Process Control of Seeded Batch Cooling Crystallization of the Metastable r-Form Glycine Using an In-Situ ATR-FTIR Spectrometer and an In-Situ FBRM Particle Counter
CRYSTAL GROWTH & DESIGN 2004 VOL. 4, NO. 5 949-953
Norihito Doki,*,† Hiroya Seki,‡ Kiyoteru Takano,‡ Haruki Asatani,‡ Masaaki Yokota,† and Noriaki Kubota† Department of Chemical Engineering, Iwate University, Morioka 020-8551, Japan, and Mitsubishi Chemical Corporation, MCC-Group Sci & Tech Research Center, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-8502, Japan Received June 29, 2004
ABSTRACT: In this paper, we report a process control strategy for the production of metastable R-form glycine crystals of a desired mean mass size by manipulating the alternating temperature profile and the final termination temperature. The seed crystals of the R-form glycine introduced were grown successfully to the size of the product with no fine crystals. Generation of the γ-glycine crystals (stable polymorph) was completely avoided. This crystallization method is flexible and easy to operate, because the alternating temperature profile can be determined on-site according to the transient supersaturation and particle count number data obtained from an in-situ ATRFTIR spectrometer and an in-situ FBRM particle counter, respectively. The termination time or batch time was also determined on-site to a point that the residual supersaturation became zero. This on-site strategy-determination technique is expected to be applied widely for a variety of polymorphic systems other than the glycine-water system as a practical method for the selective crystallization of metastable polymorphs. Introduction Polymorphism, the capability of a molecule to crystallize in multiple crystal forms that differ in molecular packing, is a frequently encountered phenomenon in pharmaceutical sciences. The development of highquality pharmaceutical products requires deep understanding and control of polymorphism, because different solid forms lead to different physical properties (solubility, crystal shape, dissolution rate, etc.), and different bioavailabilities and pharmacological effects. Polymorphic crystallization is very complicated, and it is affected by various factors such as solvent characteristics, solution concentration, cooling rate, agitation, seeding, and the presence of impurity. Many research papers dealing with the phenomenon have been published,1-5 while only a few papers have proposed practical methodologies of the selective crystallization of a desired polymorphic crystals.6-8 According to our previous study,8 seeding was effective for the polymorphism control of glycine. The metastable R-form crystals of glycine were obtained selectively by cooling crystallization as product if sufficient seeds of the same R-form crystals were added to the system at the initial stage of a batch. In addition, the product crystals, which were all the grown seeds, had a unimodal size distribution with no fine crystals. Sufficient seed loading was only one condition to grow selectively the metastable R-form glycine crystals. However, we needed several batch trials in advance to determine the sufficient amount of the seeds. As for a practical operation in industry, it would be more at* To whom correspondence should be addressed. E-mail:
[email protected]. † Iwate University. ‡ Mitsubishi Chemical Corporation.
tractive if we can develop another method that does not need such preliminary batch trials. For this purpose, it is essential to measure solution concentration and particle numbers on-line during crystallization. An in-situ ATR-FTIR technique has been shown, by recent papers,9-12 to be successfully applied to the monitoring of batch crystallization processes of organic compounds. The solubility curve and the limit of metastable zone width were also determined for several solute/solvent systems,11 and on-line measurements of supersaturation during batch crystallizations were also performed.9-13 An in-situ focused beam reflectance measurement (LASENTEC-FBRM) particle counter has been used as a tool for monitoring industrial crystallization processes by measuring the distribution of the chord length of particles and the particle count number. However, only a few papers14,15 concerning this technique has been published, probably because this technique does not give an actual particle size and the particle number density. As an alternative on-line monitoring tool of batch crystallization, Mougin et al.16,17 examined a technique of ultrasonic spectroscopy. They determined, through this technique, crystal size distribution and solid concentration, and deduced the kinetic parameters of secondary nucleation and crystal growth from these data during batch crystallization of Lglutamic acid. They also examined the crystal polymorphism. However, these in-situ measurement techniques have not been used for the control of polymorphic crystallization, but used only for the monitoring of a process. The important thing from a practical point of view is to develop a methodology of the control of crystal size and polymorphism in batch crystallization. In this paper, we report a reliable and reproducible technique of batch cooling crystallization to produce a
10.1021/cg030070s CCC: $27.50 © 2004 American Chemical Society Published on Web 08/05/2004
950 Crystal Growth & Design, Vol. 4, No. 5, 2004
metastable polymorph with a controlled size. The solution concentration was measured in-situ with an ATRFTIR spectrometer (Mettler Toledo ReactIR), and the particle count number was also measured on-line with a focused beam reflectance measurement (LASENTECFBRM) particle counter. Seed crystals introduced into a crystallizer were grown by cooling. Fine particles (grown secondary nuclei), which were generated unavoidably during cooling, were dissolved by heating the crystallizer discontinuously on the way of cooling. The heating strategy can be determined on-line by using the transient information of supersaturation (ATR-FTIR), particle count number (FBRM), and temperature. This crystallization method is practical and flexible, because (1) the temperature profile can be decided on-site, (2) the size of product crystals can be estimated from a simple mass balance, and (3) the polymorphism of the product (grown seeds) is also guaranteed. Glycine was used as a model polymorphic compound. It has three polymorphic forms, R, β, and γ. The metastable R- and the stable γ-forms are crystallized from aqueous solution. The β-form, which does not crystallize from aqueous solution at ordinary temperatures,18 is the least stable in aqueous solution at any temperature. Ferrari et al.19 reported that, for the transformation of the βto R-form in ethanol/water solution, the rate-controlling step is the dissolution of the β-form crystals.
