Inclusion Complexes In Solid State Research Articles

ChemInform Abstract: Inclusion and Optical Resolution of Guest Molecules by Selected Synthetic Dihydroxy‐ and Trihydroxy‐Host Compounds Containing Heterocyclic Scaffolds

AbstractReview: 39 refs.

The protection of Nifedipin from photodegradation due to complex formation with β-cyclodextrin

Abstract The inclusion complex β-cyclodextrin:nifedipin was prepared in solid state by coprecipitation with 1:1 mol ratio. The structure of the obtained complex and nifedipin was characterized by use of X-ray diffraction (XR), infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), and differential scanning calorimetry (DSC) methods. The photodegradation of nifedipin and the β-cyclodextrin:nifedipin inclusion complex in solid state was monitored under natural daylight by infrared spectroscopy, whereby the free nifedipin degraded four to five times faster than the complexed nifedipin. The photodegradation products of both free and complexed nifedipin, formed during irradiation at 350 nm (with corresponding energy flux of 18 W m−2) were monitored by liquid chromatography during various time intervals. The speed of formation of nitroso- and nitro-phenyl derivatives by nifedipin irradiation was significantly higher than those of complexed nifedipin irradiation, which indicates its increased photostability in the inclusion complex. The effect on this property is significant because it contributes both to the improvement of the therapeutic effect of nifedipin and to the safer application thereof.

Inclusion complexation of weakly acidic NSAID with β-cyclodextrin: selection of arginine, an amino acid, as a novel ternary component

The purpose of the present study was to investigate the influence of an amino acid, arginine, as a ternary component on the complexation of Lornoxicam, a poorly water-soluble and weakly acidic anti-inflammatory agent, with β-cyclodextrin (β-CD). The molecular inclusion of Lornoxicam with βCD alone and in combination with ternary component was aimed at improvement in solubility and, subsequently, dissolution rate limited oral absorption. The solid complexes of Lornoxicam and β-CD with or without arginine (binary and ternary systems, respectively) were prepared as Freeze dried product in different stoichiometric ratios. The formation of inclusion complexes in solid state was confirmed by using classical instrumental techniques like IR, DSC, XRD, and in liquid state by phase solubility analysis, UV spectroscopy, HPLC and 1H NMR. The in vitro dissolution and the saturation solubility of complex are determined analyzing by UV spectrophotometer. Assay and level of related substance was monitored by developed RP-HPLC method. Inclusion ternary complex of Lornoxicam with β-CD and arginine showed significant improvement in dissolution compared with uncomplexed drug and binary system. This improved physicochemical behavior of ternary complex with the novel inclusion of an arginine translated into enhanced in vitro dissolution of Lornoxicam compared with standard rapid marketed formulation.

Solid state characterization of domperidone: Hydroxypropyl-b-cyclodextrin inclusion complex

The purpose of the present study was to prepare inclusion complex of domperidone with hydroxylpropyl-β-cyclodextrin in order improved the solubility and hence to increase dissolution of domperidone. An effect of concentration of hydroxylpropyl-β-cyclodextrin on the aqueous solubility of domperidone was determined by phase-solubility method. The aqueous solubility of domperidone increased as a function of hydroxylpropyl-β-cyclodextrin concentration, showing AL type diagram. Solid domperidone/hydroxylpropyl-β-cyclodextrin complex was prepared in ratio 1:1 by ultrasonication and kneading method. Solid state inclusion complex was characterized by FTIR, powder X-ray diffraction and differential-scanning calorimetry techniques. FTIR studies showed intactness of drug in complex whereas powder diffraction studies showed that hydroxylpropyl-β-cyclodextrin complex was amorphous. Solubility studies showed that complexation increased domperidone solubility as compared to pure drug in 0.1M hydrochloric acid and distilled water. Drug content confirms that ultrasonication is one of the efficient methods to prepare inclusion complex. Dissolution data of inclusion complexes also indicated that there is 1.4 folds increase in dissolution as compared to pure drug and was observed in case of inclusion complexes prepared by ultrasonication.

