Preparation and physicochemical characterization of carbamazepine (CBMZ): para-sulfonated calix[n]arene inclusion complexes

The formation of inclusion complexes with para-sulfonated calix[n]arene (PSC[n]A) was studied for carbamazepine (CBMZ), a poorly water soluble anticonvulsant drug. The effect of PSC[4]A and PSC[6]A on aqueous solubility of carbamazepine was studied extensively. The complete complexation of the drug was achieved after 48 h of shaking with PSC[n]A in water and evaporation of water to get solid complex. The interaction between PSC[n]A and CBMZ in solid state inclusion complexes was accomplished by aqueous phase solubility studies, HPLC, DSC, PXRD, FTIR, UV–Vis, and FT-Raman spectroscopy. The solubility of CBMZ increases as a function of PSC[n]A concentration. The results of the two phase solubility experiments are in good conformity to signify the formation of 1:1 (PSC[6]A:CBMZ) and 2:1 PSC[4]A:CBMZ complexes. The order of dissolution rate of CBMZ is inclusion complex > physical mixture > drug alone. The purpose of this study was to enhance solubility resulting in high dissolution rate and bioavailability of this essentially water insoluble drug.     

Host–guest interactions of 6-benzyladenine with normal and modified cucurbituril: 1H NMR,UV absorption spectroscopy and phase solubility methods

Guest–host inclusion complexes between 6-benzyladenine (6-BA), cucurbit[7]uril (Q[7]), symmetrical tetramethylcucurbit[6]uril (TMeQ[6]) and meta-hexamethyl-substituted cucurbit[6]uril (HMeQ[6]) in aqueous solution were investigated by ¹H NMR, UV absorption spectroscopy and phase solubility studies. The ¹H NMR spectra analysis revealed that the hosts selectively bound the phenyl moiety of the guests. Absorption spectroscopic analysis defined the stability of the host–guest inclusion complexes. A host:guest ratio of 1:1 was measured quantitatively as (5.63 ± 0.26) × 10⁴, (1.94 ± 0.17) × 10³ and (2.89 ± 0.23) × 10³ mol L^? 1 for the Q[7]-6-BA, TMeQ[6]-6-BA and HMeQ[6]-6-BA systems, respectively. Phase solubility diagrams were analysed through rigorous procedures to obtain estimates of the complex formation constants for Q[n]-6-BA complexation. The formation constants were (1.29 ± 0.24) × 10⁴ L mol^? 1 for Q[7]-6-BA, (3.20 ± 0.17) × 10³ L mol^? 1 for TMeQ[6]-6-BA and (3.52 ± 1.01) × 10³ L mol^? 1 for TMeQ[6]-6-BA. Furthermore, phase solubility studies showed that 6-BA solubility increased as a function of Q[7], TMeQ[6] and HMeQ[6] concentrations. The thermodynamic parameters of the complex formation were also determined. The formation of inclusion complexes between 6-BA and Q[7] was enthalpy controlled, suggesting that hydrophobic and van der Waals interactions were the main driving forces. Our results demonstrated that the complexation of 6-BA with Q[n] could be used to improve the solubility of 6-BA.     

Evaluation and solubility improvement of Carvedilol: PSC[n]arene inclusion complexes with acute oral toxicity studies

The aqua phobic molecules that are practically insoluble in aqueous media demonstrate a staggeringly slow intrinsic dissolution rate. In this work, we exemplify the utility of calixarenes as a tool to form inclusion complexes with Carvedilol (CDL). It is poorly water soluble drug. CDL is a Biopharmaceutical Classification System (BCS) Class II drug and it is a nonselective β-adrenegenic blocking agent with α1-blocking activity. It is mainly used in the management of hypertension. The maximum complexation of the drug was accomplished after 48?h of stirring with para sulphonato calix[4]arene (PSC[4]arene) and para sulphonato calix[6]arene (PSC[6]arene) in water and evaporation of water to acquire solid complexes. The study includes characterisation of both the complexes—physical mixtures of drug and PSC[4]arene and PSC[6]arenes by different methods like Fourier-transform infra red spectroscopy, differential scanning calorimetry and powder X-ray diffraction, proton nuclear magnetic resonance. This studies shows that there is electrostatic interaction between drug and PSC[n]arenes. The complexation was determined by phase solubility study. The prepared complexes exhibited improved in vitro dissolution profile and decreased in vivo acute oral toxicity compared to the pure drug.     

