Preparation and evaluation of inclusion complexes of commercial sunscreens in cyclodextrins and montmorillonites: performance and substantivity studies

Herein we describe inclusion complexes of commercial sunscreens in cyclodextrins and montmorillonites to generate new sunscreen derivatives with optimized functional properties such as water resistance and skin adherence. Four cyclodextrins (alpha-, beta-, and gamma-cyclodextrin, and beta-dimethyl cyclodextrin) and two montmorillonites (sodium and alkylammonium) were investigated for encapsulating some commercial sunscreens. Our results reveal a good yield and inclusion products with functional properties obtained by using kneading technique on Eusolex 2292 and Eusolex 6007 in beta-cyclodextrin and solubilization method on Eusolex 6007 and NeoHeliopan MA in montmorillonite. In addition, molecular modeling studies indicated flexibility as important for the intercalation of the host molecule.     

Host–guest inclusion system of mangiferin with β-cyclodextrin and its derivatives

The characterization, inclusion complexation behavior and binding ability of the inclusion complexes of mangiferin (MGF) with β-cyclodextrin and its derivatives (hydroxypropyl-β-cyclodextrin (HPβCD), sulfobutyl ether β-cyclodextrin (SBEβCD) and mono (6-ethylene-diamino-6-deoxy)-β-cyclodextrin (ENβCD)) were investigated in both solution and solid state by means of PL spectroscopy, ¹H and 2D NMR, XRD, TG and DSC. The results showed that the water solubility and thermal stability of MGF were significantly increased in the inclusion complex with cyclodextrins. The MGF/CDs complexes will be potentially useful for the design of a novel formulation of mangiferin for herbal medicine.     

Effect of Humidity on The Formation and Stability of Acetaminophen-β-Cyclodextrin Inclusion Complexes

Abstract

The effect of humidities (75% RH and 100% RH) on the inclusion complex formation and crystallizing behavior of physical mixture and ground mixture of acetaminophen with α-cyclodextrin, β-cyclodextrin or microcrystalline cellulose at 30 °C were studied by DSC thermal analysis, X-ray diffractometer, IR spectrophotometer. The change of water content in the physical mixture and ground mixture when stored at 30 °C, 75% RH or 100% RH was determined. The results indicate that the inclusion complex formation and crystallizing behavior of these mixtures were dependent on the relative humidity and types of cyclodextrins. The physical mixture of acetaminophen and β-cyclodextrin stored at 30 °C and 100% RH was transformed to crystalline inclusion complex, but stored at 75% RH still exhibited a behavior of physical mixture. The ground mixture of acetaminophen and β-cyclodextrin was converted amorphous inclusion complex to crystalline inclusion complex whether stored at 75% RH or 100% RH. However, physical mixture and ground mixture of acetaminophen and α-cyclodextrin or microcrysatlline cellulose when stored at 75% RH or 100% RH belonged to a crystalline physical mixture.     

Inclusion complexes of fluorofenidone with β-cyclodextrin and hydroxypropyl-β-cyclodextrin

Background: Fluorofenidone is a novel antifibrotic drug and its aqueous solubility is low. Aim: This study was to prepare and characterize inclusion complexes of fluorofenidone (AKF-PD) with β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD). Method: The AKF-PD/cyclodextrins (CDs) inclusion complexes were prepared by coprecipitation and freeze-drying, respectively. The solubility enhancement of AKF-PD was evaluated by phase solubility method. Inclusion complexation in solid phase was studied by X-ray diffraction (XRD) and differential thermal analysis (DTA). The dissolution profiles of AKF-PD/CDs inclusion complexes were investigated and compared with those of their physical mixtures and AKF-PD alone. Results: The phase solubility diagrams of AKF-PD with β-CD and HP-β-CD were of A_L-types, and the solubility of AKF-PD could be increased by 51.5% for β-CD at 0.014 M and 794.0% for HP-β-CD at 0.254 M. The results from XRD and DTA suggested that AKF-PD could form inclusion complex with β-CD or HP-β-CD. The dissolution rate of AKF-PD from the inclusion complexes was much more rapid than AKF-PD alone. Conclusions: The formulation of AKF-PD/CDs inclusion complexes showed superior performance in improving dissolution properties of AKF-PD.     

