Biomedical subjects

Kohsaku Kawakami

Publications and source records attributed to Kohsaku Kawakami.

11 recordsLinked to original sources

PubMed2007

Reversibility of enantiotropically related polymorphic transformations from a practical viewpoint: thermal analysis of kinetically reversible/irreversible polymorphic transformations.

Although enantiotropically related polymorphic transitions are thermodynamically reversible with temperature and pressure, they may be observed as either reversible or irreversible in practical investigations. This behavior may be explained simply by a difference in the energy barrier for the transition. However, this difference may have a significant effect on strategy in formulation development. This article summarizes the characteristics of enantiotropic transitions with reference to the literature. Also provided are careful investigations of polymorphic transitions by thermal analysis, which is the most promising method to investigate transition behavior.

Calorimetry, Differential Scanning↗

PubMed2006

Solubilization behavior of a poorly soluble drug under combined use of surfactants and cosolvents.

The solubilization behavior of a poorly soluble model drug, phenytoin (PHT), under combined use of surfactants (sodium dodecyl sulfate (SDS), Tween 80) and cosolvents (dimethylacetoamide (DMA), ethanol, poly(ethylene glycol) 400 (PEG), glycerol) was examined. The solubility of PHT in the aqueous surfactant solutions increased linearly with increase of the surfactant concentration. The solubility of PHT in water-cosolvent mixtures roughly followed the log-linear model, which is widely accepted to explain the solubilization behavior of poorly soluble compounds in water-cosolvent mixtures, except for the case of glycerol, in which the solubility was minimal at 10% (w/v) of glycerol. When the cosolvents were added to the aqueous surfactant solutions, their effect on the solubility depended on the combination of the surfactant and the cosolvent. The most striking increase in solubility was observed with DMA, regardless of the type of surfactant. When ethanol was added, an increase in the solubility was observed with the Tween 80 solution, while a dramatic decrease was found with the SDS solution. The addition of glycerol or PEG to the surfactant solutions had only a minor impact on the solubility. These solubilization behaviors of PHT in the surfactant-cosolvent mixtures were partially explained by the solubility model introduced in our previous paper [Kawakami, K., Miyoshi, K., Ida, Y., 2004. Solubilization behavior of poorly soluble drugs with combined use of Gelucire 44/14 and cosolvent. J. Pharm. Sci. 93, 1471-1479]. Addition of the cosolvents to the surfactant solutions generally offered only a small advantage from the viewpoint of improving solubility because of the decrease in the solubilization capacity of the micelles.

Algorithms↗

PubMed2006

Crystallization of sucrose glass under ambient conditions: evaluation of crystallization rate and unusual melting behavior of resultant crystals.

Isothermal crystallization of sucrose glass under ambient condition was investigated by powder X-ray diffraction, isothermal microcalorimetry, and water sorption/desorption analysis. Isothermal microcalorimetry measurements showed that the crystallization behavior was affected by the compression force applied to starting amorphous materials. The crystallization rate was analyzed by X-ray diffraction measurements to establish that the rate could well be explained by the Avrami-Erofeev equation. In the water sorption/desorption analysis, the weight change during the crystallization was elucidated by supposing that desorption proceeded from the crystallized part. The sucrose crystallized at relatively low temperature conditions showed completely different melting behavior from that of intact sucrose, although the crystal form was most likely to be identical. This difference could be explained by defects in the lattice structure produced during the crystallization and the desorption process. Correlation was found between the melting temperature and the water content just before the crystallization. Defects in the crystal structure were partially modified by annealing as has been found in relaxation studies of amorphous materials.

Calorimetry, Differential Scanning↗

PubMed2005

Impact of the amount of excess solids on apparent solubility.

PURPOSE: The impact of excess solids on the apparent solubility is examined. METHODS: The apparent solubility of some model drugs was measured in various buffered solutions, with various amounts of excess solid. To help understand the dependence of the solubility on the amount of solid, we evaluated the dissolution and crystallization rates of indomethacin (IDM), one of the model drugs, at near-equilibrium conditions. RESULTS: In the case of IDM, the apparent solubility decreased with an increase in the solid amount at pH 5 and 6. On the other hand, it increased with an increase in the solid amount at pH 6.5 and 7. The crystallization and dissolution rates of IDM decreased and increased, respectively, with an increase in pH values, and became equal at between pH 6 and 7. Therefore, the apparent solubility was most likely to be affected by the balance between the crystallization and dissolution rates. The apparent solubility of other model drugs showed the same trend, although the dependency on the solid amount was not as significant as in the case of IDM. CONCLUSIONS: The apparent solubility was affected by the amount of solid for all the model drugs investigated. This was most likely to be caused by a competition between the crystallization and dissolution rates.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2005

Effect of salt type on hygroscopicity of a new cephalosporin S-3578.

