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.     

The Effect of Parenterally Administered Cyclodextrins on the Pharmacokinetics of Coadministered Drugs

Cyclodextrins are used increasingly to formulate otherwise poorly soluble molecules for clinical use. Cyclodextrins, such as 2-hydroxypropyl-ß-cyclodextrin (HPßCD) and sulfobutylether ß-cyclodextrin (SBEßCD), are found in marketed parenteral drug formulations. Depending upon the relative affinities of a coadministered medication for cyclodextrin and plasma proteins, complexation with HPßCD or SBEßCD may alter its pharmacokinetics (PK). To explore this possibility, we applied a previously developed model for competitive binding of drugs with HPßCD and human serum albumin to a variety of commonly administered medications. We modeled this potential interaction in medications chosen on the basis of a hypothetical detrimental effect of HPßCD complexation with their therapeutic action (e.g., antibiotics), supplemented by a composite listing of concurrent medications. Stability constant (K_1:1) values for drug-HPßCD 1:1 inclusion complexes were extracted from our own data and the literature. The K_1:1 values for the drugs tested ranged from 2 to 40,000 M^- 1 and the plasma protein binding from about 20% to over 99%. None of the 63 drugs examined in the present study had a sufficiently high K_1:1 value for HPßCD complexation to affect plasma protein binding to a degree that would be expected to alter their PK substantively, for example, to require increased doses.     

Fluorimetric Studies of the Formation of Riboflavin-β-Cyclodextrin Inclusion Complex: Determination of the Stability Constant by use of a Non-linear Least-squares Model

The non-linear least-squares model for calculation of the stability constant (K_st) of a drug-cyclodextrin complex has been used in fluorimetry studies. Complexation of riboflavin with β-cyclodextrin (β-CyD) was monitored fluorimetrically by measuring changes in the fluorescence intensity of the vitamin in the presence of various amounts of β-CyD. Formation of an inclusion complex was confirmed in the solid state by differential scanning calorimetry (DSC) and in aqueous solution by proton nuclear magnetic resonance spectroscopy (¹H NMR). The experimental K_st value (2112 M^?1) derived from the fluorimetry studies appeared to fit well to a 1:1 drug-to-cyclodextrin molar ratio according to the non-linear mathematical model. The model is particularly suitable for fluorescent compounds of which fluorescence intensity is influenced by the presence of cyclodextrins.     

Influence of Hydroxypropyl β-Cyclodextrin on the Stability of Benzylpenicillin in Chloroacetate Buffer

Hydroxypropyl β-cyclodextrin (HPβCyD) has been shown to stabilize a wide variety of chemically distinct pharmaceutical entities through inclusion-complex formation between drug and cyclodextrin. The effect of HPβCyD on the acid-catalysed hydrolysis of benzylpenicillin (penicillin G) was evaluated in chloroacetate buffer at pH 2.20. At penicillin G: cyclodextrin molar concentration ratios from 1:1 to 1:10, HPβCyD effected stabilization of penicillin G by 1.56- to 5.21-fold. At all temperatures, the observed first-order rate constant (k_obs) values assumed a non-linear, Michaelis-Menten type decrease as a function of increasing HPβCyD concentration. Degradation of penicillin G complexed with HPβCyD (penicillin G-HPβCyD), was approximately ninefold slower than uncomplexed penicillin G. The proportion of penicillin G degrading in either of these forms was, in turn, determined by the equilibrium constant for the complexation. The apparent thermodynamic and activation parameters for the complexation between penicillin G and HPβCyD have also been evaluated. The negative standard enthalpy change (ΔH^°) for the complexation implied that the penicillin G-HPβCyD complex would be predisposed towards enhanced stability, and thus the k_obs value for the hydrolysis of penicillin G decreased with reduction of temperature in these systems. The lack of difference between the enthalpies of activation (ΔH?) for the hydrolysis of uncomplexed and complexed penicillin G seemed to be compensated by the significant difference between the entropies of activation (ΔS?) for these hydrolytic reactions. The results indicate that HPβCyD represents a viable means of stabilization of penicillin G solutions at the pH employed in this study.     

