Dissolution properties and characterization of halofantrine-2-hydroxypropyl-beta-cyclodextrin binary systems

Halofantrine (HF) is a poorly water-soluble antimalarial drug with low bioavailability. Complex formation of HF.HCl and 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) in aqueous solution and in solid state as well as the possibility of improving the solubility and dissolution rate of the drug though complexation with the cyclodextrin were investigated. Phase-solubility profile indicated that the solubility of the drug was significantly increased in the presence of HP-beta-CD and was classified as AL-type, indicating 1:1 stoichiometric inclusion complexes and an apparent stability constant value of 2300 M(-1). Solid inclusion complexes of HF, HCl and the cyclodextrin at 1:1 molar ratios were prepared by physical mixture, kneading, co-evaporation and freeze-drying methods and characterized by X-ray diffraction and Infra-red spectroscopy. The solubility and dissolution rates of HF.HCl from the complexes were determined and found to be dependent on the preparation method of the complexes. Dissolution profile of the drug was markedly enhanced by complex formation with the cyclodextrin and the product prepared by the freeze-drying method exhibited the most superior dissolution properties compared to the other methods used in this study. The results suggest that the complexation of HF.HCl with HP-beta-CD could improve therapeutic efficacy of the drug though enhanced absorption expected from increased drug dissolution.     

Solubility enhancement of celecoxib using beta-cyclodextrin inclusion complexes.

Celecoxib has very low water solubility. It forms a complex with beta-cyclodextrin (betaCD) both in aqueous and in solid state. It was observed that due to formation of the inclusion complex, the solubility and dissolution rate of celecoxib were enhanced. The formation of 1:1 complex with betaCD in solution was confirmed by phase solubility and spectral shift studies. The apparent stability constants calculated by these techniques were 881.5 and 341.5 M(-1), respectively. The solid inclusion complexes of celecoxib and betaCD were prepared by the kneading method using different molar proportions of betaCD, and formation of solid inclusion complexes of celecoxib and betaCD at different molar ratios were confirmed by differential scanning calorimetry. Enhancement of dissolution rates with increasing quantity of betaCD in the complex was observed. It was also observed that the complexes exhibit higher dissolution rates than the pure drug and physical mixture.     

Preparation & characterization of solid inclusion complex of cefpodoxime proxetil with beta-cyclodextrin

Cefpodoxime proxetil (CPDX-PR) is an oral cephalosporin antibiotic with poor aqueous solubility and bioavailability. Effect of beta-cyclodextrin on aqueous solubility and dissolution rate of cefpodoxime proxetil was evaluated by the formation of solid inclusion complexes in 1:2 molar ratio of drug: cyclodextrin. Phase solubility study was carried out whereby a typical B's type curve was obtained thus, indicating a 1:2 stoichiometric ratio for optimum complex formation. Solid inclusion complexes in 1:2 molar ratios were prepared by using methods such as physical mixture, solvent evaporation and freeze drying. Prepared complexes were characterized by fourier transform infrared spectroscopy (FT-IR) differential scanning calorimetry (DSC), powder x-ray diffraction (PXRD) and scanning electron microscopy (SEM). Results of in vitro studies appraised of an increased solubility and dissolution rate of cefpodoxime proxetil on complexation with beta- cyclodextrin (P < 0.05) as compared to CPDX-PR alone. Amongst the complexes prepared by different methods, the complex prepared by freeze drying showed the highest dissolution rate (P< 0.01). The in vitro antimicrobial activity of cefpodoxime proxetil and its freeze dried complex (1:2) was studied against both antibiotic-susceptible and antibiotic-resistant clinical isolates of Neisseria gonorrhoeae. The freeze dried complex (1:2) inhibited all penicillin-susceptible strains and penicillinase-producing strains at 0.015 microg/ml concentration. Chromosomally resistant strains which were not responsive to penicillin were inhibited by the complex at 0.125 microg/ml concentration. The study revealed that complexation of cefpodoxime proxetil with beta-cyclodextrin effectively enhanced the aqueous solubility and in vitro antibacterial activity.     

