東 顕二郎

Miconazole salts and cocrystals were studied to improve the physicochemical properties of miconazole. Maleate, hemifumarate, and hemisuccinate were prepared and characterized by powder X-ray diffractometry, differential scanning calorimetry, and single crystal X-ray diffractometry. The intrinsic dissolution rate and stability of each miconazole crystal form were compared to those of freebase and nitrate to evaluate the optimal crystal form. Crystal structure analysis indicated that maleate was a salt formed by proton transfer from the acid to the imidazole group of miconazole. Hemifumarate and hemisuccinate were determined to be cocrystals formed by hydrogen bonding between the acids and the base in their crystal lattices. Intrinsic dissolution tests showed that the formation of salts and cocrystals improved the dissolution rate of miconazole. Stability tests of preliminary formulations prepared with each crystal form indicated that maleate and hemifumarate were unstable at 80°C and generated a specific degraded product, i.e., a Michael adduct, between miconazole and the acids. Hemisuccinate had a superior intrinsic dissolution rate and stability, and is thus considered a promising crystal form of miconazole.

Effects of p-hydroxybenzoate (paraben) ester chain length on the stoichiometry and structure of grinding-induced inclusion complexes with cholic acid (CA) were investigated. Physicochemical properties of the ground mixture were evaluated by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) spectroscopy, and solid-state nuclear magnetic resonance (NMR) measurements. Ethyl-, n-propyl-, and isopropyl-parabens formed equimolar inclusion complexes with CA, and the complex structures were of the β-trans bilayer type. In contrast, the stoichiometry of the CA-paraben complex was 2:1, and the structure was of the α-gauche bilayer type when isobutylparaben was used as a guest molecule. Although the stoichiometries and structures of the complexes differed, solid-state NMR showed that the molecular states of parabens in the complexes were similar and independent of the ester chain length. Complexes between CA and parabens with longer substituent groups (C >4) were not observed. Steric effects induced by increasing the guest size are likely to influence the overall structure of inclusion complexes. Mechanical forces and thermal activation by grinding were important factors in the mechanism of CA-paraben complex formation.

α-Glucosylhesperidin (Hsp-G), a functional food additive, significantly enhances the solubility and bioavailability of poorly water-soluble drugs despite little surface activity. Herein, we present investigations into the underlying mechanism by nuclear magnetic resonance techniques. A concentration dependence of the chemical shift of Hsp-G protons correlated well with a mass-action law model, indicating self-association of Hsp-G molecules. The critical micelle concentration was 5.0 mg/mL (6.5 mM) at 37°C. The gradual rather than abrupt chemical shift variation upon Hsp-G aggregation would be different mode to conventional surfactants. Dynamic light scattering and two-dimensional nuclear Overhauser effect spectroscopy measurements demonstrated that Hsp-G molecules self-associated into particular small micelles, with the flavanone skeleton forming a hydrophobic core, and surrounding sugar groups working as a shell. The packing of the hydrophobic portion is not strictly oriented and the intermolecular arrangement of micelle shell is loose. Solubility enhancement was due to the incorporation of drugs into Hsp-G micelle, with naringenin being more soluble than flurbiprofen. This difference is possibly related to the structural similarities between the hydrophobic portion and the micelle core. Hsp-G micellization process with little loss of surface tension is a unique observation in surface and interface science.

