Interactions In Inclusion Complexes Research Articles

Inclusion Complexes Between β‐cyclodextrin and the Anticancer Drug 5‐Fluorouracil for its Solubilization: a Molecular Dynamics Study at Different Stoichiometries

AbstractCyclodextrins (CDs) are natural macrocyclic oligosaccharides able to solubilize hydrophobic drugs in water improving their bioavailability, thanks to favorable noncovalent interactions particularly in their hydrophobic cavity. Using a simulation protocol proposed in previous work, in this theoretical study based on Molecular Mechanics (MM) and Molecular Dynamics (MD) methods, inclusion complexes between β‐cyclodextrin and 5‐Fluorouracil (5‐FU) are investigated. 5‐FU is an anticancer drug hardly soluble in water used for more than 50 years. This drug is mainly administered by intravenous injection for the treatment of inner cancers or as a cream in the case of skin‐related cancers. For drug delivery applications, it is important to characterize stable inclusion complexes at different drug concentrations in order to enhance the anticancer activity by maintaining lower dose, thus reducing cytotoxic effects on the normal cells, causing several negative impacts in the course of treatment. In this work, the structure and stability of the host–guest complexes β‐CD:5‐FU in a 1:1 and 1:2 stoichiometries are investigated because this drug is relatively small compared to the size of the hydrophobic β‐CD cavity. The 5‐FU complexes with CDs allow its solubilization, thanks to favorable van der Waals interactions. Interestingly, these intermolecular interactions in inclusion complexes may also affect the release profile. MD simulations are a powerful tool to evaluate interactions between hydrophobic anticancer drugs and hydrophilic carriers with an inner hydrophobic cavity such as CDs and oligosaccharides in general.

A Piroxicam Inclusion Complexation for Solubility Enhancement: Design and Development

Published on:June 2022 Journal of Young Pharmacists, 2022; 14(2):192-197 Original Article | doi:10.5530/jyp.2022.14.36 Authors: Saravanakumar Kasimbedu1,*, Shilpaja Chella1, Bharathi T1, Nagaveni Pommala2, Durga Srinivasa Rao Mannepalli3 1Department of Pharmaceutics, Sree Vidyanikethan College of Pharmacy, Sree Sainath Nagar, Tirupati, Andhra Pradesh, INDIA. 2Department of Pharmaceutics, S.V.U. College of Pharmaceutical Sciences, S.V. University, Tirupati, Andhra Pradesh, INDIA.3Department of Pharmaceutics, Jagan’s Institute of Pharmaceutical Sciences, Muthukur, SPSR Nellore, Andhra Pradesh, INDIA. Abstract: Background: Over last few years, the physical and chemical characteristics of inclusion complexes have generated a lot of attention. One of the most important reasons for this is the significance of enzyme-substrate and drug-receptor interactions in inclusion complexes. Materials and Methods:The aim of the study was to design Piroxicam’s inclusion complexation, to improve its solubility by the reduction of particle size which leads to improve the particle surface area thereby increases the wettability of the mixture. Physical mixture, co-grinded mixture, kneading and solvent evaporation method were used to prepare the inclusion complexation of Piroxicam with β-cyclodextrin at 1:0.5, 1:1, and 1:2 w/w (Piroxicam/β-cyclodextrin) ratios. Results: Differential scanning calorimetry, Fourier-transform infrared and X-ray diffraction and scanning electron microscopy studies were used to investigate the interaction of Piroxicam with β-cyclodextrin. From scanning electron microscopic studies, it was observed that crystalline were formed as spherical in shape with rough surface, small piece and Pure Piroxicam in crystalline form with rough surfaces. From Scanning electron microscopic studies, it was observed that amorphous were formed as spherical in shape with smooth surface, wide piece and β-Cyclodextrine in amorphous form with rough surfaces. Conclusion: The inclusion complexations of Piroxicam with β-cyclodextrin exhibited higher saturation solubility and dissolution rate than that of the pure drug of Piroxicam. Formulation K2 showed more drug release rate by reducing the particle size with complexation technique like kneading technique.Keywords: Co-grinded mixture, Inclusion Complexation, Kneading, Wetting Property, Particle Shap

Redox-responsive poly(ionic liquid) microgels explored as the building blocks for supramolecular assembly