The Solid-State Inclusion Complex between the Mono-Anion of Calix[4]Arene and Protonated Diamino-Bicycloundecane

Diamino-bicycloundecane mono-deprotonates H-calix[4]arene and the solid-structure of the resulting salt has been determined by X-ray crystallography. Two different complexes are present in the structure with the Diamino-bicycloundecane cation held in the calix[4]arene cavity by CH-p interactions. In the packing there is a hydrogen-bonded polymeric chain. Both the complexes formed layered structures with differing inter-layer distances.

Preparation and physicochemical characterization of carbamazepine (CBMZ): para-sulfonated calix[n]arene inclusion complexes

The formation of inclusion complexes with para-sulfonated calix[n]arene (PSC[n]A) was studied for carbamazepine (CBMZ), a poorly water soluble anticonvulsant drug. The effect of PSC[4]A and PSC[6]A on aqueous solubility of carbamazepine was studied extensively. The complete complexation of the drug was achieved after 48 h of shaking with PSC[n]A in water and evaporation of water to get solid complex. The interaction between PSC[n]A and CBMZ in solid state inclusion complexes was accomplished by aqueous phase solubility studies, HPLC, DSC, PXRD, FTIR, UV–Vis, and FT-Raman spectroscopy. The solubility of CBMZ increases as a function of PSC[n]A concentration. The results of the two phase solubility experiments are in good conformity to signify the formation of 1:1 (PSC[6]A:CBMZ) and 2:1 PSC[4]A:CBMZ complexes. The order of dissolution rate of CBMZ is inclusion complex > physical mixture > drug alone. The purpose of this study was to enhance solubility resulting in high dissolution rate and bioavailability of this essentially water insoluble drug.

Intratumoral Delivery of β-Lapachone via Polymer Implants for Prostate Cancer Therapy

beta-Lapachone (ARQ 501, a formulation of beta-lapachone complexed with hydroxypropyl-beta-cyclodextrin) is a novel anticancer agent with selectivity against prostate cancer cells overexpressing the NAD(P)H:quinone oxidoreductase-1 enzyme. Lack of solubility and an efficient drug delivery strategy limits this compound in clinical applications. In this study, we aimed to develop beta-lapachone-containing polymer implants (millirods) for direct implantation into prostate tumors to test the hypothesis that the combination of a tumor-specific anticancer agent with site-specific release of the agent will lead to significant antitumor efficacy. Survival assays in vitro were used to test the killing effect of beta-lapachone in different prostate cancer cells. beta-Lapachone release kinetics from millirods was determined in vitro and in vivo. PC-3 prostate tumor xenografts in athymic nude mice were used for antitumor efficacy studies in vivo. beta-Lapachone killed three different prostate cancer cell lines in an NAD(P)H:quinone oxidoreductase-1-dependent manner. Upon incorporation of solid-state inclusion complexes of beta-lapachone with hydroxypropyl-beta-cyclodextrin into poly(D,L-lactide-co-glycolide) millirods, beta-lapachone release kinetics in vivo showed a burst release of approximately 0.5 mg within 12 hours and a subsequently sustained release of the drug ( approximately 0.4 mg/kg/d) comparable with that observed in vitro. Antitumor efficacy studies showed significant tumor growth inhibition by beta-lapachone millirods compared with controls (P < 0.0001; n = 10 per group). Kaplan-Meier survival curves showed that tumor-bearing mice treated with beta-lapachone millirods survived nearly 2-fold longer than controls, without observable systemic toxicity. Intratumoral delivery of beta-lapachone using polymer millirods showed the promising therapeutic potential for human prostate tumors.

Physicochemical properties of antifungal drug–cyclodextrin complexes prepared by supercritical carbon dioxide and by conventional techniques

Antifungal drugs are the most common systemic drugs used for the treatment of oropharyngeal candidiasis, which is the first symptom of HIV infection. However, the efficacy and bioavailability of these drugs have been limited by their poor aqueous solubility and dissolution rate. Therefore, the aim of this study was to investigate the effect of different preparation methods (i.e. kneading, coevaporation, sealed-heating, and a solid inclusion technique using supercritical carbon dioxide carrier (SC CO 2-inclusion)) for obtaining solid inclusion complexes between β-cyclodextrin and three antifungal drugs (itraconazole, econazole, and fluconazole). The physicochemical properties of the different products were characterized by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and powder X-ray diffractometry (PXRD). For the complexes prepared by the SC CO 2-inclusion method, the effects of temperature and pressure have also been investigated. Results suggested the possibility of complex formation between β-cyclodextrin and the three antifungal agents, and indicated that inclusion formation was influenced by the preparation technique. SC CO 2-inclusion method proved to be an effective technique for preparing solid-state inclusion complexes between β-cyclodextrin and antifungal drugs, avoiding the use of organic solvents. Moreover, temperature of the SC CO 2 played a major role in promoting drug–carrier interactions, whereas pressure had limited effects.

