Solute Concentration Prediction Using Chemometrics and ATR-FTIR Spectroscopy
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Journal of Crystal Growth 231 (2001) 534–543 Solute concentration prediction using chemometrics and ATR-FTIR spectroscopy Timokleia Togkalidou, Mitsuko Fujiwara, Shefali Patel, Richard D. Braatz* Department of Chemical Engineering, School of Chemical Sciences, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, BoxC-3, Urbana, IL 61801-3792, USA Received 15 November 2000; accepted 18 May 2001 Communicated by R.W. Rousseau Abstract The fundamental processes of crystal nucleation and growth are strongly dependent on the solute concentration. A significant limitation to the development of reliable techniques for the modeling, design, and control of crystallization processes has been the difficulty in obtaining highly accurate supersaturation measurements for dense suspensions. Attenuated total reflection Fourier transform infrared spectroscopy is coupled with chemometrics to provide highly accurate in situ solute concentration measurement in dense crystal slurries. At the 95% confidence level, the chemometric techniques provided solute concentration estimates with an accuracy of 70:12 wt% for potassium dihydrogen phosphate. r 2001 Published by Elsevier Science B.V. PACS: 81.10.Dn; 64.75.+g Keywords: A1. Solubility; A2. Growth fromsolutions; B1. Phosphates; B3. Infrared devices 1. Introduction between the actual solute concentration and the saturated solute concentration. A primary limitation to the systematic modeling One technique is to measure the refractive index and control of crystallization processes is the [1–4]. Although this method can work when there difficulty in obtaining accurate in situ measure- is significant change in the refractive index with ments of solute concentration in the dense slurries solute concentration, the method is sensitive to typical of industrial crystallization operations. ambient light and air bubbles. Another approach High accuracy is needed because the nucleation to obtaining solute concentration measurements is and growth kinetics that are fundamental to the to sample the crystal slurry, filter out the crystals, modeling of crystallization are strongly dependent and then measure the density of the liquid phase. on the supersaturation, which is the difference This procedure has been demonstrated on-line for the cooling crystallization of potassiumnitrate in *Corresponding author. Tel.: +1-217-333-5073; fax: 1+217- water [5–8]. The use of an external sampling loop 333-5052. can lead to operational difficulties such as clogging E-mail address: [email protected] (R.D. Braatz). of the screen used to filter out the crystals, and to 0022-0248/01/$ - see front matter r 2001 Published by Elsevier Science B.V. PII: S 0022-0248(01)01518-4 T. Togkalidou et al. / Journal of Crystal Growth 231 (2001) 534–543 535 fluctuations in temperature in the sampling that the depth of penetration of the infrared loop. This latter problemis especially impor- energy field into the solution is smaller than the tant for crystals with a small metastable zone liquid phase barrier between the probe and solid width, where a slight reduction in temperature crystal particles. Hence, when the ATR probe is can cause crystals to nucleate in the densitometer, inserted into a crystal slurry, the substance in leading to inaccurate solute concentration immediate contact with the probe will be the liquid measurements. solution of the slurry, with negligible interference In the crystallization of electrolytes, the solute fromthe solid crystals. That the crystals do not concentration can be estimated by placing a significantly affect the infrared spectra collected conductivity probe in the crystal slurry [9–11]. using the ATR probe has been verified experimen- Frequent re-calibration of the probe limits its tally [18,19]. The accuracy of solute concentration usefulness in long-termindustrial crystalli- measurements in past studies, however, has not zation applications. An indirect method of deter- been as high as could be hoped. mining the solute concentration is to use calori- Chemometrics has been used with various metry, in which the measurements of temperature spectroscopic techniques for quantitative and and flow rates are combined with a dynamic qualitative analysis of complex spectra [23–25]. energy balance of the crystallizer [12–14]. This Its application with FTIR spectroscopy includes approach has been demonstrated for the batch quantitative analysis of latex on coated paper [26], crystallization of adipic acid in water [15]. Solute determination of rubber additives [27], determina- concentration estimates determined from calori- tion of blood serumconstituents [28,29], and metry can be expected to drift as the crystallization identification and quantitation