorimetry, time-resolved fluorescence, SEM, TEM, FT-IR, 1H NMR, DSC, powder XRD and PM3 methods. Single emission was observed in aqueous solution where as dual emission (excimer) noticed in the CD solutions. Both drugs form 1:1 drug-CD complexes in lower CD concentrations and 1:2 CD-drug2 complexes in the higher CD concentrations. Time-resolved fluorescence studies indicated that both drugs showed single exponential decay in water and biexponential decay in CD. Nano-sized self-aggregated particles of drug-CD were found by TEM studies. Molecular modeling studies indicated that aliphatic chain part of the drug was entrapped in the CD cavity. Thermodynamic parameters and binding affinity of complex formation of the CD were determined according to PM3 method. The PM3 results were in good agreement with the experimental results.
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The interaction of alkaline earth metal cations including Be2+, Mg2+, Ca2+, Sr2+ and Ba2+ with cyclic peptides containing 3 or 4 (S) alanine molecules (CyAla3 and CyAla4) was investigated by density functional theory (DFT-CAM-B3LYP and DFT-B3LYP). A mixed basis set including 6-31+G(d) for C, H, O, Be2+, Mg2+, Ca2+ and LANL2DZ for Sr2+ and Ba2+ were used for calculations. The optimized structures, binding energies, and various thermodynamic parameters of free ligands and related metal cation complexes were determined. The order of strength of interaction energies was found as Be2+ > Mg2+ > Ca2+ > Sr2+ > Ba2+. Vibrational frequency calculations showed that the selected cyclic peptides and their complexes with the alkaline earth metal cations were at local minima of their potential energy surfaces. In addition, it was found that the larger cavity CyAla4 ligand, can hold the alkaline metal cations better than CyAla3 molecule when the same metal cation is in the structure of complex. Moreover, analyzing the geometry of [M/CyAla3]2+ and [M/CyAla4]2+ complexes indicated that the aggregation with metal cation, caused substantial changes in the geometrical parameters of ligands.
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Thymol (TH) is a natural compound extracted from plants. In the present study, the β-cyclodextrin (βCD) complex of TH as the main constituent of thyme essential oil, was synthesized by freeze-drying (FD) method and TH/βCD inclusion complexes loaded chitosan (CS) nanoparticles (NPs). Phase solubility studies presented that the formation of inclusion complex enhanced water solubility of TH in the presence of βCD also the stability constant was obtained 965 M⁻¹. The TH/βCD-ICs and TH/βCD-CS NPs were characterized using UV-Vis absorption, FT-IR, ¹HNMR, XRD, and SEM. Moreover, the theoretical study of molecular modeling demonstrated the most desirable mode of TH encapsulated into the βCD cavity. Complexes exhibited 1:1 host: guest stoichiometry. The antibacterial effect of TH/βCD-ICs and TH/βCD-CS NPs was investigated against gram-positive Staphylococcus aureus and gram-negative Escherichia coli bacteria. The antioxidant test indicated that complexes exhibited better antioxidant activities compared to the pure TH through free radical scavenging assay.
Article
Complexation of alpha- and beta-anomers of adamantyl galactosides and adamantyl mannosides, having different configuration of the chiral linker connecting the sugar and the adamantamine (AMA) subunits, with beta-cyclodextrin (beta-CD) was investigated by means of NMR spectroscopy, microcalorimetric titrations and computational studies. The synthesis of adamantyl galactosides is also reported. The experimental investigations are consistent with the formation of 1:1 complexes in which the hydrophilic part of the guest protruded out of the secondary rim. The beta-cyclodextrin was shown to be a rather efficient binder for the examined guests in water, primarily as a consequence of the enthalpically favourable inclusion of the adamantyl moiety within the hydrophobic cavity of the host. The structures of AMA derivatives complexes were modelled by combination of molecular and quantum mechanics - B3LYP/6-31G(d) in implicitly modelled water (PCM). The differences in the stability of primary and secondary complexes were observed. The main reasons for that could be more pronounced dehydration of the hydrophilic part of the guest upon complete adamantane inclusion in the complexes of primary type and the different hydrogen bonding pattern at the primary and secondary CD rims.
Article
The present work was carried out with the purpose of evaluating the effect of β-cyclodextrin (β-CD), sodium lauryl sulfate (SLS) and polyethylene glycol 200 (PEG 200) on the solubilization of lamotrigine by means of phase-solublility studies and solubility prediction using Jouyban-Acree model. The experimental solubility values of various mixtures were fitted to the equation and fitting accuracy of solubility data to this model was evaluated. A quantitative relationship between the solubilizing agents was assessed and the predictive accuracy of the Jouyban-Acree model and its applicability assuring reliable prediction of the model in binary systems was studied. The significance of the simultaneous presence of SLS and β-CD on lamotrigine solubility was studied in binary solvent mixture.
