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.     

Bioactive permethrin/beta-cyclodextrin inclusion complex

Permethrin is popularly used in a variety of therapeutic areas. However, the poor water solubility of permethrin seriously limits its wider clinical applications. The present study demonstrates that solubility of permethrin in aqueous solution can considerably increase in the presence of beta-cyclodextrin (beta-CD). Extensive experimental data along with computational modeling reveal the formation of stable permethrin/beta-CD inclusion complexes, including permethrin(beta-CD) and permethrin(beta-CD)2, through hydrophobic binding. Both permethrin(beta-CD) and permethrin(beta-CD)2 complexes coexisted in aqueous solution, and the ratio of the concentration of permethrin(beta-CD) complex to that of permethrin(beta-CD)2 complex was dependent on the concentration of beta-CD. The complexation of permethrin with beta-CD significantly improved the bioavailability of permethrin and, therefore, increased the bioactivity. The significant increase of the bioactivity of permethrin in the presence of beta-CD provides an effective approach to improve the practical use of permethrin in public health and agriculture.     

Rapamycin-cyclodextrin complexation: improved solubility and dissolution rate

The objective of this study was to improve poor aqueous solubility and dissolution properties of anticancer drug rapamycin through formation of inclusion complexes with natural and modified cyclodextrins. Of the cyclodextrins tested, ??-cyclodextrin and hydroxypropyl-??-cyclodextrin did not complex with rapamycin. However, complexes of rapamycin with ??-cyclodextrin, methyl-??-cyclodextrin and hydroxypropyl-??-cyclodextrin were prepared and characterized by techniques such as Fourier Transform infrared spectroscopy, differential scanning calorimetry, phase solubility analysis and in vitro dissolution studies. According to the characterization data for the complexes, rapamycin water solubility was highly enhanced by all three ??-cyclodextrins with methyl-??-cyclodextrin complex resulting in particularly higher solubility enhancement. FTIR spectra and DSC thermograms supported the formation of inclusion complexes. The complexes showed highly improved dissolution rate in water. Complexation with cyclodextrin derivatives such as methyl-??-cyclodextrin and hydroxypropyl-??-cyclodextrin can provide promising alternatives for the formulation of rapamycin.     

The terfenadine/β-cyclodextrin inclusion complex

Journal of Inclusion Phenomena and Macrocyclic Chemistry - Terfenatine (TFN) is a very hydrophobic antiallergic drug. It exists in three polymorphic and two solvated forms and is practically...     

Study of benznidazole–cyclodextrin inclusion complexes, cytotoxicity and trypanocidal activity

The current chemotherapy for Chagas disease is still based on benznidazole, which has low solubility, but complexation with cyclodextrins provides a way of increasing the solubility. The objective of this work was to characterize the inclusion complexes formed between benznidazole (BNZ) and randomly 2-methyled-β-cyclodextrin (RM-β-CD) in aqueous solution and study cytotoxicity and trypanocidal. BNZ:RM-β-CD solution complex systems were prepared and characterized using the phase solubility diagram, nuclear magnetic resonance and a photostability assays, also to investigate the in vitro trypanocidal activity with epimastigote forms of Trypanossoma cruzi and the study of cytotoxicity against mammal cells. The phase-solubility diagram displayed an A _L-type feature, providing evidence of the formation of soluble inclusion complexes. The continuous variation method showed the existence of a complex with 1:1 stoichiometry. Toxicity assays demonstrated that inclusion complexes were able to reduce the toxic effects caused by benznidazole alone and that this did not interfere with the trypanocidal activity of the benznidazole. The use of inclusion complexes benznidazole:cyclodextrin is thus a promising alternative for the development of a safe and stable liquid formulation and a new option for the treatment of Chagas disease.     

A facile approach to construct hyaluronic acid shielding polyplexes with improved stability and reduced cytotoxicity

A facile approach for polymer gene carriers was used to construct hyaluronic acid (HA) shielding polyplexes due to the electrostatic interaction. By adding HA to PEI/DNA complexes, the ξ-potential of ternary polyplexes was changed from positive to negative. Spherical particles with diameter about 250nm were observed. Ethidium bromide exclusion assay indicated that the electrostatic complexation was loosened after addition of HA. However, DNA disassembly did not occur. The proper reason was that the intensity of negative charges was not strong enough to release DNA from the complexes in our experiment. The stability of PEI/DNA/HA polyplexes in physiological condition was improved and the cytotoxicity was reduced. Comparing with PEI/DNA polyplexes, the uptake and transfection efficiency of HA shielding polyplexes was lower for HEK293T cells probably due to the reduced adsorptive endocytosis, whereas it was higher for HepG2 cells due to HA receptor mediated endocytosis. This facile approach to constructing HA shielding polyplexes might have great potential application in non-viral gene delivery research and tumor therapy.     

