Hydrophobic Cyclodextrin Research Articles

Hydrophobic cyclodextrin dimer-assisted self-healing elastomer: movable crosslinks of pseudo-rotaxane with recyclable and separable functionality

A movable cross-linked elastomer derived from a pseudo-rotaxane by utilizing a dimer structure exhibits facile healing and good stretching.

Solubility and solvation features of native cyclodextrins in 1-ethyl-3-methylimidazolium acetate

The comprehension of the mechanism entailing efficient solvation of cyclodextrins (CD) by green solvents is of great relevance to boost environmentally sustainable usages of smart supramolecular systems. Here, 1-ethyl-3-methylimidazolium acetate, an ecofriendly ionic liquid (IL), is considered as an excellent solvent for native CDs. This IL efficiently dissolves up to 40 wt.% β- and γ-CD already at ambient temperature and X-ray scattering indicates that CDs do not tend to detrimental flocculation under these drastic concentration conditions. Simulation techniques reveal the intimate mechanism of CD solvation by the ionic species: while the strong hydrogen bonding acceptor acetate anion interacts with CD's hydroxyl groups, the imidazolium cation efficiently solvates the hydrophobic CD walls via dispersive interactions, thus hampering CD's hydrophobic driven flocking. Overall the amphiphilic nature of the proposed IL provides an excellent solvation environment for CDs, through the synergic action of its components.

Preferentially released miR-122 from cyclodextrin-based star copolymer nanoparticle enhances hepatoma chemotherapy by apoptosis induction and cytotoxics efflux inhibition

Chemotherapy, as one of the most commonly used treatment modalities for cancer therapy, provides limited benefits to hepatoma patients, owing to its inefficient delivery as well as the intrinsic chemo-resistance of hepatoma. Bioinformatic analysis identified the therapeutic role of a liver-specific microRNA — miR-122 for enhancing chemo-therapeutic efficacy in hepatoma. Herein, a cyclodextrin-cored star copolymer nanoparticle system (sCDP/DOX/miR-122) is constructed to co-deliver miR-122 with doxorubicin (DOX) for hepatoma therapy. In this nanosystem, miR-122 is condensed by the outer cationic poly (2-(dimethylamino) ethyl methacrylate) chains of sCDP while DOX is accommodated in the inner hydrophobic cyclodextrin cavities, endowing a sequential release manner of miR-122 and DOX. The preferentially released miR-122 not only directly induces cell apoptosis by down regulation of Bcl-w and enhanced p53 activity, but also increases DOX accumulation through inhibiting cytotoxic efflux transporter expression, which realizes synergistic performance on cell inhibition. Moreover, sCDP/DOX/miR-122 displays remarkably increased anti-tumor efficacy in vivo compared to free DOX and sCDP/DOX alone, indicating its great promising in hepatoma therapy.

Water-insoluble polymer-free uniform nanofibers of peracetylated cyclodextrin by electrospinning

Hydrophobic cyclodextrin (CD) nanofibers were produced by the electrospinning of peracetylated β-CD without requiring any polymer as a carrier matrix. Native β-CD was peracetylated through the reaction with acetic anhydride, and the conversion of all hydroxyl groups into acetyl was confirmed by NMR, XPS, and TGA analyses. The peracetyl modification drastically boosted the thermal stability of the β-CD molecules. The electrospinning of the peracetylated β-CD from its highly concentrated solutions (180% (w/v)) in DMF led to bead-free nanofibers, while electrospinning at the concentrations of 140 and 160% (w/v) CDs resulted in beads and beaded nanofibers, respectively. The electrospinning process parameters such as applied voltage, flow rate, and tip-to-collector distances were systematically altered to produce a uniform nanofiber structure. The flow rate had the most drastic effect on the diameter and morphology of the resultant nanofibers: A threefold rise in the fiber diameter was observed with increasing the flow rate from 0.1 to 2 mL h−1. Similarly, higher electrical field increased the fiber diameter due to higher mass flow, while boosting the tip-to-collector distance did not reveal any significant change on the fiber diameter. The stability of the peracetylated β-CD nanofibers was observed in water for 24 h without any significant morphological change; however, the dissolution of the nanofiber mat was observed with a long-time exposure to water. We demonstrated production of hydrophobic uniform CD nanofibers without using any carrier polymer.

