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Journal of Crystal Growth 310 (2008) 46474651

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Journal of Crystal Growth

journal homepage: www.elsevier.com/locate/jcrysgro

An interpretation of the metastable zone width concerning primary nucleation in anti-solvent crystallization
Noriaki Kubota
Department of Chemical Engineering, Iwate University, 4-3-5 Ueda, Morioka 020-8551, Japan

a r t i c l e in fo
Article history: Received 28 May 2008 Received in revised form 13 July 2008 Accepted 17 August 2008 Communicated by K. Sato Available online 29 August 2008 PACS: 64.60.Qb Keywords: A1. Metastable zone width A1. Nucleation A1. Supersaturated solutions A2. Industrial crystallization

abstract
A new model is proposed to interpret metastable zone widths (MSZWs) obtained for anti-solvent crystallization. The MSZW is dened as an excessive anti-solvent composition or supersaturation at which the number density of accumulated grown primary nuclei has reached a xed value when the anti-solvent is continuously added at a constant rate into the initial saturated solution. In the model, the steady-state primary nucleation in the bulk solution is assumed to be achieved instantaneously at any time. The effects of stirrer speed, anti-solvent addition rate, MSZW detection method and anti-solvent addition location are interpreted for the literature data measured for the anti-solvent crystallization of benzoic acid [D. OGrady, M. Barrett, E. Casey, B. Glennon, Trans. Chem. Eng. Res. Des. 85 (A) (2007) 945]. & 2008 Elsevier B.V. All rights reserved.

1. Introduction In anti-solvent crystallization, supersaturation is created by adding an anti-solvent into the solution. It is widely used in chemical and pharmaceutical industries, because materials whose temperature coefcient of solubility is low can be crystallized easily and materials unstable at elevated temperatures can be crystallized safely. Although there are a number of industrial applications of anti-solvent crystallization, it has not been studied extensively and its mechanism is not well understood, compared to cooling crystallization. In particular, only a few papers dealing with the metastable zone width (MSZW) can be found in the literature. The MSZW reects the nucleation characteristics of a system and is considered to be useful in exploring nucleation kinetics. An interesting paper was published by OGrady et al. [1] on the MSZW in the anti-solvent crystallization of benzoic acid, where water was added as an anti-solvent into the saturated ethanol water solution. They analyzed the measured MSZWs by using a modied Nyvlt model, whose original version [2] was proposed for cooling crystallization. A problem in the original (and also in the modied) model is that the primary nucleation rate is given in mass basis. It is needless to say that the nucleation rate should be

given in number basis. Another problem is that different nucleation kinetics are deduced from the measured MSZWs even for the same material system under the same crystallization condition depending on the experimental methods used. Recently a new model [3] was proposed for MSZWs obtained in the cooling crystallization from unseeded solutions, and experimental data in the literature were reasonably interpreted. In this new model the metastable limit or the point of MSZW is dened as a supercooling at which the number density of accumulated crystals (grown primary nuclei) has reached a xed (but unknown) value. In the present paper, a new model is developed by applying a similar denition of MSZWs to anti-solvent crystallization and an attempt is made to interpret experimental MSZW data reported by OGrady et al. [1]. The effects on MSZW of stirrer speed, anti-solvent addition rate, method of detecting the point of MSZW and antisolvent addition location (or mixing of anti-solvent with solution) will be discussed by using the new model.

2. Theory 2.1. MSZW in terms of excessive anti-solvent composition DA Solvent and solute compositions in anti-solvent crystallization have been expressed in a variety of ways [1,410]. In the present paper, the solute composition C is dened, according to the literature [1,4,5], by the mass ratio of solute to solvent and the

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E-mail address: nkubota@iwate-u.ac.jp 0022-0248/$ - see front matter & 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jcrysgro.2008.08.049

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Nomenclature exponent in Eq. (15) composition of anti-solvent, kg anti-solvent/kg solvent A1 A at t 0 (the starting point) or A of an initial saturated solution, kg anti-solvent/kg solvent DA supersaturation in terms of excessive anti-solvent composition dened by DA (AA1) kg anti-solvent/ kg solvent DAm metastable zone width in terms of DA, kg antisolvent/kg solvent C solute composition, kg solute/kg solvent C1 solute composition at t 0 or solute composition of the initial saturated solution, kg solute/kg solvent C0 solubility in anti-solvent-free solution, kg solute/kg solvent DC supersaturation in terms of solute composition, dened by (C1C*), kg solute/kg solvent DCm metastable zone width in terms of DC, kg solute/kg solvent Jm primary nucleation rate in mass basis dened by Eq. (14) kg/(kg solvent s) Jn primary nucleation rate in number basis dened by Eq. (2) no./(kg solvent s) a A

