Continuous Crystallization and Polymorph Dynamics in the l-Glutamic

Article pubs.acs.org/OPRD

Continuous Crystallization and Polymorph Dynamics in the L‑Glutamic Acid System Tsai-Ta C. Lai,† Steven Ferguson,† Laura Palmer,‡ Bernhardt L. Trout,† and Allan S. Myerson*,† †

Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue 66-568, Cambridge, Massachusetts 02139, United States ‡ Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, United Kingdom S Supporting Information *

ABSTRACT: Polymorph dynamics of L-glutamic acid were examined during continuous mixed suspension mixed product removal (MSMPR) crystallization as a function of residence time and temperature. Results indicate that it is possible to selectively produce metastable or stable polymorphs via a kinetically controlled crystallization in an MSMPR crystallizer by manipulating the crystallizer temperature and residence time. Additionally, on the basis of experimental and modeling studies, it was found that seeding is not necessarily sufficient to alter polymorphism at a given steady state, indicating that this traditional polymorph control strategy may not be applicable in MSMPR systems. The competition between nucleation and growth kinetics of the metastable α form and the stable β form is the major factor in determining the polymorphic outcome at particular steady state conditions. A metastable steady state with a population of the stable β polymorphic was experimentally obtained at 25 °C and 120 min residence time where a small perturbation from the α form could induce a change in the steady state polymorphism. This “polymorphic transformation”, unlike the traditional solvent-mediated transformation, is a result of the interplay of kinetic driving forces. In addition, our dynamic simulation suggests that long residence times (>17.4 h) are required to obtain a steady state of the stable β form when operating at temperatures of 25 °C. Our studies indicate one challenge for designing a MSMPR crystallization will be the interplay of growth and nucleation kinetics of the various forms at conditions which produce the desired yield and polymorph. crystal size distribution (CSD).4−7 Nevertheless, very few studies have been conducted on the control of polymorphism in continuous crystallization.8 Although there are exhaustive studies on polymorph dynamics and control in batch systems, there is no systematic study in the continuous case. The fundamental differences between batch and continuous crystallization, notably, the residence time distribution and nucleation dynamics, indicates that the polymorph control strategies used in batch operation may not be applicable in the continuous case. It is very possible that one may not be able to obtain the desired polymorph under the optimal process condition where the desired yield, purity, and CSD are achieved. In the batch crystallization process, nucleation is dominant at the beginning of the process when supersaturation is high. Depending on the temperature and nucleation kinetics, metastable or stable forms (or a mixture of the two) will be obtained. Crystal growth becomes significant after the first appearance of nuclei. Nucleation is then limited as supersaturation is depleted by crystal growth. As the mother liquor concentration drops below the solubility of the metastable polymorphs due to the growth of the most stable crystals, the metastable crystals may convert to a more stable form by solution-mediated conversion, and with a sufficient time period

1. INTRODUCTION Crystallization is an important separation and purification process used in the pharmaceutical, chemical, and food industries. It is particularly important in pharmaceutical manufacturing since more than 90% of all pharmaceutical products contain active pharmaceutical ingredients (APIs) in crystalline forms.1 Crystallization is based on the phase transition of molecules from the solution to the solid state. The orderly structured crystalline facilitates impurity rejection from the solid product, which makes the isolation process energy efficient and cost-effective. However, crystalline compounds can adopt different packing arrangement or conformation in the crystal lattice while being molecularly identical. Such phenomenon is known as polymorphism. Polymorphism is very common among organic crystals. It is reported that more than 50% of API compounds are polymorphic.2 Changing from one polymorph to another can cause variations in solid solubility, stability, crystal morphology as well as other important physical and chemical properties. These changes in physical properties can significantly affect the quality of the final product by influencing the bioavailability of the APIs and the drug processability in downstream processes, such as filtration, drying, and tableting.3 Therefore, control of polymorphism is a vital issue in pharmaceutical crystallization. In recent years, there has been increased interest in moving pharmaceutical manufacturing from batch to continuous processes due to economic and control benefits.2 Recent work on continuous crystallization of pharmaceuticals has focused on methods to achieve the desired yield, purity and © XXXX American Chemical Society

Special Issue: Continuous Processes 14 Received: May 28, 2014

A

dx.doi.org/10.1021/op500171n | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

Figure 1. X-ray powder diffraction patterns of (a) the metastable α form and (b) the stable β form.

