Tuning the Phytoglycogen Size and Aggregate Structure with Solvent Quality: Influence of Water-Ethanol Mixtures Revealed by X-ray and Light Scattering Techniques.

Phytoglycogen (PG) is a hyperbranched polysaccharide with promising properties for biomedical and pharmaceutical applications. Herein, we explore the size and structure of sweet corn PG nanoparticles and their aggregation in water-ethanol mixtures up to the ethanol mole fraction xEtOH = 0.364 in dilute concentrations using small-angle X-ray scattering (SAXS) and dynamic light scattering (DLS) measurements. Between 0 ≤ xEtOH ≤ 0.129, the conformation of PG contracts gradually decreasing up to ca. 80% in hydrodynamic volume, when measured shortly after ethanol addition. For equilibrated PG dispersions, SAXS suggests a lower PG volume decrease between 19 and 67% at the corresponding xEtOH range; however, the inflection point of the DLS volume contraction coincides with the onset of reduced colloidal stability observed with SAXS. Up to xEtOH = 0.201, the water-ethanol mixtures yield labile fractal and globular aggregates, as evidenced by their partial breakup under mild ultrasonic treatment, demonstrated by the decrease in their hydrodynamic size. Between 0.235 ≤ xEtOH ≤ 0.364, PG nanoparticles form larger, more cohesive globular aggregates that are less affected by ultrasonic shear forces.

Preparation and Spectroscopic Characterization of Inclusion Complexes of 3D Ball-Milled Rifampicin with ß-cyclodextrin and γ-cyclodextrin : 3D Ball-Milled Rifampicin with ß-cyclodextrin and γ-cyclodextrin.

Rifampicin (RFP) solutions, intended to reduce incidence of prosthetic graft infection, were prepared as three-dimensional ground mixtures (3DGMs) using ß-cyclodextrin (ßCD) and γ-cyclodextrin (γCD) and characterized for their spectroscopic properties and solubility. Phase solubility diagrams revealed that 3DGMs (RFP/ßCD and RFP/γCD) produced a complex at 1:1 molar ratio. Pulsed field gradient nuclear magnetic resonance experiments indicated that the diffusion coefficients for RFP/ßCD and RFP/γCD were similar to the respective diffusion coefficients for ßCD and γCD. Rotating-frame Overhauser effect spectroscopy NMR spectra revealed the existence of a new exchanger peak for RFP/γCD, suggesting an intermolecular interaction different from that of RFP/ßCD. Differential scanning calorimetry confirmed the presence of endothermic peak at 191 °C indicating the manifestation of RFP in the inclusion complex. Interestingly, molecular interactions from the complexes, RFP/ßCD and RFP/γCD, revealed different patterns of inclusion in the 3DGMs. In RFP/ßCD, nuclear Overhauser effect spectroscopy NMR spectra indicated cross peaks for the protons of the methyl group of RFP and the protons (H-5 and H-6) in the ßCD cavity. The methyl group of RFP interacted with the narrow rim of ßCD. With RFP/γCD, cross peaks were due to the protons of the methyl group of RFP and the protons of the cavity of γCD suggesting multiple inclusion patterns. The observed multiple cross peaks affirm the inclusion of RFP into the CD cavity which enhanced its solubility by 1.6-2.0-fold when prepared as 3DGMs as RFP/ßCD and RFP/γCD, respectively.

Inclusion Complexes of Daidzein with Cyclodextrin-Based Metal-Organic Framework-1 Enhance Its Solubility and Antioxidant Capacity.

