Continuous flow synthesis of a pharmaceutical intermediate: a computational fluid dynamics approach.

Continuous flow chemistry has the potential to greatly improve efficiency in the synthesis of active pharmaceutical ingredients (APIs); however, the optimization of these processes can be complicated by a large number of variables affecting reaction success. In this work, a screening design of experiments was used to compare computational fluid dynamics (CFD) simulations with experimental results. CFD simulations and experimental results both identified the reactor residence time and reactor temperature as the most significant factors affecting product yield for this reaction within the studied design space. A point-to-point comparison of the results showed absolute differences in product yield as low as 2.4% yield at low residence times and up to 19.1% yield at high residence times with strong correlation between predicted and experimental percent yields. CFD was found to underestimate the product yields at low residence times and overestimate at higher residence times. The correlation in predicted product yield and the agreement in identifying significant factors in reaction performance reveals the utility of CFD as a valuable tool in the design of continuous flow tube reactors with significantly reduced experimentation.

Real-time understanding of lignocellulosic bioethanol fermentation by Raman spectroscopy.

BACKGROUND: A substantial barrier to commercialization of lignocellulosic ethanol production is a lack of process specific sensors and associated control strategies that are essential for economic viability. Current sensors and analytical techniques require lengthy offline analysis or are easily fouled in situ. Raman spectroscopy has the potential to continuously monitor fermentation reactants and products, maximizing efficiency and allowing for improved process control. RESULTS: In this paper we show that glucose and ethanol in a lignocellulosic fermentation can be accurately monitored by a 785 nm Raman spectroscopy instrument and novel immersion probe, even in the presence of an elevated background thought to be caused by lignin-derived compounds. Chemometric techniques were used to reduce the background before generating calibration models for glucose and ethanol concentration. The models show very good correlation between the real-time Raman spectra and the offline HPLC validation. CONCLUSIONS: Our results show that the changing ethanol and glucose concentrations during lignocellulosic fermentation processes can be monitored in real-time, allowing for optimization and control of large scale bioconversion processes.

Oxygen gas sensing by luminescence quenching in crystals of Cu(xantphos)(phen)+ complexes.

We have shown that crystals of the highly emissive copper(I) compounds [Cu(POP)(dmp)]tfpb, [Cu(xantphos)(dmp)]tfpb, [Cu(xantphos)(dipp)]tfpb, and [Cu(xantphos)(dipp)]pftpb, (where POP = bis[2-(diphenylphosphino)phenyl]ether; xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; dmp = 2,9-dimethyl-1,10-phenanthroline; dipp = 2,9-diisopropyl-1,10-phenanthroline (dipp); tfpb(-) = tetrakis(bis-3,5-trifluoromethylphenylborate); and pftpb = tetrakis(pentfluorophenyl)borate) are oxygen gas sensors. The sensing ability correlates with the amount of void space calculated from the crystal structures. The compounds exhibit linear Stern-Volmer plots with reproducible K(SV) constants from sample to sample; these results reinforce the observations that the sensing materials are crystalline and the sensing sites are homogeneous within the crystals. The long lifetime (∼30 µs), high emission quantum yield (ϕ = 0.66), appreciable K(SV) value (5.65), and very rapid response time (51 ms for the 95% return constant) for [Cu(xantphos)(dmp)]tfpb are significantly better than those for the [Cu(NN)(2)]tfpb complexes studied previously and compare favorably with [Ru(4,7-Me2phen)(3)](tfpb)(2), (K(SV) = 4.76; 4,7-Me(2)phen = 4,7-dimethyl-1,10- phenanthroline). The replacement of precious metals (like Ru or Pt) with copper may be technologically significant and the new compounds can be synthesized in one or two steps from commercially available starting materials. The strictly linear Stern-Volmer behavior observed for these systems and the absence of a polymer matrix that might cause variability in sensor to sensor sensitivity may allow a simple single-reference point calibration procedure, an important consideration for an inexpensive onetime limited use sensor that could be mass produced.

