Sulphamethizole-Cyclodextrin-Hydroxy Propylmethyl Cellulose Multicomponent Complexes

The effect of cyclodextrin complexation of sulphamethizole (SM) was studied. Two systems were prepared with two cyclodextrin derivatives, β-cyclodextrin (BCD) and hydroxypropyl-β-cyclodextrin (HPBCD): binary complexes and multicomponent systems (cyclodextrins and a hydroxylpropylmethyl cellulose K4M). Inclusion complexes were prepared by freeze-drying and characterized by thermal analysis (DSC) and X-ray diffractometry. The presence of the polymer in the solution increases the effect of cyclodextrins – specially BCD – on the solubility of SM. In solid state, binary inclusion complexes enhance the dissolution behaviour of SM but, from the multi-component complexes, the polymer controls the release of the drug. This revised version was published online in August 2006 with corrections to the Cover Date.     

Preparation and characterization of inclusion complexes of carvedilol with methyl-β-cyclodextrin

Aim of the present work was to investigate the effect of methyl-β-cyclodextrin (MβCD) on the solubility and dissolution rate of carvedilol (CAR), a drug used orally for the treatment of hypertension. Phase solubility studies showed an A_L-type diagram indicating the formation of inclusion complex in 1:1 molar ratio. Solid binary systems of the drug with MβCD were prepared by various methods. Physicochemical characterizations were performed using Fourier Transformation Infrared Spectroscopy, Differential Scanning Calorimetry and powder X-Ray Diffractometry. It could be concluded that CAR can form inclusion complex with MβCD. The dissolution profiles of inclusion complexes were determined and compared with those of CAR alone and the physical mixture. The dissolution rate of CAR was increased by MβCD inclusion complexation remarkably.     

Preparation and evaluation of binary and ternary inclusion complexes of fenofibrate/hydroxypropyl-β-cyclodextrin

This study aimed to investigate the effect of hydroxypropyl methylcellulose on the complexation of fenofibrate and hydroxypropyl-β-cyclodextrin (HP-β-CD). Initially, phase solubility studies with an excess amount of drug in the HP-β-CD solutions with and without hydroxypropyl methylcellulose (HPMC) were investigated. Both of the binary and ternary complexes were prepared by ball-milling. The complexes were characterized by Fourier transform infrared spectroscopy (FI-IR), X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC) and nuclear magnetic resonance spectroscopy (¹H-NMR). The A_L type phase-solubility diagram revealed that the complexes of fenofibrate and HP-β-CD were formed with molecular ratio of 1:1. The results of FT-IR, XPRD, DSC and ¹H NMR analysis show the formulation of inclusion complexes. In conclusion, the interaction occurrs between fenofibrate and HP-β-CD in the complexes, and the existence of HPMC effectively improves the complexation efficiency and stability constant. The in vitro dissolution test suggests ternary complex is superior to binary complex in terms of the release of fenofibrate.     

Effect of preparation method on complexation of Cefdinir with β-cyclodextrin

The inclusion behaviour of β-cyclodextrin (βCD) was studied toward Cefdinir (CEF) in order to enhance the solubility and dissolution rate, following cyclodextrin complexation. Drug cyclodextrin solid systems were prepared by conventional methods of kneading (KN), co-evaporation (CE), spray drying (SD) and with a novel approach of microwave irradiation (MWI). The formation of inclusion complexes with βCD in the solid state, were confirmed by Differential scanning calorimetry (DSC), Fourier Transform Infrared spectroscopy (FTIR) and Scanning Electron Microscopy (SEM) studies, and comparative studies on the in vitro dissolution of CEF were carried out. Characterization of binary system by DSC, FTIR and SEM indicated that SD and MWI method resulted in formation of true complexes. Binary systems showed significant increase in dissolution rate as compared to plain drug. Amongst the binary systems MWI products were prepared in least time with better yield and highest dissolution rate.     