Daidzein, an aglycone-type isoflavone, is useful in the prevention of atherosclerotic cardiovascular diseases. However, the solubility of daidzein remains relatively low even with pharmaceutical interventions (e.g., γ-cyclodextrin inclusion complex). In the present study, daidzein-cyclodextrin-metal organic framework solid dispersion complexes were prepared by the solvent evaporation method. The physicochemical properties of the complex and its effect on the solubility of daidzein were evaluated. The enhancement effect of a cyclodextrin-metal organic framework on the antioxidant properties of daidzein was verified using a diphenyl-picrylhydrazyl radical scavenging test. Powder X-ray diffraction results showed that the characteristic diffraction peaks of daidzein and cyclodextrin-metal organic framework disappeared and new peaks (2θ = 7.1°, 16.5°) were observed. FT-IR measurements showed that the peak derived from the carbonyl group of daidzein shifted to the lower wavenumber. NOESY 1H-1H NMR showed cross peaks at the proton on the resorcinol side of daidzein and the proton (H-5, H-6) in a cyclodextrin-metal organic framework. Dissolution rate of daidzein at 5 min in distilled water was 0.06% for daidzein alone while the daidzein inclusion complex was about 100%. When fasted state simulated intestinal fluid was used, the dissolution rate of the daidzein complex was about 71% compared with that of daidzein alone (~ 3.0%) at 5 min. The daidzein inclusion complex improved the antioxidant capacity to ~ 1.3 times (17.8 µg/mL) compared to the IC50 of daidzein alone (22.9 µg/mL). Preparations of cyclodextrin-metal organic framework inclusion complexes will be a platform in developing pharmaceutical formulations to enhance the bioavailability and activity of drugs.

Preparation and characterization of triamterene complex with ascorbic acid derivatives.

The purpose of this study was to prepare solid dispersions of triamterene (TRT) with ascorbic acid (AA) or ascorbic acid 2 glucoside (AA2G) and to evaluate their physical properties. Solid dispersions were prepared by dissolving each sample in an organic solvent and evaporation (EVP). Powder X-ray diffraction (PXRD) revealed a halo pattern for EVP1 (AA/TRT = 1/1) and EVP2 (AA2G/TRT = 1/1). In differential scanning calorimetry (DSC), endothermic peaks due to the melting of TRT and AA disappeared for EVP1 (AA/TRT = 1/1), and the melting peaks of TRT and AA2G disappeared for EVP2 (AA2G/TRT = 1/1). Fourier transform infrared (FT-IR) spectroscopy revealed broadened peaks for EVP1 (AA/TRT = 1/1) and EVP2 (AA2G/TRT = 1/1) due to the hydroxyl groups (-OH) of AA and the amino groups (-NH2) of TRT and also revealed a peak shift due to the pteridine skeleton (C = N) of TRT. In near-infrared absorption (NIR) spectroscopy, peaks due to the hydroxyl groups (-OH) of AA and AA2G were found for EVP1 (AA/TRT = 1/1) and EVP2 (AA2G/TRT = 1/1), respectively. A peak due to the amino groups (-NH2) was evident. This suggested the formation of an evaporation, in which TRT interacted with AA or AA2G. In the dissolution test, the dissolved fraction of TRT alone after 3 min was 30%, whereas the fractions were enhanced to approximately 90% for EVP1 (AA/TRT = 1/1) and EVP2 (AA2G/TRT= 1/1). Results confirmed that dissolution properties were improved as a result of complex formation. The above findings indicated improvement the dissolution properties of TRT.

Formulation study on retinoic acid gel composed of iota-carrageenan, polyethylene oxide and Emulgen® 408.

In the present study, all-trans retinoic acid (RA) gels formulated with various compositions of polyethylene oxide (Emulgen®) and iota-carrageenan (ι-CG) were prepared and their physicochemical properties were evaluated. The compression energy, which is the work required to compress the product through a fixed distance, increased with increasing amount of ι-CG or Emulgen®. The adhesion energy and displacement decreased with increasing amount of ι-CG or Emulgen® due to the progression of gel formation. From the results of the sensory tests, the properties of RA gels such as adhesiveness, gel strength and spreadability seemed to be adjustable depending on the condition of skin by varying the components of RA gels. Through photostability study, the expiration date and storage conditions of RA gels were determined as "4°C for 28 d with no exposure to light."

Molecular states of p-dimethylaminobenzonitrile coground with ß-cyclodextrin investigated using solid-state fluorescence spectroscopy.