Host–guest system of 4-nerolidylcatechol in 2-hydroxypropyl-β-cyclodextrin: preparation, characterization and molecular modeling

The interaction of 4-nerolidylcatechol (4-NRC), a potent antioxidant agent, and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) was investigated by the solubility method using Fourier transform infrared (FTIR) methods in addition to UV–Vis, ¹H-nuclear magnetic resonance (NMR) spectroscopy and molecular modeling. The inclusion complexes were prepared using grinding, kneading and freeze-drying methods. According to phase solubility studies in water a B_S-type diagram was found, displaying a stoichiometry complexation of 2:1 (drug:host) and stability constant of 6494 ± 837 M^?1. Stoichiometry was established by the UV spectrophotometer using Job’s plot method and, also confirmed by molecular modeling. Data from ¹H-NMR, and FTIR, experiments also provided formation evidence of an inclusion complex between 4-NRC and HP-β-CD. 4-NRC complexation indeed led to higher drug solubility and stability which could probably be useful to improve its biological properties and make it available to oral administration and topical formulations.     

Characterisation and antiproliferative activity of irinotecan and sulphonatocalixarene inclusion complex

The interaction between water-soluble sulphonatocalix[4]arene (SC4A) and irinotecan (CPT-11) was investigated by using UV spectrophotometry. Inclusion complex of SC4A with CPT-11 was confirmed by ¹H NMR and DSC analysis. Water solubility study showed that SC4A has remarkable solubilisation on CPT-11 and the complex has good water solubility. The antiproliferative activity of the complex was evaluated. The results showed that the complexation of CPT-11 with SC4A increases the antiproliferative activity of CPT-11.     

Inclusion Interactions of Cucurbit[7]uril with Adenine and its Derivatives

Interactions of cucurbit[7]uril (Q[7] host) with guest adenine (g1), adenosine (g2) and 2′,3′-o-isopropylideneadenosine (g3) were studied in details by ¹H NMR, UV absorption spectroscopy, fluorescence spectroscopy and high performance liquid chromatography (HPLC) methods. We found that the suitable pH range for interaction was between 1 and 7, and the optimal pH range was between 2 and 4. The ¹H NMR analysis indicated that Q[7] selectively interacted with the adenine moiety of the guests g1 and g2, while Q[7] selectively interacted with the D-ribose sugar ring moiety of the guest g3. Moreover, ¹H NMR spectra showed that the exchange between the bound guest and the free guest was fast on the NMR time scale for the Q[7]-g1 and Q[7]-g2 systems. However, an obvious equilibrium between the bound host/guest and the unbound host/guest were observed in the Q[7]-g3 complex. Several methods were used to determine quantitatively the stability of the three host–guest inclusion complexes formed between Q[7] and the guests. The formation constants by UV and fluorescence were 1.90 × 10⁵ L mol^? 1 and 1.34 × 10⁵ L mol^? 1 for Q[7]-g1, 9.41 × 10⁴ L mol^? 1 and 4.24 × 10⁴ L mol^? 1 for Q[7]-g2, 4.50 × 10⁴ L mol^? 1 and 3.62 × 10⁴ L mol^? 1 for Q[7]-g3, respectively. HPLC method was also introduced to explore the interactions between Q[7] and the adenine and its derivatives. The formation constants of the host–guest inclusion complexes, as determined by HPLC, were 6.76 × 10⁴ L mol^? 1 for Q[7]-g1, 1.80 × 10⁴ L mol^? 1 for Q[7]-g2, 3.01 × 10⁴ L mol^? 1 for Q[7]-g3 respectively. Our study suggested that Q[7] could be a suitable host for the delivery of bioactive molecules, such as the adenine and its derivatives.     