Carbamazepine bilayer tablets combining hydrophilic and hydrophobic cyclodextrins as a quick/slow biphasic release system

This work aimed to explore the combination of hydrophilic and hydrophobic cyclodextrins to prepare bilayer tablets that can perform as quick/slow biphasic release systems of a poorly soluble drug. This formulation approach is of particular interest for treatments that require a rapid action followed by sustained therapeutic levels. Carbamazepine (CBZ), an antiepileptic and anticonvulsant agent, was used as a model of a BCS Class 2 drug. Hydroxypropyl-β-cyclodextrin (HPβCD) was chosen as complexing agent in the rapid release layer. Differently, triacetyl-β-cyclodextrin (TAβCD) was tested as controlling release agent in the sustained release layer. Croscarmellose sodium was utilized as superdisintegrant in the rapid release layer, and sodium stearyl fumarate was applied as anti-adherent lubricant in both layers. Bilayer tablets were characterized through several techniques. The results highlighted the feasibility of the combination of HPβCD/CBZ inclusion complex with croscarmellose sodium in the rapid release layer to achieve fast dissolution for the first 30–45 min, and TAβCD as controlling agent in the sustained release layer of the bilayer tablets to obtain a prolonged release during 720 min. In conclusion, combinations of hydrophilic and hydrophobic cyclodextrins may help addressing the formulation of poorly soluble drugs in bilayer tablets as a fast/slow biphasic release system.

Effect of hydrophilic and hydrophobic cyclodextrins on the release of encapsulated allyl isothiocyanate (AITC) and their potential application for plastic film extrusion

ABSTRACTAllyl isothiocyanate (AITC), a natural pungent flavor from wasabi and horseradish, is well‐known antimicrobial agents against foodborne pathogens. However, its highly volatile nature and low thermal stability restrict its application in the food packaging industry. Also, its strong organoleptic characteristics hinder its application at a higher dosage. We encapsulated AITC in β‐cyclodextrin (β‐CD) and triacetyl‐β‐CD (TA‐β‐CD) and evaluated the performance as slow releasing active compounds through low‐density polyethylene (LDPE)–cyclodextrins (CDs) matrix. Also, the thermal, optical, mechanical, and barrier properties of two ternary blends, LDPE/β‐CD/AITC(L‐CDs) and LDPE/TA‐β‐CD/AITC(L‐TACDs), were investigated to compare their compatibility under the plastic extrusion process. During the 15 days of the storage period, L‐TACDs maintained more consistent AITC release and a higher concentration than L‐CDs. Also, the blending of LDPE and TA‐β‐CD was more compatible with that of LDPE and β‐CD. No significant optical, mechanical, and barrier property changes were observed in LDPE with less than 3% of TA‐β‐CD while L‐CDs showed substantial agglomeration on the ternary blend films and the lower mechanical and barrier properties than pure LDPE. The results indicate that the LDPE films containing TA‐β‐CD/AITC can be applied as an effective antimicrobial packaging material for food and nonfood applications. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019, 136, 48137.

Shear thinning/self-healing hydrogel based on natural polymers with secondary photocrosslinking for biomedical applications

Injectable hydrogel systems are useful in many biomedical applications, including drug or cell delivery carriers and scaffolds. Here, we describe the design and characterization of a shear thinning hydrogel that undergoes a disassembly when shear forces are applied during injection and is self-healing once the shear forces are removed. This hydrogel is based on a cyclodextrin modified alginate, and a methacrylated gelatin which initially forms through a weak guest-host interaction between hydrophobic cyclodextrin cavities and the aromatic residue of gelatin. Methacrylated gelatin possesses photocrosslinkable functionalities which can go through a light-initiated polymerization to create secondary crosslinking sites and further crosslink the matrix. The shear thinning and self-healing behavior of these gels monitored in low and high strain range, viscosity of the hydrogels components and gelation kinetic were studied. The rheological analyses showed the formation of shear thinning gels which were further stabilized by visible light exposure. The cytotoxicity of the hydrogels towards human mesenchymal stem cells were assessed and the rate of mass loss over a week period was studied.