Article
We investigated, using first principle calculations, the inclusion process of anticoagulant Warfarin (Warf) in two cavitand supramolecules: β-cyclodextrin (β-CD) and p-tert-butylcalix[4]arene (Calix). We considered all plausible cases of inclusion which differ by the moiety of Warf pointing to Head (H) or Tail (T) part of β-CD or to upper rim of Calix. ‘A’ and ‘B’ orientations correspond respectively to phenyl or chromone group entering first in the host cavity. The results obtained from PM3, ONIOM2 (B3LYP/6-31G(d):PM3) and ONIOM2 (WB97X-D/6-31G(d):PM3) for two partitioning models, B3LYP/6-31G(d) and 6-31 ++G(d,p) basis sets gave that ‘AH’ led to the optimum structure for Warf@β-CD, while the most favorable conformer is in ‘BH’ orientation for Warf@Calix complex. The obtained structures correspond to ‘Endo’ and ‘Exo’ complexes, respectively. The treatment of some host atoms with high level, additional to the guest in ONIOM2, do better estimate intermolecular interactions, especially hydrogen bonds in Warf@β-CD, which was not the case for Warf@Calix complex. Moreover, we determined Frontier Molecular Orbitals (FMO) from which we inferred global reactivity descriptors, which suggest the best stability of β-CD complex. Finally, we used two models to reach a deeper understanding of the type and magnitude of intermolecular interactions between guest and host molecules. The first is Natural Bond Orbital (NBO) analysis which quantifies the donor-acceptor interactions. The second known as Bader's Quantum Theory of Atom In Molecule (QTAIM) uses the topological analysis of the electron charge density. The two approaches led to similar results as far as forces stabilizing structures are concerned.
Article
The inclusion complex of ceftazidime (CF) with hydroxypropyl-γ-cyclodextrin (HP-γ-CD) was prepared. The inclusion behavior and interactions of CF with HP-γ-CD was carried out in both the solution and the solid state by UV/vis, FT-IR, NMR and molecular docking techniques. All the obtained information demonstrated the formation of CF-CD inclusion complex. The CF-CD inclusion complex exhibited different spectroscopic features and properties from CF. The results suggested that CF-CD inclusion complex was established with 1:1 stoichiometry. It was found that a part of CF molecule, the thiazole ring with sulfur and nitrogen atoms with C = O and C = N bands of CF was included in the HP-γ-CD cavity. Also the solubility and stability of CF-HP-γ-CD was significantly improved and consequently the bioavailability of CF through CF-CD inclusion complex was effectively improved over free CF. Based on the enhancement of absorbance of CF in the presence of HP-γ-CD a sensitive spectroscopic method for the CF determination was developed.
Article
Cyclodextrin (CD) is a subset of the macrocyclic structural class, which is an important class of small organic agents that are useful functional excipients. They have wide range application possibilities in different fields of sciences such as material preparation, medicine, analytical chemistry, and separation processes. They are used widely in pharmaceutical formulations and drug delivery for increasing the water solubility of low soluble drugs and drug candidates. Due to the ring structure, they behave differently than smaller molecules and may be capable of hitting new classes of targets. A macrocyclic molecule presents varied functionality and stereochemical complexity in a pre-organized conformation of the ring structure. This can result in high selectivity and affinity for protein targets while conserving enough bioavailability to arrive at intracellular locations. Regardless of these valuable features, and the verified success of several marketed macrocycle drugs isolated from natural compounds, this class has been little explored in drug development. This study describes some of the key features of the CDs therapeutic discovery. Also, the application of computational chemistry approaches such as QSAR/QSPR, molecular docking, and molecular/quantum mechanics for modeling of CD–drug system is reviewed briefly.
Article
Cyclic peptides, because of their unique spatial conformations, simplicity, and limited conformational freedom, are widely used as model molecules for larger peptides in chemistry and biochemistry. In this work, the ionization energies and photoelectron spectra of different conformers of the cyclic peptides (n = 2–15) were calculated using the symmetry-adapted cluster-configuration interaction (SAC-CI) method and D95 + (d,p) basis set in the gas phase. The calculated photoelectron spectra were used to study the electronic structures of the cyclic peptides. It was observed that the first ionization energy of the cyclic peptides decreases with the ring size, reaches a minimum, and then increases. In addition, the first ionization band of the cyclic peptides was assigned to the ionization of the lone electron pairs of the nitrogen atoms, although there are π electrons of the CO bond and the lone electron pairs of oxygen atoms in the structure of the peptides.
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The inclusion complex of β-cyclodextrin (β-CD) with benzoguanamine (BGA) has been investigated in three states. UV-Visible and fluorescence spectral techniques are used in liquid state. FTIR, NMR and MASS techniques are used in solid state and virtual state studies are done by molecular simulation work. The binding constants for the formation of 1:1 BGA:β-CD inclusion complex is estimated by UV-Visible and fluorescence spectral techniques. The chemosensory ability of BGA:β-CD complex was investigated thoroughly for various metal cations and we found the emission of complex showed a linear increase in the intensity for Ce4+ with the linearity range of 1000 μM-2000 μM. Sensitivity analysis shows good sensing for Ce4+ with the LOD of 671 μM and LOQ of 2034 μM. Our result suggests that the BGA:β-CD inclusion complex would be promising material for developing solid state sensory device for sensing Ce4+.
