Types Of Inclusion Complexes Research Articles

Enhancing solubility and stability of piperine using β-cyclodextrin derivatives: computational and experimental investigations

Piperine (PP), a natural alkaloid found in black pepper, possesses significant bioactivities. However, its use in pharmaceutical applications is hindered by low water solubility and susceptibility to UV light degradation. To overcome these challenges, we investigated the potential of β-cyclodextrin (βCD) and its derivatives with dimethyl (DMβCD), hydroxy-propyl (HPβCD) and sulfobutyl-ether (SBEβCD) substitutions to enhance the solubility and stability of PP. This study employed computational and experimental approaches to examine the complexation between PP and βCDs. The results revealed the formation of two types of inclusion complexes: the P-form and M-form involving the insertion of piperidine moiety and the methylene-di-oxy-phenyl moiety, respectively. These complexes primarily rely on van der Waals interactions. Among the three derivatives, the PP/SBEβCD complex exhibited the highest stability followed by HPβCD, as attributed to maximum atom contacts and minimal solvent accessibility. Solubility studies confirmed the formation of inclusion complexes in a 1:1 ratio. Notably, the stability constant of the inclusion complex was approximately two-fold higher with SBEβCD and HPβCD compared to βCD. The DSC thermograms provided confirmation of the formation of the inclusion complex between the host and guest. These findings highlight the potential of βCD derivatives to effectively encapsulate PP, improving its solubility and presenting new opportunities for its pharmaceutical applications. Communicated by Ramaswamy H. Sarma

Affinity and putative entrance mechanisms of alkyl sulfates into the β-CD cavity

Cyclodextrins (CDs) are novel pharmaceutical excipients and are widely used in the pharmaceutical industry and drug delivery due to their ability to form host–guest complexes. There are countless structural features of guest molecules responsible for the efficiency of guest–CD interactions. Among these factors, the hydrophobic moieties of a guest and their size are commonly considered to govern its binding affinity to CD molecules. Experimentally, it is often challenging to extract structural and dynamic information at the atomic scale about CD inclusion complexes, especially in the aqueous phase. Therefore, this study consisted of experimental (isothermal titration calorimetry and conductometric titration) and in silico analysis to rigorously characterize the interactions of β -CD with three alkyl sulfates of different hydrophobic chain lengths: sodium dodecyl sulfate (S12S), sodium decyl sulfate (S10S) and sodium octyl sulfate (S8S) in aqueous solutions. We find that the hydrophobic interactions are not always a key factor leading to the formation of stable inclusion complexes. Our results demonstrate that van der Waals interactions contribute more to complexation efficiency for sulfates with a longer hydrophobic tail, whereas electrostatic interactions are more pronounced for sulfates with shorter ones. Furthermore, we propose and discuss for the first time the putative mechanisms of the guest entering the host cavity conditioned by the lengths of hydrocarbon chains of alkyl sulfates. Finally, we prove that different types of inclusion complexes can exist in a conformational equilibrium depending on the size of a guest tail.

AN ADDUCT: 5-FLUOROURACIL INCORPORATED β-CD INCLUSION COMPLEX FOR SOLUBILITY AND STABILITY ENHANCEMENT IN DOSAGE FORMS

Objective: Current work aimed to enhance solubility and stability of 5-fluorouracil drugs by preparing inclusion complex with β-cyclodextrin. Methods: In this study, inclusion complex preparation ratio selected on the basis of slope and Kc (binding constant) value in between 5-fluorouracil-β-cyclodextrin and best method out of the physical mixture, kneading method, and co-evaporation method for solubility and stability enhancement is selected on the basis of % yield, drug content, dissolution rate study and stability study. Results: Based on the phase solubility graph, a 1:1 ratio was selected for complex formation by Kc value which decided a quite stable form of a complex. The characterization of all three types of inclusion complex was performed by DSC and SEM. It proved that different moiety of the complex was formed, but all are quite stable with negligible interaction. The kneading method as the best inclusion complex at ratio 1:1 was selected after evaluating by performing percent yield and drug content and dissolution rate study for solubility profile and physical appearance, drug content, and drug release study for stability profile. Conclusion: We finally conclude that the Kc value proved that the inclusion complex is quite stable and ready to convert in any dosage form of choice. Inclusion complex formed by kneading method is one of the best options among all three techniques for solubility and stability enhancement of drug, which definitely help for a 5-fluorouracil drug to convert into a better dosage form to treat carcinoma.

