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Comparison of dielectric constant meter with turbidity meter and focused beam reflectance measurement for metastable zone width determination
chemical engineering research and design 9 0 ( 2 0 1 2 ) 259–265
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Comparison of dielectric constant meter with turbidity meter and focused beam reflectance measurement for metastable zone width determination Guangwen He a,∗ , Martin W. Hermanto a , Martin Tjahjono a , Pui Shan Chow a , Reginald B.H. Tan a,b , Marc Garland a a
Institute of Chemical & Engineering Sciences, A*STAR (Agency for Science, Technology and Research), 1 Pesek Road, Jurong Island, Singapore 627833, Singapore b Department of Chemical & Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117576, Singapore
a b s t r a c t This work demonstrates a detailed process analytical technology (PAT) comparison study of dielectric constant measurement with turbidity measurement and focused beam reflectance measurement (FBRM) in detecting phase transitions during crystallization of three model solutions, namely stearic acid–ethyl acetate, paracetamol–ethanol and carbamazepine–methanol. The cloud and clear points determined by the dielectric constant measurement are found to be in close agreement with those obtained from the other two well-established PAT tools. A calibration technique can be further applied on the dielectric constant to improve the accuracy of the cloud point detection. The results have shown that the dielectric constant meter can be reliably used for metastable zone width (MZW) determination. This study opens new opportunities for the use of the dielectric constant meter as a simple and inexpensive alternative PAT tool for process monitoring of solution crystallization. Crown Copyright © 2011 Published by Elsevier B.V. on behalf of The Institution of Chemical Engineers. All rights reserved. Keywords: Dielectric constant; Metastable zone width; Process analytical technology; Phase transition
1.
Introduction
Solution crystallization has been widely used for the formation, separation and purification of synthetic intermediates, final solid products in fine chemical, pharmaceutical and agrochemical industries (Mullin, 2001; Myerson, 2001). The metastable zone width (MZW), which denotes the region between the solubility curve and the onset of nucleation (Mullin, 2001), marks an operating boundary during solution crystallization processes to avoid excessive secondary nucleation thus ensuring the required size and size distribution of the final crystalline particles. The information on MZW is therefore essential for the crystallization processes. This parameter is known to be process dependent and can be influenced by numerous factors including cooling rate, solvent
∗
composition, mechanical agitation, impurities in the solution, etc. (Nyvlt et al., 1985). Many process analytical technologies (PATs) have been developed in the past decade for in situ determination of the MZW during solution crystallization processes (Kumar et al., 1996; Groen and Roberts, 2001; Lewiner et al., 2001; Fujiwara et al., 2002; Löffelmann and Mersmann, 2002; Marciniak, 2002; Gürbüz and Özdemir, 2003; Parsons et al., 2003; Genceli et al., 2005; Pöllänen et al., 2006; Schöll et al., 2006; O’Grady et al., 2007; Simon et al., 2009a). These techniques include, but are not limited to, direct visual observation using hot stage microscopy (HSM) (Kumar et al., 1996), in-process video microscopy (PVM) (Barrett and Glennon, 2002) and bulk video imaging (Simon et al., 2009b); detection of the presence of solid particles using focused beam reflectance measurement (FBRM) (Fujiwara et al., 2002; Schöll et al., 2006; O’Grady et al., 2007) and turbidity meter (Parsons et al., 2003); thermal method using differential scanning calorimeter (DSC) (Myerson and Jang, 1999); and monitoring of the solute
Corresponding author. Tel.: +65 6796 3779. E-mail address: he [email protected] (G. He). Received 24 May 2011; Received in revised form 5 July 2011; Accepted 9 July 2011
0263-8762/$ – see front matter Crown Copyright © 2011 Published by Elsevier B.V. on behalf of The Institution of Chemical Engineers. All rights reserved.
doi:10.1016/j.cherd.2011.07.005
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Fig. 1 – Schematics of the experimental setups. (a) The 250-mL jacketed crystallizer: (1) turbidity probe; (2) thermocouple; (3) dielectric constant probe; and (4) magnetic stirrer bar. (b) The l-L jacketed crystallizer: (1) overhead motor; (2) turbidity probe; (3) thermocouple; (4) dielectric constant probe; (5) FBRM probe; (6) baffle; and (7) impeller.
concentration change via bulk solution property measurements using attenuated reflection-Fourier transform infrared (ATR-FTIR) (Groen and Roberts, 2001; Lewiner et al., 2001; Fujiwara et al., 2002; Pöllänen et al., 2006; Schöll et al., 2006; O’Grady et al., 2007; Trifkovica et al., 2009), ultra-violet–visible (UV–vis) spectroscopy (Simon et al., 2009a), densitometer (Marciniak, 2002), ultrasonic velocity meter (Marciniak, 2002; Gürbüz and Özdemir, 2003), quartz crystal sensor (Löffelmann and Mersmann, 2002), conductivity and refractive index meter (Genceli et al., 2005), etc. In our previous work, we have demonstrated the first use of a dielectric constant meter, coupled with an automated data logging module for in situ monitoring of a solution crystallization process (He et al., 2010). The dielectric constant measurement offers an alternative PAT tool for in situ monitoring of solution crystallization. The instrument is also relatively inexpensive when compared to some other measurements as mentioned above (i.e. HSM, FBRM, ATR-FTIR, densitometer, etc.). In the present contribution, a more detailed PAT comparison in monitoring solution crystallization is carried out using dielectric constant meter and other more established techniques, namely, turbidity meter and/or FBRM. Three different model solution crystallization processes, namely stearic acid in ethyl acetate, paracetamol in ethanol, and carbamazepine in methanol are investigated. These three model solution systems have different nucleation/growth characteristics which can facilitate a wider assessment on the accuracy of each measurement technique. In this study, a systematic calibration of the dielectric constant meter is also performed and applied to improve the accuracy of the cloud and clear points determined using this technique. The results show that a more accurate MZW can be estimated from the gap between the loci of the cloud and clear points. Finally, this study also confirms the generality of the calibration models used (obtained from experiments done in a 250-mL crystallizer), by applying these models for determining the cloud and clear points of the crystallization experiments performed in a different scale crystallizer (i.e. 1L crystallizer). The cloud and clear points determined using this calibration approach are found to be more accurate and
in close agreement with those detected by turbidity measurement and FBRM.
2.
Experimental
2.1.
Materials
Stearic acid (Sigma, 95%), paracetamol (Sigma, 98.0–101.0%) and carbamazepine (Suzhou Sintofarm) were used as received. HPLC grade of ethyl acetate, ethanol and methanol used in this study were purchased from Fisher Scientific.
2.2.