Figure 2. Optical microscope image of (a) the metastable α form and (b) the stable β form.

mixed product removal (MSMPR) crystallizers.15 Since the dynamics in PFR is rather similar to that in batch, the MSMPR system is considered as the model crystallizer system in this paper to elucidate polymorph dynamics in continuous crystallization. This paper reports on polymorph dynamics in continuous crystallization. L-glutamic acid is selected as the model compound. It is monotropic with one metastable α polymorph and one stable β polymorph. The compound is widely used for studying polymorphism.16−18 The effect of process parameters, i.e. crystallizer residence time and temperature, on L-glutamic acid polymorphism in MSMPR crystallizer is studied experimentally. In addition, the efficacy of seeding is evaluated and discussed on the basis of experiment and modeling results.

all the crystals in the batch are converted to the thermodynamically most stable form at the final temperature. Many batch polymorph control strategies are developed on the basis of the crystallization dynamics described above. Seeding of the desired polymorph is one of the most direct and common polymorph control strategies in batch systems. It is designed with a carefully controlled desupersaturation profile in order to avoid the primary nucleation of undesired polymorphs.9−11 Additives addition and solvent selection are other common techniques utilized to either inhibit the primary nucleation of the unwanted forms or to enhance/inhibit the solvent-mediated transformation toward the most stable form, depending on whether or not the most stable polymorph is desired.12−14 However, unlike batch operation, in continuous crystallization, nucleation (particularly secondary nucleation) is always occurring. In addition, crystals are constantly removed from the crystallizer. Thus, the efficacy of seeding in controlling polymorphism in continuous systems may be low since the initial seeds are washed out after several residence times. That being said, it is still interesting to investigate whether different seeding conditions can lead to different steady states. In addition, since continuous processes do not operate at equilibrium conditions and must have finite supersaturation at the exit, it is possible for the steady state concentration to be higher than the solubility of both the most stable polymorph and one or more metastable polymorphs. This is particularly true if the differences in solubility of different polymorphs are small. Thus, in many cases, solvent-mediated transformation to the most stable form cannot occur at normal operating conditions. Under a continuous reactor design perspective, the residence time distribution (RTD) of any continuous crystallization process can be represented by a combination of nonmixing plug flow reactors (PFR) and perfect mixing mixed suspension

2. EXPERIMENTAL SECTION Materials. The model compound selected in this paper is Lglutamic acid. This amino acid has two polymorphs: the metastable α form and the most stable β form. The most stable β polymorph (>99% pure) was obtained from Sigma-Aldrich, St. Louis, U.S.A. The metastable α form was produced from fast cooling of aqueous L-glutamic acid solution with a concentration of 40 g/kg solvent. The solution, stirring at 300 rpm, was heated up to 85 °C until clear and crash cooled to 15 °C. Primary nucleation occurred shortly after the reactor temperature reached 15 °C. Immediately afterwards, the slurry was filtered, washed and dried. The crystals polymorphism was further verified by X-ray powder diffraction (XRPD) to be pure α polymorph. The XRPD patterns and the optical microscope images of the two polymorphs are shown in Figure 1 and Figure 2, respectively. The metastable α crystals are prismatic, whereas the most stable β crystals are needles. B



Article

Liquid- and Solid-State Characterization. The mother liquor concentration during MSMPR crystallization was measured using Fourier transform infrared spectroscopy (FTIR). All measurements were conducted offline using a FlowIR instrument from Mettler Toledo. Liquid samples were filtered and heated to 70 °C to ensure no crystallization occurring after being taken out from the crystallizer. The absorbance of the carboxylate stretching band at 1402 cm−1 was used for the LGA solute concentration measurement. The polymorphism of the solids was characterized by Raman spectroscopy and X-ray powder diffraction (XRPD). Although only used as a qualitative measuring tool for L-glutamic acid polymorph mass content, Raman spectroscopy (RAMANRXN2 HYBRID, Kaiser) was utilized for determining the extent of the polymorph crystallization process. It allows online monitoring of polymorph transformation and crystallization dynamics in the MSMPR crystallizer. The characteristic peak for the metastable α form is at 472 cm−1, while the characteristic peak for the stable β form is at 468 cm−1. The characteristic peak’s intensity remains relatively constant upon reaching the steady state. Quantitative measurement for the polymorphic content was determined offline by XRPD, which was obtained using a PANalytical X’Pert PRO Theta/Theta powder X-ray diffraction system with a monochromatic Cu Kα radiation source and nickel filter (λ = 1.5418 Å). The characteristic peak for the metastable α form is at 26° and that for the stable β form is at 10°. Standard samples were prepared by mixing pure α and β crystals. The detection limit for XRPD is about 1 wt %. In addition, focus beam reflectance measurement (FBRM) from Lasentec was applied to track the evolution of particle sizes. The Lasentec S400 probe measured the chord length distribution (CLD) online.

Experimental Setup. The MSMPR crystallizer is set up as illustrated in Figure 3. The main component of the system is a

Figure 3. Schematic plot for the MSMPR crystallizer.

300-mL glass-jacketed crystallizer (VWR International) with overhead mechanical stirring (IKA) and internal temperature control (Thermo Scientific SC100-A25). In all crystallization experiments, the working volume in the crystallizer was 150 mL and was controlled by the position of the outlet. The outlet utilized an intermittent withdrawal scheme which was set to remove all the slurry above the controlled level. Each withdrawal took away 10% of the slurry volume every one tenth of a residence time. This removal scheme ensured that there was no size classification upon withdrawal. The withdrawal rate was sufficiently high such that there was no slurry residual left in the outlet tubing (discharge time was around 30 s). The MSMPR system was run for up to 140 h without clogging issues. The crystal size distribution in the crystallizer was monitored online by focus beam reflectance measurement, FBRM (Lasentec, Mettler Toledo). Batch Crystallization Experiment. A batch cooling crystallization experiment was carried out with the same vessel (300-mL glass-jacketed crystallizer) used for the MSMPR. An aqueous L-glutamic acid solution with 40 g/kg solvent was prepared by dissolving β form L-glutamic acid in deionized water at 85 °C. The clear solution was then cooled in the batch to the set-point temperature (25 or 45 °C) and was then held until equilibrium. Continuous Crystallization Experiment. Cooling crystallization was performed using the MSMPR platform described previously. A 40 g/kg solvent L-glutamic acid aqueous solution was prepared as feed solution. The feed was kept at 85 °C and pumped into the crystallizer at constant flow rate by a peristaltic pump (Masterflex, Thermo Scientific). The inlet flow rate was set in accordance to the desired residence time. The inlet transfer lines were heated with 85 °C hot water to avoid primary nucleation in the feed stream. The MSMPR was operated either with or without seeding. For an unseeded MSMPR, the crystallizer was first operated as a batch with clear L-glutamic acid solution (40 g/kg solvent) until primary nucleation occurred and crystals became visible in the suspension. Subsequently, the feed was added to the crystallizer, and the intermittent withdrawal scheme was initiated. For a seeded MSMPR, the crystallizer was started up with the addition of either pure β or pure α crystals to the clear solution. In this paper, the amount of crystals added is presented as the seed mass compared to the solid mass in an equilibrium batch. The particle size distribution, crystal polymorphism, and solute concentration were monitored from startup phase to steady state.

3. EXPERIMENTAL RESULTS 3.1. Solvent-Mediated Transformation in Batch. Batch crystallization of L-glutamic acid was used to obtain preliminary knowledge of the compound’s polymorph kinetics. The unseeded batch experiments with an initial concentration of 40 g/kg solvent were conducted under 25 and 45 °C, respectively. The polymorph mass content at a given time was acquired by XRPD. Combined with the mother liquor concentration data obtained from FTIR measurement, the time evolution of the mass density of the two polymorphs was determined. The experimental results are presented in Figure 4 and Figure 5. It was found that in both cases, the metastable α form was the dominating form at the beginning of the

Figure 4. Mass density profile of α and β form L-glutamic acid in 25 °C batch crystallization experiment. C



Article

concept was applied for designing experimental conditions of MSMPR systems. The experiment conditions were selected as summarized in Table 1. Note that the residence time was set below 2 h to avoid clogging issues in the inlet tubes. Table 1. Experimental conditions for unseeded MSMPR cooling crystallization experiments metastable α form

target polymorph:

stable β form

expt 1 expt 2 expt 3 expt 4 expt 5 temperature (°C) residence time (min) flow rate of feed stream (mL/min) agitation rate (rpm) feed concentration (g/ kg solvent)

Figure 5. Mass density profile of α and β forms of L-glutamic acid in 45 °C batch crystallization experiment.