Temperature-Dependent Dynamical Evolution in Coum/SBE-β-CD Inclusion Complexes Revealed by Two-Dimensional FTIR Correlation Spectroscopy (2D-COS).

A combination of Fourier transform infrared spectroscopy in attenuated total reflectance geometry (FTIR-ATR) and 2D correlation analysis (2D-COS) was applied here for the first time in order to investigate the temperature-dependent dynamical evolution occurring in a particular type of inclusion complex, based on sulfobutylether-β-cyclodextrin (SBE-β-CD) as hosting agent and Coumestrol (7,12-dihydorxcoumestane, Coum), a poorly-soluble active compound known for its anti-viral and anti-oxidant activity. For this purpose, synchronous and asynchronous 2D spectra were calculated in three different wavenumber regions (960–1320 cm−1, 1580–1760 cm−1 and 2780–3750 cm−1) and over a temperature range between 250 K and 340 K. The resolution enhancement provided by the 2D-COS offers the possibility to extract the sequential order of events tracked by specific functional groups of the system, and allows, at the same time, the overcoming of some of the limits associated with conventional 1D FTIR-ATR analysis. Acquired information could be used, in principle, for the definition of an optimized procedure capable to provide high-performance T-sensitive drug carrier systems for different applications.

Probing Inclusion Complexes of Pentoxifylline and Pralidoxim inside Cyclic Oligosaccharides by Physicochemical Methodologies

Abstract Structurally different Molecules namely Pentoxifylline and Pralidoxim were chosen along with α-cyclodextrin and β-cyclodextrin to study host-guest inclusion phenomena. The formations of host guest inclusion complexes were confirmed by studying 1H-NMR spectra, FT-IR spectra, apparent molar volume and viscosity co-efficient. The stabilities of inclusion complexes were compared calculating the binding constant from UV-VIS spectroscopic study. The 1:1 stoichiometry of the inclusion complexes were also determined by analysing the Jobs plot and surface tension data. The values for Gibbs’ free energy were found negative for both the processes. Based on all the above experiments the inclusion processes were found feasible for both the compounds. These types of inclusion complexes are of high interest in the field of research and industry as these are used as drug delivery systems.

Effect of solution pH on complex formation between epi-type catechin and β-cyclodextrin

The effect of solution pH on the formation of an inclusion complex between (−)-epigallocatechin gallate (EGCg: pKa = 7.5) and β-cyclodextrin (β-CD) was investigated by isothermal titration calorimetry and 1H-NMR spectroscopy. The formation of an inclusion complex (EGCg-β-CD) depended on the solution pH; two different types of inclusion complexes were formed at 1:1 molar ratio in acid/neutral solutions, and only one type of complex was formed in the basic solution. The first type of EGCg-β-CD with larger association constant was formed independently of pH, with the AC-ring of EGCg being deeply inserted into the cavity of β-CD and the B-ring existing near the secondary hydroxyl group of β-CD. On the other hand, the formation of the second type depended on the solution pH. The B′-ring of EGCg was included in the case of acid and neutral solutions, but the formation of an inclusion complex in the basic solution was difficult due to the ionization of the 4″-OH on the B′-ring. 1H-NMR spectroscopy supported these results. These results suggested that when determining the structures of EGCg-β-CD in an aqueous solution, it is necessary to consider unionized and ionized forms of EGCg.

Multiple inclusion complex formation of protonated ellipticine with cucurbit[8]uril: thermodynamics and fluorescence properties

The encapsulation of protonated ellipticine (EH+) in the cavity of cucurbit[8]uril (CB8) was studied in water at pH 4 with spectrophotometric, fluorescence spectroscopic and isothermal calorimetric measurements. The formation of three types of inclusion complexes was observed depending on the host and guest concentrations. Not only one, but also two EH+ was capable of encapsulation in CB8 in 37 μM EH+ solution and the thermodynamics of the binding steps were revealed. The produced very stable complexes showed markedly different absorption and fluorescence properties. When large excess of CB8 was employed in dilute (0.49 μM) EH+ solution, sequential binding of two CB8 occurred to the monomer alkaloid bringing about a substantial alteration in the fluorescence decay kinetics. The driving force of the 1:2 guest:host complex formation was much lower than that of 1:1 encapsulation.

