Review pubs.acs.org/OPRD
Single-Frequency Ultrasonic Crystallization Monitoring (UCM): Innovative Technique for In-Line Analyzing of Industrial Crystallization Processes Patrick Frohberg* and Joachim Ulrich Center for Engineering Science, Thermal Process Engineering, Martin Luther University Halle-Wittenberg, D-06099 Halle (Saale), Germany ABSTRACT: The development, principles, and application of the single-frequency, ultrasonic crystallization monitoring (UCM) technique is discussed. It is shown that the three most important process parameters to control industrial crystallization processes (mean crystal size, suspension density, and liquid concentration) can be monitored simultaneously in-line by means of only one measuring technique holding two sensors. A proof of concept is presented that clearly shows the feasibility and applicability of the UCM method. In demarcation to alternative PAT in the field of industrial crystallization, advantages, potentials, and limits are outlined and discussed with particular reference to the applicability of the technology and the material systems together with the transferability to other substances as well as the scale-up ability of the underlying mathematical model. Additionally, the reliability of the UCM technique is validated by comparing the results with established and commercially available PAT for the solid phase.
1. INTRODUCTION Since its formal introduction by the U.S. Food and Drug Administration (FDA), process analytical technologies (PAT) have been increasingly being explored and adopted for crystallization processes and are currently an area of high interest, especially for the pharmaceutical industry.1−4 PAT can be defined as a system for designing, analyzing, and controlling manufacturing through timely measurements of critical quality and performance attributes of raw and in-process materials and processes with the goal to ensure the final product quality (FDA adopted by ICH Q8 guidance and ASTM International Technical Committee E55).2 The quality of solid products such as pharmaceuticals, agrochemicals, commodities, or fine chemicals is related to the desired purity, crystal size, crystal size distribution (CSD), stability, modification, and shape. Furthermore, the crystalline products strongly influence the required downstream processes such as filtration, drying, and milling.1,5,6 To ensure these requirements, with appropriate accuracy, precision and reproducibility adequate analytical techniques, capable of monitoring in-line process parameters during the crystallization process are needed.6 Therefore, PAT technologies are developed which are able to provide a wealth of real-time data for the understanding and control of crystallization processes, especially, by an in-line use.1 The demand-related PAT include, without any claim to comprehensiveness, conductivity, density, turbidity, ultrasonic (single frequency), in-line microscopy, laser backscattering (FBRM or 3D ORM), laser diffraction, attenuated total reflectance Fourier transformation infrared (ATR-FTIR), attenuated total reflectance mid-infrared (ATR-MIR) spectroscopy, near-infrared (NIR) spectroscopy, ultraviolet−visible (UV−vis) spectroscopy, or ultrasonic attenuation spectroscopy (UAS), which correlates ultrasonic attenuation with a spectra of frequencies.5,7 The measuring techniques based on conductivity, density, or turbidity show limitations in electrically © XXXX American Chemical Society
nonconducting, dense, concentrated, or optically opaque solutions but show, on the other hand, economic advantages due to their relatively low costs. Further, it has to be recognized that there is a lack of robustness, a comparatively high complexity regarding process conditions and handling and their limitation to measure either the solid or the liquid phase (excluding the acoustical methods), but not simultaneously.5 If applicable, ultrasonic-based technologies often show clear advantages over many aforementioned techniques. Derived from the fact that most materials are ultrasonically transparent, ultrasound is universally applicable by means of analyzing a broad variety of sample types.8,9 However, the UAS shows its limits in the very complex analysis of the obtained data. Analogously to the laser backscattering and laser diffraction, the mathematical models to calculate the CSD and hence the mean crystal size are extremely complex.10,11 As a consequence, a high complexity of the measuring technique (construction and handling) and of the final data