In this study, poly(ionic liquid) (PIL) microgel functionalized by ferrocene (Fc) was fabricated via a facile one-step cross-linking copolymerization in selective solvent. The results demonstrated that the sizes of PIL microgels could be well-tuned through the feeding ratio of IL monomers to the cross-linker. The presence of Fc groups in PIL microgel was confirmed through ultraviolet–visible (UV–vis), inductively coupled plasma optical emission spectrometer (ICP-OES) and Fourier transform infrared (FT-IR) measurements, as well as cyclic voltammetry (CV) technique. In addition, Fc-anchored PIL microgels were found to be electrochemically active and could respond reversibly to the redox stimulus. As a prototype application, Fc-anchored PIL microgels were explored as the building blocks for the supramolecular self-assembly. Through the host-guest inclusion complexation interaction of Fc group with β-cyclodextrin (β-CD) dimer, PIL microgels could undergo a reversible association and dissociation. Importantly, an enhanced peak current could be achieved when PIL microgel-supported Fc groups were complexed with β-CD dimer. The founding thus pave a way toward fabricating supramolecular systems using nanoparticles as the building blocks, which will find wide applications in smart material, drug delivery and electrochemistry.

Dual Stimuli-Responsive Supramolecular Self-Assemblies Based on the Host-Guest Interaction between β-Cyclodextrin and Azobenzene for Cellular Drug Release.

Health has always been a hot topic of concern, whereas cancer is one of the largest security risks to human health. Although the existing drug delivery systems (DDSs) have been extensively reported and commercially applied, there are still some issues that have yet to be well-resolved, including the toxicity, side-effects, and targeted therapy efficiency of drugs. Consequently, it is still necessary to develop a novel, highly efficient, controlled and targeted DDS for cancer therapy. For this, a supramolecular polymer, β-CD-g-PDMAEMA@Azo-PCL, was designed and developed through the host-guest inclusion complexation interactions between a host polymer, β-cyclodextrin-graft-poly(2-(dimethylamino)ethyl methacrylate) (β-CD-g-PDMAEMA), and a guest polymer, azobenzene modified poly(ε-caprolactone) (Azo-PCL), and was characterized by various analysis techniques. The supramolecular assembly was examined in various pH environments and/or under UV-vis irradiation, showing the formation of supramolecular assemblies from regular spherical shapes to irregular aggregates with various hydrodynamic diameters. The 2D NOESY NMR studies showed the formation of inclusion complexation between Azo-PCL and β-CD-g-PDMAEMA and between β-CD and the side groups of PDMAEMA. The supramolecular assemblies could encapsulate doxorubicin to form spherical core-shell drug-carrying micelles with an entrapment efficiency of 66.1%. The effects of external environment stimuli on the in vitro drug release were investigated, showing light- and pH-modulated drug release properties. The cytotoxicity assessment indicated that the blank supramolecular micelles were nontoxic, whereas the drug-loaded micelles exhibited comparable or even superior anticancer activity to the anticancer activity of free DOX and inhibition of cancer cell proliferation. Therefore, the developed supramolecular assemblies can potentially be used as drug-controlled release carriers.

Quantitative and qualitative analyses of intermolecular interactions in neutral/deprotonated aspirin@β-CD inclusion complexes: QTAIM and NBO analyses

Most of the researches in supramolecular chemistry area are focused on the conventional hydrogen bonds without taking into account unconventional intermolecular interactions. The nature and strength of the conventional and unconventional interactions in inclusion complexes formed between neutral aspirin (ASA) and its deprotonated form (ASA−) with β-cyclodextrin (β-CD) have been studied. It was conducted through combining atoms in molecules (AIM) theoretical criteria suggested by Koch and Popelier and natural bond orbital (NBO) analyses by means of dispersion-corrected density functional theory (DFT-D3) with the functional B3LYP using cc-pvdz basis set in the gas phase. We have found five intermolecular closed-shell interaction groups responsible for neutral ASA:β-CD and deprotonated ASA−:β-CD inclusion complexes stability: One is conventional O–H···O bond group. The four C–H···O, C–H···C, O–H···H–C and C–H···H–C groups are nonconventional. Also, with respect to the Koch and Popelier criteria, some of them present the properties of a hydrogen bond, while others do not. The non-covalent interaction energies are calculated using Espinosa approach. Finally, according to the AIM and NBO analyses, the topological parameters (electron density ρb and its Laplacian ∇2ρb), estimated interaction energies (Eint), and the stabilization energy E(2) of both complexes were correlated with the intermolecular bond lengths.