Preparation and characterization of cyclodextrin complexes of doxycycline hyclate for improved photostability in aqueous solution

Doxycycline hyclate is Biopharmaceutical Classification System, class I drug (high solubility and high permeability), but it is associated with poor photostability. It is in the class of tetracycline antibiotic, which is used to treat various infections, but its bioavailability is compromised due to its sensitivity to light and aqueous instability. In this paper, the influence of inclusion complexation with different cyclodextrins, i.e., αCD, γCD, HPβCD and RMβCD, on the photostability of doxycycline hyclate in aqueous media was investigated. Host–guest inclusion complexes were prepared by freeze- drying method. The prepared complexes were characterized for drug content, SEM, XRPD, in vitro permeation studies and photostability studies. XRPD showed diffused peaks for most of the complexes, while SEM showed irregularly shaped particles. The formulation D20 (Drug: γCD in 1:20 molar ratio) showed the highest % drug content (83.72?±?1.2%), and the formulations D1 (Drug: αCD in 1: 2 molar ratio) showed the lowest % drug content among all the CD complexes. It was found that the photodegradation of the drug was reduced significantly upon complexation. For Drug: CD complexes, the photostability of the aqueous solution of drug/CD complexes was found to be in the order of γCD?>?RMβCD?>?HPβCD?>?αCD with maximum photostability shown by Drug: γCD (1:20 molar ratio) complex. The obtained results suggested that cyclodextrin complexation can be used as an alternative approach for increasing the photostability of doxycycline hyclate.

     

Solubility and dissolution enhancement of saquinavir mesylate by inclusion complexation technique

The objective of the present study was to formulate inclusion complex of saquinavir mesylate to improve the aqueous solubility and dissolution rate. Saquinavir mesylate is a BCS class II drug having low aqueous solubility and therefore low oral bioavailability. In the present study, inclusion complex of saquinavir mesylate with hydroxypropyl-β-cyclodextrin were prepared by kneading method. Inclusion complex were characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), ¹H NMR studies, and Fourier transform infrared spectroscopy and evaluated for in vitro dissolution, and phase solubility studies. DSC and XRD study demonstrated that there was a significant decrease in crystallinity of pure drug present in inclusion complex, which resulted in an increased dissolution rate of saquinavir mesylate and ¹H NMR studies strongly, confirmed that the inclusion complex has formed. Inclusion complexation results in improvement in solubility and dissolution rate. The inclusion complexation would be suitable method for dissolution and bioavailability enhancement of saquinavir mesylate.     

Effect of Hydrophilic Polymer on Solubilization of Fenofibrate by Cyclodextrin Complexation

The present work investigates the possibility of improvement of the complexation efficiency of cyclodextrin towards a drug by adding a third auxiliary component (hydrophilic polymer). Phase solubility Analysis at 25 °C was used to investigate the interaction of the drug in both the binary systems (viz. Drug-Cyclodextrin and Drug-Polymer) and the ternary system (Drug-Cyclodextrin-Polymer). The combined use of polymer and cyclodextrin was clearly more effective in enhancing the aqueous solubility of the fenofibrate in comparison with the corresponding drug-cyclodextrin or drug-polymer binary systems. Hydrophilic polymers increased the complexation efficacy of cyclodextrin towards fenofibrate (as shown by the increased stability constants of the complexes). Polyvinyl Pyrollidone (PVP) was found to be most effective in enhancing the solubilization of fenofibrate by β-Cyclodextrin, the best results were obtained in ternary system with β-Cyclodextrin in presence of 1%w/v (PVP). Formulated ternary system with optimized drug:cyclodextrin:polymer ratio of 1:3.5:1 w/w resulted in a significant improvement in the dissolution rate of fenofibrate and showed 90% dissolution efficiency (D.E) as compared to around 15% and 83% of the plain drug and binary system respectively. DSC studies was carried out to characterize the ternary complex.     