Interaction of [d-Trp6, Des-Gly10] LHRH Ethylamide and Hydroxy Propyl β-Cyclodextrin (HPβCD): Thermodynamics of Interaction and Protection from Degradation by α-Chymotrypsin

Purpose: The purpose of this study is to investigate the mechanisms and thermodynamics of the interaction between hydroxypropyl β-cyclodextrin (HPβCD) and [d-Trp ⁶, des-Gly ¹⁰] LHRH ethylamide (deslorelin), a peptide drug. Methods: We used UV and Fluorescence spectroscopy to study the interaction of HPβCD and deslorelin. Circular dichroism was used to study the conformational changes induced in deslorelin upon interaction with HPβCD. The thermodynamics of the interaction of deslorelin and HPβCD was studied using isothermal titration calorimetry (ITC). We also determined the effect of HPβCD on the degradation of deslorelin by α-chymotrypsin. Results: UV and fluorescence spectroscopy indicated that HPβCD induced a change in polarity of the environment surrounding the chromophores of deslorelin. Wavelength selective fluorescence indicated an increase in the fluorescence polarization of deslorelin with an increase in excitation wavelength in the presence of HPβCD suggesting that tryptophan is present in a media of reduced mobility. Circular dichroism studies indicated that HPβCD stabilizes the conformation of deslorelin. In addition, ITC indicated an exothermic reaction between deslorelin and HPβCD with a low enthalpy of binding of ～?600 cal/mol and a binding affinity of ～1.25 × 10 ² M^{? 1}. Finally, the rate of degradation of deslorelin by α-chymotrypsin was decreased by 33% in the presence of HPβCD. Conclusions: These results indicate that there is an interaction between HPβCD and deslorelin, which involves the inclusion of aromatic amino acids of deslorelin into the hydrophobic cavity of the cyclodextrin. This inclusion, providing steric hindrance, may be one of the mechanisms by which HPβCD reduces enzymatic hydrolysis of deslorelin.     

Enhancement of norfloxacin solubility via inclusion complexation with β-cyclodextrin and its derivative hydroxypropyl-β-cyclodextrin

The objectives of the study were to investigate the effects of β-cyclodextrin (βCD) and hydroxypropyl-β-cyclodextrin (HPβCD) on the solubility and dissolution rate of norfloxacin prepared using three different methods, at drug to cyclodextrin weight ratios of 1:1, 1:2, 1:4 and 1:8. All the methods increased the solubility and dissolution rate of norfloxacin via inclusion complexation with βCD and HPβCD. Norfloxacin was converted from crystalline to amorphous form through inclusion complexation. Solvent evaporation method was the most effective method in terms of norfloxacin solubilisation, while inclusion complex of HPβCD has higher solubility than βCD complex when prepared using the same procedure.     

Effect of 2-Hydroxypropyl-β-cyclodextrin on Percutaneous Absorption of Methyl Paraben

A potential use of 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) to solubilize methyl paraben and to suppress its percutaneous absorption was examined, and compared with nonionic surfactant HCO-60. HP-β-CyD significantly increased the solubility of methyl paraben in water, where the apparent 1:1 stability constant of the soluble complex was determined to be 2150 M^?1. The in-vitro cutaneous permeability of methyl paraben through an isolated skin of hairless mouse was suppressed by HP-β-CyD, thus promoting the bioconversion of methyl paraben to the less toxic metabolite, p-hydroxybenzoic acid (p-HBA) in the epidermis. These effects of HP-β-CyD were greater than those of HCO-60. HP-β-CyD (2% w/v) reduced the in-vivo percutaneous absorption of methyl paraben by 66% 24 h after the topical application of a solution containing [¹⁴C]methyl paraben to hairless mouse skin. Additionally, the percutaneous absorption of [¹⁴C]HP-β-CyD was confirmed to be extremely low. These results suggest that HP-β-CyD is useful in liquid preparations of methyl paraben for topical application.     