PURPOSE: Effect of salt type on hygroscopicity was evaluated using S-3578 salts. METHODS: The hydration behavior of a sulfate and a nitrate salt of S-3578 were evaluated by powder X-ray diffraction (PXRD), simultaneous measurement of PXRD-differential scanning calorimetry (DSC), moisture sorption analysis, simultaneous measurement of thermogravimetric/differential thermal analyses, and solid state 13C-nuclear magnetic resonance (C-NMR). RESULTS: The sulfate salt incorporated two types of lattice water to form a monohydrate or a trihydrate. Additional water could also be absorbed as channel water to expand the lattice structure. The activation energy for dehydration was very high, probably due to steric hindrance in the lattice structure. The nitrate salt incorporated only one water molecule per compound as the lattice water. The additional water was absorbed as channel water as observed for the sulfate salt. X-ray diffractograms showed little dependence on the salt type under the ambient condition. The hydration number was likely to be affected by the size of the counter acids. CONCLUSIONS: The hygroscopicity of S-3578 salts was significantly altered by the salt type. The difference in the amount of the lattice water could be explained in terms of the difference in the molecular size of the counter acids.

Absorption↗

PubMed2005

Calorimetric investigation of the structural relaxation of amorphous materials: evaluating validity of the methodologies.

Although the potential advantages of the amorphous solid state is widely recognized among pharmaceutical researchers, its industrial applications have been mainly limited to freeze-dried injectable formulations where the amorphous form is naturally produced. Applications in oral dosage forms have been limited due, at least in part, to the poor state of knowledge regarding physical properties and stability of amorphous materials. Relaxation behavior is perhaps one of the most important physical characteristics of amorphous materials because relaxation kinetics are closely related to physical and chemical stability. Although recent developments in calorimetry methodology have facilitated detailed characterization of relaxation behavior, some experimental difficulties remain, and quantitative analysis of structural relaxation is still under development. This review focuses on the calorimetric investigation of the structural relaxation of drugs and excipients, and discusses the difficulties in the experimental evaluation of the relaxation time by those methods. We also present an original investigation of the impact of increases in relaxation time during an annealing experiment on the values of relaxation time, tau, and stretched exponential constant, beta, obtained from analysis of the experiment according to the Kohlraush-Williams-Watts kinetic model. Using results from a numerical simulation, we find that the values of tau and beta obtained from the data analysis are too large and too small, respectively, but the value of stretched relaxation time, tau(beta), remains reliable. The time dependence of the relaxation time is likely to play an important role in the non-Arrhenius behavior of pharmaceutical glasses.

Algorithms↗

PubMed2004

Solubilization behavior of poorly soluble drugs with combined use of Gelucire 44/14 and cosolvent.

Gelucire 44/14 is a surface-active excipient that can solubilize poorly soluble drugs. We investigated its solubilization behavior when coexisting with dimethylacetoamide (DMA) or dimethylsulfoxide (DMSO), both of which are also expected to enhance drug solubility. Gelucire was confirmed to form micelles by surface tension and fluorescence measurements both in water and water/cosolvent mixtures. Light-scattering measurements revealed that DMA and DMSO affect the micellar morphology in a different manner. DMA helped form large structures by being entrapped in the hydrophobic region of the micelles and/or inducing the aggregation. DMSO was likely to be anchored to the interfacial layer and did not induce micelle growth. Two model drugs, phenytoin and indomethacin, were employed to observe the solubilization behavior of poorly soluble drugs in Gelucire/cosolvent mixtures. The solubility of these drugs in the mixtures could be explained very well by using the new solubility model introduced in this article. Addition of cosolvents to the Gelucire solution did not enhance the solubility very much, and thus the combined use of cosolvents with Gelucire offered only little advantage from the viewpoint of solubility.

Chemistry, Pharmaceutical↗

PubMed2003

Direct observation of the enthalpy relaxation and the recovery processes of maltose-based amorphous formulation by isothermal microcalorimetry.

