Cyclodextrin Derivatives Research Articles

Hot-melt extrusion as a continuous manufacturing process to form ternary cyclodextrin inclusion complexes

The aim of this study was to evaluate hot-melt extrusion (HME) as a continuous process to form cyclodextrin (CD) inclusion complexes in order to increase the solubility and dissolution rate of itraconazole (ITZ), a class II model drug molecule of the Biopharmaceutics Classification System. Different CD derivatives were tested in a 1:1 (CD:ITZ) molar ratio to obtain CD ternary inclusion complexes in the presence of a polymer, namely Soluplus® (SOL). The CD used in this series of experiments were β-cyclodextrin (βCD), hydroxypropyl-β-cyclodextrin (HPβCD) with degrees of substitution of 0.63 and 0.87, randomly methylated β-cyclodextrin (Rameb®), sulfobutylether-β-cyclodextrin (Captisol®) and methyl-β-cyclodextrin (Crysmeb®).Rheology testing and mini extrusion using a conical twin screw mini extruder were performed to test the processability of the different CD mixtures since CD are not thermoplastic. This allowed Captisol® and Crysmeb® to be discarded from the study due to their high impact on the viscosity of the SOL/ITZ mixture. The remaining CD were processed by HME in an 18mm twin screw extruder. Saturation concentration measurements confirmed the enhancement of solubility of ITZ for the four CD formulations. Biphasic dissolution tests indicated that all four formulations had faster release profiles compared to the SOL/ITZ solid dispersion. Formulations of HPβCD 0.63 and Rameb® even reached 95% of ITZ released in both phases after 1h.The formulations were characterized using thermal differential scanning calorimetry and attenuated total reflectance infra-red analysis. These analyses confirmed that the increased release profile was due to the formation of ternary inclusion complexes.

Fluorescently Labeled Cyclodextrin Derivatives as Exogenous Markers for Real-Time Transcutaneous Measurement of Renal Function.

Evaluation of renal function is crucial for a number of clinical situations. Here, we reported a novel exogenous fluorescent marker (FITC-HPβCD) to real-time assess renal function by using a transcutaneous fluorescent detection technique. FITC-HPβCD was designed based on the principle of renal clearance of designed drugs. It displays favorable fluorescent properties, high hydrophilicity, low plasma protein binding, and high stability in porcine liver esterase as well as in plasma and nontoxicity. More importantly, FITC-HPβCD can be efficiently and rapidly filtered by glomerulus and completely excreted into urine without proximal tubular reabsorption or secretion in rat models. Additionally, the marker was well-tolerated, with nearly 100% urinary recovery of the given doses, and no metabolism were found. Relying on this novel kidney function marker and transcutaneous devices, we demonstrate a rapid, robust, and convenient approach for real-time assessing renal function without the need of time-consuming blood and urine sample preparation. Our work provides a promising tool for noninvasive real-time monitoring of renal function in vivo.

Monosubstituted Cyclodextrins as Precursors for Further Use

Cyclodextrin derivatives find use in a broad field of applications (e.g., nanomaterials, biomedical applications, catalysis, separation techniques, sensors etc.), with monosubstitution allowing cyclodextrins to be attached to various types of surfaces or for a new feature to be introduced onto a cyclodextrin skeleton (recognition, catalysis, …). Although an enormous number of monosubstituted cyclodextrin derivatives have been synthesised, this review focuses only on the synthesis of several interesting monosubstituted derivatives (allyl, cinnamyl, propargyl, formylmethyl, carboxymethyl, azido and amino) suitable for further modifications. These derivatives allow the synthesis of an unlimited number of desired cyclodextrin derivatives. Using a cyclodextrin derivative already monosubstituted with a suitable functional group is much easier than the optimisation of monosubstitution for every new cyclodextrin derivative desired.

Enantioselective Gas Chromatography with Derivatized Cyclodextrins in the Flavour and Fragrance Field

AbstractThis article deals with enantioselective gas chromatography (Es‐GC) utilizing cyclodextrin derivatives as chiral stationary phases (CSPs) for chiral recognition in the flavour and fragrance field. It consists of two main parts. The first one concerns cyclodextrins and their use in Es‐GC, and it deals with their introduction and evolution as CSPs in GC, together with some theoretical aspects involved with enantiomeric separation and their consequent influence on routine chiral recognition. The second part reports on the strategy of chiral recognition in routine analysis with cyclodextrin derivatives as CSP, illustrated with examples from the authors’ everyday experiences. This part describes how to identify enantiomers or to measure their excess or ratio determination in complex mixtures; in particular, it discusses the opportunities offered by multidimensional and fast GC techniques, the role of mass spectrometry, and the application of total analysis systems to chiral recognition.