Study of the Complexation Behaviour of Fexofenadine with β-Cyclodextrin

Fexofenadine is a selective histamine H(1) receptor antagonist, used for relief of the symptoms of allergy. However its aqueous solubility is very poor. Solid inclusion complexes of fexofenadine and β-cyclodextrin were prepared at the molar ratios of 1:1 and 1:2 by kneading, and coprecipitation methods to improve its solubility. Characterization of the complexes was performed using infrared spectroscopy, X-ray diffractometry, and in vitro dissolution studies. Fexofenadine was found to exhibit interaction with β-cyclodextrin both in solid and liquid state. Phase solubility studies indicated that fexofenadine forms a stable complex with β-cyclodextrin. Both IR spectroscopy and X-ray diffractometry studies indicated interaction of fexofenadine with β-cyclodextrin. Kneading method at 1:1 and co-precipitation method at 1:1 and 1:2 molar ratios showed significant interaction. In vitro dissolution studies confirmed the same results.     

Complexation of the interferon inducer, bropirimine, with hydroxypropyl-β-cyclodextrin

Bropirimine (ABPP) is an orally active immunomodulator that increases endogenous alpha-interferon and other cytokines used clinically against carcinoma in situ of the bladder. The oral absorption of ABPP is poor because its low solubility in water. The purpose of this study is to develop a technological procedure useful to increase the water solubility of ABPP. To this end, the interaction of ABPP with several cyclodextrin derivatives--, β-, γ- and hydroxypropyl-β-cyclodextrin with a degree of substitution 2.7 (HPβCD) was studied and the effect of the complexation process on the water solubility of the drug was evaluated. The best results were obtained with the hydroxypropyl derivative, HPβCD, that interacts in a 1:1 drug:cyclodextrin molar ratio. The inclusion complex ABPP–HPβCD was characterized in solution by nuclear magnetic resonance (¹H-NMR). The solid inclusion complex was obtained by freeze-drying and characterized by differential scanning calorimetry (DSC), X-ray diffractometry and mass spectrometry. The dissolution rate of ABPP from the HPβCD solid inclusion complex was increased compared to the powdered drug but not differences were found between the complex and a physical mixture with a similar molar ratio. The increase of the dissolution rate of the drug can be attributed to the breakdown in solution of the drug dimers in the presence of the cyclodextrin and to the complex formation.     

Modulated dissolution rate from the inclusion complex of antichagasic benznidazole and cyclodextrin using hydrophilic polymer

Benznidazole (BNZ) is the primary chemotherapeutic agent for treating Chagas’ disease; however, its poor water solubility and irregular oral absorption lead to the treatment failure in the chronic phase. The aim of this work was to investigate the utility of the polymer hydroxypropyl methylcellulose (HPMC) in controlling the release of BNZ from solid inclusion complexes with cyclodextrin to overcome the problem of its bioavailability. Preliminary studies of solubility were conducted in solution using selected β-cyclodextrin derivatives according to an experimental mixture design. The best cyclodextrin composition was used to produce solid-state systems by kneading in the presence or absence of HPMC. The formulations were characterized by different physico-chemical techniques, including the dissolution rate. Hydroxypropyl-β-cyclodextrin (HPβCD) produced the greatest improvement in drug solubility and was selected for the development of solid systems. Assays confirmed the production of true inclusion complexes between BNZ and HPβCD. The dissolution rate of the BNZ-HPβCD system was markedly increased, while the presence of HPMC retarded drug release. An optimal formulation obtained by the combination of kneading systems developed in appropriate ratios could be a promising drug delivery system with a prolonged therapeutic effect coupled with more balanced bioavailability. The produced systems present interesting perspectives for Chagas’ therapy.     