PURPOSE: The applicability of isothermal microcalorimetry (IMC) for evaluating enthalpy relaxation and recovery processes of amorphous material was assessed. METHODS: A maltose-based formulation was prepared by freeze-dry method. Differential scanning calorimetry (DSC) was used to investigate its glass transition and relaxation behaviors. IMC was applied to quantitatively analyze the relaxation and the recovery processes. The IMC data were analyzed using a derivative of the Kohlrausch-Williams-Watts equation. RESULTS: The glass transition temperature of the formulation and its fictive temperature stored at 15 degrees C for 1 year were 62 and 32 degrees C, respectively. DSC study showed that annealing below the fictive temperature increased the enthalpy recovery, but it was decreased by annealing at higher temperatures. IMC enabled direct observation of the heat flow during both the relaxation and the recovery processes. The decay constant for the recovery process (recovery time) was much smaller and less sensitive to the temperature than that for the relaxation process (relaxation time). CONCLUSIONS: IMC was successfully used to obtain quantitative information on both relaxation and recovery processes of amorphous material. The relaxation parameters obtained by this method could explain the thermodynamic behavior of the formulation.

Calorimetry↗

PubMed2002

Microemulsion formulation for enhanced absorption of poorly soluble drugs. I. Prescription design.

Microemulsion formulations, which can be used to improve the bioavailability of poorly soluble drugs, were designed using only pharmaceutical excipients. Several types of oils and surfactants were tested and it was found that propyleneglycol monoalkyl ester and glycerol monoalkyl ester were solubilized easily in an aqueous medium by various types of surfactants. Although propyleneglycol dialkyl ester was difficult to be solubilized, the solubility was significantly enhanced by mixing it with glycerol monoalkyl ester at the ratio of 1:1. The most suitable surfactants for preparing microemulsion formulations were HCO-40, HCO-60, Tween 80, BL-9EX and Pluronic P84. The use of additional surfactants such as sodium dodecyl sulfate or sodium deoxycholate significantly improved the solubilization capacity of the oils, although formulations free of these surfactants were also available. These microemulsion formulations can be administered as a form of water-in-oil microemulsion or surfactant-oil mixture, and are expected to convert to oil-in-water microemulsion in the small intestine.

Absorption↗

PubMed2002

Microemulsion formulation for enhanced absorption of poorly soluble drugs. II. In vivo study.

Oral administration study of microemulsion formulations, which are known to improve the bioavailability of poorly soluble drugs, was performed using rats. Nitrendipine was used as a poorly soluble model drug, and its absorption was enhanced significantly by employing the microemulsion formulations compared to a suspension or an oil solution. The effect of the fed state on the oral absorption of nitrendipine became insignificant with the microemulsion formulations, although it affected the absorption from the suspension formulation significantly. The absorption behavior also varied with the type of surfactant. The absorption from Tween 80-based formulation was very rapid, while HCO-60-based formulation showed prolonged plasma concentration profile. However, the absorption from BL-9EX (polyoxyethylene alkyl ether)-based formulation was hardly observed. Damage to the gastrointestinal mucosa, which seems to be a serious problem of surfactant-based formulations, also differed with the type of surfactant employed. HCO-60 and Tween 80-based formulations were mild to the organs, while BL-9EX-based formulation caused serious damage. The behavior and absorption mechanism of the microemulsion formulations are discussed.

Administration, Oral↗

PubMed2002

Assessment of amorphous content by microcalorimetry.

The amorphous content of model drugs was evaluated by isotherm microcalorimetry. Two model drugs were employed; lactose as a hydrophilic one and erythromycin as a hydrophobic one. When amorphous lactose was loaded in a sample cell with a water vial, a sharp exothermic peak due to the crystallization was observed. When a mixture of the amorphous and the crystalline forms was loaded, the peak area of the exothermic heat flow was proportional to the amorphous content. Quantification could be done with much higher accuracy than by the X-ray powder diffraction method reported in earlier literature. When erythromycin was used as a model drug, the crystallization was not completed by water but by organic solvents, which can dissolve erythromycin. The most adequate solvent for erythromycin was acetonitrile, of which the suitability was elucidated in terms of solubility and vapor pressure. This is the first report in which the role of the vapor pressure on crystallization behavior is discussed. The time needed to obtain the crystallization peak was controlled by mixing acetonitrile with water. The strategy to obtain the crystallization peak by microcalorimetry, which enables quantification of the amorphous content with high accuracy, is discussed.

Anti-Bacterial Agents↗