Changes in molecular states of p-dimethylaminobenzonitrile (DMABN) coground with ß-cyclodextrin (ß-CD) were examined using solid-state fluorescence measurements. Formation of a DMABN/ß-CD inclusion complex by coprecipitation was confirmed by powder X-ray diffraction measurement. The powder X-ray diffraction pattern of the ground mixture was a halo pattern and differed from the pattern of the mixture prepared by coprecipitation. Solid-state fluorescence measurements revealed emission by DMABN crystals in a twisted intermolecular charge-transfer state at 473 nm. DMABN in the DMABN/ß-CD coprecipitate had a fluorescence emission peak at 393 nm due to its planar structure. In contrast, DMABN in a DMABN/ß-CD ground mixture had an emission peak at 473 nm due to its twisted structure. Grinding time-dependent structural changes in DMABN were evaluated using fluorescence lifetime and relative quantum yield measurements. Structural changes in DMABN in the DMABN/ß-CD coprecipitate from a planar to a twisted structure were observed with grinding. DMABN, dispersed in microcrystalline cellulose (CC) molecules in a DMABN/CC ground mixture, had a fluorescence emission peak at 473 nm. However, the excitation spectrum of a DMABN/ß-CD ground mixture differed from that of DMABN in CC. These results indicated that the molecular state of DMABN accommodated in the ß-CD cavity differs between the coprecipitate and the ground mixture.

Development of sarpogrelate external preparation for intractable pain control. I. Pre-formulation study on application of modified beta-cyclodextrins.

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.

[Solid states fluorescence study of p-dimethylaminobenzonitrile by co-grinding with cyclodextrins].

The molecular status of a freeze-dried sample or a ground mixture of p-dimethylaminobenzonitrile (DMABN) with alpha-, beta-, or gamma-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 alpha-CD/DMABN, beta-CD/DMABN, and gamma-CD/DMABN systems, respectively. It was speculated that DMABN molecules existed as a twisted form in the cavity of alpha-CD, and as a plane structure in that of beta-CD or gamma-CD. On the other hand, fluorescence emission peaks of ground mixtures of DMABN with alpha-, beta-, or gamma-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 alpha-CD and of around 400 nm in beta- and gamma-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.

[Participation of pharmacist CRC in practical on-site training--a survey by questionnaires for pharmacy students].

In order to estimate the 4th grade-students' knowledge regarding clinical trials, we carried out the questionnaire survey to the students being about to take practice in hospitals, and could collect answers from 163 students. This survey revealed that about 25% of the students could not draw the difference between "clinical trial" and "clinical research". As for the question about the technical terms regarding the clinical trial, clear correlation between students' learning experience and their knowledge was suggested. Furthermore, over 46% of the students answered that the pharmacists acting as clinical research coordinator (CRC) could not recruit new subjects, and ca. 40% of the students answered that the pharmacists acting as CRC could prescribe new drug. These misunderstandings seemed to result in the fact that most of the students could not have any chance to actually watch CRC's work related to the university curriculum. Based on the findings described above, sharing the information on the clinical trial between hospitals and universities seemed to be required to deepen students' understanding.

Photochemically stabilized formulation of dacarbazine with reduced production of algogenic photodegradants.

The present study aimed to develop a photochemically stabilized formulation of dacarbazine [5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide; DTIC] for reducing the production of algogenic photodegradant (5-diazoimidazole-4-carboxamide; Diazo-IC). Photochemical properties of DTIC were characterized by UV-visible light spectral analysis, reactive oxygen species (ROS) assay, and photostability testing. A pharmacokinetic study was conducted after intravenous administration of DTIC formulations (1 mg-DTIC/kg) to rats. DTIC exhibited strong absorption in the UVA range, and photoirradiated DTIC exhibited marked ROS generation. Thus, DTIC had high photoreactive potential. After exposure of DTIC (1 mM) to simulated sunlight (250 W/m2) for 3 min, remaining DTIC and yielded Diazo-IC were estimated to be ca. 230 µM and 600 µM, respectively. The addition of radical scavenger (1 mM), including l-ascorbic acid, l-cysteine (Cys), l-histidine, D-mannitol, l-tryptophan, or l-tyrosine, to DTIC (1 mM) could attenuate DTIC photoreactions, and in particular, the addition of Cys to DTIC brought ca. 34% and 86% inhibition of DTIC photodegradation and Diazo-IC photogeneration, respectively. There were no significant differences in the calculated pharmacokinetic parameters of DTIC between DTIC and DTIC with Cys (0.67 mg/kg). From these findings, the supplementary use of Cys would be an effective approach to improve the photostability of DTIC with less production of Diazo-IC.