crystallization process, indicating that L-glutamic acid follows the Ostwald’s rule of stages that the thermodynamically less stable crystal formations are kinetically more favorable during nucleation.19 As the mother liquor (ML) concentration decreased below the solubility of the α polymorph, the stable β crystals grew at the expense of the metastable α crystals. Both batch experiments reached equilibrium shortly after all α crystals were depleted. The time required for complete solventmediated transformation was found to be shorter at higher temperatureunder 25 °C full transformation to the stable polymorph was about 45 h, while it only took 6 h under 45 °Ca result of a generally faster growth/dissolution kinetics and a larger solubility difference between the metastable and stable polymorphs at higher temperature. Based on the batch results shown in Figure 4 and Figure 5, it is postulated that, with the same feed concentration, the stable form is more favorable under high temperature and long residence time, and vice versa for the metastable polymorph, as illustrated in Figure 6. Although there are fundamental

expt 6

25 30 5

25 60 2.5

25 90 1.67

25 120 1.25

45 60 2.5

45 120 1.25

300 40

300 40

300 40

300 40

300 40

300 40

3.2. Polymorph-Selective Crystallization in Unseeded MSMPR. The L-glutamic acid polymorph selectivity for these MSMPRs was examined experimentally and summarized in Table 1. Let us first consider Expt 2 (25 °C and 60 min residence time). After startup, only the metastable α crystals were observed. As shown in Figure 7a, steady state was achieved after 2 residence times (120 min) with no β form detectable in the course of the experiment. The chord length distribution measured by FBRM and an optical image of the crystals at steady state are presented in Figure 7b. The experiment was run at steady state for another 72 h, or 72 residence times, and there was no detectable amount of β crystals during the experiment. The results were verified with both XRPD and Raman spectroscopy. Herein, a polymorph selective MSMPR crystallization was demonstrated experimentally for the first time. However, it is important to note that this particular polymorphic pure steady state may not be stable. It is possible that with some process disturbances, e.g. β crystals nucleated somewhere in the crystallizer, the crystallization process may shift to a new steady state where the stable β form is the dominated polymorph. The stability of the polymorphic pure steady state is discussed in section 3.4. As summarized in Table 2, all the MSMPR experiments conducted under 25 °C contained only α form at steady state whereas the case under 45 °C showed only β polymorph. The polymorphism of the MSMPR crystallization process was very sensitive to the crystallizer temperature. In addition, it is important to note that the steady state mother liquor concentrations measured for all the MSMPR experiments were higher than the solubility of both polymorphs. This

Figure 6. Illustration of MSMPR process design strategies to achieve polymorph-selective continuous crystallization.

differences in nucleation kinetics and residence time distribution between batch and MSMPR crystallization, this design

Figure 7. Experimental results of the 25 °C, 60 min residence time MSMPR. (a) Time evolution of ML concentration and α form mass fraction and (b) cord length distribution and optical image of the α crystals at steady state. D



Article

Table 2. Experimental results from the unseeded cooling crystallization of L-glutamic acid under various MSMPR residence times and temperatures single stage MSMPR (25 °C, unseeded)

a

expt 1

expt 2

residence time (min)

30

60

ML concentration (g/kg solvent) polymorphisma

24.65 pure α

25.24 pure α

ML concentration (g/kg solvent) polymorphisma

28.60 pure α

22.36 pure α

expt 3

single stage MSMPR (45 °C, unseeded) expt 4

90 startup results 28.36 pure α steady state results 19.74 pure α

expt 5

expt 6

120

60

120

24.79 pure α

30.25 mixture (β: 33 wt %)

28.83 mixture (β: 28 wt %)

18.24 pure α

35.32 pure β

26.41 pure β

Polymorph purity is based on the results from XRPD which has a detection limit of 1 wt %.

multiple steady states were achieved during crystallization, the system quickly transformed to the most stable state. Experimental results support the latter postulation as presented in section 3.4. 3.4. Stability of the Polymorphic Pure Steady State. The stability of the polymorphic pure steady state strongly depends on the competition of nucleation and growth kinetics between the metastable α form and the stable β form. It is best illustrated by the seeding experiment presented in Figure 8.