Photoinduced Homolysis of Alkyl–Cobalt(III) Bonds in a Cyclodextrin Cage

AbstractPhotodecomposition of methyl– and ethyl–CoIII complexes of meso‐tetrakis(4‐sulfonatophenyl)porphyrin (CH3– and C2H5–CoIIITPPSs) was used as a reaction probe to study the cage effect of cyclodextrin capsules formed by two per‐O‐methylated β‐cyclodextrin (TMe‐β‐CD) molecules and their covalently linked dimer, Ph2CD. The photodecomposition of CH3–CoIIITPPS under aerobic conditions was markedly suppressed in the presence of TMe‐β‐CD and Ph2CD, while C2H5–CoIIITPPS was less affected. Alkyl–CoIIITPPS formed two types of inclusion complex with Ph2CD, the alkyl groups in Type 1 being located at the opposite side of the phenyl linker of Ph2CD and those in Type 2 being located at the same side. The photodecomposition of C2H5–CoIIITPPS in Type 1 proceeded via an ethylperoxo complex, while that in Type 2 occurred via a radical pair generated in a narrow, rigid cage to form ethylene and CoIITPPS.

Binding interaction of a newly developed bisindole drug molecule with α-cyclodextrin: face to face shielding of indole hoops

Binding interactions of a newly developed drug molecule namely 3,3′-bis(indolyl)-4-chlorophenylmethane (BICPM) with α-cyclodextrin have been studied using steady state and picosecond time resolved fluorometric techniques. A significant increase both in steady state anisotropy (r) and in the average rotational correlation time in the CD environments compared with that in a pure aqueous phase indicates that the rotational dynamics of BICPM are substantially slowed down upon binding with the α-cyclodextrin. Critical spectral analysis reveals the formation of two types of inclusion complex between the fluorophore and α-cyclodextrin (α-CD) depending on the relative population of the two. The stoichiometries and association constants of these complexes have been determined by monitoring the fluorescence data. Hydrodynamic radii of the formed 1 : 2 probe-α-cyclodextrin supramolecular complex have also been determined. From the determined hydrodynamic radii and from molecular docking analysis it is argued that probably two CD cavity shields the indole moiety in a face-to-face manner.

A study of supramolecular host–guest interaction of dothiepin and doxepin drugs with cyclodextrin macrocycles

Inclusion complexation behavior of dothiepin (DOT) and doxepin (DOX) with two cyclodextrins (α-CD and β-CD) were studied by absorption, fluorescence, time resolved fluorescence, scanning electron microscope (SEM), transmission electron microscope (TEM), Fourier transformation infrared spectroscopy (FT-IR), differential scanning colorimetry (DSC), powder X-ray diffraction (PXRD), proton nuclear magnetic resonance (1H NMR) and molecular modeling methods. Absorption and fluorescence spectral studies reveal that both drugs form different types of inclusion complexes with α-CD and β-CD. DOT and DOX exhibit short life time in aqueous medium (DOT∼2.29ns, DOX∼1.89ns) and higher in CD medium (DOT:α-CD∼3.45ns, DOT:β-CD∼4.84ns, DOX:α-CD∼3.55ns and DOT:β-CD∼4.33ns). The supramolecular structure of the nano-sized sphere and agglomerate was established by TEM. Alkyl chain and aromatic ring protons of the drug molecule are entrapped in the CD nanocavities. The significant proton chemical shifts give evidence for expected inclusion complex formation. PM3 calculations suggest that the alkyl chain encapsulation is most energetically favored in α-CD. The positive free energy and entropy changes indicated that both inclusion complexation processes are non-spontaneous and entropy driven.

