Evaluation for the Mixing Performance of a Microreactor with Inline ...

Research Paper

Journal of Chemical Engineering of Japan, Vol. 46, No. 11, pp. 770–776, 2013

Evaluation for the Mixing Performance of a Microreactor with Inline Measurement Yukako Asano1, Shigenori Togashi 1 and Yoshishige Endo2 1 2

Hitachi Research Laboratory, Hitachi, Ltd., 832-2 Horiguchi, Hitachinaka-shi, Ibaraki 312-0034, Japan Infrastructure Systems Company, Hitachi, Ltd., 603 Kandatsumachi, Tsuchiura-shi, Ibaraki 300-0013, Japan

Keywords: Microreactor, Mixing Performance, Inline Measurement, Villermaux–Dushman Reaction, Methanol–Ethanol Mixing Process We have evaluated the mixing performance of a microreactor with inline ultraviolet (UV) and Fourier transform-infrared (FT-IR) measurement. We performed the well-known Villermaux–Dushman reaction with inline and offline UV measurements. Absorbance was continuously reproduced at each flow rate with inline measurement. The difference between the inline and offline measurement results was within ±5% at faster flow rates than 2 mL/min. However, the difference between the inline and offline measurement results at 1 mL/min occurred because the sample changed until the start of offline measurement. It is shown that “real-time” monitoring and more accurate analyses were performed with this inline measurement system. We have also performed the methanol–ethanol mixing process with inline FT-IR measurement. The absolute slope of absorbance peak height with changing from methanol to a mixing solution became larger as the flow rate increased, while it hardly changed at faster flow rates than 10 mL/min (1.0×10−5 m3/min).This suggests that the mixing performance improved as the flow rate increased, while the mixing performance was saturated at faster flow rates. The tendency in the mixing performance was in good agreement with that obtained from the Villermaux–Dushman reaction. Therefore, it has been confirmed that the mixing performance of microreactors could be appropriately evaluated with inline UV or FT-IR measurement.

Received on March 29, 2013; accepted on August 8, 2013 DOI: 10.1252/jcej.13we054 Correspondence concerning this article should be addressed to Y. Asano (E-mail address: [email protected]).

Inline measurement is considered to be valid for more accurate optimization of reaction conditions, regardless of limits on the kinds of analyses. Recently, according to guidance by the FDA (U.S. Food and Drug Administration), PAT (Process Analytical Technology) has been required, which has been defined as a mechanism to design, analyze, and control pharmaceutical manufacturing processes through real-time (i.e., timely) measurement with the goal of ensuring final product qualities (U.S. Food and Drug Administration, 2004). Microreactor technologies could give manufacturing processes in accordance with the PAT mechanism, because of their continuous flow processes and good reproducibility of products. In particular, truly “real-time” measurements might be realized by incorporating an inline measurement system in a microreactor system. Thus it has become important to make inline measurement (Brodmann et al., 2012; Carter et al., 2012). In this work, we incorporated an inline UV (ultraviolet) or FT-IR (Fourier transform-infrared spectroscopy) measurement system in a microreactor system. UV absorbance depends on excitation energies of electrons. In contrast, IR absorbance depends on vibration energies and slight difference in molecular structures is reflected particularly in the fingerprint region. The mixing performance of a microreactor was evaluated by real-time measurement of products with these two kinds of inline measurement methods. We confirmed the difference between current offline and inline UV measurement in the well-known Villermaux–Dushman reaction for the evaluation of the mixing performance of a

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Introduction A microreactor is a device that has micro channels on micrometer order and enables chemical reactions to be performed in a reaction space several orders of magnitude smaller than in conventional batch reactors (Hessel et al., 2004, 2005). In a small reaction space with a high surfaceto-volume ratio, microreactors provide fast mixing and have accurate thermal and reaction time control (Benson and Ponton, 1993; Bier et al., 1993; Ehrfeld et al., 1999). Continuous flow in microreactors also enables reaction processes to be monitored, controlled, and analyzed (Asano et al., 2010). Product quality is usually monitored by “offline” convoluted analytical equipment, such as HPLC (high performance liquid chromatography), GC (gas chromatography), and NMR (nuclear magnetic resonance). It takes time for the sample to be analyzed because of prior processing for analyses or a large quantity of the sample. Accurate analytical results may not be obtained for reactions that rapidly proceed with side products or intermediates. In contrast, “inline” analytical equipment limits the use of more simple analyses such as photoanalyses. However, inline measurement can realize “real-time” monitoring without time lag between the start of sampling and analysis.

