Kunikazu Moribe

Chiba University, Tiba, Chiba, Japan

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Publications (113)267.47 Total impact

  • M. Hata · K. Moribe · S. Ando · Y. Tozuka · K. Yamamoto
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    ABSTRACT: The equimolar complexation behavior of urea or thiourea with 2-alcoxybenzamides has been studied by theoretical calculations. Structural models for the calculation were constructed from the X-ray crystallographic structures of 2-methoxybenzamide (MB) crystal and 2-ethoxybenzamide (EB)-thiourea, MB-thiourea, and MB-urea equimolar cocrystals. Structural optimization for EB—urea equimolar cocrystal was performed by the density functional theory (DFT) method (B3LYP/6-31G** level) and the complexation energy was determined using the DFT with higher order basis set (6–31+G**). Energetic stabilization by the equimolar complexation was observed in the three equimolar complexes. The reason why the amide group of MB is out-of-plane in unprocessed MB crystals is well explained by the calculations. It was suggested that intermolecular hydrogen bonding increases in the out-of-plane structure of MB and that subsequently leads to stabilization in the crystal. The amide group of MB or EB was inplane by the complex formation with urea or thiourea. Finally, we predict the possibility of EB-urea equimolar complex formation in terms of the complexation energy.
    No preview · Article · Dec 2015 · Journal of Structural Chemistry
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    Preview · Article · Nov 2015 · Asian Journal of Pharmaceutical Sciences
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    Preview · Article · Nov 2015 · Asian Journal of Pharmaceutical Sciences
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    ABSTRACT: A novel type of spectrum, the one-dimensional power spectrum (1D-PS), was designed for the discrimination of adhesive packing tapes, i.e., kraft tapes. The 1D-PS offered complementary information to that provided by the improved two-dimensional PS (2D-PS), which was calculated using our previously established image processes combined with a two-dimensional fast Fourier transform (2D-FFT) to obtain information about the spatial periodicity within kraft tapes. The 1D-PS was calculated using a three-step image process: (i) the 2D-FFT was applied to 50 randomly selected areas in a transmitted light image; (ii) the obtained 2D-PSs were accumulated without applying a logarithmic transform; (iii) the wavenumber and the maximum intensity were plotted on the x-axis and y-axis, respectively. Through an intra-roll comparison, the 1D-PSs collected from single rolls showed similar profiles. In an inter-roll comparison, the 1D-PSs from 50 commercially available brand-name products were classified into 29 groups. The 1D-PSs contained other useful information than that provided by the improved 2D-PSs: they presented more peaks and absolute intensity with a wider range. The 1D-PSs enabled us to compare the spectra quickly and easily, owing to their unchanging profiles regardless of the orientation of the scanned images. A combined use of the 1D-PSs with the improved 2D-PSs-both spectrum types being convenient, rapid, non-destructive, and applicable to dirty and/or damaged samples-could further improve the identification of kraft tapes.
    No preview · Article · Oct 2015 · Forensic science international
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    ABSTRACT: Solid dispersion using Eudragit E PO (EPO) improves the dissolution of poorly water-soluble drugs in acidic solutions; however, the dissolution extremely decreases in neutral solutions. In this report, ternary solid dispersions containing probucol (PBC), EPO, and saccharin (SAC) were prepared to enable high drug dissolution at neutral pH. Cryogenic-grinding was used to obtain ternary solid dispersions. Dissolution tests at neutral pH values were conducted to confirm the usefulness of the cryogenic-ground mixture (cryo-GM). The molecular state of each component and intermolecular interactions in the ternary cryo-GM were evaluated using powder X-ray diffraction (PXRD) and (13) C solid-state NMR including spin-lattice relaxation time evaluation. PBC dispersed in ternary cryo-GM had an improved dissolution in neutral solutions. PBC and SAC were in amorphous states in EPO polymer matrices. The weak hydrophobic interaction between PBC and EPO and the ionic bond or hydrogen bond between EPO and SAC were demonstrated. These two molecular interactions improved the dissolution of PBC in neutral solutions. Preparation of ternary solid dispersion is a potential method of improving drug solubility and absorption. © 2015 Royal Pharmaceutical Society.