[Evidence-based quality management of clinical formulations: determination of expiration date of powdered medicine prepared by grinding tablets].

Beraprost sodium (BPS) is often used for pediatric patients with pulmonary hypertension. The purpose of this study was to determine the expiration date of the powdered medicine prepared by grinding tablets. In the present study, the hygroscopicity and stability of the beraprost tablet (DORNER tablet), ground Dorner tablet and powder formulation (Dorner powder) consisting of the ground DORNER tablet and lactose (EFC lactose) were investigated after storage at various relative humidities (RHs) and light exposures. While the DORNER tablets and ground DORNER tablets were found to adsorb significant amounts of water vapor at an RHs of greater than 51.0%, Dorner powder scarcely adsorbed water. The stability of BPS in the Dorner powder decreased after storage under 3000 lux for 90 days. From these results, the expiration date and storage conditions of Dorner powder were determined to "90 days without exposure to light." We also investigated the stability of BPS in solutions of various pH values on the assumption that Dorner powder may be given to pediatric patients after dissolving in soft drinks. Because BPS degraded significantly below pH 2, pharmacists should alert patients not to take Dorner powder with acidic soft drinks.

Photochemical Mechanism of Riboflavin-Induced Degradation of Famotidine and a Suggested Pharmaceutical Strategy for Improving Photostability.

The present study aimed to clarify the mechanism of photodegradation of famotidine with riboflavin (FMT/RF), and to develop a photochemically stabilized formulation of FMT/RF. Photochemical properties of RF were characterized by UV-VIS spectral analysis, reactive oxygen species (ROS) assay, and photostability testing. Pharmacokinetic study was conducted in rats after intravenous administration of FMT (1 mg/kg) formulation containing RF (0.01 mg/kg). The UV-VIS spectral pattern of RF partly overlapped with the sunlight spectrum, and ROS generation from photoirradiated RF was remarkable; thus, RF had high photoreactive potential. In the photostability testing, after irradiation (250 W/m(2)), degradation rate for FMT in FMT/RF was ca. 11-fold higher than that in FMT alone. The addition of radical scavengers to FMT/RF led to attenuated photodegradation of FMT/RF; in particular, the addition of L-ascorbic acid (vitamin C; VC) to FMT/RF showed ca. 86% inhibition of the photodegradation of FMT/RF. The pharmacokinetic study on FMT indicated that the addition of VC (1 mg/kg) to FMT/RF had no significant impact on the pharmacokinetic behavior of FMT. These findings suggest that ROS-mediated photochemical reaction would be involved in the photodegradation pathway of FMT/RF, and the complementary use of VC might be an attractive approach to improve the photostability of FMT/RF.

Influence of dehydration temperature on water vapor adsorption, dissolution behavior and surface property of ampicillin.

