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Sulfobutylether β-cyclodextrin (SBE-β-CD) is a polyanionic cyclic oligosaccharide that contains glucopyranose units forming a torus ring-like structure. SBE-β-CD is gifted with many favorable properties viz. relatively high solubility (>50 folds compared to β-CD), improved stability, and biocompatibility that praised SBE-β-CD as a smart polymer for drug delivery applications. Commercially, SBE-β-CD is popular by its brand name Captisol®. The present review discusses the structure, properties, and preparation methods of SBE-β-CD-based inclusion complexes (ICs). Furthermore, we discuss here the preparation and applications of SBE-β-CD ICs-based nanoparticulate drug delivery systems, which combines the merits of both, ICs (enhanced solubility) and nanoparticles (NPs, targeted therapy). Patents on and FDA-approved Captisol®-enabled products are tabulated in the benefit of readers. The toxicological aspects and current clinical status of SBE-β-CD or SBE-β-CD-based products are briefly explained in the present review. In our opinion, the present review would be a pathfinder to allow dissemination of information on SBE-β-CD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Novel complexes of two different solid forms of Albendazol and β-cyclodextrin were investigated in an attempt to obtain promising candidates for the preparation of alternative matrices used in pharmaceutical oral formulations. The interaction between each form of Albendazol and β-cyclodextrin was studied in solution and solid state, in order to investigate their effect on the solubility and dissolution rate of Albendazol solid forms. The solid supramolecular systems were characterized using a variety of techniques including natural-abundance 13 C cross-polarization magic-angle-spinning nuclear magnetic resonance, powder X-ray diffraction, Fourier transform-infrared spectroscopy and scanning electron microscopy. The results obtained showed the highest increment of solubility and dissolution rate, in simulated gastric fluid, for the Albendazole II:β-cyclodextrin systems. Thus, these new complexes constitute an interesting alternative for improving the oral bioavailability of Albendazol., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The purpose of this study was to improve the physicochemical and biological properties of chloramphenicol (CP) by multicomponent complexation with β-cyclodextrin (β-CD) and N-acetylcysteine (NAC). The present work describes the ability of solid multicomponent complex (MC) to decrease biomass and cellular activity of Staphylococcus by crystal violet and XTT assay, and leukocyte toxicity, measuring the increase of reactive oxygen species by chemiluminescence, and using 123-dihydrorhodamine. In addition, MC was prepared by the freeze-drying or physical mixture methods, and then characterized by scanning electron microscopy and powder X-ray diffraction. Nuclear magnetic resonance and phase solubility studies provided information at the molecular level on the structure of the MC and its association binding constants, respectively. The results obtained allowed us to conclude that MC formation is an effective pharmaceutical strategy that can reduce CP toxicity against leukocytes, while enhancing its solubility and antibiofilm activity., (Copyright © 2016. Published by Elsevier Ltd.)