Characterization of cyclodextrin complexes with turmeric oleoresin

Turmeric rhizome oleoresin (TRO) was successfully solubilised in aqueous solution by forming inclusion complexes with β-cyclodextrin (BCD) and γ-cyclodextrin (GCD). To investigate molecular associations of BCD and/or GCD with the oleoresin, phase solubility studies were undertaken, using 1,8-cineole (C 10H 18O) and ar-tumerone (C 15H 20O) as marker compounds to represent turmeric oleoresin. In the presence of cyclodextrins, the solubility of 1,8-cineole and ar-tumerone were enhanced. Based on the stability constant, k 1:1, the GCD-complex was at least twice effective than BCD. Solid state inclusion complexes were also prepared, using kneading (K) and co-precipitation (CP) methods, and analysed using Fourier transform infrared (FTIR) spectrometry and scanning electron microscopy (SEM). The shift of C O stretching to higher wavenumbers and strengthening of the C O stretching band indicated the formation of a complex between CD and TRO. The new solid phase formed using the co-precipitation method, had a crystal structure which was completely different from the original morphology of oleoresin and cyclodextrins.

Solubility enhancement of kinetin through host–guest interactions with cucurbiturils

We explored the use of cucurbiturils to form inclusion complexes to overcome the solubility problems of kinetin, a plant cytokinin. Inclusion complexes between kinetin and Q[7], TMeQ[6] and HMeQ[6] in aqueous solution and in solid state were investigated by phase solubility studies, 1H NMR and IR. The effects of pH and temperature on complex stability were also investigated. Phase solubility studies showed that kinetin solubility increased in a linear fashion as a function of Q[7] and TMeQ[6] concentrations. However, kinetin solubility increased first, then decreased as the HMeQ[6] concentration increased, and the maximum solubility of kinetin was achieved at 4.95 mM in HMeQ[6]. The solubility of kinetin as well as the stability constant of its complex with Q[7] were affected by the pH of the medium. The thermodynamic parameters of the complex formation were also determined, and it showed that the formation of the inclusion complexes between kinetin and Q[7] was enthalpy controlled, suggesting that hydrophobic and van der Waals interactions were the main driving forces. Moreover, we found that the size of the cavity of cucurbituril played an important role in the association process. The formation of inclusion complexes between Q[7], TMeQ[6] and HMeQ[6] with kinetin was confirmed by 1H NMR, and IR spectroscopy showed the presence of inclusion complexes in solid state. Our results demonstrated that the complexation of kinetin with Q[n] could be used to improve the solubility of kinetin in aqueous solution.

Mapping Out the Molecular Interplay in Monohalobenzene Inclusion Complexes ofp-H-calix[5]arene Using Hirshfeld Surfaces

Solid-state inclusion complexes of p-H-calix[5]arene with fluoro-, chloro-, bromo-, and iodobenzene have been structurally authenticated using X-ray diffraction data with a detailed analysis of the Hirshfeld surfaces facilitating an understanding of the type and nature of intermolecular interactions in the supermolecules and extended structures. All but the iodobenzene complexes are isostructural forming columnar arrays involving three crystallographically related 1:1 host–guest supermolecules (halobenzene∩calix[5]arene); three halobenzene molecules from different supermolecules are associated via C−H···X interactions for hydrogen atoms ortho to the halogen atoms, effectively creating a larger cavity from close proximity of three calix[5]arenes. The iodobenzene inclusion complex has sheets of calixarenes rather than columns in the extended packing, presumably due to the increased size of iodine circumventing the formation of the aforementioned interplay of three halobenzene molecules.