A number of papers have reported that the large cavity of γ-CyD is favorable for inclusion of C(60) and forms a 1:2 (C(60):γ-CyD) complex, whereas it is thought to be difficult for β-CyD to form a complex at the molecular level. This is because the cavity size of β-CyD (0.78 nm) is smaller than the van der Waals diameter of C(60) (1.0 nm). In this paper, we will report on the formation of the stable C(60) nanoparticles by the hydrophilic 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) layer through weak interaction on the surface of the nanoparticles. C(60) was coground with β-CyD, γ-CyD or HP-β-CyD mainly in a 1:2 molar ratio by an automatic magnetic agitating mortar, the coground powders were dispersed in water, and the resulting solutions were filtered through a pore size of 0.8 μm filter. The γ-CyD and HP-β-CyD systems gave transparent colloidal solutions consisting of C(60)/CyD nanoparticles with the size lower than 100 nm, with high yields (about 100%). The C(60)/HP-β-CyD nanoparticles are physically stable, keeping a small size for more than 28 days, whereas the γ-CyD nanoparticles are readily aggregated to form large particles (>800 nm). Solid and liquid NMR spectroscopic studies including measurements of spin-lattice relaxation times indicated that C(60) interacted with γ-CyD and HP-β-CyD in the solid and colloidal solutions. When compared with the γ-CyD nanoparticles, adsorption studies of a hydrophobic dye on the surface of C(60)/CyD nanoparticles indicated that the surface of the HP-β-CyD nanoparticles is largely covered by HP-β-CyD molecules forming hydrophilic hydration layers. The present results suggest that HP-β-CyD is useful for the preparation of C(60) nanoparticles and medical applications such as photodynamic therapy, in spite of having a cavity size smaller than that of γ-CyD.

Effect of dicarboxylic acids : malonic acid (MA), succinic acid (SUA), and glutaric acid (GA), on the preferential cocrystal formation with carbamazepine (CBZ) was investigated. Stoichiometries of CBZ / MA, CBZ / SUA and CBZ / GA cocrystals formed were 2 / 1, 2 / 1 and 1 / 1. When CBZ / SUA ground mixture (GM) was coground with MA, CBZ / SUA cocrystal still remained, i.e., no exchange reaction occurred. On the other hand, exchange reaction occurred when CBZ / MA GM was coground with SUA. CBZ / SUA cocrystal was formed by ternary cogrinding of CBZ, MA and SUA. In CBZ, MA and GA system, preferential cocrystal formation was observed for CBZ / GA. The results of cryogenic cogrinding suggested that preferential CBZ / GA cocrystal formation was due to the stable and rapid crystallization. Preferential CBZ /GA cocrystal formation was assumed when CBZ, SUA and GA ternary cogrinding was performed. Structure and stability of cocrystal, mechanism of cocrystal formation and grinding energy affected the preferential cocrystal former exchange reactions.

The structure of a crystalline γ-cyclodextrin (γ-CD) ternary complex containing salicylic acid (SA) and flurbiprofen (FBP) prepared by sealed heating was investigated. FBP/γ-CD inclusion complex was prepared by coprecipitation; its molar ratio was determined as 1/1. Powder X-ray diffraction measurements showed that the molecular packing of γ-CD changed from hexagonal to monoclinic columnar form by sealed heating of SA with dried FBP/γ-CD inclusion complex, indicating ternary complex formation. The stoichiometry of SA/FBP/γ-CD was estimated as 2/1/1. Solid-state transformation of γ-CD molecular packing upon water vapor adsorption and desorption was irreversible for this ternary complex, in contrast to the reversible transition for the FBP/γ-CD inclusion complex. The ternary complex contained one FBP molecule in the cavity of γ-CD and two SA molecules in the intermolecular space between neighboring γ-CD column stacks. Infrared and (13) C solid-state NMR spectroscopies revealed that the molecular states of SA and FBP changed upon ternary complex formation. In the complex, dimer FBP molecules were sandwiched between two γ-CD molecules whereas each monomer SA molecule was present in the intermolecular space of γ-CD. Ternary complex formation was also observed for other drug-guest systems using naproxen and ketoprofen. Thus, the complex can be used to formulate variety of drugs.