Concurrent sensing of benzene and oxygen by a crystalline salt of tris(5,6-dimethyl-1,10-phenanthroline)ruthenium(II).

The complex [Ru(5,6-Me2Phen)3]tfpb2 has been examined as a solid-state benzene and oxygen sensor. The crystalline solid undergoes a reversible vapochromic shift of the emission lambda max to higher energy in the presence of benzene. Additionally, in the presence of oxygen the solid exhibits linear Stern-Volmer quenching behavior. When simultaneously exposed to benzene vapor and oxygen the crystals uptake benzene which inhibits the diffusion of oxygen in the lattice; very little quenching is observed. However, when benzene is removed from the carrier gas, partial loss of benzene occurs and oxygen diffusion is restored resulting in quenching of the emission. The practicality of this crystalline solid as a benzene sensor was investigated by examination of a lower concentration of benzene vapor (0.76%).

A chromatographic approach for fluorescence reduction in liquid Raman analysis.

In this study a chromatographic approach for fluorescence reduction in liquid Raman analysis has been evaluated. The idea behind the approach is to apply a chromatographic separation step prior to Raman analysis in order to separate fluorescing compounds from other components of interest, thus facilitating better quantitative and qualitative analysis of the latter components. A real-time liquid-core Raman waveguide detector designed for chromatographic applications was used in the study, thus providing real-time chemical pretreatment of liquid samples for Raman analysis. Twenty aqueous mixtures of additives frequently found in beverages were analyzed, and for comparative purposes the mixtures were also analyzed in the Raman waveguide detector without chromatographic separation and with a conventional immersion probe. Both qualitatively and quantitatively satisfying results were obtained using the chromatographic Raman approach, and the technique provided possibilities for quantitative and qualitative assessments superior to the two other instrumental setups. The technique may provide additional benefits through sensitivity enhancements, and the approach is simple, inexpensive, and easy to implement in the average applied Raman laboratory. The analysis of various chemical systems and factors such as system stability over time need further evaluation in order to confirm the general applicability of the approach.

Characterization and quantitation of a tertiary mixture of salts by Raman spectroscopy in simulated hydrothermal vent fluid.

This article will demonstrate that Raman spectroscopy can be a useful tool for monitoring the chemical composition of hydrothermal vent fluids in the deep ocean. Hydrothermal vent systems are difficult to study because they are commonly found at depths greater than 1000 m under high pressure (200-300 bar) and venting fluid temperatures are up to 400 degrees C. Our goal in this study was to investigate the use of Raman spectroscopy to characterize and quantitate three Raman-active salts that are among the many chemical building blocks of deep ocean vent chemistry. This paper presents initial sampling and calibration studies as part of a multiphase project to design, develop, and deploy a submersible deep sea Raman instrument for in situ analysis of hydrothermal vent systems. Raman spectra were collected from designed sets of seawater solutions of carbonate, sulfate, and nitrate under different physical conditions of temperature and pressure. The role of multivariate analysis techniques to preprocess the spectral signals and to develop optimal calibration models to accurately estimate the concentrations of a set of mixtures of simulated seawater are discussed. The effects that the high-pressure and high-temperature environment have upon the Raman spectra of the analytes were also systematically studied. Information gained from these lab experiments is being used to determine design criteria and performance attributes for a deployable deep sea Raman instrument to study hydrothermal vent systems in situ.

Development of an in situ fiber optic Raman system to monitor hydrothermal vents.

The development of a field portable fiber optic Raman system modified from commercially available components that can operate remotely on battery power and withstand the corrosive environment of the hydrothermal vents is discussed. The Raman system is designed for continuous monitoring in the deep-sea environment. A 785 nm diode laser was used in conjunction with a sapphire ball fiber optic Raman probe, single board computer, and a CCD detector. Using the system at ambient conditions the detection limits of SO(4)(2-), CO(3)(2-) and NO(3)(-) were determined to be approximately 0.11, 0.36 and 0.12 g l(-1) respectively. Mimicking the cold conditions of the sea floor by placing the equipment in a refrigerator yielded slightly worse detection limits of approximately 0.16 g l(-1) for SO(4)(-2) and 0.20 g l(-1) for NO(3)(-). Addition of minerals commonly found in vent fluid plumes also decreased the detection limits to approximately 0.33 and 0.34 g l(-1) respectively for SO(4)(-2) and NO(3)(-).