Evaluation of antibacterial activity of caffeic acid encapsulated by β-cyclodextrins

Abstract

Context: Caffeic acid is described as antibacterial, but this bioactive molecule has some issues regarding solubility and stability to environmental stress. Thus, encapsulation devices are required. Objective: The aim of this work was to study the effect of the caffeic acid encapsulation by cyclodextrins on its antibacterial activity. Materials and methods: The interactions between the caffeic acid and three cyclodextrins (β-cyclodextrin (βCD), 2-hydroxypropyl-β-cyclodextrin (HPβCD) and methyl-β-cyclodextrin were study. Results and discussion: The formation of an aqueous soluble inclusion complex was confirmed for βCD and HPβCD with a 1:1 stoichiometry. The βCD/caffeic acid complex showed higher stability than HPβCD/caffeic acid. Caffeic acid antibacterial activity was similar at pH 3 and pH 5 against the three bacteria (K. pneumoniae, S. epidermidis and S. aureus). Conclusions: The antibacterial activity of the inclusion complexes was described here for the first time and it was shown that the caffeic acid activity was remarkably enhanced by the cyclodextrins encapsulation.     

Use of a nonlinear least-squares model for the kinetic determination of the stability constant of cyclodextrin inclusion complexes

The nonlinear least-squares model for the calculation of the stability constants (K_st) of drug:cyclodextrin complexes was used in kinetic studies. Complexation of riboflavin (R) with hydroxypropyl-β-cyclodextrin (HP:β-CD) was monitored kinetically by measuring the rate of photodegradation of R exposed to ultraviolet light in the presence of increasing concentrations of HP:β-CD. Formation of inclusion complex was confirmed in aqueous solution by proton nuclear magnetic resonance spectroscopy (¹H-NMR). The experimental K_st value (3321 M⁻¹), derived from the kinetic studies, appeared to fit well to a 1:1 drug: cyclodextrin molar ratio according to the nonlinear mathematical model. The model is particularly suitable for the study of cyclodextrin as a stabilizing system for compounds that are sensitive to light, oxygen, temperature or the media which contain them.     

Alginate-Based Hydrogel Containing Minoxidil/Hydroxypropyl-β-Cyclodextrin Inclusion Complex for Topical Alopecia Treatment

Cutaneous minoxidil (MXD) formulations were developed with the intent to reduce the side effects of the cosolvents propylene glycol and ethanol, frequently used in commercial MXD solutions. Completely aqueous alginate-based hydrogels were investigated and MXD aqueous solubility was improved using inclusion complexes with hydroxypropyl-β-cyclodextrin (HP-β-CD) at 2 different molar substitution degree (MS), namely 0.65 and 0.85. HP-β-CD MS 0.65 was selected for its improved solubilizing ability toward MXD. At concentration of 39% w/v, this cyclodextrin increased the intrinsic aqueous solubility of MXD of about 22-fold. The calculated complexation constant was 2309 ± 20 M^?1, and the inclusion process was spontaneous and enthalpically driven. Nuclear magnetic resonance studies (Job plot, ¹H, 2D correlations spectroscopy, nuclear overhauser effect spectroscopy, and rotating-frame overhauser enhancement spectroscopy) confirmed the stoichiometry 1:1 between MXD and HP-β-CD providing information about the exact geometry of the inclusion complex. Rheological and in vitro release studies performed on the formulation loaded with MXD 3.5% w/w proved that the inclusion complex increased the viscosity of the hydrogel modulating the release of the free drug. Furthermore, the hydrogel formulation facilitate MXD to permeate into the skin and did not damage epidermis, suggesting that these completely aqueous MXD delivery systems can be proposed as alternative formulations to commercial solutions.     