Several specimens of anhydrous ampicillin were prepared by heating the ampicillin trihydrate at 100, 120, 140 and 160 degrees C. The effects of dehydration temperature on water vapor adsorption, dissolution behavior and surface property were investigated. The water vapor adsorption of anhydrous ampicillin was studied at 89% relative humidity, 40 degrees C and the water vapor adsorption rate was found to decrease with increase of dehydration temperature. Dissolution profiles of the various anhydrous specimens were investigated in 96% ethanol at 35 degrees C by the static disk method. The anhydrous form prepared at higher dehydration temperature exhibited faster dissolution rate. Solid phase transformation from the anhydrous form to the trihydrate form occurred during the dissolution test. The rate of phase transformation during the dissolution test decreased with increasing dehydration temperature. Topographic difference of the anhydrous forms prepared at 100 and 160 degrees C was not observed by scanning electron microscopy (SEM) and atomic force microscopy (AFM); however, difference of the microstructural properties was apparently observed by the AFM phase image. Surface free energy study revealed that when ampicillin was dehydrated at high temperature, the sample surface became more hydrophobic resulting in less interaction force with water and slow water sorption rate. From the results, we concluded that the polarity of sample surface induced by dehydration of ampicillin would affect the phase transformation and dissolution behavior.

Rapid adsorption and entrapment of benzoic acid molecules onto mesoporous silica (FSM-16).

Changes in the molecular state of benzoic acid (BA) in the presence of folded sheet mesoporous material (FSM-16), which has uniformly sized cylindrical mesopores and a large surface area, were assessed with several analyses. When BA was blended with FSM-16 for 5 min (BA content=30%), the X-ray diffraction peaks of BA crystals disappeared, suggesting an amorphous state. Fluorescence analysis of the mixture showed a new fluorescence emission peak for BA at 386 nm after mixing with FSM-16. Fluorescence lifetime analysis of the BA component in the mixture at 386 nm showed a longer lifetime in comparison with that of BA crystals. The solid-state (13)C CP/MAS and PST/MAS NMR spectra of the mixture with FSM-16 showed a significantly different spectral pattern from the mixture with nonporous glass, whose NMR spectra were identical to those of BA crystals. These results indicate that BA molecules disperse quickly into the hexagonal channels of FSM-16 by a simple blending procedure and adsorbed BA molecules had clearly different physicochemical properties to BA crystals.

Formation of fine drug particle by cogrinding with cyclodextrins. Part II. The influence of moisture condition during cogrinding process on fine particle formation.

The purpose of this study was to investigate the effect of moisture condition during cogrinding process on fine drug particle formation. Cogrinding of cyclodextrins (CDs) and pranlukast (PRK) hemihydrate was performed in various moisture conditions at a mixing molar ratio of 2:1 (CDs:PRK) and the formation of PRK submicron particle was investigated. The moisture content in the cogrinding process significantly affected the fine particle formation. More than 90% of pranlukast loaded transformed to submicron particles when coground with alpha-CD, beta-CD or gamma-CD containing the specific amount of water for each CD system. Fine particle formation of PRK was considered as a particular phenomenon to cyclodextrins, since the submicron particles could not be formed when D-mannitol, lactose or microcrystalline cellulose (MCC) was used as a cogrinding additive. Moreover, the appearance and disappearance of fine particle formation was found to be reversible depending on the existence of water during the grinding process.

Supercritical carbon dioxide treatment as a method for polymorph preparation of deoxycholic acid.

A new polymorph of deoxycholic acid (DCA) was formed by using a supercritical carbon dioxide treatment. Deoxycholic acid crystals were stored in a pressure vessel purged with carbon dioxide at 12MPa, 60 degrees C for definite intervals. After storage for 1h in supercritical carbon dioxide (SC-CO2), new X-ray diffraction (XRD) peaks, not found in the bulk DCA crystal, were observed at 2theta = 7.4 degrees, 9.7 degrees and 14.0 degrees. The intensities of the new diffraction peaks increased with an increase in storage time, whereas the intensities of the diffraction peaks due to bulk DCA crystal decreased. On the DSC curves, the crystals obtained showed an exothermic peak at around 155 degrees C followed by the melting peak of bulk DCA crystal at 175 degrees C. By the temperature-controlled powder XRD measurement, the crystals obtained were found to be a metastable form of DCA. The polymorphs of DCA have not been reported; therefore, the SC-CO2 treatment would be a peculiar method to obtain a DCA polymorph.

Effects of dehydration temperature on water vapor adsorption and dissolution behavior of carbamazepine.