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Pluronics (tri-block copolymers) have a significant role in the pharmaceutical industry and are being used to enhance the solubility and delivery of hydrophobic drugs in different marketed formulations. However, instability and unsatisfactory drug-loading capacity are the major weak spots of these pluronic micelles. The present research work is designed to solve the existing issues by the solubilization study of hydrophobic drugs in different pluronic micelles at variable temperatures. The solubilization of the hydrophobic antiepileptic drug lamotrigine (LAM) in five different pluronic micelles viz. P84, P85, F127, F108, and F68 was studied at different temperatures, 37, 47, and 57 °C, using UV–visible spectroscopy. The solubilization of LAM in pluronic micelles increased with the increase in temperature. Small-angle neutron scattering (SANS) measurements were used to observe the morphological and structural changes taking place in pluronics by increasing the temperature. The SANS results showed the morphological changes of spherical P84 micelles to prolate ellipsoidal micelles at 57 °C due to remarkable increase in the aggregation number. This morphological conversion was further confirmed by the heat transfer method (HTM) and dynamic light scattering (DLS) measurements. DLS measurements confirmed that LAM-loaded micelles showed a greater hydrodynamic diameter (Dh) compared to unloaded micelles, assuring LAM solubilization in the pluronic micelles. The rate of controlled release of LAM from five different pluronic micelles was accessed by using different kinetic models to evaluate the in vitro release profile. This is the first report in which HTM measurements are established for the analysis of morphological changes in the thermoresponsive pluronic micelles in real time. The present work corroborates how we can control the drug-loading capacity, morphological structure of the drug carrier, as well as drug release by simply changing the temperature of pluronic micellar media.
Article
Isoeugenol is a natural dual antioxidant/prooxidant. In this research, the inclusion complex (IC) of isoeugenol with 2-hydroxypropyl-β-cyclodextrin (HPβCD) was prepared via the ultrasound (US) method. The US assisted isoeugenol/HPβCD-IC was investigated by various characterization techniques such as UV–Vis absorption, fluorescence, powder X-ray diffraction, Fourier transform infrared spectroscopy, thermal gravimetric analysis and differential scanning calorimetry. Absorption, fluorescence and infrared studies indicated that the alkyl chain of isoeugenol was deeply included in the HPβCD cavity. Through determinations of phase solubility and water solubility studies, significant enhancement of isoeugenol water solubility was confirmed after IC formation with the HPβCD. Thermal data proved that the IC formation significantly enhanced the thermal stability of isoeugenol. Antioxidant test results indicated that isoeugenol/HPβCD-IC exhibited better antioxidant activity than free isoeugenol due to its solubility enhancement. Furthermore, the isoeugenol/HPβCD-IC showed higher antibacterial activity of 96 ± 0.2% and 97 ± 0.5% against Staphylococcus aureus and Escherichia coli bacteria, respectively.
Article
Phthalyl sulfacetamide (PSA) is an antibiotic sulfonamide. In this study, inclusion complexes (ICs) of α- (αCD) and β-cyclodextrin (βCD) were prepared in aqueous solution and in solid state with PSA using the ultrasonication (US) process. The structural and thermal characteristics of the US-assisted ICs were investigated by UV–Vis absorption, fluorescence, Fourier transform infrared (FT-IR) spectroscopy, proton nuclear magnetic resonance (¹H NMR) spectroscopy, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and computational modeling techniques. The improved dissolution of PSA in the presence of CD was confirmed by UV–Vis absorption. The experimental and computational modeling studies proved that the stoichiometry of the ICs was 1:1 for PSA/CD-ICs. It was also observed that the IC formation between βCD and PSA was the strongest when compared to αCD host. The enhanced thermal stability of PSA was achieved for PSA/CD-ICs when compared to pure form of PSA. FT-IR, ¹H NMR and computational modeling studies indicated that biologically active sulfonamide group (ring-A) of PSA was encapsulated in the hydrophobic CD cavity. The stability of ICs in terms of energetic, thermodynamic and electronic properties was verified and the PSA/βCD-IC revealed higher stability compared to that of PSA/αCD-IC, as determined by PM3 method.
Article
Cyclic peptides are exciting novel hosts for chiral and molecular recognition. In this work, the inclusion complexes of cyclic decapeptide (CDP) with the 1-phenyl-1-propanol enantiomers (E-PP) are firstly studied using the density functional theory (DFT) B3LYP method. Our calculated results indicated that S(-)-1-phenyl-1-propanol (S-PP) could form a more stable inclusion complex with CDP than that of R(+)-1-phenyl-1-propanol (R-PP). The obvious differences in binding energy and thermodynamics data suggest that the cyclic decapeptide could differentiate the two enantiomers. Furthermore, molecular dynamics simulation results have supported the conclusions obtained by DFT. The current investigation shows that cyclic peptide is a desirable host molecule for chiral and molecular recognition.