Drug nanoparticle formulation using ascorbic acid derivatives and its therapeutic uses have recently been introduced. Hydrophilic ascorbic acid derivatives such as ascorbyl glycoside have been used not only as antioxidants but also as food and pharmaceutical excipients. In addition to drug solubilization, drug nanoparticle formation was observed using ascorbyl glycoside. Hydrophobic ascorbic acid derivatives such as ascorbyl mono- and di-n-alkyl fatty acid derivatives are used either as drugs or carrier components. Ascorbyl n-alkyl fatty acid derivatives have been formulated as antioxidants or anticancer drugs for nanoparticle formulations such as micelles, microemulsions, and liposomes. ASC-P vesicles called aspasomes are submicron-sized particles that can encapsulate hydrophilic drugs. Several transdermal and injectable formulations of ascorbyl n-alkyl fatty acid derivatives were used, including ascorbyl palmitate.

Fentanyl base and β-cyclodextrin (β-CD) were coground at 1:1 and 1:2 molar ratios (fentanyl: β-CD) and the physicochemical characteristics of the mixtures were studied using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), solid state (13)C nuclear magnetic resonance (NMR) spectroscopy and powder X-ray diffraction (PXRD) measurement. Additionally, portions of the coground samples were exposed to high relative humidity to investigate fentanyl and β-CD interactions. The results of DSC and PXRD analyses indicate that the ground mixtures are in an amorphous state, and the FTIR measurements show hydrogen bonding interactions between fentanyl and β-CD. Solid state (13)C NMR indicates that a fentanyl/β-CD inclusion compound is formed in the humidified mixture. Furthermore, PXRD data from the humidified mixtures are similar to the PXRD patterns from the inclusion complex.

A novel complex of salicylic acid (SA) and gamma-cyclodextrin (gamma-CD) was obtained via the sealed-heating method. The influence of the water content of gamma-CD on the complex formation with SA by sealed-heating process was investigated. Quantitative determination of SA revealed that sealed-heated samples of SA and gamma-CD with low water content (0.8-5.4%) formed the SA/gamma-CD = 2:1 complex, while the samples with high water content (8.5-11.5%) formed the SA/gamma-CD = 4:1 complex. The molecular arrangements of gamma-CD in 2:1 and 4:1 complexes were determined by powder X-ray diffraction measurements to be in monoclinic-columnar and tetragonal-columnar forms, respectively. The results of infrared spectroscopy and (13)C solid-state NMR measurements showed that two types of SA molecules resided in the 4:1 complex, whereas only one type of SA molecules existed in the 2:1 complex. The obtained 2:1 complex was assumed to contain two SA molecules per one gamma-CD, with the SA molecules existing in the intermolecular spaces formed by the gamma-CD columns. In the case of the 4:1 complex, two SA molecules were incorporated into the intermolecular spaces while the other two SA molecules were included within the gamma-CD cavity.

The effects of particle size on the skin permeation and retention of piroxicam (PXC) in an aqueous suspension were investigated. PXC particles of about 23 nm, 173 nm, and 2.1 microm in size were prepared by the cogrinding of PXC/polyvinylpyrrolidone (PVP) K12/sodium dodecyl sulfate physical mixture (mean particle size, 9.6 microm) using a vibrational rod and ball mills. Particles were stable after storage in 0.1 m acetate buffer (pH 4.5) for 24 h. The amount of PXC that permeated and was retained in hairless mouse skin increased with the reduction of particle size up to 23 nm. Amorphous PXC was formed when PXC was coground with PVP, though the amorphous formation did not affect the amount of PXC permeated. Reduction of particle size to less than 50 nm, and the subsequent increase in surface area of PXC nanocrystals appeared to affect skin permeation and retention behavior.

A crystalline ternary complex was prepared by sealed-heating of naproxen (NPX) with a flurbiprofen (FBP)/gamma-cyclodextrin (gamma-CD) inclusion complex. The dissolution rates of NPX and FBP in the ternary complex were almost the same, indicating that FBP and NPX from the complex dissolved simultaneously. The ternary CD complex showing a fascinating dissolution property could be a new formulation for combination therapies.

L-ascorbyl 2,6-dipalmitate (ASC-DP), a fatty ester derivative of ascorbic acid, is poorly soluble in water and does not spontaneously form micelles or liposomal structures in water. In this study, we attempted to prepare an ASC-DP/surfactant nano-sized complex as a carrier for hydrophobic drugs. Samples were prepared by hydrating a solvent-evaporated film of ASC-DP/surfactant at a molar ratio of 1:1. Among the surfactants tested, distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG) was found to form stable nanoparticles with ASC-DP (average particle size: ca. 67 nm). Several hydrophobic drugs were incorporated in the ASC-DP/DSPE-PEG nanoparticles. Stability, toxicity, and blood residence of the drug-containing ASC-DP/DSPE-PEG nanoparticles were evaluated using amphotericin B (AmB) as the model drug. By intravenously administering mice with the formulations, we determined the minimum lethal dose of Fungizone, a formulation of AmB solubilized with sodium deoxycholate, was 3.0 mg/kg, while that of AmB/ASC-DP/DSPE-PEG nanoparticles was 10.0 mg/kg. When 2.0 mg/kg, Fungizone was administered, the mice showed higher renal and hepatic toxicities. Intravenously administered AmB/ASC-DP/DSPE-PEG nanoparticles demonstrated higher concentration in plasma than Fungizone. Thus, the ASC-DP/DSPE-PEG nanoparticle system appears to be a promising delivery system for hydrophobic drugs.

Coloration of mefenamic acid (MFA) was investigated in the presence of mesoporous silica FSM-16 with 16.0 A (Oc) and 45.0 A (Doc) pore diameter. The color change of MFA/FSM-16 physical mixture from white to deep blue was observed by sealed-heating (SH) and the subsequent humidification (HU). The coloration and the color difference were caused by the changes of chroma and lightness. In the case of MFA/FSM-16 (Oc), coloration was not observed by SH treatment only. Powder X-ray diffraction data indicated that difference of the dispersed states of MFA molecules in FSM-16 mesopore affected the coloration. MFA adsorbed on the silica surface and MFA in the mesopore were differentiated by thermogravimetric analysis. Solid-state (13)C-NMR showed that the molecular mobility of MFA was increased in the dispersed state in FSM-16 mesopores compared to the crystalline state. Structural changes of silanol groups in FSM-16 by humidification were observed by solid-state (29)Si-NMR. MFA adsorption in FSM-16 mesopore by SH as well as changes of the surface state of FSM-16 by HU affected the coloration of MFA.

The purpose of this study was to elaborate the relationship between the (13)C CP/MAS NMR spectra and the recrystallization behavior during the storage of troglitazone solid dispersions. The solid dispersions were prepared by either the solvent method or by co-grinding. The recrystallization behavior under storage conditions at 40 degrees C/94% RH was evaluated by the Kolmogorov-Johnson-Mehl-Avrami (KJMA) equation. Solid dispersions prepared by the solvent method or by prolonged grinding brought about inhibition of the nucleation and the nuclei growth at the same time. No differences in the PXRD profiles were found in the samples prepared by the co-grinding and solvent methods, however, (13)C CP/MAS NMR showed significant differences in the spectra. The correlation coefficients using partial least square regression analysis between the PXRD profiles and the apparent nuclei-growth constant or induction period to nucleation were 0.1305 or 0.6350, respectively. In contrast, those between the (13)C CP/MAS NMR spectra and the constant or the period were 0.9916 or 0.9838, respectively. The (13)C CP/MAS NMR spectra had good correlation with the recrystallization kinetic parameters evaluated by the KJMA equation. Consequently, solid-state NMR was judged to be a useful tool for the prediction of the recrystallization behavior of solid dispersions.