Intestinal Safety of Water-soluble β-Cyclodextrins in Paediatric Oral Solutions of Spironolactone: Effects on Human Intestinal Epithelial Caco-2 Cells

Effects of water-soluble β-cyclodextrins (βCDs) on intestinal epithelial integrity were investigated, to establish the safe use of these βSCDs as solubilizers of spironolactone in paediatric enteral solutions. Mannitol permeability and transepithelial resistance (TER) of human intestinal epithelial Caco-2 cell monolayers during exposure to dimethyl-β-cyclodextrin (DMβCD), hydroxypropyl-β-cyclodextrin (HPβCD) and sulphobutyl ether β-cyclodextrin (SBEβCD) were followed. Staining methods were used to discern cells with damaged membranes and to study the integrity of cytoskeletal actin and tight junctions. Cytotoxicity of the βCDs was tested by effects on intracellular dehydrogenase activity. Exposure to HPβSCD and SBEβCD solutions had only minor effects on the integrity of Caco-2 cell monolayers. In contrast, DMβCD clearly increased the epithelial permeability for the hydrophilic marker [¹⁴C]mannitol across Caco-2 monolayers, decreased TER and showed a dose-dependent cytotoxicity. According to staining, DMβCD increased the permeability of the apical cell membrane without discernable effects on cytoskeletal actin. HPβCD and SBEβCD appear to be safe additives for use in enteral spironolactone preparations with respect to their acute local effects on epithelial integrity.     

Inclusion complex of clausenidin with hydroxypropyl-β-cyclodextrin: Improved physicochemical properties and anti-colon cancer activity

The long-term objective of the present study was to prepare, physicochemically characterize and determine the anticancer of clausenidin/hydroxypropyl-β-cyclodextrin (Clu/HPβCD) inclusion complex. We used differential scanning calorimetry, X-ray diffractometer, fourier transform infrared spectroscopy, ultraviolet–visible spectrophotometer and ¹³C and ¹H nuclear magnetic resonance followed by in vitro anticancer assays. The orientation and intermolecular interactions of Clausenidin within cyclodextrin cavity were also ascertained by molecular docking simulation accomplished by AutoDock Vina. The guest molecule was welcomed by the hydrophobic cavity of the host molecule and sustained by hydrogen bond between host/guest molecules. The constant drug release with time, and increased solubility were found after successful complexation with HPβCD as confirmed by physicochemical characterizations. Clausenidin had greater cytotoxic effect on colon cancer HT29 cells when incorporated into HPβCD cavity than dissolved in DMSO. Also, from a comparison of cell viability between normal and cancer cells, a reduced side effect was observed. The Clu/HPβCD inclusion complex triggered reactive oxygen species-mediated cytotoxicity in HT29 cells. The inclusion complex-treated HT29 cells showed cell cycle arrest and death by apoptosis associated with caspases activation. The presence of HPβCD seems to aid the anticancer activity of clausenidin.     

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.     

Systemic administration of 2‐hydroxypropyl‐β‐cyclodextrin to symptomatic Npc1‐deficient mice slows cholesterol sequestration in the major organs and improves liver function

In Niemann–Pick type C (NPC) disease, loss‐of‐function mutations in either NPC1 or NPC2 result in progressive accumulation of unesterified cholesterol (UC) and glycosphingolipids in all organs, leading to neurodegeneration, pulmonary dysfunction and sometimes liver failure. There is no cure for this disorder. Studies using primarily NPC mouse models have shown that systemic administration of 2‐hydroxypropyl‐β‐cyclodextrin (2HPβCD), starting in early neonatal life, diminishes UC accumulation in most organs, slows disease progression and extends lifespan. The key question now is whether delaying the start of 2HPβCD treatment until early adulthood, when the amount of entrapped UC throughout the body is markedly elevated, has any of the benefits found when treatment begins at 7 days of age. In the present study, Npc1^?/? and Npc1^+/+ mice were given saline or 2HPβCD subcutaneously at 49, 56, 63 and 70 days of age, with measurements of organ weights, liver function tests and tissue cholesterol levels performed at 77 days. In Npc1^?/? mice, treatment with 2HPβCD from 49 days reduced whole‐liver cholesterol content at 77 days from 33.0 ± 1.0 to 9.1 ± 0.5 mg/organ. Comparable improvements were seen in other organs, such as the spleen, and in the animal as a whole. There was a transient increase in biliary cholesterol concentration in Npc1^?/? mice after 2HPβCD. Plasma alanine aminotransferase and aspartate aminotransferase activities in 77‐day‐old 2HPβCD‐treated Npc1^?/? mice were reduced compared with saline‐treated controls. The lifespan of Npc1^?/? mice given 2HPβCD marginally exceeded that of the saline‐treated controls (99 ± 1.1 vs 94 ± 1.4 days, respectively; P < 0.05). Thus, 2HPβCD is effective in mobilizing entrapped cholesterol in late‐stage NPC disease leading to improved liver function.     

