Microreactor array

Siclovan, O., Fluorescence spectroscopy and multivariate spectral descriptor analysis for high-throughput multiparameter optimization of polymerization conditions of combinatorial 96-microreactor arrays, J. Comb. Chem. 2003, 5, 8-17. 

The coupling of a microreactor array in combination with an X-ray camera was used by Grunwaldt et al. (2007) to record the XAFS spectra of ten catalysts simultaneously. In this feasibility exercise, the arrangement comprised a spectroscopic cell with ten sample compartments (2 or 5 mm in thickness) that were filled with meshed and sieved catalyst particles. There was little detail provided about the heating and gas flow arrangement, but the cell could be heated (although the preliminary data were all recorded after flowing either a Ff2 helium or Cb—helium mixture at room temperature). 

Figure S.3. Example of a first-order measurement of combinatorial materials. Polymer branching from measurements of fluorescence spectra from each polymerized material in a 96-element microreactor array at a single excitation wavelength. (A) Reflected-hght image of the microreactor array (B) representative fluorescence spectrum from a single microreactor in the array.

An example of the first-order measurement approach of combinatorial materials is illustrated in Figure 5.3. Measurements of fluorescence spectra of solid polymerized materials were performed directly in individual microreactors. A view of the 96-microreactor array is shown in Figure 5.3A. Several chemical parameters in the combinatorial samples were identified from these measurements. The spectral shape of the fiuorescence emission with an excitation at 340 nm provided the information about the concentration of the branched product in the polymer and the selectivity of a catalyst used for the melt polymerization. A representative fiuorescence spectrum (along with an excitation line at 340 nm) from a single microreactor in the array is illustrated in Figure 5.3B. The first-order measurements were used for the optimization of melt-polymerization reaction conditions as described in Section 5.1. 

In the examples provided in this section, combinatorial methods were used to improve the properties of an industrial aromatic polymer, such as melt-polymerized bisphenol-A polycarbonate. The reactions were performed in 96-well microtiter glass plates that served as 96-microreactor arrays in a sequence of steps of increasing temperature with a maximum temperature of 280°C. An example of one of the 96-microreactor arrays after melt-polymerization is shown in Figure 5.3A. For melt-polymerization of bisphenol-A polycarbonate, the starting reaction components included diphenyl carbonate and bisphenol-A monomers and a catalyst (e.g., NaOH). The materials codes used in the examples are presented in Table 5.2. Intermediate species include polycarbonate oligomers and phenol. The bisphenol-A polycarbonate polymer often contains a branched side product that produces a detectable fluorescence signal and other species that can include nonbranched end-groups and cyclics. We used fluorescence spectroscopy for nondestructive chemical analysis of melt-polymerized bisphenol-A polycarbonate. The key attractive... 

Table 5.3. Variable Input Parameters (Process Conditions) for High-Tbrou put Multiparameter Optimization of Polymerization Conditions of Combinatorial 96-Microreactor Arrays ...

Multiple melt-polymerization reactions are performed using mixtures of A and B at different ratios with different amounts of catalyst C. Catalyst amounts are expressed as certain fractions of 10" mol of catalyst per mole of component B. In process optimization experiments, polymeric materials are fabricated in five microreactor arrays under different intra- and inter-... 

For the determination of the key process parameters and their respective values, fluorescence spectra from five 96-microreactor arrays were collected and processed. The normalized spectra are presented in Figure 5.7. The spectral features of the polymeric materials in the microreactors contain a wealth of information about the chemical properties of the materials that were extracted using PCA. According to the PCA results, the first two principal components (PCs) accounted for more than 95% of the spectral variation among all spectra. Thus the first two PCs were used for an adequate description of the fluorescence spectra. Results of the principal components analysis of the spectra from all 96-microreactor arrays as a function of catalyst concentration C are presented in Figure 5.8. The plot demonstrates the existence of the major general trend in the spectral descriptors where the variation in scores of both PCs strongly depends on concentration of component C for all screened process parameters. 

Figure 5.7. Normalized fluorescence spectra of the polymeric materials made in the 96-microreactor arrays under all experimental conditions. From ret 73.

Figure 5.9. Results of the principal components analysis of the spectra of the polymeric materials made in the 96-microreactor arrays with variable intra-array (.4 and B) and interarray (C and D) parameters (A) volume (B) ratio A/B (C) flow rate (D) dwell time. Levels asterisks—smallest plus—medium X—largest. For values, see Table 5.3. From ref. 73.

We next performed a more extensive analysis to consider the spectral descriptors in individual 96-microreactor arrays. The data were analyzed as a function of catalyst concentration, reaction volume, and ratio AIB at different flow rates of inert gas and dwell times. In our analysis are evaluated... 

To determine the optimal levels of the identified process conditions, a more detailed evaluation was performed. Euchdean distances between different clusters of spectral descriptors and the uncertainty in these distances were computed using Eq. (5.2). Calculations were performed between spectral descriptors associated with materials produced with different amounts of catalyst and ratios AIB in all 96-microreactor arrays. 

Figure 5.10 provides plots of the calculations of Euclidean distance between the spectral descriptors of two representative 96-microreactor arrays. The largest Euclidean distances indicate the best conditions for material differentiation. The best inter-array conditions were found to be a 6-L/min flow rate of inert gas and 20-min dwell time. The best intra-array conditions were a combination of the catalyst concentration of 2 to 4 equivalents and ratio AIB of 1.2 to 1.4 (Figure 5.10B). Results for the reaction variability for these representative microreactor arrays are presented in Figure 5.11.The smallest relative standard deviation (RSD) of spectral features indicates the best reaction reproducibihty. This figure illustrates that...

The multivariate 7 and Q statistics control charts for the fluorescence spectra of the one of the 96-microreactor arrays discussed in Section 5.1 are presented in Figure 5.13.These control charts illustrate that several samples exceed the 95% confidence limits for the T and Q statistics described by... 

Figure 5.13. Multivariate statistical indicators for combinatorial production of melt polycarbonate in one of the 96-microreactor arrays (A) control chart (B) Q residual control chart (dotted lines in A and B) 95% confidence limits.

In addition to these organic syntheses, biochemical production of compounds in microreactors has also been performed. A microreactor array which enables high-throughput cell-free protein synthesis was developed [4]. The microreactor array is composed of a temperature control chip and a reaction chamber chip. The temperature control chip is a glass-made chip on which temperature control devices, heaters, and temperature sensors are fabricated with an indium tin oxide (ITO) resistive material. The reaction chamber chip is fabricated by micromolding of polydimethylsiloxane (PDMS)... 

Yamamoto T, Nojima T, Fujii T, (2002) PDMS-glass hybrid microreactor array with embedded temperature control device. Application to cell-free protein synthesis. Lab Chip 2 197-202... 

Cell-free protein synthesis was performed using polydimethylsiloxane (PDMS)-based microreactor arrays [22]. The microreactor array chip comprised a temperature control chip made of glass and a disposable reaction chamber chip made of PDMS. To evaluate the performance of this microreactor array, rat adipose-type fatty acid binding protein, glyceraldehyde-3-phosphate dehydrogenase, cyclophilin, and firefly luciferase were synthesized from their respective DNA templates using a cell-free extract prepared from Escherichia coli. 

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