Anhydrous carbamazepine was prepared by heating carbamazepine dihydrate at 60, 80, 100, 120, and 140 degrees C and used to investigate the effects of dehydration temperature on water vapor adsorption and dissolution behavior. The hydration rate of anhydrous carbamazepine at 75, 83, and 95% relative humidity and 25 degrees C decreased with increasing heating temperature. From the dissolution study by the rotating disk method, the calculated solubility of anhydrous carbamazepine was about 2.5 times higher than that of the dihydrate. The rate of phase transformation from the anhydrous form into the dihydrate during the dissolution process decreased with an increase in sample preparation temperature. These phenomena were further studied by thermal analysis, specific surface area measurement, density measurement, small-angle X-ray scattering, and wide-angle powder X-ray diffraction. As the heating temperature was raised, the specific surface area was reduced and the density was increased; furthermore, the average of the solid part calculated by the Debye method with small-angle X-ray scattering increased. The anhydrous carbamazepine prepared at lower heating temperatures was found to have a more porous structure and was seen by wide-angle powder X-ray diffraction to comprise both anhydrous forms I and II.

Differentiated thermal crystallization from amorphous chenodeoxycholic acid between the ground specimens derived from the polymorphs.

Crystallization behavior of amorphous chenodeoxycholic acid (CDCA) was studied using X-ray diffraction (XRD), infrared (IR) spectroscopy and differential scanning calorimetry (DSC). The two polymorphs of CDCA, form I (mp 166 degrees C) and form III (mp 119 degrees C), were ground with a vibrational mill. The ground samples of both crystal forms showed halo X-ray diffraction patterns. DSC curves of the amorphous samples derived from the form I and form III showed exothermic peaks due to the crystallization to the form I at 120 and 147 degrees C, respectively. When the ground form III was mixed with the ground form I, the crystallization temperature shifted to a lower temperature as the content of the ground form I increased. In the case of co-ground sample of form I and form III, the crystallization to form I crystals proceeded by two different modes. These results indicate that the physicochemical state was different among the ground samples of the form I and form III, and that the crystal nuclei played an important role on the crystallization process of the amorphous CDCA.

Investigation of the release behavior of diethylhexyl phthalate from polyvinyl chloride tubing for intravenous administration based on HCO60.

The release behavior of diethylhexyl phthalate (DEHP) from polyvinyl chloride (PVC) tubing, which composes materials in an intravenous administration set (IAS), was investigated using polyoxyethylated hydrogenated castor oil (HCO60) in physiological saline (PS), distilled water for injection (DWI), and ribose, fructose, and glucose (TZ) solutions. The amount of DEHP released increased with increasing HCO60 concentration, and the cumulative amount of DEHP released after 4h increased in the following order: 50% TZ

Modification of physicochemical and mechanical properties of shellac by partial hydrolysis.

The shellac was modified by partial hydrolysis with 2.0% (w/w) NaOH for different times. The hydrolysed shellac was then evaluated for physicochemical and film properties in comparison with native shellac. The tablets coated with native and hydrolysed shellac were also evaluated. The results demonstrated that acid value (AV) of shellac increased with prolongation of hydrolysis time. The solubility of shellac in buffer solution (pH < or = 7) gradually increased with increasing hydrolysis time. The films prepared from hydrolysed shellac were more flexible and soft than those prepared from native shellac. The increasing of flexibility was correlated with the increasing of soft resin in shellac. The water vapor permeability of hydrolysed shellac film was lower than that of native shellac film. The higher acid permeability of the tablet coated with hydrolysed shellac was observed. In ethanol-based film coating, shellac had lower solubility and thus lower drug dissolution from coated tablets was observed. In ammonia-based film coating, the solubility of shellac was improved higher nearby pH 7.0 by an ammonium neutralisation method because of forming well-soluble salts, thereby higher drug dissolution was obtained. Partial hydrolysis provided modified shellac, which is more effective for ammonium salt formation, thus very higher drug dissolution was achieved in the ammonia-based coated tablets.