Characterization of silk fibroin based films loaded with rutin–β-cyclodextrin inclusion complexes

In this study, cyclodextrin inclusion complexes with rutin were prepared via co-precipitation method. Stability constant and solubility energy of beta-cyclodextrin complex were calculated as 262 M^?1 and 1,737 kJ mol^?1, respectively. Aqueous solubility of rutin was increased with inclusion complex of beta-cyclodextrin. The effect of temperature on both aqueous solubility of free rutin, and its inclusion complex was also studied. Characterization of cyclodextrin complexes were conducted with UV–Vis spectrophotometry, Fourier transform infrared spectroscopy, X-ray diffractometry, differential scanning calorimetry, thermal gravimetric analysis, nuclear magnetic resonance spectroscopy and scanning electron microscopy techniques. Characterization results supported formation of inclusion complexes. Dissolution profiles of rutin, physical mixture and inclusion complex of rutin were observed at 37 °C. Dissolution results proved the effect of cyclodextrin addition on solubility rate of rutin. After loading rutin and its complexes into silk fibroin based films, release tests were performed at 37 °C in neutral pH conditions for 24 h. Most of the rutin were released from silk fibroin films within the first 5 h and the rest of it was released slowly (sustained release). Electron microscope analyses showed that films had homogenous and dense morphologies. These results revealed that silk fibroin is useful for preparing bioactive films loaded with natural compounds and for modifying their release behaviour at physiological conditions.     

Structural and thermodynamic aspects of complexation of a calix[4]resorcinarene with diverse cations in water-organic media

Solvation of a calix[4]resorcinarene and its anions in water-organic media of varying composition was characterized by solubility measurements, acid-base titration and X-ray structural analysis. Methanol, 2-propanol, and DMSO capable of developing calix[4]resorcinarene solvated complexes of varying structure and stability were used as the organic component. It was revealed that the influence of the organic component of water-organic solvents on the stability of guest-host complexes formed by some organic and complex cations with calix[4]resorcinarene anions depended on the structure of the complexes.     

Preparation and characterization of cyclodextrin inclusion complex of naringenin and critical comparison with phospholipid complexation for improving solubility and dissolution

Naringenin, a flavonoid specific to citrus fruits shows a variety of therapeutic effects like anti-inflammatory, anticarcinogenic, and antitumour effects. But it is associated with some limitations like poor water solubility, poor dissolution, lower half-life, and rapid clearance from the body. With the aim of improving amorphous nature, water solubility, and dissolution profile of naringenin and its complexes were prepared with β-cyclodextrin in three different molar ratios (1:1, 1:2, and 1:3) by solvent evaporation method. These complexes were characterized for solubility, drug content, chemical interaction (using FTIR), phase transition behavior (using DSC), crystallinity (using XRPD), surface morphology (using SEM), and in vitro dissolution study. The results were also critically compared with the results obtained from naringenin-phospholipid complexes (from author’s previous study). The prepared complexes showed high drug content (ranging from 69.53 to 84.38 %) and about two fold improvement in water solubility (from 41.81 to 76.31 μg mL^?1 in the complex with 1:3 ratio). SEM of the complexes showed irregular and rough surface morphology. FTIR, DSC, and XRPD data confirmed the formation of the complex. Unlike the free naringenin which showed a total of only 48.78 % drug release at the end of 60 min, the complex showed 98.0–100 % in dissolution study. Thus it was concluded that the β-cyclodextrin of naringenin may be of potential use for improving bioavailability of poorly soluble phytoconstituents/herbal drugs. On critical comparison with the phospholipid complex of naringenin both the techniques were found almost equally effective in improving the solubility and the dissolution performance of naringenin in the complex form.     

Determination of Tryptophan using a p-Sulfonated Calix [4,6,8]arene Modified Gold Electrode

The ability of p-sulfonated calix[n]arenes (n = 4, 6, 8) to form complexes with tryptophan was studied. The electrochemical properties of these complexes immobilized on gold surfaces were examined by cyclic voltammetry. Parameters affecting the performance of the modified electrodes including the arene concentration, scan rate, applied potential, and pH were optimized. Under the optimal conditions, the method had a linear response to tryptophan between 1 × 10^?7 M and 1 × 10^?5 M with a detection limit of 3 × 10^?8 M. The interaction of the tryptophan–p-sulfonated calix[4]arene complex was more stable than the tryptophan–p-sulfonated calix[6]arene and p-sulfonated calix[8]arene complexes. Molecular modeling calculations indicated that electrostatic interactions and structural matching effects were predominant stabilizing factors. The modified electrodes demonstrated good reproducibility and high selectivity, illustrating their effectiveness for analytical measurements.     