k0 kn kN km m Nr n (N/V)det

(N/V)m RA RC tm

number-based primary nucleation constant in Eq. (2) no./(kg solvent s) number-based primary nucleation constant in Eq. (5) ank0 constant in Eq. (15) mass-based primary nucleation constant in Eq. (14) mass-based primary nucleation order in Eq. (14) stirrer speed, rpm number-based primary nucleation order in Eqs. (2) and (5) number density of grown primary and secondary nuclei accumulated by the time the MSZW is reached, no./m3 number density of grown primary nuclei accumulated by the time the MSZW is reached, no./m3 specic anti-solvent addition rate dened by Eq. (1), kg anti-solvent/(kg solvent s) rate of increase in supersaturation DC, kg solute/(kg solvent s) time the MSZW is reached, s anti-solvent composition coefcient of solubility (Eq. (3)), (kg solute/kg solvent)/(kg anti-solvent/kg solvent)

anti-solvent composition A is expressed as the mass ratio of antisolvent to solvent. For simplicity, we consider the case that solvent-free (non-diluted) anti-solvent with no solute is added into the initial solution saturated with the solute. According to OGrady et al. [1], the specic anti-solvent addition rate RA is dened by dDA RA dt (1)

where DA is excessive anti-solvent composition dened by DA AA1, and A is anti-solvent composition at any time t and A1 is the anti-solvent composition of an initial solution saturated with the solute (see Fig. 1). On the other hand, the primary nucleation rate Jn can be written in an approximate form as a function of supersaturation DC [1,4]: Jn k0 DC n (2)

where DC (C1C*). C1 is the initial saturated solute composition and C* is the equilibrium solute composition (solubility) at a point A (see Fig 1). It is noted that there is no virtual change in solute composition before the MSZW is reached. The solubility C* can be assumed to be given by a linear function of the anti-solvent composition A [1] (see also Fig. 1) as C n aA C 0 (3)

where a is the anti-solvent composition coefcient of solubility and C0 is the solubility at A 0 (anti-solvent-free solution). The supersaturation DC ( C1C*) is related to DA ( AA1) by

DC aDA
Inserting Eq. (4) into Eq. (2) gives Jn kn DAn

(4)

(5)

where kn ank0. Similarly as for cooling crystallization discussed in the previous paper [3], the MSZW is dened as an excessive anti-solvent composition at which the number density of grown primary nuclei has reached a xed value of (N/V)m. The value of (N/V)m can be calculated simply by integrating the nucleation rate Jn ( d(N/V)/dt) with respect to time from zero to tm, the time the MSZW is reached:   Z N=V m   Z tm N N d Jn dt (6) V m V 0 0 where N is the number of accumulated grown primary nuclei and V is the solution volume, both of which increase with time in case of anti-solvent crystallization. Here, the steady-state primary nucleation rate Jn is assumed to be achieved instantaneously at

Fig. 1. A schematic diagram showing the relation between excessive anti-solvent composition DA and supersaturation DC.

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any moment during the measurement of MSZW, as suggested by Sohnel and Mullin [11] for solutions of moderate supersaturation and low viscosity. If the anti-solvent is added at a constant specic rate RA, Eq. (6) is changed to the following equation by using the relation of dt d(DA)/RA (see Eq. (1)),   Z DAm N J n =RA dDA (7) V m 0 where the upper limit of integration DAm is the MSZW in terms of excessive anti-solvent composition DA and corresponds to the time tm. After inserting Eq. (5), integration of Eq. (7) with the assumption of unchanged kn and n (i.e., the steady-state primary nucleation) gives     N kn (8) DAm n1 V m n 1RA and rearranging Eq. (8) leads to  1=n1 N=V m 1=n1 DAm n 1 RA kn

It must be noted that Eq. (13) includes no parameter regarding the measurement technique. Therefore, the modied Nyvlt model cannot explain the experimental fact why the measured MSZW depends on the experimental technique used for the detection of the point of MSZW.