suggests that there was a possibility of primary nucleation of both polymorphs when the MSMPR systems were at the polymorphic pure steady state. Nevertheless, the effect of crystal growth and the subsequent secondary nucleation from the nondominant polymorph was not significant enough to cause a noticeable change in the system’s polymorphism before being washed out from the MSMPR. 3.3. The Effect of Seeding on the Polymorphism at Steady State. Seeding is particularly important for polymorph control in batch crystallization. However, its efficacy in the MSMPR system has not been studied in the literature. It is known that the seed crystals would be washed out in several residence times; however, it is possible that different seeding conditions may lead to different steady states (multiple steady states). The 25 °C MSMPR with a residence time of 60 min was used to examine the effect of seeding on steady state polymorphism. Different amounts of β crystals were added to the clear solution during startup before any primary nucleation event could be observed via FBRM. The experimental results of the seeding experiments are summarized in Table 3. It was Table 3. Experimental results for seeded MSMPR under 25°C single stage MSMPR (25 °C, residence time = 60 min) seeding condition seed mass (wt % to equilibrium batch) 5 polymorphisma pure β steady state results ML concentration (g/kg solvent) 23.35 polymorphisma pure α time to reach s.s. (# of residence times) 4

50 pure β

100 pure β

23.55 pure α 7

23.43 pure α 9

Figure 8. Steady state transition from β to α polymorph in seeded 25 °C MSMPR (120 min residence time): (a) polymorph mass density profiles and (b) optical images of the collected crystal samples.

Herein, the MSMPR was run at 25 °C with 120 min residence time. The amount of β seeds added was equivalent to 100% of the crystal mass in an equilibrium batch. Due to the massive amount of seeding, the concentration dropped from 40 g/kg solvent to around 26 g/kg solvent soon after the startup process. During startup, there was no nucleation of the metastable α form observed as confirmed by XRPD. However, the mass deposition rate of the β crystals when subject to the 120 min residence time was not sufficient to maintain the low ML concentration, and the solute concentration eventually went up to around 31 g/kg. During the course of this first part of the experiment, there was no detectable amount of α crystal based on XRPD and Raman measurement. A quasi-steady state was reached and maintained for about one residence time. Nonetheless, the increase in concentration enhanced the probability of primary nucleation of the metastable α form. Eventually, one α crystal was identified within the collected crystal sample under optical microscope, and its polymorphism

a

Polymorph purity is based on the results from XRPD which has a detection limit of 1 wt %.

found that the steady state condition remained unchanged. Even in the extreme case where the amount of β form seeds added was equivalent to the mass of β polymorph in an equilibrium batch at 25 °C, all the seeds along with the newly generated β crystals from the secondary nucleation of existing seeds were washed out completely in 10 residence times. The α polymorph eventually became the only crystalline formation detectable in the crystallizer. These experimental results suggested that seeding was unable to alter the steady state polymorphism. This could be the fact that the kinetic pathways connecting the initial conditions with the multiple steady states were not fully explored via seeding. Another possibility is that there was only one stable steady state. Thus, even if the E



Article

where kg,i and kb,i are temperature-dependent prefactors, Csat,i is the polymorph solubility at given temperature and MT,i is the total solid mass per crystallizer volume of a specific polymorph. The population balance equations of the two polymorphs are coupled by the total mass balance of L-glutamic acid, in solid and liquid states. The mass deposition rate was calculated from the crystal linear growth rate and the total surface area. The total crystals surface area was further estimated from the second moment of the particles and a shape factor, ka,i. The time evolution of the L-glutamic acid solute mass concentration can be written as

was confirmed with Raman spectroscopy. The XRPD measurement at this time point did not exhibit the characteristic peaks for α polymorph, indicating that the mass fraction of the α form was less than 1 wt %. Interestingly, this small amount of α polymorph turned out to be much more favorable kinetically in growth and nucleation and became the dominated polymorph in the crystallizer. The results are illustrated by the optical image and mass fraction data shown in Figure 8. This experimental finding indicates that at 25 °C with a residence time of 120 min the β polymorph specific steady state is unstable. Small perturbation from the primary nucleation of the α form is sufficient to move the system away from the original state toward the new α polymorph specific steady state. This steady state transition is completely different from the solvent-mediated transformation in batch which is based on thermal dynamic driving forces. The polymorph transformation herein was a result of kinetic driving forces.

C −C dC 1 = in − τ dt 2

(2)

⎛ C ⎞b − 1⎟⎟ MT2/3 Bi = kb , i⎜⎜ ,i ⎝ Csat, i ⎠

(3)

i=α ,β

ρi Gika , i

∫0

∞

ni ·x 2dx (4)

where Cin is the inlet concentration, and ρ is the crystal density. The densities of the two polymorphs are assumed to be identical and are equal to 1540 kg/m3. The initial and boundary conditions are given below.