Preparation of itraconazole/HP-β-CD inclusion complexes using supercritical aerosol solvent extraction system and their dissolution characteristics

The purpose of this study was to investigate the feasibility of a supercritical fluid process, called aerosol solvent extraction system (ASES), for producing solid-state inclusion complexes of itraconazole (ITR) with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). ITR was complexed with HP-β-CD at temperatures of 35–55 °C, pressures of 83–140 bar, CO 2 densities of 0.498–0.801 g/cm 3, and solution concentrations of 1–5% (w/v). The ASES-processed inclusion complex powders were observed to consist of agglomerates of very fine (100–500 nm) particles. From the experimental results of X-ray diffraction and differential scanning calorimetry, it was found that ITR intermolecularly interacted with the HP-β-CD cavity, resulting in the formation of inclusion complex. Furthermore, the ASES-processed ITR/HP-β-CD powders showed a significant enhancement in the ITR solubility (up to 753.6 μg/mL) in an aqueous medium of pH 1.2. The aqueous solubility of ITR increased with pressure at a constant temperature, and we could obtain a relatively high solubility of 341 μg/mL at 140 bar and 35 °C. In a solution concentration range of 1–5% (w/v), the solubility increased with decreasing concentration, yielding 289–407 μg/mL. When the molar ratio of ITR to HP-β-CD was varied from 1:1 to 1:3, the ITR solubility increased with HP-β-CD content, giving a value of 753.6 μg/mL for the 1:3 ratio. For the ASES-processed ITR/HP-β-CD powders, the percent dissolution of ITR also increased considerably and about 90% of ITR was dissolved within 5–10 min.

Preparation and Property Screening of the Solid Inclusion Complex of Norfloxacin with p-Sulfonated Calix[4]arene

The complexation of norfloxacin (NFLX) by p-sulfonated calix[4]arene (SC4A) in aqueous solution has been studied by fluorescence spectroscopy and 1H NMR spectroscopy. A 1:1 stoichiometry and a 8086 L mol(-1) stability constant of the NFLX-SC4A complex was obtained by spectrofluorometric titrations. The equimolar solid state inclusion complex of NFLX-SC4A was prepared by the co-precipitation method and then characterized by various techniques, including differential scanning calorimetry (DSC), X-ray powder diffractometry (XRD), Fourier-transform infrared analysis (FT-IR) and scanning electron microscopy (SEM). The experimental results of these chemical property screenings confirmed that NFLX and SC4A can form a stable host-guest complex in the solid state, and SC4A appears to function as a complexing and solubilizing agent for NFLX.

Study on inclusion complexes of hydroxypropyl-β-cyclodextrin with tanshinone IIA

The inclusion complex formation of tanshinone IIA (Tan IIA) with hydroxypropyl-β-cyclodextrin (HPCD) was studied by using phase solubility method, and the formation constant for tanshinone IIA-HPCD-dextrin was determined. The effect of temperature on the reaction was studied through thermodynamics, and the changes inentropy, enthalpy, and free energy of the reaction were calculated. The molecular modeling provided further evidence for the formation of the inclusion complexes. Stable inclusion complex in solid state was characterized by IR spectra.

Evaluation of host-guest complex formation between a benzimidazolic derivative and cyclodextrins by UV-VIS spectrophotometry and differential scanning calorimetry

Interactions between a benzimidazolic derivative, omeprazole (OME), beta-cyclodextrin (βCD) and a chemically modified βCD, methyl-beta-cyclodextrin (MβCD) were investigated in aqueous solution by UV-VIS spectroscopy and in solid state by differential scanning calorimetry (DSC). Phase solubility studies were used to evaluate the complexation in aqueous solution. The two solubility diagrams obtained were AL type, indicating the formation of a drug-cyclodextrin complex with 1:1 stoichiometry. The complex of OME with MβCD showed a higher stability constant (K S) than those with βCD. Some evidences of inclusion complexation in solid state were obtained from DSC. Only in thermal curves of OME-βCD lyophilized product and in OME-MβCD spray-dried and lyophilized systems the melting point of the drug disappeared completely suggesting the possible formation of an inclusion complex.