Comparative Study on Inclusion Complexation of Maltosyl-β-cyclodextrin,Heptakis(2,6-di-O-methyl)-β-cyclodextrin and β-Cyclodextrin with Fucosterol in Aqueous and Solid State

Abstract— The complexation of fucosterol with three kinds of β-cyclodextrin (β-CyD) was investigated in aqueous solution and in the solid state. The solubility of fucosterol increased significantly on its complexation with maltosyl-β-CyD and heptakis(2,6-di-O-methyl)-β-CyD (DM-β-CyD), while no appreciable increase was observed when complexed with β-CyD. The stability constant of complexation with β-CyD estimated from solubility determinations was greater for a 1:2 complex than for a 1:1 complex. On the other hand, 1:1 complexation of fucosterol with maltosyl-β-CyD or DM-β-CyD was greater than 1:2 complexation. The solid complexes were obtained in molar ratios of 1:2 and 1:3 for β-CyD and maltosyl-β-CyD complexes, respectively. The inclusion behaviour of fucosterol with maltosyl-β-CyD was compared with β-CyD in the solid state using DSC, powder X-ray diffractometry and CP/MAS ¹³C NMR. Maltosyl-β-CyD showed different inclusion behaviour compared with β-CyD, and produced an amorphous structure of fucosterol on complex formation. The dissolution rate of fucosterol-maltosyl-β-CyD complex was significantly faster than other complexes due to its high aqueous solubility and amorphous structure.     

Enhancement of solubility and permeability of Candesartan cilexetil by using different pharmaceutical interventions

The poor solubility and wettability of Candesartan cilexetil (CAN) leads to poor dissolution and hence, low bioavailability after oral administration. The aim of the present study was to improve the solubility and dissolution rate and hence the permeability of CAN by preparing solid dispersions/inclusion complexes. Solid dispersions were prepared using PEG 6000 [hydrophilic polymer] and Gelucire 50/13 [amphiphilic surfactant] by melt agglomeration (MA) and solvent evaporation (SE) methods in different drug-to-carrier ratios, while inclusion complexes were made with hydroxypropyl-β-cyclodextrin (HP-β-CD) [complexing agent] by grinding and spray drying method. Saturation solubility method was used to evaluate the effect of various carriers on aqueous solubility of CAN. Based on the saturation solubility data, two drug-carrier combinations, PEG 6000 (MA 1:5) and HP-β-CD (1:1 M grinding) were selected as optimized formulations. FTIR, DSC, and XRD studies indicated no interaction of the drug with the carriers and provided valuable insight on the possible reasons for enhanced solubility. Dissolution studies showed an increase in drug dissolution of about 22 fold over the pure drug for PEG 6000 (MA 1:5) and 12 fold for HP-β-CD (1:1 M grinding). Ex-vivo permeability studies revealed that the formulation having the greatest dissolution also had the best absorption through the chick ileum. Capsules containing solid dispersion/ complex exhibited better dissolution profile than the marketed product. Thus, the solid dispersion/inclusion complexation technique can be successfully used for enhancement of solubility and permeability of CAN.     

β-cyclodextrin complexes of celecoxib: Molecular-modeling, characterization, and dissolution studies

Celecoxib, a specific inhibitor of cycloxygenase-2 (COX-2) is a poorly water-soluble nonsteroidal anti-inflammatory drug with relatively low bioavailability. The effect of beta-cyclodextrin on the aqueous solubility and dissolution rate of celecoxib was investigated. The possibility of molecular arrangement of inclusion complexes of celecoxib and beta-cyclodextrin were studied using molecular modeling and structural designing. The results offer a better correlation in terms of orientation of celecoxib inside the cyclodextrin cavity. Phase-solubility profile indicated that the solubility of celecoxib was significantly increased in the presence of beta-cyclodextrin and was classified as AL-type, indicating the 1:1 stoichiometric inclusion complexes. Solid complexes prepared by freeze drying, evaporation, and kneading methods were characterized using differential scanning calorimetry, powder x-ray diffractometry, and scanning electron microscopy. In vitro studies showed that the solubility and dissolution rate of celecoxib were significantly improved by complexation with beta-cyclodextrin with respect to the drug alone. In contrast, freeze-dried complexes showed higher dissolution rate than the other complexes.     