    No preview · Article · Aug 2015
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    ABSTRACT: Amorphous solid dispersions of phenytoin (diphenylhydantoin: DPH) and glibenclamide (GBM) with Eudragit(®) S 100 (S100) were prepared by a spray-drying. At low drug loading ratios, DPH dissolved simultaneously with S100. However, at high drug loading ratios the DPH dissolution rates were significantly reduced in comparison with those of S100 because of the rapid crystallization of DPH during the dissolution test. All of the DPH molecules in the low drug loading spray-dried sample (SPD) intimately interacted with the S100 matrix. In the SPDs with high drug loadings, only some of the DPH molecules interacted with the S100 matrix, while the excess DPH formed DPH-rich domains. When these domains contacted the water during the dissolution test, the amorphous DPH were more easily transformed into a crystalline form. In contrast to the solid dispersion of DPH/S100, that of GBM/S100 showed the simultaneous dissolution independent of the drug loading ratio. GBM was retained in an amorphous state during the dissolution test even at high drug loadings, although GBM-rich domains were formed. The miscibility at the molecular level as well as the stability of the amorphous state of drug are crucial factors to enhance the drug dissolution rate by the simultaneous dissolution with the polymer. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Aug 2015 · International Journal of Pharmaceutics
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    ABSTRACT: The chemical stability of suplatast tosilate (ST) was evaluated under dry conditions at 60 °C, with a focus on the polymorphic forms and crystal uniformity. The intact α-form, namely α-C type crystals, was crystallized rapidly by adding isopropyl ether into an ethanolic solution of ST. The α-C type crystals exhibited low stability at 60 °C. In addition to the α-C type crystals, two types of α-form crystals with different uniformities, namely α-A and α-B type crystals, were prepared. The α-A type crystals were prepared by conversion from the η-form in aqueous acetone, while the α-B type crystals were prepared by recrystallization from 2-propanol at a low supersaturation level. The stability of the α-form crystals was as follows: α-A > α-B > α-C. The uniformity of ST crystals was determined according to the newly developed high performance liquid chromatography (HPLC) method. The α-C type crystals exhibited inferior chemical stability due to unstable crystalline phases. They showed preferential enrichment and exhibited a unique optical resolution phenomenon. The observed unstable crystalline phases were produced during the crystallization process. α-A type crystals, which had high regularity, exhibited excellent stability. Overall, we prepared and evaluated the structures of α-form crystals with different uniformities.
    No preview · Article · Jun 2015 · Journal of Drug Delivery Science and Technology
  • Kunikazu Moribe · Kenjirou Higashi
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    ABSTRACT: Various kinds of nanoparticle formulation have been developed to improve the bioavailability of poorly water-soluble drugs. Drug nanocrystal technology using wet milling has been applied for active pharmaceutical ingredients and some of them are commercially available. Nanonization of drug as nanocrystal enables improvement of dissolution rate, dispersibility, and the formulation stability. Newly developed drug nanocrystals are expected to be used not only as oral but also as parenteral and transdermal formulations. In this review, production technology, property, and physicochemical characterization of poorly water-soluble drug nanocrystals are introduced. © 2015, Japan Society of Drug Delivery System. All rights reserved.
    No preview · Article · Jun 2015 · Drug Delivery System
  • Kiichi Egami · Kenjirou Higashi · Keiji Yamamoto · Kunikazu Moribe
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    ABSTRACT: The crystallization behavior of a pharmaceutical drug in nanoparticles was directly evaluated by force curve measurements of atomic force microscopy (AFM) in aqueous solution. A ternary spray-dried sample (SPD) was prepared by spray-drying the organic solvent containing probucol (PBC), hypromellose (HPMC), and sodium dodecyl sulfate (SDS). The amorphization of PBC in the ternary SPD was confirmed by powder X-ray diffraction (PXRD) and solid-state (13)C NMR measurements. A nanosuspension containing quite small particles 25 nm in size was successfully prepared immediately after dispersion of the ternary SPD into water. Furthermore, solution-state (1)H NMR measurements revealed that a portion of HPMC coexisted with PBC as a mixed state in the freshly prepared nanosuspension particles. After storing the nanosuspension at 25°C, a gradual size increase of the nanoparticles was observed, and the particle size changed to 93.9 nm after 7 days. AFM enabled the direct observation of the morphology and the agglomeration behavior of the nanoparticles in water. Moreover, AFM force-distance curves were changed from (I) to (IV) depending on the storage period as follows: (I) complete indentation within the applied force of 1 nN, (II) complete indentation with the applied force of 1-5 nN, (III) partial indentation with the applied force of 5 nN, and (IV) nearly no indentation with the applied force of 5 nN. This stiffness increase of the nanoparticles was attributed to the gradual changes in the molecular state of PBC from the amorphous to the crystal state. Solid-state (13)C NMR measurements of the freeze-dried samples demonstrated the presence of metastable PBC Form II crystals in the stored nanosuspension, strongly supporting the AFM results.