Preparation, characterization and pharmacodynamic activity of supramolecular and colloidal systems of rosuvastatin–cyclodextrin complexes

In the present study influence of nature of selected cyclodextrins (CDs) and of methods of preparation of drug–CD complexes on the oral bioavailability, in vitro dissolution studies and pharmacodynamic activity of a sparingly water soluble drug rosuvastatin (RVS) was investigated. Phase solubility studies were conducted to find the interaction of RVS with β-CD and its derivatives, which indicated the formation of 1:1 stoichiometric inclusion complex. The apparent stability constant (K_1:1) calculated from phase solubility diagram were in the rank order of β-CD < hydroxypropyl-β-cyclodextrin (HP-β-CD) < randomly methylated-β-cyclodextrin (RM-β-CD). Equimolar drug–CD solid complexes prepared by different methods were characterized by the Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffractometry (XRD). FTIR study demonstrated the presence of intermolecular hydrogen bonds and ordering of the molecule between RVS and CDs in inclusion complexes. DSC and XRD analysis confirmed formation of inclusion complex by freeze dried method with HP-β-CD and RM-β-CD. Aqueous solubility and dissolution studies indicated improved dissolution rates of prepared complexes in comparison with drug alone. Moreover, CD complexes demonstrated of significant improvement in reducing total cholesterol and triglycerides levels as compared to pure drug. However the in vivo results only partially agreed with those obtained from phase solubility studies.     

Supramolecular Detoxification of Colchicine through Electrochemical Recognition

The complex characteristics of p-sulfonated calix[n]arene and colchicine were examined using various techniques. Cyclic voltammetry indicated that the structural matching and electrostatic interactions were the dominant stabilizing factors for the host–guest complexes. The method showed a long linear voltammetric range for p-sulfonated calix[4]arene from 1?×?10^?8 to 1?×?10^?6?mol?L^?1 with a detection limit of 3?×?10^?9?mol?L^?1. Ultraviolet absorption spectroscopy confirmed that a 1:1 ratio complex was formed. Molecular mechanics showed that the benzene ring of colchicine entered the p-sulfonated calix[4]arene cavity. The solubility of colchicine increased with the p-sulfonated calix[4]arene concentration 50-fold from 0.13 to 6.4?mol?L^?1. The simulation of cell membrane permeability indicated that colchicine was released from the colchicine-p-sulfonated calix[4]arene complex and entered the hydrophobic micelles. These results show that p-sulfonated calix[4]arene is suitable as a drug carrier for colchicine. This work has expanded applications of drug loading, transport, and targeted release for the treatment of gout.     

Solid state characterization of the inclusion complex of valsartan with methyl β-cyclodextrin

In this work, we illustrate the usefulness of cyclodextrins, namely, methyl-β-cyclodextrin (MβCD), an amorphous, methylated derivative of the natural β-cyclodextrin, as a tool to form an inclusion complex with Valsartan (VAL), a poorly water soluble drug. The phase solubility study showed A_L type of curve with slope less than one indicating the formation of complexes in 1:1 molar ratio of drug and CD. The stability constant was found to be 538.14 ± 5.4 Mole^?1. Solid binary systems between VAL and MβCD were prepared experimentally in a stoichiometry 1:1 by different techniques (physical mixing, kneading, co-evaporation). Afterward these products were characterized by Fourier transform infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), Scanning electron microscopy (SEM) and ¹H Nuclear magnetic resonance study (¹H NMR). The results obtained suggested that co-evaporation methods yield a higher degree of amorphous entities suggesting the formation of inclusion complex between VAL and MβCD. The dissolution of VAL from the binary systems was studied to select the most appropriate system for the formulation development. It was concluded that the preparation technique played an important role in the dissolution behavior of the drug and the inclusion complex between VAL and MβCD obtained by co-evaporation method allowed better performance.     

