Phase Solubility Profiles Research Articles

Antifungal activity of econazole nitrate/cyclodextrin complex: Effect of pH and formation of complex aggregates.

Econazole nitrate (ECN) is a weakly basic drug with very low aqueous solubility that hampers its permeation through biological membranes and results in low ECN bioavailability. Formation of drug/cyclodextrin (drug/CD) inclusion complexes is a formulation technology that can be applied to enhance drug solubility in aqueous media. The aim of this study was to determine the effect of CD complexation and pH adjustments on the ECN solubility. The ECN pH-solubility and ECN/CD phase-solubility profiles were determined. The solubility of ECN in aqueous acidic solutions containing α-cyclodextrin (αCD) was relatively high and much higher than in aqueous γ-cyclodextrin (γCD) solutions under same conditions. The complexation efficiency of the ECN/CD complex was relatively low for the unionized drug. Formation of ECN/CD inclusion complex was verified by proton nuclear magnetic resonance spectroscopy. Formation of ECN/CD complexes enhanced the drug stability during autoclaving. γCD complexes self-assembled to form nano- and microparticles whereas αCD complexes had negligible tendency to self-assemble. Formation of CD complex nano- and microparticles was investigated by dynamic light scattering and by drug permeation through semipermeable membranes of different molecular weight cut-off. The largest aggregate fraction was observed for the unionized ECN in aqueous pH 7.5 solution containing high CD concentration, that is 10% (w/v) CD. It was shown that in acidic solutions ECN/αCD can enhance the antifungal activity to filamentous fungi. This was associated with the increased ECN solubility and increase of readily available ECN molecules in aqueous αCD solutions.

Interaction of native CDs and their hydroxypropyl derivatives with parabens in aqueous solutions. Part 2: evaluation of paraben/cyclodextrin complex aggregation

Cyclodextrins (CDs) and their inclusion complexes are known to self-assemble in aqueous solutions to form aggregates and the physicochemical characteristics of guest molecules have been linked to the aggregate formation. A series of parabens was selected as model compounds due to their small size (aromatic ring fits in the cavity) and different side chain length. In Part 1 it was demonstrated that CDs and parabens form a range of soluble and insoluble complexes dependent on the type of CD (native or hydroxypropylated αCD, βCD or γCD) and the length of the alkyl residue of the parabens. Furthermore, phase-solubility studies suggested that higher order complexes (e.g., aggregates) were formed. Here we apply osmometry and permeation studies to evaluate if and how the alkyl chain length of the parabens influences the process of aggregate formation. Furthermore, the possible effect of CD aggregates on permeation profile of parabens is also elucidated. Changes in osmometry correlate with the type pf phase-solubility profile. For AL-types total osmolality remained unchanged throughout experiment, while for B-types the osmolality of systems displayed significant changes mainly due to precipitation of poorly-soluble complexes. The permeation method is an effective and useful method to detect and evaluate self-assembly of CDs and to detect aggregate formation in aqueous γCD and HPβCD solutions containing parabens. Generally, all parabens modified the natural aggregation behavior of HPβCD and γCD as the apparent critical aggregation concentration (cac) values for paraben/CD systems decreased compared to those of pure aqueous CD solutions. The longer the alkyl side chain, the greater was the promotion of aggregates formation (methyl < ethyl < propyl < butyl) and, consequently, more and larger aggregates are formed. These superstructures are responsible for the observed changes in apparent cac and flux values, as well as, for the observed slopes greater than unity for the phase-solubility diagrams.