evaluation led to the requirement of specially trained personnel with expert knowledge, which, together with the expensive equipment causes costs. This, in turn finally led to a more expensive PAT which hinders an industrial market penetration and therefore limits the methods to applications in research and development. This is exemplified by the acoustic emission (AE) introduced and applied by Gherras et al.12 AE describes a technique for inline monitoring, batch cooling solution crystallization operations which is based on a transducer and acoustically coupled to materials undergoing dynamic changes. Following the concept that phase transitions occur during crystallization, acoustic elastic waves emitted by the process were considered Special Issue: Process Analytical Technologies (PAT) 14 Received: December 19, 2013
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and characterized by a number of parameters. The study shows the potential of the AE technique to monitor polythermal batch crystallization in pure solvents and in the presence of impurities by providing information on the liquid and the solid phase evolving in the suspension. However, the AE technique led to the necessity of processing a huge amount of multivariate data by advanced statistical techniques to distinguish the relevant parameters and to calibrate the acoustic sensor.12 This in turn corresponds to the aforementioned problems of ultrasonicbased technologies. As a result of this situation, efforts towards the development of new sensing technologies that guarantee constant product quality in industrial crystallization by means of inexpensive and robust PAT tools are made. In particular, these include bulk video imaging (BVI), 3D CSD, or dielectric constant measurements.5,13−15 Considering the above-mentioned problems and arising challenges, a simple, less complex, universal applicable and robust ultrasonic technique referred to as “Ultrasonic Crystallization Monitoring Technique − UCM” in conjunction with a proof of concept based on commercially available instruments was introduced by the research group of Ulrich1,5,6,16,17 and will be presented consecutively.
Figure 1. Determination of the metastable zone width between nucleation and saturation point at different cooling rates using the ultrasound technique.20
metastable zone width (e.g., ref 21). Herewith, the ultrasound technique proves its potential as an instrument to detect the metastable zone width of industrial, real multicompound solutions. Tititz-Sargut and Ulrich22 applied an ultrasonic measuring technique not only to determine the metastable zone width of unseeded potassium nitrate, potassium sulfate, and ammonium sulfate solutions at different cooling rates, but also introduced a protected sensor (shielded by a sieve in order to avoid crystals disturbing the reading for the “clear” liquid) to determine the change of ultrasonic velocity and temperature of the liquid phase in a reliable and appropriate sensitive manner in the presence of crystals. Moreover, Sayan and Ulrich23 found an influence of different solid contents on the ultrasonic velocity in the form of a strong relation between the particle size and/or suspension density and the measured ultrasonic velocity in the liquid phase. A protected ultrasound sensor was used to eliminate the above-mentioned effect of particle size and/or suspension density on ultrasound velocity. However, problems concerning the measurement of the concentration in the solution of multiphase systems have been revealed.22 With the state of the art available at that time (until 2007), the ultrasound velocity was the only measurable quantity, and as a result two of the mentioned three key factors (liquid concentration, mean crystal size, and suspension density) had to be kept constant to determine the appropriate third factor. Later, with the introduction of the attenuation as a measurable variable from one and the same sensor, two of the key factors became determinable. Following from this, the two unknown quantities, mean crystal size and suspension density, can be calculated by measuring ultrasound velocity and attenuation with one sensor associated with a minimum of three calibration experiments, if the liquid phase remains unchanged.6 In order to control the crystal size and the suspension density (two of the three key parameters to indicate the progress of a crystallization process) the solid phase has to be considered. For the description of the solid phase in the dispersion, the dependence of ultrasound velocity and attenuation on the particle size distribution and suspension density can be used.6 Approaches for the determination of the particle size and the suspension density by the interaction of particles with ultrasound waves of different wavelengths and resulting attenuation spectra are already published, and their limitations were mentioned in the Introduction.6,24−26 Pertig et al.6 demonstrated that the combination of different signals, i.e., the ultrasound velocity and the attenuation obtained at only one frequency provides accurate information on the solid phase in a saturated solution, a mean size and wide