Copyright © 2013  Journal The Society of Chemical of Chemical Engineering Engineers, of Japan

Fig. 1 Schematic of the Villermaux–Dushman reaction

microreactor, and then applied inline FT-IR measurement to the methanol–ethanol mixing process.

Fig. 2 Microreactor system for the Villermaux–Dushman reaction used in this study

1. Experimental Method 1.1 Evaluation for the mixing performance of a microreactor using the Villermaux–Dushman reaction with inline UV measurement We adopted the Villermaux–Dushman reaction in order to evaluate the mixing performance of a microreactor (Fournier et al., 1996a, 1996b; Ehrfeld et al., 1999), which is one of the most widely used methods. The Villermaux– Dushman reaction is represented by Eqs. (1)–(3) and shown in Figure 1. The reaction in Eq. (1) is an acid-base reaction, while that in Eq. (2) is a reduction-oxidation (redox) reaction. These reactions are parallel competing reactions and the reaction in Eq. (1) is faster than that in Eq. (2). +

CH3COO + H → CH3COOH

(1)

5I− + IO3 − +6H+ → 3I2 +3H2O

(2)

I2 + I− → I3−

(3)

−

As shown in the figure, when the mixing performance is poor, the reaction in Eq. (1) cannot completely mask the reaction in Eq. (2) and I2 is produced. The reaction in Eq. (2) is followed by the reaction in Eq. (3). The produced I3− is spectroscopically measured by mean of UV absorbance at around 352 nm. Therefore, UV absorbance becomes larger as the mixing performance becomes worse. We used the evaluation method developed by Ehrfeld et al. (1999). A 0.1374 mol/L [kmol/m3] hydrochloric acid (HCl) solution, 0.0319 mol/L [kmol/m3] potassium iodide (KI) in a 1.33 mol/L [kmol/m3] sodium acetate (CH3COONa) solution, and 0.00635 mol/L [kmol/m3] potassium iodate (KIO3) in a 1.33 mol/L [kmol/m3] sodium acetate solution were prepared. The last two solutions were combined at the ratio of 1 : 1, just before the start of experiments because KI can react with KIO3 in the presence of light as described later (Eq. (4), Ebato et al., 2008). Figure 2 shows a microreactor system for the Villermaux–Dushman reaction used in this study. The hydrochloric acid solution and the obtained combined solution were introduced into a microreactor via the introduction region (PTFE tube, OD: 3 mm, ID: 1.5 mm, and length: 1.5 m) and mixed at the ratio of 1 : 1. A product solution was obtained from the extraction region (PTFE tube, OD: 3 mm, ID: 2 mm, and length: 0.3 m). This extraction region was set as short and broad as possible to minimize further progress of mixing and reaction. The introduction region, microreacVol. 46  No. 11  2013

Fig. 3 Laboratory microreactor system used in this study (Hitachi, Ltd., 2013)