Investigation of inclusion complexes of sulfamerazine with α- and β-cyclodextrins: An experimental and theoretical study

Inclusion complexation behavior and binding ability of sulfamerazine (SMRZ) with α- and β-cyclodextrins (α-CD and β-CD) were investigated. The formation of inclusion complexes are studied by UV–visible, fluorescence, time-resolved fluorescence, 1H NMR, FT-IR, DSC, XRD, SEM, TEM and molecular modeling methods. Both experimental and PM3 results indicated that the SMRZ is partially encapsulated in the CD cavity. The different spectral shifts observed in both the CDs indicate that different types of inclusion complexes are formed. Nanosecond time-resolved fluorescence studies demonstrated that SMRZ exhibit biexponential decay in water and triexponential decay in CD solutions. The resonance of the aromatic protons of SMRZ showed remarkably upfield shift in the complexes suggested that the aniline ring deeply encapsulated in the CD cavity. The amino and amido stretching vibrations at 3483cm−1 and 3379cm−1 respectively are strongly affected in the inclusion complexes. DSC curves for the inclusion complexes exhibited a broad endothermic effect from 106.4°C, 123.8°C and 234.5 6°C for α-CD and 118.2°C and 231.4°C for β-CD. TEM images of both inclusion complexes are forms a nanochain like agglomerated structures with a width ranging from 40nm to 100nm. Thermodynamic parameters and binding affinity of the inclusion complex formation were determined and discussed.

Effect of pH on the formation of inclusion complexes between β-lactam antibiotics and 2-hydroxypropyl-β-cyclodextrin in aqueous solution

The complexation of β-lactam antibiotics, amoxicillin (AMPC), ampicillin (ABPC) and benzylpenicillin (PCG), with 2-hydroxypropyl-β-cyclodextrin (HPCD) was studied at various pH values using microcalorimetry, 1H NMR spectroscopy, and molecular dynamic simulation. In the strong acid solution, two different types of inclusion complex with a 1:1 stoichiometry, Complex I with a phenyl ring of β-lactam antibiotics penetrated into the cavity of HPCD and Complex II with a penam included in the cavity, were formed by hydrophobic interaction, and Complex II was more stable than Complex I. In aqueous solution at pH≥4.5, only Complex I was formed, where the penam of PCG was more deeply penetrated into the cavity to keep it stable than those of AMPC and ABPC. The charged carboxyl-group on the penam was less affinity to form Complex II.

Photoinduced and dark complexation of unsaturated viologen analogues containing two ammonium tails with cucurbit[8]uril

Complex formation between cucurbit[8]uril (CB[8]) and unsaturated viologen analogues 1a,b bearing two ammoniopropyl substituents was studied using 1H NMR spectroscopy and X-ray diffraction. The complex stability constants were measured by 1H NMR titration. CB[8] was found to encapsulate 1,2-di(4-pyridyl)ethylene derivative (E)-1a in water/acetonitrile solution to form only inclusion complex of 1 : 1 composition. The high stability of CB[8]·1a (lg K1:1 ≥ 5) is apparently due to the possibility of hydrogen bond formation between two NH3+ groups of 1a and the OC fragments of both portals of CB[8]. Contrarily, the derivative of 1,2-di(4-quinolyl)ethylene (E)-1b gave three types of inclusion complexes upon mixing with CB[8]. The stability of the 1 : 1 complex (lg K1:1 = 4.6) is decreased compared to (E)-1a, suggesting a poorer fit with respect to the bulky (E)-1b in the cavity of CB[8] for the simultaneous hydrogen bonding of the both ammonium groups. This is the driving force for the formation of an unusual 2 : 1 complex, {CB[8]}2·(E)-1b. The expanded π-system of (E)-1b allows also two tetracationic molecules of the acceptor to form a 1 : 2 complex owing to stacking interactions. Crystallization of a 1b/CB[8] mixture under irradiation resulted in an inclusion complex of the Z-isomer of 1b. The supramolecular complex is formed because the shape of (Z)-1b fits well to the host cavity and the ammonium groups form a system of hydrogen bonds with oxygen atoms of both portals of CB[8]. The features of crystalline complexes CB[8]·(Z)-1b and CB[8]·HClO4 are discussed.