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Naphthalene excited dimer (excimer) fluorescence is observed in the presence of ß- and ?-cyclodextrin (CD) at elevated naphthalene (NAP) concentrations (100 µM) but not at low NAP concentrations (5 µM). This is attributed to formation of 2:2 CD:NAP complexes in the former situation. Complexes of NAP with hydroxypropyl ß-CD are exclusively 1:1 and no excimer emission is observed. Complexes of NAP with a-CD do not show excimer emission either but the complex stoichiometry is 2:1 CD:NAP in this case. The formation constants for both the 1:1 and 2:2 ß-CD:NAP complexes have been determined and they have been found to depend on the ionic strength of the salting out agent NaCl. K1:1 = 377 ± 35 M-1 in the absence of salt and 657 ± 60 M-1 at 1 M NaCl. The corresponding values for K2:2 are (1.0 ± 0.2) × 104 and (4.0 ± 0.5) × 104 M-1, respectively. Stern-Volmer fluorescence quenching studies of the 1:1 and 2:2 species by water-based quenchers (NaI and CsBr) show that both types of complexes protect the fluorophore from the quencher. However, the more completely encapsulated NAP in the 2:2 complex is protected to a greater extent. This is also the case for the 2:2 ?-CD:NAP complex. This protective effect is reflected in the observed rate constants for NAP quenching. For example, kQ = 7.1 × 109 M-1 s-1 for NaI in the absence of CD. This is reduced to 2.1 × 109 M-1 s-1 for the 1:1 complex and 1.2 × 109 M-1 s-1 for the 2:2 complex when 10 mM ß-CD is present. A similar pattern is observed for CsBr as quencher. The 2:2 complexes are disrupted in the presence of additives such as linear alcohols and surfactants. The implications of these results for application of CDs for drug stabilization are discussed.
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 AM1 and PM3 modeling of β-hydroxyethyl ether and α-(1→4)-glucobiose indicated that PM3 is advantageous to AM1 in cyclodextrin (CD) chemistry. The conclusion was supported by direct structure optimization of α- and β-CD with AM1 and PM3, in which AM1 gave badly distorted geometries due to unreasonable hydrogen bonding, whereas PM3 reproduced the crystalline structures rather well. Ab initio calculation was for the first time performed on CD, demonstrating the feasibility of this method for future studies concerning CD chemistry. The results also provided valuable insights into the driving forces in CD molecular recognition.
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The complexation of terfenadine (Terf) with β-cyclodextrin (β-CD) in solution and solid state has been investigated by phase solubility diagram (PSD), differential scanning calorimetry (DSC), powder X-ray diffractometry (PXD) and proton nuclear magnetic resonance (1H-NMR). The PSD results indicated that the salt saturation with the buffer counter ion (citrate−2, H2PO4−1 and Cl−1 ions) of Terf (pK a=9.5) and the hydrophobic effect play in tandem to increase the value of the complex formation constant (K11) measured at different conditions of pH, ionic strength, buffer type and buffer concentration. The correlation of the free energy of complex formation (ΔG11) with the free energy of inherent solubility of Terf (ΔGSo) obtained by changing the pH, ionic strength and buffer concentration was used to measure the contribution of the hydrophobic effect (desolvation) to complex formation. The hydrophobic effect was found to constitute 57.8% of the driving force for complex stability, while other factors including specific interactions contribute −13.4kJ/mol. 1H-NMR spectra of Terf–citrate and Terf–HCl salts gave identical chemical shift displacements (ΔΔ) upon complexation, thus indicating that the counter anions are positioned somewhere outside of the β-CD cavity. DSC, XRPD and 1H-NMR proved the formation of solid Terf/acid/β-CD ternary complexes.
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To evaluate the usefulness of routine monitoring of serum lamotrigine concentration. Literature was accessed through MEDLINE (1990-January 2001). Key search terms included lamotrigine, pharmacokinetics, and epilepsy. A decision-making algorithm was used to evaluate the clinical evidence to support or refute the routine use of serum lamotrigine concentrations to adjust doses. The value of serum lamotrigine concentration monitoring remains controversial, primarily because clear relationships between concentration and pharmacologic response (either efficacy or toxicity) have not been demonstrated. Serum concentration monitoring of lamotrigine is not recommended as a tool for routine dose adjustment.
Article
This study involves initial Hartree-Fock and Density Functional theory calculations on the molecular recognition of the cyclodextrins. The α-cyclodextrin-acetophenone complexation system was investigated with PM3, HF/3-21G* and B3LYP/3-21G* methods. The results indicated that the inclusion orientation in which the acetyl group of the acetophenone points towards the secondary hydroxyls of the α-cyclodextrin was preferable in energy. The steric effect was supposed as the physical reason of such a behavior. Hence, the simple rule the anti-parallel arrangement of the dipoles of the host and guest molecules in the cyclodextrin complexation is not generally applicable.