Highly effective binding and inverse fluorescent behavior of palmatine and l-tetrahydropalmatine alkaloids by p-sulfonatocalixarenes

The effects of pressure and solvent were examined for the inclusion complexation of phenothiazine dyes and trans-4-[4-(dimethylamino)styryl]-1-methylpyridinium (St-4Me) with water-soluble p-sulfonatocalix[8]arene (Calix-S8). Depending on the bulkiness of the guest dyes, external pressures and solvent polarity increase the inclusion equilibrium constants of dyes with Calix-S8. From the pressure dependence of the inclusion equilibria, the reaction volumes for inclusion by Calix-S8 in the alcohol-water mixtures were estimated to be negative values (?19.8 to ?5.29 cm³ mol^?1 for the phenothiazine dyes and ?13.1 to ?9.85 cm³ mol^?1 for St-4Me). Analysis of the results of the high pressure indicated that the intrinsic volume change related to inclusion into the Calix-S8 cavity plays an important role in the inclusion of Calix-S8, depending on the bulkiness of the guest molecules. Based on ¹H NMR measurements, the structures of the inclusion complexes of Calix-S8 with phenothiazine dyes have been established and the differences in the inclusion behaviors of the phenothiazine dyes and St-4Me are discussed.     

Effect of external factors on the curcumin/2-hydroxypropyl-β-cyclodextrin: in vitro and in vivo study

The effect of 2-hydroxypropyl-β-cyclodextrin (HPβCD) on solubility, stability and oral bioavailability of curcumin by external factors adjustment, was investigated with an aim of a simple, stable and effective formulation. The phase solubility studies showed the solubility of curcumin increased slightly with increasing pH. However, the apparent stability constant (K _S) were found to decrease with increasing pH from 1.29?×?10⁴?M^?1 at pH 3.0 to 5.22?×?10³?M^?1 at pH 7.0. The thermodynamic parameters were calculated for inclusion complex formation in aqueous solution. Interestingly, it could be concluded that the degrees of curcumin stability improved by HPβCD grew with increasing drug–cyclodextrin binding ability. Furthermore, in vivo study not only revealed that the bioavailability of curcumin after oral administration to rats was significantly improved by curcumin/HPβCD inclusion complex, but also showed more dramatic changes in the plasma concentration–time curve (1752.76–866.70?ng?mL^?1?h) and the peak plasma concentration (370.10–178.11?ng?mL^?1) of drug by formation of complexes in pH 3–7 solution.     

Inclusion complexes of Schiff bases as phytogrowth inhibitors

This article details the preparation, characterization and phytotoxic evaluation of several Schiff base inclusion complexes obtained from β-cyclodextrin and p-sulfonic acid calix[6]arene. The inclusion complexes (1:1 molar ratio) were prepared by mixing a 5 mmol L^?1 aqueous solution (containing 1 % DMSO) of Schiff bases (guests) with aqueous solution (containing 1 % DMSO) of 5 mmol L^?1 of β-cyclodextrin or p-sulfonic acid calix[6]arene (hosts). The host–guest systems were characterized via a series of NMR experiments. The ability of the complexes to interfere with the radicle elongation of Sorghum bicolor (dicotyledonous species) and Cucumis sativus (monocotyledonous species) was evaluated. After 48 h, the inclusion complexes inhibited the radicle elongation of both species from 11 to 56 %. The formation of inclusion complexes was also investigated theoretically by molecular dynamics simulations in aqueous solution through implicit approach. Based on the experimental observation, the phytotoxic activity evaluated can be attributed to the formation of host–guest systems. This was supported by the theoretical findings based on stable interaction energy analyses for all the studied supramolecular systems.     

Characterization and cytotoxicity of a benzocaine inclusion complex

Benzocaine (BZC), is a local anesthetic widely used in topical formulations as well as in throat pastilles. A disadvantage is that the compound presents low aqueous solubility. The present work describes the preparation and characterization of an inclusion complex between BZC and β-cyclodextrin (β-CD), followed by cytotoxicity assays. The association constant (Ka) was calculated using solubility isotherms, at different temperatures, and an HPLC procedure, at room temperature, employing a reverse phase C18 column, with a mobile phase consisting of water/acetonitrile. Ka obtained with solubility isotherms at temperatures of 25, 35, and 45 °C were 229.8, 317.1, and 520.3 M^?1, respectively. Employing HPLC, Ka was 38.0 M^?1. The difference in the Ka value could be explained because HPLC analyses were conducted using organic solvent, which affected the host–guest interaction. Moreover, the continuous flow could have altered the degree of association of the drug with β-CD. The BZC/CD inclusion complex was characterized using infrared spectroscopy, thermogravimetry, and X-ray diffraction. Analysis showed a good agreement with literature, suggesting that the complex was established. Cytotoxicity assays using fibroblast V79 cells showed that BZC/CD formulation was not cytotoxic, demonstrating its potential to reduce the toxicity of the anesthetic. The assays demonstrated an effective interaction between BZC and CD, and that the inclusion complex was less toxic to V79 cells than the plain BZC, turning it a good alternative to decrease its toxicity when administered to patients.     