Rapid quantification of carotenoids and fat in Atlantic Salmon (Salmo salar L.) by Raman spectroscopy and chemometrics.

Raman spectroscopy (785 nm excitation) was used to determine the overall carotenoid (astaxanthin and cantaxanthin) and fat content in 49 samples of ground muscle tissue from farmed Atlantic salmon (Salmo salar L.). Chemically determined contents ranged from 1.0 to 6.8 mg/kg carotenoids and 36 to 205 g/kg fat. In addition to the raw Raman spectra, three types of spectral preprocessing were evaluated: the first derivative, subtraction of the fitted fourth-order polynomial (POLY), and the intensity normalized versions of POLY (POLY-SNV). Further, variable selection based on significance testing by use of jack-knifing was performed on each spectral data set. Partial least-squares regression resulted in a root mean square error of prediction of 0.33 mg/kg (R = 0.97) for carotenoids for the variable selected versions of all the preprocessed spectral data sets. The fat content was best estimated by the variable selected POLYSNV, resulting in a root mean square error of prediction of 15.5 g/kg (R = 0.95). Both preprocessing and variable selection improved the regression models significantly. The results demonstrate that Raman spectroscopy is a suitable method for simultaneous, rapid, and nondestructive quantification of both pigments and fat in ground salmon muscle tissue.

Sequential switch of biomineral crystal morphology using trivalent ions.

Many biominerals are laminated such that crystal shape or habit changes from layer to layer thus yielding exquisitely designed composite materials with tightly controlled properties. Although lamination in biominerals is usually performed using peptides and proteins, here we introduce a new strategy by which sequential addition or depletion of inorganic trivalent ions in a supersaturated solution can be used to switch the surface morphology of calcium oxalate monohydrate (COM) back and forth, resulting in either the growth of flat crystalline sheets or of nanostructures oriented perpendicular to the surface. We propose that the occupation of a Ca(2+) site by Eu(3+) ion switches the orientation of the COM unit cell. The need to compensate the third charge forces coordination of Eu(3+) to an additional oxalate ion ((-)OOC-COO(-)) in an orientation that is not compatible with the initial unit cell. This mechanism of switching the orientation of the unit cell is unique, as it does not involve the use of expensive and thermally labile biomolecules. Suggestions of how to extend this strategy to engineer non-biological nanocomposites are given.

Characterization and use of a Raman liquid-core waveguide sensor using preconcentration principles.

A novel Raman sensor using a liquid-core optical waveguide is reported, implementing a Teflon-AF 2400 tube filled with water. An aqueous analyte mixture of benzene, toluene and p-xylene was introduced using a 1000 microl sample loop to the liquid-core waveguide (LCW) sensor and the analytes were preconcentrated on the inside surface of the waveguide tubing. The analytes were then eluted from the waveguide using an acetonitrile-water solvent mixture injected via a 30 microl eluting solvent loop. The preconcentration factor was experimentally determined to be 14-fold, in reasonable agreement with the theoretical preconcentration factor of 33 based upon the sample volume to elution volume ratio. Raman spectra of benzene, toluene and p-xylene were obtained during elution. It was found that analytically useful Raman signals for benzene, toluene and p-xylene were obtained at 992, 1004 and 1206 cm(-1), respectively. The relative standard deviation of the method was 3% for three replicate measurements. The limit of detection (LOD) was determined to be 730 ppb (parts per billion by volume) for benzene, exceptional for a system that does not resort to surface enhancement or resonance Raman approaches. The Raman spectra of these test analytes were evaluated for qualitative and quantitative analysis utility.