4. DYNAMIC SIMULATION In this section, a mathematical model of L-glutamic acid crystallization was used to study the polymorph dynamics of MSMPR continuous crystallization. The dynamic model consists of population balance equations (PBEs) and a mass balance equation of the polymorphic solids and the mother liquor. A numerical methodthe method of characteristics was introduced to solve the complex partial integro-differential equations. Based on the steady state simulation, the numerical model was first used to estimate the kinetic parameters of both the L-glutamic acid α and β polymorphs. It was then utilized to study the effect of seeding and residence time on polymorphism in MSMPR crystallization. The modeling results were consistent with the experimental findings. 4.1. Governing Equations. One dimension population balance model was introduced to describe the crystallization of L-glutamic acid polymorphs. For a single-stage MSMPR crystallizer with clear feed solution, the population balance equation of a specific polymorph can be written as ∂ni ∂n n + Gi i = − i (i = α , β) (1) ∂t ∂x τ where ni(t, L) is the number density distribution of polymorph i, x represents the crystal size, G is the size-independent crystal linear growth rate, and τ is the residence time of the MSMPSR crystallizer. Several assumptions were introduced to arrive at this equation: • ideal mixing for liquids and solids • size-independent crystal growth • suspension volume in the crystallizer did not change with crystallization and was fixed at the set point value at all times • suspension properties (e.g., solid density, crystal size distribution) at the outlet were identical to that in the crystallizer For simplicity of parameter estimation, semi-empirical equations were utilized for describing growth and nucleation: ⎛ C ⎞g ⎜ − 1⎟⎟ Gi = kg , i⎜ ⎝ Csat, i ⎠

∑

ni(t = 0, x) = ni,seed

(5)

C(t = 0) = C0

(6)

ni(t , x = 0) =

Bi Gi

(7)

where ni,seed represents the number density distribution of the seeds and C0 is the solute concentration during startup. 4.2. Numerical Method: the Method of Characteristics. The method of characteristics, a discretization method, is applied to solve the complex partial integro-differential equations. The method, typically applied to first-order partial differential equations, is the numerical technique that finds the curves on the x−t hyperplane, or characteristic curves, along which the PDEs can be converted to a family of ODEs.20,21 By solving the ODEs with the given initial conditions along the characteristic curves, the solution of the original PDEs can be obtained in the Lagrangian framework. On the basis of the method of characteristics, we converted the population balance equations above into the following equations: dxi = Gi dt

(8)

dni n = − i + h(t , x) dt τ

(9)

where h(t,x) is the birth function that captures secondary nucleation. Assuming a quadratic nuclei size distribution within a critical length, r0, the birth function is written as ⎞ ⎛ 4⎛ r ⎞2 h = B ·⎜ − 2 ⎜x − 0 ⎟ + 1⎟ for 0 ≤ x ≤ r0 2⎠ ⎠ ⎝ r0 ⎝

(10)

The initial conditions of the ODEs are determined by the seeding conditions. ni(t = 0, xi ,seed) = ni ,seed

(11)

Equation 8 and equation 9 are solved along characteristics curves as shown in Figure 9. The seed crystals are sampled by several characteristics partitioned under a geometric scale as shown by the solid curves in Figure 9. As the smallest sized characteristic curve grows to the largest nuclei size, r0, a new characteristic curve is then introduced to represent the newF



Article

one steady state is shown in Figure 10a). However, the same parameter estimation strategy cannot be applied to the β polymorph. This is due to the difficulty of finding a stable steady state with reasonable residence times at 25 °C where the β form is the only polymorph present. As a result, the kinetic parameters of the β polymorph were instead fitted to the dynamic response of the system as opposed to the steady state. We used the dynamic data from startup with pure β form seeding until a quasi-steady state was reached where no α crystals were detected for a sufficient amount of time. One example for this is the first 200 min of the MSMPR experiment shown in Figure 8. The numerical method presented in the previous section was adopted for the parameter estimation scheme herein. The results of the parameter fitting for the β polymorph are presented in Table 4, and the calculated size distribution at the quasi-steady state based on these fitted parameters is demonstrated in Figure 10b. 4.4. Dynamic simulation. The fitted kinetic parameters were applied in the population balance model presented above to study the polymorphism of L-glutamic acid in MSMPR crystallization at 25 °C. Note that, mathematically, it is obvious that both α polymorphic pure and β polymorphic pure steady states are solutions to the governing equations. Hence, it is vital to determine the dynamic pathway leading toward these steady states and also to assess their stability. Herein, the effect of two process parameters, i.e. the seed weight and the MSMPR residence time, on the steady state polymorphism was examined. The effect of the seed weight on polymorph dynamic is numerically studied on the basis of the same seeding conditions given in Table 3. The residence time of the simulated MSMPR was set to be 60 min which is in accordance with the experimental conditions. Similar to the experimental results, although starting with a high mass ratio, the β polymorph did not have sufficient secondary nucleation to sustain its polymorph dominancy. The β crystals were washed out whilst α polymorph, starting with just 1 wt %, became the only form present in the crystallizer at steady state. In addition, as demonstrated in Figure 11, increasing the initial seed weight had limited effect on the polymorph dynamic response. It took