Structure and dynamics of tetrakis(thiophosphinato)resorcinarene complexes of silver(I), gold(I), and palladium(II)

The coordination chemistry of the tetrakis(thiophosphinato)resorcinarene sulfur-donor ligands [(C6H2CH{CH2CH2Ph})4{OC(O)R}4{OP(=S)Ph2}4] (L), where R = OCH2Ph, 4-C6H4CH3, C6H11, C4H3S, or OCH2CCH, is reported. Both silver(I) and gold(I) form cationic complexes of the type [LM2]2+, in which the ligand acts as a bis(chelate) in forming complexes with linear S-M-S (M = Ag or Au) stereochemistry. Gold(I) also forms the unusual complex [L(AuCl)2][LAu2]2+, which forms a supramolecular polymer through intermolecular aurophilic attractions. Palladium(II) forms the complex [LPd2Cl2(mu-Cl)2], in which the dipalladium(II) unit extends the natural bowl structure of the resorcinarene. The solid-state and solution conformations of the complexes, as determined by X-ray structure determination and NMR spectroscopy, respectively, are similar, but several complexes were found to exhibit dynamic behavior in solution, involving either conformational mobility of the resorcinarene unit or intermolecular ligand exchange.     

Improvement of opipramol base solubility by complexation with β-cyclodextrin

Opipramol (OPI), a tricyclic antidepressant and anxiolytic compound, is administered orally in the form of a dihydrochloride. Salt form of the drug has a higher solubility in water and hence bioavailability and stability. A similar effect can be achieved by closing the hydrophobic part of the drug molecule in the cyclodextrin cavity. The paper presents opipramol inclusion complexes with beta-cyclodextrin (β-CD) in 1:1 molar ratio. Studies on the formation of inclusion complexes were carried out both in solution and in the solid state. The formation and physicochemical characterisation of the complexes were determined by UV spectroscopic measurement (UV–vis), Fourier Transform Infrared (FTIR) Spectroscopy, ¹H Nuclear Magnetic Resonance (¹H NMR, 2D NOESY NMR), thermoanalytical methods (TGA – Termogravimetric analysis, DSC – differential scanning calorimetry), X-ray diffractometry (XRD) and scanning electron microscopy (SEM). The phase solubility profile with β-CD was classified as the A_N- type, indicating the formation of the inclusion complex with a drug.     

Solubility and Kinetic Release Studies of Naproxen and Ibuprofen in Soluble Epichlorohydrin-β-cyclodextrin Polymer

Naproxen (NAP) and ibuprofen (IBU) are poor water soluble anti-inflammatory drugs. A water-soluble epichlorohydrin-β-cyclodextrin polymer (β-CDEPI) was synthesized in a highly basic aqueous solution and at a molar ratio β-CD/EPI of 1:12. Drug solubility and kinetic release of NAP and IBU from the inclusion complexes they form with β-CDEPI as host was studied. Water solubility for both drugs in the presence of this polymer increased (NAP 0.28 mmol and IBU 0.40 mmol per gram of β-CDEPI). The apparent inclusion constants for both drugs in β-CDEPI were calculated from the solubility-phase diagrams with K_incl values of 4300 ± 100 L.mol^? 1 for NAP and 5100 ± 300 L.mol^? 1 for IBU. Kinetic release of Ibuprofen gave a pure Fick trend (t^1/2) behavior. However, for Naproxen a zero order was obtained (t). These results indicate that the nature and bulkiness of the drugs are ruling these kinetic behaviors in the environment of a highly branched polymer.