Doki et al.
Figure 1. Transient crystal count number and temperature.
1. Experimental Section 1.1. Batch Cooling Crystallization. Batch cooling crystallization for the glycine-water system was performed in a nonbaffled crystallizer of 500 mL working capacity equipped with an ATR-FTIR probe, an FBRM D600 probe, and a temperature sensor. An aqueous solution of glycine, saturated at 50 °C with respect to the R-form crystals, was introduced into the crystallizer at 60 °C and kept at this temperature for 1 h under gentle agitation. The agitator used was a four-bladed marine propeller. Then, the agitation speed was adjusted to 300 min-1, and the solution was cooled linearly at a cooling rate of 0.3 °C/min. Dry seed crystals of the R-form were added just at the moment when the temperature reached the saturation point of 50 °C. The crystallization process was monitored by the in-situ measurements of particle count number, supersaturation, and temperature by using the FBRM particle counter, the ATR-FTIR spectrometer, and the temperature sensor, respectively. When the crystal count number increases to a certain point, of which a value can be chosen appropriately on-site, the intermittent heating was started until the crystal count number returned to the value of the original seed crystals and then the cooling was started again and continued at the same cooling rate. This heating operation was repeated twice during the course of cooling to the final termination temperature of 20 °C (see Figure 1). It must be noted, however, that the heating operation can be designed on-site as desired, and the number of repeating times of the heating operation depends on the heating duration and the termination temperature of a batch. The cooling was ceased when the supersaturation with respect to the metastable R-form crystals became zero. The produced crystals were separated by filtration from the final slurry under vacuum and dried overnight in the air at room temperature. Powder XRDs of the product crystals were measured to ascertain their polymorphic form. The crystals of the R-form, produced by a rapid cooling technique,20 were used as seeds after classified by sieving. The average size of the seeds used was 300 µm, which was calculated as an arithmetic mean of the two successive sieve openings of 250 and 350 µm. The polymorphic form of the seeds was confirmed by powder XRD to be the R-form. 1.2. Calibration Relationship among ATR-FTIR Spectra, Concentration, and Temperature. (a) ATR-FTIR
Figure 2. ATR-FTIR spectra obtained for the glycine solution of different concentrations. Spectra. In Figure 2, ATR-FTIR spectra are shown for the glycine solution of different concentrations at 50 °C. The weak band at about 3200 cm-1 is assigned to the antisymmetric stretch of the NH3+ group. Other features related to glycine were also found toward lower wavenumbers: the antisymmetric stretch of the carboxyl group at 1580-1590 cm-1, the deformation of the NH3+ group at 1515-1500 cm-1, the CH2 band at 1445-1430 cm-1, the symmetric stretch of the carboxylic group at 1414-1400 cm-1, the CH2 wagging band at about 1333-1332 cm-1, the rocking of the NH3+ group at 1120-1135 cm-1, the symmetric stretch of the -CN group at 1030-1045 cm-1, the CH2 rocking band at about 920-935 cm-1, and the symmetric stretch of the -C-C at about 890905 cm-1. With the increase in concentration, the heights of all these peaks increase. (b) Total Peak Area of ATR-FTIR Spectra versus Temperature. In Figure 3, the total peak area of ATR-FTIR spectra AT, which was defined as the sum of area under each peak related to glycine, was calculated from the measured spectra over a wide range of temperature from the undersaturated region to the supersaturated region for glycine aqueous solutions of different. The calculated total peak area AT of ATRFTIR spectra was correlated successfully with the temperature T and the saturation temperature Ts (as a measure of concentration) by the following equation
AT ) f(Ts) + (T - Ts)g(Ts)
(1)
where f(Ts) and g(Ts) are constants governed solely by Ts, a measure of the solution concentration. The first term f(Ts) of the right-hand side of eq 1 represents the total peak area at a
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Crystal Growth & Design, Vol. 4, No. 5, 2004 951
Figure 4. Confirmation of the validity of the supersaturation measured with the ATR-FTIR method. Comparison with a weighing method. Figure 3. Calibration curves of total peak area of ATR-FTIR spectrum vs temperature for the glycine solution of different concentrations. saturation temperature Ts of a given solution and the second term takes into account the extent of deviation of the total peak area from that of the saturated condition. The functions f(Ts) and g(Ts) were determined respectively as best fit curves to the measured data as follows with a least-squares method.
f(Ts) ) 6.93 × 102Ts1.75
(2)
g(Ts) ) 8.34 × 103e(-16.6/Ts)
(3)
The total peak area data look to be reasonably correlated by eq 1 along with eqs 2 and 3 (see Figure 3). The calibration curve of eq 1 thus obtained was used to calculate on-line the transient saturation temperature Ts of the solution during crystallization using a transient data set of temperature T and the total peak area AT of ATR-FTIR. The saturation temperature Ts thus calculated was then converted automatically to the transient solution concentration using the solubilityversus-temperature relationship,21 and the transient supersaturation was determined on-line. (c) Confirmation of the Validity of Supersaturation Measurement by ATR-FTIR Spectroscopy. The solution concentration was compared between those obtained by the ATR-FTIR method and a weighing method. The weighing method was performed by evaporating solvent from a given amount of the sample solution to dryness at 80 °C on a hot plate and weighing. Those results are shown in Figure 4, where the transient solution concentration obtained from a simple batch cooling crystallization is depicted. The solution concentrations obtained by the two methods are nearly the same. The validity of the ATR-FTIR method was thus confirmed to be valid. 1.3. Crystal Count Number versus Actual Number of Crystals. The FBRM particle counter is an in-line particle and droplet monitoring system that was developed by LASENTEC Co.22 The converged laser beam is projected through the sapphire window of the probe into particle suspension, and it is scanned at a high speed. Because of the high scanning speed, the movement of particles does not have any effect on the measurement. As particles pass by the window surface, the beam will intersect the edge of a particle and the particle then will begin to backscatter laser light. The backscatter continues until the beam has reached the opposite edge of the particle. Thus, the chord length of the particle, a straight line between any two points on the edge of a particle, is measured from the time period of backscatter, and accordingly the number of backscatter (corresponding to the particle count number) per unit time is collected for particles coming on the window
Figure 5. Crystal count number vs actual number of crystals present in the crystallizer. surface. Therefore, the particle count number is neither absolute particle number in suspension nor absolute particle number density. The FBRM particle counter was examined using model suspensions of the R-form glycine crystals, which were classified by the two successive sieves. The crystals of four different average size were used (42, 165, 300, and 460 µm). The amount of the crystals was varied over a wide range. The suspension medium was a glycine solution saturated at 50 °C. The particles counting were conducted at this saturation temperature. The results are shown in Figure 5, where the particle count number per minute is plotted as a function of the number of particles suspended in the whole crystallizer. A linear relation can be seen on the log-log paper. No effect of particle size is observed. Therefore, we can conclude that the particle count number measured by the FBRM particle counter, although it is not absolute value, can be treated as a measure of the absolute number of particles in the crystallizer. It must be noted that the slope of the line, determined by a leastsquares method, was smaller than unity (and it was 0.91). This is probably due to the overlapping of particles in the range of high particle number densities.
2. Results and Discussion 2.1. Crystallization by using ATR-FTIR and FBRM. Figure 1 shows the transient crystal count number and temperature during crystallization. After the start of a run or the moment of seeding, the crystal
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Figure 7. A photograph of the product crystals obtained. Figure 6. Transient supersaturation and temperature.