Solution crystallization
Solutions of stearic acid–ethyl acetate (SA–EtAc, 80 g/kg solvent), paracetamol–ethanol (PAC–EtOH, 240 g/kg solvent) and carbamazepine–methanol (CBZ–MeOH, 115 g/kg solvent) were used as model solution systems. Cooling crystallization and heating dissolution experiments of all three model solutions were conducted in both 250-mL and 1-L jacketed crystallizers. The experimental setups are shown in Fig. 1. The 1-L flatbottomed glass crystallizer with an inner diameter of 100 mm contains four glass baffles which enhance mixing of the solution. A stainless-steel marine-type impeller with a diameter of 42 mm driven by a variable speed overhead stirrer motor was utilized to agitate the system. The crystallizer setup was sealed properly using Parafilm® such that the evaporation of solvent could be greatly reduced. The temperature was controlled by a water circulator (Julabo FP50) equipped with a thermal couple (Julabo Pt100). A temperature ramping profile with the same heating and cooling rates was applied on the solutions. The solutions were pre-heated to 40 ◦ C and kept for ca. 1 h to ensure solution homogeneity; they were then slowly cooled at 10 ◦ C at constant rates (0.2 and 0.1 ◦ C/min for the 250-mL and 1-L crystallizers, respectively) and kept at 10 ◦ C for a certain period of time (20 min and 1 h for the 250-mL and 1-L crystallizers, respectively); finally they were heated back to 40 ◦ C using the same rates. In situ dielectric constant, turbidity and focused beam reflectance measurements of the solutions were performed
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Turbidity
Dielectric Constant
NDC 20
DDC
15
NTurb
DTurb
Temperature (ºC)
30
PAT Measurements (a.u.)
35 30 25 20
Dielectric Constant
15
0
NTurb
60
120
180
240
0
300
60
120
DTurb
using a dielectric constant meter (Scientifica 870) coupled with a data logging module (USB-9215A, National Instruments), a colorimeter (Brinkmann PC920) and a FBRM probe (Lasentec D600X), respectively. The corresponding measurements were recorded every 10 s using LabVIEW SignalExpress 2009 (National Instruments), an in-house Visual Basic® program and Control Interface Software (Lasentec), respectively. Note that the FBRM probe was only inserted into the 1-L crystallizer but not into the 250-mL crystallizer due to space constraints.
Calibration of solution using dielectric constant
The dielectric constant of a given solution system is known to be strongly dependent on temperature and solute concentration (Fröhlich, 1958). The calibration work on the solutions of paracetamol–ethanol (Hermanto et al., 2011) and carbamazepine–methanol were performed in the 250-mL crystallizer. The solutions were pre-heated to 40 ◦ C and kept for 20 min; they were then slowly cooled to different temperatures at 0.2 ◦ C/min (see Table S1 in supporting information for detailed conditions of the CBZ–MeOH solutions). In situ dielectric constant measurements were recorded every minute. Since the calibration measurements are only valid when the solutions are homogeneous, these calibration experiments were conducted under the solubility limit.
Results and discussion
3.1. Solution crystallization in the 250-mL jacketed crystallizer Three different model solution crystallization processes, namely stearic acid in ethyl acetate, paracetamol in ethanol, and carbamazepine in methanol were simultaneously monitored using two different techniques, namely dielectric constant and turbidity measurements in the 250-mL jacketed crystallizer. The temperature and PAT measurement profiles during the cooling–heating cycle for the three model solutions are shown in Figs. 2–4. Points N and D denote two different types of phase transition, namely the cloud and clear points, respectively. The cloud points determined using the dielectric constant meter and the turbidity meter are denoted as NDC and NTurb , respectively. These points correspond to the onset of nucleation during cooling. Theoretically, the cloud point should
240
300
Fig. 3 – PAT measurement profiles of paracetamol–ethanol solution (240 g/kg solvent) in the 250-mL crystallizer. The dash lines mark the discrepancies of the cloud and clear point measurements between dielectric constant meter and turbidity meter. indicate the appearance of the first crystal. In the present experiments, the occurrence of the cloud point was detected through different underlying principles by two PAT techniques. In the case of dielectric constant meter, the cloud point was observed through a drop of the solution dielectric constant resulting from a sudden decrease in solute concentration due to primary nucleation. NDC was taken as the point right before the drop (Figs. 2 and 3), or the point where the slope changes (Fig. 4) on the dielectric constant profile. In the case of turbidity meter, the emergence of solids from the homogeneous solution was detected through the change in the optical property. NTurb was determined when the absorbance reached 2% of its maximum value of the turbidity profile. It is expected that the occurrence of the first crystal takes place before either the drop of the dielectric constant or the change in optical property of the solution. Therefore, points NDC and NTurb should be regarded as approximations of the onset of nucleation. The clear point is defined as the disappearance of the last crystal during the heating process, i.e. the end of dissolution,
Temperature
40
Turbidity
NDC
35
Temperature (ºC)
Fig. 2 – PAT measurement profiles of stearic acid–ethyl acetate solution (80 g/kg solvent) in the 250-mL crystallizer.
180
Time (min)
Time (min)
3.
DDC
10
10
2.3. meter
Turbidity
NDC
30
Dielectric Constant
25
DDC
20 15
NTurb
DTurb
PAT Measurements (a.u.)
Temperature (ºC)
35
25
Temperature
40
PAT Measurements (a.u.)
Temperature
40
10 0
60
120
180
240
300
Time (min) Fig. 4 – PAT measurement profiles of carbamazepine–methanol solution (115 g/kg solvent) in the 250-mL crystallizer. The dash lines mark the discrepancies of the cloud and clear point measurements between dielectric constant meter and turbidity meter. The changes of slope triggered by two phase transitions are indicated by the tangent lines on the dielectric constant profile.
which was indicated by point DDC , marking a change of trend on the dielectric constant profile. In the case of turbidity measurement, the clear point DTurb was determined when the absorbance dropped below 2% of its maximum value of the turbidity profile. Note that the locus of the clear points asymptotically approaches the solubility curve when the heating rate is slow. The metastable zone width (MZW) of a given solution could be subsequently estimated as the gap between the loci of the cloud and clear points. In Fig. 2, stearic acid exhibited rapid nucleation/growth kinetics in ethyl acetate upon cooling, which resulted in abrupt changes of dielectric constant of the solution upon both the onset of nucleation and the end of dissolution. In such circumstance, the cloud and clear points can easily be determined from the dielectric constant profile. These cloud and clear points are nearly identical to those detected by the turbidity meter. Fig. 3 shows that the PAC–EtOH solution has responded differently upon cooling. The dielectric constant profile of the solution shows different characteristics due to the relatively moderate nucleation/growth kinetics. The cloud and clear points can still be directly identified as the changes in the dielectric constant profile are quite significant. However, this cloud point lagged the one determined by the turbidity meter. It is well recognized in the field that, due to the nature of measurement, techniques detecting the presence of particles are known to be more sensitive as compared to those monitoring solution bulk properties (Fujiwara et al., 2002; Simon et al., 2009b). For the clear point detection, there is no marked difference observed from these two PAT tools. In contrast to the SA–EtAc and PAC–EtOH solutions, where significant changes were observed in the dielectric constant profile, the dielectric constant of the CBZ–MeOH solution varied only slightly upon phase transitions (Fig. 4). After the onset of nucleation, only subtle change of slope was observed and this led to more obscure cloud point identification. One plausible explanation is that the CBZ crystals nucleate and/or grow slowly such that the expected drop in the dielectric constant caused by decreasing solute concentration is offset by the temperature influence (note that decrease in temperature leads to increase in dielectric constant (He et al., 2010)). Similar phenomenon is observed and analogous explanation can be postulated for the clear point detection. As seen in Fig. 4, there is no marked difference between the two PAT tools in the clear point identification. Similar to the PAC–EtOH solutions, the cloud point detected by the dielectric constant meter lagged the one detected by the turbidity meter.
3.2.