A second compound is generally associated with oligosaccharides as a strategy to maximize the solubilizing effect for nonpolar compounds. This study elucidated the role and the mechanism whereby liquid compounds interact in these supramolecular aggregates in the solubilization of triamcinolone. Three different oligosaccharides (beta-cyclodextrin, 2-hydroxipropil-beta-cyclodextrin, and randomly methylated beta-cyclodextrin) and two potent co-solvents (triethanolamine and N-methyl pyrrolidone) were carefully evaluated by using three distinct experimental approaches. Incredibly stable complexes were formed with cyclodextrins (CDs). The structure of the complexes was elucidated by magnetic resonance spectra 2D-ROESY. The interactions of the protons of ring "A" of the drug with H(3) and H(5) protons of the CD cavity observed in the binary complexes remained in both ternary complexes. Unlike the observed ternary associations with triethanolamine, N-methyl pyrrolidone competed with the triamcinolone CD cavity and considerably decreased the stability of the complex and the solubility of the drug. The molecular dynamics (MD) and quantum mechanics:molecular mechanics (QM:MM) calculations supported that triethanolamine stabilized the drug-CD interactions for the conformer identified in the 2D-ROESY experiments, improving the quality and uniformity of the formed complex. The role played by the co-solvent in the ternary complexes depends on its specific ability to interact with the CD cavity in the presence of the drug, which can be predicted in theoretical studies to select the best candidate., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The aim of this study was to improve the solubility of chloramphenicol and reduce the production of reactive oxygen species (ROS) in leucocytes induced by this drug, using complexation. Multicomponent complexes were prepared by the addition of β-cyclodextrin with glycine or cysteine. Nuclear magnetic resonance and phase solubility studies provided information at the molecular level on the structure of the complexes and their association binding constants, respectively. In the solid state, all systems were extensively characterized by Fourier-transform infrared spectroscopy, scanning electron microscopy, thermal analysis and X-ray powder diffraction. Antimicrobial activity of inclusion complexes was investigated by agar diffusion methods. Finally ROS determination by chemiluminescence was used to investigate the effect of complex formation on the potential toxicity in human leucocytes. These studies revealed that multicomponent complexes can increase the aqueous solubility of chloramphenicol as well as reducing the stress by ROS production in leucocytes and maintaining its microbiological activity., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Large oral doses of ACZ lower the intraocular pressure (IOP), but usually lead to a multitude of systemic side effects, including gastrointestinal upset. The present study was undertaken to evaluate the effect of ACZ on the histological structure of rat duodenal mucosa and to assess a possible protective role of the complex formation of ACZ with HP-β-CD, either separately or in combination with a third compound, on the gut epithelial layer by histological and ultrastructural examinations of sections of rat duodenum exposed to ACZ or its formulations. In addition, the transport process of ACZ and its binary or ternary complexes across the duodenal mucosa by means of the single-pass intestinal perfusion (SPIP) method in rats was evaluated. Evidence was found that ACZ alters intestinal permeability and induces damage to the rat small intestine. In contrast, ACZ-induced intestinal injury may be abrogated by ACZ complexation. In addition, the complexation of ACZ with HP-β-CD, alone or in combination with a third compound, facilitated significant levels of ACZ uptake across the rat duodenal segment. Ternary complexes of ACZ with HP-β-CD in combination with TEA (triethanolamine) or calcium ions were found to provide an excellent approach that enabled an increased apparent permeability of ACZ across the duodenal epithelium, with a concomitant ability to preserve the integrity of the gut epithelium from ACZ-induced injury. These results could be useful for the design and development of novel ACZ formulations that can reduce GI toxicity, while still maintaining their essential therapeutic efficacies., (Copyright © 2014. Published by Elsevier B.V.)

The interaction of methotrexate (MTX) with beta-cyclodextrin (β-CD) in the presence of triethanolamine (TEA) was investigated with the aim to elucidate the mechanism whereby self-assembly cyclodextrin systems work in association with this third component. Solubility diagram studies showed synergic increment of the MTX solubility to be about thirty-fold. Experiments using 2D ROESY and molecular modeling studies revealed the inclusion of aromatic ring III of the drug into β-CD cavity, in which TEA contributes by intensifying MTX interaction with β-CD and stabilizes MTX:β-CD:TEA ternary complex by electrostatic interaction. The maintenance of these interactions in solid phase was also studied in ternary MTX:β-CD:TEA and comparisons were made with freeze dried binary MTX:β-CD and physical mixtures. FTIR studies evidenced that MTX-β-CD interaction remained in solid ternary complexes, which was also supported by thermal (differential scanning calorimetry (DSC), thermogravimetric analysis (TG)/first derivative of TG analysis (DTG) and C,N,H elementary analysis) and structural (X-ray diffraction analysis, (XRD)) studies, mainly regarding the increment of drug stability. The efficient in vitro drug dissolution studies successfully demonstrated the contribution of ternary complexes, which highlights the importance of this possible new raw material for further applications in drug delivery systems.