Improved in vitro dissolution parameters and in vivo hypolipidemic efficiency of atorvastatin calcium through the formation of hydrophilic inclusion complex with cyclodextrins

An aim of the present study was to improve the dissolution of the inherently low water solubility hypolipidemic agent, Atorvastatin calcium (ATC), through the preparation and characterization of ATC with cyclodextrins (CDs) inclusion complexes employing different techniques. A second goal was to study the in vivo hypolipidemic efficacy of ATC‐complexes with enhanced dissolution characteristics. Inclusion complexation of ATC with β‐cyclodextrin (β‐CD) and hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) was evaluated in aqueous and solid states. ATC formed inclusion complexes with β‐CD and HP‐β‐CD depending to a great extent upon ATC ionization state. Evaporation and freeze‐drying were the most efficient techniques to achieve complexation. In contrast, kneading was an inefficient tool to create true inclusion complexes, which could reflect the hindrance of drug–CDs interactions in the semisolid medium. The ATC:CD ratio of 1:2 showed better dissolution characteristics compared to a 1:1 ratio. Moreover, the in vivo hypolipidemic activities of ATC‐CDs (β‐CD and HP‐β‐CD) complexes were greater (P<0.05) than the other investigated formulations. Thus the nature of the carrier did not play a critical role in the dissolution characteristics of the inclusion system. In contrast, the carrier molar ratio, and the employed complexation technique were found to be key factors in enhancing the ATC dissolution rate, yielding performances as well as the in vivo hypolipidemic efficacies. Drug Dev Res 72: 379–390, 2011. © 2011 Wiley‐Liss, Inc.     

Competitive displacement of drugs from cyclodextrin inclusion complex by polypseudorotaxane formation with poloxamer: implications in drug solubilization and delivery

The competitive interactions between the poly-[propylene oxide] (POO)-poly-[ethylene oxide] (PEO) block copolymer poloxamer 407 (Pluronic F127) and two drugs, triamcinolone acetonide and ciclopirox olamine, by the formation of inclusion complexes with two cyclodextrin hydrophilic derivatives, hydroxypropyl-β-cyclodextrin (HPβCD; molar substitution (MS) 0.65) and partially methylated-β-cyclodextrin (MβCD; MS 0.57), were studied by means of one-dimensional (1)H NMR, 2D ROESY experiments, solubility studies and drug release studies. 1D and 2D NMR and solubility studies indicate that both triamcinolone acetonide and ciclopirox olamine form stable inclusion complexes with the cyclodextrin derivatives. In the case of ciclopirox olamine the complex was more stable at pH 1. Effective complexation of poloxamer with the two cyclodextrins (CDs) was also evidenced by NMR analysis, and competitive displacement of the drugs from the CD cavity by the polymer was observed. Drug solubility in CD solutions was not modified by the addition of polymers, indicating that a decrease in solubility due to the competitive displacement is probably compensated by the solubilizing effect of polymer micellization. Finally, polypseudorotaxanes formation has a significant influence on the release of the drugs studied. Changes in the release rate depend on the stability of drug-CD inclusion complex and on cyclodextrin concentration in the bulk solution; so polypseudorotaxane formation can be employed to modulate drug controlled release from thermosensitive hydrogels.     

Improvement of dissolution and suppository release characteristics of flurbiprofen by inclusion complexation with heptakis(2,6-di-O-methyl)-beta-cyclodextrin

The inclusion behavior of methylated beta-cyclodextrins, heptakis(2,6-di-O-methyl)-beta-cyclodextrin and heptakis-(2,3,6-tri-O-methyl)-beta-cyclodextrin in solution and the solid state was compared with that of natural beta-cyclodextrin using an anti-inflammatory drug, flurbiprofen, as a guest molecule. Stability constants were determined by the solubility method at various temperatures, and the thermodynamic parameters were calculated for inclusion complex formation in aqueous solution. The solid complexes were obtained in a molar ratio of 1:1, and their dissolution behavior and release from suppository bases were examined. The data suggest that the inclusion mode of the complex with 3 is somewhat different from that of the complexes with 1 and 2. From a practical point of view, 2 seems to be particularly useful for improving the pharmaceutical properties of flurbiprofen in various dosage forms.     