Calibration of dielectric constant
In both PAC–EtOH and CBZ–MeOH solutions, cloud point detection by dielectric constant meter was less sensitive as compared to the turbidity meter, due largely to the nature of measurement. The dielectric constant of a given solution correlates strongly with the coupled effects of temperature and solute concentration (Fröhlich, 1958; He et al., 2010). To decouple such effects, calibration was carried out by measuring dielectric constant of solutions with different temperatures and concentrations, as shown in our previous work (Hermanto et al., 2011). The calibration technique was applied accordingly to improve the accuracy of the cloud point detection.
DDC'
NDC'
40 35
Temperature
240 200
Turbidity (a.u.)
30 160
Concentration
25
120 20 80 15 NTurb
DTurb
10 0
60
120
180
240
40
Concentration (g/kg solvent)
chemical engineering research and design 9 0 ( 2 0 1 2 ) 259–265
Temperature (ºC)
262
300
Time (min) Fig. 5 – The temperature, turbidity and predicted solute concentration profiles of paracetamol–ethanol solution (240 g/kg solvent) in the 250-mL crystallizer. The dash lines mark the discrepancies of the cloud and clear point measurements between dielectric constant meter and turbidity meter. NDC and DDC are the cloud and clear points determined from the solute concentration profile (obtained from calibrated dielectric constant measurements), respectively.
3.2.1.
Paracetamol–ethanol solution
The formulation of calibration model of the dielectric constant for paracetamol–ethanol solution has been performed in our previous work (Hermanto et al., 2011). The best-fitting calibration model based on logarithmic–polynomial expansion was obtained: ln (ε) = 5.7508 − 3.1749 × 10−1 x − 1.0625 × 10−2 T + 9.7920 × 10−3 Tx − 5.0386x2 + 6.7731 × 10−3 T 2
(1)
where ε is the dielectric constant of solution, x is the mole fraction of the solute and T is the absolute temperature. Using Eq. (1), the dielectric constant profile of the PAC–EtOH solution shown in Fig. 3 was transformed into a solute concentration profile (Fig. 5). It is recognized that dielectric constant measurements are affected by the presence of solids (see Fig. S1 in supporting information for details). Therefore, the obtained solute concentration profiles do not correspond to the actual solute concentrations when solids are formed in the solution. This transformation, nevertheless, can successfully decouple the effect of temperature on the dielectric constant and leads to a clearer presentation of the effect of “solute concentration” on dielectric constant. Consequently, the cloud and clear points can be more clearly identified by the abrupt changes in the solute concentration profile upon the phase transitions. The results show that remarkable improvement on the cloud point identification is achieved by the present calibration technique. The previously observed lag in detection as compared to the turbidity meter is greatly reduced (see Table 1). With respect to the clear point determination, the results show that there is no significant difference in the detection resulting from turbidity measurement, noncalibrated and calibrated dielectric constant measurement.
3.2.2.
Carbamazepine–methanol solution
Analogously, the calibration measurements on the CBZ–MeOH solution were performed in this study and a calibration model for CBZ–MeOH solution was derived (see supporting
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Table 1 – Cloud and clear points of the three model solutions, stearic acid–ethyl acetate (80 g/kg solvent), paracetamol–ethanol (240 g/kg solvent) and carbamazepine–methanol (115 g/kg solvent) detected using turbidity and dielectric constant meters in the 250-mL crystallizer. Cloud point, N (◦ C) DC (non-calib.)
DC (calib.)
Turb
DC (non-calib.)
DC (calib.)
Turb
31.58 15.18 16.37
N/A 15.99 17.70
31.46 16.72 18.43
33.51 34.56 29.84
N/A 34.56 30.31
33.29 34.72 29.84
110
Concentration
100
Temperature
20
90
15 NTurb
80
DTurb
10 60
120
180
240
35 30
Dielectric Constant
25
NDC
DDC
20
10
300
0
Time (min)
NTurb
DTurb
NFBRM
DFBRM
120
240
360
480
600
720
Time (min)
information for details): ln(ε) = 5.1921 − 6.7402 × 10−3 T − 8.4111 × 10−1 x (2)
Using Eq. (2), the dielectric constant profile of the CBZ–MeOH solution shown in Fig. 4 was transformed into a solute concentration profile (Fig. 6). As compared to the dielectric constant profile, the solute concentration profile exhibits clearer changes upon the two phase transitions. The cloud point can also be more accurately determined since the effect of temperature on dielectric constant has been decoupled. These results show that the calibration technique could be used to improve not only the clarity, but also the accuracy of the cloud point detection. With respect to the clear point determination, the results show that there is no significant difference in the detection by all methods.
3.3. Solution crystallization in the 1-L jacketed crystallizer Similar cooling crystallization and heating dissolution experiments were performed for the three model solution systems in the 1-L jacketed crystallizer. In this setup, solution crystallization processes were simultaneously monitored using three different techniques, namely dielectric constant, turbidity measurements and FBRM. The cloud point (NFBRM ) and clear point (DFBRM ) were determined when the total counts reached and dropped below 2% of its maximum values, respectively. Meanwhile, NDC , NTurb , DDC , and DTurb were determined in the same way as those in the 250-mL crystallizer.
Fig. 7 – PAT measurement profiles of stearic acid–ethyl acetate solution (80 g/kg solvent) in the 1-L crystallizer. The temperature and PAT measurement profiles in the 1-L crystallizer were shown in Figs. 7–9 for the solutions of SA–EtAc, PAC–EtOH and CBZ–MeOH, respectively. The results are mostly similar to those obtained in the 250-mL crystallizer except for the dielectric constant profile of the CBZ-MeOH solution. In the 250-mL crystallizer, the dielectric constant only deviated slightly and no significant changes were observed upon both the onset of nucleation and the end of dissolution (Fig. 4). On the contrary, the changes in the dielectric constant profile triggered by both phase transitions were much more obvious in the 1-L crystallizer (Fig. 9). These differences are partly attributed to the dissimilar mixing characteristics in the crystallizers. Indeed, several different factors that affect mixing such as crystallizer geometry, stirrer type, vessel size, etc. are noted in these two crystallizers. Further
Temperature NDC
40
Turbidity
35
Temperature (ºC)
Fig. 6 – The temperature, turbidity and predicted solute concentration profiles of carbamazepine–methanol solution (115 g/kg solvent) in the 250-mL crystallizer. The dash lines mark the discrepancies of the cloud and clear point measurements between dielectric constant meter and turbidity meter.
+ 1.2005 × 10−2 Tx − 6.7076x2
FBRM
15
70 0
Turbidity
PAT Measurements (a.u.)
Temperature (ºC)
DDC' Turbidity (a.u.)
30 25
120
NDC'
35
Temperature
40
PAT Measurements (a.u.)
130 40
Temperature (ºC)
SA–EtAc PAC–EtOH CBZ–MeOH
Clear point, D (◦ C)
Concentration (g/kg solvent)
Solution
FBRM
30 25 20
DDC
Dielectric Constant
15
NTurb
10
DTurb DFBRM
NFBRM 0
120
240
360
480
600
720
Time (min) Fig. 8 – PAT measurement profiles of paracetamol–ethanol solution (240 g/kg solvent) in the 1-L crystallizer. The dash lines mark the discrepancies of the cloud and clear point measurements between dielectric constant meter and the other PAT tools.