tor, and extraction region were immersed in a temperature controlled bath to keep the mixing and reaction temperature at 293.15 K. We used a laboratory microreactor system produced by Hitachi, Ltd. as a microreactor system (Figure 3) (Hitachi, Ltd., 2013). This equipment consists of a liquid feed unit and a temperature controlled unit for microreactors, which are controlled by a monitoring unit. Figure 3 also shows a microreactor used in this study. This microreactor had multilayer channels contracting toward the downstream, and was made from Hastelloy C-276 alloy. The channel width and length after multilayer channels were contracted were 0.5 mm and 434 mm, respectively. The minimum diffusion length in a layer was 8.1 µm on the downstream side (Hitachi, Ltd., 2013). We evaluated the mixing performance of a microreactor on the basis of the absorbance of the product solution at 352 nm. The absorbance was measured with the inline UV measurement system, USB2000+ by Ocean Optics, Inc. on the downstream side (Ocean Optics, Inc., 2013). Specifications of the inline UV measurement system used in this study are shown in Table 1. At least the flow rate of 300 mL/ min (3.0×10−4 m3/min) can be applied to this inline measurement system when using the solution whose viscosity is similar to that of water. The flow rate can be set as the flow rate less than 150 mL/min (1.5×10−4 m3/min) per syringe. For comparison, the absorbance of the product solution obtained from the system shown in Figure 4 was also measured offline using a cuvette with the light pass of 10 mm. The absorbance linearly increased threefold in 15 min, because of the side reaction between KI and KIO3 in the presence of light as described later (Eq. (4), Ebato et al., 2008). Thus, all offline measurements were made as fast as possible 771

Table 1

Specifications of the inline UV measurement system used in this study (Ocean Optics, Inc., 2013)

Wavelength region Entrance slit width Wavelength resolution Sampling time Light pass

250–800 nm 100 µm 1 nm 1 ms 10 mm

Fig. 5 Microreactor system for the methanol–ethanol mixing process used in this study Table 2

Specifications of the inline FT-IR measurement system used in this study (Mettler-Toledo International, Inc., 2013)

Wavenumber (wavelength) region

Fig. 4 Microreactor system for the Villermaux–Dushman reaction for offline measurement used in this study

Wavenumber resolution Sampling time Internal volume of DiComp sensor

4000–650 cm−1 (2500–15386 nm) 4 cm−1 1s 50 µL

(Ehrfeld et al., 1999). 1.2 Evaluation for the mixing performance of a microreactor using the methanol–ethanol mixing process with inline FT-IR measurement We also adopted a simple methanol–ethanol mixing process in order to evaluate the mixing performance of a microreactor. Methanol and ethanol are cheap and easilyobtainable reagents to give IR absorbance. Figure 5 shows a microreactor system for the methanol–ethanol mixing process used in this study. Methanol and ethanol were introduced into a microreactor via the introduction region (PTFE tube, OD: 3 mm, ID: 1.5 mm, and length: 1.5 m) and mixed at the ratio of 1 : 1. A mixing solution was obtained from the extraction region (PTFE tube, OD: 3 mm, ID: 2 mm, and length: 0.3 m). This extraction region was set as short and broad as possible to minimize further progress of mixing. The mixing process was performed at room temperature (about 293.15 K). We also used a similar laboratory microreactor system and microreactor as shown in Figure 3 (Hitachi, Ltd., 2013). The absorbance of the mixing solution was measured with the inline FT-IR measurement system on the downstream side. We adopted the inline FT-IR measurement system equipped with an integrated attenuated total reflectance (ATR) gold sealed diamond sensor (referred to as a DiComp sensor) with 50 µL (5×10−8 m3) by Mettler-Toledo International, Inc. (Brodmann et al., 2012; Carter et al., 2012; Mettler-Toledo International, Inc., 2013) Specifications of the inline FT-IR measurement system used in this study are shown in Table 2. At least the flow rate of 300 mL/min (3.0×10−4 m3/min) can be applied to this inline measurement system when using the solution having a viscosity is similar to that of water. The flow rate can be set as the flow rate less than 150 mL/min (1.5×10−4 m3/min) per syringe.