of trace gases progresses. Less popular methods for solute [30,31]. concentration measurement, which have similar The main contribution of this paper is to weaknesses, are summarized in some review demonstrate that highly accurate measure- papers [16,17]. ments of solute concentration can be provided A limitation to the aforementioned methods for by ATR-FTIR spectroscopy and chemo- supersaturation measurement is the inability to metrics. Attention is made to quantifying the track the concentrations of multiple dissolved accuracy of the chemometric predictions, the species or multiple solvents. Crystallization pro- sensitivity of the results to estimated noise levels, cesses, when used for separations purposes, have and the sensitivity of the results to selection of the more than one solute. Most pharmaceutical calibration data. Raman and infrared spectro- crystallization processes have multiple solutes scopy at various solution concentrations can be and/or solvents (multiple solvents occur in used to elucidate the molecular structure in antisolvent or ‘‘drowning out’’ crystallization). solution, which is needed to identify the crystal All reactive crystallization processes have growth mechanism (see Ref. [32] and references multiple chemical species. A significant advant- cited therein). Such analysis is beyond the scope of age of spectroscopy techniques is the ability this paper. to measure concentrations in multicomponent The paper begins with a brief review of a solutions. chemometric approach referred to as robust The feasibility of attenuated total reflection chemometrics, which provides accurate estimates (ATR) Fourier transforminfrared (FTIR) spectro- of prediction accuracy, and automatically selects scopy for the in situ measurement of solute amongst multiple chemometric methods. This is concentration in dense crystal slurries has been followed by the experimental procedure, results, demonstrated [18–22]. In ATR-FTIR spectro- discussion, and conclusions.1 scopy, the infrared spectrumis characteristic of the vibrational structure of the substance in immediate contact with the ATR immersion 1 A preliminary version of these results were published in a probe. A crystal in the ATR probe is selected so proceedings paper [33]. 536 T. Togkalidou et al. / Journal of Crystal Growth 231 (2001) 534–543 2. Theory 3. Experimental procedure When predicting solution concentration, includ- 3.1. Materials and instruments ing multiple absorbances in the calibration model averages measurement noise over multiple spectral Absorbance spectra were obtained by a DIP- frequencies and allows the explicit consideration of PER-210 ATR-FTIR immersion probe with two peak shifts. The strong correlations within the data reflections manufactured by Axiom Analytical. make it impossible to construct an accurate ZnSe was used as the internal reflectance element. ordinary least squares (OLS) model between the The probe was attached to a Nicolet Protege 460 multiple absorbances and the solution concentra- FTIR spectrophotometer connected to a 333 MHz tion. The ability of the chemometric methods of PentiumII running OMNIC 4.1a software from principal component regression (PCR) [34] and Nicolet Instrument Corporation. The spectro- partial least squares (PLS) [35,36] to handle highly meter was purged with N2 gas 1 h before and correlated data allows these chemometrics meth- while measurements were being taken to reduce ods to construct calibration models based on the effects of CO2 absorption in its optical path. A multiple absorbances. spectral resolution of 4 cmÀ1 was used as a The calibration model has the form compromise between scan speed and resolution. Samples were made by dissolving appropriate y ¼ bTx; ð1Þ amounts of potassium dihydrogen phosphate (KH2PO4; KDP) obtained fromFisher Scientific where y is the output prediction (a solution or Aldrich in deionized water. The sample was concentration), x the vector of inputs (often called stirred using an overhead mixer. The sample predictor variables, in this paper these are the IR temperature was controlled using a Neslab GP- absorbances and the temperature), and b is the 200 water bath and was measured every 2 s using a vector of regression coefficients. There are numer- Fluke 80TK thermocouple attached to a DT3004 ous chemometrics methods, most being variations data acquisition board fromData Translation. of PLS or PCR, which can give very different The temperature readings were averaged during calibration models for some data sets [34,37–39]. the duration of each scan. The robust chemometrics approach is to apply several chemometrics methods, and then to select 3.2. Constant concentration measurements the calibration model which gives the most accurate predictions [40]. The six different methods Specified amounts of KDP and deionized water considered were: