Kunikazu Moribe

Chiba University, Tiba, Chiba, Japan

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Publications (78)189.48 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: We investigated the drug solubilization mechanism of α-glucosyl stevia (Stevia-G) which was synthesized from stevia (rebaudioside-A) by transglycosylation. (1)H and (13)C NMR peaks of Stevia-G in water were assigned by two-dimensional (2D) NMR experiments including (1)H-(1)H correlation, (1)H-(13)C heteronuclear multiple bond correlation, and (1)H-(13)C heteronuclear multiple quantum coherence spectroscopies. The (1)H and (13)C peaks clearly showed the incorporation of two glucose units into rebaudioside-A to produce Stevia-G, supported by steviol glycoside and glucosyl residue assays. The concentration-dependent chemical shifts of Stevia-G protons correlated well with a mass-action law model, indicating the self-association of Stevia-G molecules in water. The critical micelle concentration (CMC) was 12.0mg/mL at 37°C. The aggregation number was 2 below the CMC and 12 above the CMC. Dynamic light scattering and 2D (1)H-(1)H nuclear Overhauser effect spectroscopy (NOESY) NMR experiments demonstrated that Stevia-G self-associated into micelles of a few nanometers in size with a core-shell structure, containing a kaurane diterpenoid-based hydrophobic core and a glucose-based shell. 2D (1)H-(1)H NOESY NMR measurements also revealed that a poorly water-soluble drug, naringenin, was incorporated into the hydrophobic core of the Stevia-G micelle. The Stevia-G self-assembly behavior and micellar drug inclusion capacity can achieve significant enhancement in drug solubility.
    International journal of pharmaceutics 02/2014; · 2.96 Impact Factor
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    ABSTRACT: The inhibitory effect on drug crystallization in aqueous solution was evaluated using various forms of hydroxypropyl methylcellulose acetate succinate (HPMCAS). HPMCAS suppressed crystallization of carbamazepine (CBZ), nifedipine (NIF), mefenamic acid, and dexamethasone. The inhibition of drug crystallization mainly derived from molecular level hydrophobic interactions between the drug and HPMCAS. HPMCAS with a lower succinoyl substituent ratio strongly suppressed drug crystallization. The inhibition of crystallization was affected by pH, with the CBZ crystallization being inhibited at a higher pH due to the hydrophilization of HPMCAS derived from succinoyl ionization. The molecular mobility of CBZ in an HPMCAS solution was evaluated by 1D-(1)H-NMR and relaxation time measurements. CBZ mobility was strongly suppressed in the HPMCAS solutions where strong inhibitory effects on CBZ crystallization were observed. The mobility suppression of CBZ in the HPMCAS solution was derived from intermolecular interactions between CBZ and HPMCAS leading to an inhibition of crystallization. The effect of HPMCAS on the drug dissolution rate was evaluated using an NIF/HPMCAS solid dispersion. The dissolution rate of NIF was increased when HPMCAS with a higher succinoyl substituent ratio was used.
    International journal of pharmaceutics 01/2014; · 2.96 Impact Factor
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    ABSTRACT: The intermolecular interaction between mefenamic acid (MFA), a poorly water-soluble non-steroidal anti-inflammatory drug, and Eudragit® EPO (EPO), a water-soluble polymer, is investigated in their supersaturated solution using high-resolution magic-angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy. The stable supersaturated solution with a high MFA concentration of 3.0 mg/mL is prepared by dispersing the amorphous solid dispersion into a d-acetate buffer at pH 5.5 and 37 ºC. By virtue of MAS at 2.7 kHz, the extremely broad and unresolved 1H resonances of MFA in one-dimensional 1H NMR spectrum of the supersaturated solution are well resolved, thus enabling the complete assignment of MFA 1H resonances in the aqueous solution. Two-dimensional (2D) 1H/1H nuclear Overhauser effect spectroscopy (NOESY) and radio frequency-driven recoupling (RFDR) under MAS conditions reveal the interaction of MFA with EPO in the supersaturated solution at an atomic level. The strong cross-correlations observed in the 2D 1H/1H NMR spectra indicate a hydrophobic interaction between the aromatic group of MFA and the backbone of EPO. Furthermore, the aminoalkyl group in the side chain of EPO forms a hydrophilic interaction, which can be either electrostatic or hydrogen bonding, with the carboxyl group of MFA. We believe these hydrophobic and hydrophilic interactions between MFA and EPO molecules play a key role in the formation of this extremely stable supersaturated solution. In addition, 2D 1H/1H RFDR demonstrates that the molecular MFA-EPO interaction is quite flexible and dynamic.