2. ULTRASONIC CRYSTALLIZATION MONITORING TECHNIQUE (UCM): SIMULTANEOUSLY IN-LINE MEASURING OF LIQUID AND SOLID PHASE BY MEANS OF ONLY ONE MEASURING DEVICE 2.1. Development and Proof of Concept. To quantify the progress in industrial crystallization processes the mean crystal size, the suspension density, and the liquid concentration are the key factors. Therefore, the real time control of the nucleation and the crystal growth based on the information from the ongoing process (liquid and solid phase) is of high importance to obtain the desired product amount and quality which refers to the purity, the crystal size, and the CSD.6 Monitoring and control of the liquid phase serves to evaluate the supersaturation (the driving force) and to further maintain the desired crystal growth rate. Applied in-line, the crystallization process can be kept within the metastable zone, and a spontaneous nucleation can be prevented. Omar and Ulrich18 established and evaluated the ultrasonic velocity technique to determine the concentration in the liquid state by using a commercially available sensor. It has been found that the ultrasonic technique, used in situ, is capable of measuring online the concentration even if it is supersaturation within the metastable zone. Furthermore, Omar et al.19 showed how the metastable zone width can be determined offline. Figure 1 exemplarily shows the determination of the metastable zone width for solutions of citric acid carried out with the ultrasonic measuring device. The undersaturated solution is cooled until the signal reports strong changes (concentration change due to nucleation). Thereafter, the solution is heated again (the nuclei are dissolved again) until the curve hits the cooling curve (meaning the liquid is homogeneous again). The merging point represents saturation. The accuracy of the nucleation and saturation temperature ranges from ±0.1 to ±1 °C, depending on the substance or the multicomponent system. The different cooling rates show different widths of the metastable zones. The higher the cooling rate the higher the metastable zone, as expected. The same clear results can be seen when ppm’s of additives/impurities influence the B
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thermore, a scale-up of this technique to a pilot plant was shown, and a direct transferability of the developed laboratoryscale calibration models was found.16 In conclusion, it can be emphasized that the UCM technique evolved (and is still evolving) as an inexpensive and reliable alternative PAT to monitor and/or control industrial crystallization processes. 2.2. Principal Procedure. The first step for the implementation of the UCM are calibration experiments to determine the parameters for the mathematical model (model identification) which is required for the calculation of the liquid and the solid phase.5 A detailed calibration procedure for the liquid concentration was described by Omar and Ulrich.18 For the investigated urea−water system, Stelzer et al.5 found a correlation (R2 = 0.999) for the concentration (c), which is dependent on the temperature (T) and the ultrasonic velocity in the liquid phase (ν1) as
range of suspension densities (5−40 wt %). Exemplarily, different suspension densities with several particle size fractions of urea crystals were investigated by an ultrasonic probe. The data of the model identification and the results of the fits, represented as lines, are shown in Figure 2.
(β4 + β5T )2
c=
4β22 −
Figure 2. Ultrasound velocity and attenuation measured as a function of suspension density and different particle sizes of urea.6
−
β1T 2 + β3T + β6 − (ν1 − νcorrect) β2
β4 + β5T 2β2
(1)