Interaction of native cyclodextrins and their hydroxypropylated derivatives with parabens in aqueous solutions. Part 1: evaluation of inclusion complexes

Due to their antimicrobial activity, parabens (i.e. alkyl esters of p-hydroxybenzoic acid) are widely used as preservatives in several industries (pharmaceutical, food, cosmetic). Although being extremely effective, their usage is hampered by their low aqueous solubility. Several formulation strategies can be applied to enhance their solubility, one of which is formation of water-soluble cyclodextrin (CD) complexes. Formation of inclusion complexes has been proved to be a good approach to increase solubility of lipophilic drugs and other active ingredients. Some research has been done in this field. However, a complete and comprehensive study on how the alkyl chain length of parabens influences the complex formation, aggregation and formation of insoluble complexes is still lacking. Phase-solubility studies showed that all the very water-soluble hydroxypropylated CDs form linear (AL) type phase-solubility profiles with all tested parabens. The poorly soluble βCD did also form AL-type profiles with methyl and ethyl paraben while the βCD complexes of propyl and butyl paraben have limited solubility in water and, thus displayed B-type profiles. The paraben complexes of αCD and γCD all had limited solubility in water and, thus, displayed B-type phase-solubility profiles. Fourier-transformed infrared spectroscopy, Differential scanning calorimetry and X-ray powder diffraction were applied to elucidate the nature of the solid phases from the phase-solubility studies. They consistently showed the presence of solid pure paraben over the CD concentration range studied when AL-type profiles were observed, and precipitation of poorly soluble paraben/CD complexes when B-type were observed (i.e. during and after the B-type plateau region). These studies demonstrate that the composition of solid phases is related to the type of phase-solubility profile. It was also shown that in aqueous CD solutions, paraben solubilization increase with increasing side chain length (i.e. methyl < ethyl < propyl < butyl), as well as, with increasing size of the CD cavity (i.e. αCD < βCD < γCD). This statement is valid for linear region of phase-solubility diagrams (i.e. A- and B-type).

Studies on pH and temperature dependence of inclusion complexes of bisdemethoxycurcumin with β-cyclodextrin derivatives

The effect of pH and temperature on the inclusion complexes of bisdemethoxycurcumin (BDMC) with sulfobutylether-β-cyclodextrin (SBE-β-CD) and methylated-β-cyclodextrin (M-β-CD) were investigated by phase solubility and fluorescence spectroscopy methods. pH and temperature variations are in the range of pH 6.0-8.5 and 298.2-313.2 K, respectively. The phase solubility profiles of BDMC by UV-Vis spectrophotometry in the presence of SBE-β-CD and M-β-CD were classified as AL-type, indicating the formation of 1:1 inclusion complexes under experimental conditions, in agreement with the conclusion obtained by fluorescence analysis. Based on the complexation constants KC, the values of enthalpy and entropy changes for the complex formation were obtained from the Van't Hoff equation. Dissolution enthalpy and entropy were calculated from the intrinsic solubilities of BDMC. Different influence of temperature on the total solubility and intrinsic solubility was discussed based on the difference between dissolution enthalpy and complexation enthalpy. The effect of pH and cyclodextrin (CD) structure on the solubility and aqueous stability of BDMC were also discussed. These experimental results were confirmed by molecular modeling which showed that the aromatic ring of BDMC was included inside the hydrophobic cavity of CD and M-β-CD was more closely integrated with BDMC.

Methyl-β-cyclodextrin quaternary ammonium chitosan conjugate: nanoparticles vs macromolecular soluble complex.

PurposeThe present study aimed to compare a novel cyclodextrin–polymer–drug complex in solution with a dispersed supramolecular nanosize system, made of the same complex, for ability to carry dexamethasone (DEX) across excised rat intestine.ResultsMethyl-β-cyclodextrin-quaternary ammonium chitosan conjugate (QA-Ch-MCD) was obtained by covalent grafting through a 10-atom spacer. The conjugate was characterized by 1H-NMR, resulting in 24.4% w/w of MCD content. Phase solubility profile analysis of the QA-Ch-MCD/DEX complex yielded an association constant of 14037 M−1, vs 4428 M−1 for the plain MCD/DEX complex. Nanoparticle (NP) dispersions resulted from ionotropic gelation of the QA-Ch-MCD/DEX complex by sodium tripolyphosphate, leading to 9.9%±1.4% drug loading efficiency. The mean diameter and zeta potential for NP were 299±32 nm (polydispersity index [PI] 0.049) and 11.5±1.1 mV, respectively. Those for QA-Ch-MCD/DEX were 2.7±0.4 nm (PI 0.048) and 6.7±0.6 mV. QA-Ch-MCD/DEX solutions and corresponding NP dispersions were compared in vitro for water-assisted transport through mucus, DEX permeation through excised rat intestine, and ex vivo mucoadhesivity. The complex showed higher mucoadhesion and lower transport rate through mucus; also, it provided faster drug permeation across excised rat intestine.ConclusionCarrier adhesion to mucus surface has played a most important role in favoring transepithelial permeation. Then, within the concerns of the present study, the use of NP seems not to provide any determinant advantage over using the simpler macromolecular complex.