Cholesterol-Targeted Anticancer and Apoptotic Effects of Anionic and Polycationic Amphiphilic Cyclodextrin Nanoparticles

Amphiphilic cyclodextrins (CDs) are biocompatible derivatives of natural CDs and are able to form nanoparticles or polyplexes spontaneously. In this study, nanoparticles prepared from nonionic (6OCaproβCD) or cationic amphiphilic CD (PC βCDC6) were used comparatively to develop nanoparticles intended for breast cancer therapy. The characterization of these nanoparticles was performed both by in vitro and cell culture studies. Furthermore, the apoptotic and cytotoxic effects of blank amphiphilic CDs were demonstrated by various mechanistic methods including Caspase-8 activity, lipid peroxidation assay, TUNEL assay, Tali®-based image analysis, cholesterol assay, and gene expression studies. Blank nanoparticles exerted cytotoxicity against a variety of cancer cells (MCF-7, HeLa, HepG2, and MB49) but none to healthy cells (L929, G/G). Interestingly, blank 6OCaproβCD and blank PC βCDC6 derivatives were found to be intrinsically effective on cell number and membrane integrity of MCF-7 cells in apoptosis studies. Further in-depth studies were performed to elucidate the selective mechanism of anticancer action in MCF-7 cells caused by these amphiphilic CDs. In conclusion, blank amphiphilic CD nanoparticles induced apoptosis through mitochondrial pathway targeted to cholesterol microdomains in cancer cell membrane.

Predicting the binding free energy of the inclusion process of 2-hydroxypropyl-β-cyclodextrin and small molecules by means of the MM/3D-RISM method

A protocol to calculate the binding free energy of a host–guest system is proposed based on the MM/3D-RISM method, taking cyclodextrin derivatives and their ligands as model systems. The protocol involves the procedure to identify the most probable binding mode (MPBM) of receptors and ligands by means of the umbrella sampling method. The binding free energies calculated by the MM/3D-RISM method for the complexes of the seven ligands with the MPBM of the cyclodextrin, and with the fluctuated structures around it, are in agreement with the corresponding experimental data in a semi-quantitative manner. It suggests that the protocol proposed here is promising for predicting the binding affinity of a small ligand to a relatively rigid receptor such as cyclodextrin.

Quality by Design-Guided Development of a Capillary Electrophoresis Method for the Chiral Purity Determination of Ambrisentan

A quality by design approach utilizing experimental design methodologies was applied to develop a CE method to evaluate the enantiomeric purity of (S)-ambrisentan, a selective endothelin receptor antagonist used for the treatment of pulmonary arterial hypertension. Initial method scouting was performed by screening native cyclodextrins (CDs) as well as neutral CD derivatives and a positively charged derivative at pH 5 and pH 9, identifying γ-CD as suitable selector at pH 5. Upon defining the critical quality attributes and the critical process parameters, i.e., chiral resolution and run time, method development was performed by application of a screening design for the identification of the significant variables and, subsequently, by a response surface methodology for obtaining the design space. A Plackett–Burman design was employed for robustness testing. The final working point conditions used a background electrolyte composed of a 50-mM sodium acetate buffer, pH 4.0, containing 30 mM γ-CD in a 75-μm ID fused-silica capillary with an effective length of 40 cm at an applied voltage of 25 kV and a capillary temperature of 25 °C. The method was validated according to the ICH Q2(R1) guideline and allowed the determination of a relative concentration of the (R)-enantiomer of 0.1 %.

ChemInform Abstract: Cyclodextrins as Protective Agents of Protein Aggregation: An Overview

AbstractReview: 72 refs.

Formulation and Evaluation of Cyclodextrin Inclusion Complex Tablets of Carvedilol

Objective: The aim of this series of experiments was to improve the solubility of a poorly soluble drug. Materials and Methods: Binary inclusion complexes of carvedilol and cyclodextrins derivatives were prepared by kneading method. Their solubility and dissolution behavior were compared with that of the pure drug and the marketed formulation of carvedilol. Results: Saturation solubility studies indicate that the solubility of the drug was increased and X-ray diffraction, differential scanning calorimetry, scanning electron microscopy showed that the crystalline nature of drug was lost or decreased significantly in the inclusion complex, indicating the drug was present in a solubilized form in the formulation. All inclusion complex tablets showed increase in dissolution rate than tablet prepared with pure drug. Formulation FT8 showed faster drug release in comparison to other formulations and data were fitted to various kinetic models. The mechanism of drug release from tablets was found to be Supercase 2 Transport. Stability studies suggested that there was no significant degradation or changes taking place in the tablets during the study period. Conclusion: It can be concluded that the inclusion complexation technique is an effective approach for the dissolution rate improvement of water insoluble drugs such as carvedilol.