in which an additional mathematical term (νcorrect) was integrated to correct the influence of particles smaller than the mesh size (90 μm) of the cage from the protected sensor. Considering the solid phase, the ultrasound velocity (νs) and attenuation (a) for defined sieve cuts and suspension densities of urea crystals in saturated urea−water solutions were recorded and could be identified for calculating the suspension density (φ) and mean crystal size (d50) as follows:
For the validation of the experimental conditions and the measured ultrasound velocity and attenuation, appropriate functions considering the effects of different suspension densities and particle sizes are required (see section 2.2). It can be seen, that the use of only five points for each particle size fraction of urea to fit the functions leads to a high agreement between the data points and the fitted lines.6 As a consequence, only one measuring technique with two sensors, one protected for the liquid and one unprotected for the solid side, is required to monitor a crystallization process (more specific for the mean particle size and the suspension density).6 Stelzer et al.5 carried out a proof of concept to demonstrate the feasibility and usability of the developed ultrasonic crystallization monitoring technique (UCM) for industrial ammonium sulfate and urea crystals. For the calculation of the mean crystal size and the suspension density simple mathematical models are applied which clearly differentiate the UCM from the UAS. In the latter case, attenuation and frequency were correlated at different spectra in complex models.5,27,24 The functionality of this simple, reliable, robust, and universally applicable method for in-line monitoring and controlling of the liquid and solid phases by means of only one measuring device with two sensors was proven.5 Helmdach et al.16 analyzed 12 different pharmaceutical compounds by the UCM technique to determine the concentrations and metastable zone widths and compared the results with respect to the applicability for inorganic and nonpharmaceutical compounds. While for the majority of the inorganic compounds an excellent applicability of the measuring technique was found, a number of pharmaceutical compounds, however, showed limitations. Nowadays in a high number of cases when the velocity of sound provides only a weak or an unusable signal, however, the attenuation leads to usable results (see e.g., ref 16). The investigated substances were grouped according their sensitivity to ultrasound concentration measurements. Fur-
ϕ=
⎛1 β1 ⎞ ν12 ⎜ ⎟ − − − ⎜β 2β2 ⎟⎠ 4β22 β2(ν − β3a3)2 ⎝ 2 β12
d50 = β1aϕ β2
(2) (3)
The fitted parameters βi of eqs 1−3 were listed by Stelzer et al.5 Effects caused by changes of temperature and liquid concentration and scattering effects caused by the growing crystal size and suspension density were taken into account. Only the possible effects of viscosity were not as yet included in the model of Stelzer et al.5 Stelzer et al.5 carried out a total of 20 calibration experiments for the solid and five for the liquid phase. A reduction to only three experiments for the solid phase with an appropriate accuracy was also demonstrated.17 More detailed information about calibration experiments for the solid phase can be found in the works of Pertig et al.6,17 The last step of the UCM procedure is the in-line measurement of ultrasonic velocity and attenuation during the crystallization process for the calculation of concentration, suspension density, and mean crystal size as process parameters. Finally, the fast Fourier transformation, covering 30 data points to reduce the scattering of the experimental signals, was applied to smooth the calculated data.5 2.3. Experimental Methods. The crystal growth experiments were carried out using a temperature-controlled, jacketed glass crystallizer equipped with a stirrer and two ultrasound sensors (LiquiSonic 30, SensoTech GmbH, Germany). Urea (purity >99.6%) has been selected as model substance to carry C
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out the proof of concept.5 The experimental setup is schematically shown in Figure 3.
Figure 4. Temperature and concentration as a function of experimental time with solubility data.5 Figure 3. Schematic experimental setup.5