To optimize the formulation of in-hospital sarpogrelate (SPG) preparation for external use, various cyclodextrins (CDs) were investigated for their ability to improve the aqueous solubility and chemical stability of SPG. Although hydrolysis of SPG was markedly accelerated at above pH 7.0 in aqueous solution, the addition of modified beta-CD resulted in suppressed SPG hydrolysis. Addition of sulfobutylether-beta-CD (SBE-beta-CD, Captisol had the most significant stabilization effect. Phase solubility diagram and (1)H-NMR analyses indicated that dimethyl-beta-CD and SBE-beta-CD formed significantly stable inclusion complexes with SPG in aqueous solution, thereby contributing to both the increased solubility and chemical stabilization of SPG. In terms of the clinical safety of CD derivatives, SBE-beta-CD was determined to be the most suitable solubilizing agent for external SPG preparation.

A novel ofloxacin-oxalic acid complex was prepared by the cogrinding method. The obtained complex was characterized by powder X-ray diffraction (PXRD), infrared (IR), solid-state nuclear magnetic resonance (NMR), and terahertz (THz) spectroscopy. The PXRD measurement revealed that the ofloxacin-oxalic acid complex induced by cogrinding was formed at a molar ratio of 1:2. Weak interaction between two components, not a hydrogen bonding, was found by IR and solid-state NMR spectroscopy. The distinctive THz spectrum showed that the vibrational modes of the complex were different from those of the starting materials, suggesting that THz spectroscopy is an alternative tool to evaluate complex formation through weak interactions.

Sealed-heating of salicylic acid (SA) and polyethylene glycol (PEG)/γ-cyclodextrin (CD)-polypseudorotaxane induced a novel complex formation wherein SA was inhabited in the intermolecular spaces formed by the γ-CD/polypseudorotaxane columns. Incorporation of SA into the PEG/γ-CD-polypseudorotaxane structure was clarified by powder X-ray diffraction measurements and 13C-solid-state NMR spectroscopy. Different water vapor adsorption and desorption behaviors between the novel complex and PEG/ γ-CD-polypseudorotaxane confirmed the incorporation of SA molecules into the intermolecular spaces in the complex. © 2009 American Chemical Society.

Prednisolone nanoparticles were prepared in the presence of a hydrophilic polymer and a surfactant by the aerosol solvent extraction system (ASES). A ternary mixture of prednisolone, polyethylene glycol (PEG), and sodium dodecyl sulfate (SDS) dissolved in methanol was sprayed through a nozzle into the reaction vessel filled with supercritical carbon dioxide. After the ASES process was repeated, precipitates of the ternary components were obtained by depressurizing the reaction vessel. When a methanolic solution of prednisolone/PEG 4000/SDS at a weight ratio of 1:6:2 was sprayed under the optimized ASES conditions, the mean particle size of prednisolone obtained after dispersing the precipitates in water was observed to be ca. 230 nm. Prednisolone nanoparticles were not obtained by the binary ASES process for prednisolone, in the presence of either PEG or SDS. Furthermore, ternary cryogenic cogrinding, as well as solvent evaporation, was not effective for the preparation of prednisolone nanoparticles. As the ASES process can be conducted under moderate temperature conditions, the ASES process that was applied to the ternary system appeared to be one of the most promising methods for the preparation of drug nanoparticles using the multicomponent system.

Modes of molecular interaction between prednisolone and mesoporous materials have been investigated by the technique of solid-state NMR. Folded sheet mesoporous material (FSM-16) was used as host material and prednisolone was used as guest molecule. A suspension of FSM-16 in prednisolone dichloromethane solution was evaporated to prepare the evaporated samples. (13)C NMR spectroscopy was used as well as powder X-ray diffractometry and differential scanning calorimetry. Crystalline behavior of prednisolone disappeared in the evaporated samples, indicating the monomolecular dispersion of prednisolone in FSM-16 matrices. NMR peak shifts and broadening could be attributed to the molecular interaction between the A ring of prednisolone and FSM-16. Thermal properties of prednisolone were investigated after heat treatment of the evaporated samples. The results indicated that the thermal stability of the dispersion made from FSM-16 of large pore size was superior to that from FSM-16 of small pore size. Hydrocortisone was used to compare the dispersion state with prednisolone. It was suggested that the double bond at the C-1 and C-2 positions of prednisolone might play an important role in the process of adsorption of prednisolone to FSM-16.