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NDC
a
Turbidity
FBRM
30 25
DDC Dielectric Constant
20 15
NTurb
10
DTurb
120
240
360
12
DC calib Turbidity
8
4
DFBRM
NFBRM 0
16
MZW (°C)
Temperature (ºC)
35
20 DC non-calib
PAT Measurements (a.u.)
Temperature
40
480
600
720
0
SA-EtAc
Time (min)
PAC-EtOH
CBZ-MeOH
Solution System Fig. 9 – PAT measurement profiles of carbamazepine–methanol solution (115 g/kg solvent) in the 1-L crystallizer. The dash lines mark the discrepancies of the cloud and clear point measurements between dielectric constant meter and the other PAT tools.
20 DC non-calib
16
MZW (°C)
study on the effect of mixing on the dielectric constant profile is beyond the scope of this work. In general, the clear points determined by all three PAT techniques, namely, turbidity measurement, FBRM, dielectric constant measurement (both non-calibrated and calibrated) coincide with each other, with average difference of ca. 0.5 ◦ C (Table 2). Similar to the previous observations in the 250mL crystallizer, the cloud point detection in both PAC–EtOH and CBZ–MeOH solutions by the dielectric constant meter still lagged when compared to those by the turbidity meter and FBRM. However, such lag was absent in the case of SA–EtAc solution due to the relatively fast nucleation/growth and dissolution kinetics. In order to improve the accuracy of cloud point detection in both PAC–EtOH and CBZ–MeOH solutions, their dielectric constant profiles (Figs. 8 and 9) are transformed into the solute concentration profiles (see Figs. S4 and S5 in supporting information for details) using the previously obtained calibration models (Eqs. (1) and (2)). Note that although these calibration models were developed for the solution crystallization in the 250 mL crystallizer, they are related only to the solution properties and therefore should be applicable for the same solution system performed in other experimental setups. The cloud and clear points were subsequently identified by the abrupt changes in the solute concentration profile upon the phase transitions. The results show remarkable improvement on the cloud point identification in both solutions. The previous lags in detection as compared to the turbidity meter and FBRM are significantly reduced (Table 2). Accordingly, this study also confirms the generality of the calibration models which can be utilized in other crystallizer setups.
b
DC calib Turbidity
12
FBRM
8
4
0 SA-EtAc
PAC-EtOH
CBZ-MeOH
Solution System Fig. 10 – The metastable zone width of the three model solutions estimated by the cloud and clear points determined using different PAT tools (a) in the 250-mL crystallizer; and (b) in the 1-L crystallizer. Note that the calibration of the dielectric constant of SA–EtAC solution was not performed because the cloud and clear points determined non-calibrated dielectric constant measurements were in excellent agreement with those obtained by turbidity and FBRM measurements.
3.4.
Determination of metastable zone width
In both 250-mL and 1-L crystallizers, all three PAT techniques detect not only the cloud point temperature that indicates the onset of nucleation, but also the clear point temperature that can be approximated as the solubility limit when the heating rate during the dissolution of particles is low (Granberg and Rasmuson, 1999; Heryanto et al., 2007; Liu et al., 2008). The MZW of different solutions can be estimated as the gap between the loci of cloud and clear points detected by different PAT tools (Fig. 10). The results show that dielectric constant meter can be used to provide a reliable estimate of the MZW,
Table 2 – Cloud and clear points of the three model solutions, stearic acid–ethyl acetate (80 g/kg solvent), paracetamol–ethanol (240 g/kg solvent) and carbamazepine–methanol (115 g/kg solvent) detected using a FBRM probe, a turbidity meter and a dielectric constant meter in the 1-L crystallizer. System
SA–EtAc PAC–EtOH CBZ–MeOH
Cloud point, N (◦ C)
Clear point, D (◦ C)
FBRM
Turb
DC (non-calib.)
DC (calib.)
FBRM
Turb
DC (non-calib.)
DC (calib.)
32.11 21.51 11.97
32.1 21.61 12.09
32.17 20.01 11.33
N/A 21.56 12.02
33.53 34.84 29.24
33.53 34.99 29.59
33.23 35.35 29.98
N/A 35.29 30.19
chemical engineering research and design 9 0 ( 2 0 1 2 ) 259–265
and its accuracy can be improved through the calibration technique as shown above.
4.
Conclusion
In this work, comparison studies between dielectric constant meter and more established PAT tools, namely turbidity meter and FBRM in monitoring solution crystallization processes have been carried out. The results have shown that the dielectric constant meter can be used to detect the cloud and clear points such that the MZW can be reliably estimated. As a technique that measures solution bulk property, the dielectric constant measurement depends on the coupled effects of temperature and solute concentration. As a result, dielectric constant meter is inherently less sensitive in detecting phase transitions as compared to techniques that detect presence of solids such as turbidity meter and FBRM. In view of this, a calibration technique is applied accordingly to transform the dielectric constant profile to a solute concentration profile, which results in more accurate cloud point detection. The cloud and clear points determined using this calibration approach are in close agreement with those detected by turbidity measurement and FBRM. This study opens new opportunities for the use of the dielectric constant meter as a simple and inexpensive alternative PAT tool in the field of crystallization process monitoring.
Acknowledgment This work was supported by the Science and Engineering Research Council of A*STAR (Agency for Science, Technology and Research), Singapore.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.cherd.2011.07.005.