Fouling Resistance and Physicochemical Properties of Polyamide Thin‐Film Composite Membranes Modified with Functionalized Cyclodextrins

AbstractThermal and mechanical properties and fouling resistance of polyamide thin‐film composite (PA‐TFC) membranes modified with amino‐cyclodextrins and diethylamino‐cyclodextrins are investigated. It was found that the decomposition temperatures of the modified membranes were 500°C and were not significantly different with those of the unmodified membranes. Differential scanning calorimetry (DSC) studies showed that the modified membranes with heating melting temperatures in the range 112.5–113.8°C were more crystalline than the unmodified membranes due to the presence of cyclodextrin derivatives on the interfacial layer. The crystallization temperatures (Tc) were found to range between 128.75 and 129.03°C and the glass transition temperatures (Tg) ranged between 78.67 and 79.33°C. The modified PA‐TFC membranes were found to have comparable ultimate tensile strengths (UTS) to the unmodified membranes, except for the membranes modified with amino‐β‐CDs, with a UTS of 20.00 ± 0.50 MPa. The PA‐TFC membranes had a lower water uptake percentage due to their enhanced crystallinity. However, these materials had a higher water permeate flux due to the hydrophilic nature of the modified membranes enhanced by the rich hydroxyl groups on the CDs. The modified PA‐TFC membranes also exhibited high MgSO4 salt rejection and fouling resistance capacities compared to unmodified membranes. Different pH levels resulted in different fouling resistance patterns of the membranes. Therefore, the membranes modified with functionalized CDs were thermally and mechanically stable, had enhanced crystallinity, high divalent salt rejection and fouling resistance under different pH conditions.

Cyclodextrins as Protective Agents of Protein Aggregation: An Overview.

Cyclodextrins are extensively used in different fields (e.g., catalysis, chromatography, pharma, supramolecular chemistry, bioorganic chemistry, and bioinorganic chemistry), and their applications have been widely reviewed. Their main application in the field of pharmaceutical is as a drug carrier. This review overviews, for the first time, the use of cyclodextrins and their derivatives as antiaggregant agents in a number of proteins (e.g., amyloid-β, insulin, recombinant human growth hormone, prion protein, transthyretin, and α-synuclein) and some multimeric enzymes. There are many diseases that are correlated to protein misfolding and amyloid formation processes affecting numerous organs and tissues. There are over 30 different amyloid proteins and a number of corresponding diseases. Alzheimer's disease is the most common neurodegenerative disease. Treatment of these diseases is still a goal to reach, and many molecules are studied in this perspective. Cyclodextrins have also been studied, and they show great potential; as such, further studies could be very promising. This review aims to be a stimulus for the design of new cyclodextrin derivatives to obtain multifunctional systems with antiaggregant activity.

Host-guest inclusion systems of daidzein with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutyl ether-β-cyclodextrin (SBE-β-CD): Preparation, binding behaviors and water solubility

Daidzein is an isoflavone of naturally abundance existing in plants and foods which has attracted much attention for its significant benefits on human health. However, its application was severely limited by its poor solubilities, instability and low bioavailability. To overcome these drawbacks, inclusion complexes of daidzein with two cyclodextrin (CD) derivatives, i.e., 2-hydropropyl-β-cyclodextrin (HP-β-CD) and sulfobutyl ether-β-cyclodextrin (SBE-β-CD) were prepared and characterized both in solution and solid state by 1D and 2D NMR, XRD, SEM and elemental analyses. Fluorescence spectroscopy and the Job plot were used to demonstrate a mainly 1:1 inclusion mode between daidzein and CDs. Their thermal stabilities were evaluated with TG and DSC experiments. Moreover, water solubility of daidzein was significantly improved by inclusion complexation with CDs. These results might suggest valuable approaches to developments of new pharmaceutical formulations of daidzein.

Solute-Solvent Interactions in Aqueous Solutions of Sulfobutyl Ether-β-cyclodextrin As Probed by UV-Raman and FTIR-ATR Analysis.

A vibrational study by means of UV-Raman and FTIR-ATR measurements has been performed on sulfobutyl ether β-cyclodextrin (SBE-β-CD)-water solutions, as a function of concentration and temperature, with the aim to provide a molecular-scale explanation of the enhanced performances as carrier agent exhibited by this modified macrocycle with respect to natural cyclodextrin. The attention has been mainly paid to the modifications induced on the vibrational band assigned to the O-H stretching intramolecular mode, in turn related to the dynamical rearrangement occurring in the hydrogen bonding (HB) network of water molecules. The results of our measurements clearly showed a characteristic "structure-breaker" effect on the tetrahedral HB arrangements induced on water molecules by increasing of both temperature and solute concentration, allowing us to also extract thermodynamic parameters. These results could be a key step for a clearer understanding of the connection between the dynamical properties of hydration water and the complexing ability of this cyclodextrin derivative.

Chromatographic Characterization of a New Cationic β-CD Based Stationary Phase Prepared by Dynamic Coating

Cyclodextrin-based stationary phases are frequently used for separation of various isomers. The main reason for applying new cyclodextrin (CD) derivatives for HPLC stationary phases is the improvement of separation efficiency. This paper introduces a new stationary phase prepared by dynamic coating of ion-exchanger with a newly synthesized cationic derivative of β-cyclodextrin. This mono-substituted derivative of β-cyclodextrin contains two tetraalkylammonium groups in its side chain. Diverse sets of analytes were tested to reveal the separation potential of the derivatized stationary phase. This dynamically coated stationary phase exhibited mostly better selectivity and resolution than a commercial chemically bonded β-cyclodextrin stationary phase. Mixtures of analytes were baseline resolved in shorter analysis time. Furthermore, interactions participating in the retention mechanism were identified using a linear free energy relationship approach and ionic interaction study. Lower hydrophobicity and higher ability to interact as hydrogen bond donor affect retention on the coated stationary phase. Even though the ionic interaction study confirmed that the surface of the ion-exchanger was modified by dynamic coating, the ionic interactions still contributed to the retention mechanism on the coated stationary phase.

Capillary electrophoretic enantioseparation of basic drugs using a new single-isomer cyclodextrin derivative and theoretical study of the chiral recognition mechanism.

A novel single-isomer cyclodextrin derivative, heptakis {2,6-di-O-[3-(1,3-dicarboxyl propylamino)-2-hydroxypropyl]}-β-cyclodextrin (glutamic acid-β-cyclodextrin) was synthesized and used as a chiral selector in capillary electrophoresis for the enantioseparation of 12 basic drugs, including terbutaline, clorprenaline, tulobuterol, clenbuterol, procaterol, carvedilol, econazole, miconazole, homatropine methyl bromide, brompheniramine, chlorpheniramine and pheniramine. The primary factors affecting separation efficiency, which include the background electrolyte pH, the concentration of glutamic acid-β-cyclodextrin and phosphate buffer concentration, were investigated. Satisfactory enantioseparations were obtained using an uncoated fused-silica capillary of 50 cm (effective length 40 cm) × 50 μm id with 120 mM phosphate buffer (pH 2.5-4.0) containing 0.5-4.5 mM glutamic acid-β-cyclodextrin as background electrolyte. A voltage of 20 kV was applied and the capillary temperature was kept at 20°C. The results proved that glutamic acid-β-cyclodextrin was an effective chiral selector for studied 12 basic drugs. Moreover, the possible chiral recognition mechanism of brompheniramine, chlorpheniramine and pheniramine on glutamic acid-β-cyclodextrin was investigated using the semi-empirical Parametric Method 3.

Cyanoethylation of cyclodextrin derivatives

The synthesis of novel cyanoethylated cyclodextrin derivatives from previously prepared intermediates is described. It was found the alcohols at the primary face of cyclodextrins readily react to add to acrylonitrile, but similar additions from hydroxyl groups of the secondary face appear to be more difficult. The obtained cyanides could be reduced to form the corresponding amines.

Theoretical investigation of microcystin-LR, microcystin-RR and nodularin-R complexation with α-, β-, and γ-cyclodextrin as a starting point for the targeted design of efficient cyanotoxin traps

The interactions of three abundant cyanotoxins, namely microcystin-LR, microcystin-RR and nodularin-R with α-, β-, and γ-cyclodextrin in water were structurally and thermodynamically investigated by a computationally affordable methodology using the semi-empirical PM7 method in conjunction with an implicit treatment of solvent effects by the conductor-like screening model (COSMO). As an in silico methodology, PM7(COSMO) offers the advantage of being more environment-friendly than experimental approaches, provided that its computational accuracy limitations are properly accounted for. The results suggest the formation of 1:1 complexes via partial inclusion of the hydrophobic side-chain of cyanotoxins inside the cyclodextrin cavity preferably via the wider opening, further stabilized by hydrogen bonds between hydrophilic groups of the interacting molecules. Enthalpy and entropy changes upon complexation result in a binding efficiency increasing with cyclodextrin size, along with an increase dependent on cyanotoxin, in the order nodularin-R<microcystin-RR<microcystin-LR. The calculated binding efficiency trends are in accordance with literature experimental results demonstrating the reliability and utility of the PM7(COSMO) level of theory in modeling the interactions of cyanotoxins with cyclodextrins. In addition, the method has the ability to describe the structural features of the complexes. Therefore, it may be considered as a valuable computational tool for the targeted design of efficient cyanotoxin filtration agents utilizing cyclodextrin derivatives. The environmental benefits from the theoretical screening of non-toxic carbohydrate macrocycles as effective scavengers of harmful cyanotoxins satisfy the growing demand for sustainable chemistry solutions to practical problems of worldwide significance.

Synthesis and Utilization of Trialkylammonium-Substituted Cyclodextrins as Water-Soluble Chiral NMR Solvating Agents for Anionic Compounds.

Cationic trialkylammonium-substituted α-, β-, and γ-cyclodextrins containing trimethyl-, triethyl-, and tri-n-propylammonium substituent groups were synthesized and analyzed for utility as water-soluble chiral nuclear magnetic resonance (NMR) solvating agents. Racemic and enantiomerically pure (3-chloro-2-hydroxypropyl)trimethyl-, triethyl-, and tri-n-propyl ammonium chloride were synthesized from the corresponding trialkyl amine hydrochloride and either racemic or enantiomerically pure epichlorohydrin. The ammonium salts were then reacted with α-, β-, and γ-cyclodextrins at basic pH to provide the corresponding randomly substituted cationic cyclodextrins. The (1) H NMR spectra of a range of anionic, aromatic compounds was recorded with the cationic cyclodextrins. Cyclodextrins with a single stereochemistry at the hydroxy group on the (2-hydroxypropyl)trialkylammonium chloride substituent were often but not always more effective than the corresponding cyclodextrin in which the C-2 position was racemic. In several cases, the larger triethyl or tri-n-propyl derivatives were more effective than the corresponding trimethyl derivative at causing enantiomeric differentiation. None of the cyclodextrin derivatives were consistently the most effective for all of the anionic compounds studied.

Enabling technologies and green processes in cyclodextrin chemistry.

The design of efficient synthetic green strategies for the selective modification of cyclodextrins (CDs) is still a challenging task. Outstanding results have been achieved in recent years by means of so-called enabling technologies, such as microwaves, ultrasound and ball mills, that have become irreplaceable tools in the synthesis of CD derivatives. Several examples of sonochemical selective modification of native α-, β- and γ-CDs have been reported including heterogeneous phase Pd- and Cu-catalysed hydrogenations and couplings. Microwave irradiation has emerged as the technique of choice for the production of highly substituted CD derivatives, CD grafted materials and polymers. Mechanochemical methods have successfully furnished greener, solvent-free syntheses and efficient complexation, while flow microreactors may well improve the repeatability and optimization of critical synthetic protocols.

Recent Development of Copolymeric Delivery System for Anticancer Agents Based on Cyclodextrin Derivatives.

Core-shell structured aggregates of amphiphilic block copolymer are hopefully drug delivery system because of their ability to encapsulate hydrophobic drugs, and their hydrophilic shell can prolong retention time of drugs in the blood circulation system. Cyclodextrin is a kind of hydrophilic polysaccharide containing multiple hydroxyl groups, providing an inner hole that can load small molecule through host-guest interaction. These hydroxyl groups or their derived functional ones are utilized in conjugation with polymeric chains to form block copolymers. These copolymers can not only encapsulate hydrophobic drugs, but also encapsulate hydrophilic drugs (like DNA, protein, etc) through hydrophobic, host-guest or electrostatic interactions, which strengthen interaction between drugs and materials compared with general copolymers, indicating that formed drug delivery systems are more stable. By introduction of target molecule, they also achieve selective delivery of drugs to specific tissues or organs. So, several researchers are stimulated to carry out many studies for the development of cyclodextrin copolymeric drug delivery systems in recent. In this review, we focus the cyclodextrin copolymers' application in the anticancer agents' delivery.