    No preview · Article · Jun 2015 · Molecular Pharmaceutics
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    ABSTRACT: A variable-temperature 1H NMR study was performed to investigate the effects of the molecular weight of poly(ethylene glycol) (PEG) in PEG-lipids and cholesterol addition to the lipid bilayer on PEG chain flexibility at the liposomal surface. PEG-lipids, i.e., l-α-distearoylphosphatidylethanolamine (DSPE)-PEG, with PEG molecular weights of 750, 2000, and 5000 were modified to liposomes of ca. 100 nm. The 1H NMR peak of PEG in DSPE-PEG was overlapped by broad and sharp peaks, corresponding to rigid and flexible PEG components, respectively. When the PEG molecular weight was increased, the PEG peak became sharp, indicating that long-chain PEGs were more flexible on the liposome surface. The proportion of flexible components projecting into the water phase increased as the PEG chain length increased. Peak sharpening also occurred when the cholesterol content was increased from 0 to 30 mol%, demonstrating that cholesterol incorporation into the lipid bilayer enhanced the PEG chain flexibility. In addition, the PEG chain flexibility significantly increased when cholesterol was delocalized in the lipid bilayer at concentrations above 20 mol%. Lateral diffusion of the lipid with the presence of cholesterol in the lipid bilayer significantly affected the PEG chain flexibility.
    No preview · Article · Jun 2015 · Colloids and Surfaces A Physicochemical and Engineering Aspects
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    ABSTRACT: In this study, we examined the stabilization mechanism of drug supersaturation by hypromellose (HPMC) and polyvinylpirrolidone (PVP). The poorly water-soluble drugs, phenytoin (diphenylhydantoin, DPH), and its synthesized derivatives monomethylphenytoin (MDPH) and dimethylphenytoin (DMDPH) were used. DPH supersaturation was efficiently maintained by both HPMC and PVP. HPMC maintained the supersaturation of MDPH and DMDPH in a similar manner to that of DPH, whereas the ability of PVP to maintain drug supersaturation increased as follows: DPH > MDPH > DMDPH. Caco-2 permeation studies and nuclear magnetic resonance measurements revealed that the permeability and molecular state of the drug in a HPMC solution barely changed. In fact, the solubilization of the drug into PVP changed its apparent permeability and molecular state. The drug solubilization efficiency by PVP was higher and followed the order: DPH > MDPH > DMDPH. The different drug solubilization efficiencies most likely result from the different strengths in the intermolecular interaction between the DPH derivatives and PVP. The difference in the stabilization mechanism of drug supersaturation by HPMC and PVP could determine whether the efficient maintenance of the drug supersaturation was dependent on the drug species. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.
