Inclusion complex of the antiviral drug acyclovir with cyclodextrin in aqueous solution and in solid phase (original) (raw)
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Physicochemical characterization of efavirenz–cyclodextrin inclusion complexes
AAPS …, 2009
Efavirenz (EFV) is an oral antihuman immunodeficiency virus type 1 drug with extremely poor aqueous solubility. Thus, its gastrointestinal absorption is limited by the dissolution rate of the drug. The objective of this study was to characterize the inclusion complexes of EFV with β-cyclodextrin (β-CD), hydroxypropyl β-CD (HPβCD), and randomly methylated β-CD (RMβCD) to improve the solubility and dissolution of EFV. The inclusion complexation of EFV with cyclodextrins in the liquid state was characterized by phase solubility studies. The solid-state characterization of various EFV and CD systems was performed by X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy analyses. Dissolution studies were carried out in distilled water using US Pharmacopeia dissolution rate testing equipment. Phase solubility studies provided an A L -type solubility diagram for β-CD and A P -type solubility diagram for HPβCD and RMβCD. The phase solubility data enabled calculating stability constants (K s ) for EFV-βCD, EFV-HPβCD, and EFV-RMβCD systems which were 288, 469, and 1,073 M −1 , respectively. The physical and kneaded mixtures of EFV with CDs generally provided higher dissolution of EFV as expected. The dissolution of EFV was substantially higher with HPβCD and RMβCD inclusion complexes prepared by the freeze drying method. Thus, complexation with HPβCD and RMβCD could possibly improve the dissolution rate-limited absorption of EFV.
Enhanced oral bioavailability of acyclovir by inclusion complex using hydroxypropyl-β-cyclodextrin
Drug Delivery, 2013
The therapeutic potential of acyclovir is limited by the low oral bioavailability owing to its limited aqueous solubility and low permeability. The present study was a systematic investigation on the development and evaluation of inclusion complex using hydroxypropylb-cyclodextrin for the enhancement of oral bioavailability of acyclovir. The inclusion complex of acyclovir was prepared by kneading method using drug: hydroxypropyl-b-cyclodextrin (1:1 mole). The prepared inclusion complex was characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, NMR spectroscopy and evaluated in vitro by dissolution studies. In vivo bioavailability of acyclovir was compared for inclusion complex and physical mixture in rat model. Phase solubility studies indicate the formation of acyclovirhydroxypropyl-b-cyclodextrin complex with higher stability constant and linear enhancement in drug solubility with increase in hydroxypropyl-b-cyclodextrin concentration. Characterization of the prepared formulation confirms the formation of acyclovir-hydroxypropyl-b-cyclodextrin inclusion complex. Dissolution profile of inclusion complex demonstrated rapid and complete release of acyclovir in 30 min with greater dissolution efficiency (90.05 AE 2.94%). In vivo pharmacokinetic data signify increased rate and extent of acyclovir absorption (relative bioavailability $160%; p50.0001) from inclusion complex, compared to physical mixture. Given the promising results in the in vivo studies, it can be concluded that the inclusion complex of acyclovir could be an effective and promising approach for successful oral therapy of acyclovir in the treatment of herpes viruses.
Dhaka University Journal of Pharmaceutical Sciences, 2013
Nelfinavir is a poorly water-soluble antiretroviral drug with relatively low bioavailability. In the present study, the practically insoluble drug, nelfinavir (NFV) and its inclusion complexes with hydroxypropyl-?-cyclodextrin (HP-?-CD) were investigated to improve the aqueous solubility and the dissolution rate of the drug, thus enhancing its bioavailability. The phase solubility diagram with HP-?-CD was classified as AL-type at all temperatures investigated, indicating the formation of higher order complexes. The apparent complexation constants (K1:1) calculated from phase solubility diagram were 145.49, 188.45 and 255.54 M-1 at 25, 37 and 45 ± 0.5°C, respectively. Aqueous solubility and dissolution studies indicated that the dissolution rates were remarkably increased; this could be mainly attributed to the improved solubility and dissolution associated with inclusion complex between drug and HP- ? -CD. Absence of endothermic and characteristic diffraction peaks corresponding to ...
1999
Abstract. The interaction in solution between 2,4-dichlorophenoxyacetic acid with α- and β-cyclodextrins was evaluated by phase solubility studies. Association constants were calculated by this technique. The stoichiometries were 1: 2 and 1: 1 for the α- and β-cyclodextrin complexes, respectively. In order to corroborate the complexation and the knowledge of structural aspects of the host: guest interaction, proton nuclear magnetic resonance (1H-NMR) spectroscopy was employed. The application of the continuous variation technique corroborated the calculated complex stoi-chiometries by solubility assays. Complementary NOE studies were applied in order to corroborate the proposed complex structures. Key words: solubility, 1H-NMR, stoichiometry, cyclodextrins 1.
A thermodynamic study of the cyclodextrin-UC781 inclusion complex using a HPLC method
Journal of inclusion phenomena and macrocyclic chemistry, 2012
UC781, a very potent HIV-1 non-nucleoside reverse transcriptase inhibitor with extreme hydrophobicity and poor water solubility, is under development as a topical vaginal microbicide product to prevent HIV transmission. In this study, the thermodynamic behavior of the interaction between UC781 with three cyclodextrins (CDs): β-cyclodextrin (βCD), hydroxypropyl-β-cyclodextrin (HPβCD) and methyl-β-cyclodextrin (MβCD), was investigated using a reversed-phase HPLC method. A mobile phase consisting of acetonitrile: H2O (30:70) solution containing various CD concentrations was used. The retention time at different temperatures was determined to evaluate the inclusion process. The influence of βCDs on the solubility and hydrophobicity of UC781 was characterized by retention time values. The results showed that the inclusion capacity of cyclodextrins follows the order MβCD > βCD > HPβCD. An enthalpy-entropy compensation effect was also observed. In addition, the results revealed that ...