Synthesis, characterization and studies on host-guest interactions of inclusion complexes of metformin hydrochloride with β–cyclodextrin

In this research paper, we describe a study on the inclusion complex formation between Metformin hydrochloride (MF) and beta-cyclodextrin (β-CD) in order to improve the sustained release, dissolution and oral bioavailability of the drug MF. Metformin hydrochloride is a drug used for treating non-insulin-dependent diabetes mellitus and for polycystic ovary syndrome. The host-guest solid inclusion complex of MF with β-CD is prepared by Microwave irradiation method along with conventional methods such as physical mixture, kneading method and co-precipitation method. The phase solubility studies suggested the 1:1 stoichiometry and revealed the solubility of MF is enhanced during the inclusion complex formation between MF and β-CD. The value of the apparent stability constant was found to be 61.11 M−1. The rate of dissolution of the drug was found to be highest (95% in 60 min) for the inclusion complex prepared by microwave irradiation method. Inclusion complexes were characterized by using FTIR, FESEM, PXRD, DSC and 1HNMR techniques. All the instrumentation techniques revealed that microwave and co-precipitation methods form true inclusion complexes. Different parameters such as apparent molar volume (Vϕ), partial molar volume at infinite dilution (Vϕ0) have been determined by using the experimental density data. Apparent molar and partial molar parameters concerning volumetric predict that the host-guest interactions prevailed in the ternary system of MF, β-CD and distilled water. Microwave irradiation completes the process of inclusion complex formation in a very short duration of time and is a more environment-friendly method. Thus microwave irradiation can be utilized as an advanced, time-saving and cost-effective method for the generation of MF/β-CD inclusion complexes.

Study of specific interactions in inclusion complexes of amine-terminated PAMAM dendrimer/flavonoids by experimental and computational methods

ABSTRACTPolyamidoamine (PAMAM) dendrimers have a multifunctional structure, able to encapsulate molecules for pharmacological applications. We evaluated the specific interaction that govern the encapsulating and affinity of one group of natural and synthetic flavonoids into the G5-PAMAM dendrimers. The complexation and capture percent of one flavonoid series into G5-PAMAM dendrimers, under neutral and acid pH conditions, were studied through UV–Vis spectroscopy. Additionally, only three of the flavonoids (two synthetic and one natural) were studied by high-performance liquid chromatography (HPLC) and molecular dynamic (MD) simulation, at neutral pH to calculate the affinity constants (Kd) and binding free energies (ΔGb). From spectroscopic results, we observed that the encapsulation was much more rapid at low pH than at neutral pH, which was attributed to a greater number of cavities inside the dendrimer. The MD simulations suggested that the more compact molecular structure at neutral pH reduces the capture kinetics. Finally, the relative binding free energies calculated using MD simulations showed the same tendency as the experimental data for the three complexes. These affinities appear to be due to a complex balance of different contributions, which cannot be attributed to hydrogen bonds or charge–charge interactions alone. Nevertheless, we suggest that a protocol including UV–Vis, HPLC, and MD simulation can be a powerful predictive tool to determine the affinity of drug binding to nanocarriers.

Polymeric hollow spheres assembled from ALG-g-PNIPAM and β-cyclodextrin for controlled drug release

In this paper, thermo-sensitive polymeric hollow spheres assembled from sodium alginate-graft-poly(N-isopropylacrylamide) (ALG-g-PNIPAM) and β-cyclodextrin (β-CD) were prepared for controlled release of 5-fluorouracil (5-FU). In aqueous solutions, β-CD and PNIPAM formed rod-like segments through inclusion complexation interactions and sodium alginate acted as coil segments, which resulted in the formation of hollow structures. The size and wall thickness of assemblies increased with the increase of β-CD in mixtures. The lower critical solution temperature (LCST) of hollow spheres varied in the range of 35–37°C. The hollow spheres exhibited high drug loading efficiency for 5-FU due to the hydrophilic cavities. The initial composition of mixtures, temperature and pH had a significant effect on the inclusion ability and drug release. Increasing temperatures above the LCST or decreasing pH to acidic conditions, a more rapid release rate was observed.