Effects of Grinding with Microcrystalline Cellulose and Cyclodextrins on the Ketoprofen Physicochemical Properties

Ground mixtures of ketoprofen (KETO) with native crystalline β-cyclodextrin, amorphous statistically substituted methyl-β-cyclodextrin, and microcrystalline cellulose were investigated for both solid phase characterization (differential scanning calorimetry (DSC) powder X-ray diffractometry, and infrared (IR) spectrometry) and dissolution properties (dispersed amount and rotating disk methods) to evaluate the role of the carrier on the performance of the final product. The effects of different grinding conditions, partial sample dehydration, and 1 year storage at room temperature were also investigated. The results pointed out the importance of the carrier nature on the efficiency of the cogrinding process. Both cyclodextrins were much more effective than was microcrystalline cellulose, even though no true inclusion complex formation occurred by mechanochemical activation. The best results were obtained from ground mixtures with methyl-β-cyclodextrin, which showed the best amorphizing and solubilizing power toward the drug and permitted an increase of approximately 100 times its intrinsic dissolution rate constant, in comparison with the approximate 10 times increase obtained from ground mixtures with β-cyclodextrin.     

Interaction of Cyclomaltononaose (δ-CD) with Several Drugs

The effects of δ-cyclodextrin (δ-CD; cyclomaltononaose) on solubility of 14 drugs that are slightly soluble or insoluble in water were studied and compared with those of conventional cyclodextrins (CDs) such as α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), and γ-cyclodextrin (γ-CD). In general, δ-CD had a weak complex-forming ability with the drugs examined in comparison with β-CD and γ-CD. However, in the case of digitoxin, δ-CD enhanced solubility of the guest molecules. To determine the mechanism of inclusion complex formation of δ-CD with digitoxin, the interaction of both drugs was investigated by the solubility method and spectroscopic methods such as ultraviolet (UV) and ¹H-NMR (nuclear magnetic resonance). The changes in chemical shift (¹H) and hypsochromic shift of UV suggested that digitoxin was partially included in the cavity of δ-CD.     

Pharmaceutical Uses of Cyclodextrins and Derivatives

Abstract

Due to their particular conformation, cyclodextrins have the remarkable characteristic of being able to include various kinds of molecule inside their hydrophobic cavity, conferring on them an environmental hydrophily. These inclusion compounds have completely new pharmacotechnical properties, but the most important ones concern increases in water solubility and bioavailability. When administered orally, the inclusion compounds decompose, allowing the free active ingredient to be absorbed by the gastro-intestinal mucosa. However, a certain proportion of inclusion compound is absorbed without any dissociation.

Some cyclodextrin derivatives are very interesting because of their very high water solubility, and also because of their low parenteral toxicity compared with the original β-cyclodextrin. However, in parenteral administration, it is absolutely necessary to study the pharmacokinetic and pharmacological characteristics of the inclusion compound, which must be considered as the true active ingredient.     

Sulfobutylether-β-cyclodextrin/chitosan nanoparticles enhance the oral permeability and bioavailability of docetaxel

The aim of this research is to develop novel chitosan nanoparticles including cyclodextrins complexes for docetaxel (DTX), evaluate the performance of nanoparticles which could enhance the oral permeability and bioavailability of DTX in vitro and in vivo. DTX/sulfobutylether-β-cyclodextrin inclusion complexes were made and it was the main ingredient to prepare the DTX/sulfobutylether-β-cyclodextrin/chitosan nanoparticles due to their promising physicochemical properties. DTX/sulfobutylether-β-cyclodextrin/chitosan nanoparticles were prepared by the ionic gelation of chitosan with tripolyphosphate in the presence of cyclodextrins. Results indicated that DTX/sulfobutylether-β-cyclodextrin inclusion complexes and docetaxel/sulfobutylether-β-cyclodextrin/chitosan nanoparticles both had good performances in the studies of release and the rat small intestinal absorption in vitro. DTX/sulfobutylether-β-cyclodextrin/chitosan nanoparticles showed preferable capability in improving the small intestinal absorption and inhibiting the efflux of DTX. In pharmacokinetics study, the DTX/sulfobutylether-β-cyclodextrin/chitosan nanoparticles increased the AUC_0→t and decreased the clearance significantly, and the oral relative bioavailability of the DTX/sulfobutylether-β-cyclodextrin/chitosan nanoparticles was as high as 1447.53% compared to the pure DTX formulation. The DTX/sulfobutylether-β-cyclodextrin/chitosan nanoparticles prepared in this study have a good prospect for oral administration as an alternative of current DTX formulations.     