    Molecular Pharmaceutics 11/2013; · 4.57 Impact Factor
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    ABSTRACT: We found four new polymorphic forms (γ-, ɛ-, ζ-, and η-forms) of suplatast tosilate (ST) by recrystallization and seeding with ST-analogous compounds; three polymorphic forms (α-, β-, and δ-forms) of ST have been previously reported. The physicochemical properties of these new forms were investigated using infrared (IR) spectroscopy, solid-state nuclear magnetic resonance (NMR) spectroscopy, differential scanning calorimetry, and powder X-ray diffractometry. The presence of hydrogen bonds in the new forms was assessed from the IR and solid-state NMR spectra. The crystal structures of the ɛ- and η-forms were determined from their powder X-ray diffraction data using the direct space approach and the Monte Carlo method, followed by Rietveld refinement. The structures determined for the ɛ- and η-forms supported the presence of hydrogen bonds between the ST molecules, as the IR and solid-state NMR spectra indicated. The thermodynamic characteristics of the seven polymorphic forms were evaluated by determining the solubility of each form. The α-form was the most insoluble in 2-propanol at 35°C, and was thus concluded to be the most stable form. The ɛ-form was the most soluble, and a polymorphic transition from the ɛ- to the α-form was observed during solubility testing.
    International journal of pharmaceutics 11/2013; · 2.96 Impact Factor
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    ABSTRACT: We examined the inhibitory effect of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) on drug recrystallization from a supersaturated solution using carbamazepine (CBZ) and phenytoin (PHT) as model drugs. HPMC-AS HF grade (HF) inhibited the recrystallization of CBZ more strongly than that by HPMC-AS LF grade (LF). 1D-(1)H-NMR measurements showed that the molecular mobility of CBZ was clearly suppressed in the HF solution compared to that in the LF solution. Interaction between CBZ and HF in a supersaturated solution was directly detected using nuclear Overhauser effect spectroscopy (NOESY). The cross-peak intensity obtained using NOESY of HF protons with CBZ aromatic protons was greater than that with the amide proton, which indicated that CBZ had hydrophobic interactions with HF in a supersaturated solution. In contrast, no interaction was observed between CBZ and LF in the LF solution. Saturation transfer difference NMR measurement was used to determine the interaction sites between CBZ and HF. Strong interaction with CBZ was observed with the acetyl substituent of HPMC-AS although the interaction with the succinoyl substituent was quite small. The acetyl groups played an important role in the hydrophobic interaction between HF and CBZ. In addition, HF appeared to be more hydrophobic than LF because of the smaller ratio of the succinoyl substituent. This might be responsible for the strong hydrophobic interaction between HF and CBZ. The intermolecular interactions between CBZ and HPMC-AS shown by using NMR spectroscopy clearly explained the strength of inhibition of HPMC-AS on drug recrystallization.