Cyclodextrin solubilization of celecoxib: solid and solution state characterization

The low aqueous solubility of celecoxib (CCB) hampers its oral bioavailability and permeation from aqueous environment through biological membranes. The aim of this study was to enhance the aqueous solubility of CCB by complexation with cyclodextrin (CD) in the presence of water-soluble polymer. The effects of different CDs (αCD, βCD, γCD, 2-hydroxypropyl-β-cyclodextrin and randomly methylated β-cyclodextrin (RMβCD)) and mucoadhesive, water-soluble polymers (hydroxypropyl methylcellulose (HPMC), chitosan and hyaluronic acid) were investigated. The phase solubility profiles and CCB/CD complex characteristics were determined. RMβCD exhibited the greatest solubilizing effect of the two CDs tested. However, γCD was also selected for further investigations due to its safety profile. Addition of polymer to the aqueous CD solutions enhanced the CD solubilization. Formation of CCB/RMβCD/HPMC and CCB/γCD/HPMC ternary complexes resulted in 11 and 19-fold enhancement in the apparent complexation efficiency in comparison to their CCB/CD binary complex, respectively. The size of ternary complex aggregates in solution were determined to be from about 250 to about 350 nm. The data obtained from Fourier transform infra-red, differential scanning calorimetry and powder X-ray diffraction indicated presence of CCB/CD inclusion complexes in the solid state. Proton nuclear magnetic resonance data demonstrated that CCB was partially and totally inserted into the hydrophobic central cavities of RMβCD and γCD.     

Inclusion complexes of <Emphasis Type="Italic">p</Emphasis>-hydroxybenzoic acid esters and γ-cyclodextrin

The alkyl esters of p-hydroxybenzoic acid (parabens) are commonly used as preservatives in cosmetics, food products and pharmaceutical formulations because of their wide range antimicrobial activity. However, the usage of parabens in aqueous media has been hampered, especially parabens with long alkyl chains, due to their low aqueous solubility. One approach to increase their solubility is cyclodextrins (CDs) complexation to form water-soluble inclusion complexes. γCD has the widest hydrophobic central cavity and the highest water solubility among natural CDs. Hence, inclusion complexes between γCD and parabens of various alkyl chain lengths were investigated. Results from phase-solubility studies show that methyl- and ethylparaben form various complexes of paraben/γCD (i.e. 1:1, 2:1, etc.) while the 1:1 complex was dominant in propyl- and butylparaben/γCD complex solution. Moreover, the effect of the paraben complexation on the critical aggregation concentration (cac) of γCD in aqueous solutions was determined. It was found that the longer the paraben alkyl chain was the more influence it had on the γCD cac. In pharmaceutical formulations the mixture of parabens (i.e. binary, ternary and quaternary) has been used to maximize antimicrobial effect. It is important to determine how mixtures of parabens affect the solubility of γCD and its cac values upon formation of inclusion complexes. Competition of the different parabens for a space in the γCD central cavity was evaluated by comparing the γCD cac values obtained in presence of the individual parabens and their mixtures.     

Water soluble complexes of methyl β-cyclodextrin and sulconazole nitrate

Complexation between methyl β-cyclodextrin (Me βCD) and sulconazole nitrate (SULC) was realized both under freeze drying and ultrasonication conditions. The process was carried out in solution and in solid state. In solution, the complexation was evaluated using solubility studies, nuclear magnetic resonance spectroscopy (¹H-NMR) and UV–Vis absorption studies. In the solid state, differential scanning calorimetry (DSC), and X-ray diffraction studies were used. Solubility studies indicate the existence of inclusion complexes between SULC and Me βCD. ¹H-NMR data showed that the inclusion complexes have different structures, according with the method we used for synthesis: for the freeze dried method the complex is obtained by complexation of dichlorobenzene ring of SULC into inner cavity of CD while for ultrasonication method the complex is obtained by complexation of imidazole graph of SULC into the CD molecule. DSC and X-ray studies bring supplementary information concerning the formation of complex Me βCD–SULC. As a result of the inclusion process into Me βCD, the solubility of SULC increase significant, being 10 times more comparative with the pure drug. We anticipate that these modifications will have a significant impact on the biological effects of the drug, making the SULC–Me βCD complex an appropriate candidate for a new drug delivery system.     