In-vitro dissolution rate and molecular docking studies of cabergoline drug with β-cyclodextrin

The physicochemical properties and dissolution profile of cabergoline drug (CAB) with β-cyclodextrin (β-CD) inclusion complex were investigated by the UV spectroscopy. The inclusion complex has used to calculate the stability constant and gives the stoichiometry molar ratio is 1:1 between CAB and β-CD. The phase solubility diagram and the aqueous solubility of CAB (60%) was found to be enhanced by β-CD. In addition, the phase solubility profile of CAB with β-CD was classified as AL-type. Binary systems of CAB with β-CD were prepared by Physical mixture, Kneading and solvent evaporation methods. The solid-state properties of the inclusion complex were characterized by Fourier transformation-infrared spectroscopy, Differential scanning calorimetry, Powder X-ray diffractometric patterns and Scanning electron microscopic techniques. Theoretically, β-CD and CAB inclusion complex obtained by molecular docking studies, it is in good correlation with the results obtained through experimental methods using the Schrödinger software program. In-vitro dissolution profiles of the inclusion complexes were carried out and obvious increase in dissolution rate was observed when compared with pure CAB drug and the complexes.

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.

DISSOLUTION ENHANCEMENT OF DIACEREIN USING WATER SOLUBLE CARRIER BY SOLID DISPERSION TECHNOLOGY

Diacerein is generally used in the treatment of Osteoarthritis , this drug comes under the class anthraquinone. The drug is practically insoluble in water and exhibits exceptionally slow and intrinsic dissolution rate with poor bioavailability. In the present study, diacerein and I²-cyclodextrin (I²-CD) solid dispersions were prepared with a view to study the effect and influence of I²-CD on the solubility and dissolution rate of this poorly aqueous soluble drug. Phase solubility profile revealed that the solubility of diacerein was significantly increased in the presence of I²-CD and indicating the possible 1:1 stoichiometric inclusion complex with a stability constant of 339.66 M-1. Effect of variable such as drug: Carrier ratios were studied. Physical characterization of the solid dispersion was characterized by Fourier transform infrared spectroscopy (FT-IR), Differential scanning calorimetry (DSC) and X-ray diffraction studies (XRD). These studies revealed that a distinct loss of drug crystallinity in the solid dispersion is ostensibly accounting for enhancement of dissolution rate in distilled water containing 0.1% Tween 80. The scanning electron microscopy (SEM) study revealed that all the binary systems appeared as agglomerates and exhibiting the presence of a homogenous solid phase which could also be responsible for the enhanced dissolution rate in comparison with the pure drug. The drug release from the prepared solid dispersion exhibited a first order kinetics. Solid dispersion of diacerein showed a 7.66 times fold increase in dissolution rate over the pure drug.

Improvement of opipramol base solubility by complexation with β-cyclodextrin

Opipramol (OPI), a tricyclic antidepressant and anxiolytic compound, is administered orally in the form of a dihydrochloride. Salt form of the drug has a higher solubility in water and hence bioavailability and stability. A similar effect can be achieved by closing the hydrophobic part of the drug molecule in the cyclodextrin cavity. The paper presents opipramol inclusion complexes with beta-cyclodextrin (β-CD) in 1:1 molar ratio. Studies on the formation of inclusion complexes were carried out both in solution and in the solid state. The formation and physicochemical characterisation of the complexes were determined by UV spectroscopic measurement (UV–vis), Fourier Transform Infrared (FTIR) Spectroscopy, 1H Nuclear Magnetic Resonance (1H NMR, 2D NOESY NMR), thermoanalytical methods (TGA – Termogravimetric analysis, DSC – differential scanning calorimetry), X-ray diffractometry (XRD) and scanning electron microscopy (SEM). The phase solubility profile with β-CD was classified as the AN- type, indicating the formation of the inclusion complex with a drug.