Figure 9. Schematic plot for the evolution of the characteristic curves during crystallization.

born crystals. By tracking the number density distribution of the characteristic curves, the dynamics of the crystals population was acquired. 4.3. Parameter Estimation. Kinetic parameters for nucleation and growth of α and β L-glutamic acid were estimated against experimental data obtained from the 25 °C MSMPR experiments. Notably, the solute concentrations as measured by IR spectroscopy and crystal size distribution as estimated from FBRM were used. For α polymorph, the parameters were fitted to the steady state experimental data under the residence time of 30, 60, 90, and 120 min. It is important to note that under these steady states there was no detectable amount of β polymorph existing in the crystallizer as verified by XRPD. The estimated kinetic parameters are presented in Table 4, and the fitted size distribution under Table 4. Estimated parameters for growth and nucleation at 25°C parameter

α form

β form

kg (μm/min) g (−) kb (#/(m3·min)) b (−)

0.78 1.31 2.02 × 105 2.62

0.095 1.10 5.96 × 104 2.81

Figure 10. Fitted crystal size distribution of MSMPR (25 °C and residence time of 120 min) under (a) steady state with only α polymorph detectable and (b) quasi-steady state with only β polymorph detectable. G



Article

necessary to achieve desirable polymorph purity while maintaining high yield.

5. CONCLUSION In this paper, polymorphism in MSMPR crystallization was studied. The experiments demonstrated the possibility of controlling polymorphism in MSMPR via manipulating crystallizer residence time and temperature. Using L-glutamic acid as model compound, it was shown that it was possible to produce either polymorph through steady state operations. On the basis of the experimental and modeling studies, the polymorph obtained at steady state was found to be independent of the seeding conditions, indicating that seeding may not be applicable in controlling polymorphism in MSMPR crystallization. The competition of nucleation and growth kinetics between the metastable α form and the stable β form was found to be a major factor in determining the stability of the polymorphic pure steady states. In the 25 °C, β-seeded MSMPR experiment, a steady state transition from the most stable polymorph to the metastable polymorph was identified. Unlike the traditional solvent-mediated transformation which is based on thermodynamic driving forces, the polymorph transformation herein was a result of the interplay of kinetic driving forces which induced instability of the β polymorphic pure steady state. In addition, our dynamic simulation suggests that unreasonably long residence time is required to have pure β form as the stable steady state when operating under low temperature (25 °C). Thus, our findings indicate one challenge for designing a MSMPR crystallization process that, while low temperature is desired for achieving high yield, it may be problematic for obtaining the desired polymorph. More studies on the polymorph dynamic in continuous crystallization are crucial for designing a process that achieves high polymorph selectivity while retaining high yield.

Figure 11. Dynamic response of the polymorph mass ratio with different seed weights: 1.6, 16, and 32 g/kg solvent.

about 6, 8, and 9 h residence times to reach steady state for the seed weight of 1.6, 16, and 32 g/kg solvent, respectively. Consistent with the experimental findings, the simulated results indicate that the traditional seeding technique cannot be applied for polymorph control in MSMPR crystallization. Experimentally, it was found that α form was the only detectable polymorph at steady state in the 25 °C MSMPR under reasonable residence time (30−120 min). Therefore, an interesting question to consider is that under what condition the β stable polymorph would become the dominant polymorph in the 25 °C MSMPR. Figure 12 demonstrates

■

ASSOCIATED CONTENT

S Supporting Information *

Solute concentration measurement calibration, polymorph mass content measurement calibration. This material is available free of charge via the Internet at http://pubs.acs.org.

Figure 12. Steady state polymorph mass ratio (β form mass fraction) under different MSMPR residence time at 25 °C.