Effect of the hydrophobic nature of triacetyl-beta-cyclodextrin on the complexation with nicardipine hydrochloride: physicochemical and dissolution properties of the kneaded and spray-dried complexes

The inclusion ability of triacetyl-beta-cyclodextrin (TAbetaCD), a hydrophobic cyclodextrin (CD) derivative was examined, using nicardipine hydrochloride (NC) as model drug. The binary compounds were prepared in a 1 : 1 molar ratio by the kneading and the spray-drying techniques. In order to confirm the complexation between NC and TAbetaCD in the solid state, differential scanning calorimetry, X-ray diffractometry, Fourier transformation-infrared spectroscopy and scanning electron microscopy were carried out and the results were compared with the corresponding physical mixture in the same molar ratio. The kneaded product presented only slight modifications on the drug physicochemical and morphological properties, which could mean that no complex formation occurred during this process. In contrast, spray-drying was found to produce inclusion complexes with amorphous nature. In vitro dissolution studies were carried out in simulated gastric (pH 1.2) and intestinal (pH 6.8) fluids, according to the United States Pharmacopoeia (USP) basket method. The NC in vitro release from the kneaded and spray-dried products was markedly retarded in both dissolution media. However, this retarding effect was significantly more evident for the spray-dried compound. It was concluded that the formation of real inclusion complexes could only be achieved by the spray-drying method.     

Cyclodextrin in Artificial Enzyme Model, Rotaxane, and Nano-material Fabrication

The methods of obtaining and physicochemical properties of inclusion complexes of amlodipine (AM) and felodipine (FL) with methyl-β-cyclodextrin (MCD) clathrates have been studied. Solid complexes were obtained by two methods: the kneading one and lyophilization with the drug and MCD at the molar ratio of 1:1. The identity of the obtained clathrates was confirmed by IR, ¹³C-NMR spectra and DSC measurements. The process of AM and FL complexation with MCD was shown to involve the aromatic ring, the carbonyl groups in the ester bonds and the carbon atoms of the DHP ring linked via the ester bonds. One of the aims of complexation was to improve the drug solubility, so the dissolution rate of the obtained clathrates was tested. As a result of the inclusion complexes formation of AM, obtained both by kneading and lyophilization, the solubility of this therapeutic drug increased 3 times. The inclusion complex formation with FL and MCD brought the most dramatic increase in FL solubility, which increased 16 times.     

Inclusion Complexation of Anti-HIV Drug with β-Cyclodextrin

The purpose of present investigation was to investigate the effect of complexation of Nelfinavir Mesylate (NM) – an Anti-HIV drug with Beta-cyclodextrin (β-CD) on its dissolution characteristics and subsequent effect on its absorption properties and bioavailability. Phase solubility studies were conducted to find the interaction of NM with β-CD. Physical mixing and milling method were used for complexation. The inclusion complexes were characterized by X-ray diffractometry, FT-IR and NMR studies and further studied by in-vitro dissolution testing. The plain NM and complex was subjected to intestinal absorption studies by using Everted intestinal sac model. Data was treated statistically by Mann–Whitney U test. Pharmacokinetic studies were carried out in rabbits using cross over design and data was treated by Student’s t test. Phase solubility studies confirmed 1:1 complex formation of NM with β-CD with stability constant of 204.84 M⁻¹. In-vitro dissolution studies of inclusion complexes of NM with β-CD prepared by milling method (T ₉₀=60.89 min) showed better dissolution rate kinetics in distilled water in comparison with plain NM (T ₉₀=374.31). The increased solubility with decreased crystallinity is attributed by inclusion of NM in the cavity of β-CD, which was further confirmed by instrumental studies. Intestinal absorption studies further supports these findings by showing 2.13 times enhancement in the absorption rate of complex as compared to plain NM. The percent relative bioavailability of complex in rabbits was 185.37 as compared to the plain NM.     