A Study on Improvement of Solubility of Rofecoxib and its effect on Permeation of Drug from Topical Formulations

Rofecoxib, a practically insoluble cox-2 selective nonsteroidal antiinflammatory agent was subjected to improvement in solubility by preparing its binary mixtures with β cyclodextrin using various methods such as physical mixing, co-grinding, kneading with aqueous methanol and co-evaporation from methanol-water mixture. Characterization of the resulting binary mixtures by differential scanning calorimetry and X-ray diffraction studies indicated partial amorphization of the drug in its binary mixtures. In vitro dissolution studies exhibited remarkable increase in rate and extent of dissolution of the drug from its complexes with β -cyclodextrin. Pure rofecoxib as well as its co-ground binary mixture were formulated as aqueous gels for topical application. In vitro skin permeation of rofecoxib from formulation containing rofecoxib-cyclodextrin complex was significantly higher (p<0.05) at 1, 2, 12, 18 and 24 hr as compared to formulation containing pure rofecoxib. This could be attributed to better solubility of binary mixture in the aqueous gel vehicle leading to greater concentration gradient between the vehicle and skin and hence higher flux of the drug.     

羟丙基-β-环糊精对格列齐特增溶作用的研究

目的:研究羟丙基-β-环糊精(HP-β-CD)包合对难溶性药物格列齐特(GZ)溶解度和溶出度的增强作用。方法:分别采用研磨法、超声法和冷冻干燥法制备GZ的HP-β-CD包合物,测定其溶解度和溶出度,并与GZ原料药,GZ与HP-β-CD的物理混合物进行比较。用差热扫描量热法,红外光谱对包合物进行物相鉴别。结果:HP-β-CD与GZ形成包合物使其溶解度提高6.8倍。结论:HP-β-CD能大幅度地提高GZ的溶解度和溶出度。     

Improvement of solubility and dissolution properties of clotrimazole by solid dispersions and inclusion complexes

Solid dispersions of a slightly water-soluble drug, clotrimazole, were prepared in different weight ratios using polyethyleneglycol 4000 and different molecular weight polyvinyl pyrrolidones as carriers. Moreover, binary and ternary β-cyclodextrin complexes were prepared in different molar ratios. Both solid dispersions and β-cyclodextrin complexes were prepared by solvent evaporation technique. A phase solubility method was used to evaluate the effect of the tested carriers on the aqueous solubility of clotrimazole. The dissolution of all the preparations was tested using the USP paddle method. The selected solid dispersions and inclusion complexes were characterized by differential scanning calorimetry and X-ray powder diffractometry studies, and results clarified the role of the tested carriers in decreasing the crystallinity of clotrimazole and complexing abilities. Based on physical characters and in vitro drug release pattern, polyvinylpyrrolidone solid dispersions (1:1 weight ratio) and ternary cyclodextrin complexes (clotrimazole-β-cyclodextrin complexes with either polymer, 1:1 molar ratio) were selected as ideal batches for suppositories. Suppocire AM/50 mg carbopol 940, was chosen as a suppository base and the suppositories were prepared by molding technique. The prepared suppositories were characterized for weight variation, softening time and drug content. All these properties were found to be ideal. The in vitro drug release pattern was determined in citrate buffer (pH 4.5) containing 1% sodium lauryl sulfate. The in vitro release of clotrimazole from its solid dispersions and inclusion complexes incorporated suppositories was markedly improved when compared to the intact drug incorporated suppositories. Polyvinyl pyrrolidone solid dispersions incorporated suppositories were found to possess excellent antifungal activity.     

Improvement of water solubility and in vitro dissolution rate of gliclazide by complexation with beta-cyclodextrin

Inclusion complexes of gliclazide with beta-cyclodextrin were prepared using different two methods: neutralization and recrysstalization. Host-guest interactions were studied in the solid state by X-ray diffractometry and infrared spectroscopy. The stability constant between gliclazide and beta-cyclodextrin was calculated from the phase solubility diagram. It was found that the neutralization technique and a solid complex of gliclazide with beta-cyclodextrin in a molar ratio of 1.5:1 could be used to prepare the amorphous state of drug inclusion complexes. The dissolution rates of gliclazide from the inclusion complex made by neutralization was much faster than the pure drug, physical mixture of drug and cyclodextrin, recyristalization system and also comparable to the data reported in literature. Results of this report indicate that beta-cyclodextrin could be useful for the solid gliclazide formulations as it may results in a more rapid and uniform release of the drug.     