Influence of Method of Preparation on Inclusion Complexes of Naproxen with Different Cyclodextrins

Abstract

The aim of this study is to increase the solubility of naproxen by inclusion complex formation with α, β, γ, hydroxypropylbeta and dimethylbetacyclodextrin. The apparent stability constants were calculated from the slope and intercept of the AL-solubility diagrams. The solid inclusion complexes of naproxen with cyclodextrins in 1:1 molar ratio were prepared by the kneaded-mix, spray-drying and freeze-drying method. The formation of inclusion complexes in the solid state were confirmed by X-Ray diffractometry I.R. spectroscopy and differential scanning calorimetry. The dissolution rate of naproxen from the inclusion complexes was much more rapid than naproxen alone. The best results were obtained with β-cyclodextrin inclusion complex prepared by the spray-drying method.     

Solubility and Dissolution Rate of Progesterone-Cyclodextrin-Polymer Systems

ABSTRACT

This contribution focused on the solubility improvement of the poorly water-soluble steroid hormone progesterone which, in its natural state, presents a reduced oral bioavailability. In the first part of this study, two simple, reproducible methods that were candidates for use in the preparation of inclusion complexes with cyclodextrins were investigated. Solubility capacities of the progesterone complex with hydroxypropyl-β-CD (HPβ-CD), hydoxypropyl-γ-CD (HPγ-CD), permethyl-β-CD (PMβ-CD), and sulfobutylether-β-CD (SBEβ-CD), prepared by the freeze-drying and precipitation methods, were evaluated by Higuchi phase solubility studies. The results showed that HPβ-CD and PMβ-CD were the most efficient among the four cyclodextrins for the solubilization of progesterone, with the highest apparent stability constants. Therefore, dissolution studies were conducted on these latest progesterone/cyclodextrin complexes and physical mixtures. Two additional natural cyclodextrins, β-CD and γ-CD, were taken as references. Hence, the influence of more highly soluble derivatives of β‐CD (HPβ-CD, PMβ-CD) on the progesterone dissolution rate, in comparison to pristine β-CD, alongside an increase in the cavity width for γ-CD versus β-CD, were investigated. The dissolution kinetics of progesterone dissolved from HPβ-CD, PMβ-CD, and γ-CD revealed higher constant rates in comparison to β-CD. Therefore, the aim of the second part of this study was to investigate the possibility of improving the dissolution rate of progesterone/β-CD binary systems upon formation of ternary complexes with the hydrophilic polymer, PEG 6000, as β-CD had the smallest progesterone solubility and dissolution capacity among the four cyclodextrins studied (β‐CD, HPβ-CD, HPγ-CD and PMβ-CD). The results indicated that dissolution constant rates were considerably enhanced for the 5% and 10% progesterone/β-CD complexes in PEG 6000.

The interaction of progesterone with the cyclodextrins of interest on the form of the binary physical mixtures, complexes, or ternary complexes were investigated by differential scanning calorimetry (DSC) and Fourier transformed-infrared spectroscopy (FT-IR). The results proved that progesterone was diffused into the cyclodextrin cavity, replacing the water molecules and, in case of ternary systems, that the progesterone β-cyclodextrin was well dispersed into PEG, thus improving progesterone bioavailability for subsequent oral delivery in the same way as derivatized cyclodextrins. The present work proves that ternary complexes are promising systems for drug encapsulation.     