Analysis of the phase solubility diagram of a phenacetin/competitor/beta-cyclodextrin ternary system, involving competitive inclusion complexation

The competitive inclusion complexations in the ternary phenacetin/competitors/beta-cyclodextrin (beta-CyD) systems were investigated by the solubility method, where m-bromobenzoic acid (m-BBA) and o-toluic acid (o-TA) were used as competitors. The solubility changes of the drug and competitors as a function of beta-CyD concentration in the ternary systems were formulated using their stability constants and intrinsic solubilities. The decrease in solubility of phenacetin by the addition of competitors could be quantitatively simulated by the formulation, when both drug and competitor give A(L) type solubility diagrams. On the other hand, when one of the guests gives a B(S) type solubility diagram, its solubility change was clearly reflected in that of the another guest, i.e., phenacetin gave an A(L) type solubility diagram in the binary phenacetin/beta-CyD system and o-TA gave a B(S) type diagram in the binary o-TA/beta-CyD system, but in the ternary phenacetin/o-TA/beta-CyD system, a new plateau region appeared in the original A(L) type diagram of phenacetin. This was explained by the solubilization theory of Higuchi and Connors. The solubility analysis of the ternary drug/competitor/CyD systems may be particularly useful for determination of the stability constant of a drug whose physicochemical and spectroscopic analyses are difficult, because they can be calculated by monitoring the solubility change of a competitor, without monitoring that of a drug. Furthermore, the present results suggest that attention should be paid to the type of the phase solubility diagram, as well as the magnitude of the stability constant and the solubility of the complex, for a rational formulation design of CyD 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.     

Heat-resistant, pyridine-based polyamides containing ether and ester units with improved solubility

<正>A diamine containing ether and ester units,as basic monomer for the preparation of polyamides,was prepared via three consecutive reactions.Nucleophilic substitution reaction of 1,4-dihydroxy benzene with 4-nitrobenzoyl chloride produced 4-hydroxyphenyl 4-nitrobenzoate(HPNB).Reduction of nitro groups to amino groups using Fe and HC1 resulted in preparation of 4-hydroxyphenyl 4-aminobenzoate(HPAB).The diamine was synthesized through nucleophilic substitution reaction of HPAB with 2,6-dichloropyridine The precursors and diamine were fully characterized by common methods,and the diamine was polycondensed with different diacid chlorides in the presence of an acid scavenger to prepare new polyamides.The polyamides were characterized,and their physical properties including thermal stability and behavior, inherent viscosity and solubility were studied.     

Novel cardo polyamides with high solubility,thermally stability,and flame retardancy

Abstract

A new monomeric building block was prepared via three consecutive reactions. 4-(4-Nitrobenzyl)pyridine was catalytically reduced to 4-(4-aminobenzyl)pyridine by converting the nitro to amino group. In second step, the later compound was reacted with 3,5-dinitrobenzoyl chloride to obtain a dinitro compound which finally was converted to a new diamine by reduction of nitro groups. Polycondensation reactions of the diamine with diacidchlorides led to preparation of novel cardo polyamides with high thermal stability and flame retardancy, as well as improved solubility. The structure-property relations were studied by varying the diacidchlorides to investigate the effect of symmetry and aromaticity on the polymers.     

Precipitation and complex solubility of zirconium sulfate

Summary The solubility boundaries of systems obtained by mixing aqueous zirconium nitrate solutions with solutions of lithium-, potassium-, or magnesium-sulfate were determined as a function of p_H. Distinct complex solubility ranges have been established in the excess of zirconium and sulfate salts, respectively.

---

Zusammenfassung Die L?slichkeitsgrenzen von Zirkoniumsulfat wurden in Abh?ngigkeit von p_H tyndallometrisch bestimmt. Das Zirkoniumsulfat wurde durch F?llung von w?sserigen Zirkoniumnitrat-L?sungen mit Lithium-, Kaliumoder Magnesiumsulfat-L?sungen dargestellt. Im überschu? von Zirkonium- oder Sulfatsalzen wurde eine ausgepr?gte Komplexbildung beobachtet.

---

---

Supported by the U.S. Army Research Office (Durham), Grant No. DA-ARO(D)-31-124-G-656.     

Chitosan/carboxymethyl cashew gum polyelectrolyte complex: synthesis and thermal stability

Chitosan/carboxymethyl cashew gum polyelectrolyte complexes were synthesized using different proportions of chitosan (CH) and carboxymethyl cashew gum (CMCG). The optimum CH:CMCG ratio was 25:75, which produced highest product yield. Polyelectrolyte (PEC) samples were characterized by thermogravimetric analysis and FT-IR spectroscopy. Parameters such as initial and maximal degradation temperatures and activation energy (E_a) were determined. Activation energies follows the order CMCG > CH > PECs samples. Infrared analysis from residual products after heating at 280 °C in different times indicated that cleavage of the glycosidic bond and formation of unsaturated products occurred.     