Modified β-Cyclodextrin (SBE7-β-CyD) with Viscous Vehicle Improves the Ocular Delivery and Tolerability of Pilocarpine Prodrug in Rabbits

The complexation of pilocarpine prodrug, O,O'-dipropionyl-(1,4-xylylene) bispilocarpate, with various β-cyclodextrin (β-CyD) derivatives was studied by the phase solubility method. The effects of coadministered sulphobutyl ether β-CyD (SBE7-β-CyD) with and without poly(vinyl alcohol) (PVA) on the miotic response and eye irritation of the prodrug were investigated in pigmented rabbits. The pilocarpine prodrug formed 1:1 inclusion complexes with variably substituted sulphobutyl ether derivatives of β-CyD (SBE4-β-CyD and SBE7-β-CyD), and 1:1 and 1:2 complexes with hydroxypropyl-β-CyD (HP-β-CyD) at pH 7:4. Coadministered SBE7-β-CyD eliminated the eye irritation due to the pilocarpine prodrug, but also decreased the miotic response. Ocular absorption of the prodrug was improved by increasing the viscosity of prodrug/SBE7-β-CyD solution with PVA without inducing any eye irritation. Eye irritation due to viscous prodrug/SBE7-β-CyD solutions was comparable with isotonic NaCl solution. We conclude that administration of pilocarpine prodrug in viscous SBE7-β-CyD solution decreases substantially eye irritation while ocular absorption is not affected.     

Enhanced oral bioavailability of acyclovir by inclusion complex using hydroxypropyl-β-cyclodextrin

Abstract

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 hydroxypropyl-β-cyclodextrin for the enhancement of oral bioavailability of acyclovir. The inclusion complex of acyclovir was prepared by kneading method using drug: hydroxypropyl-β-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 acyclovir–hydroxypropyl-β-cyclodextrin complex with higher stability constant and linear enhancement in drug solubility with increase in hydroxypropyl-β-cyclodextrin concentration. Characterization of the prepared formulation confirms the formation of acyclovir–hydroxypropyl-β-cyclodextrin inclusion complex. Dissolution profile of inclusion complex demonstrated rapid and complete release of acyclovir in 30?min with greater dissolution efficiency (90.05?±?2.94%). In vivo pharmacokinetic data signify increased rate and extent of acyclovir absorption (relative bioavailability ～160%; p?<?0.0001) 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.     

吡罗昔康与β-环糊精包合物结构的核磁共振研究

本文采用¹HNMR和二维NOE等方法研究了吡罗昔康与β-环糊精包合物的结构。化学位移变化和NOE的结果提示,在溶液中二者的摩尔比为1:1时,主要是药物的苯环部份包藏在β-环糊精的空腔内。     

The interaction of nifedipine with selected cyclodextrins and the subsequent solubility–permeability trade-off

The purpose of this study was to investigate the interaction of 2-hydroxypropyl-β-cyclodextrin (HPβCD) and 2,6-dimethyl-β-cyclodextrin (DMβCD) with the lipophilic drug nifedipine and to investigate the subsequent solubility–permeability interplay. Solubility curves of nifedipine with HPβCD and DMβCD in MES buffer were evaluated using phase solubility methods. Then, the apparent permeability of nifedipine was investigated as a function of increasing HPβCD/DMβCD concentration in the hexadecane-based PAMPA model. The interaction with nifedipine was CD dependent; significantly higher stability constant was obtained for DMβCD in comparison with HPβCD. Moreover, nifedipine displays different type of interaction with these CDs; a 1:1 stoichiometric inclusion complex was apparent with HPβCD, while 1:2 stoichiometry was apparent for DMβCD. In all cases, decreased apparent intestinal permeability of nifedipine as a function of increasing CD level and nifedipine apparent solubility was obtained. A quasi-equilibrium mass transport analysis was developed to explain this solubility–permeability interplay; the model enabled excellent quantitative prediction of nifedipine’s permeability as a function of CD concentrations. This work demonstrates that when using CDs in solubility-enabling formulations, a trade-off exists between solubility increase and permeability decrease that must not be overlooked. This trade-off was found to be independent of the type of CD–drug interaction. The transport model presented here can aid in striking the appropriate solubility–permeability balance in order to achieve optimal overall absorption.     