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Gürbüz, H., Özdemir, B., 2003. Experimental determination of the metastable zone width of borax decahydrate by ultrasonic velocity measurement. J. Cryst. Growth 252, 343–349. He, G., Tjahjono, M., Chow, P.S., Tan, R.B.H., Garland, M., 2010. In situ determination of metastable zone width using dielectric constant measurement. Org. Process Res. Dev. 14, 1469–1472. Hermanto, M.W., He, G., Tjahjono, M., Chow, P.S., Tan, R.B.H., Garland, M., 2011. Calibration of dielectric constant to improve the detection of cloud and clear points in solution crystallization. Chem. Eng. Res. Des., doi:10.1016/j.cherd.2011.1004.1012. Heryanto, R., Hasan, M., Abdullaha, E.C., Kumoro, A.C., 2007. Solubility of atearic acid in various organic solvents and its prediction using non-ideal solution models. ScienceAsia 33, 469–472. Kumar, F.J., Moorthy, S.G., Jayaraman, D., Subramanian, C., 1996. Estimation of metastable zone width, interfacial energy and growth rates of KTiOPO4 crystallizing from K6 P4 O13 flux by hot stage microscopy. J. Cryst. Growth 160, 129–135. Lewiner, F., Klein, J.P., Puel, F., Févotte, G., 2001. On-line ATR FTIR measurement of supersaturation during solution crystallization processes calibration and applications on three solute/solvent systems. Chem. Eng. Sci. 56, 2069–2084. Liu, W., Dang, L., Black, S.N., Wei, H., 2008. Solubility of carbamazepine (form III) in different solvents from (275 to 343) K. J. Chem. Eng. Data 53, 2204–2206. Löffelmann, M., Mersmann, A., 2002. How to measure supersaturation? Chem. Eng. Sci. 57, 4301–4310. Marciniak, B., 2002. Density and ultrasonic velocity of undersaturated and supersaturated solutions of fluoranthene in trichloroethylene, and study of their metastable zone width. J. Cryst. Growth 236, 347–356. Mullin, J.W., 2001. Crystallization. Butterworth-Heinemann, Oxford. . Myerson, A.S. (Ed.), 2001. Handbook of Industrial Crystallization, Butterworth-Heinemann, Oxford. Myerson, A.S., Jang, S.M., 1999. A comparison of binding energy and metastable zone width for adipic acid with various additives. J. Cryst. Growth 156, 459–466. Nyvlt, J., Sohnel, O., Matuchova, M., Broul, M., 1985. The Kinetics of Industrial Crystallization. Elsevier, New York. O’Grady, D., Barrett, M., Casey, E., Glennon, B., 2007. The effect of mixing on the metastable zone width and nucleation kinetics in the anti-solvent crystallization of benzoic acid. Chem. Eng. Res. Des. 85, 945–952. Parsons, A.R., Black, S.N., Colling, R., 2003. Automated measurement of metastable zones for pharmaceutical compounds. Trans. IChemE A 81, 700–704. Pöllänen, K., Häkkinen, A., Reinikainen, S.-P., Louhi-Kultanen, M., Nyström, L., 2006. A study on batch cooling crystallization of sulphathiazole process monitoring using ATR-FTIR and product characterization by automated image analysis. Chem. Eng. Res. Des. 84, 47–59. Schöll, J., Vicum, L., Müller, M., Mazzotti, M., 2006. Precipitation of l-glutamic acid: determination of nucleation kinetics. Chem. Eng. Technol. 29, 257–264. Simon, L.L., Nagy, Z.K., Hungerbuhler, K., 2009a. Comparison of external bulk video imaging with focused beam reflectance measurement and ultra-violet spectroscopy for metastable zone identification in food and pharmaceutical crystallization processes. Chem. Eng. Sci. 64, 3344–3351. Simon, L.L., Nagy, Z.K., Hungerbuhler, K., 2009b. Endoscopy-based in situ bulk video imaging of batch crystallization processes. Org. Process Res. Dev. 13, 1254–1261. Trifkovica, M., Sheikhzadeha, M., Rohani, S., 2009. Determination of metastable zone width for combined anti-solvent/cooling crystallization. J. Cryst. Growth 14, 3640–3650.
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Chemical Engineering Research and Design journal homepage: www.elsevier.com/locate/cherd
Comparison of dielectric constant meter with turbidity meter and focused beam reflectance measurement for metastable zone width determination Guangwen He a,∗ , Martin W. Hermanto a , Martin Tjahjono a , Pui Shan Chow a , Reginald B.H. Tan a,b , Marc Garland a a
Institute of Chemical & Engineering Sciences, A*STAR (Agency for Science, Technology and Research), 1 Pesek Road, Jurong Island, Singapore 627833, Singapore b Department of Chemical & Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117576, Singapore
a b s t r a c t This work demonstrates a detailed process analytical technology (PAT) comparison study of dielectric constant measurement with turbidity measurement and focused beam reflectance measurement (FBRM) in detecting phase transitions during crystallization of three model solutions, namely stearic acid–ethyl acetate, paracetamol–ethanol and carbamazepine–methanol. The cloud and clear points determined by the dielectric constant measurement are found to be in close agreement with those obtained from the other two well-established PAT tools. A calibration technique can be further applied on the dielectric constant to improve the accuracy of the cloud point detection. The results have shown that the dielectric constant meter can be reliably used for metastable zone width (MZW) determination. This study opens new opportunities for the use of the dielectric constant meter as a simple and inexpensive alternative PAT tool for process monitoring of solution crystallization. Crown Copyright © 2011 Published by Elsevier B.V. on behalf of The Institution of Chemical Engineers. All rights reserved. Keywords: Dielectric constant; Metastable zone width; Process analytical technology; Phase transition
1.
Introduction
Solution crystallization has been widely used for the formation, separation and purification of synthetic intermediates, final solid products in fine chemical, pharmaceutical and agrochemical industries (Mullin, 2001; Myerson, 2001). The metastable zone width (MZW), which denotes the region between the solubility curve and the onset of nucleation (Mullin, 2001), marks an operating boundary during solution crystallization processes to avoid excessive secondary nucleation thus ensuring the required size and size distribution of the final crystalline particles. The information on MZW is therefore essential for the crystallization processes. This parameter is known to be process dependent and can be influenced by numerous factors including cooling rate, solvent
∗
composition, mechanical agitation, impurities in the solution, etc. (Nyvlt et al., 1985). Many process analytical technologies (PATs) have been developed in the past decade for in situ determination of the MZW during solution crystallization processes (Kumar et al., 1996; Groen and Roberts, 2001; Lewiner et al., 2001; Fujiwara et al., 2002; Löffelmann and Mersmann, 2002; Marciniak, 2002; Gürbüz and Özdemir, 2003; Parsons et al., 2003; Genceli et al., 2005; Pöllänen et al., 2006; Schöll et al., 2006; O’Grady et al., 2007; Simon et al., 2009a). These techniques include, but are not limited to, direct visual observation using hot stage microscopy (HSM) (Kumar et al., 1996), in-process video microscopy (PVM) (Barrett and Glennon, 2002) and bulk video imaging (Simon et al., 2009b); detection of the presence of solid particles using focused beam reflectance measurement (FBRM) (Fujiwara et al., 2002; Schöll et al., 2006; O’Grady et al., 2007) and turbidity meter (Parsons et al., 2003); thermal method using differential scanning calorimeter (DSC) (Myerson and Jang, 1999); and monitoring of the solute
Corresponding author. Tel.: +65 6796 3779. E-mail address: he [email protected] (G. He). Received 24 May 2011; Received in revised form 5 July 2011; Accepted 9 July 2011
0263-8762/$ – see front matter Crown Copyright © 2011 Published by Elsevier B.V. on behalf of The Institution of Chemical Engineers. All rights reserved.
doi:10.1016/j.cherd.2011.07.005
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Fig. 1 – Schematics of the experimental setups. (a) The 250-mL jacketed crystallizer: (1) turbidity probe; (2) thermocouple; (3) dielectric constant probe; and (4) magnetic stirrer bar. (b) The l-L jacketed crystallizer: (1) overhead motor; (2) turbidity probe; (3) thermocouple; (4) dielectric constant probe; (5) FBRM probe; (6) baffle; and (7) impeller.
concentration change via bulk solution property measurements using attenuated reflection-Fourier transform infrared (ATR-FTIR) (Groen and Roberts, 2001; Lewiner et al., 2001; Fujiwara et al., 2002; Pöllänen et al., 2006; Schöll et al., 2006; O’Grady et al., 2007; Trifkovica et al., 2009), ultra-violet–visible (UV–vis) spectroscopy (Simon et al., 2009a), densitometer (Marciniak, 2002), ultrasonic velocity meter (Marciniak, 2002; Gürbüz and Özdemir, 2003), quartz crystal sensor (Löffelmann and Mersmann, 2002), conductivity and refractive index meter (Genceli et al., 2005), etc. In our previous work, we have demonstrated the first use of a dielectric constant meter, coupled with an automated data logging module for in situ monitoring of a solution crystallization process (He et al., 2010). The dielectric constant measurement offers an alternative PAT tool for in situ monitoring of solution crystallization. The instrument is also relatively inexpensive when compared to some other measurements as mentioned above (i.e. HSM, FBRM, ATR-FTIR, densitometer, etc.). In the present contribution, a more detailed PAT comparison in monitoring solution crystallization is carried out using dielectric constant meter and other more established techniques, namely, turbidity meter and/or FBRM. Three different model solution crystallization processes, namely stearic acid in ethyl acetate, paracetamol in ethanol, and carbamazepine in methanol are investigated. These three model solution systems have different nucleation/growth characteristics which can facilitate a wider assessment on the accuracy of each measurement technique. In this study, a systematic calibration of the dielectric constant meter is also performed and applied to improve the accuracy of the cloud and clear points determined using this technique. The results show that a more accurate MZW can be estimated from the gap between the loci of the cloud and clear points. Finally, this study also confirms the generality of the calibration models used (obtained from experiments done in a 250-mL crystallizer), by applying these models for determining the cloud and clear points of the crystallization experiments performed in a different scale crystallizer (i.e. 1L crystallizer). The cloud and clear points determined using this calibration approach are found to be more accurate and
in close agreement with those detected by turbidity measurement and FBRM.