■

AUTHOR INFORMATION

Corresponding Author

*Telephone: 617-452-3790. Fax: 617-253-2072. E-mail: [email protected].

the polymorph mass fraction of β form at the stable steady states under different residence time. It was found that at least 13 h of residence time is required such that the β polymorph would consist more than 50 wt % of crystals at steady state. To have the β form to be the only polymorph detectable in the crystallizer, i.e. β mass fraction >99 wt %, the residence time shall be greater than 17.4 h. Such process condition is rather unfeasible in practice. It would take about 6 days for the system to reach steady state based on the simulation. Therefore, to obtain the desired stable β polymorph, one challenge for designing a MSMPR crystallization process is that, while low temperature is desired for achieving high yield, it may pose problems for polymorph control. It is difficult to obtain the stable β form with the target polymorph mass fraction under reasonable residence time. Although the studies were done with only L-glutamic acid as model compound, the concern herein is valid for all polymorphic compounds that have undesired polymorphs containing relatively fast nucleation and growth kinetics. Further studies of process design and control are

Notes

The authors declare no competing financial interest.

■ ■

ACKNOWLEDGMENTS We acknowledge the Novartis-MIT Center for Continuous Manufacturing for funding and technical guidance. REFERENCES

(1) Variankaval, N.; Cote, A. S.; Doherty, M. F. AIChE J. 2008, 54 (7), 1682−1688. (2) Lee, A. Y.; Erdemir, D.; Myerson, A. S. Annu. Rev. Chem. Biomol. Eng. 2011, 2, 259−280. (3) Morissette, S. L.; Almarsson, O.; Peterson, M. L.; Remenar, J. F.; Read, M. J.; Lemmo, A. V.; Ellis, S.; Cima, M. J.; Gardner, C. R. Adv. Drug Delivery Rev. 2004, 56 (3), 275−300. (4) Alvarez, A. J.; Myerson, A. S. Cryst. Growth Des. 2010, 5, 2219− 2228. H



Article

(5) Wong, S. Y.; Tatusko, A.; Trout, B. L.; Myerson, A. S. Cryst. Growth Des. 2012, 12, 5701−5707. (6) Ferguson, S.; Morris, G.; Hao, H.; Barrett, M.; Glennon, B. Chem. Eng. Sci. 2013, 104, 44−54. (7) Quon, J. L.; Zhang, H.; Alvarez, A.; Evans, J. M.; Myerson, A. S.; Trout, B. L. Cryst. Growth Des. 2012, 12, 3036−3044. (8) Woo, X. Y.; Tan, R. B. H.; Braatz, R. D. Cryst. Growth Des. 2009, 9, 156−164. (9) Hermanto, M. W.; Chiu, M. S.; Braatz, R. D. AIChE J. 2009, 55, 2631−2645. (10) Kee, N. C. S.; Tan, R. B. H.; Braatz, R. D. Cryst. Growth Des. 2009, 9, 3044−3051. (11) Kee, N. C. S.; Arendt, P. D.; Tan, R. B. H.; Braatz, R. D. Cryst. Growth Des. 2009, 9, 3052−3061. (12) Davey, R. J.; Blagden, N.; Potts, G. D.; Docherty, R. J. Am. Chem. Soc. 1997, 119, 1767−1772. (13) Torbeev, V.; Shavit, E.; Weissbuch, I.; Leiserowitz, L.; Lahav, M. Cryst. Growth Des. 2005, 5 (6), 2190−2196. (14) Hermanto, M. W.; Chiu, M. S.; Woo, X. Y.; Braatz, R. D. AIChE J. 2007, 53 (10), 2643−2650. (15) Randolph, A. D.; Larson, M. A. Theory of Particulate Processes; Academic Press: New York, 1971 (16) Schöll, J.; Bonalumi, D.; Vicum, L.; Mazzotti, M. Cryst. Growth Des. 2005, 6 (4), 881−891. (17) Ono, T.; ter Horst, J. H.; Jansens, P. J. Cryst. Growth Des. 2004, 4 (3), 465−469. (18) Ni, X.; Valentine, A.; Liao, A.; Sermage, S. B. C.; Thomson, G. B.; Roberts, K. J. Cryst. Growth Des. 2004, 4 (6), 1129−1135. (19) Hilfiker, R. Polymorphism: In the Pharmaceutical Industry; Wiley VCH: Weinheim, 2006 (20) Kumar, S.; Ramkrishna, D. Chem. Eng. Sci. 1996, 51 (8), 1333− 1342. (21) Kumar, S.; Ramkrishna, D. Chem. Eng. Sci. 1997, 52 (24), 4659−4679.

I


Continuous Crystallization and Polymorph Dynamics in the l-Glutamic

Recommend Documents