Solid-state characterization and dissolution properties of ezetimibe–cyclodextrins inclusion complexes

The objectives of this research were to prepare and characterize inclusion complex of Ezetimibe (EZE) with cyclodextrins (β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HPβ-CD)) and to study the effect of complexation on the dissolution rate of EZE, a water insoluble drug. Phase solubility curve was classified as A _P -type for both cyclodextrins, indicating the 2:1 stoichiometric ratio for β-CD–EZE and HPβ-CD – EZE inclusion complexes. The inclusion complexes in the molar ratio of 2:1 (β-CD–EZE and HPβ-CD–EZE) were prepared by various methods such as kneading, coevaporation and physical mixing. The molecular behaviors of drug in all samples were characterized by fourier-transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies. The results of these studies indicated that complex prepared by kneading and coevaporation methods showed inclusion of the EZE molecule into the cyclodextrins cavities. The highest improvement in in-vitro dissolution profiles was observed in complex prepared with hydroxypropyl-β-cyclodextrin using co-evaporation method. Mean dissolution time and similarity factor indicated significant difference between the release profiles of EZE from complexes and physical mixtures and from pure EZE.     

Preparation and physicochemical characterization of carbamazepine (CBMZ): para-sulfonated calix[n]arene inclusion complexes

The formation of inclusion complexes with para-sulfonated calix[n]arene (PSC[n]A) was studied for carbamazepine (CBMZ), a poorly water soluble anticonvulsant drug. The effect of PSC[4]A and PSC[6]A on aqueous solubility of carbamazepine was studied extensively. The complete complexation of the drug was achieved after 48 h of shaking with PSC[n]A in water and evaporation of water to get solid complex. The interaction between PSC[n]A and CBMZ in solid state inclusion complexes was accomplished by aqueous phase solubility studies, HPLC, DSC, PXRD, FTIR, UV–Vis, and FT-Raman spectroscopy. The solubility of CBMZ increases as a function of PSC[n]A concentration. The results of the two phase solubility experiments are in good conformity to signify the formation of 1:1 (PSC[6]A:CBMZ) and 2:1 PSC[4]A:CBMZ complexes. The order of dissolution rate of CBMZ is inclusion complex > physical mixture > drug alone. The purpose of this study was to enhance solubility resulting in high dissolution rate and bioavailability of this essentially water insoluble drug.     

Solubilizing effect of the p-phosphonate calix[n]arenes towards poorly soluble drug molecules such as nifedipine, niclosamide and furosemide

This article reports the solubilization of the practically water insoluble drug molecules such as nifedipine, niclosamide and furosemide by guest:host inclusion complexation with p-phosphonates calix[n]arenes as drug soluble agent. This complexation studies were carried out by using the phase solubility technique. From the obtained results, it was observed that the solubility of drug molecules was significantly increased in the presence of calix[n]arene host molecules. The increase in solubility of drugs by the calix[n]arene was most probably due to inclusion complexation between drug molecules and cavities of the calixarene skeleton similar to drug:cyclodextrin complexes.     