Cyclodextrin inclusion of four phenylurea herbicides: determination of complex stoichiometries and stability constants using solution 1H NMR spectroscopy

An inclusion complex formation between α- and β-cyclodextrin and four phenylurea analogues, namely metobromuron, monolinuron, monuron and fenuron, is reported. Complex formation was established using solution ¹H NMR spectroscopy. Complex stoichiometries were determined by the method of continuous variation using the chemically induced shifts of both the host and guest protons. An analysis of the spectroscopic data revealed the stoichiometry as 1:1 in all cases while a further analysis of the same data yielded values for the association constant K ranging from 208 to 2749 M^? 1. From the observed chemical shifts it was deduced that in all cases, only the guest aromatic ring enters the host cavities, the substituted urea moiety protruding from the secondary rim in the case of α-cyclodextrin, but from the primary rim in the case of β-cyclodextrin.     

Sertaconazole-HPβCD-pluronic F127 solid inclusion complexes: characterization and effect on drug solubility

The influence of Pluronic^® F127 (PF127) on hydroxypropyl-β-cyclodextrin (HP-βCD) complexation in solid state with sertaconazole, a highly active but poorly soluble antifungal drug, and its repercussion on drug solubilization and release rate were evaluated. Solid ternary systems comprising sertaconazole: HP-βCD:PF127 were obtained by (i) kneading of blends wetted with methanol:phosphate buffer; (ii) freeze-drying of filtered suspensions; and (iii) cast of films of filtered suspensions in an oven at 37°C. Two levels of PF127 concentrations were evaluated, one below (0.1%) and other above (5%) the critical micellar concentration (CMC). Physical mixtures were used as references. Differential scanning calorimetry, Raman spectroscopy and X-ray difractometry showed that PF127 did not significantly interfere in the complexation process, as confirmed by the total amount of sertaconazole nitrate (SN) dissolved. Nevertheless, the presence of 5% PF127 significantly delayed the release owing to its ability to form a gel layer. These ternary systems are potentially useful to combine drug solubilization ability with control of drug release.     

Angiotensin converting enzyme inhibitors/cyclodextrin inclusion complexes: solution and solid-state characterizations and their thermal stability

Angiotensin converting enzyme (ACE) inhibitors have recently gained attention as a new class of drug in the therapeutic management of glaucoma. However, the application of eye drops is limited because of their chemical instability in aqueous solutions. To overcome such a problem, cyclodextrins (CDs) were introduced to form inclusion complexes. Three ACE inhibitors, namely, captopril, quinapril and fosinopril (FOS), were chosen and the effect of CDs on their thermal stability in aqueous solutions was investigated. All three drugs formed inclusion complexes of 1:1 stoichiometry with all three natural CDs and the FOS/γCD inclusion complex possessed the highest stability constant, resulting in thermal stability enhancement. Furthermore, the addition of antioxidants could greatly enhance the thermal stability of FOS in the presence of γCD in aqueous solutions. The inclusion complex formation of FOS/γCD was further examined by computational and experimental characterizations. All these characterization results confirmed that FOS and γCD formed a true inclusion complex that provided drug stabilization in the aqueous eye drop medium.

     

Photophysics of 4-(N,N-dimethylamino)cinnamaldehyde/ alpha-cyclodextrin inclusion complex.

This paper reports the probing of alpha-cyclodextrin (alpha-CD) cavities with the help of dual emission properties of 4-N,N dimethylamino cinnamaldehyde (DMACA) in aqueous solution. An interesting feature could be observed that due to 1:1 complexation DMACA is encapsulated within alpha-CD in two distinctly different types of orientation as revealed from the relative positions and the intensity of locally excited state localized within donor and acceptor subunits (LE) and twisted intramolecular charge transfer (TICT) bands. In one situation the dimethylamino group is directed towards the larger rim of the cavity and in other the orientation is just the opposite. The different types of complexes were found to be excited selectively in different wavelength regions.     

Characterization of lidocaine:hydroxypropyl-β-cyclodextrin inclusion complex

An inclusion complex was prepared between the local anesthetic lidocaine (LDC) and hydroxypropyl-β-CD (HP-β-CD). The complex was characterized by thermal analysis (differential scanning calorimetry, DSC), UV absorption and high-pressure liquid chromatography (HPLC). DSC results were indicative of complexation, due to the loss of the characteristic endothermic peak of LDC (77 °C). Phase-solubility diagrams allowed the determination of the association constant between LDC and HP-β-CD (35.7 ± 4.7 M⁻¹). The rate of LDC release decreased after complexation and thermodynamic parameters from the HPLC studies (ΔG° = −2.65 kJ/mol) revealed that a stable complex was formed.     

Study on structure and characterization of inclusion complex of gossypol/beta cyclodextrin

The inclusion complex of beta-cyclodextrin with gossypol was synthesized by using a convenient method of microwave irradiation. The structure of the complex was determined by 1H NMR, IR spectroscopy, and as well as the elemental analysis; the thermal stability was studied by means of differential thermal analysis (DTA) and thermogravimetric analysis (TGA). The association constant between gossypol and beta-cyclodextrin measured via UV spectroscopy was 4462M(-1) at room temperature, following stoichiometry 1:2.