Development of Fast-Dissolving Tablets of Flurbiprofen-Cyclodextrin Complexes

The present study was aimed at developing a tablet formulation based on an effective flurbiprofen-cyclodextrin system, able to allow a rapid and complete dissolution of this practically insoluble drug. Three different cyclodextrins were evaluated: the parent β-cyclodextrin (previously found to be the best partner for the drug among the natural cyclodextrins), and two amorphous, highly soluble β-cyclodextrin derivatives, i.e., methyl-β-cyclodextrin and hydroxyethyl-β-cyclodextrin. Equimolar drug-cyclodextrin binary systems prepared according to five different techniques (physical mixing, kneading, sealed-heating, coevaporation, and colyophilization) were characterized by Differential Scanning Calorimetry, x-ray powder diffractometry, infrared spectroscopy, and optical microscopy and evaluated for solubility and dissolution rate properties. The drug solubility improvement obtained by the different binary systems varied from a minimum of 2.5 times up to a maximum of 120 times, depending on both the cyclodextrin type and the system preparation method. Selected binary systems were used for preparation of direct compression tablets with reduced drug dosage (50 mg). Chitosan and spray-dried lactose, alone or in mixture, were used as excipients. All formulations containing drug-cyclodextrin systems gave a higher drug dissolved amount than the corresponding ones with drug alone (also at a dose of 100 mg); however, the drug dissolution behavior was strongly influenced by formulation factors. For example, for the same drug-cyclodextrin product the time to dissolve 50% drug varied from less than 5 minutes to more than 60 minutes, depending on the excipient used for tableting. In particular, only tablets containing the drug kneaded with methyl-β-cyclodextrin or colyophilized with β-cyclodextrin and spray-dried lactose as the only excipient satisfied the requirements of the Food and Drug Administration (FDA) for rapid dissolving tablets, allowing more than 85% drug to be dissolved within 30 minutes. Finally, it can be reasonably expected that the obtained drug dissolution rate improvement will result in an increase of its bioavailability, with the possibility of reducing drug dosage and side effects.     

Effects of grinding with microcrystalline cellulose and cyclodextrins on the ketoprofen physicochemical properties

Ground mixtures of ketoprofen (KETO) with native crystalline β-cyclodextrin, amorphous statistically substituted methyl-β-cyclodextrin, and microcrystalline cellulose were investigated for both solid phase characterization (differential scanning calorimetry (DSC) powder X-ray diffractometry, and infrared (IR) spectrometry) and dissolution properties (dispersed amount and rotating disk methods) to evaluate the role of the carrier on the performance of the final product. The effects of different grinding conditions, partial sample dehydration, and 1 year storage at room temperature were also investigated. The results pointed out the importance of the carrier nature on the efficiency of the cogrinding process. Both cyclodextrins were much more effective than was microcrystalline cellulose, even though no true inclusion complex formation occurred by mechanochemical activation. The best results were obtained from ground mixtures with methyl-β-cyclodextrin, which showed the best amorphizing and solubilizing power toward the drug and permitted an increase of approximately 100 times its intrinsic dissolution rate constant, in comparison with the approximate 10 times increase obtained from ground mixtures with β-cyclodextrin.     