    No preview · Article · Jun 2015 · Journal of Pharmaceutical Sciences
  • Keisuke Ueda · Kenjirou Higashi · Keiji Yamamoto · Kunikazu Moribe
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    ABSTRACT: Quantitative evaluation of drug supersaturation and nanoparticle formation was conducted using in situ evaluation techniques, including nuclear magnetic resonance (NMR) spectroscopy. We prepared a ternary complex of carbamazepine (CBZ) with hydroxypropyl methylcellulose (HPMC) and sodium dodecyl sulfate (SDS) to improve the drug concentration. Different preparation methods, including grinding and spray drying, were performed to prepare the ternary component products, ground mixture (GM) and spray-dried sample (SD), respectively. Although CBZ was completely amorphized in the ternary SD, CBZ was partially amorphized with the remaining CBZ crystals in the ternary GM. Aqueous dispersion of the ternary GM formed nanoparticles of around 150 nm, originating from the CBZ crystals in the ternary GM. In contrast, the ternary SD formed transparent solutions without a precipitate. The molecular-level evaluation using NMR measurements revealed that approximately half a dose of CBZ in the ternary GM dispersion was present as nanoparticles; however, CBZ in the ternary SD was completely dissolved in the aqueous solution. The characteristic difference between the solid states, followed by different preparation methods, induced different solution characteristics in the ternary GM and SD. The permeation study, using a dialysis membrane, showed that the CBZ concentration dissolved in the bulk water phase rapidly reduced in the ternary SD dispersion compared to the ternary GM dispersion; this demonstrated the advantage of ternary GM dispersion in the maintenance of CBZ supersaturation. Long-term maintenance of a supersaturated state of CBZ observed in the ternary GM dispersion rather than in the ternary SD dispersion was achieved by the inhibition of CBZ crystallization owing to the existence of CBZ nanoparticles in the ternary GM dispersion. Nanoparticle formation, combined with drug amorphization, could be a promising approach to improve drug concentrations. The detailed elucidation of solution characteristics using in situ evaluation techniques will lead to the formation of useful solid dispersion and nanoparticle formulations, resulting in improved drug absorption. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · May 2015 · European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences
  • Yuki Hasegawa · Kenjirou Higashi · Keiji Yamamoto · Kunikazu Moribe
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    ABSTRACT: A nanosuspension of piroxicam (PXC) and poloxamer 407 (poloxamer) prepared by the wet milling method was directly evaluated at the molecular level from the viewpoint of both solution and solid phases. (13)C solution-state NMR measurements revealed a reduction in the concentration of dissolved poloxamer in the nanosuspension. Furthermore, the fraction of dissolved polyethylene oxide (PEO) chain, which is the hydrophilic part of poloxamer, was higher than that of dissolved polypropylene oxide (PPO) chain, the hydrophobic part. (13)C suspended-state NMR and Raman spectroscopies detected both solid-state PXC and poloxamer involved in the nanoparticles. Interestingly, the coexistence of crystalline and amorphous PXC in the nanoparticle was demonstrated. The yellow color of the nanosuspension strongly supported the existence of amorphous PXC. Changes in the peak intensity depending on the contact time in the suspended-state NMR spectrum revealed that the PEO chain of poloxamer in the nanoparticle had higher mobility compared with the PPO chain. The PEO chain should project into the water phase and form the outer layer of the nanoparticles, whereas the PPO chain should face the inner side of the nanoparticles. Amorphous PXC could be stabilized by intermolecular interaction with the PPO chain near the surface of the nanoparticles, whereas crystalline PXC could form the inner core.
    No preview · Article · Apr 2015 · Molecular Pharmaceutics
  • Keisuke Ueda · Kenjirou Higashi · Keiji Yamamoto · Kunikazu Moribe
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    ABSTRACT: The maintenance mechanism of the supersaturated state of poorly water-soluble drugs, glibenclamide (GLB) and chlorthalidone (CLT), in hydroxypropyl methylcellulose acetate succinate (HPMC-AS) solution was investigated at a molecular level. HPMC-AS suppressed drug crystallization from supersaturated drug solution and maintained high supersaturated level of drugs with small amount of HPMC-AS for 24 h. However, the dissolution of crystalline GLB into HPMC-AS solution failed to produce supersaturated concentrations, although supersaturated concentrations were achieved by adding amorphous GLB to HPMC-AS solution. HPMC-AS did not improve drug dissolution and/or solubility but efficiently inhibited drug crystallization from supersaturated drug solutions. Such an inhibiting effect led to the long-term maintenance of the amorphous state of GLB in HPMC-AS solution. NMR measurements showed that HPMC-AS suppressed the molecular mobility of CLT depending on their supersaturation level. Highly supersaturated CLT in HPMC-AS solution formed a gel-like structure with HPMC-AS, in which the molecular mobility of the CLT was strongly suppressed. The gel-like structure of HPMC-AS could inhibit the reorganization from drug prenuclear aggregates to the crystal nuclei and delay the formation of drug crystals. The prolongation subsequently led to the redissolution of the aggregated drugs in aqueous solution and formed the equilibrium state at the supersaturated drug concentration in HPMC-AS solution. The equilibrium state formation of supersaturated drugs by HPMC-AS should be an essential mechanism underlying the marked drug concentration improvement.