Molecular simulation of hydroxypropyl-beta-cyclodextrin with hydrophobic selective Cox-II chemopreventive agent using host-guest phenomena

The present investigation outlays the host-guest penetration of hydrophobic selective Cox-II chemopreventive agent, celecoxib (CXB), with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) using inclusion complexation phenomena. Phase solubility studies conducted at 37 degrees C and 25 degrees C revealed typical A(L)-type curve for the HP-beta-CD indicating the formation of soluble complexes. The inclusion complexes in the molar ratio of 1:1 and 2:1 (CXB-HP-beta-CD) were prepared by kneading technique. The formation of inclusion complexes and the molecular simulation of CXB protons with HP-beta-CD cavity in all samples were testified by 1H-NMR, DSC, powder-XRD, SEM and FTIR and UV/visible spectroscopy. The results of these studies indicated that complex (prepared by kneading method) in molar ratio of 1:1 exhibited better improvement in in vitro dissolution profiles as compared to 1:2 complex. Mean in vitro dissolution time indicated significant difference in the release profiles of CXB from complexes and physical mixtures as compared to pure CXB.     

Controlled release of nifedipine from mucoadhesive tablets of its inclusion complexes with beta-cyclodextrin

Mucoadhesive tablets formulated with nifedipine (N) alone and its inclusion complexes with beta-cyclodextrin (betaCD) and the mucoadhesive polymers sodium carboxy methylcellulose and carbopol were investigated with a view to the design of oral controlled release tablets of nifedipine. As nifedipine is practically insoluble in water and aqueous fluids, its complexation with betaCD was investigated to improve its solubility and dissolution rate. Complexation of nifedipine with betaCD has markedly enhanced the solubility and dissolution rate of nifedipine. The phase solubility studies indicated the formation of a N-betaCD inclusion complex with a stability constant of 121.9 M(-1). A 20.6 fold increase in the dissolution rate of nifedipine was observed with N-betaCD (1:2) solid inclusion complex. Mucoadhesive tablets formulated employing nifedipine alone gave very low dissolution, whereas those formulated employing its betaCD inclusion complexes gave slow, controlled and complete release spread over a period of 12 h. Drug release from these tablets followed zero order kinetics up to 85-90% release and the release was diffusion controlled. Good controlled release two layered tablet formulations of nifedipine, satisfying the theoretical sustained release requirements based on its pharmacokinetics, were developed using its inclusion complexes with betaCD.     

Development of effervescent tablets containing benzonidazole complexed with cyclodextrin

Objectives Benznidazole (BNZ), the primary chemotherapy agent used to treat Chagas disease, has poor aqueous solubility, which results in low bioavailability. The purpose of this work was to develop stable effervescent tablets using an inclusion complex of BNZ with cyclodextrin (CD). Method In the first phase, different CDs were evaluated according to their ability to improve the aqueous solubility of BNZ. Then, inclusion complexes of BNZ in the solid state were produced by the kneading method and the complexes were evaluated using several physical–chemical assays. Finally, effervescent tablets were prepared according to a complete 3² factorial design. The effects of the concentration of CD and effervescent mixture on the dissolution rate and physical stability of tablets were evaluated. Key findings Hydroxypropyl‐β‐cyclodextrin produced the greatest improvement in the aqueous solubility of BNZ, almost 20‐times greater than the water system. Solid systems produced with BNZ and CD showed physical–chemical interactions and increased the drug dissolution rate, suggesting the formation of a true solid inclusion complex. Moreover, the effervescent matrix of the tablets was effective in improving the dissolution behaviour of BNZ complexed with CD. Conclusions Effervescent tablets produced using an inclusion complex of BNZ with CD suggest a possible improvement in the bioavailability of BNZ, and this could represent a relevant advance in Chagas therapy.