Article
The ONIOM method was applied to the interaction of nevirapine with the HIV-1 reverse transcriptase binding site. The isolated complex of pyridine (part of nevirapine) and methyl phenol (part of Tyr181) was found at the MP2/6-31+G(d) level to have stacking interaction with 8.8 kcal/mol binding energy. Optimization of nevirapine and Tyr181 geometry in the pocket of 16 amino acid residues at the ONIOM3(MP2/6-31G(d):HF/3-21G:PM3) level gave the complex structure with weak hydrogen bonding but without stacking interaction. The binding energy of 8.9 kcal/mol comes almost entirely from the interaction of nevirapine with amino acid residues other than Tyr181.
Article
Equilibrium constants for the formation of inclusion compounds of 3-hydroxy-2-naphthoic acid with β-cyclodextrin were determined in aqueous solutions, in the absence and presence of buffers, by the steady-state fluorescence Benesi–Hildebrand method. Almost all the buffers that are usually used have been tested and they are found to have an influence on the formation constants. We suggest that buffers should not be used in aqueous solutions of cyclodextrins unless the experimental error is unacceptable. Furthermore, we obtained the inclusion compound formation constants (Ksalt) of β-CD with some buffer components by using a fluorescence competitive inhibition technique. NaClO4, KClO4, KCl, KHC8H4O4, KH2C6H5O7 and NaHC4H4O6 can form 1:1 inclusion complexes with β-cyclodextrin (Ksalt>0) while KF, K2SO4, NaH2PO4, NaAc, Na2HPO4 and NaHCO3 cannot (Ksalt<0).
Article
Brooker’s merocyanine (4-[(1-methyl-4(1H)-pyridinylidene)ethylidene]-2,5-cyclohexadien-1-one) is a dye molecule that has a unique photochemical/protolytic isomerization cycle. The cis to trans isomerization of the neutral molecule occurs only in one direction with the addition of photochemical energy. When the dye molecule is complexed with β-cyclodextrin, however, the isomerization occurs spontaneously without further energy required. To understand the difference between the native dye molecule and the complex, the molecular structures of the cis and trans isomers of Brooker’s merocyanine in β-cyclodextrin were optimized using the semi-empirical PM3 method as well as the hybrid ONIOM method which models the cyclodextrin at the PM3 level and the dye molecule using B3LYP/6-31g(d). The most stable complexes were similar in binding energy, although the molecular structures were quite different. The ONIOM optimized structures resulted in an increase in the planarity of the conjugated dye molecule when compared to the PM3 model. The trans isomer in the β-cyclodextrin cavity was also characterized experimentally using 1H-NMR complexation-induced shifts, and the results were found to be in good agreement with the proposed structure from the molecular modeling. Finally, the calculated thermodynamic properties of the trans isomer complex were compared to experimental results, and it became clear that water within the cavity must be included in the analysis to obtain accurate theoretical values.
Article
PM3 was applied to the complexation of α-cyclodextrin with benzaldehyde and acetophenone satisfactorily. The results, in agreement with the experimental observations, suggest that the orientation in which the substituent groups of the guest compounds located near the secondary hydroxyls of the α-cyclodextrin cavity was favorable in energy for both α-cyclodextrin–benzaldehyde and α-cyclodextrin–acetophenone complexes.
Article
Semi-empirical PM3 and density function theory B3LYP/3-21G* calculations in vacuo and in water were performed upon the inclusion complexation of β-cyclodextrin (CD) with 4,4′-benzidine and o-tolidine, respectively. The results obtained from both methods consistently indicate that the complex of β-CD·o-tolidine is more stable than that of β-CD·4,4′-benzidine energetically. The negative enthalpy changes calculated from the statistical thermodynamic calculation at 1 atm and 298.15 K suggest that both the inclusion complexation are favored enthalpy-driven processes. Compared with the complexation of 4,4′-benzidine with β-CD, the introduction of methyl-sidearm to o-tolidine undoubtedly strengthens van der Waals interactions between β-CD and o-tolidine, which is inferred from the more negative enthalpy change of the inclusion complexation of β-CD and o-tolidine.
Article
Molecular mechanics calculations were employed to study the inclusion of some 1,2,4-oxadiazol derivatives in β-cyclodextrin in vacuum and in the presence of water as a solvent using MM + force field. The driving forces for complexation in both environments are dominated by nonbonded van der Waals host–guest interactions with little electrostatic contribution. Among 1,2,4-oxadiazole derivatives investigated in this work, 3,3´-bis(1,2,4-oxadiazol-5(4H)-one) (H2OD) forms the least stable 1:1 complex and the stability increases as the chain length increases.
Article
The inclusion process of 2′-hydroxyl-5′-methoxyacetophone (Hma) with β-cyclodextrin (β-CD), as well as their other seven possible interaction types, was investigated theoretically. The data suggest that: (1) the inclusion complex formed by Hma entering into the cavity of β-CD from its wide side (the secondary hydroxyl group side) is more stable than that from its narrow side (the primary hydroxyl group side); (2) the formation of the inclusion complex is predicted to be an enthalpy-driven process in gas phase and an enthalpy–entropy co-driven process in aqueous solution, which is in accord with the experimental results; (3) other different interaction types between Hma and β-CD should be also possibly found experimentally due to their negative binding energy (ΔE) though their distributions differ greatly. At last, comparative study of the interactions of β-CD with Hma and its two isomers, paeonol (Pae) and acetovanillone (Ace), are investigated and their obvious differences in binding energy and enthalpy change suggest that the β-CD could identify the three isomers.