    Molecular Pharmaceutics 09/2013; · 4.57 Impact Factor
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    ABSTRACT: We characterized cromolyn sodium (CS) hydrates and evaluated their molecular states in low-dose formulations using Na-multiquantum magic-angle spinning (MQMAS) nuclear magnetic resonance (NMR) analysis. Two CS hydrates, low-water-content hydrated form and high-water-content hydrated form containing 2-3 and 5-6 hydrates, respectively, were prepared by humidification. Single-crystal X-ray diffraction and powder X-ray diffraction analysis revealed that these CS hydrates contained sodium channel structures and that water molecules were adsorbed on the sodium nucleus. (13) C-cross-polarization/MAS NMR spectra of these hydrates revealed similar results, confirming that the water molecules were adsorbed not on the cromolyn skeletons but mainly on the sodium nucleus. In contrast, (23) Na-MQMAS NMR analysis allowed us to clearly distinguish these hydrates without discernible effects from quadrupolar interaction. Thus, MQMAS NMR analysis is a valuable tool for evaluating salt drugs and their formulations. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
    Journal of Pharmaceutical Sciences 07/2013; · 3.13 Impact Factor
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    ABSTRACT: Nano-formulation of poorly water-soluble drugs has been developed to enhance drug dissolution. In this review, we introduce nano-milling technology described in recently published papers. Factors affecting the size of drug crystals are compared based on the preparation methods and drug and excipient types. A top-down approach using the comminution process is a method conventionally used to prepare crystalline drug nanoparticles. Wet milling using media is well studied and several wet-milled drug formulations are now on the market. Several trials on drug nanosuspension preparation using different apparatuses, materials, and conditions have been reported. Wet milling using a high-pressure homogenizer is another alternative to preparing production-scale drug nanosuspensions. Dry milling is a simple method of preparing a solid-state drug nano-formulation. The effect of size on the dissolution of a drug from nanoparticles is an area of fundamental research, but it is sometimes incorrectly evaluated. Here, we discuss evaluation procedures and the associated problems. Lastly, the importance of quality control, process optimization, and physicochemical characterization are briefly discussed.
    Current pharmaceutical design 03/2013; · 4.41 Impact Factor
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    ABSTRACT: The aim of this study was to confirm whether light anhydrous silicic acid (Aerosil) could exhibit a stabilizing effect on the physical stability of solid dispersion under humidified conditions. Ternary solid dispersions consist of 50% troglitazone, and various ratios of polyvinyl pyrrolidone and Aerosil were prepared using the co-milling method and then evaluated for their crystallizing behavior under storage conditions. The results showed that Aerosil has a stabilizing effect against crystallizing in the dihydrate of troglitazone under humidified conditions and has an appropriate ratio range (Troglitazone/PVP/Aerosil = 50/30–20/20–30) in the ternary solid dispersion, when considering total quality satisfaction such as physical stability and dissolution. Furthermore, it was found that hydrophobized Aerosil R805 has a stronger stabilizing effect than hydrophilic Aerosil 200. The stabilizing mechanism was discussed based on the comparative results and possible molecular interaction.
    Advanced Powder Technology 01/2013; · 1.65 Impact Factor
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    ABSTRACT: The purpose of this study was to evaluate quantitatively the effects of fluoride on the solubility and crystallinity of carbonated apatites (CAPs) after its incorporation into the crystal lattice using the metastable equilibrium solubility (MES) distribution method. Fluoride-incorporated CAPs (F-CAPs) of two different carbonate levels (3 and 5%) and fluoride contents from 0 to 20,000 µg/g were synthesized. X-ray diffraction experiments and Rietveld analysis were conducted to obtain crystallite microstrain and unit cell parameters. Acetate buffer MES solution media were prepared at two solution fluoride concentrations (0.2 and 2.0 mg/l) and at two pHs (5.0 and 5.7). The unit cell a-axis values of the F-CAPs were found to decrease as the fluoride content increased, consistent with the fluoride being incorporated into the crystal lattice. The fluoride concentrations in the MES solution media were high enough to provide a 'swamping' effect such that the fluoride released from the F-CAPs during dissolution was minimal in changing the solution fluoride concentration. Employing the MES distribution superposition method, it was shown that the surface complex possessing the fluorapatite (FAP) stoichiometry [Ca(10)(PO(4))(6)F(2)] accounted for the MES distribution behavior of all experiments. In addition, the mean pI(FAP) [the value of -log(a(Ca)(10)a(PO)((4))(6)a(F)(2)) calculated from the ionic activity product based on FAP stoichiometry of the MES dissolution media in which 50% of the F-CAPs had dissolved] correlated well with the crystallite microstrain parameters of the F-CAPs. The incorporated fluoride in the F-CAPs showed only modest effects on F-CAP crystallinity and solubility.