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Fig. 6 Continuous measurement results at the wavelength of 352 nm with inline UV measurement

2. Results and Discussion 2.1 Evaluation for the mixing performance of a microreactor using the Villermaux–Dushman reaction with inline UV measurement Figure 6 shows the continuous measurement results at the wavelength of 352 nm with inline UV measurement. In the figure, the Villermaux–Dushman reaction progressed with changing the total flow rate from 1 to 15 mL/min (1×10−6–1.5×10−5 m3/min), and finally washing was performed with pure water. Here, measurement was continuously maintained even when the reagents were introduced into syringes or KI and KIO3 solutions were mixed just before introduction into a syringe. As shown in the figure, absorbance was reproduced at each flow rate. Absorbance changed only when the total flow rate was changed, because of worse mixing condition just after introducing solution and the side reaction between KI and KIO3 in the presence of light as described later (Eq. (4), Journal of Chemical Engineering of Japan

Fig. 7 Comparison of inline and offline UV measurement results at the wavelength of 352 nm

Ebato et al., 2008). Figure 7 shows the comparison of inline and offline UV measurement results at the wavelength of 352 nm. As shown in the figure, in both inline and offline UV measurement, absorbance became smaller as the total flow rate increased, while it hardly changed at faster flow rates than 10 mL/min (1.0×10−5 m3/min). From the schematic of the Villermaux–Dushman reaction in Figure 1, this showed that the mixing performance became better as the total flow rate increased, while the mixing performance was saturated at faster flow rates than 10 mL/min (1.0×10−5 m3/min). The difference between the inline and offline UV measurement results was within ±5% when the total flow rates were 2, 5, and 10 mL/min (2×10−6, 5×10−6, and 1.0×10−5 m3/min). However, the offline UV absorbance was clearly larger than the inline one at the total flow rate of 1 mL/min (1×10−6 m3/min). This came from the fact that a cuvette with the light pass of 10 mm was used in offline UV measurement. It took a longer time to start measurement after the product solution came from the extraction region, as the total flow rate became slower. It is known that KI and KIO3 react by light and produce I3−, which is a measurement object in the Villermaux– Dushman reaction as shown in Eq. (4).

8KI + KIO3 +3H2O +8hv → 3I3− +6OH− +9K+

(4)

In Eq. (4), h and ν are the Planck constant and light frequency, respectively, and therefore hν shows the light energy (Ebato et al., 2008). The volume of cuvette was 3.5 mL (3.5×10−6 m3) and it took more than 3 min until the start of measurement at the total flow rate of 1 mL/min (1×10−6 m3/min). The offline UV absorbance was considered to be about 1.4 times larger than the inline one, because the absorbance linearly increased threefold in 15 min as described before. As shown in Figure 7, the offline UV absorbance (0.67) was 1.3 times larger than the inline one (0.52) and this experimental ratio was nearly in accordance with the above calculation one. Therefore, the difference between the inline and offline measurement results at the total flow rate of 1 mL/min (1×10−6 m3/min) occurred because the sample changed until the start of offline measurement. It was shown that Vol. 46  No. 11  2013

Fig. 8 Continuous measurement results with inline FT-IR measurement

Fig. 9 Enlarged view of Figure 8 and estimation method for the slope and intercept of the absorbance peak heights

“real-time” monitoring and more accurate analyses were performed with this inline measurement system. 2.2 Evaluation for the mixing performance of a microreactor using the methanol–ethanol mixing process with inline FT-IR measurement Figure 8 shows the continuous measurement results with inline FT-IR measurement. An enlarged view is also shown in Figure 9. The IR spectra clearly showed resonances at the wave number of 1026 cm−1 (wave length of 9747 nm) for methanol and at 1050 cm−1 (9524 nm) for ethanol. In Figure 8, after introducing methanol at the flow rate of 2 mL/min (2×10−6 m3/min), the methanol–ethanol mixing process progressed with the 1 : 1 ratio of methanol and ethanol with changing the total flow rate from 1 to 20 mL/min (1×10−6–2.0×10−5 m3/min). Here, measurement was continuously maintained even when methanol and ethanol were introduced into syringes. As shown in Figure 8, it took 0.5–1 min at the total flow rate of 10 mL/min (1.0×10−5 m3/min), i.e., 5–10 mL (5×10−6–1.0×10−5 m3) for replacing methanol with the methanol–ethanol mixing solution. It is known that feeding 4–5 times the amount of liquid of the internal volume is needed for replacing liquid inside in flow systems such as HPLC (GL Science, Inc., 2013). The sum of the internal volume of the microreactor and that of the extraction region was about 2 mL (2.0×10−6 m3/min). The volume of 5–10 mL (5×10−6–1.0×10−5 m3) corresponded to about 2.5–5 times the amount of the internal volume. Therefore, this FT-IR 773

Table 3 Slopes and intercepts of the absorbance peak heights with changing from methanol to the methanol–ethanol mixing solution Total flow rate [mL/min (10−6 m3/min)] Methanol

Slope [arb. unit/min] Intercept [arb. unit] R2 value Ethanol Slope [arb. unit/min] Intercept [arb. unit] R2 value Average absolute slope

1 −0.401 2.236 0.991 0.443 0.515 0.978 0.422

measurement system was considered to be adequate for monitoring the methanol–ethanol mixing process with the microreactor. Moreover, the slope of the absorbance peak height became larger and the mixing solution approached the mixing condition much faster, as the total flow rate of methanol and ethanol increased. Also, the wobble of the absorbance peak height just after mixing became smaller, as the total flow rate became faster. It was suggested that the mixing condition became more stable, namely, the obtained solution was more homogeneously mixed, as the total flow rate increased. Furthermore, we considered the slopes of the absorbance peak heights with changing from methanol to the methanol–ethanol mixing solution depended on the mixing performance of a microreactor. As shown in Figure 9, the slope and intercept of the absorbance peak heights were obtained from the straight section data, in order to understand the time dependence of the absorbance peak heights with changing from methanol to the methanol–ethanol mixing solution. Here, the absolute slope of the absorbance peak height of methanol should be similar to that of ethanol, because the ratio of methanol and ethanol changes from 10 : 0 to 5 : 5. However, the average slope of those absolute values was estimated, because there might be measurement errors of the absorbance peak heights. Table 3 shows the slopes and intercepts of the absorbance peak heights with changing from methanol to the methanol–ethanol mixing solution. Figure 10 shows average absolute slopes of the absorbance peak heights with changing from methanol to the methanol–ethanol mixing solution and absorbance of the byproduct in the Villermaux–Dushman reaction with inline UV measurement. Here, the residence time in the DiComp sensor with the internal volume of 50 µL (5×10−8 m3) was a maximum of 3 s and it is several orders of magnitude shorter than the time for sloping the absorbance peak height (0.5–1.5 min). Also, when pure methanol and pure ethanol were introduced alternately, the slopes of the absorbance peak heights were significantly larger than those in this methanol–ethanol mixing process. Therefore, the difference of the total flow rates might hardly have effects on the slopes of the absorbance peak heights. The mixing performance could have a relationship with the slopes of the absorbance peak heights. As shown in the table, the intercepts of the absorbance peak heights of methanol were in good accordance with each other in the range of 2.210–2.288 arb. unit, and they 774

2

5

−0.670 2.244 0.966 0.798 0.466 0.963 0.734

−1.015 2.210 0.973 1.213 0.486 0.930 1.114

10 −1.214 2.288 0.996 1.208 0.390 0.928 1.211

20 −1.153 2.242 0.997 1.277 0.414 0.965 1.215

Fig. 10 Absolute slopes (averaged) of the absorbance peak height with changing from methanol to the methanol–ethanol mixing solution and absorbance of the byproduct in the Villermaux–Dushman reaction