3. Analysis of experimental data and discussion 3.1. Actual detection of the point of MSZW In the above mathematical formulation, the point of MSZW is dened as an excessive anti-solvent composition DA or a supersaturation DC at which the number density of accumulated grown primary nuclei reaches a xed (but unknown) value (N/V)m when the anti-solvent is added continuously at a constant rate. However, as discussed in the previous paper [3] for cooling crystallization, the point corresponding to (N/V)m is never directly detected in actual experiments. In the actual measurements of MSZW, the number density of crystalline particles increases more rapidly than expected from primary nucleation mechanisms only, because of subsequent secondary nucleation. Nuclei generated by primary nucleation mechanisms grow and the grown nuclei begin to generate secondary nuclei. These secondary nuclei also grow and generate the next-generation secondary nuclei and so on. This increasing fashion in particle number looks like an avalanche [12]. The point of an MSZW is the point of occurrence of the avalanche, which is detected actually as a change in a nucleation-related physical quantity [3] such as turbidity, particle count number or solution concentration, etc. The actual increasing behavior of number density of particle, which consists of grown primary and secondary nuclei, is shown conceptually with dotted lines in the N/VDA diagram (Fig. 2a). The increasing behavior may be different depending on stirrer speed, because stirrer speed has a large effect on secondary nucleation [13]. The solid line in the gure is a hypothetical (or unrealistic) line showing an increase in the number density of primary grown nuclei only. The actual total particle number density corresponding to the MSZW (DTm) is denoted by (N/V)det, in Fig. 2a, which is larger than the number density of (grown) primary nuclei (N/V)m. It is impossible to know the real (N/V)m because secondary nucleation can never be avoided in the actual measurement of MSZW. 3.2. Effect of stirrer speed on MSZW The fact may be questionable that primary nucleation, which is assumed to occur at the steady-state rate, is accelerated by such a slight increase in the stirrer speed from 325 to 475 rpm as in the experiments of OGrady et al. [1]. An interpretation assuming change in secondary nucleation rate with no change in primary nucleation kinetics (i.e., no change in kn and n in Eq. (5)) seems to meet the reality in the measurement of MSZWs. The secondary nucleation rate becomes high as the stirrer speed is increased, and hence the actual particle number density increases rapidly and the dotted line in Fig. 2a shifts to the left. Accordingly, the value of (N/V)m is indirectly lowered because the value of (N/V)det remains unchanged provided the same detection technique is used. Therefore, Eq. (9) can be modied by assuming the relation (N/V)mpNa r . However, the parameters (N/V)m and kn cannot be evaluated separately from the experimental data (DAm vs. RA). Therefore, the effect of stirrer speed is considered by putting (N/V)m/kn kNNa r , where kN and a are constants. Thus, Eq. (9) is changed to the following equation:
1=n1 1=n1 DAm kN Na RA r n 1

(9)

This is a new equation of MSZW in the anti-solvent crystallization. The theoretical MSZW thus obtained depends on the nucleation kinetics (kn and n), the specic anti-solvent addition rate RA and the method of detecting the point of MSZW. The effect of the detection method is taken into account for Eq. (9) by the term of (N/V)m. The more sensitive the measurement technique, the smaller the (N/V)m and hence the smaller the MSZW is expected to be, with no change in kn and n (i.e., no change in primary nucleation kinetics). The problem of the detection method will be discussed more in detail in Section 3.4. Taking the logarithm of both sides of Eq. (9) and rearranging give   1 N=V m 1 log log RA logDAm n 1 (10) n1 n1 kn

2.2. MSZW in terms of supersaturation DC The MSZW may also be expressed in terms of supersaturation

DC as in Mullin et al. [4], which is dened by the difference

(C1C*) (see Fig. 1). The theoretical equation can be derived in a similar way as mentioned above for Eq. (9). It is written as  1=n1 N=V m 1=n1 DC m n 1 RC (11) k0 where DCm is the MSZW in terms of DC, k0 is the primary nucleation constant in Eq. (2) and RC is the rate of increase in supersaturation DC dened by Rc dDC dt (12)

2.3. Modied Nyvlt model Incidentally, Eq. (10) is similar, in giving a linear relation between log DAm and log RA, to the modied Nyvlt equation proposed by OGrady et al. [1], which is rearranged to   1 a1 m 1 logDAm log (13) log RA m km m where km and m are the nucleation constant and nucleation order, respectively, in the following mass-based primary nucleation rate equation: J m km DAm (14)

(15)

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Fig. 2. The (N/V)DA diagrams explaining (a) stirrer speed effect, (b) anti-solvent addition rate effect, (c) detection method effect, (d) mixing (anti-solvent addition location) effect.

Eq. (15) was tted to the experimental MSZW data obtained in the experiments of OGrady et al. [1], where the anti-solvent water was added to the location close to the stirrer shaft. Under this condition of addition, rapid mixing of the anti-solvent was expected and primary nucleation is considered to occur in the bulk of the solution (not at the addition location) [1]. Fitting was made simultaneously for both the data sets, obtained at 325 and 475 rpm, by using a non-linear least-squares method. The values of the parameters were determined as kN 3.30 102, a 1.28 and n 1.92 and the following equation was obtained:
0:414 0:342 DAm 1:04N RA r

(16)

The tted lines seem to trace the experimental data satisfactorily as seen in Fig. 3 and the relation of (N/V)mp 1.28 N is concluded. Thus, the effect of stirrer speed on r MSZW is explained by considering the increase in the secondary nucleation rate with no change in the primary nucleation kinetics.

