Preparation of rapidly disintegrating tablet using new types of microcrystalline cellulose (PH-M series) and low substituted-hydroxypropylcellulose or spherical sugar granules by direct compression method

To decrease the sensation of roughness when a tablet, which is rapidly disintegrated by saliva (rapidly disintegrating tablet), is orally taken, we prepared rapidly disintegrating tablets using microcrystalline cellulose (Avicel PH-M series), a new type of pharmaceutical excipient that is spherical and has a very small particle size (particle size, 7-32 microm), instead of conventional microcrystalline cellulose (PH-102) used in the formulation of tablets containing acetaminophen or ascorbic acid as model drugs for tableting study. Tablets (200 mg) prepared using spherical microcrystalline cellulose, PH-M-06, with the smallest particle size (mean value, 7 microm) had sufficient crushing tolerance (approximately, 8 kg) and were very rapidly, disintegrated (within 15 s) when the mixing ratio of PH-M-06 to low-substituted hydroxypropylcellulose (L-HPC) was 9:1. Sensory evaluation by volunteers showed that PH-M-06 was superior to PH-102 in terms of the feeling of roughness in the mouth. Consequently, it was found that particle size is an important factor for tablet preparation using microcrystalline cellulose. It is possible to prepare drugs such as acetaminophen and ascorbic acid (concentration of approximately 50%) in the tablet form using PH-NM-06 in combination with L-HPC as a good disintegrant at a low compression force (1-6 kN). To solve the problem of poor fluidity in the preparation of these tablets, we investigated the use of spherical sugar granules (Nonpareil, NP-101 (sucrose and starch, composition ratio of 7:3), NP-103 (purified sucrose), NP-107 (purified lactose) and NP-108 (purified D-mannitol)). Rapidly disintegrating tablets can be prepared by the direct compression method when suitable excipients such as fine microcrystalline cellulose (PH-M-06) and spherical sugar granules (NP) are used.     

Profiling analysis of oligosaccharides in antibody pharmaceuticals by capillary electrophoresis

Carbohydrate chains in glycoprotein pharmaceuticals have important roles for the expression of their biological activities. Therefore, development of an assessment method for the carbohydrate chains is an important parameter for quality control of glycoprotein pharmaceuticals such as newly developed therapeutic antibodies. In this report, we applied capillary electrophoresis with laser-induced fluorescence detection to the analysis of carbohydrate chains after releasing with glycoamidase followed by derivatization with 3-aminobenzoic acid. We found that four major oligosaccharides present in antibody pharmaceuticals were successfully separated with good resolution. The present method showed good precision in both migration times and relative peak areas, and gave comparable accuracy with that using a derivatization method with 8-aminopyrene-1,3,6-trisulfonate.     

Application of proton induced X-ray emission to the qualitative and quantitative analysis of iodine in biological samples

Particle-induced X-ray emission (PIXE) was applied to evaluate the loss of volatile elements such as iodine in biological samples. The analytical quality of the method is comparable or better than spectrophotometry, which is currently believed to be the most reliable for iodine determination. The temperature dependence of volatility loss of trace iodine was characteristic, and the feature was divided into three temperature regions. The first one, ranging from room temperature to 200 °C, showed only a slight loss below 20% on drying; the second stage, between 200 °C and 350 °C, where carbonizing processes became prominent, showed a remarkable loss up to 50%; the last one, beyond 350 °C, was accompanied by a considerable loss of iodine (more than 80%) with ashing. Even in the analysis using low temperature ashing with oxygen plasma, the loss of iodine observed was considerable (nearly 80%). The significance of these findings by PIXE in trace analysis is noted to improve analytical quality of volatile elements, such as iodine in biological, medical and also environmental fields.     

A new type of palladium(0) complex having both electron-withdrawing and -donating sites in a ligand: 5,8-dihydro- and 5,8,9,10-tetrahydro-1,4-naphthoquinone complexes

A new type of palladium(0) complex, (5,8-dihydro-1,4-naphthoquinone)Pd(PPh₃)₂ and (5,8,9,10-tetrahydro-1,4-naphthoquinone)Pd(PPh₃)₂, having both olefin and quinone or dihydro-quinone sites in a ligand molecule was prepared. IR and ¹H NMR spectroscopic studies of these complexes suggested that it is the quinone or dihydro-quinone CC bond which is complexed to Pd. Ligand exchange reactions showed that the stability order of the olefinic quinone complexes was as follows: (1,4-naphthoquinone)Pd(PPh₃)₂ > (5,8-dihydro-1,4-naphthoquinone) Pd(PPh₃)₂>(5,8,9,10-tetrahydro-1,4-naphthoquinone)Pd(PPh₃)₂.     