Cyclodextrin/dextran based hydrogels prepared by cross-linking with sodium trimetaphosphate

Novel βCD-based hydrogels have been synthesized using sodium trimetaphosphate (STMP) as non-toxic reagent. Straightforward mixing of βCD with dextran and STMP in basic aqueous media led to hydrogels incorporating dextran chains, phosphate groups and βCD units. The hydrogels have been characterized by swelling measurements, XPS and 31P NMR. The swelling ratio was correlated to the content in phosphated groups, which give a polyelectrolyte character to these hydrogels. The significant rise of the swelling ratio with the βCD content increase has been attributed to a decrease of the number of phosphate-based crosslinks, the βCD units playing the role of dangling ends in the tridimensional network. Their loading capacity and their release properties have been investigated for methylene blue and benzophenone in order to demonstrate their potentiality for drug delivery. Through different interaction mechanisms, electrostatic and inclusion complex interactions, these compounds are loaded with different efficiencies. The release involves deswelling, diffusion mechanisms and partition equilibrium.

‘Click’ preparation of a novel ‘native-phenylcarbamoylated’ bilayer cyclodextrin stationary phase for enhanced chiral differentiation

This paper reports an effective approach for the fabrication of a novel hybrid bilayer cyclodextrin (CD) chiral stationary phase (CSP), where native and perphenylcarbamoylated-β-CD were successively immobilized onto silica surface via a two-step click approach to form a bilayer CD structure. By decorating the bulky phenylcarbamoylated CD onto the unmodified CD silica, the CSP can provide multiple interaction sites such as H-bonding (OH, CO, NH), steric effects, π–π, dipole–dipole and inclusion complexation interactions, which help to broaden the CSP's enantioselectivity profile and enhance the enantioselectivity to some specific analytes. A group of enantiomer pairs such as isoxazolines, bendroflumethiazide, indoprofen, diperodon, fenoterol, atropine, styrene oxide and dansyl amino acids can be baseline or partially separated on the current CSP under reversed phase high performance liquid chromatography (RP-HPLC). The selectivity and resolution of 4NPh-OPr reached 5.25 and 13.97, which is an exciting achievement for the enantioseparations by CD CSPs.

Intermolecular interactions in inclusion complexes

The whole range of interactions can be found between host and guest in supramolecular assemblies from ion-ion interactions, ion-dipole interactions, dipol-dipol interactions through hydrogen bonding, cation-π interactions, π-π stacking to van der Waals forces. Additionally, the same interactions exist between the supramolecular complex and its surrounding, i.e. solvent molecules, neighboring complexes, gases, etc. Recently the interest of scientists in the field of supramolecular chemistry is focused on design and synthesis of water-soluble synthetic macrocyclic ligands which are good receptors for biologically important guest molecules and can mimic the models of biological systems. Studying such complexes may provide new insight into the mechanisms of the formation of similar natural systems and as a consequence will help in better understanding the processes which occur in biological systems and in developing new materials with specific properties and functions. In this presentation the interactions which are stabilizing inclusion complexes of calix[n]arenes and cyclodextrins (host molecules) with guest molecules of biological interest, especially drug molecules will be discussed. This research was partly financed by the European Union within the European Regional Development Fund (POIG.01.01.02-14-102/09)

Ab initio calculations of electronic interactions in inclusion complexes of calix- and thiacalix[n]arenes and block s cations

Ab initio calculations at the HF/6-31G(d) level of theory were performed on a series of thiacalix[4]arenes and calix[6]arenes in presence and in absence of monovalent (Li+, Na+ and Cs+) and divalent cations (Ca2+ and Ba2+) respectively, in order to evaluate their particular bonding properties as host systems towards electrically charged species. NBO, as well as NBO deletion calculations were undertaken to evaluate the energy difference in the circular hydrogen bonding at the lower rim once an ion was placed inside the cavity. Disruption of this H-bonded system is dependent on the position of the ion within the guest and not on its ionic ratio. The basis set superposition error and the NBO deletion energy between the host and guest species were calculated in order to assess the interaction energy between them.