Inclusion complexation of amide-typed local anaesthetics with β-cyclodextrin and its derivatives. I. Physicochemical characterization

Qualitative aspects of the inclusion complexation of two local anaesthetics of the amide-type (LAs), bupivacaine (BVC) and lidocaine (LDC) with three cyclodextrins (CDs), β-cyclodextrin (βCD) and its alkylated derivatives 2-hydroxypropyl-β-cyclodextrin (HPβCD) and heptakis (2,6-di-o-methyl)-β-cyclodextrin (DMβCD), were studied in the solid state by infrared spectroscopy (IR) and differential scanning calorimetry (DSC). The LDC-βCD couple was also investigated in aqueous solution by nuclear magnetic resonance (¹H-NMR and ¹³C-NMR). This first part of a study dealing with improvement in LA administration provided clear indications about LA-CD complexation. Qualitative modifications in a number of peaks or bands obtained from spectral methods as well as thermal analysis signed the inclusion, showing that the freeze-drying method was suitable for obtaining inclusion complexes of LAs with CDs.     

Inclusion complexes of tadalafil with natural and chemically modified β-cyclodextrins. I: Preparation and in-vitro evaluation

The aim of this work was to investigate the inclusion complexation between tadalafil, a practically insoluble selective phosphodiesterase-5 inhibitor (PDE5), and two chemically modified β-cyclodextrins: hydroxypropyl-β-cyclodextrin (HP-β-CD) and heptakis-[2,6-di-O-methyl]-β-cyclodextrin (DM-β-CD), in comparison with the natural β-cyclodextrin (β-CD) in order to improve the solubility and the dissolution rate of the drug in an attempt to enhance its bioavailability. Inclusion complexation was investigated in both the solution and the solid state. The UV spectral shift method indicated guest–host complex formation between tadalafil and the three cyclodextrins (CDs). The phase solubility profiles with all the used CDs were classified as A_p-type, indicating the formation of higher order complexes. The complexation efficiency values (CE), which reflect the solubilizing power of the CDs towards the drug, could be arranged in the following order: DM-β-CD > HP-β-CD > β-CD. Solid binary systems of tadalafil with CDs were prepared by kneading and freeze-drying techniques at molar ratios of 1:1, 1:3 and 1:5 (drug to CD). Physical mixtures were prepared in the same molar ratios for comparison. Physicochemical characterization of the prepared systems at molar ratio of 1:5 was studied using differential scanning calorimetry (DSC), X-ray diffractometry (XRD), and Fourier-transform infrared spectroscopy (FTIR). The results showed the formation of true inclusion complexes between the drug and both HP-β-CD and DM-β-CD using the freeze-drying method at molar ratio of 1:5. In contrast, crystalline drug was detectable in all other products. The dissolution of tadalafil from all the prepared binary systems was carried out to determine the most appropriate CD type, molar ratio, and preparation technique to prepare inclusion complexes to be used in the development of tablet formulation for oral delivery of tadalafil. The dissolution enhancement was increased on increasing the CD proportion in all the prepared systems. Both the CD type and the preparation technique played an important role in the performance of the system. Irrespective of the preparation technique, the systems prepared using HP-β-CD and DM-β-CD yielded better performance than the corresponding ones prepared using β-CD. In addition, the freeze-drying technique showed superior dissolution enhancement than other methods especially when combined with the β-CD derivatives.