Intracorneal melatonin delivery using 2-hydroxypropyl-β-cyclodextrin ophthalmic solution for granular corneal dystrophy type 2

Melatonin (MT), an effective antioxidant, has therapeutic implications for granular corneal dystrophy type 2 (GCD2) treatment. Eye drop formulations containing cyclodextrins (CDs) were studied with the objective of improving MT solubility, stability, and ocular absorption, while decreasing eye irritation. MT complexes with αCD, βCD, γCD, and 2-hydroxypropyl-βCD (HPβCD) were characterized by phase solubility studies, which demonstrated Higuchi’s AL-type phase solubility profiles. The MT/HPβCD complex showed the highest MT solubility (2.75mg/mL). Ocular irritation experiments showed HPβCD inclusion alleviated irritation of the eye. After administration of MT formulations to rabbit corneas, each harvested cornea was separated into corneal epithelium, stroma, and endothelium. MT concentrations in the corneal epithelium, stroma, and endothelium for the F1-treated group were 55.5±9.24, 26.7±2.66, and 21.1±1.77μM while those for the F2-treated group were 127.2±21.01, 43.7±16.93, and 51.0±13.91μM, respectively. Stability studies for 60days showed no significant change in pH, osmolarity, and MT content. In conclusion, MT/HPβCD formulations can lower irritation, enhance MT stability, and improve therapeutic efficacy.

PH-Sensitive Supramolecular Assemblies of β-Cyclodextrin and 2-Aminodiphenylamine in Water Medium: Structure, Solubility and Stability

The influence of β-cyclodextrin on the solubility, protolytic properties, and complex formation behavior of 2-aminodiphenylamine was studied using UV spectroscopy. In accordance with the results of the spectrophotometric titration that was carried out in phosphate buffer solutions, the presence of β-cyclodextrin does not change the value of the deprotonation constant of the primary amino group of 2-aminodiphenylamine. This fact confirms that the primary amino group is not involved in the complex formation and interaction between β-cyclodextrin and 2-aminodiphenylamine occurs via the phenylimine moiety. The phase solubility profiles of 2-aminodiphenylamine in the presence of β-cyclodextin, at pH = 1.00 and pH = 5.00, indicate formation of inclusion complexes with limited solubility and can be classified as Higuchi–Connors curves of BI and BS type, respectively. The stoichiometry of the complexes and the apparent stability constants that characterize the β-cyclodextrin complexes with both protonated and neutral forms of 2-aminodiphenylamine were estimated from the dependence of absorbance intensity of the guest molecule at increasing amounts of β-cyclodextrin by the Ketelar equation. The linearity of the plots in the coordinates of the Ketelar equation proves the formation of 1:1 inclusion complexes for both protolytic forms of 2-aminodiphenylamine. It was found that inclusion complex formation is preferable for the neutral form of 2-aminodiphenylamine.

Melatonin/HPβCD complex: Microwave synthesis, integration with chitosan scaffolds and inhibitory effects on MG-63CELLS

In this study, melatonin/2-hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complex was prepared by using microwave irradiation in a very short time. Phase-solubility studies indicated a linear increase in the solubility of melatonin with HPβCD demonstrating Higuchi’s AL-type phase solubility profiles and the formation of 1:1 stoichiometric inclusion complexes. Also, the ability of inclusion complex formation was promoted at microwave conditions compared to room conditions. The structure of inclusion complex was determined by FTIR, DSC, XRD, 1H NMR and 13C NMR studies. Both of pure melatonin and melatonin/HPβCD inclusion complex were loaded into the chitosan scaffolds that were prepared by freeze-drying method and the effect of released melatonin on human osteosarcoma cells (MG-63) was investigated in vitro. Approximately 9mM melatonin concentration caused time dependent cell death by reducing the proportion of the cells in the G2/M phase rather than S phase. In conclusion, melatonin/HPβCD inclusion complex loaded chitosan scaffolds could be considered as an alternative system for the human osteosarcoma therapy.