2.
Experimental
2.1.
Materials
Stearic acid (Sigma, 95%), paracetamol (Sigma, 98.0–101.0%) and carbamazepine (Suzhou Sintofarm) were used as received. HPLC grade of ethyl acetate, ethanol and methanol used in this study were purchased from Fisher Scientific.
2.2.
Solution crystallization
Solutions of stearic acid–ethyl acetate (SA–EtAc, 80 g/kg solvent), paracetamol–ethanol (PAC–EtOH, 240 g/kg solvent) and carbamazepine–methanol (CBZ–MeOH, 115 g/kg solvent) were used as model solution systems. Cooling crystallization and heating dissolution experiments of all three model solutions were conducted in both 250-mL and 1-L jacketed crystallizers. The experimental setups are shown in Fig. 1. The 1-L flatbottomed glass crystallizer with an inner diameter of 100 mm contains four glass baffles which enhance mixing of the solution. A stainless-steel marine-type impeller with a diameter of 42 mm driven by a variable speed overhead stirrer motor was utilized to agitate the system. The crystallizer setup was sealed properly using Parafilm® such that the evaporation of solvent could be greatly reduced. The temperature was controlled by a water circulator (Julabo FP50) equipped with a thermal couple (Julabo Pt100). A temperature ramping profile with the same heating and cooling rates was applied on the solutions. The solutions were pre-heated to 40 ◦ C and kept for ca. 1 h to ensure solution homogeneity; they were then slowly cooled at 10 ◦ C at constant rates (0.2 and 0.1 ◦ C/min for the 250-mL and 1-L crystallizers, respectively) and kept at 10 ◦ C for a certain period of time (20 min and 1 h for the 250-mL and 1-L crystallizers, respectively); finally they were heated back to 40 ◦ C using the same rates. In situ dielectric constant, turbidity and focused beam reflectance measurements of the solutions were performed
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Turbidity
Dielectric Constant
NDC 20
DDC
15
NTurb
DTurb
Temperature (ºC)
30
PAT Measurements (a.u.)
35 30 25 20
Dielectric Constant
15
0
NTurb
60
120
180
240
0
300
60
120
DTurb
using a dielectric constant meter (Scientifica 870) coupled with a data logging module (USB-9215A, National Instruments), a colorimeter (Brinkmann PC920) and a FBRM probe (Lasentec D600X), respectively. The corresponding measurements were recorded every 10 s using LabVIEW SignalExpress 2009 (National Instruments), an in-house Visual Basic® program and Control Interface Software (Lasentec), respectively. Note that the FBRM probe was only inserted into the 1-L crystallizer but not into the 250-mL crystallizer due to space constraints.
Calibration of solution using dielectric constant
The dielectric constant of a given solution system is known to be strongly dependent on temperature and solute concentration (Fröhlich, 1958). The calibration work on the solutions of paracetamol–ethanol (Hermanto et al., 2011) and carbamazepine–methanol were performed in the 250-mL crystallizer. The solutions were pre-heated to 40 ◦ C and kept for 20 min; they were then slowly cooled to different temperatures at 0.2 ◦ C/min (see Table S1 in supporting information for detailed conditions of the CBZ–MeOH solutions). In situ dielectric constant measurements were recorded every minute. Since the calibration measurements are only valid when the solutions are homogeneous, these calibration experiments were conducted under the solubility limit.
Results and discussion
3.1. Solution crystallization in the 250-mL jacketed crystallizer Three different model solution crystallization processes, namely stearic acid in ethyl acetate, paracetamol in ethanol, and carbamazepine in methanol were simultaneously monitored using two different techniques, namely dielectric constant and turbidity measurements in the 250-mL jacketed crystallizer. The temperature and PAT measurement profiles during the cooling–heating cycle for the three model solutions are shown in Figs. 2–4. Points N and D denote two different types of phase transition, namely the cloud and clear points, respectively. The cloud points determined using the dielectric constant meter and the turbidity meter are denoted as NDC and NTurb , respectively. These points correspond to the onset of nucleation during cooling. Theoretically, the cloud point should
240
300
Fig. 3 – PAT measurement profiles of paracetamol–ethanol solution (240 g/kg solvent) in the 250-mL crystallizer. The dash lines mark the discrepancies of the cloud and clear point measurements between dielectric constant meter and turbidity meter. indicate the appearance of the first crystal. In the present experiments, the occurrence of the cloud point was detected through different underlying principles by two PAT techniques. In the case of dielectric constant meter, the cloud point was observed through a drop of the solution dielectric constant resulting from a sudden decrease in solute concentration due to primary nucleation. NDC was taken as the point right before the drop (Figs. 2 and 3), or the point where the slope changes (Fig. 4) on the dielectric constant profile. In the case of turbidity meter, the emergence of solids from the homogeneous solution was detected through the change in the optical property. NTurb was determined when the absorbance reached 2% of its maximum value of the turbidity profile. It is expected that the occurrence of the first crystal takes place before either the drop of the dielectric constant or the change in optical property of the solution. Therefore, points NDC and NTurb should be regarded as approximations of the onset of nucleation. The clear point is defined as the disappearance of the last crystal during the heating process, i.e. the end of dissolution,
Temperature
40
Turbidity
NDC
35
Temperature (ºC)
Fig. 2 – PAT measurement profiles of stearic acid–ethyl acetate solution (80 g/kg solvent) in the 250-mL crystallizer.
180
Time (min)
Time (min)
3.
DDC
10
10
2.3. meter
Turbidity
NDC
30
Dielectric Constant
25
DDC
20 15
NTurb
DTurb
PAT Measurements (a.u.)
Temperature (ºC)
35
25
Temperature
40
PAT Measurements (a.u.)