Article
The inclusion process involving β-cyclodextrin (β-CD) and quercetin has been investigated by using the PM3 quantum-mechanical semi-empirical method. In the β-CD quercetin inclusion complex, a large portion of the flavonoid skeleton is included in the β-CD cavity and the bond connected ring B with ring C is inclined to the molecular axis of β-CD. The orientation in which the B ring of the guest molecule located near the secondary hydroxyls of the β-CD cavity is preferred in energy. One intermolecular hydrogen bond is formed. The molecular modeling results are in agreement with the NMR observations and molecular dynamics (MD) simulations. The statistical thermodynamic calculations at 1 atm and 298.15 K by PM3 demonstrate that 1:1 quercetin/β-CD complex is favored by a negative enthalpy change.
Article
Studies of cyclodextrin chemistry by quantum chemical methods are briefly surveyed. Emphases are put on what types of quantum chemical methods can be used for cyclodextrin chemistry, how to use quantum chemical methods to find the global minimum, to study the structures, binding energies, driving forces for cyclodextrin complexes, as well as chemical reactions occurring inside cyclodextrin cavities. Problems associated with the application of quantum chemical methods in cyclodextrin chemistry are also discussed.
Article
The inclusion interaction between quercetin and β-cyclodextrin (β-CD) binding site has been investigated, based on PM3 and ONIOM2 methods. The obtained results clearly indicate that the orientation in which the B ring of the guest molecule located near the secondary hydroxyls of the β-CD cavity is preferred in the binding energy. Moreover, Analyses regarding the complex structures suggest that one hydrogen bond between 7-hydroxy group (OH) of quercetin and 6-OH of β-CD is formed. This hydrogen bond interaction plays an important role in the bound quercetin/β-CD complex.
Article
Lamotrigine (LMN) is an antiepileptic drug, with poor aqueous solubility, which might lead to erratic bioavailability. The objective of the present work was to improve the dissolution characteristics of the LMN using Hydroxy propyl β-cyclodextrin (HP β-CD), which might offer reliable bioavailability. The phase solubility profile was classified as A L -type, revealing 1:1 stoichiometric complexation, with a stability constant (Ks) of 573M−1. Binary systems of LMN and HP β-CD were prepared in different molar ratios (1:1, 1:2, 1:3 and 1:4) by kneading method. The binary systems were characterized by Fourier Transform Infrared (FT-IR) Spectroscopy, Differential Scanning Calorimetry (DSC) and Powder X-ray Diffraction Analysis (PXRD). Results revealed that in the kneaded products the entire drug was entrapped inside the HP β-CD cavity and reduction in drug crystallinity also took place, which may be responsible for improved dissolution characteristics as compared to that of the pure drug as depicted from the dissolution studies.
Article
Azobenzene derivatives in solution present thermal cis–trans isomerization through the double bond –NN–. Experimental results showed that β-cyclodextrin inhibited the isomerization process for some azoderivatives while others were not affected. As previous model studies on the inclusion complexation of cyclodextrins with various guests, offered significant insights into the non-covalent intermolecular interactions and theoretical calculations helped to illustrate the driving forces for the complexation, here we have undertaken a theoretical study of the entire process of the formation of 1:1 stoichiometry azobenzene/β-cyclodextrin structures, in order to contribute to the understanding and rationalization of the experimental results reported before. With this purpose, we first searched for a possible way of formation of each substituted azobenzene/β-cyclodextrin inclusion complex and then we have performed an analysis of the strain energy changes involved and we have also analyzed the interaction forces driving towards the different kinds of stable structures yielded by the calculation procedure.