Preparation and characterization of carbonated barium-calcium hydroxyapatite solid solutions

Particles of carbonated barium-calcium hydroxyapatite solid solutions (BaCaHap) with different Ba/(Ba+Ca) (X(Ba)) atomic ratios were prepared by a wet method at 100 degrees C and characterized by various means. The crystal phases and structures of the products strongly depended on the composition of the starting solution, that is, the Ba/(Ba+Ca) atomic ratio ([X(Ba)]) and H3PO4 concentration ([H3PO4]) in the solution. BaCaHap with X(Ba)0.43 could be prepared at [X(Ba)]0.7 by changing [H3PO4], but could never be obtained at [X(Ba)]=0.8-0.95 regardless of [H3PO4]. The carbonated calcium hydroxyapatite particles prepared at [X(Ba)]=0 were fine and short rod-shaped particles (ca. 14x84 nm). With increasing [X(Ba)] from 0 to 0.8, the particles obtained became large spherical agglomerates. The carbonated barium hydroxyapatite particles formed at [X(Ba)]=1 were long rod-shaped agglomerates (ca. 0.2x2 microm) of fine primary particles. The amount of CO2 adsorbed irreversibly on a series of BaCaHaps showed a minimum at (Ba+Ca)/(P+C) atomic ratio of around 1.56, which agreed well with the minimum cation/P ratio obtained for the other hydroxyapatites, as already reported.     

Construction of optically active CF3-containing quaternary carbon centers via stereospecific S(N)2' reaction

[reaction: see text] Phosphates from 3-substituted 4,4,4-trifluorobut-2-en-1-ols were found to be effective for construction of CF3-containing quaternary carbon centers by way of Cu(I)-catalyzed Grignard reactions in the presence of catalytic amounts of CuCN and trimethylsilyl chloride (TMSCl) in an anti S(N)2' manner.     

Perfluoroalkylated eight- and nine-membered benzoheterocycles from F-2-methyl-2-pentene

The reactions of $\text{F}$-2-methyl-2-pentene (1) with several $\text{ortho}$- difunctional benzenes afforded eight- and nine-membered benzoheterocyclic compounds carrying perfluoroalkyl groups. Salicylic acid, salicylaldehyde, and their methyl or chloro derivatives reacted in triethylamine-acetonitrile system giving perfluoroalkylated 2H,6H-1,5-benzodioxocin-2,6-dione (8) and 4H,6H-1,5-benzodioxocin (9) compounds respectively, while phthalyl alcohol and o-hydroxyphenethyl alcohol in triethylamine-diethyl ether system gave perfluoroalkylated 1H,3H,7H-2,6- and 4H,6H,7H-1,5-benzodioxonin compounds, (10) and (11). o-Aminobenzyl alcohol and (1) in diethyl ether afforded a perfluoroalkylated benzoxazocinobenzoxazocinone compound (15).     

Continuous electrophoretic separation of106Ru species in sea water and uptake of the separated fractions by sea algae

¹⁰⁶Ru chloro and nitrosyl-nitrato complexes in sea water were separated into several species by continuous electrophoresis on a filter paper curtain. Biological uptake experiments were carried out on sea algae Fucus virsoides with fractionated¹⁰⁶Ru chloro and nitrosyl-nitrato complex species in sea water. The biological uptake of¹⁰⁶Ru chloro complex species was about 8 times higher than the uptake of¹⁰⁶Ru nitrosyl-nitrato species. Electrophoretically most mobile electrically positively charged cationic species in both systems also showed about 8 times higher biological uptake than the most mobile negatively charged anionic species. A close relation of the biological uptake to the sign of the electrical charge and the electrophoretic mobility of the species is demonstrated. The results are discussed with respect to possible danger to the biological environment as a consequence of the aging of ruthenium species in sea water resulting from¹⁰⁶Ru waste disposal to the sea from a nuclear reprocessing plant. On leave of absence from the National Institute of Radiological Sciences, 9-1, 4-chome, Anagawa, Chiba-shi, Japan, on a fellowship from The Science and Technology Agency of the Japanese Govemment.     

Asymmetric crystallization of bisguanidinobenzene derivatives

We show that the mono-N-methylated and -ethylated derivatives of the achiral compound bisguanidinobenzene undergo spontaneous asymmetric crystallization into a chiral form with chiral space group P2₁2₁2₁. The absolute configurations of the chiral crystals were determined by X-ray crystallography and correlated with circular dichroism (CD) spectra recorded in the solid state. The corresponding protonated and isopropylated derivatives, by contrast, afforded achiral crystals.