Temperature
40
10 0
60
120
180
240
300
Time (min) Fig. 4 – PAT measurement profiles of carbamazepine–methanol solution (115 g/kg solvent) in the 250-mL crystallizer. The dash lines mark the discrepancies of the cloud and clear point measurements between dielectric constant meter and turbidity meter. The changes of slope triggered by two phase transitions are indicated by the tangent lines on the dielectric constant profile.
which was indicated by point DDC , marking a change of trend on the dielectric constant profile. In the case of turbidity measurement, the clear point DTurb was determined when the absorbance dropped below 2% of its maximum value of the turbidity profile. Note that the locus of the clear points asymptotically approaches the solubility curve when the heating rate is slow. The metastable zone width (MZW) of a given solution could be subsequently estimated as the gap between the loci of the cloud and clear points. In Fig. 2, stearic acid exhibited rapid nucleation/growth kinetics in ethyl acetate upon cooling, which resulted in abrupt changes of dielectric constant of the solution upon both the onset of nucleation and the end of dissolution. In such circumstance, the cloud and clear points can easily be determined from the dielectric constant profile. These cloud and clear points are nearly identical to those detected by the turbidity meter. Fig. 3 shows that the PAC–EtOH solution has responded differently upon cooling. The dielectric constant profile of the solution shows different characteristics due to the relatively moderate nucleation/growth kinetics. The cloud and clear points can still be directly identified as the changes in the dielectric constant profile are quite significant. However, this cloud point lagged the one determined by the turbidity meter. It is well recognized in the field that, due to the nature of measurement, techniques detecting the presence of particles are known to be more sensitive as compared to those monitoring solution bulk properties (Fujiwara et al., 2002; Simon et al., 2009b). For the clear point detection, there is no marked difference observed from these two PAT tools. In contrast to the SA–EtAc and PAC–EtOH solutions, where significant changes were observed in the dielectric constant profile, the dielectric constant of the CBZ–MeOH solution varied only slightly upon phase transitions (Fig. 4). After the onset of nucleation, only subtle change of slope was observed and this led to more obscure cloud point identification. One plausible explanation is that the CBZ crystals nucleate and/or grow slowly such that the expected drop in the dielectric constant caused by decreasing solute concentration is offset by the temperature influence (note that decrease in temperature leads to increase in dielectric constant (He et al., 2010)). Similar phenomenon is observed and analogous explanation can be postulated for the clear point detection. As seen in Fig. 4, there is no marked difference between the two PAT tools in the clear point identification. Similar to the PAC–EtOH solutions, the cloud point detected by the dielectric constant meter lagged the one detected by the turbidity meter.
3.2.
Calibration of dielectric constant
In both PAC–EtOH and CBZ–MeOH solutions, cloud point detection by dielectric constant meter was less sensitive as compared to the turbidity meter, due largely to the nature of measurement. The dielectric constant of a given solution correlates strongly with the coupled effects of temperature and solute concentration (Fröhlich, 1958; He et al., 2010). To decouple such effects, calibration was carried out by measuring dielectric constant of solutions with different temperatures and concentrations, as shown in our previous work (Hermanto et al., 2011). The calibration technique was applied accordingly to improve the accuracy of the cloud point detection.
DDC'
NDC'
40 35
Temperature
240 200
Turbidity (a.u.)
30 160
Concentration
25
120 20 80 15 NTurb
DTurb
10 0
60
120
180
240
40
Concentration (g/kg solvent)
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Temperature (ºC)
262
300
Time (min) Fig. 5 – The temperature, turbidity and predicted solute concentration profiles of paracetamol–ethanol solution (240 g/kg solvent) in the 250-mL crystallizer. The dash lines mark the discrepancies of the cloud and clear point measurements between dielectric constant meter and turbidity meter. NDC and DDC are the cloud and clear points determined from the solute concentration profile (obtained from calibrated dielectric constant measurements), respectively.
3.2.1.
Paracetamol–ethanol solution
The formulation of calibration model of the dielectric constant for paracetamol–ethanol solution has been performed in our previous work (Hermanto et al., 2011). The best-fitting calibration model based on logarithmic–polynomial expansion was obtained: ln (ε) = 5.7508 − 3.1749 × 10−1 x − 1.0625 × 10−2 T + 9.7920 × 10−3 Tx − 5.0386x2 + 6.7731 × 10−3 T 2
(1)
where ε is the dielectric constant of solution, x is the mole fraction of the solute and T is the absolute temperature. Using Eq. (1), the dielectric constant profile of the PAC–EtOH solution shown in Fig. 3 was transformed into a solute concentration profile (Fig. 5). It is recognized that dielectric constant measurements are affected by the presence of solids (see Fig. S1 in supporting information for details). Therefore, the obtained solute concentration profiles do not correspond to the actual solute concentrations when solids are formed in the solution. This transformation, nevertheless, can successfully decouple the effect of temperature on the dielectric constant and leads to a clearer presentation of the effect of “solute concentration” on dielectric constant. Consequently, the cloud and clear points can be more clearly identified by the abrupt changes in the solute concentration profile upon the phase transitions. The results show that remarkable improvement on the cloud point identification is achieved by the present calibration technique. The previously observed lag in detection as compared to the turbidity meter is greatly reduced (see Table 1). With respect to the clear point determination, the results show that there is no significant difference in the detection resulting from turbidity measurement, noncalibrated and calibrated dielectric constant measurement.
3.2.2.
Carbamazepine–methanol solution
Analogously, the calibration measurements on the CBZ–MeOH solution were performed in this study and a calibration model for CBZ–MeOH solution was derived (see supporting
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Table 1 – Cloud and clear points of the three model solutions, stearic acid–ethyl acetate (80 g/kg solvent), paracetamol–ethanol (240 g/kg solvent) and carbamazepine–methanol (115 g/kg solvent) detected using turbidity and dielectric constant meters in the 250-mL crystallizer. Cloud point, N (◦ C) DC (non-calib.)
DC (calib.)
Turb
DC (non-calib.)
DC (calib.)
Turb
31.58 15.18 16.37
N/A 15.99 17.70
31.46 16.72 18.43
33.51 34.56 29.84
N/A 34.56 30.31
33.29 34.72 29.84
110
Concentration
100
Temperature
20
90
15 NTurb
80
DTurb
10 60
120
180
240
35 30
Dielectric Constant
25
NDC
DDC
20
10
300
0
Time (min)
NTurb
DTurb
NFBRM
DFBRM
120
240
360
480
600
720
Time (min)
information for details): ln(ε) = 5.1921 − 6.7402 × 10−3 T − 8.4111 × 10−1 x (2)
Using Eq. (2), the dielectric constant profile of the CBZ–MeOH solution shown in Fig. 4 was transformed into a solute concentration profile (Fig. 6). As compared to the dielectric constant profile, the solute concentration profile exhibits clearer changes upon the two phase transitions. The cloud point can also be more accurately determined since the effect of temperature on dielectric constant has been decoupled. These results show that the calibration technique could be used to improve not only the clarity, but also the accuracy of the cloud point detection. With respect to the clear point determination, the results show that there is no significant difference in the detection by all methods.
3.3. Solution crystallization in the 1-L jacketed crystallizer Similar cooling crystallization and heating dissolution experiments were performed for the three model solution systems in the 1-L jacketed crystallizer. In this setup, solution crystallization processes were simultaneously monitored using three different techniques, namely dielectric constant, turbidity measurements and FBRM. The cloud point (NFBRM ) and clear point (DFBRM ) were determined when the total counts reached and dropped below 2% of its maximum values, respectively. Meanwhile, NDC , NTurb , DDC , and DTurb were determined in the same way as those in the 250-mL crystallizer.