The precision of the system was reported as follows: ±0.05 m/s for the ultrasound velocity, ±0.05 dB for the attenuation, and ±0.05 °C for the temperature.5 The first so-called protected sensor was used for the liquidphase measurements. Equipped with a cage, crystals larger than 90 μm were hindered from passing the measuring section of the sensor. In the case of an exclusive measurement of the metastable zone width in the absence of crystals the usage of an unprotected sensor is sufficient as described in the works of Omar and Ulrich18 and Omar et al.19 Additionally, a three-dimensional (3D) ORM particle size analyzer (Sequip S+E GmbH, Germany) was used to validate the reliability of the UCM technique by comparing the obtained results with an established and commercially available PAT for the solid phase.5 The crystal growth tests were described in detail by Stelzer et al.5 A defined amount of sieved urea crystals (size fraction 315− 355 μm) was added to the saturated (T = 20 °C) urea solution to adjust the suspension density to 10 wt %. The crystal growth was initiated by decreasing the temperature from 20 to 10 °C with a cooling rate of 2 K/h. The final temperature of 10 °C was kept constant to draw conclusions about the reliability of the measurement technique.5 2.4. Results and Discussion. To prove the concept of UCM, crystal growth experiments based on the developed model were carried out under dynamic crystallization conditions. The results for the liquid phase as a function of the experimental time are shown in Figure 4. Stelzer et al.5 confirmed the capability of the protected sensor for accurate in-line measurements of the liquid concentration during a dynamic crystallization process. Detailed proof and further explanations can be found in the studies of Omar and Ulrich18 as well as Tititz-Sargut and Ulrich.22 Figure 5 shows the in-line monitored results of the solid phase during a crystallization process. The suspension density and mean crystal size are increasing with decreasing the temperature of the urea solution caused by the supersaturating of the solution and, consequently, by the crystal growth of the crystals. In order to quantify the accuracy of the UCM, Stelzer et al.5 compared the obtained data (concentration, suspension density, and mean particle size) with values from the literature, preset conditions, and 3D ORM (MTS 523 PsyA CSD Particle
Figure 5. Suspension density, mean crystal size, and temperature as a function of experimental time measured by UCM.5
Analyzer, Sequip S+E GmbH, Germany). It was shown that the deviations related to the model were very small, which underlines the accuracy of the UCM technique. Furthermore, Pertig et al.6 obtained promising results while investigating ammonium sulfate suspensions. That indicates the transferability of the presented model to other substances. Thus, it was pointed out the robustness of the UCM regarding the crystal morphologies since urea crystals are elongated and ammonium sulfate crystals are orthorhombic.16,28
3. CONCLUSIONS The single-frequency ultrasonic monitoring (UCM) technique was found to be a simple, less complex, universally applicable, robust, and reliable PAT to monitor and/or control industrial crystallization processes. The introduced technique offers a simultaneous in-line measurement of liquid and solid phase by means of only one measuring device with two sensors. On the basis of the fundamental research of the working group of Ulrich18−23 the concept of the UCM technique could be proven by Pertig et al.6 and Stelzer et al.5 for inorganic salts but also for organic compounds. Furthermore, Helmdach et al.16 applied the UCM for a number of pharmaceutical compounds within different concentration ranges. The compounds were sorted according to their concentration measurement sensitivity. A high sensitivity of the ultrasound velocity for lowmolecular weight compounds was found that provides an excellent applicability for the determination of the concentration (e.g., magnesium sulfate, potassium sulfate, ammonium sulfate, urea, and glycine) and the metastable zone width (e.g., D
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(5) Stelzer, T.; Pertig, D.; Ulrich, J. J. Cryst. Growth 2013, 362, 71− 76. (6) Pertig, D.; Buchfink, R.; Petersen, S.; Stelzer, T.; Ulrich, J. Chem. Eng. Technol. 2011, 34 (4), 639−646. (7) Hlozný, L.; Sato, A.; Kubota, N. J. Chem. Eng. Jpn. 1992, 25 (5), 604−606. (8) Bucking, V.; O’Driscoll, B.; Smyth, C. Spectrosc. Eur. 2003, 15 (1), 20−25. (9) Martini, S.; Herrera, M.; Marangoni, A. J. Am. Oil Chem. Soc. 2005, 82 (5), 313−317. (10) Mougin, P.; Wilkinson, D.; Roberts, K. J. Cryst. Growth Des. 2002, 3 (1), 67−72. (11) Fairhurst, D.; Dukhin, A. S. In Science and Applications of Skin Delivery Systems; Wissenschaftliche Verlagsgesellschaft: Stuttgart, 2008; pp 185−203. (12) Gherras, N.; Serris, E.; Fevotte, G. Int. J. Pharm. 