Electrochemical study of weak inclusion complex interactions by simultaneous MCR-ALS analyses of potential step-chronoamperometric data matrices

In this article, the analytical information obtained from the chronoamperometric data of a weak host–guest complexation was analyzed by multivariate curve resolution-alternative least square (MCR-ALS) as a powerful chemometrics method. As a model system, the complexation of dopamine with β-cyclodextrin was investigated. Whilst the voltammetric behavior of dopamine does not change significantly upon complexation, its chronoamperogram is changed due to the formed complex. The analysis was performed by titrating dopamine (guest) with variable amounts of β-cyclodextrin (host). In each mole ratio of host : guest, the solution was subjected to a potential step experiment, where in each step the current was measured as a function of time. Thus, for each potential a two-fold array of current data with molar ratio in one direction and time in another direction (data matrix) was obtained. The data matrices collected at different potentials were simultaneously analyzed by MCR-ALS to earn thermodynamic parameters (e.g., stoichiometric ratio and formation constant) of cyclodextrin–dopamine complex. This is the first report of simultaneous analysis of potential step-chronoamperometric data matrices by MCR-ALS.

Spontaneous formation of temperature-responsive assemblies by molecular recognition of a β-cyclodextrin-containing block copolymer and poly(N-isopropylacrylamide)

We report the construction of novel temperature-responsive assemblies based on a double hydrophilic block copolymer (consisting of a PEG block and a β-cyclodextrin-containing block, PEG-b-PCD) and poly(N-isopropylacrylamide) (PNIPAm). Thus formed nano-assemblies exhibit a spherical morphology and have a temperature-responsive loose core. The driving force for the formation of these assemblies was found to be the inclusion complexation interaction between the hydrophobic cavity of β-cyclodextrin and the isopropyl group of PNIPAm. The particle size of these assemblies changed reversibly in response to the external temperature change. The particle size also changed with the PNIPAm/PEG-b-PCD weight ratio. A model hydrophobic drug (indomethacin) was loaded into these assemblies with a high efficiency. An in vitro release study showed that the payload could be released in a sustained manner after an initial burst release. The release rate could be switched between high and low in an ON/OFF fashion by temperature. These results demonstrate that the nano-assemblies have high potential for applications in controlled drug delivery and biomedicine when temperature responsiveness is desired.

Associative Network Based on Cyclodextrin Polymer: A Model System for Drug Delivery

Associative networks have been elaborated by mixing in aqueous media a cyclodextrin polymer to a dextran bearing adamantyl groups. The two polymers interact mainly via inclusion complexes between adamantyl groups and cyclodextrin cavities, as evidenced by the high complexation constants determined by isothermal titration microcalorimetry (approximately 10(4) L mol(-1)). Additional interaction mechanisms participating in the strength of the network, mainly hydrogen bonding and electrostatic interactions, are sensitive to the pH and ionic strength of the medium, as shown by pH-dependent rheological properties. The loading and release of an apolar model drug, benzophenone, has been studied at two pH values and different cyclodextrin polymer content. Slow releases have been obtained (10-12 days) with slower kinetics at pH 2 than at pH 7. Analysis of the experiments at pH 7 shows that drug release is controlled both by diffusion in the network and by inclusion complex interactions with cyclodextrin cavities.

PH Sensitive supramolecular assembling system between a new linear water soluble β-cyclodextrin terpolymer and an amphiphilic poly(ethylene oxide)

A linear water soluble β-cyclodextrin terpolymer (P(MVE-AM)- g-βCD) was synthesized by grafting different amounts of βCD on the copolymer P(MVE-AM). The resulting terpolymer showed a pH sensitive behaviour in aqueous solution, due to the presence of carboxylic acid groups. Whatever the substitution degree in βCD, the terpolymer behaved like a polyacid at pH 7, and had neutral properties at pH 2. The mixture of P(MVE-AM)- g-βCD with an amphiphilic poly(ethylene oxide) (PEO-Ad 3) showed an associative phase separation influenced by the pH and concentration of the medium. In the dilute range and intermediate range, associative phase separations were induced reversibly by decreasing the pH from 7 to 2. The results in the semi-dilute range showed that networks were elaborated with much stronger dynamic modulus at low pH (pH 2) than at higher pH (pH 7). Coupled inclusion complex interactions (between the adamantyl groups of PEO-Ad 3 and the cyclodextrin cavities of P(MVE-AM)- g-βCD) with hydrogen bonding (between carboxylic acid groups and PEO backbone) could be a way to modulate the strength of the interactions in supramolecular assemblies. These results suggest that the mixture of P(MVE-AM)- g-βCD with PEO-Ad 3 could be a potential pH sensitive system.

Macromolecular Assemblies Based on Coupled Inclusion Complex and Electrostatic Interactions

Macromolecular assemblies are elaborated by mixing beta-cyclodextrin-containing polymer (polybetaCD), dextran sulfate polyanion (NaDxS), and cationic amphiphiles which are adamantane derivatives (Ada1 or Ada2) in aqueous medium. These components are assembled via coupled inclusion complex interactions (adamantyl group with cyclodextrin cavity) and electrostatic attractive interactions (positive charges of Ada with negative charge of NaDxS). The structural properties are studied by viscometry and small angle neutron scattering. Ternary aggregates with larger size and lower compacities are observed as the cation concentration is increased, until phase separation occurs. The results are in good agreement with a core-shell association mechanism, the core being made of one polybetaCD chain, the shell of NaDxS chains, and the Ada amphiphiles being distributed more or less homogeneously inside the cyclodextrin cavities. The nature of the Ada counterions has a strong influence on the association as Ada1 with I(-) counterions give smaller and less compact aggregates than Ada2 with Br(-) counterions.

Complex formation of ionic liquid surfactant and β-cyclodextrin

An ionic liquid (IL) surfactant, 1-dodecyl-3-methylimidazolium hexafluorophosphate (C 12mimPF 6) can form the inclusion complexes (ICs) with β-cyclodextrin (β-CD). The surface tension measurements revealed that there were two kinds of inclusion formations, 1:1 and 1:2 (β-CD/IL) stoichiometry for β-CD-C 12mimPF 6 ICs. The inclusion complexation interaction was further confirmed by FT-IR spectra. The inclusion compound was also characterized by Powder X-ray diffraction (XRD), 13C CP/MAS NMR, 2D 1H- 1H COSY and TGA. The results showed that the host–guest system presented a channel type structure and each glucose unit of β-CD was in a similar environment. Only the tails of C 12mimPF 6 were included into the cavity of β-CD. The formation mechanism of the β-CD-C 12mimPF 6 was also discussed. It was suggested that hydrophobicity played a crucial role in supporting the formation of β-CD-C 12mimPF 6 ICs and hydrogen bonding was dispensable to maintain the channel type crystal structure. The weak hydrophobic driven force made the β-CD-C 12mimPF 6 unstable, which was reflected by TGA curves. In addition, possible inclusion structures of β-CD-C 12mimPF 6 were speculated.

Associative pH Sensitive System

New associative pH sensitive systems composed of a modified dextran bearing 2-carboxycyclohexyl carboxyl groups and neutral (p betaCD) or positively charged (p betaCDN(+))beta-cyclodextrin-co-epichlorhydrin copolymers have been synthesized and their properties were investigated as a function of pH by phase diagrams and viscosimetry. The affinity between the CD cavities and the hydrophobic guests (2-carboxycyclohexyl carboxyl groups) has been studied as a function of pH. The system with the neutral p betaCD shows a pH dependent behavior due to the lowest affinity of the guest at pH above 5 for the cavity. Associative phase separation is produced at low pH whereas soluble complexes occur at higher pH. The opposite trend is observed with the system containing the cationic p betaCDN(+). This behavior is due to the combination of electrostatic and inclusion complex interactions in this system. Addition of salt, by screening the electrostatic interactions, also strongly influences the response of the system.

E-BURP-2 excitation in the CPMG sequence for improving reliability of relaxation data in the study of guest/host interactions in inclusion complexes in water

A modification of the classical Carr–Purcell–Meiboom–Gill sequence, in which the first 90° pulse is replaced by a selective E-BURP-2 pulse, is described. It is shown that the absence of dispersion contributions in the frequency response of the selected absorption region is a pre-requisite for obtaining reliable data. The importance of leaving the water magnetization along the longitudinal axis is also pointed out. The potentialities of the method are illustrated in the study of intermolecular interactions in the case of inclusion complexes.