Nanoparticles of a poorly water-soluble drug, probucol, have been obtained by co-grinding with PVP and SDS. The purpose of this study was to investigate the effect of the alkyl chain length of sodium alkyl sulfates (CnS, n = 6, 8, 12, 16 and 18) on probucol nanoparticle formation. From the results of particle size determination and quantitative measurement of nanoparticle fraction of probucol by HPLC, it was found that the alkyl chain length of the sodium alkyl sulfate affected the probucol nanoparticle formation. The efficiency, based on the quantitative determination of nanoparticles, was in the order: C18S > C16S > C12S > C8S > C6S. Probucol nanoparticles of less than 800 nm were effectively produced (more than 95%) with the increase of the amount of surfactants. 13C solid-state NMR of co-ground mixtures showed a new peak originating from the probucol interaction with PVP together with the existence of probucol crystal peaks. Excess amounts of surfactants were expected to play an important role for stabilizing the probucol nanoparticles in the suspension via the electrostatic repulsive effect. © 2009 Elsevier B.V. All rights reserved.

The molecular status of a freeze-dried sample or a ground mixture of p-dimethylaminobenzonitrile (DMABN) with α-, β-, or γ-cyclodextrins (CDs) was examined using solid-state fluorescence measurements. A twisted intramolecular charge transfer (TICT) emission of DMABN crystals was shown at 475 nm. Emission peaks of freeze-dried samples were observed at 450, 380, and 393 nm in α-CD/DMABN, β-CD/DMABN, and γ-CD/DMABN systems, respectively. It was speculated that DMABN molecules existed as a twisted form in the cavity of α-CD, and as a plane structure in that of β-CD or γ-CD. On the other hand, fluorescence emission peaks of ground mixtures of DMABN with α-, β-, or γ-CD were observed at around 450 nm. When DMABN was ground together with microcrystalline cellulose, which cannot form an inclusion complex, only TICT emission was detected. These results suggest that the observed shift in the fluorescence peak could be due to inclusion phenomena. When the ground mixtures were crystallized under humid conditions, fluorescence emission peaks were observed at 450 nm in α-CD and of around 400 nm in β- and γ-CD systems. It is concluded that the conformation of the DMABN molecules in a crystalline CD/DMABN inclusion complex change depending on the size of the CD cavity.

Adsorption properties of 1- and 2-naphthoic acids (1- and 2-NPAs), model compounds of medicines that have naphthalene moiety such as naproxen, naphazoline, rifampicin etc., in the presence of folded sheets mesoporous materials (FSM-16) were investigated by solid-state fluorescence emission spectroscopy. The molecular states of NPAs adsorbed onto FSM-16 mesopores changed depending on the NPA concentration on the FSM-16 surface. The redshift of the fluorescence emission spectra was attributed to intermolecular overlapping of the naphthalene moieties of the NPA molecules. Results of differential scanning calorimetry indicated that 2-NPA was selectively adsorbed onto FSM-16(Oc). The maximal amounts of 1-NPA and 2-NPA adsorbed onto FSM-16(Oc), having a pore diameter of 16 Å, were estimated as 4.4% and 14.2%, respectively. In contrast, the maximal amounts of adsorbed NPAs onto FSM-16(Do), having a pore diameter of 21 Å, were almost the same, i.e., about 40%. The amount of 2-NPA adsorbed onto FSM-16(Oc) was significantly higher than that of 1-NPA; this shows that it is possible to selectively separate 1-NPA and 2-NPA by using FSM-16(Oc) as a mesoporous molecular sieve.