    Caries Research 12/2012; 47(3):193-202. · 2.51 Impact Factor
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    ABSTRACT: A solid dispersion (SPD) of carbamazepine (CBZ) with hydroxypropyl methylcellulose acetate succinate (HPMC-AS) was prepared by the spray drying method. The apparent solubility (37 °C, pH 7.4) of CBZ observed with the SPD was over 3 times higher than the solubility of unprocessed CBZ. The supersaturated solution was stable for 7 days. A higher concentration of CBZ in aqueous medium was also achieved by mixing with Poloxamer 407 (P407), a solubilizing agent. From permeation studies of CBZ using Caco-2 monolayers and dialysis membranes, we observed improved CBZ permeation across the membrane in the supersaturated solution of CBZ/HPMC-AS SPD. On the contrary, the CBZ-solubilized P407 solution exhibited poor permeation by CBZ. The chemical shifts of CBZ on the (1)H NMR spectrum from CBZ/HPMC-AS SPD solution were not altered significantly by coexistence with HPMC-AS. In contrast, an upfield shift of CBZ was observed in the CBZ/P407 solution. The spin-lattice relaxation time (T(1)) over spin-spin relaxation time (T(2)) indicated that the mobility of CBZ in the HPMC-AS solution was much lower than that in water. Meanwhile, the mobility of CBZ in P407 solution was significantly higher than that in water. NMR data indicate that CBZ does not strongly interact with HPMC-AS. CBZ mobility was suppressed due to self-association and microviscosity around CBZ, which do not affect permeation behavior. Most of the CBZ molecules in the CBZ/P407 solution were solubilized in the hydrophobic core of P407, and a few were free to permeate the membrane. The molecular state of CBZ, as evaluated by NMR measurements, directly correlated with permeation behavior.
    Molecular Pharmaceutics 09/2012; · 4.57 Impact Factor
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    ABSTRACT: Transglycosylated rutin (Rutin-G), a newly developed transglycosylated food additive, was used as a novel excipient for improving the dissolution and absorption properties of flurbiprofen. No surface activity was found up to 100mg/mL of Rutin-G concentration. No cytotoxicity to Caco-2 cells was observed even at a high level of 100mg/mL Rutin-G solution. (1)H NMR study with concentration variation revealed that Rutin-G formed small aggregates in water, with the aggregation number of Rutin-G above the critical aggregation concentration of about 5.0mg/mL being 4. Structural analyses by small-angle X-ray scattering determined the aggregate to be several nanometers in maximum length. A solubility test of flurbiprofen in the presence of Rutin-G showed that the amount of dissolved flurbiprofen increased in proportion to the amount of Rutin-G loaded. This finding indicated a stoichiometric relationship between flurbiprofen and Rutin-G. The spray-dried particles of flurbiprofen/Rutin-G showed a significantly higher dissolution rate and greater absorption profile compared with the commercial flurbiprofen powder. Taken together, the results indicate the potential application of Rutin-G in the formation of a novel nanostructure of drug/transglycosylated material.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 06/2012; 82(1):120-6. · 3.15 Impact Factor
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    ABSTRACT: Physicochemical characterization and structural evaluation of a 2:1 naproxen-nicotinamide cocrystal were performed. The 2:1 cocrystal showed rapid naproxen dissolution and less water vapor adsorption, indicating better pharmaceutical properties of naproxen. The unique 2:1 cocrystal formation was evaluated by solid-state nuclear magnetic resonance (NMR). The assignments of all H and (13) C peaks for naproxen and the cocrystal were performed using dipolar-insensitive nuclei enhanced by polarization transfer and (1) H-(13) C cross-polarization (CP)-heteronuclear correlation (HETCOR) NMR measurements. The (13) C chemical shift revealed that two naproxen molecules and one nicotinamide molecule existed in the asymmetric unit of the cocrystal. The (1) H chemical shifts indicated that the carboxylic group of the naproxen in the cocrystal was nonionized, and the CH-π interaction between naproxens was very strong. From the (1) H-(13) C CP-HETCOR NMR spectrum with contact time of 5 ms, two different synthons, carboxylic acid-amide and carboxylic acid-pyridine ring, were found between naproxen and nicotinamide. Single-crystal X-ray analysis, which supported the solid-state NMR results, clarified the geometry and intermolecular interactions in more detail. The structure is unique among pharmaceutical cocrystals because each carboxyl group of the two naproxens formed different intermolecular synthons.