Microcalorimetry of chiral surfactant-cyclodextrin interactions

The interactions of the chiral surfactants taurodeoxycholate (TDOCA) and deoxycholate (DOCA) with a range of cyclodextrins in aqueous solution have been investigated by isothermal titration microcalorimetry. In the presence of β-cyclodextrin, the apparent critical micelle concentration (cmc) of taurodeoxycholate is increased, and the enthalpy of demicellization decreased, in a manner consistent with 1:1 complexation of TDOCA with β-CD at low concentrations. There is no evidence for direct interaction of cyclodextrins with surfactant micelles. This is confirmed by more direct binding titrations. Below the cmc, TDOCA forms 1:1 host-guest complexes with β-cyclodextrin (ΔH°(bind) = -32 kJ mol(-)(1), K(diss) = 0.38 mM; 25 °C, pH 7), methyl-β-cyclodextrin (ΔH(bind) = -13 kJ mol(-)(1), K(diss) = 0.36 mM), hydroxypropyl-β-cyclodextrin (ΔH°(bind) = -12 kJ mol(-)(1), K(diss) = 0.51 mM), and γ-cyclodextrin (ΔH°(bind) = -7.3 kJ mol(-)(1), K(diss) = 0.08 mM), but not with the smaller α-cyclodextrin. At higher cyclodextrin concentrations, the calorimetric binding data are more ambiguous, suggesting 2:1 cyclodextrin/TDOCA complexation. Similar results are found with DOCA, though experiments here are limited by the tendency of DOCA to form gels in aqueous buffers. Enhanced chromatographic or electrophoretic chiral resolution observed in mixed chiral surfactant/cyclodextrin phases could be the result of increased solubility and/or the multiplicity of chiral complexes in such systems.     

Solubilization of the neutral and charged forms of 2,4,6-trichlorophenol by beta-cyclodextrin,methyl-beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin in water

The solubilities of the neutral and charged forms of 2,4,6-trichlorophenol (TCP) in β-cyclodextrin (β-CD) and two of its most used derivatives: methyl-β-cyclodextrin (MCD) and hydroxypropyl-β-cyclodextrin (HPCD) solutions were investigated. The three cyclodextrins were found to form 1:1 inclusion complexes. Binding constants estimated from an enhancement solubility method revealed that the stability of the complexes was dependent on the polarity of the compound and on the cyclodextrin used.

In general, weaker binding constants were observed for TCP with β-CD than with HPCD or MCD. The solubilization efficiencies towards TCP can be ranked in the following order: MCD > HPCD > β-CD. For all cyclodextrins, the stability constant of neutral TCP (log K_ow=3.85) was larger than that of charged TCP (log K_ow=1.4).

A precipitation occurred in TCP/β-CD solution (around 10 g/l β-CD concentration) at pH 3. However, this phenomenon is not observed for TCP/β-CD solution at pH 8.8.     

Characterization of the tableting properties of β-cyclodextrin and the effects of processing variables on inclusion complex formation,compactibility and dissolution

Abstract

The tableting properties of a number of commercially available β-cyclodextrins were characterized. Fluidity was insufficient for routine direct compression. Compactibility varied by source but was excellent. Lubrication requirements were minimal. An inclusion complex of β-cyclodextrin/Progesterone was formed and the tableting properties of the complex were compared to those of a physical mixture in both directly compressed and wet granulated products. Inclusion complexes spontaneously formed during wet granulation processing. Substantial differences in tableting properties were found as processing variables were changed. β-cyclodextrin exhibits considerable promise as a standard filler binder in tableting.     

Pharmaceutical Uses of Cyclodextrins and Derivatives

Due to their particular conformation, cyclodextrins have the remarkable characteristic of being able to include various kinds of molecule inside their hydrophobic cavity, conferring on them an environmental hydrophily. These inclusion compounds have completely new pharmacotechnical properties, but the most important ones concern increases in water solubility and bioavailability. When administered orally, the inclusion compounds decompose, allowing the free active ingredient to be absorbed by the gastro-intestinal mucosa. However, a certain proportion of inclusion compound is absorbed without any dissociation.

Some cyclodextrin derivatives are very interesting because of their very high water solubility, and also because of their low parenteral toxicity compared with the original β-cyclodextrin. However, in parenteral administration, it is absolutely necessary to study the pharmacokinetic and pharmacological characteristics of the inclusion compound, which must be considered as the true active ingredient.     

