Effect of grinding on dehydration of crystal water of theophylline

The effect of grinding on the dehydration of crystal water of theophylline has been studied. It was observed that the water content of theophylline hydrate decreased with increased grinding time. As the grinding time proceeded, the results of differential scanning calorimetry (DSC) indicated that crystal water of ground theophylline hydrate dehydrated in three steps at ca. 58, 44, and 17 degrees C, respectively. Powder X-ray diffraction study revealed that the crystal lattice of theophylline monohydrate collapsed by grinding, and part of the theophylline molecules subsequently rearranged the collapsed lattice to form theophylline anhydrate. The result of Fourier transformed infrared spectroscopy demonstrated that the hydrogen bonds between crystal water molecules and theophylline molecules were weakened or destroyed to some extent by grinding. It was supposed that crystal water in the ground theophylline hydrate might exist at least in three molecular states of different hydrogen-bonding. From DSC study, it was suggested that the ruptured hydrogen bonds of water molecules in the ground theophylline hydrate were strengthened after storage under 96.5% relative humidity at 30 degrees C.     

Application of eudragit RS to thermo-sensitive drug delivery systems. I. Thermo-sensitive drug release from acetaminophen matrix tablets consisting of eudragit RS/PEG 400 blend polymers

In order to develop the polymer materials having temperature-sensitive and high biological safety, Eudragit RS-PO and polyethylene glycol 400 (PEG 400) blend polymers (EPG) were prepared. The EPGs that have the glass transition temperature (Tg) at around the body temperature were prepared by the addition of 5--13% PEG 400 to Eudragit RS. As glassy polymers are not in thermodynamic equilibrium below their Tg, the effects of isothermal aging on the T(g)s of Eudragit RS and EPG containing 10% PEG 400 (10% EPG) were also studied at various aging temperatures. The Tg values of Eudragit RS increased with the aging time and after 30 d of aging, they apparently reached constant values which markedly differed depending on the aging temperatures. On the other hand, the Tg values of 10% EPG were almost independent of the aging temperature and reached around 33 degrees C at 30 d after aging. The ability as thermo-sensitive polymer of EPG was evaluated by the dissolution test of the acetaminophen (AAP) matrix tablets prepared with EPG. The AAP release rate from the EPG matrix tablets slightly changed below the Tg of tablets, and then, it markedly increased above the Tg. Considering high biological safety of Eudragit RS and PEG 400, EPG might be available to develop the novel thermo-sensitive drug delivery systems.     

Preparation of agglomeration-free hematite particles coated with silica and their reduction behavior in hydrogen

To prepare silica-coated hematite particles without agglomeration, the effects of solid fraction, ion content in solution, and designed layer thickness on agglomeration and dispersion behavior after silica coating were examined. Since the ion concentration remained high in suspension after the hematite particles were prepared, these particles formed aggregates by the compression of an electric double layer on the hematite and silica layer produced a solid bridge between primary hematite particles. Silica bridge formation and agglomeration were almost completely prevented by decreasing the ion concentration and solid fraction of the hematite particles. Furthermore, the effects of the silica-layer thickness and structure on the reduction of hematite to iron under hydrogen gas flow and the iron core stability under air were discussed. When the solid fraction was low in suspension to prevent agglomeration during coating, a densely packed structure of nanoparticles formed by heterogeneous nucleation was observed on the silica-layer surface. Since this structure could not completely prevent oxide diffusion, the layer thickness was increased to 40 nm to obtain a stable iron core under air. Although a dense uniform layer was produced at a high solid fraction during coating, its thickness was reduced to 20 nm to completely reduce hematite to iron.     

Magnetostriction of a single crystal of nickel observed with an X-ray four-circle goniometer

We proposed a technique to observe magnetostrictive coefficients of a single crystal specimen with X-ray diffraction. An angle between a direction of crystallographic orientation and a direction of magnetic field could be estimated with two kinds of diffraction peaks which were found with an X-ray four-circle goniometer. The magnetostriction was measured by a shift of Bragg angle. This technique was suitable for a case to observe the magnetostrictive coefficient which varied as a function of the magnetic field direction. We applied the technique to a single crystal specimen of nickel and showed dependences of the magnetostriction on the magnetic field strength and its direction around an axis of easy magnetization at room temperature.     