Chiral separation of tedizolid using charge single isomer derivatives of cyclodextrins by capillary electrokinetic chromatography

A method to enantioseparate tedizolid (TED), the second analogue after linezolid (LIN) in a truly new class of antibacterial agents, the oxazolidinones, was developed based on capillary electrokinetic chromatography using cyclodextrin as chiral pseudophase (CD-cEKC). The single isomer R-tedizolid possesses one chiral centre at C5 of the oxazolidinone ring, which is associated with the antibacterial activity of the drug. Tedizolid enantiomers are non-charged and therefore require the use of charged cyclodextrins (CCDs) as carrier hosts to achieve a velocity difference during migration. During method development, hydrophilic anionic single-isomer and moderately hydrophobic and hydrophobic cyclodextrins were tested, including heptakis-(2,3-dihydroxy-6-sulfo)-β-cyclodextrin (HS-β-CD), heptakis-(2,3-diacetyl-6-sulfo)-β-cyclodextrin (HDAS-β-CD), oktakis-(2,3-diacetyl-6-sulfo)-γ-cyclodextrin (ODAS-γ-CD) and heptakis-(2,3-dimethyl-6-sulfo)-β-cyclodextrin (HDMS-β-CD). Only CDs that have acetyl groups at the C2 and C3 positions with seven (HDAS-β-CD) or eight (ODAS-γ-CD) residues of glucopyranose units provided baseline separation of the tedizolid enantiomers with the addition of organic solvent. During the experiments, different organic solvents were tested, such as methanol, acetonitrile, tetrahydrofuran, which varied in their abilities to donate or accept protons. The best enantiomer separation results were obtained using the CD-cEKC method with 37.5mM HDAS-β-CD dissolved in 50mM formic buffer (pH 4.0) with the addition of acetonitrile (81.4:18.6, v/v) at 27ºC, normal polarity, and 12kV. Finally, the apparent binding constants for each enantiomer—HDAS-β-CD pair were calculated. Moreover, in order to evaluate the behaviour of TED and LIN enantiomers relative to chiral selector, enantioselective interactions towards the precursors of TED and LIN isomers were also investigated.

Synthesis of amphiphilic polymer networks with guest‐host properties

ABSTRACTA modular assembly procedure for producing amphiphilic polymer networks containing specific linker lengths between cyclodextrin (CD) cross‐link sites is described. The linker type and length can be selected to tune the relative hydrophilicity/hydrophobicity of the network, and the size of the guest‐host binding site can be varied by using either α‐, β‐, or γ‐CD as the node. The two‐step, one‐pot reaction sequence produces well‐defined networks with stable ether linkages that can be purified by simple washing and filtration steps. Short ethylene glycol versus long polyethylene oxide linkers result in networks that are generally insoluble in common organic solvents, but which swell to varying degrees in polar protic, polar aprotic, and chlorinated solvents such as water, methanol, ethanol, dimethylsulfoxide, dimethylformamide, methylene chloride, and chloroform. All networks swell in water and present a hydrophobic CD cavity that is available for binding nonpolar molecules. The networks should be applicable to the removal of hydrophobic contaminants, for example, pharmaceutical molecules, from water or wastewater streams. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 1824–1831

Fluorimetric determination of sulphathiazole in honey by means the formation of CDs inclusion complexes

The inclusion complex of sulphathiazole in β-cyclodextrin has been investigated. A 1:2 stoichiometry of the complex was established and formation constants K2 (42.83±3.27M−1) and K1 (4.98±0.36M−1) were calculated by using the changes produced on the native fluorescence of the drug, when included on the hydrophobic cyclodextrin cavity. An enhancement in the fluorescence emission of sulphathiazole and protection of the drug against photochemical reactions has been attained upon inclusion. In solutions of β-CD dual emission (458nm) was noticed in STZ. Formation of the inclusion complex of STZ should result in dual emission, which is due to a twisted intramolecular charge transfer band (TICT). A fluorimetric method for the determination of sulphathiazole has been proposed and applied in honey without sample treatment. The optimized fluorimetric method showed detection and quantitation limits of 9.74ng/g and 32.48ng/g, respectively. Selectivity is high, showing no cross-reactivity to other chemically related antibiotics. The results obtained for blind honey samples (mean recovery 97%), were in good agreement with those obtained by liquid chromatography separation and mass spectrometry detection (LC–MS) (mean recovery 102%), showing that the proposed method might be used for the determination of sulphathiazole residues without expensive equipment.

Pharmacokinetic Delivery and Metabolizing Rate of Nicardipine Incorporated in Hydrophilic and Hydrophobic Cyclodextrins Using Two‐Compartment Mathematical Model

The dispersion routes of cyclodextrin complexes with nicardipine (NC), such as hydrophilic hydroxypropyl-β-cyclodextrin (NC/HPβCD) and hydrophobic triacetyl-β-cyclodextrin (NC/TAβCD), through the body for controlled drug delivery and sustained release have been examined. The two-compartment pharmacokinetic model described the mechanisms of how the human body handles with ingestion of NC-cyclodextrin complexes in gastrointestinal tract (GI), distribution in plasma, and their metabolism in the liver. The model showed that drug bioavailability was significantly improved after oral administration of cyclodextrin complexes. The mathematical significance of this study to predict nicardipine delivery using pharmacokinetic two-compartment mathematical model with linear ordinary differential equations (ODE) approach represents a valuable tool to emphasize its effectiveness and metabolizing rate and diminish the side effects.

Dose Dependent Response to Cyclodextrin Infusion in a Rat Model of Verapamil Toxicity

IntroductionSulfobutylether-β-cyclodextrin (SBE-CD) is a pharmaceutical excipient known to bind verapamil. Following intravenous administration, clearance of SBE-CD approximates glomerular filtration rate. We hypothesized that infusion of SBE-CD would increase time to asystole in a rat model of verapamil toxicity in a dose-dependent manner. The objective was to demonstrate the effect of a range of SBE-CD concentrations in a rat model of verapamil toxicity.MethodsTwenty-five Wistar rats were allocated to control or 1 of 4 intervention groups. All received ketamine and diazepam anesthesia followed by verapamil infusion 32 mg/kg/h. The verapamil infusion for the intervention groups was premixed with SBE-CD in a 1:1, 1:2, 1:4, or 1:8 molar ratio (verapamil to SBE-CD). The control group infusion did not contain SBE-CD. Additional saline or water was added to the infusion so that the total volume infused was the same across groups, and the osmolality was maintained as close to physiologic as possible. Heart rate, respiratory rate, and temperature were monitored. The primary endpoint was time to asystole.ResultsVerapamil coinfused with SBE-CD in a molar ratio of 1:4 resulted in prolonged time to asystole compared to control (21.2 minutes vs 17.6 minutes, P < 0.05). There were no differences in time to asystole between control and any other intervention group. There was no significant difference in time to apnea between control and any intervention group. We assessed the effect of a range of SBE-CD concentrations and identified 1 concentration that prolonged time to asystole. Mechanisms that may explain this effect include optimal volume expansion with a hyperosmolar cyclodextrin containing solution, complexation of verapamil within the hydrophobic cyclodextrin pore, and/or complexation within micelle-like aggregates of cyclodextrin. However, mechanistic explanations for the observed findings are speculative at this point.ConclusionThe 1:4 verapamil to SBE-CD concentration was modestly effective with SBE-CD concentrations above and below this range demonstrating nonstatistically significant improvements in time to asystole.

