Raman spectroscopy as a process analytical technology tool for the understanding and the quantitative in-line monitoring of the homogenization process of a pharmaceutical suspension

The aim of this study was to propose a Process Analytical Technology (PAT) strategy for the quantitative in-line monitoring of an aqueous pharmaceutical suspension using Raman spectroscopy. A screening design was used to study the significance of process variables (mixing speed and height of the stirrer in the reactor) and of formulation variables (concentration of the active pharmaceutical ingredient (API) ibuprofen and the viscosity enhancer (xanthan gum)) on the time required to homogenize an aqueous pharmaceutical model suspension as response variable. Ibuprofen concentration (10% and 15% (w/v)) and the height of stirrer (position 1 and 2) were discrete variables, whereas the viscosity enhancer (concentration range: 1-2 g L-1) and the mixing speed (700-1000 rpm) were continuous variables. Next, a multilevel full factorial design was applied to study the effect of the remaining significant variables upon the homogenization process and to establish the optimum conditions for the process. Interactions between these variables were investigated as well. During each design experiment, the conformity index (CI) method was used to monitor homogeneity of the suspension mixing system in real-time using Raman spectroscopy in combination with a fibre optical immersion probe. Finally, a principal component regression (PCR) model was developed and evaluated to perform quantitative real-time and in-line measurements of the API during the mixing process. The experimental design results showed that the suspension homogenization process is an irregular process, for which it is impossible to model the studied variables upon the measured response variable. However, applying the PCR model it is possible to predict in-line and real-time the concentration of the API in a suspension during a mixing process. In this study, it is shown that Raman spectroscopy is a suitable PAT tool for the control of the homogenization process of an aqueous suspension. Raman spectroscopy not only allowed real-time monitoring of the homogeneity of the suspension, but also helped (in combination with experimental design) to understand the process. Further, the technique allowed real-time and in-line quantification of the API during the mixing process.     

Formation of polymer - polymer complexes in the system poly(methacrylic acid) - hydroxyethylcellulose

An interpolymer complex was prepared by mixing aqueous solutions of poly(methacrylic acid) and hydroxyethylcellulose (molar substitution 2.5) and studied by using viscometric method. The hydrogen bonding is primarily involved in these complexations, but the hydrophobic interaction plays also an important role. The complex composition is not changing with the solvents used and is stable in the temperature range 25 °C - 65 °C.     

Use of a thermal lens microscope in integrated catecholamine determination on a microchip

A new method for determination for catecholamines (CA) utilizing microchip technology and a thermal lens microscope has been developed. Microchannels with a 250 microm x 10 microm cross section were used for mixing, reaction, and detection. Epinephrine (EP), nor-epinephrine (NE), dopamine (DA), and L-dopa (LD) were determined by using coloring oxidization to aminochromes by sodium metaperiodate. A thermal lens microscope (TLM) was used for detection of the product. The sensitivity of the system was comparable for the four CA and required only 15 s for mixing of sample and reagent. The calibration lines indicated excellent linearity for concentrations of 5-20 microg mL(-1). The relative standard deviations for 10 microg mL(-1) solution were 1.08, 2.18, 2.2, and 2.5% for EP, NE, DA, and LD, respectively. CA in pharmaceutical injections were also determined by use of the system and the results correlated very well with nominal values. Results obtained by use of the integrated system suggested there was a sufficient possibility to realize high-throughput medical diagnosis systems.     

Calorimetric study of melts in the System KF - K<Subscript>2</Subscript>NbF<Subscript>7</Subscript>

The relative enthalpies of melts in the system KF - K₂NbF₇ were measured by drop-calorimetry at the temperatures 1058, 1140 and 1208 K as a function of composition. Heat capacities of melted mixtures and enthalpies of mixing were determined using the experimental data. The molar heat capacity of melts diverges slightly from additivity. The molar enthalpy of mixing of melts shows small negative deviation from ideality which decreases with decreasing temperature. The thermal effect at mixing was assigned predominantly to association reactions producing more complex fluoroniobate anions.      