Temperature dependence of the inclusion–dissociation behavior of the inclusion complexes between cationic substituted 3H-indoles and β-cyclodextrin: Design of a novel type of semi-rotaxane

We report herein the syntheses of cationic surface-active molecular probes having long oligo(ethylene glycol) chains as spacers between the cationic nitrogen and the amino nitrogen, named [2-( p-oligoethyloxyethylene amino phenyl)-3,3-dimethyl-5-ethoxycarbonyl-3H-indole] methyl dihexadecyl ammonium iodide (molecules 1a, 1b and 1c), and their interactions with β-cyclodextrin (β-CD) investigated by spectral and photophysical characterizations. It was found that the inclusion–dissociation behavior occurs for the inclusion complexes of molecules 1a and 1b with β-CD, that is, the 1:3 (guest:host) inclusion complex can be formed at lower temperatures and with increasing temperature, the 1:2 inclusion complex can be found. Molecule 1c can only form the 1:1 inclusion complex in the range of temperatures studied, even though it possesses a longer spacer than 1a and 1b. This phenomenon can be interpreted in terms of that the solvation energy of 1c is much larger than that of 1a and 1b, which is unfavorable to form a complex of higher stoichiometry. The association constants of the three types of inclusion complexes at different temperatures were estimated, from which the thermodynamic parameters were also calculated. The negative entropies and enthalpies show that the inclusion complexation is an entropically unfavorable and enthalpy-driven process.

Encapsulation of norharmane in cyclodextrin: formation of 1:1 and 1:2 inclusion complexes

Steady state absorption and fluorometric techniques have been used to investigate the photophysics of norharmane (NHM), a bioactive fluorophore, in aqueous as well as aqueous cyclodextrin (CD) environments. The absorption and steady state fluorescence spectral studies reveal the formation of two types of inclusion complexes between the fluorophore and β-cyclodextrin (β-CD) depending on the relative population of the two. The stoichiometries and association constants of these complexes have been determined monitoring the fluorescence data. α-and γ-cyclodextrin (α-CD, γ-CD) do not have appreciable effect on the spectral pattern of the fluorophore. The differential fluorimetric behavior of NHM in different CD environments has been rationalized from the variation of the relative dimensions of the probe and the CD cavities.

Multimodal inclusion complexes of ampicillin with β-cyclodextrins in aqueous solution

The inclusion complexation of ampicillin (ABPC) with β-cyclodextrin (βCD) and 2-hydroxypropyl-β-cyclodextrin (HPCD) in aqueous solution has been investigated by microcalorimetry, NMR spectrometry and molecular dynamics simulation (MDS). The heat of reaction of the complexation decreased as the pH value increased. ABPC and β-cyclodextrins formed one or two types of inclusion complexes by hydrophobic interactions and the complexation significantly depended on the species of ABPC based on the pH values of the solutions. Two different types of inclusion complexes with a 1:1 stoichiometry were realized for the cation species of ABPC in the strong acid solution. In the first type of inclusion with higher association constants of (6.0–10)×10 3 M −1, the penam ring of ABPC was inserted in the cyclodextrin cavity, whereas in the second type with lower association constants of 1.0×10 3 M −1, the phenyl ring seemed to penetrate into the cavity. The β-lactam ring of ABPC was included in both types to be protected from the acid-catalyzed hydrolysis. The zwitterion and anion species of ABPC formed only one type of inclusion complex with β-cyclodextrins, where the phenyl ring and the penam ring were included, respectively. These association constants and enthalpic changes were smaller than those for the first type inclusion complex of the cation species. These results indicate that the inclusion complexes of ABPC with β-cyclodextrins would be useful to the drug delivery system.

Mechanism for the inhibition of the acid degradation of ampicillin by 2-hydroxypropyl- β -cyclodextrin

The formation of inclusion complexes between amoxicillin (AMPC) and 2-hydroxypropyl-β-cyclodextrin (HPCD) was investigated by isothermal microcalorimetry and molecular dynamics simulation to evaluate the inhibitory effects on the degradation of AMPC in aqueous solutions at various pH. The process depended significantly on the ionic species of AMPC in the solution. In a strong acid solution, cationic AMPC and HPCD formed two different types of inclusion complexes with a 1:1 stoichiometry: the first-type had a high association constant K 1 of 4.0-8.0·103 M-1 and included the penam ring of AMPC in the HPCD cavity (Mode I), while the second-type with a K 2 of 1.0·103 M-1 contained the phenyl group of AMPC (Mode II). Furthermore, a complex with a 1:2 (AMPC:HPCD) stoichiometry was realized in a two-step reaction and was characterized by a smaller K 1:2of 4.0·102 M-1 and larger negative enthalpy and entropy changes than the complexes with a 1:1 stoichiometry. Since the β-lactam ring of AMPC could be protected by inclusion with HPCD in the 1:2 complex and Mode I of 1:1 complexes, the degradation of AMPC in the presence of HPCD was approximately four times slower than in its absence at pH 1.2 and 37°C. In weak acid and neutral solutions, zwitterionic AMPC and HPCD formed only one type of inclusion complex with a 1:1 stoichiometry, where the phenyl group was included (Mode II). AMPC was very stable in these solutions (t 1/2=226 h at pH=6.0) and there is little significant difference in the degradation rate between complexed AMPC and uncomplexed AMPC. Thus, the results indicated that the inclusion complex of AMPC with HPCD, effectively increasing the stability of AMPC in a strong acidic solution like that the stomach, would be useful for eradicating Helicobacter pylori infection and as a drug delivery system.