Study to explore the mechanism to form inclusion complexes of β-cyclodextrin with vitamin molecules
Scientific Reports, 2016
Host–guest inclusion complexes of β-cyclodextrin with two vitamins viz., nicotinic acid and ascorbic acid in aqueous medium have been explored by reliable spectroscopic, physicochemical and calorimetric methods as stabilizer, carrier and regulatory releaser of the guest molecules. Job’s plots have been drawn by UV-visible spectroscopy to confirm the 1:1 stoichiometry of the host-guest assembly. Stereo-chemical nature of the inclusion complexes has been explained by 2D NMR spectroscopy. Surface tension and conductivity studies further support the inclusion process. Association constants for the vitamin-β-CD inclusion complexes have been calculated by UV-visible spectroscopy using both Benesi–Hildebrand method and non-linear programme, while the thermodynamic parameters have been estimated with the help of van’t Hoff equation. Isothermal titration calorimetric studies have been performed to determine the stoichiometry, association constant and thermodynamic parameters with high accura...
Journal of Solution Chemistry, 2011
The physicochemical properties of 4-hydroxy-7-methoxy-3-phenyl-2H-chromen-2-one (4HC) and β-cyclodextrins (CDs) inclusion complexes were investigated. The phase solubility profile of 4HC with β-cyclodextrin derivatives was classified as A L-type. Stability constants for complexes with 1:1 molar ratios were calculated from the phase solubility diagrams and indicate the following trend: DMβCD > HPβCD > βCD. The highest value of the binding constant was for 4HC-DMβCD; the binding association constant (K a) for this complex was determined at different temperatures and the thermodynamic data indicate that 4HC-DMβCD association is mainly an entropically driven process. 1 H NMR and ROESY were carried out, revealing that 4HC is embedded in the apolar cavity of DMβCD with the 4OH group buried in the cyclodextrin cavity with the phenyl group outside, near the primary rim. These results are in agreement with ORAC FL values; the decrease in the antioxidant activity of 4HC-DMβCD is explained by the effective protection of the hydroxyl group due to complexation. Keywords 4-Hydroxycoumarin • Cyclodextrins • Inclusion complex • 2D-ROESY • Thermodynamic study • ORAC FL
Beilstein journal of organic chemistry, 2017
Tricyclic fused-ring cyclobenzaprine (1) and amitriptyline (2) form 1:1 inclusion complexes with β-cyclodextrin (β-CD) in the solid state and in water solution. Rotating frame NOE experiments (ROESY) showed the same geometry of inclusion for both 1/β-CD and 2/β-CD complexes, with the aromatic ring system entering the cavity from the large rim of the cyclodextrin and the alkylammonium chain protruding out of the cavity and facing the secondary OH rim. These features matched those found in the molecular dynamics (MD) simulations in solution and in the solid state from single-crystal X-ray diffraction of 1/β-CD and 2/β-CD complexes. The latter complex was found in a single conformation in the solid state, whilst the MD simulations in explicit water reproduced the conformational transitions observed experimentally for the free molecule.
Preparation and solid state properties of cyclodextrin complexes of selected drug molecules
1999
A large number of pharmaceutically important drugs are poorly soluble in water. This study focuses on the 'smart' molecule that can enhance the solubility and hence increase the bioavailability of these drugs. This molecule is a cyclodextrin and is known to form inclusion compounds with various drug molecules. The preparation of P-cyclodextrin CP-CD), y-cyclodextrin (y-CD), heptakis(2,6-di-O-J, methyl)-p-cyclodextrin (Dimeb) and heptakis(:J>•tri-0-methyl)-P-cyclodextrin (Trimeb) 3, complexes with clofibric acid as well as the heptakis(2j•tri-O-methyl)-p-cyclodextrin (Trimeb) complex with clofibrate is reported. The complexes were characterised by thermogravimetric analysis (TG), differential scanning calorimetry (DSC), ultraviolet spectrophotometry (UV), infrared spectroscopy (IR), X-ray powder diffraction (XRD) and single crystal X-ray analysis. Infrared spectroscopy for the four inclusion complexes of clofibric acid showed a significant shift of the C=O stretching frequency in the complexed drug relative to the uncomplexed drug. The crystal structures of the complexes, except that of the Dimeb complex with clofibric acid, were solved. The guest molecules in the P-and y-CD complexes were found to be disordered, preventing detailed interpretation of the mode of inclusion. The guest molecules in the two Trimeb complexes were resolved and the modes of inclusion were revealed. The aliphatic chains of the guests were found to be inserted in the cavity, while the chlorophenyl rings protrude from the secondary side of the Trimeb molecule. Kinetics of dehydration studies for P-and y-CD complexes of clofibric acid, as well as for their
2015
The main objective of this study was to investigate different manufacturing processes claimed to promote inclusion complexation between different drugs and cyclodextrins (econazole and α-cyclodextrin; indomethacin and methyl-β-cyclodextrin; olanzapine and methyl-β-cyclodextrin; flurbiprofen and methyl-β-cyclodextrin) in order to enhance the apparent solubility and dissolution properties of drugs. Specifically, the effectiveness of supercritical carbon dioxide processing for the preparation of solid drug-cyclodextrin inclusion complexes was investigated and compared to other preparation methods. Nitrate, besylate, sulfosalicylate dihydrate and maleate salts of econazole were synthesised. The solid drug-cyclodextrin inclusion complexes were prepared by physical mixing, freeze drying from aqueous solution and processing with supercritical carbon dioxide. The complexes were evaluated by scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction, 1H-nuclear...