A mycelium with polyelectrolyte complex-bunched hyphae: several important factors affecting on the fermentation performance at a very high cell density

We have reported in the previous paper (Colloids Surf. B (2006) in press) a marked increase in the rate of gluconic acid production at a very high cell concentration (40 g/l) of filamentous fungus (Aspergillus niger IFO 31012) which was immobilized with polyelectrolyte complex consisting of potassium poly(vinyl alcohol) sulfate and trimethylammonium glycol chitosan iodide [6-O-(2-hydroxyethyl)-2-(trimethylammonio)-chitosan iodide]. The present study was carried out to look at what factors play a crucial role in this enhancement. We measured viscosity of broth, mass-transfer coefficient (k(L)a) for oxygen and diffusion coefficient of glucose (substrate). It has become apparent that there is only a difference in the diffusion coefficient of glucose between the free and immobilized cells. Therefore, we believe that the diffusion limitation by substrates as a problem in submerged mycelial processes is improved by immobilization based on polyelectrolyte complexes.     

Evaluation of physicochemical properties on the blending process of pharmaceutical granules with magnesium stearate by thermal effusivity sensor

Magnesium Stearate (MgSt) is a widely used lubricant for preventing tablet compression trouble. It is known that the powder characteristic of MgSt is different among MgSts manufactured by different methods and conditions. These differences affect blending efficiency with pharmaceutical additives. The purpose of this study is to evaluate the physicochemical properties of MgSt by thermal effusivity sensor for in-process monitoring of powder blending. MgSts having different physicochemical properties and granulated sugar spheres were used for model excipients. V-blender was used for powder blending. Thermal effusivity values of each of the ingredients in the blend were measured using one of the sensors prior to placing the ingredient in the blender. The effect of magnesium stearate addition to uniform ingredients can be clearly identified using the sensors. Compared to effusivity data and powder density, effusivity data correlated with the powder characteristics of magnesium stearate. These results suggested that effusivity can be used for end point detection of blending process for various magnesium stearates with sugar sphere. When various magnesium stearates were added to the granule, required time for achieving homogeneous powder blend was different. Blending behavior would be affected by the physicochemical characters. Blend uniformity and blended states of granules containing magnesium stearate can be detected nondestructively without intricate sampling process. Thermal effusivity sensors are an efficient tool to monitor the real time blending behavior of pharmaceutical ingredients.     

LCST behavior of copolymers of N-isopropylacrylamide and N-isopropylmethacrylamide in water

The lower critical solution temperature (LCST) behavior of copolymers of N-isopropylacrylamide (NiPA) and N-isopropylmethacrylamide (NiPMA) in water was studied as a function of the copolymer composition, using a combination of turbidity measurements and differential scanning calorimetry (DSC). The copolymers were prepared by free radical polymerization using N,N-dimethylformamide as a solvent and α,α′-azobis(isobutyronitrile) as an initiator. The copolymer composition was determined by elemental analysis. It was found that the temperature (T _c) at which the copolymer undergoes a phase transition, i.e., LCST, increases linearly with increasing the mole fraction (f _m) of NiPMA in the copolymer, within the T _c range from 32?°C (at f _m?=?0; NiPA homopolymer) to 42?°C (at f _m?=?1; NiPMA homopolymer). Also found from heating DSC thermograms were the linear dependencies of the enthalpy (ΔH) and entropy (ΔS) changes at T _c upon f _m. However, the ΔH (5.5?kJ/unit-mol) at f _m?=?1 was slightly smaller than that (5.7?kJ/unit-mol) of poly(N-n-propylacrylamide) but considerably smaller than that (7.8?kJ/unit-mol) of poly(N-n-propylmethacrylamide). The same trend was observed in the f _m dependence of ΔS. These results were discussed in terms of the structural effects of the NiPMA monomer unit on the heat-induced phase transition in water of poly(NiPA-co-NiPMA)s. It was suggested that a strong interaction of water with the amide group in the NiPMA would raise the transition temperature, but a local dehydration which occurs around the isopropyl side chain would not lead to large changes in the enthalpy and entropy at T _c.     