Phase equilibria of the ternary system vinyl acetate/(R,S)-1-phenylethanol/carbon dioxide at high pressure conditions

Phase equilibrium measurements, correlations and predictions are presented for the binary systems (R,S)-1-phenylethanol/CO₂ and vinyl acetate/CO₂ and for the ternary system vinyl acetate/(R,S)-1-phenylethanol/CO₂. Experiments for the ternary system were performed in the temperature range of 323–343 K and in the pressure range of 7–12 MPa, using a high pressure phase equilibrium apparatus with a high pressure visual variable volume cell. Phase compositions were determined by taking samples of each phase and analysing them by gas chromatography. Equilibrium data were correlated with the Peng–Robinson equation of state combined with the Mathias–Klotz–Prausnitz mixing rule. A good correlation of both phases behaviour was obtained with an average absolute deviation (AAD) of 6.80%. Predictions for the binary sub-systems and for the ternary system were performed using the Peng–Robinson and the Soave–Redlich–Kwong equation of state, with the predictive mixing rule MHV1.     

Gas phase spectroscopy of HNO3 in the region 2000-8500 cm(-1)

Spectra of gas phase HNO3 were collected in the region 2000-8500 cm(-1) using Fourier-transform infrared spectroscopy. This region is dominated by the nu1 O-H stretching mode but also contains many previously unreported combination bands and overtones. This work marks the first observation of Fermi resonance the 2nu1 O-H stretching overtone. Previously unobserved bands were assigned and integrated intensities were obtained. For bands already reported in the literature, comparisons of relative intensities are presented when possible. This work gives a brief discussion on the trends in overtone intensities and on mode mixing in HNO3 in relation to previous experimental and theoretical studies.     

Contribution to thermochemical studies of 0.8[xB_2O_3-(1-x)SiO_2]-0.2Na_2O glasses

Calorimetric measurements in 0.8[xB_2O_3-(1-x)SiO_2]-0.2Na_2O glasses and melts are performed in HF calorimetry at 298 K and lead borate calorimetry at 973 K,respectively.Mixing enthalpy is affected by both temperature and composition.At 298 K,the mixing enthalpies are slightly negative and components are miscible at that temperature in the whole composition range.At 973 K, the sign of the mixing enthalpies reflect the tendency to phase separation at silica-rich compositions,which is avoided for kinetic ...     

1-(4-甲氧基)苯甲酰基-3-(4,6-二甲基嘧啶-2-氨基)硫脲的晶体结构、 理论计算及生物活性

2-氨基-4,6-二甲基嘧啶与硫氰酸钾、4-甲氧基苯甲酰氯在乙酸乙酯中反应, 合成了1-(4-甲氧基)苯甲酰基-3-(4,6-二甲基嘧啶-2-氨基)硫脲, 并用X射线单晶衍射法测定其晶体结构, 晶体属单斜晶系, 空间群为P21/n, 晶胞参数为: a＝1.0134(4) nm, b＝1.3172(5) nm, c＝1.0988(4) nm, β＝91.671(8)°, V＝1.4661(9) nm3, Dc＝1.433 g/cm3, μ＝0.234 mm－1, F(000)＝664, Z＝4, R1＝0.0571, wR2＝0.1328. 运用Gaussian 03程序, 对标题化合物进行了HF/6-31＋g(d)和B3LYP/6-31＋g(d)水平的几何全优化和频率计算, 并对其成键情况及自然键轨道(NBO)进行了分析. 初步实验证明该化合物具有良好的生物活性.     

Millisecond kinetics on a microfluidic chip using nanoliters of reagents

This paper describes a microfluidic chip for performing kinetic measurements with better than millisecond resolution. Rapid kinetic measurements in microfluidic systems are complicated by two problems: mixing is slow and dispersion is large. These problems also complicate biochemical assays performed in microfluidic chips. We have recently shown (Song, H.; Tice, J. D.; Ismagilov, R. F. Angew. Chem., Int. Ed. 2003, 42, 768-772) how multiphase fluid flow in microchannels can be used to address both problems by transporting the reagents inside aqueous droplets (plugs) surrounded by an immiscible fluid. Here, this droplet-based microfluidic system was used to extract kinetic parameters of an enzymatic reaction. Rapid single-turnover kinetics of ribonuclease A (RNase A) was measured with better than millisecond resolution using sub-microliter volumes of solutions. To obtain the single-turnover rate constant (k = 1100 +/- 250 s(-1)), four new features for this microfluidics platform were demonstrated: (i) rapid on-chip dilution, (ii) multiple time range access, (iii) biocompatibility with RNase A, and (iv) explicit treatment of mixing for improving time resolution of the system. These features are discussed using kinetics of RNase A. From fluorescent images integrated for 2-4 s, each kinetic profile can be obtained using less than 150 nL of solutions of reagents because this system relies on chaotic advection inside moving droplets rather than on turbulence to achieve rapid mixing. Fabrication of these devices in PDMS is straightforward and no specialized equipment, except for a standard microscope with a CCD camera, is needed to run the experiments. This microfluidic platform could serve as an inexpensive and economical complement to stopped-flow methods for a broad range of time-resolved experiments and assays in chemistry and biochemistry.     