    Journal of Pharmaceutical Sciences 04/2012; 101(9):3214-21. · 3.13 Impact Factor
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    ABSTRACT: A new 2/1 carbamazepine (CBZ)/malonic acid (MA) cocrystal polymorph form C was formed using a vibrational rod mill, whereas the known cocrystal polymorph form A was prepared using a ball mill. IR measurements showed that the interaction between CBZ and MA in cocrystal form C was formed by amide-carboxylic acid heterosynthons, similar to that in cocrystal form A. However, NMR results showed that the molecular states of CBZ at the dibenzazepine ring appeared to be different, which could be due to variation in either the conjugation of the aromatic rings or the π-π interaction of CBZ. Factors affecting the formation of cocrystal polymorphs, such as heat and force, were investigated to clarify the formation mechanism.
    International journal of pharmaceutics 04/2012; 431(1-2):237-40. · 2.96 Impact Factor
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    ABSTRACT: The mechanism of drug nanoparticle formation of phenytoin (DPH) and its derivatives monomethylphenytoin (MDPH) and dimethylphenytoin (DMDPH) was investigated. The drug, polyvinylpyrrolidone K17 (PVP), and sodium dodecyl sulfate were coground to obtain the ground mixture (GM). The DPH GM was amorphous; however, MDPH and DMDPH GMs contained drug crystals. Spectral changes in infrared and (13)C solid-state nuclear magnetic resonance were observed in the DPH GM, partially observed in the MDPH GM, and hardly observed in the DMDPH GM. Mean particle sizes of the DPH, MDPH, and DMDPH GM nanosuspension were almost the same; however, stability after storage differed in the order of DPH > MDPH > DMDPH. The intermolecular interaction between the drug and PVP reflected not only the crystallinity of the drug in the GM but also the stability of the GM suspension. The size and stiffness of drug nanoparticles were evaluated using atomic force microscopy. Crystallization of the amorphous GM and agglomeration of the primary nanocrystals were observed in the DPH GM suspension. In contrast, primary nanocrystals were observed in the DMDPH GM suspension. The size of the drug nanocrystals formed from the different molecular states of the drug in the GM reflects the agglomerated states in water and stability.
    Journal of Pharmaceutical Sciences 04/2012; 101(9):3413-24. · 3.13 Impact Factor
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    ABSTRACT: Solid-state (13)C nuclear magnetic resonance (NMR) spectroscopy that included relaxation time measurement was utilized to evaluate the yellow coloration of evaporated samples (EVPs) of indomethacin (IMC) with commercially available folded sheet mesoporous materials (TMPS). Colorimetric analysis by visible light reflection spectroscopy clarified the color differences in each sample: deep yellow-colored melt-quenched amorphous IMC, a slightly yellow-colored EVP of TMPS-1.5 (pore size: 1.8nm), and a yellow-colored EVP of TMPS-7 (pore size: 7.3nm). The color of EVPs changed from yellow to white after washing with ethanol, indicating the reversible coloration without a chemical reaction. Powder X-ray diffractometry and differential scanning calorimetry demonstrated that the EVPs of TMPS-7 entrapped greater amounts of amorphous IMC into the mesopore than TMPS-1.5. The amount of amorphous IMC in the mesopores could affect the strength of yellow coloration. Solid-state (13)C NMR spectroscopy that included spin-lattice relaxation time (T(1)) measurement revealed that the mobility of the aromatic rings of amorphous IMC in TMPS mesopores was higher than that in melt-quenched amorphous IMC. The difference in color between amorphous IMC in TMPS mesopores and melt-quenched amorphous IMC can be explained by their distinct intramolecular π-conjugation systems.
    International journal of pharmaceutics 03/2012; 429(1-2):38-45. · 2.96 Impact Factor
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    ABSTRACT: Structural evaluation of probucol nanoparticles coground with polyvinylpyrrolidone K17 and sodium dodecyl sulfate for 90 min was performed by solid-state nuclear magnetic resonance (NMR) spectroscopy and atomic force microscopy (AFM) with force-distance curve analysis. The results of solid-state NMR indicated that the cogrinding changed crystalline probucol to amorphous form. The number-averaged mean heights of probucol particles in the ground mixture (GM) suspension were determined by AFM to be 6 and 15 nm for freshly prepared and 24h-stored samples, respectively. Nucleation and the subsequent crystal growth might have occurred after the GM was dispersed in water. The presence of probucol nanocrystals and agglomeration of the primary probucol nanoparticles were recognized by AFM force-distance curve analysis. AFM could be a promising tool to evaluate the structure of nanoparticles as well as their agglomeration behavior in aqueous media.