Advanced Technologies for Oral Controlled Release: Cyclodextrins for Oral Controlled Release

Cyclodextrins (CDs) are used in oral pharmaceutical formulations, by means of inclusion complexes formation, with the following advantages for the drugs: (1) solubility, dissolution rate, stability, and bioavailability enhancement; (2) to modify the drug release site and/or time profile; and (3) to reduce or prevent gastrointestinal side effects and unpleasant smell or taste, to prevent drug-drug or drug-additive interactions, or even to convert oil and liquid drugs into microcrystalline or amorphous powders. A more recent trend focuses on the use of CDs as nanocarriers, a strategy that aims to design versatile delivery systems that can encapsulate drugs with better physicochemical properties for oral delivery. Thus, the aim of this work was to review the applications of the CDs and their hydrophilic derivatives on the solubility enhancement of poorly water-soluble drugs in order to increase their dissolution rate and get immediate release, as well as their ability to control (to prolong or to delay) the release of drugs from solid dosage forms, either as complexes with the hydrophilic (e.g., as osmotic pumps) and/or hydrophobic CDs. New controlled delivery systems based on nanotechnology carriers (nanoparticles and conjugates) have also been reviewed.

Constrained photophysics of partially and fully encapsulated charge transfer probe (E)-3-(4-Methylaminophenyl) acrylic acid methyl ester inside cyclodextrin nano-cavities: Evidence of cyclodextrins cavity dependent complex stoichiometry

The polarity sensitive intra-molecular charge transfer (ICT) emission from (E)-3-(4-Methylaminophenyl) acrylic acid methyl ester (MAPAME) is found to show distinct changes once introduced into the nano-cavities of cyclodextrins in aqueous environment. Movement of the molecule from the more polar aqueous environment to the less polar, hydrophobic cyclodextrin interior is marked by the blue shift of the CT emission band with simultaneous fluorescence intensity enhancement. The emission spectral changes on complexation with the α- and β-CD show different stoichiometries as observed from the Benesi–Hildebrand plots. Fluorescence anisotropy and lifetime measurements were performed to probe the different behaviors of MAPAME in aqueous α- and β-CD solutions.

An interesting molecular-assembly of β-cyclodextrin pipelines with embedded hydrophilic nickel maleonitriledithiolate

A unique tubular molecular-assembly, constructed by β-cyclodextrin and Na[Ni(mnt)(2)], was identified by X-ray crystallography. Inclusion complex Na[Ni(mnt)(2)]@β-cyclodextrin (1) crystallized in space group P2(1)2(1)2 as hydrated head-to-head, tail-to-tail, and head-to-tail host pipelines with negatively charged [Ni(mnt)(2)](-) guests included, exhibiting a 3 : 1 (host : guest) stoichiometry. The hydrophilic transition-metal coordination compound (Na[Ni(mnt)(2)]) was embedded within a hydrophobic cyclodextrin cavity, which resulted in a β-cyclodextrin trimer motif and one-third "empty" host packing model in the crystal. Induced circular dichroism (ICD) spectra of inclusion complex 1 was investigated, which indicated the same penetration pattern of the guests in host cavities in solution phase as that discovered in the crystal structure. In addition, PM3 quantum chemistry calculations strongly supported the co-conformational alignments of inclusion complex 1 that was identified in the crystal as well as in the solution.