Morphology and surface states of colloidal probucol nanoparticles after dispersion of probucol/polyvinylpyrrolidone (PVP)/sodium dodecyl sulphate (SDS) ternary ground mixture into water were investigated by atomic force microscopy (AFM). The observed particles had core-shell structure, i.e. drug nanocrystals were covered with PVP and SDS complex. The AFM phase image and the force curve analyses indicated that probucol nanoparticles with PVP K17 showed layer structure, compared to those with PVPK12. The structural difference was explainable in terms of the molecular states of PVP-SDS complex on the particle surface. These findings support not only the mechanism of drug nanoparticle formation but also the in vivo absorption results with the almost same particle size of ca. 40 nm.

川崎病院は過疎地域医療を担っており，患者の多くは高齢者である．そこで，地域医療における高血圧，糖尿病患者を対象に，後発品に対する意識調査を行った． その緕果，30歳代～90歳代の103名より回答があった．このうち，薬剤費が経済約な負担であると回答した者は，約50％であった．また，64％の患者は薬剤費について医師に相談したことがなく，68％の患者が後発品を認知していないことがわかった． 続いて，院外薬局において糖尿病用薬，脂質異常症治療薬および血圧降下薬について一般名処方を行った患者84名を対象に，後発品に関する意識調査を行った． その結果，一般名処方を行った患者の50％が後発品への切り替えを希望した．一方，後発品への変更を希望しなかった患者は，後発品の有効性や安全性に疑問を抱いていることも明らかとなった． 以上のことから，高齢者に対する後発品の啓発活動においては，後発品の使用により患者の経済約負担を軽滅すること，また，後発品の有効性や安全性は先発品と同等であると説明することが重要であると考えられた．

PURPOSE: Effects of polyvinylpyrrolidone (PVP) molecular weight on the solid-state intermolecular interactions among probucol/PVP/sodium dodecyl sulfate (SDS) ternary ground mixtures (GM) and the formation of nanoparticles were investigated by solid-state NMR spectroscopy. MATERIALS AND METHODS: Ternary GMs of probucol were prepared with PVP (K12, K17, K30 or K90) and SDS at a weight ratio of 1:3:1 and were ground for 15, 30 and 60 min. Solid-state interactions were evaluated using powder X-ray diffraction (PXRD) and solid-state cross polarization/magic angle spinning (CP/MAS) (13)C NMR spectroscopy. A high resolution scanning electron microscopy (SEM) was employed to observe nanoparticles of probucol in the GM. RESULTS: The solid-state (13)C CP/MAS NMR results indicate that the low molecular weight PVP interacts with probucol and SDS more strongly than the high molecular weight PVP in the ternary GM. This finding was consistent with the result that smaller drug nanoparticles were obtained using low molecular weight of PVP. SEM images of probucol/PVP K12/SDS confirmed the presence of nanoparticles (15-25 nm) in the GM. CONCLUSIONS: Grinding-induced solid-state interactions among drug, PVP and SDS could be detected using solid state (13)C NMR. The interactions in both probucol-PVP and PVP-SDS should occur simultaneously to generate nanometer-sized particles of probucol.

Molecular states of salicylic acid (SA) in amylose complexes prepared by sealed-heating were investigated. The powder X-ray diffraction patterns revealed the possibility of the inclusion formation due to the structural change in amylose from a 6₁-helix, which designates six glucose units per helical turn, to a 7₁-helix and an 8₁-helix depending on the concentration of guest molecules. Carbon thirteen solid state cross-polarization and magic angle spinning NMR spectra showed that the molecular states of SA in the 7₁-helix and 8₁-helix amylose complexes were similar to those in β-cyclodextrin (CD) and γ-CD inclusion complexes, respectively. It was concluded that one SA molecule was included in the cavity of one unit of amylose helix for the 7₁-helix amylose complex and two SA molecules for the 8₁-helix amylose complex.