    No preview · Article · Feb 2015 · Molecular Pharmaceutics
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    ABSTRACT: The purpose of this study was to characterize the non-aqueous nanosuspension of a hydrophilic drug prepared by bead milling for cutaneous application. Riboflavin was used as the model hydrophilic drug. The non-aqueous nanosuspensions were prepared by grinding riboflavin with zirconia beads using eight non-aqueous bases. The mean particle size of riboflavin in the suspensions ranged from 206 to 469 nm, as determined by the dynamic light scattering method. Among the well-dispersed samples, riboflavin nanosuspension prepared in oleic acid was selected for evaluation of the drug permeability through rat skin. The cumulative amount and permeation rate of riboflavin from the nanosuspension were approximately three times higher than those for unprocessed riboflavin in oleic acid. Fluorescence imaging of the riboflavin nanosuspension suggested improved penetration of riboflavin into the stratum corneum. Furthermore, the addition of polysorbate 65 or polyglyceryl-6 polyricinoleate to the nanosuspension prepared in oleic acid markedly improved the riboflavin dispersibility. These results show that the preparation of a nanosuspension in a non-aqueous base by bead milling is one of the simple methods to improve the skin permeability of hydrophilic drugs.
    Preview · Article · Feb 2015 · CHEMICAL & PHARMACEUTICAL BULLETIN
  • R. Chiba · Y. Kuroiwa · K. Higashi · K. Yamamoto · K. Moribe
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    ABSTRACT: In this study, as-synthesized mesoporous silica preloaded with pyrene was synthesized, and then its physical properties and molecular state of pyrene were evaluated. The product had mesoporous structure from small-angle X-ray scattering and scanning electron microscopy measurements. Nitrogen gas adsorption and solid-state NMR measurements confirmed that the pore spaces were filled with Pluronic P123 (P123) and pyrene. Mobility of P123 inside the pore was investigated by solid-state NMR measurement. Mobility of hydrophilic PEO chain decreased in the pore. Solid-state fluorescence measurement was used to examine the encapsulation state of pyrene. Molecular state of pyrene was compared before and after the calcination process. At a low loading amount, pyrene-loaded calcined mesoporous silica showed the superior excimer emission, whereas pyrene-loaded as-synthesized mesoporous silica gave the predominant monomer emission. The results revealed that the presence of P123 could contribute to the dispersion improvement of pyrene at the molecular level.
    No preview · Article · Dec 2014 · Journal of Drug Delivery Science and Technology
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    ABSTRACT: Two polymorphic forms of a sulfathiazole (STZ):oxalic acid (OXA) 1:1 complex were successfully prepared by different cogrinding methods and characterized by multiple analytical techniques. Rod-milled and ball-milled ground mixtures had different powder X-ray diffraction patterns, showing polymorph formation of the STZ-OXA complex (complex A and complex B). The heat of fusion from differential scanning calorimetry curves and terahertz time-domain spectra helped differentiating the polymorphs. According to infrared spectra, C-13 NMR chemical shifts, and the relative intensities of N-15 NMR peaks, both polymorphs were salts where the proton of a -COOH group in OXA was transferred to a -NH2 group in STZ. High-resolution H-1 NMR and H-1-C-13 heteronuclear correlation NMR spectra indicated that complex B in powder form had a cocrystal type structure compared to complex A having a clathrate-type structure. Complex B structure suggested by solid-state NMR coincided well with the experimentally determined one, which was formed from three layers of thiazole rings, benzene rings, and OXAs, by using single-crystal X-ray diffraction (SC-XRD) measurement. Advanced solid-state NAIR spectroscopy measurements was useful to elucidate the structure of a polymorph, for which SC-XRD data are not available, by referring to the SC-XRD data of another polymorph.