Effective detection of peptides containing cysteine sulfonic acid using matrix-assisted laser desorption/ionization and laser desorption/ionization on porous silicon mass spectrometry

Cysteine sulfonic acid-containing peptides, being typical acidic peptides, exhibit low response in matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. In this study, matrix conditions and the effect of diammonium hydrogencitrate (DAHC) as additive were investigated for ionization of cysteine sulfonic acid-containing peptides in MALDI. A matrix-free ionization method, desorption/ionization on porous silicon (DIOS), was also utilized to evaluate the effect of DAHC. When equimolar three-component mixtures of peptides carrying free cysteine, cysteine sulfonic acid, and carbamidomethyl cysteine were measured by MALDI using a common matrix, alpha-cyano-4-hydroxycinnamic acid (CHCA), no signal corresponding to cysteine sulfonic acid-containing peptide could be observed in the mass spectrum. However, by addition of DAHC to CHCA, the peaks of cysteine sulfonic acid-containing peptides were successfully observed, as well as when using 2,4,6-trihydroxyacetophenone (THAP) and 2,6-dihydroxyacetophenone with DAHC. In the DIOS mass spectra of these analytes, the use of DAHC also enhanced the peak intensity of the cysteine sulfonic acid-containing peptides. On the basis of studies with these model peptides, tryptic digests of oxidized peroxiredoxin 6 were examined as a complex peptide mixture by MALDI and DIOS. In MALDI, the peaks of cysteine sulfonic acid-containing peptides were observed when using THAP/DAHC as the matrix, but this was not so with CHCA. In DIOS, the signal from cysteine sulfonic acid-containing peptides was suppressed; however, the use of DAHC significantly enhanced the signal intensity with an increase in the number of observed peptides and increased signal-to-noise ratio in the DIOS spectra. The results show that DAHC in the matrix or on the DIOS chip decreases discrimination and suppression effects in addition to suppressing alkali-adduct ions, which leads to a beneficial effect on protonation of peptides containing cysteine sulfonic acid.     

Novel approach to DPI carrier lactose with mechanofusion process with additives and evaluation by IGC

The effect of lactose carrier surface property on the inhalation profile of dry powder inhaler (DPI) was evaluated using a micronized drug (Compound A) by inverse gas chromatography (IGC). Mechanofusion with magnesium stearate (Mg-St) or sucrose stearate increased the fine particle fraction (FPF), considered to be due to decrease in the interaction between Compound A and the lactose carrier. The effect of Compound A concentration on FPF was smaller in mechanofusion-processed lactose compared to intact lactose, especially when processed with Mg-St. The relationship between the IGC parameters of the lactose and FPF was also investigated. FPF increased as both the dispersive component of the surface energy and acidity similarity between the lactose carriers and Compound A increased. Although further investigation is necessary, it could be suggested that acidity similarity decreases the interaction between Compound A and lactose, thus contributing to the increase in the FPF. In conclusion, (1) mechanofusion with Mg-St or sucrose stearate could be an effective method to improve FPF of a DPI drug formulation; (2) IGC would be a valuable method to investigate the interaction between a drug and the DPI carrier; and (3) a relationship between surface acidity and inhalation profile was suggested.     

Large-scale synthesis of 1,1,3,3,6-pentamethyl-1,3-disilaindan-5-ol via a CoBr2/Zn-catalyzed [2+2+2] cycloaddition reaction

1,1,3,3,6-Pentamethyl-1,3-disilaindan-5-ol (2) is a key intermediate in the synthesis of new sila-substituted gonadotropin releasing hormone receptor antagonists, such as 1. In order to produce sufficient quantities of 1 for pharmacological and toxicological evaluation, an efficient synthesis of 2 has been developed. (1,1,3,3,6-Pentamethyl-1,3-disilaindan-5-yl)methanal (11) was synthesized in a one-pot procedure. CoBr₂/Zn-catalyzed [2+2+2] cycloaddition of diyne 3 with the commercially available monoalkyne 15 was achieved through a slow addition of 3 and CoBr₂ to a mixture of 15 and zinc powder in refluxing acetonitrile, giving rise to 5-(diethoxymethyl)-1,1,3,3,6-pentamethyl-1,3-disilaindane (14). In-situ aqueous acidification yielded 11. Conversion to 2 was then achieved via a Baeyer-Villiger oxidation followed by hydrolysis under basic condition. This novel methodology is useful, not only for the rapid, large-scale synthesis of 2, but also for the synthesis and development of new sila-substituted drugs derived from 11.