Preparation and physicochemical characterization of omeprazole:methyl-beta-cyclodextrin inclusion complex in solid state

In this work, we illustrate the usefulness of cyclodextrins, namely, methyl-β-cyclodextrin (MβCD), an amorphous, methylated derivative of the natural β-cyclodextrin (βCD), as a tool to form an inclusion complex with omeprazole (OME), a poorly water soluble drug. Solid binary systems between OME and MβCD were prepared experimentally in a stoichiometry 1:1 by different techniques (physical mixing, kneading, spray-drying and freeze-drying). Afterward these products were characterized by Fourier transformation-infrared spectroscopy (FTIR); X-ray diffractometry (XRD) and scanning electron microscopy (SEM). The results obtained suggest that spray-drying and freeze-drying methods yield a higher degree of amorphous entities suggesting the formation of inclusion complexes between OME and MβCD.

Release Characteristics of Iodine Encapsulated in Cyclodextrins

The effect of cyclodextrins (CDs) on water solubility of iodine was investigated. Modified CDs greatly enhanced the solubility of iodine. On the contrary, enhancement by natural CDs was rather moderate whereby the solubility was only doubled at the highest β-CD concentration examined. Desorption experiment of iodine from solution was carried out with addition of various CDs to study the effect of CDs on iodine retention. α-CD was the most efficient in retarding iodine desorption. Later, various concentrations of α-CD were used in the desorption experiment to observe its volatile suppression effect and determine the stability constant of iodine/α-CD complexation. At α-CD concentration of 10.3 mM, no lost of iodine from the solution was detected. A model was developed for desorption of iodine from the solution based on mass transfer theory. The stability constant K given by this model was 3.28×104 M−1 which was in the same order as the value estimated in this study by solubility method and as well those reported by other authors. In release experiments of solid state inclusion complexes, stability of inclusion complex powders decreased in the order of α-CD>β-CD>randomly methylated β-CD (RM-β-CD).

A comparison of 1H-13C cross polarization and magic angle spinning dynamics of the α-, β- and γ-cyclodextrin inclusion complexes of benzaldehyde

Abstract The solid state inclusion complexes of benzaldehyde with α-, β- and γ-cyclodextrins have been studied by cross-polarization and magic angle spinning solid state NMR techniques (CPMAS-NMR). The effects of complexation on the mobility of the guest have been analyzed in terms of nuclear relaxation parameters such as 13C spin-lattice relaxation (T1), 1H spin-lattice relaxation in the rotating frame (T1ρ(H)), and cross polarization transfer (TCH). It is proposed that large variations observed in the TCH values of the guest in the three complexes may be interpreted in terms of motion with correlation times in the range between ca. 0.1–5.0 msec. These motions may strongly affect the extent of the heteronuclear dipolar coupling partially responsible in determining the rates of cross polarization.

C.P.-M.A.S. 13C-N.M.R. study of some solid-state inclusion complexes of cyclomalto-oligosaccharides with para-substituted benzenes

Cross polarisation—magic-angle sample spinning 13C-n.m.r. spectral have been measured in the solid state for p-nitrophenol, p-iodophenol, and their inclusion complexes with cyclomaltohexaose, cyclomaltoheptaose, and methylated cyclomaltohexaose. Analysis of the line-shapes of the resonances and the dipolar-dephasing experiments indicate that the guest molecules undergo motion in the host cavities, whereas the host molecules are almost static. The mode and rate of guest motion depend on the size of the cavity.

Structure and molecular dynamics of solid-state inclusion complexes of cyclodextrin and permethylated cyclodextrin with benzaldehyde studied by high-resolution CP/MAS13C NMR

The structure and molecular dynamics of the benzaldehyde inclusion-complexes with α-andβ-cyclodextrins and permethylated α-cyclodextrin in the solid state have been studied by high-resolution cross-polarization/magic angle sample-spinning13C NMR spectroscopy. It is shown that the guest benzaldehyde molecule undergoes motion in the host cyclodextrin cavity and the rate of motion depend on the cavity size. In the α-cyclodextrin complex, compared to β-and permethylated α-cyclodextrin complexes, the benzaldehyde motion is severely restricted, but under high-vacuum benzaldehyde is released more easily from the cavity.