Complexation of ebastine with β-cyclodextrin derivatives

Complexation of ebastine (EB) with hydroxypropyl and methyl-β-cyclodextrin (HP-β-CD and Me-β-CD) was studied in aqueous solutions and in the solid state. The formation of inclusion complexes in aqueous solutions was analysed by the solubility method. The assays were designed using low CD concentrations compared with the solubility of these derivatives in order to avoid non-inclusion phenomena and to obtain a linear increase in EB solubility as a function of CD concentration. The values of complexation efficiency for HP-β-CD and Me-β-CD were 1.9 × 10^?2 and 2.1 × 10^?2, respectively. It seems that the non polar character of the methyl moiety slightly favoured complexation. In relation to solid state complexation, 1:1 EB:CD systems were prepared by kneading, and by heating a drug-CD mixture at 90 ºC. They were analysed using X ray diffraction analysis by comparison with their respective physical mixtures. A complex with a characteristic diffraction pattern similar to that of the channel structure of β-CD was formed with Me-β-CD in 1:1 melted and 1:2 EB:CD kneaded systems. Complexation with HP-β-CD was not clearly evidenced because only a slight reduction of drug crystallinity was detected. Finally, the loading of EB in two β-CD polymers cross-linked with epichlorohydrin yielded 7.3 and 7.7 mg of EB/g polymer respectively.     

Inclusion complexes of phosphorylated daidzein derivatives with β-cyclodextrin: Preparation and inclusion behavior study

In the present work the feasibility of β-cyclodextrin in complexation was explored, as a tool for improving the solubility and biological ability of daidzein derivatives. A series of phosphorylated daidzein derivatives featuring different chain lengths were synthesized through a modified Atherton-Todd reaction and their inclusion complexes with βCD were prepared by coprecipitation method. The inclusion complexation behavior was studied by fluorescence, UV, FT-IR, MS and (1)H NMR. The results showed that only phosphorylated daidzein derivative carrying small substituent group ((C(2)H(5)O)(2)PO) entered the cavity of βCD and formed 1:1 inclusion complex. The formation constant was 175(mol/L)(-1).     

Study of benznidazole–cyclodextrin inclusion complexes, cytotoxicity and trypanocidal activity

The current chemotherapy for Chagas disease is still based on benznidazole, which has low solubility, but complexation with cyclodextrins provides a way of increasing the solubility. The objective of this work was to characterize the inclusion complexes formed between benznidazole (BNZ) and randomly 2-methyled-β-cyclodextrin (RM-β-CD) in aqueous solution and study cytotoxicity and trypanocidal. BNZ:RM-β-CD solution complex systems were prepared and characterized using the phase solubility diagram, nuclear magnetic resonance and a photostability assays, also to investigate the in vitro trypanocidal activity with epimastigote forms of Trypanossoma cruzi and the study of cytotoxicity against mammal cells. The phase-solubility diagram displayed an A _L-type feature, providing evidence of the formation of soluble inclusion complexes. The continuous variation method showed the existence of a complex with 1:1 stoichiometry. Toxicity assays demonstrated that inclusion complexes were able to reduce the toxic effects caused by benznidazole alone and that this did not interfere with the trypanocidal activity of the benznidazole. The use of inclusion complexes benznidazole:cyclodextrin is thus a promising alternative for the development of a safe and stable liquid formulation and a new option for the treatment of Chagas disease.     

Preparation and evaluation of inclusion complexes of diacerein with β-cyclodextrin and hydroxypropyl β-cyclodextrin

The objective of this research was to improve the aqueous solubility, dissolution rate and, consequently, bioavailability of diacerein, along with avoiding its side effect of diarrhea, by complexation with β-cyclodextrin (β-CD) and HP-β-cyclodextrin (HP-β-CD). Phase solubility curve was classified as an A_N type for both the CDs, which indicated formation of complex of diacerein with β-CD and HP-β-CD in 1:1 stoichiometry and demonstrating that both CDs are proportionally less effective at higher concentrations. The complexes were prepared by kneading method and were evaluated to study the effect of complexation on aqueous solubility and rate of dissolution in phosphate buffer (pH 6.8). Based on the dissolution profile HP-β-CD was selected for preparing fast disintegrating tablet of diacerein which was compared with marketed formulation (MF-J). The HP-β-CD complex was probed for Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction studies which evidenced stable complex formation and increase in amorphousness of diacerein in complex. In brief, the characterization studies confirmed the inclusion of diacerein within the non-polar cavity of HP-β-CD. HP-β-CD complex showed improved in vitro drug release profile compared to pure drug and similar to that of marketed formulation respectively.