Thermosensitive Pluronic&amp;reg; hydrogel: prolonged injectable formulation for drug abuse

The main objective of this study was to investigate thermosensitive Pluronic F-127 (PF-127) hydrogel for the modified release of a potent alcohol and opioid antagonist, naltrexone (NTX) hydrochloride, in a subcutaneous injectable dosage form. The NTX hydrogels were prepared by the cold method, and the in vitro release profiles of various formulations were evaluated at 37°C using the Franz diffusion cell system. We examined the different PF-127 concentrations, pH of solution, and inorganic salts on drug release from these gels. The data showed an increase in PF-127 content from 20% to 35%, resulting in a decrease in the rate of NTX release. Among the formulations prepared in different pH solutions, pH 7.4 produced the slowest drug release rate. The addition of inorganic salts had no significant effect on drug release. However, these factors appeared to have limited effects on drug release rate. Therefore, to achieve a sustained-release formulation, a NTX and triacetyl β-cyclodextrin (TAβCD) complex was evaluated. The binary systems of NTX/TAβCD in different molar ratios were prepared by the kneading method, and complex formation was demonstrated by differential scanning calorimetry. The results of the current in vitro study indicate that PF-127 gel formulations containing drug complexes with hydrophobic cyclodextrin could be useful for the preparation of a controlled delivery system of water-soluble drugs such as NTX, for a period of more than 140 hours.

ChemInform Abstract: Development and Pharmaceutical Evaluation of Hydrophobic Cyclodextrin Derivatives as Modified-Release Drug Carriers

Hydrophobic cyclodextrin (CyD) derivatives, such as 2,6-di-O-ethyl-beta-CyD (DE-beta-CyD), 2,3,6-tri-O-ethyl-beta-CyD (TE-beta-CyD), carboxymethylethyl-beta-CyDs (CME-beta-CyDs) with different degrees of substitution, 2,3,6-tri-O-acyl-beta-CyDs with different alkyl chains (C1-C12) were prepared and their chemical structures and physicochemical properties were elucidated. Furthermore, possible utilities of hydrophilic and hydrophobic CyD derivatives as modified-release drug carriers were evaluated on the basis of in vitro/in vivo correlations. The results obtained in this study are as follows: (1) Hydrophilic CyDs such as 2-hydroxypropyl-beta-CyD are useful as immediate-release type carriers for poorly water-soluble drugs such as nifedipine. (2) Hydrophobic CyDs such as ethylated and acylated beta-CyDs can be used as prolonged-release type carriers for water-soluble drugs such as diltiazem hydrochloride, buserelin acetate and molsidomine. (3) Enteric CME-beta-CyD derivatives are useful as delayed-release type carriers, and also as stabilizers for prostaglandin E and carmofur which are labile under alkaline conditions. (4) Various release rates can be obtained by combining hydrophilic and hydrophobic CyD derivatives in appropriate mixing ratios, e.g., double-layer tablets consisting of beta-CyD complex and DE-beta-CyD/CME-beta-CyD complexes released drugs rapidly at an initial stage, followed by slow release. The combination of CyD derivatives and pharmaceutical additives was also useful to modify the release rate of various drug molecules.

Primary photodynamics of a biomimetic model of photoactive yellow protein (PYP)

The present work aims at characterizing the photophysical behavior of a first biomimetic cyclodextrin model (CD-PYP1) of the photoactive site of photoactive yellow protein (PYP). The hydrophobic cyclodextrin cavity in which the chromophore self-includes, mimics its local environment within the protein. The photoinduced behavior of deprotonated CD-PYP1 (dp-CD-PYP1) has been probed by femtosecond transient-absorption spectroscopy and compared to those of the free deprotonated chromophore (pCT(-)) and of wild-type PYP. The excited-state deactivation of dp-CD-PYP1 is found to be non-exponential, with slower time components and higher quantum yield of fluorescence than pCT(-). Like in PYP, the non-exponential decay is attributed to ground-state structural heterogeneities of the self-inclusion complexes. A long-lived photoproduct is observed in the transient spectra of dp-CD-PYP1 and identified as the cis isomer. The isomerization quantum yield of dp-CD-PYP1 is estimated to be about 4%, in contrast with the free chromophore in solution which does not photoisomerize at all. This demonstrates the active role of the cyclodextrin environment to promote the photoisomerization of the chromophore, as is thought to be the case for wild-type PYP. The effects of chromophore inclusion in the cyclodextrin on the photoinduced processes are rationalized within the framework of recent theoretical calculations involving two competitive deactivation channels: (i) trans to cis isomerization and (ii) rotation of the phenolate group, leading to trans ground-state recovery. Inclusion is proposed to favor isomerization by hindering the rotation of the phenolate group. Optimizing the structure of this first model in order to better reproduce the primary photoresponse of PYP thus appears very promising.