    No preview · Article · Sep 2014 · Crystal Growth & Design
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    ABSTRACT: The effects of drug-crystallization inhibitor in bile acid/lipid micelles solution on drug permeation was evaluated during the drug crystallization process. Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) was used as a drug-crystallization inhibitor, which efficiently suppressed dexamethasone (DEX) crystallization in a gastrointestinal fluid model containing sodium taurocholate (NaTC) and egg-phosphatidylcholine (egg-PC). Changes of molecular state of supersaturated DEX during the DEX crystallization process was monitored in real time using proton nuclear magnetic resonance ((1)H NMR). It revealed that DEX distribution to bulk water and micellar phases formed by NaTC and egg-PC was not changed during the DEX crystallization process even in the presence of HPMC-AS. DEX permeation during DEX crystallization was evaluated using dissolution/permeability system. The combination of crystallization inhibition by HPMC-AS and DEX micellar encapsulation led to considerably higher DEX concentrations and improvement of DEX permeation at the beginning of the DEX crystallization process. Crystallization inhibition by HPMC-AS can efficiently work even in the micellar solution, where NaTC/egg-PC micelles encapsulates some DEX. It was concluded that a crystallization inhibitor contributed to improvement of permeation of a poorly water-soluble drug in gastrointestinal fluid.
    No preview · Article · Jun 2014 · European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences
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    ABSTRACT: Molecular networks based on noncovalent bonds have resonant frequencies in the terahertz (THz) region. THz spectroscopy is a powerful tool for identifying molecular bonds, such as intermolecular or intramolecular hydrogen bonds, in pharmaceuticals. A THz chemical imaging (TCI) system was developed by combining a THz time-domain spectrometer with a translational stage to obtain two-dimensional distributions of molecular networks in tablet samples. Since THz spectral peaks of pharmaceuticals are broad at room temperature, multicomponent chemical analysis with the TCI system has some limitations. In this paper, we describe multicomponent chemical analysis of pharmaceuticals using a sample chamber cooled by a cryostat. TCI measurement at low temperature sharpens spectral peaks and/or shifts peak frequencies, enabling us to determine the distribution of several kinds of pharmaceuticals in a tablet. The TCI system provides THz images of polymorphic form distribution of famotidine binding with D-mannitol in an over-the-counter pharmaceutical tablet. Furthermore, the molecular mechanics method was used to determine the vibrational modes of the peaks in the spectra of famotidine polymorphic forms.
    Full-text · Article · May 2014 · Journal of The Electrochemical Society
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    ABSTRACT: Eleven guest drugs with planar structures were incorporated into the intermolecular spaces between polyethylene glycol/γ-cyclodextrin (γ-CD)-polypseudorotaxanes by a sealed-heating method. Drug incorporation changed the crystal packing of γ-CD from hexagonal- to monoclinic-columnar forms, without dependence on the guest species. The incorporation of guest drugs was size dependent and stoichiometric. Guest drugs with one benzene ring and maximum cross sectional areas of ca. 40–55 Å2 exhibited a drug to γ-CD stoichiometry of 2:1. Meanwhile, the stoichiometry was 1:1 for drugs with 2–3 benzene rings and maximum cross sectional areas of ca. 60–75 Å2. More sterically bulky drugs (four and five benzene rings) did form complexes, though the complexation efficiency was insufficient to form stoichiometric complexes, due to steric hindrance. The volume of intermolecular space of the host was estimated to be larger than that of a β-CD cavity and as large as that of a γ-CD cavity. Hydrophobic and van der Waals interactions worked as driving forces for the complexation because polycyclic aromatic hydrocarbons with high log P values formed the complex. The dissolution property of the hydrophobic pharmaceutical drug naproxen was clearly improved by the complexation because naproxen existed in a monomolecular state in the complex.
    No preview · Article · May 2014 · Crystal Growth & Design

Publication Stats

1k Citations
267.47 Total Impact Points

Institutions

  • 1995-2015
    • Chiba University
      • • Graduate School of Pharmaceutical Sciences
      • • Faculty of Pharmaceutical Sciences
      Tiba, Chiba, Japan
  • 2008
    • Astellas Pharmaceutical
      Northbrook, Illinois, Japan