Capillary electrophoretic separation and theoretical study of inclusion complexes of sulfobutyl ether β‐cyclodextrin with estrogens

AbstractFive estrogens (2‐hydroxyestrone, 2‐methoxyestradiol, estrone, estriol, and 17α‐estradiol) and two stereoisomers (17α‐ and 17β‐estradiol) have been successfully separated using capillary electrophoresis with anionic sulfobutyl ether β‐cyclodextrin (SBE‐β‐CD). The SBE‐β‐CD used in the separation was a mixture of positional and regional isomers containing from 1 to 10 sulfobutyl ether groups with an average degree of substitution of four per cyclodextrin; thus, a tetra‐SBE substituted CD, SBE[4]‐β‐CD, has been chosen as the model host molecule in the present study. Relative to the position of the cavity, three initial arrangements of the 4 SBE groups, 0‐, 2‐, and 4‐up, have been considered. In addition two types of inclusion complexes, cis and trans orientations, are also considered for each estrogen. In the cis structure the SBE group of the cyclodextrin and the phenol group of the estrogen are on the same side, while in the trans structure the two groups are on opposite sides. The objective of the present study is to perform PM3 (Parametric Method 3) semiempirical molecular orbital calculations on these six inclusion complexes (12 different orientations) for each SBE[4]‐β‐CD to correlate the migration order with their relative stability. Theoretical calculations have shown that only when SBE groups are perpendicular to the axis of CD (0‐up arrangement), the cavity is open on both sides for incoming guest molecules. A correlation was observed between the total heats of formation for the cis and trans estrogen‐CD inclusion complexes of the same estrogen and the electrophoretic migration time although the relationship is not linear, suggesting that both orientations may occur simultaneously. In other two SBE[4]‐β‐CDs, the narrower side of the cavity is partially capped due to the formation of intra‐hydrogen bonds among three of the four SBE groups. Thus, a guest molecule can enter the cavity from the wide end of the cavity only. As a result, the estrogen molecules protrude from the cavity in most cases. © 2004 Wiley Periodicals, Inc. Int J Quantum Chem, 2004

Crystal structure of an inclusion complex between chiral monoaza-15-crown-5 and S(–)-1-phenyl-ethyl ammonium percholorate

Abstract A new type of inclusion complex, S(–)-1 phenyl ethyl ammonium percholorate complex of R-(–)-2-ethyl - N - benzyl - 4, 7, 10, 13 - tetraoxa -1- azacyclopentadecane, has been prepared and studied by NMR, IR and single crystal X-ray diffraction techniques. The compound crystallizes in space group P21 with cell dimensions a = 10.0000(8), b = 12.281(2), c = 12.331(1)Å, β = 102.052(7), Z = 2 The host-guest complex is held together by a strong system of hydrogen bonds between the two protons of the ammonium ion as well as the nitrogen and four oxygen atoms of the crown ether The C—O and C—C distances of the 15-membered ring average 1.418 and 1.501 Å while the O—C—C and C—O—C angles average 110.2 and 113.3°. The average N—C distance is 1.476 Å.

Synergetic activation of "silent receptor" sites leading to a new type of inclusion complex: integration of a 64-membered ring comprising K+ and SO4(2-) ions into a molybdenum oxide-based nanoobject.

The new type of inclusion species [Mo(VI)114Mo(V)32O429(H2O)50(KSO4)16]30- comprising 16 encapsulated K+ and SO4(2-) ions shows an unusual 64-membered [K(SO4)]16 ring integrated into a wheel-shaped type nanocluster host; it is formed by a synergetically induced functional complementarity and represents a text-book example of a very complex non-biological material.