4-(Succinimido)-1-butane sulfonic acid as a Bronsted acid catalyst for synthesis of pyrano[4,3-b]pyran derivatives under solvent-free conditions

4-(Succinimido)-1-butane sulfonic acid as an efficient and reusable Bronsted acid catalyzed the synthesis of pyrano[4,3-b]pyran derivatives under solvent-free conditions.The catalyst can be prepared by mixing succinimide and 1,4-butanesultone that is more simple and safer than the preparation of succinimide sulfonic acid.This method has the advantages of high yield,clean reaction,simple methodology and short reaction time.The catalyst could be recycled without significant loss of activity.     

Solubilization of (+)-α-Pinene by Cyclodextrin/Surfactant Mixed Systems

The mixing effects of 6-O-α-D-glucosyl-β-cyclodextrin (G-β-CD) and surfactants on the solubilization of (+)-α-pinene (αP, a fragrance) in aqueous solution were studied using a head-space gas chromatography technique. The findings show that the mixing of G-β-CD and surfactant result in negative synergistic effects on the solubility of αP.     

Study on the production of a xylanolytic complex frompenicillium canescens 10-10c

We screened about a hundred microorganisms (including unidentified yeasts, fungi, and bacteria) for their ability to produce xylanolytic enzymes. About 40 of them were hemicellulolytic; among these, we selectedPenicillium canescens 10- 10c for detailed study because of its ability to produce an interesting enzymatic complex in quantity. The xylanase complex was cellulase-free, and had an optimal activity at pH 4.6–5.0 and 55–60?C on birchwood xylan. The best production was on soya meal and wheat straw; expression of the xylanase was repressed by glucose, xylose, and lactose. The optimization of culture medium and mode (fed-batch) enabled us to improve the production three to four times. The importance of the mixing conditions on the biomass and xylanase production is also reported.     

4-(Succinimido)-1-butane sulfonic acid as a Brönsted acid catalyst for synthesis of pyrano[4,3-b]pyran derivatives under solvent-free conditions

4-(Succinimido)-1-butane sulfonic acid as an efficient and reusable Brönsted acid catalyzed the synthesis of pyrano[4,3-b]pyran derivatives under solvent-free conditions. The catalyst can be prepared by mixing succinimide and 1,4-butanesultone that is more simple and safer than the preparation of succinimide sulfonic acid. This method has the advantages of high yield, clean reaction, simple methodology and short reaction time. The catalyst could be recycled without significant loss of activity.     

Numerical study of a novel induced-charge electrokinetic micro-mixer

A novel micro-mixer based on the induced-charge electrokinetic motion of an electrically conducting particle is proposed and numerically demonstrated in this paper. For most microfluidic applications, it is desired to mix different streams of solutions rapidly in a continuous flow mode. Therefore, in this work, we consider a mixing chamber containing an electrically conducting particle and the mixing chamber is located in the middle of a microchannel. Vortices are generated around the electrically conducting particle in an aqueous solution due to the interaction of the applied electric field and the induced surface charge on the particle. These vortices will enhance significantly the mixing of different solutions around the particle. The effectiveness of mixing the two streams entering the mixing chamber is numerically studied as functions of the applied electric field. Excellent mixing can be achieved in this system under two perpendicularly applied electric fields. The proposed micro-mixer is simple and easy to be fabricated for lab-on-a-chip applications.     