were close to the absorbance peak height of about 2.25 arb. unit when only methanol was introduced. On the other hand, the intercepts of the absorbance peak heights of ethanol were slightly variable in the range of 0.390–0.515 arb. unit, but they were close to the absorbance peak height of about 0.45 arb. unit with only methanol introduced. Thus it was considered that the slopes were adequately obtained from the estimation method shown in Figure 9. Also the R2 values were in the range of 0.928–0.997 and the absorbance peak height was linear with respect to time. It was considered to suggest good mixing performance of the microreactor. As shown in the figure, the absolute slope became larger as the total flow rate increased, while it hardly changed at faster flow rates than 10 mL/min (1.0×10−5 m3/min). This was considered to suggest that the mixing rate became larger and the mixing performance became better as the total flow rate increased, while the mixing rate hardly changed and the mixing performance was saturated at faster flow rates than 10 mL/min (1.0×10−5 m3/min). On the other hand, the absorbance of the byproduct in the Villermaux–Dushman reaction by inline UV measurement became smaller as the total flow rate increased, while it hardly changed at faster flow rates than 10 mL/min (1.0×10−5 m3/min). As described in the previous section, this suggested that the mixing performance became better as the total flow rate increased, while the mixing performance was saturated at faster flow rates than 10 mL/min (1.0×10−5 m3/min). This tendency in the mixing performance was in good agreement with that obtained from the absolute slope of the absorbance peak height. Therefore, it was shown that the absolute slope of the abJournal of Chemical Engineering of Japan

sorbance peak height with changing from methanol to the methanol–ethanol mixing solution had a correlation with the mixing performance of a microreactor.

Conclusions We evaluated the mixing performance of a microreactor with UV and FT-IR measurement. We confirmed the difference between current offline and inline UV measurement in the well-known Villermaux–Dushman reaction for evaluation of the mixing performance of microreactors, and then applied inline FT-IR measurement to the methanol–ethanol mixing process. The Villermaux–Dushman reaction progressed with changing the total flow rate from 1 to 15 mL/min (1×10−6– 1.5×10−5 m3/min), and finally washing was performed with pure water. Absorbance was continuously reproduced at each flow rate with inline UV measurement. For comparison, the absorbance was also measured offline by using a cuvette. In both inline and offline UV measurements, absorbance became smaller as the total flow rate increased, while it hardly changed at faster flow rates than 10 mL/min (1.0×10−5 m3/min). This showed that the mixing performance improved as the total flow rate increased, while the mixing performance was saturated at faster flow rates than 10 mL/min (1.0×10−5 m3/min). The difference between the inline and offline UV measurement results was within ±5% at faster total flow rates than 2 mL/min (2×10−6 m3/min). However, the difference between the inline and offline measurement results at the total flow rate of 1 mL/min (1×10−6 m3/min) occurred because the sample changed until the start of offline measurement. It was shown that “real-time” monitoring and more accurate analyses were performed with this inline measurement system. The methanol–ethanol mixing process also progressed at the 1 : 1 ratio of methanol and ethanol with changing the total flow rate from 1 to 20 mL/min (1×10−6–2.0×10−5 m3/min). The absolute slope of absorbance peak height with changing from methanol to the methanol–ethanol mixing solution became larger as the total flow rate increased, while it hardly changed at faster flow rates than 10 mL/min (1.0×10−5 m3/min). This suggested that the mixing rate became larger and the mixing performance became better as the total flow rate increased, while the mixing rate hardly changed and the mixing performance was saturated at faster flow rates than 10 mL/min (1.0×10−5 m3/min). The tendency in the mixing performance was in good agreement with that obtained from the Villermaux–Dushman reaction. Thus, it was shown that the absolute slope of the absorbance peak height with changing from methanol to the methanol–ethanol mixing solution had a correlation with the mixing performance of a microreactor. Therefore, it was confirmed that the mixing performance of microreactors could be appropriately evaluated with inline UV or FT-IR measurement. Vol. 46  No. 11  2013

In a future work, we would like to utilize microreactor systems including inline measurement systems for more accurate optimization of reaction conditions, beginning with the mixing performance of microreactors. Also, we would like to confirm the validity and reliability of the evaluation method for the mixing performance of microreactors using the methanol–ethanol mixing process with inline FT-IR measurement, by application to other microreactors. Moreover, we would like to advance large-scale pharmaceutical production corresponding to the PAT mechanism by such microreactor systems. Acknowledgement We would like to thank Mr. Masato Fueki of Mettler-Toledo International, Inc. for his useful discussion about the inline FT-IR measurement of the methanol–ethanol mixing process.

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