2012, 439 (1− 2), 109−119. (13) Simon, L. L.; Nagy, Z. K.; Hungerbuhler, K. Org. Process Res. Dev. 2009, 13 (6), 1254−1261. (14) Kempkes, M.; Vetter, T.; Mazzotti, M. Chem. Eng. Sci. 2010, 65 (4), 1362−1373. (15) He, G.; Tjahjono, M.; Chow, P. S.; Tan, R. B. H.; Garland, M. Org. Process Res. Dev. 2010, 14 (6), 1469−1472. (16) Helmdach, L.; Feth, M. P.; Ulrich, J. Org. Process Res. Dev. 2013, in press. (17) Pertig, D., Stelzer, T., Ulrich, J. In Proceedings, ISIC 2011 (18th International Symposium of Industrial Crystallization); AIDIC: Milano, 2011; pp 158−159. (18) Omar, W.; Ulrich, J. Cryst. Res. Technol. 1999, 34 (3), 379−389. (19) Omar, W.; Strege, C.; Ulrich, J. Chem. Technol. 1999, 51 (5), 286−290. (20) Omar, W.; Ulrich, J. In Cryst. Growth Org. Mater. 4, Int. Workshop; Shaker: Aachen, 1997; pp 294−301. (21) Ulrich, J.; Strege, C. J. Cryst. Growth 2002, 237−239, 2130− 2135. (22) Titiz-Sargut, S.; Ulrich, J. Chem. Eng. Process: Process Intensif. 2003, 42 (11), 841−846. (23) Sayan, P.; Ulrich, J. Chem. Eng. Process.: Process Intensif. 2002, 41 (3), 281−287. (24) Dukhin, A. S.; Goetz, P. J. Langmuir 1996, 12 (21), 4987−4997. (25) Hipp, A. K.; Storti, G.; Morbidelli, M. Langmuir 2001, 18 (2), 391−404. (26) Mougin, P.; Wilkinson, D.; Roberts, K. J. Cryst. Growth Des. 2002, 2 (3), 227−234. (27) Babick, F.; Hinze, F.; Stintz, M.; Ripperger, S. Part. Part. Syst. Charact. 1998, 15 (5), 230−236. (28) Mullin, J. W. Crystallization; Butterworth Heinemann: Oxford, 2001. (29) Ulrich, J., Jones, M. J. In Industrial Crystallization Process Monitoring and Control; Chianese, A.; Kramer, H. J., Eds.; Wiley-VCH: Weinheim, 2012; pp 59−68.
glycine, ibuprofen, citric acid, and paracetamol). However, an application for a number of high-molecular weight pharmaceutical compounds seems to be limited. In addition, Ulrich and Jones29 summarized a range of materials, both organic and inorganic, where ultrasound velocity measurements can be gainfully employed for concentration measurements. With regards to applications in industrial crystallization processes, the applicability of the UCM in a pilot-plant scale was investigated using three model compounds: paracetamol, acetylsalicylic acid, and L-glutamic acid.16 Helmdach et al.16 found a direct transferability of the calibration models developed at lab scale to a pilot-plant scale, provided that the influence of gas bubbles in the pilot plant is low. In summary, the UCM technique can be applied for the determination of the metastable zone width, nucleation and growth kinetics, seeding events, and detection of phase transitions (e.g., model substance citric acid)16 for a wide range of materials. The range of measurements with high accuracy in the desired field of industrial crystallization is ensured through particle sizes between 100 and 800 μm and suspension densities between 5 and 40 wt %. Thus, the application, even in optically nontransparent media where other optical processes fail, clearly shows that the presented UCM technique provides sufficient in-line process control of the liquid and the solid state. The introduced results of the UCM technique prepare the ground for the establishment as an alternative to the currently commercially available and used PAT with the potential to close the gap between the industrially applied technologies, which are inexpensive but limited in their application, such as density, conductivity and, on the other hand, the more expensive spectroscopy- or laser-based techniques. Finally can be stated, that the combined use of appropriate analytical technologies along with smart modeling, which is already far advanced, leads to the promised success and unveils all benefits of having real-time process analytical data in crystallization processes.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Tel. +49 345 5528400. Notes
The authors declare no competing financial interest.
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ABBREVIATIONS AE, Acoustic emission; ATR-MIR, Attenuated total reflectance mid infrared; ATR-FTIR, Attenuated total reflectance Fourier transformation infrared; BVI, Bulk video imaging; CSD, Crystal size distribution; FBRM, Focused beam reflectance measurements; FDA, Food and Drug Administration; NIR, Near infrared; ORM, Optical reflectance monitoring; PAT, Process analytical technologies; UAS, Ultrasonic attenuation spectroscopy; UCM, Ultrasonic crystallization monitoring; UV−vis, Ultraviolet−visible
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REFERENCES
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