Fig. 7 – PAT measurement profiles of stearic acid–ethyl acetate solution (80 g/kg solvent) in the 1-L crystallizer. The temperature and PAT measurement profiles in the 1-L crystallizer were shown in Figs. 7–9 for the solutions of SA–EtAc, PAC–EtOH and CBZ–MeOH, respectively. The results are mostly similar to those obtained in the 250-mL crystallizer except for the dielectric constant profile of the CBZ-MeOH solution. In the 250-mL crystallizer, the dielectric constant only deviated slightly and no significant changes were observed upon both the onset of nucleation and the end of dissolution (Fig. 4). On the contrary, the changes in the dielectric constant profile triggered by both phase transitions were much more obvious in the 1-L crystallizer (Fig. 9). These differences are partly attributed to the dissimilar mixing characteristics in the crystallizers. Indeed, several different factors that affect mixing such as crystallizer geometry, stirrer type, vessel size, etc. are noted in these two crystallizers. Further
Temperature NDC
40
Turbidity
35
Temperature (ºC)
Fig. 6 – The temperature, turbidity and predicted solute concentration profiles of carbamazepine–methanol solution (115 g/kg solvent) in the 250-mL crystallizer. The dash lines mark the discrepancies of the cloud and clear point measurements between dielectric constant meter and turbidity meter.
+ 1.2005 × 10−2 Tx − 6.7076x2
FBRM
15
70 0
Turbidity
PAT Measurements (a.u.)
Temperature (ºC)
DDC' Turbidity (a.u.)
30 25
120
NDC'
35
Temperature
40
PAT Measurements (a.u.)
130 40
Temperature (ºC)
SA–EtAc PAC–EtOH CBZ–MeOH
Clear point, D (◦ C)
Concentration (g/kg solvent)
Solution
FBRM
30 25 20
DDC
Dielectric Constant
15
NTurb
10
DTurb DFBRM
NFBRM 0
120
240
360
480
600
720
Time (min) Fig. 8 – PAT measurement profiles of paracetamol–ethanol solution (240 g/kg solvent) in the 1-L crystallizer. The dash lines mark the discrepancies of the cloud and clear point measurements between dielectric constant meter and the other PAT tools.
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NDC
a
Turbidity
FBRM
30 25
DDC Dielectric Constant
20 15
NTurb
10
DTurb
120
240
360
12
DC calib Turbidity
8
4
DFBRM
NFBRM 0
16
MZW (°C)
Temperature (ºC)
35
20 DC non-calib
PAT Measurements (a.u.)
Temperature
40
480
600
720
0
SA-EtAc
Time (min)
PAC-EtOH
CBZ-MeOH
Solution System Fig. 9 – PAT measurement profiles of carbamazepine–methanol solution (115 g/kg solvent) in the 1-L crystallizer. The dash lines mark the discrepancies of the cloud and clear point measurements between dielectric constant meter and the other PAT tools.
20 DC non-calib
16
MZW (°C)
study on the effect of mixing on the dielectric constant profile is beyond the scope of this work. In general, the clear points determined by all three PAT techniques, namely, turbidity measurement, FBRM, dielectric constant measurement (both non-calibrated and calibrated) coincide with each other, with average difference of ca. 0.5 ◦ C (Table 2). Similar to the previous observations in the 250mL crystallizer, the cloud point detection in both PAC–EtOH and CBZ–MeOH solutions by the dielectric constant meter still lagged when compared to those by the turbidity meter and FBRM. However, such lag was absent in the case of SA–EtAc solution due to the relatively fast nucleation/growth and dissolution kinetics. In order to improve the accuracy of cloud point detection in both PAC–EtOH and CBZ–MeOH solutions, their dielectric constant profiles (Figs. 8 and 9) are transformed into the solute concentration profiles (see Figs. S4 and S5 in supporting information for details) using the previously obtained calibration models (Eqs. (1) and (2)). Note that although these calibration models were developed for the solution crystallization in the 250 mL crystallizer, they are related only to the solution properties and therefore should be applicable for the same solution system performed in other experimental setups. The cloud and clear points were subsequently identified by the abrupt changes in the solute concentration profile upon the phase transitions. The results show remarkable improvement on the cloud point identification in both solutions. The previous lags in detection as compared to the turbidity meter and FBRM are significantly reduced (Table 2). Accordingly, this study also confirms the generality of the calibration models which can be utilized in other crystallizer setups.
b
DC calib Turbidity
12
FBRM
8
4
0 SA-EtAc
PAC-EtOH
CBZ-MeOH
Solution System Fig. 10 – The metastable zone width of the three model solutions estimated by the cloud and clear points determined using different PAT tools (a) in the 250-mL crystallizer; and (b) in the 1-L crystallizer. Note that the calibration of the dielectric constant of SA–EtAC solution was not performed because the cloud and clear points determined non-calibrated dielectric constant measurements were in excellent agreement with those obtained by turbidity and FBRM measurements.
3.4.
Determination of metastable zone width
In both 250-mL and 1-L crystallizers, all three PAT techniques detect not only the cloud point temperature that indicates the onset of nucleation, but also the clear point temperature that can be approximated as the solubility limit when the heating rate during the dissolution of particles is low (Granberg and Rasmuson, 1999; Heryanto et al., 2007; Liu et al., 2008). The MZW of different solutions can be estimated as the gap between the loci of cloud and clear points detected by different PAT tools (Fig. 10). The results show that dielectric constant meter can be used to provide a reliable estimate of the MZW,
Table 2 – Cloud and clear points of the three model solutions, stearic acid–ethyl acetate (80 g/kg solvent), paracetamol–ethanol (240 g/kg solvent) and carbamazepine–methanol (115 g/kg solvent) detected using a FBRM probe, a turbidity meter and a dielectric constant meter in the 1-L crystallizer. System
SA–EtAc PAC–EtOH CBZ–MeOH
Cloud point, N (◦ C)
Clear point, D (◦ C)
FBRM
Turb
DC (non-calib.)
DC (calib.)
FBRM
Turb
DC (non-calib.)
DC (calib.)
32.11 21.51 11.97
32.1 21.61 12.09
32.17 20.01 11.33
N/A 21.56 12.02
33.53 34.84 29.24
33.53 34.99 29.59
33.23 35.35 29.98
N/A 35.29 30.19
chemical engineering research and design 9 0 ( 2 0 1 2 ) 259–265
and its accuracy can be improved through the calibration technique as shown above.
4.
Conclusion
In this work, comparison studies between dielectric constant meter and more established PAT tools, namely turbidity meter and FBRM in monitoring solution crystallization processes have been carried out. The results have shown that the dielectric constant meter can be used to detect the cloud and clear points such that the MZW can be reliably estimated. As a technique that measures solution bulk property, the dielectric constant measurement depends on the coupled effects of temperature and solute concentration. As a result, dielectric constant meter is inherently less sensitive in detecting phase transitions as compared to techniques that detect presence of solids such as turbidity meter and FBRM. In view of this, a calibration technique is applied accordingly to transform the dielectric constant profile to a solute concentration profile, which results in more accurate cloud point detection. The cloud and clear points determined using this calibration approach are in close agreement with those detected by turbidity measurement and FBRM. This study opens new opportunities for the use of the dielectric constant meter as a simple and inexpensive alternative PAT tool in the field of crystallization process monitoring.
Acknowledgment This work was supported by the Science and Engineering Research Council of A*STAR (Agency for Science, Technology and Research), Singapore.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.cherd.2011.07.005.
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