A New Approach for Quantitative Determination of γ-Cyclodextrin in Aqueous Solutions: Application in Aggregate Determinations and Solubility in Hydrocortisone/γ-Cyclodextrin Inclusion Complex

Fast and simple high-pressure liquid chromatographic (HPLC) method with charged aerosol detector (CAD) was developed for quantitation of γ-cyclodextrin (γCD) in aqueous solutions. The chromatographic system consisted of a C18 column (i.e., the stationary phase) and an aqueous mobile phase containing 7% (v/v) methanol. Calibration curve was obtained over the γCD concentration range of 0.005%-1% (w/v). The limit of detection and quantitation of γCD were 0.0001% and 0.0002% (w/v), respectively. Formation of γCD aggregates in aqueous solution and their critical aggregation concentration (cac) were determined by both conventional dynamic light scattering method and permeation method using HPLC-CAD for quantitative determination of γCD. The cac of γCD was determined to be 0.95% (w/v) and the amount of γCD self-aggregates increased with increasing γCD concentrations. Also, the developed HPLC-CAD method was used to determine the γCD phase-solubility profile in an aqueous hydrocortisone (HC)/γCD complexation medium. The maximum concentration of dissolved γCD and HC was determined to be 1.47% and 0.31% (w/v), respectively. The membrane permeation method was shown to be a reliable method for determination of metastable γCD aggregates. The HPLC-CAD method was successfully applied for quantitative determination of γCD in aqueous solutions during permeation and phase-solubility studies.

Physicochemical Characterization and In-Vitro Dissolution Enhancement of Bicalutamide-Hp-Β-Cd Complex

Abstract: Inclusion complex has been used as effective metllhod to improve the dissolution properties and bioavailability of poorly water soluble drugs. The aim of present study was to improve the dissolution rate of poorly soluble drug, bicalutamide (BIC), by cyclodextrin inclusion complexation. The phase solubility profile of bicalutamide with hydroxypropyl-β-Cyclodextrin (HP- β-CD) was classified as An-type. Stability constant with 1:2 molar ratio was calculated from the phase solubility diagram. Gibbs free energy (ΔGtr) values were negative, indicating the spontaneous nature of BIC solubilization. Solid inclusion complexes were prepared at 1:1.5, 1:2 drug/carrier ratio by physical mixing, kneading method and solvent evaporation techniques. Optimized complex was characterized by using FTIR and differential scanning calorimetry. It could conclude that stability of BIC and the absence of well define drugpolymer interaction. Inclusion complex prepared by kneading method showed the most improvement in wettability and dissolution rate as compare with pure BIC and physical mixture. Tablets prepared using optimized ratio with HP-β-CD showed significant improvement in the release profile of BIC as compared with marketed tablets (CALUT).

Carboxymethyl and hydrazide functionalized β-cyclodextrin derivatives: A systematic investigation of complexation behaviours with the model hydrophobic drug dexamethasone

Cyclodextrins (CDs) are typically functionalized to increase their solubility or provide reactive functional groups suitable for grafting onto polymer supports designed for controlled release applications. In this work, a systematic investigation was performed on the binding behaviour of the model drug dexamethasone with βCD derivatives functionalized with a small, negatively charged moiety (carboxyl groups, CM) and a large, neutral, reactive moiety (hydrazide groups, Hzd), both free and grafted to dextran. Solubilization capacities and thermodynamic parameters were examined through phase solubility analysis, the method of continuous variation, and isothermal titration calorimetry. Alternate mechanisms of solubilization were also investigated by probing aggregation of both free and complexed βCD derivatives using nanoparticle tracking analysis. CM/βCD and Hzd/βCD derivatives exhibited similar complexation behaviours with dexamethasone: 1:1 stoichiometry, linear phase solubility profiles, and consistent binding enthalpies. Increased functionalization reduced the complex stability constant as well as the complexation efficiency, while polymer grafting resulted in no significant change in binding properties. CM/βCD derivatives complexed with dexamethasone formed more and larger aggregates, while Hzd/βCD derivatives formed significantly fewer, smaller aggregates and dextran-grafted βCD did not aggregate. Such characterization of βCD derivatives provides a framework for designing βCDs as pharmaceutical excipients or drug binding sites in drug delivery vehicles.