Preparation, Characterization and &lt;I&gt;In Vitro&lt;/I&gt; Evaluation of a New Nucleotide Analogue Prodrug Cyclodextrin Inclusion Complexes

Bis(tbutyl-S-acyl-2-thioethyl)-cytidine monophosophate is a new cytotoxic mononucleotide prodrug which have been developed to reverse the cellular resistance to nucleoside analogues. Unfortunately, its in vivo utilisation was hampered by its poor water solubility, raising the need of a molecular vector capable to mask its physicochemical characteristics although without affecting its cytotoxic activity. Hydroxypropyl-beta-cyclodextrin was used to prepare the prodrug inclusion complexes, allowing it to be solubilized in water and hence to be used for in vitro and in vivo experiments. A molar ratio of the cyclodextrin: prodrug of 3 was sufficient to obtain complete solubilization of the prodrug. The inclusion complex was characterized by differential scanning calorimetry, which revealed the disappearance of the melting peak of the prodrug suggesting the formation of inclusion complex. Proton Nuclear Magnetic Resonance spectroscopy provided a definitive proof of the inclusion complex formation, which was evidenced by the large chemical shift displacements observed for protons located in the interior of the hydrophobic cyclodextrin cavity. The complex retained its cytotoxic activity as shown by in vitro cell survival assays on murine leukemia cells. These results provided a basis for potential therapeutic applications of co-formulation of this new nucleotide analogue with hydroxypropyl-beta-CD in cancer therapy.

Study of the complexation of risperidone and 9-hydroxyrisperidone with cyclodextrin hosts using affinity capillary electrophoresis and 1H NMR spectroscopy

The complexation of risperidone (Risp) and 9-hydroxyrisperidone (9-OH-Risp), atypical antipsychotics, with seven cyclodextrins (CDs) of pharmaceutical interest (native and hydroxypropylated (HP) α-, β-, γ-CDs and methyl (Me)-β-CD) was studied by affinity capillary electrophoresis (ACE) and nuclear magnetic resonance spectroscopy (NMR) for acidic pH 2.5 and physiological pH 7.4. The 1:1 stoichiometry of the complexes was established by 1H NMR spectroscopy using the continuous variation method developed by Job. The apparent binding constants of the 14 complexes at both pH were determined by ACE through the linear Scott's plots. The NMR spectroscopy investigation of the binding constants was achieved for the two CDs allowing the highest complexation: the β-CD and Me-β-CD. Both ACE and NMR spectroscopy studies provide similar conclusions by considering the influence of the 9-hydroxylation, the influence of the CD substitution and the influence of the pH. Moreover, the NMR spectroscopy results have allowed to suppose a pH-dependent inclusion mechanism. A thermodynamic study was then performed by ACE at both pH for the Risp·Me-β-CD and 9-OH-Risp·Me-β-CD complexes: the opposite signs of the entropic change (Δ S° < 0 at pH 2.5 and Δ S° > 0 at pH 7.4) confirms the influence of the pH on the complexation mechanism and the possible difference in the depth of the analyte inclusion in the hydrophobic cavity of the CD. Last, the two-dimensional ROESY (rotating-frame Overhauser spectroscopy) ( 1H– 1H) and HOESY (heteronuclear Overhauser effect spectroscopy) ( 19F– 1H) experiments have proved the inclusion of the aromatic part of the Risp and 9-OH-Risp in the hydrophobic CD cavity and lead us to propose a model of complexation.