Calorimetric study of melts in the system KF - K2TaF7

Enthalpy increment measurements on melts in the system KF-K₂TaF₇ were carried out by drop calorimetry at temperatures between 298 K and 1063, 1103 and 1143 K for selected compositions. Heat capacities of the melted mixtures and enthalpies of mixing have been determined. Careful calorimetric experiments showed small but distinct non-ideality of the melt. The molar heat capacity of melt exhibits small positive divergence from additivity. The molar enthalpy of mixing shows negative deviation from ideality which decreases with increasing temperature. The thermal effect at mixing was assigned predominantly to association reactions producing more complex fluorotantalate anions. The formation of complex anions with lower coordination number of Ta may not be excluded.      

De novo designed contrasteric Diels-Alder reactions of 5-(2-oxazolynyl)-1,2,3,4,5-pentamethylcyclopentadiene

5-(2-Oxazolynyl)cyclopentadiene was designed on the basis of the orbital mixing rule to react with dienophiles with highly contrasteric manner in Diels-Alder reactions. The design was validated by the synthesis and reactions of the corresponding pentamethyl derivative, 5-(2-oxazolynyl)-1,2,3,4,5-pentamethylcyclopentadiene, to afford the products with the ratios of syn/anti=89-93/11-7.     

Microfluidic mixing using contactless dielectrophoresis

The first experimental evidence of mixing enhancement in a microfluidic system using contactless dielectrophoresis (cDEP) is presented in this work. Pressure-driven flow of deionized water containing 0.5?μm beads was mixed in various chamber geometries by imposing a dielectrophoresis (DEP) force on the beads. In cDEP the electrodes are not in direct contact with the fluid sample but are instead capacitively coupled to the mixing chamber through thin dielectric barriers, which eliminates many of the problems encountered with standard DEP. Four system designs with rectangular and circular mixing chambers were fabricated in PDMS. Mixing tests were conducted for flow rates from 0.005 to 1?mL/h subject to an alternating current signal range of 0-300?V at 100-600 kHz. When the time scales of the bulk fluid motion and the DEP motion were commensurate, rapid mixing was observed. The rectangular mixing chambers were found to be more efficient than the circular chambers. This approach shows potential for mixing low diffusivity biological samples, which is a very challenging problem in laminar flows at small scales.     

Catalytic Oxidation of the Side Chain of Alkylaromatics Using a Triphasic System

The triphasic system formed on mixing aqueous hypochlorite, bromide, a hydrocarbon and a phase transfer catalyst can be a remarkably powerful catalytic system for the side-chain-oxidation of alkylaromatics     

Quantifying Fluid Mixing with the Shannon Entropy

Summary: We introduce a methodology to quantify the quality of mixing in various systems, including polymeric ones, by adapting the Shannon information entropy. For illustrative purposes we use particle advection of two species in a two‐dimensional cavity flow. We compute the entropy by using the probability of finding a suitable chosen group/complex of particles of a given species, at a given location. By choosing the size of the group to be in direct proportion to the overall concentration of the components in the mixture we ensure that the entropic measure is maximized for the case of perfect mixing, that is, when at each location the component concentration is equal to the corresponding overall component concentrations. The scale of observation role in evaluating mixing is analyzed using the entropic methodology. We also illustrate the effect of initial conditions on mixing in a laminar system, typical in operations involving polymers.

     

Spectrophotometric determination of copper(II) at low mug l(-1) levels using cation-exchange microcolumn in flow-injection

A simple spectrophotometric flow-injection method is reported for the highly sensitive and fast determination of copper(II). The method is based on the formation of coloured Cu(II)-(4-methylpiperidinedithiocarbamate)(2) complex when the copper solutions are introduced into a tertiary reagent stream containing 4-methylpiperidinedithiocarbamate. The coloured complex is then selectively monitored at 435 nm. To increase interactions between copper(II) and colour forming reagent and preconcentrate of copper(II), a microcolumn containing strong cation exchange resins was placed between injection manifold and spectrophotometer. The system required no mixing chamber and allowed a sample throughput >60 sample h(-1). The calibration graph was linear in the range 5-100 mug l(-1). The detection limit was <0.5 mug l(-1) for 20 mul injection volume of copper(II) ion solution. The developed method was applied to environmental, copper processing water, and ore samples.