Inclusion Complexes of Daidzein with Cyclodextrin-Based Metal-Organic Framework-1 Enhance Its Solubility and Antioxidant Capacity.

Daidzein, an aglycone-type isoflavone, is useful in the prevention of atherosclerotic cardiovascular diseases. However, the solubility of daidzein remains relatively low even with pharmaceutical interventions (e.g., γ-cyclodextrin inclusion complex). In the present study, daidzein-cyclodextrin-metal organic framework solid dispersion complexes were prepared by the solvent evaporation method. The physicochemical properties of the complex and its effect on the solubility of daidzein were evaluated. The enhancement effect of a cyclodextrin-metal organic framework on the antioxidant properties of daidzein was verified using a diphenyl-picrylhydrazyl radical scavenging test. Powder X-ray diffraction results showed that the characteristic diffraction peaks of daidzein and cyclodextrin-metal organic framework disappeared and new peaks (2θ = 7.1°, 16.5°) were observed. FT-IR measurements showed that the peak derived from the carbonyl group of daidzein shifted to the lower wavenumber. NOESY 1H-1H NMR showed cross peaks at the proton on the resorcinol side of daidzein and the proton (H-5, H-6) in a cyclodextrin-metal organic framework. Dissolution rate of daidzein at 5 min in distilled water was 0.06% for daidzein alone while the daidzein inclusion complex was about 100%. When fasted state simulated intestinal fluid was used, the dissolution rate of the daidzein complex was about 71% compared with that of daidzein alone (~ 3.0%) at 5 min. The daidzein inclusion complex improved the antioxidant capacity to ~ 1.3 times (17.8 µg/mL) compared to the IC50 of daidzein alone (22.9 µg/mL). Preparations of cyclodextrin-metal organic framework inclusion complexes will be a platform in developing pharmaceutical formulations to enhance the bioavailability and activity of drugs.

Solubility of Piperine and Its Inclusion Complexes in Biorelevant Media and Their Effect on Attenuating Mouse Ileum Contractions.

This study evaluated the solubility of piperine (PP) in biorelevant media and the effect of its ground mixtures (GMs) and coprecipitates (CPs) on intestinal contractions when presented in inclusion complexes with α-, ß-, and γ-cyclodextrins (CDs). In the powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) measurements, CP (PP/αCD) and CP (PP/γCD) suggest the formation of inclusion complexes. The 1H-nuclear magnetic resonance (NMR) analysis showed the integrated intensity ratios of CP (PP/αCD) and CP (PP/γCD) protons to be 1/2 and 1/1, the same as the respective molar ratios in the respective GM inclusion complexes. The intestinal contraction test confirmed that the intestinal contraction rate of carbachol (CCh) in the presence of 2.0 × 10-5 M PP was comparable to that in the absence of PP. On the other hand, CP (PP/αCD), GM (PP/αCD = 1/2), and GM (PP/ßCD = 1/1) formed inclusion complexes that significantly suppressed the intestinal contractility at PP 1.0 × 10-8 M. No significant differences were observed between CP and GM. The solubility of the PP/αCD inclusion complex was 6-7 times higher than that of PP in the fasted-state-simulated intestinal fluid (FaSSIF, pH 6.5). PP functioned to suppress intestinal contraction by forming an inclusion complex. Based on this result, PP/αCD might be expected to be effective as an antidiarrheal.

Preparation and characterization of triamterene complex with ascorbic acid derivatives.

The purpose of this study was to prepare solid dispersions of triamterene (TRT) with ascorbic acid (AA) or ascorbic acid 2 glucoside (AA2G) and to evaluate their physical properties. Solid dispersions were prepared by dissolving each sample in an organic solvent and evaporation (EVP). Powder X-ray diffraction (PXRD) revealed a halo pattern for EVP1 (AA/TRT = 1/1) and EVP2 (AA2G/TRT = 1/1). In differential scanning calorimetry (DSC), endothermic peaks due to the melting of TRT and AA disappeared for EVP1 (AA/TRT = 1/1), and the melting peaks of TRT and AA2G disappeared for EVP2 (AA2G/TRT = 1/1). Fourier transform infrared (FT-IR) spectroscopy revealed broadened peaks for EVP1 (AA/TRT = 1/1) and EVP2 (AA2G/TRT = 1/1) due to the hydroxyl groups (-OH) of AA and the amino groups (-NH2) of TRT and also revealed a peak shift due to the pteridine skeleton (C = N) of TRT. In near-infrared absorption (NIR) spectroscopy, peaks due to the hydroxyl groups (-OH) of AA and AA2G were found for EVP1 (AA/TRT = 1/1) and EVP2 (AA2G/TRT = 1/1), respectively. A peak due to the amino groups (-NH2) was evident. This suggested the formation of an evaporation, in which TRT interacted with AA or AA2G. In the dissolution test, the dissolved fraction of TRT alone after 3 min was 30%, whereas the fractions were enhanced to approximately 90% for EVP1 (AA/TRT = 1/1) and EVP2 (AA2G/TRT= 1/1). Results confirmed that dissolution properties were improved as a result of complex formation. The above findings indicated improvement the dissolution properties of TRT.