Fig. 3. The effects of stirrer speed and anti-solvent addition rate on MSZW of the sufcient mixing case. The anti-solvent water was added to the location close to the stirrer shaft. Data were taken from OGrady et al. [1].

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3.3. Effect of anti-solvent addition rate on MSZW The effect of specic anti-solvent addition rate RA on MSZW is described by Eq. (16) as already shown in Fig. 3 by the solid lines. This effect can be explained as follows as the result of a decrease in the quantity Jn/RA with an increase in RA. The number density (N/V) of accumulated grown primary nuclei increases with time and it can be written as a function of DA with RA as a parameter:     N kn (17) DAn1 V n 1RA This equation is obtained by integrating the nucleation rate Jn from time zero to t. It is clear from Eq. (17) that the particle 1 number density (N/V) increases more slowly by the factor R A as the addition rate is increased. The effect of RA is schematically shown in the (N/V)DA diagram (Fig. 2b). The value of DAm (MSZW), corresponding to a xed value of (N/V)m, is detected later and becomes larger as the anti-solvent addition rate is increased. The anti-solvent addition rate effect can thus be explained without considering change in primary nucleation kinetics or time needed for change in solution structure (cluster or embryo formation) or without considering change in primary nucleation kinetics. This corroborates the above assumption that the primary nucleation rate is achieved instantaneously at any moment. 3.4. Problem concerning the technique of detecting MSZW OGrady et al. [1] measured MSZWs by using a Fourier transform infrared (FT-IR) spectrometer and an FRBM particle counter. The MSZW obtained by the FBRM method was smaller than that obtained by the FT-IR method. This can be explained by assuming a smaller value of (N/V)det, and hence a smaller value of (N/V)m for the FBRM method with unchanged nucleation kinetics as shown in Fig. 2c. It is shown that the more sensitive the detection technique, the smaller the MSZW. 3.5. Effect of mixing (or addition location) on MSZW A high local supersaturation may be created at the anti-solvent addition location if mixing is insufcient. OGrady et al. [1] investigated the effect of mixing on MSZW by changing the addition location. In Fig. 4, the MSZWs obtained when the antisolvent was added to the location close to the crystallizer wall (J and K) are compared with the corresponding data (dotted lines of Eq. (16)) obtained when the anti-solvent was added to the location close to the shaft of the impeller. When the addition location is close to the vessel wall, the effect of the anti-solvent addition rate becomes less pronounced and, at a lower stirrer speed of 325 rpm, the MSZW does not increase monotonically but it passes through the maximum and decreases, as the anti-solvent addition rate is increased. Such irregular addition rate effects are considered to be due to the additional local primary nucleation caused by insufcient mixing at the addition location. It is shown in Fig. 2d (N/VDA diagram) that the point of (N/V)m is moved to the left by the added local primary nucleation due to a high rate of increase in (N/V). Another effect of the addition location is that the effect of stirrer speed in insufcient mixing is reversed from that observed for the case of sufcient mixing. As seen in Fig. 4, the lower the stirrer speed, the smaller the MSZW (higher nucleation rate) in case of insufcient mixing. This reverse effect can also be attributed to the additional local primary nucleation caused by a

Fig. 4. The effects of stirrer speed and anti-solvent addition rate on MSZW of the insufcient mixing case. The anti-solvent water was added to the location close to the vessel wall. Data were taken from OGrady et al. [1].

higher local supersaturation due to poorer mixing at the addition location.

4. Conclusions 1. The new model for the MSZW in the anti-solvent crystallization was presented and the mathematical equations describing the MSZW as a function of excess anti-solvent composition (Eq. (9)) and supersaturation (Eq. (11)) were derived. 2. The literature data reported for anti-solvent crystallization of benzoic acid from ethanolwater mixed solutions with water as an anti-solvent were analyzed. The stirrer speed effect on MSZW was explained by considering secondary nucleation, which accelerates the rate of increase in the actual number density of particles. The effect of anti-solvent addition rate is attributed to a result of change in Jn/RA. The detection method effect is the problem of detector sensitivity. Addition location has an effect on MSZW through the additional local primary nucleation caused by a high local supersaturation induced by the insufcient mixing of the anti-solvent with the bulk solution. 3. No change in primary nucleation kinetics Jn (kn and n in Eq. (5)) is considered in all these explanations. In addition, it can be assumed that the steady-state primary nucleation in the bulk solution is achieved instantaneously at any moment during the measurement of MSZW. References
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