Article
This article provides extensive comparisons for the MMFF94, MMFF94s, CFF95, CVFF, MSI CHARMm, AMBER*, OPLS*, MM2*, and MM3* force fields to experimental and high-quality ab initio data for conformational energies and to scaled ab initio data for hydrogen-bonded complexes. Some comparisons are also presented for CHARMM 22. The tests of conformational energies consisted of two sets of comparisons to experiment and one more extensive set of comparisons to relatively high-quality ab initio data. As in the derivation of MMFF94, scaled HF/6-31G* energies and geometries were used to assess the reasonableness of the calculated intermolecular interaction energies and geometries. The comparisons for intermolecular interactions appear to be the first broadly based comparisons to appear in the chemical literature. Taken together, the comparisons reveal that most of the force fields make sizable errors and frequently produce qualitatively incorrect results for both conformational and intermolecular-interaction energies. For example, three of the force fields produce individual errors in conformational energy of more than 10 kcal/mol, and four rate thiophene as a stronger hydrogen-bond acceptor than ammonia. Only MMFF94 and MMFF94s perform consistently well. Some MMFF deficiencies are apparent, however, particularly for conformational energies of halocyclohexanes. These deficiencies, and others recently found for condensed-phase simulations, will need to be addressed in any future reparameterization of MMFF. The quantum-chemical data used in this work have been placed on the Computational Chemistry List web site. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 730–748, 1999
Article
The IMOMM, IMOMO, and ONIOM methods have been proven to be powerful tools for the theoretical treatment of large molecular systems where different levels of theory are applied to different parts of a molecule. Within this framework we present a modified handling of the link atoms which are introduced to terminate the dangling bonds of the model system. Using this new scheme the definition of the combined energy gradient, the Hessian matrix, and the integration of higher derivatives of the energy with respect to nuclear coordinates and the electric field vector becomes straightforward. This allows for the first time the consistent combination of vibrational frequencies and the calculation of other molecular properties such as IR intensities, Raman intensities as well as dipole moments, polarizabilities, and hyperpolarizabilities. Test calculations for some typical as well as unusual examples and partitioning schemes are presented to demonstrate the power and limitations of the method and to provide guidelines for its applicability. Users of the method are strongly advised to test, calibrate and confirm for themselves the validity of the method combination and the model subsystem for the properties they want to calculate.
Article
Despite the remarkable thermochemical accuracy of Kohn–Sham density-functional theories with gradient corrections for exchange-correlation [see, for example, A. D. Becke, J. Chem. Phys. 96, 2155 (1992)], we believe that further improvements are unlikely unless exact-exchange information is considered. Arguments to support this view are presented, and a semiempirical exchange-correlation functional containing local-spin-density, gradient, and exact-exchange terms is tested on 56 atomization energies, 42 ionization potentials, 8 proton affinities, and 10 total atomic energies of first- and second-row systems. This functional performs significantly better than previous functionals with gradient corrections only, and fits experimental atomization energies with an impressively small average absolute deviation of 2.4 kcal/mol.
Article
We investigated the effects of K(+) and Na(+) ions on the formation of α-cyclodextrin complexes with ionized aromatic carboxylic acids. Using solution calorimetry and (1)H NMR, we performed the thermodynamic and structural investigation of α-cyclodextrin complex formation with benzoic and nicotinic acids in different aqueous solutions containing K(+) and Na(+) ions as well as in pure water. The experiments show that the addition of sodium ions to solution leads to a decrease in the binding constants of the carboxylic acids with α-cyclodextrin as compared to pure water and solutions containing potassium ions. From another side, the effect of potassium ions on the binding constants is insignificant as compared to pure water solution. We suggest that the selectivity of cation pairing with carboxylates is the origin of the difference between the effects of sodium and potassium ions on complex formation. The strong counterion pairing between the sodium cation and the carboxylate group shifts the equilibrium toward dissociation of the binding complexes. In turn, the weak counterion pairing between the potassium cation and the carboxylate group has no effect on the complex formation. We complemented the experiments with molecular modeling, which shows the molecular scale details of the formation of cation pairs with the carboxylate groups of the carboxylic acids. The fully atomistic molecular simulations show that sodium ions mainly form direct contact pairs with the carboxylate group. At the same time, potassium ions practically do not form direct contact pairs with the carboxylate groups and usually stay in the second solvation shell of carboxylate groups. That confirms our hypotheses that the selective formation of ion pairs is the main cause of the difference in the observed effects of sodium and potassium salts on the guest-host complex formation of α-cyclodextrin with aromatic carboxylic acids. We propose a molecular mechanism explaining the effects of salts, based on competition between the cations and α-cyclodextrin for binding with the ionized carboxylic acids.
Article
In lamotrigine [systematic name: 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine], C(9)H(7)Cl(2)N(5), (I), the asymmetric unit contains one lamotrigine base molecule. In lamotriginium chloride [systematic name: 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazin-2-ium chloride], C(9)H(8)Cl(2)N(5)(+).Cl(-), (II), the asymmetric unit contains one lamotriginium cation and one chloride anion, while in lamotriginium nitrate, C(9)H(8)Cl(2)N(5)(+).NO(3)(-), (III), the asymmetric unit contains two crystallographically independent lamotriginium cations and two nitrate anions. In all three structures, N-H...N hydrogen bonds form an R(2)(2)(8) dimer. In (I) and (II), hydrophilic layers are sandwiched between hydrophobic layers in the crystal packing. In all three structures, hydrogen bonds lead to the formation of a supramolecular hydrogen-bonded network. The significance of this study lies in its illustration of the differences between the supramolecular aggregation in the lamotrigine base and in its chloride and nitrate salts.
Article
The solid-state properties and dissolution behaviour of lamotrigine in its inclusion complex with beta-cyclodextrin (betaCD) and solid dispersions with polyvinylpyrrolidone K30 (PVP K30) and polyethyleneglycol 6000 were investigated. The phase solubility profile of lamotrigine with betaCD was classified as AL-type, indicating formation of a 1:1 stoichiometry inclusion complex, with a stability constant of 369.96+/-2.26 M(-1). Solvent evaporation and kneading methods were used to prepare solid dispersions and inclusion complexes, respectively. The interaction of lamotrigine with these hydrophilic carriers was evaluated by powder X-ray diffractometry, Fourier transform infrared spectroscopy and differential scanning calorimetry. These studies revealed that the drug was no longer present in crystalline state but was converted to an amorphous form. Among the binary systems tested, PVP K30 (1:5) showed greatest enhancement of the solubility and dissolution of lamotrigine.
Article
Lamotrigine is a chemically novel antiepileptic drug which has not been adequately assessed for its antineuralgic properties. It was used in a double-blind placebo controlled crossover trial in 14 patients with refractory trigeminal neuralgia. Patients continued to take a steady dose of carbamazepine or phenytoin throughout the trial over a 31-day period. Each arm of the trial lasted 2 weeks with an intervening 3-day washout period. The maintenance dose of lamotrigine was 400 mg. Lamotrigine was superior to placebo (P = 0.011) based on analysis of a composite efficacy index which compared the numbers of patients assigned greater efficacy on lamotrigine with those assigned greater efficacy on placebo. Efficacy for one treatment over another was determined according to a hierarchy of: (i) use of escape medication; (ii) total pain scores; or (iii) global evaluations. Eleven of the 13 patients eligible for inclusion in the composite efficacy index showed better efficacy on lamotrigine compared with placebo. Global evaluations further suggested that patients did better on lamotrigine than placebo (P = 0.025). The adverse reactions with both lamotrigine and placebo were predominantly dose-dependent effects on the central nervous system. A 14th patient withdrew from the study due to severe pain during the placebo arm of the trial. It would appear that lamotrigine has antineuralgic properties.
Article
Postherpetic neuralgia (PHN) is a syndrome of often intractable neuropathic pain following herpes zoster (shingles) that eludes effective treatment in many patients. To determine the efficacy and safety of the anticonvulsant drug gabapentin in reducing PHN pain. Multicenter, randomized, double-blind, placebo-controlled, parallel design, 8-week trial conducted from August 1996 through July 1997. Sixteen US outpatient clinical centers. A total of 229 subjects were randomized. A 4-week titration period to a maximum dosage of 3600 mg/d of gabapentin or matching placebo. Treatment was maintained for another 4 weeks at the maximum tolerated dose. Concomitant tricyclic antidepressants and/or narcotics were continued if therapy was stabilized prior to study entry and remained constant throughout the study. The primary efficacy measure was change in the average daily pain score based on an 11-point Likert scale (0, no pain; 10, worst possible pain) from baseline week to the final week of therapy. Secondary measures included average daily sleep scores, Short-Form McGill Pain Questionnaire (SF-MPQ), Subject Global Impression of Change and investigator-rated Clinical Global Impression of Change, Short Form-36 (SF-36) Quality of Life Questionnaire, and Profile of Mood States (POMS). Safety measures included the frequency and severity of adverse events. One hundred thirteen patients received gabapentin, and 89 (78.8%) completed the study; 116 received placebo, and 95 (81.9%) completed the study. By intent-to-treat analysis, subjects receiving gabapentin had a statistically significant reduction in average daily pain score from 6.3 to 4.2 points compared with a change from 6.5 to 6.0 points in subjects randomized to receive placebo (P<.001). Secondary measures of pain as well as changes in pain and sleep interference showed improvement with gabapentin (P<.001). Many measures within the SF-36 and POMS also significantly favored gabapentin (P< or =.01). Somnolence, dizziness, ataxia, peripheral edema, and infection were all more frequent in the gabapentin group, but withdrawals were comparable in the 2 groups (15 [13.3%] in the gabapentin group vs 11 [9.5%] in the placebo group). Gabapentin is effective in the treatment of pain and sleep interference associated with PHN. Mood and quality of life also improve with gabapentin therapy.
Article
A correlation-energy formula due to Colle and Salvetti [Theor. Chim. Acta 37, 329 (1975)], in which the correlation energy density is expressed in terms of the electron density and a Laplacian of the second-order Hartree-Fock density matrix, is restated as a formula involving the density and local kinetic-energy density. On insertion of gradient expansions for the local kinetic-energy density, density-functional formulas for the correlation energy and correlation potential are then obtained. Through numerical calculations on a number of atoms, positive ions, and molecules, of both open- and closed-shell type, it is demonstrated that these formulas, like the original Colle-Salvetti formulas, give correlation energies within a few percent.
Article
Background: Lamotrigine is an antiepileptic agent that has been shown to be an effective adjunctive treatment for refractory partial and generalized seizures. It is now licensed in more than 70 countries for this indication. There is very little published material about the effects of acute overdose with lamotrigine. Case report: We describe the findings in a patient following the deliberate ingestion of a large amount of lamotrigine (stated 4.5 g, absorbed estimated 2.9 g), in excess of that previously described in the literature. The main clinical features were ataxia and rotary nystagmus. Electrocardiogram was unremarkable. Peak measured concentration of lamotrigine was 35.8 mg/L and half-life 19.5 hours, suggesting linear kinetics in overdose.