    International journal of pharmaceutics 02/2012; 427(2):365-71. · 2.96 Impact Factor
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    ABSTRACT: This study focused on two-dimensional fast Fourier transform (2D-FFT) as a new technique for the discrimination of kraft tapes, which is a kind of adhesive packing tape. The 2D power spectrum (2D-PS) obtained by applying 2D-FFT to an image enables us to obtain information about the spatial periodicity, even if the periodicity is invisible within the image. However, in the case of kraft tape, peaks in the 2D-PS are too unclear to determine its periodicity. We developed novel analytical image processes combined with 2D-FFT. 2D-FFT was applied to 50 randomly selected areas in a transmitted light image of kraft tape. The 2D-PSs were calculated from each area without applying a logarithmic transformation, accumulated, and processed by the removal of the area surrounding the center, and finally normalized for visualization. These processes enhanced the peaks and eliminated local variations. Through an intra-roll comparison, the 2D-PSs collected from a roll were similar in the location of the peaks and in their patterns at low frequency area. Using an inter-roll comparison, the 2D-PSs from 50 commercially available brand-name products were classified into 26 groups based on these peaks and patterns. All results demonstrate that this method, which is convenient, rapid, and non-destructive, could be a valuable tool for the identification of kraft tapes.
    Forensic science international 02/2012; 220(1-3):59-66. · 2.10 Impact Factor
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    Pharmaceutical Research 02/2012; · 4.74 Impact Factor
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    ABSTRACT: The stabilization mechanism of a supersaturated solution of mefenamic acid (MFA) from a solid dispersion with EUDRAGIT(®) EPO (EPO) was investigated. The solid dispersions were prepared by cryogenic grinding method. Powder X-ray diffractometry, in vitro dissolution test, in vivo oral absorption study, infrared spectroscopy, and solid- and solution-state NMR spectroscopies were used to characterize the solid dispersions. Dissolution tests in acetate buffer (pH 5.5) revealed that solid dispersion showed > 200-fold higher concentration of MFA. Supersaturated solution was stable over 1 month and exhibited improved oral bioavailability of MFA in rats, with a 7.8-fold higher area under the plasma concentration-versus-time curve. Solid-state (1)H spin-lattice relaxation time (T(1)) measurement showed that MFA was almost monomolecularly dispersed in the EPO polymer matrix. Intermolecular interaction between MFA and EPO was indicated by solid-state infrared and (13)C-T(1) measurements. Solution-state (1)H-NMR measurement demonstrated that MFA existed in monomolecular state in supersaturated solution. (1)H-T(1) and difference nuclear Overhauser effect measurements indicated that cross relaxation occurred between MFA and EPO due to the small distance between them. The formation and high stability of the supersaturated solution were attributable to the specifically formed intermolecular interactions between MFA and EPO.
    Pharmaceutical Research 01/2012; 29(10):2777-91. · 4.74 Impact Factor

Publication Stats

289 Citations
189.48 Total Impact Points


  • 2003–2014
    • Chiba University
      • Graduate School of Pharmaceutical Sciences
      Tiba, Chiba, Japan
  • 2012
    • Osaka University of Pharmaceutical Sciences
      Gihu, Gifu, Japan
    • Shionogi & Co., Ltd.
      Ōsaka, Ōsaka, Japan
  • 2009–2011
    • Josai University
      Saitama, Saitama, Japan
    • Daiichi Sankyo Company
      • Formulation Technology Research
      Tokyo, Tokyo-to, Japan
  • 2008
    • Astellas Pharmaceutical
      Northbrook, Illinois, Japan
    • Chugai pharmceutical
    • Mahidol University
      • Department of Manufacturing Pharmacy
      Bangkok, Bangkok, Thailand
  • 2004–2006
    • University of Yamanashi
      • • Faculty of Medicine
      • • Department of Pharmacy
      Kōhu, Yamanashi, Japan