Syntheses and crystal structures of two piperine derivatives.

The title compounds, 5-(2H-1,3-benzodioxol-5-yl)-N-cyclo-hexyl-penta-2,4-dienamide, C18H21NO3 (I), and 5-(2H-1,3-benzodioxol-5-yl)-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one C16H17NO3 (II), are derivatives of piperine, which is known as a pungent component of pepper. Their geometrical parameters are similar to those of the three polymorphs of piperine, which indicate conjugation of electrons over the length of the mol-ecules. The extended structure of (I) features N-H⋯O amide hydrogen bonds, which generate C(4) [010] chains. The crystal of (II) features aromatic π-π stacking, as for two of three known piperine polymorphs.

Evaluation of the Molecular State of Piperine in Cyclodextrin Complexes by Near-Infrared Spectroscopy and Solid-State Fluorescence Measurements.

The purpose of this study was to evaluate the physicochemical properties of piperine (PP) in ground mixtures (GMs) of PP with α-, ß-, or γ-cyclodextrin (CD) under conditions of humidity, heat, and humidity-heat. In solid-state fluorescence measurements, the fluorescence maxima for GM (PP/αCD = 1/2), GM (PP/ßCD = 1/1), and GM (PP/γCD = 1/1) were observed at 463, 472, and 469 nm, respectively. On the other hand, the humidified GMs exhibited maxima at 454, 460, and 465 nm, while the humidified-heated samples displayed fluorescence maxima at 455, 455, and 469 nm, respectively. Therefore, the molecular behavior of PP with α, ß, and γCD was concluded to vary upon the coordination of water molecules. NIR and solid-state fluorescence measurements revealed that the molecular behavior of PP inside the α, ß, and γCD cavity changed by water and heat factors depends on the mobility of the methylenedioxyphenyl group.

Characterization of the Dissolution Behavior of Piperine/Cyclodextrins Inclusion Complexes.

In this study, the physicochemical properties and solubility of inclusion complexes of ground mixtures (GMs) of piperine (PP), a pungent ingredient of pepper, with α- and γ-cyclodextrin (CD) were studied. From the solubility results, the PP/αCD inclusion molar ratio was determined to be 1/2, while that of PP/γCD was 1/1, according to the AP-type phase diagram of PP/αCD and the BS-type one of PP/γCD. The powder X-ray diffraction and differential scanning calorimetry analyses confirmed the formation of GM complexes with molar ratios of PP/αCD = 1/2 and PP/γCD = 1/1. The Raman analysis revealed the disappearance of the bands corresponding to the C=C, O-CH2-O, -CH, and aliphatic C=C moieties of the methylene dioxyphenyl fragment of PP in the spectra of the inclusion complexes. In the dissolution tests, GM (PP/αCD = 1/2) and GM (PP/γCD = 1/1) showed higher solubility than free PP and the analogous physical mixtures. Furthermore, after 60 min, GM (PP/αCD = 1/2) exhibited higher solubility than GM (PP/γCD = 1/1). In the 1H-1H nuclear Overhauser effect spectroscopy measurements, GM (PP/αCD = 1/2) was found to present a head-to-head inclusion structure via the aliphatic C=C and methylene dioxyphenyl groups of PP and the two αCD molecules. In contrast, it was confirmed that γCD interacts with the O-CH2-O functionality of the methylene dioxyphenyl group of PP in a molar ratio of 1/1. It was thus concluded that the differences in the PP/CD structures influence the solubility of the inclusion complexes.

Changes in the Physicochemical Properties of Piperine/ß-Cyclodextrin due to the Formation of Inclusion Complexes.

Piperine (PP) is a pungent component in black pepper that possesses useful biological activities; however it is practically insoluble in water. The aim of the current study was to prepare a coground mixture (GM) of PP and ß-cyclodextrin (ßCD) (molar ratio of PP/ßCD = 1/1) and subsequently evaluate the solubility of PP and physicochemical properties of the GM. DSC thermal behavior of the GM showed the absence of melting peak of piperine. PXRD profile of the GM exhibited halo pattern and no characteristic peaks due to PP and ßCD were observed. Based on Job's plot, the PP/ßCD complex in solution had a stoichiometric ratio of 1/1. Raman spectrum of the GM revealed scattering peaks assigned for the benzene ring (C=C), the methylene groups (CH2), and ether groups (C-O-C) of PP that were broaden and shifted to lower frequencies. SEM micrographs showed that particles in the GM were agglomerated and had rough surface, unlike pure PP and pure ßCD particles. At 15 min of dissolution testing, the amount dissolved of PP in the GM was dramatically increased (about 16 times) compared to that of pure PP. Moreover the interaction between PP and ßCD cavity was detected by (1)H-(1)H NMR nuclear Overhauser effect spectroscopy NMR spectroscopy.