Kenjirou Higashi

Inhibitory Effect of Hydroxypropyl Methylcellulose Acetate Succinate on Drug Recrystallization from a Supersaturated Solution Assessed Using Nuclear Magnetic Resonance Measurements

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-1H 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.

Characterization and evaluation of miconazole salts and cocrystals for improved physicochemical properties.

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.

Physicochemical characterization and structural evaluation of a specific 2:1 cocrystal of naproxen-nicotinamide.

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.

Prediction of recrystallization behavior of troglitazone/polyvinylpyrrolidone solid dispersion by solid-state NMR

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.

Salicylic Acid/γ-Cydodextrin 2:1 and 4:1 Complex Formation by Sealed-Heating Method

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.

Nanoparticle formation from probucol/PVP/sodium alkyl sulfate co-ground mixture

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. (13)C 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.

Formation of stable hydrophilic C60 nanoparticles by 2-hydroxypropyl-β-cyclodextrin.

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.

Molecular states of prednisolone dispersed in folded sheet mesoporous silica (FSM-16).

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.

Effects of Cogrinding with β-Cyclodextrin on the Solid State Fentanyl

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.

Characterization of ofloxacin–oxalic acid complex by PXRD, NMR, and THz spectroscopy

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.