A 5,7-dimethoxyflavone/hydroxypropyl-β-cyclodextrin inclusion complex with anti-butyrylcholinesterase activity.

This study aimed to improve the water solubility of 5,7-dimethoxyflavone (5,7-DMF) isolated from Kaempferia parviflora by complexation with 2-hydroxypropyl-β-cyclodextrin (HPβ-CD). The phase solubility profile of 5,7-DMF in the presence of HPβ-CD was classified as AL-type and indicated a 1:1 mole ratio. Differential scanning colorimetry, X-ray diffraction, NMR and SEM analyses supported the formation of a 5,7-DMF/HPβ-CD inclusion complex involving the A ring of 5,7-DMF inside the HPβ-CD cavity. This is the first example of CD inclusion with the A ring of non-hydroxyl flavones. The stability and binding constants of the complexes were determined using the phase solubility and UV-vis absorption spectroscopy, respectively. The water solubility of 5,7-DMF was increased 361.8-fold by complexation with HPβ-CD and overcame the precipitation problem observed in aqueous buffers, such as during in vitro anti-butyrylcholinesterase activity assays. The 1:1 mole ratio of the 5,7-DMF/HPβ-CD complex showed a 2.7-fold higher butyrylcholinesterase inhibitory activity (in terms of the IC50 value) compared to the non-complexed compound.

Sildenafil citrate monohydrate–cyclodextrin nanosuspension complexes for use in metered-dose inhalers

Sildenafil is a selective phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction and pulmonary hypertension. Sildenafil citrate monohydrate was complexed with α-, hydroxypropyl-β- and γ-cyclodextrin (α-CD, HP-β-CD and γ-CD, respectively) to enhance its water solubility. The complexes of sildenafil citrate monohydrate with all types of CDs were characterized by phase solubility diagrams, (1)H and (13)C NMR, and dielectric constants. Sildenafil citrate monohydrate complexed with CDs was developed as nanosuspensions for use in a pressurized metered-dose inhaler (pMDI). Sildenafil citrate monohydrate pMDI formulations were prepared by a bottom-up process using dried ethanol as a solvent and HFA-134a as an antisolvent and propellant in order to form nanosuspensions. A 3×3 factorial design was applied for the contents of the dried ethanol and HFA-134a propellant. The phase solubility profiles of the sildenafil and cyclodextrins were described as AL type with a mole ratio 1:1. The piperazine moiety of sildenafil formed an inclusion in the cavity of the CDs. The particle diameters of the sildenafil citrate monohydrate suspensions in pMDIs were all within a nanosuspension size range. An assay of the sildenafil content showed that the formation of complexes with CDs was close to 100%. In the case of the formulations with CDs, the emitted doses varied within 97.4±10.8%, the fine particle fractions (FPFs) were in a range of 45-81%, the fine particle dose (FPD) was 12.6±2.0 μg and the mass median aerodynamic diameters (MMADs) were 1.86±0.41 μm. In contrast, the formulations without CDs produced a low emitted dose of sildenafil (<60%). Therefore, only sildenafil citrate monohydrate pMDI formulations containing CDs were suitable for use as aerosols.