Molecular dynamics simulations of the interactions between β-cyclodextrin derivatives and single-walled carbon nanotubes

Since cyclodextrins (CDs) were discovered to be an excellent reagent to disperse carbon nanotubes (CNTs), they were used for the construction of CD/CNT based electrodes. Therefore, it is crucial to investigate the interactions between CDs and CNTs for their applications. Herein, β-cyclodextrin (β-CD) and their four derivatives, 2-O-(2-hydroxypropyl)-β-cyclodextrin (2-HP-β-CD), 6-O-(2-hydroxypropyl)-β-cyclodextrin (6-HP-β-CD), 2-O-(2-hydroxybutyl)-β-cyclodextrin (2-HB-β-CD) and 6-O-(2-hydroxybutyl)-β-cyclodextrin (6-HB-β-CD), were employed to investigate the interactions with single-walled carbon nanotubes (SWNTs) both in anhydrous and aqueous conditions by molecular dynamics simulation. The results showed that the interactions between SWNTs and CDs were strongly influenced by the structures of CDs such as substituted group and position. The attractive interactions between SWNTs and CDs monotonically increased with the radius of SWNT. Van der Waals attraction was the dominating force for CDs wrapped onto the surface of the nanotube ropes. Therefore, the results could provide a fundament for the choice of CDs in their further applications.     

Extraction of Volatile PAHs from Air by Use of Solid Cyclodextrin

An approach for extraction of polycyclic aromatic hydrocarbons (PAHs) from air using solid cyclodextrin is presented. A comparison study in which β-cyclodextrin is replaced by α-cyclodextrin provides evidence that β-cyclodextrin extracts vapor phase PAHs by formation of inclusion complexes rather than by association or adsorption interactions. Thus, solid cyclodextrin complexes with vapor phase PAHs and thereby reduces their volatilities. The gas-solid interaction of the PAHs with β-cyclodextrin and the effect of β-cyclodextrin on the volatilities of these compounds are discussed. Fluorescence and absorbance spectroscopies are used to examine the variables that affect the formation of the PAH complexes with the solid cyclodextrin. The use of this system for improved ambient air sampling is proposed.     

Enhanced Aqueous Solubility of Phenolic Antioxidants Using Modified β-Cyclodextrins

Abstract

Phenolic antioxidants are useful additives with a possible role in cancer chemoprevention. This study describes inclusion complexation between phenolic antioxidants (butylated hydroxyanisole, BHA; butylated hydroxytoluene, BHT) and hydroxypropyl-β-cyclodextrins (HPB) or hydroxyethyl-β-cyclodextrin (HEB) and their characterization by phase solubility analysis, Xray diffraction and infrared (IR) spectroscopy. The complexes were prepared by shaking an aqueous mixture of the antioxidant with each of the cyclodextrins (1:1 molar) at 40 °C for six days and lyophilizing the resulting clear solution. Each of the complexes dissolved instantaneously in water. Phase solubility analysis indicated a more pronounced increase in the aqueous solubility of BHA compared to that of BHT. Xray diffraction patterns of the antioxidant-cyclodextrin complexes indicated a shift from crystalline pattern of the antioxidant to an amorphous pattern for the complexes. Also, the IR spectra of the BHA-cyclodextrin complexes indicated an almost complete disappearance or at least a shift in the -C-O-C- stretch (1200 cm^-1) compared to the corresponding stretch observed for BHA alone or a physical mixture (1:1) of BHA and each of the cyclodextrins. Furthermore, the sharp -OH absorption (3600 cm^-1) is retained in a physical mixture of BHT with either cyclodextrin (1:1) whereas this stretch is not observed in the IR spectra of either BHT-cyclodextrin complexes. These evidences indicate the formation of an inclusion complex between the antioxidants and each of the cyclodextrins.     

Dissolution Characteristics of Nifedipine Complexes with β-Cyclodextrins

Abstract

Formation of nifedipine complexes with β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and DIMEB in solution was studied by the phase solubility method. Solid complexes of nifedipine were prepared by partial and complete solubilization of nifedipine using the freeze- and spray-drying techniques. The complexation led to an improvement in the dissolution rate of the drug. The relative potency of β-cyclodextrins to enhance the dissolution rate of nifedipine was in order: p-cyclodextrin < hydroxypropyl-β-cyclodextrin < DIMEB, which clearly fits the magnitude of stability constant data of the complexes. The dissolution rates of the free drug, complexes, and physical mixture of drug and cyclodextrins from constant surface area disks were also investigated.