The solid-state properties of novel complexes of β-cyclodextrin and two different solid forms of norfloxacin were investigated at the molecular level, in an attempt to obtain promising candidates for the preparation of alternative matrices used in pharmaceutical oral formulations. In order to evaluate the physical properties inherited from the different polymorphs, these supramolecular systems were characterized using a variety of spectroscopic techniques including natural-abundance (13) C cross-polarization magic-angle-spinning (CP-MAS) nuclear magnetic resonance (NMR), powder X-ray diffraction, and Fourier transform infrared spectroscopy. The intrinsic proton spin-lattice relaxation times detected in (13) C CP-MAS NMR spectra are used to confirm and distinguish the complex formation, as well as to provide better insights into the molecular fragments that are involved in the interaction with β-cyclodextrin., (© 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Hydrochlorothiazide (HCT) is one of the most commonly prescribed antihypertensive drugs. In an attempt to gain an insight into the physicochemical and molecular aspects controlling the complex architecture of native β-cyclodextrin (β-CD) with HCT, we performed multiple-temperature-pH isothermal titration calorimetric measurements of the HCT:β-CD system, together with proton nuclear magnetic resonance spectroscopy ((1)H NMR), phase solubility analysis, and molecular modeling methods. The A(L)-type diagrams, obtained at different pH values and temperatures, suggested the formation of soluble 1:1 inclusion complexes of β-CD with HCT. The corresponding stability constants (K(1:1)) were determined by phase solubility studies and compared with those obtained by ITC, with good agreement between these two techniques being found. The three-dimensional array of the complex was studied by (1)H NMR and molecular modeling methods. Both techniques confirmed the formation of the inclusion complex, with good agreement between the experimental and theoretical techniques regarding the HCT binding mode to β-CD. Also, the forces involved in the association process were determined, both from the thermodynamic parameters obtained by ITC (association enthalpy, binding constant, Gibbs free energy, and entropy) and from energetic decomposition analyses derived from computational methods. We concluded that the formation of the HCT:β-CD complex was enthalpy driven, with the inclusion mode of HCT being highly dependent on its ionization state. In all cases, sustained hydrogen bond interactions with hydroxyl groups of β-CD were identified, with the solvation energy limiting the affinity. Regarding the pH and temperature dependence, lower affinity constants were found at higher HCT ionization states and temperatures.

The complex formation of chlorhexidine digluconate (CHX-G(2)) with hydroxypropyl-β-cyclodextrin (HPβCD) was studied using NMR spectroscopy. The results revealed that this surfactant agent shows an monomer/aggregate equilibrium, which is dependent on the concentration of this drug. This equilibrium can be modified by the presence of HPβCD, which reduces the aggregation of the CHX-G(2) molecules. An inclusion process of the CHX-G(2) aromatic residue within the cyclodextrin cavity was confirmed by 2D ROESY spectroscopy. (1)H NMR titration studies of CHX-G(2) with HPβCD in D(2)O confirmed the formation of higher order complexes between CHX-G(2) and HPβCD. Moreover, the addition of HPβCD into CHX-G(2) solutions forms insoluble aggregates. Such insoluble aggregates may result in the stacking of CHX-G(2) molecules on the surface of the CHX-G(2):HPβCD complexes., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Here, we describe the chemical characterization of the inclusion complex between diclofenac (DCF) and methyl-beta-cyclodextrin (M-beta-CD) in the presence or absence of monoethanolamine (MEA). Several techniques were used to analyze the complex both in solution and in the solid state. Solubility of DCF was increased by the addition of M-beta-CD. However, the DCF solubility increase was more significant by the addition of M-beta-CD in the presence of MEA. In vitro permeation experiments through excised human skin revealed that DCF was enhanced by M-beta-CD. Nevertheless, further improvement in the flux and the permeability coefficient of DCF was obtained by the ternary system DCF-M-beta-CD-MEA., (2010 Elsevier Masson SAS. All rights reserved.)

Importance of the Field: Acetazolamide (ACZ), a carbonic anhydrase inhibitor (CAI), and other oral CAIs have been an integral part of antiglaucoma therapy for > 40 years. ACZ is used orally for the reduction of intraocular pressure in patients suffering from glaucoma. However, this treatment leads to unpleasant systemic side effects. The answer to the undesirable effects of ACZ is the topical delivery of this drug into the eye, where it could elicit its physiological action. However, the development of a topical formulation of ACZ is limited by its poor ocular bioavailability, which can be largely attributed to its poor penetration coefficient and poor biphasic solubility., Areas Covered in This Review: This review offers an overview of different approaches to delivering ACZ to the eye, highlighting the potential of the ternary system ACZ:HP-beta-CD:TEA as a tool for formulating aqueous ACZ eye drop solutions., What the Reader Will Gain: A critical analysis is provided to highlight the key issues to design formulations containing hydrophilic cyclodextrins., Take Home Message: The ACZ:HP-beta-CD:TEA complex is an important new approach to improve the ocular bioavailability of this drug. This approach may be applied to other CAIs in the future.