Solubility Enhancement of the Poorly Water-Soluble Antiulcer Drug Famotidine by Inclusion Complexation

Aqueous solubility is a critical factor for optimum drug delivery. In the present study, we investigated the potential of drug-cyclodextrin complexation as an approach for improving the solubility and bioavailability of famotidine, an H2-receptor antagonist and acid reducing drug which has poor solubility and bioavailability. Solubility improvement of drug by β-cyclodextrin was done by simple complexation approach using physical, kneading and co-precipitation methods and compared with physical mixture. Phase solubility profile indicated that the solubility of famotidine was significantly increased in presence of β-cyclodextrin and shows a linear graph with β-cyclodextrin indicating formation of inclusion complexes in a 1:1 molar ratio. β-Cyclodextrin-famotidine mixture have maximum stability constant 1477.6 M-1. The inclusion complex ratio 1:1 of kneading mixture was selected based on drug release profile and compared with physical mixture. Further characterization was done by using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) to identify the physicochemical interaction between drug and carrier and its effect on dissolution. Dissolution rate studies for selected inclusion complex was performed in 0.1 N HCl (pH 1.2), phosphate buffer (pH 7.5) and distilled water (pH 6.8) and compared these to pure drug profile which was found to be 2.34 fold increase in distilled water, 1.83 fold in HCl and 2.01 fold in phosphate buffer (pH 7.5). These results suggest that the kneaded complex of famotidine with β-cyclodextrin as hydrophilic complexation agent can substantially enhance the solubility and dissolution rate. Such complex has promising potential to improve the bioavailability of famotidine.&#x0D;

Studies on the Preparation, Characterization, and Solubility of 2-HP-β-Cyclodextrin-Meclizine HCI Inclusion Complexes

Meclizine HCl is a poorly water-soluble drug having a very slow-onset of action. The effect of 2-hydroxypropyl-β-cyclodextrins and β-cyclodextrins on its aqueous solubility and dissolution rate was investigated. The phase solubility profile indicated that the solubility of Meclizine HCl was significantly increased in the presence of both 2-hydroxypropyl-β-cyclodextrin and β- cyclodextrin; an extend of increase being more for 2-hydroxypropyl-β-cyclodextrin. It was classified as AL-type, indicating the 1:1 stoichiometric inclusion complexes. The complexes formed were quite stable. The solid complexes prepared by physical mixtures, kneading methods, and co-precipitation methods were characterized using differential scanning calorimetry and FTIR. An in vitro study showed that the solubility and dissolution rate of Meclizine HCl were significantly improved by complexation with 2-hydroxypropyl-β-cyclodextrin. Tablet formulation using 1:1 kneading complex of Meclizine HCl and 2-hydroxypropyl-β-cyclodextrin with drug equivalent to 25 mg was prepared by a direct compression method. A dissolution study of prepared tablets was performed in 0.5% SLS in water (pH 7.0). Almost 96% drug was released from the formulation at the end of 30min. A comparison study of prepared tablets was done with marketed a Meclizine HCl 25 mg conventional tablet. From the results of dissolution study, it was found that the prepared formulation was showing better release, which was statistically significant P < 0.01 than a marketed tablet (paired t-test). Only 54% drug release was observed from the marketed tablet at the end of 30 min. Hence this study concludes that the solubility enhancement of Meclizine HCl could be successfully achieved using the inclusion complexation technique.

Characterization and molecular modeling of the inclusion complexes of 2-(2-nitrovinyl) furan (G-0) with cyclodextrines

The objective of this study was to prepare and characterize complexes of 2-(2-nitrovinyl) furan (G-0) with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutyl ether-β-cyclodextrin (SBE-β-CD). The solid inclusion complexes were prepared using kneading and freeze-drying methods. Phase solubility profiles were used to obtain the apparent stability constants and the complexation efficiency. They were classified as A(L) type for both systems: the apparent stability constants K(1:1) of the complexes were 48.7 and 79.2 M(-1) for HP-β-CD and SBE-β-CD respectively. The solid inclusion complexes were evaluated by means of differential scanning calorimetry (DSC), X-ray diffraction (XRD) and nuclear magnetic resonance spectroscopy (NMR). Especially the use of the two-dimensional ROESY spectrum was useful to confirm the presence of an inclusion complex. The spatial configuration of the drug inside the cyclodextrin cavity was investigated using molecular modeling studies. The latter results were in agreement with the experimental data. Inclusion complexes of G-0 with HP-β-CD contributed to improve the chemical stability of the drug in the presence of other commonly used pharmaceutical excipients.