count number increases continuously by secondary nucleation mechanisms. At the moment when 40 min elapsed, the suspension was heated to dissolve the nuclei generated. The heating was stopped at the time (59 min, point A) when the particle count number returned to the original value of the seeds added. Then the cooling was started again and followed by the second heating operation. The second heating was stopped similarly when the particle count number returned to the original value, and the temperature was lowered linearly to the termination temperature of 20 °C. At the final stage of cooling, the particle count number did not change as observed in Figure 1. This is because the supersaturation was kept low by the growth of a large amount of crystals present. It is known that the large amount of crystals can suppress secondary nucleation.8 The transient supersaturation data obtained through the in-situ ATR-FTIR spectrometer are shown in Figure 6. The supersaturation with respect to the R-form glycine ∆CR, becomes minus on heating for a short period. During the time of minus supersaturation, the nuclei of the metastable R-form glycine crystals are seen to be decreasing in number by dissolution. However, in this experiment, the γ-form nuclei were unlikely to dissolve because the supersaturation with respect to the γ-form glycine was almost positive except for the short period during the second heating operation, which is indicated in Figure 6 as the area of hatched lines. It was fortunate, however, that the γ-form nuclei did not appear during the cooling process. To avoid nucleation of the γ-form glycine, the heating should be continued to make the solution undersaturated with respect to the γ-form glycine. This can be done easily on-site by observing the transient supersaturation. The termination time or batch time can be determined on-site according to the transient superaturation. Actually, the crystallization was stopped in this study at 210 min where the supersaturation was completely consumed. In Figure 7, a photograph of the product is shown. All the crystals were judged as the metastable R-form glycine from the morphology.8 The metastable R-form was also confirmed by the XRD pattern observed. It is concluded that the technique described here, which uses on-line data of supersaturation from an ATR-FTIR spectrometer and particle count number from a FBRM particle counter, was successfully applied for the production of the metastable R-form glycine
crystals. This technique is expected to be applied as widely for the crystallization of metastable polymorphs. 2.2. Mean Mass Size of Final Product Crystals and Seed-Loading Ratio. The mean mass size of final product crystals normalized with the mean mass seed size Lp/Ls can be calculated from eq 4 if the seed-loading ratio Csis known. Equation 4 is obtained by a simple mass balance assuming no nucleation, no crystal breakage, no agglomeration of seed crystals, no crystal habit change, and no residual supersatutation at the end of the batch.23,24
(
)
Lp 1 + Cs ) Ls Cs
1/3
(4)
where Cs is the seed-loading ratio, defined as the ratio of the mass of seed crystals to the theoretical crystal yield, which can be calculated from the initial and final solution concentrations. The theoretical mean mass size of the final product was calculated as 714 µm from eq 4 at the seed-loading ratio of Cs ) 0.08. This theoretical size agreed with the experimental value (702 µm) with a relative error of 1.7%. Alternatively, we can design a crystallization strategy to produce crystals of a desired mean mass size by manipulating the seed amount, the initial concentration of the solution, and the final termination temperature. 2.3. Development of Crystal Size Distribution during a Batch. Additional experiments were performed to know how the crystal size distribution developed in this seeded batch crystallization of the R-form glycine. Crystallization was interrupted before the end of a batch at points A and B (see Figures 1 and 6), respectively, and the crystal size distribution was evaluated for these two points by sieving. The results are shown in Figure 8. The size distribution is seen to shift to the right with time, keeping its shape the same. This development of crystal size distribution obtained clearly indicates that the seed crystals grow without generation of fine crystals. Conclusions The metastable R-form glycine was obtained selectively by batch cooling crystallization, in which the seed crystals of the R-form introduced at the beginning were grown to the product without generation of fine crystals. (1) The solution was heated twice intermittently during cooling to the termination temperature of 20 °C to dissolve fine crystals unavoidably generated. The
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Crystal Growth & Design, Vol. 4, No. 5, 2004 953 Ws Wth
mass of the seeds added [kg] theoretical crystal yield [kg]
References
Figure 8. Development of the crystal size distribution during crystallization.
cooling and heating strategy was designed on-site according to in-situ information of the supersaturation, the particle count number, and the temperature. (2) The on-site strategy-design-technique used here is expected to be applied widely for selective crystallization of metastable polymorphs other than glycine. (3) The in-situ ATR-FTIR spectroscopy was successfully used to monitor the supersaturation of the solution of glycine. (4) The FBRM particle counter was used to monitor the number of particles of the R-form glycine crystals present in the crystallizer. Acknowledgment. This study was conducted as part of the Research Project of the Intelligent Manufacturing System in Japan in 2003 (Title: Intelligent Design and Control of Batch Crystallization Processes. Domestic Code No. 0134, Common name: SINC-PRO). Glossary Cs cR cγ ∆cR ∆cγ L Ls Lp
seed loading ratio () Ws/Wth) [-] solubility of the R-form glycine [kg/100 kg-water] solubility of the γ-form glycine [kg/100 kg-water] c - cR, supersaturation with respect to the R-form glycine [kg/100 kg-water] c - cγ, supersaturation with respect to the γ-form glycine [kg/100 kg-water] crystal size [µm] mean mass size of seed crystals [µm] mean mass size of product crystals [µm]
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CG030070S