The complex formation between three structurally related sulfonamides (sulfadiazine (SDZ), sulfamerazine (SMR), and sulfamethazine (SMT)) and beta-cyclodextrin (beta-CD) was studied, by exploring its structure affinity relationship. In all the cases, 1:1 stoichiometries were determined with different relative affinities found by phase solubility (SDZ:beta-CD > SMR:beta-CD > SMT:beta-CD) and nuclear magnetic resonance (NMR) (SMT:beta-CD > SMR:beta-CD > SDZ:beta-CD) studies. The spatial configurations determined by NMR were in agreement with those obtained by molecular modeling, showing that SDZ included its aniline ring into beta-CD, while SMR and SMT included the substituted pyrimidine ring. Energetic analyses demonstrated that hydrophobicity is the main driving force to complex formation., ((c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association)

In order to enhance the ocular bioavailability of acetazolamide (ACZ), a multicomponent complex with hydroxypropyl-ss-cyclodextrin (HP-ss-CD) and triethanolamine (TEA) was prepared to be applied topically. In vitro corneal permeation across isolated rabbit cornea of proposed ACZ formulations and the marketed AZOPT(R) formulation (1% w/v brinzolamide) was studied. Formulations were also tested for their effect on the intraocular pressure (IOP) in rabbits. (1)H- and (13)C-NMR experiments were undertaken to verify the real inclusion of ACZ in the ACZ-HP-ss-CD-TEA multicomponent complex. The binding of ACZ to HP-ss-CD in the presence of TEA is described. The increase of TEA concentration decreases the apparent equilibrium constant for the ACZ-HP-ss-CD complex. The ternary system ACZ-HP-ss-CD-TEA seemed to be able to reduce IOP in about 30%. This effect was sustained for 4 h after instillation. In vitro corneal permeation studies demonstrated that the ACZ permeation was increased. RMN experiments indicated that TEA can weaken the association between ACZ and HP-ss-CD increasing the drug ocular hypotensive effect by increasing the free drug available for absorption. Our formulations were considered practically non-irritant. These results indicate that the ternary system ACZ-HP-ss-CD-TEA might be a useful tool for formulating aqueous ACZ eye drop solutions.

The main objective of this work was to study an inclusion complex between enalapril (ENA), and beta-cyclodextrin (beta-CD). From nuclear magnetic resonance (NMR) we determined that the complex showed a 1:1 stoichiometry, with an apparent formation constant (K(C)) of 439 and 290 M(-1) for the cis and trans isomers, respectively. The molecular modeling and NMR techniques demonstrated that the aromatic moiety of ENA was inserted into the hydrophobic cavity of beta-CD. When studying the chemical stability of ENA complexed to beta-CD, a clear stabilizing effect was observed in both the aqueous solution and solid state.

The aim of our work was to develop a multicomponent inclusion complex of acetazolamide (ACZ) in order to investigate the combined effect of hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and triethanolamine (TEA) on the solubility of ACZ and its possibility of ophthalmic delivery. Phase solubility study was used to evaluate the complexation in solution at 25 degrees C. Complex formation was also evaluated by comparing the infrared (FT-IR) spectra of the solid complexes with a simple physical mixture containing the same amount of ACZ. FT-IR experiments provided data indicating that the carbonamido group of ACZ is involved in the inclusion process. In vitro release data showed that both formulations, containing the freeze-dried ternary complex and the corresponding simple physical mixture of ACZ with HP-beta-CD and TEA presented the fastest release rate of ACZ. These results suggest that the ACZ-HP-beta-CD-TEA complex represents an effective novel formulation to enhance ACZ solubility in water, turning it promising for ophthalmic administration.

Binary and multicomponent systems complexes prepared with HP-beta-CD and/or with monoethanolamine (MEA), diethanolamine (DEA) or triethanolamine (TEA) were obtained. The results of solid-state studies indicated the presence of strong interactions between the components in the binary and the ternary systems. Drug solubility and dissolution rate in water were notably improved by employing the HP-beta-CD and the alkanolamines. The combined use of cosolvency and complexation with MEA in the presence of HP-beta-CD on the permeation of flurbiprofen through the human skin was evaluated. The combination of IPM, PG, and HP-beta-CD yield the highest permeation for the flurbiprofen-MEA complex.