Reliable and Selective Crystallization of the Metastable r-Form Glycine by Seeding Norihito Doki,* Masaaki Yokota, Kanako Kido, Shigeko Sasaki, and Noriaki Kubota
CRYSTAL GROWTH & DESIGN 2004 VOL. 4, NO. 1 103-107
Department of Chemical Engineering, Iwate University, 4-3-5 Ueda, Morioka, 020-8551 Japan Received July 10, 2003;
Revised Manuscript Received September 30, 2003
ABSTRACT: This paper describes a reliable method to selectively produce metastable R-form glycine crystals with a controlled size in batch cooling crystallization. Seeding had a large effect both on the polymorphism and the size distribution of the product crystals. In the case of sufficient seed loadings of the R-form crystals, the metastable R-form crystals were obtained selectively as a product. Simultaneously, the crystal size distribution became unimodal with no fine crystals. However, at low seed loadings, mixtures of both the metastable R- and stable γ-form crystals were obtained. The measurement of supersaturation transient suggested that the low supersaturation caused by the growth of sufficient seeds played a key role in suppressing nucleation of the metastable R- and γ-form crystals, whereas, with no seeding, only the stable γ-form crystals were obtained. The seeding technique presented here could be a general and practical method to produce metastable polymorphs with controlled crystal size. Introduction Polymorphs are crystals of different structures but are chemically identical. They can exhibit different crystalline shapes and different physical properties such as density, solubility, and bioavailability. Generally, only one specific crystalline phase will have the required product properties. Therefore, a reproducible or reliable crystallization of a desired polymorph is considerably important in industry. A stable polymorph can be obtained without difficulty by allowing sufficient crystallization time at an appropriate operating condition, because it is thermodynamically stable. However, a metastable polymorph cannot be obtained straightforwardly. It can be obtained only by preventing it from transforming to a stable phase. Polymorphic crystallization is affected by various factors. There are many reports dealing with the effects of such factors. These factors are solvent characteristics,1,2 solution concentration,3,4 cooling rate,3 agitation,5 impurity concentration,6 and seeding.7,8 According to Beckmann et al.,7 the metastable phase A of abecarnil, a partial agonist of the benzodiazepine receptor, was selectively crystallized by seeding from isopropyl acetate solution both in laboratory and pilot scale crystallizers. The sufficient amount of the seeds should have been added to prevent the metastable A abecarnil from transforming to the stable C form. However, thorough quantitative discussion was not given on the amount and the size of seed crystals to be added. In addition, no discussion on the size of the product crystals is given, although it is another important product property in industry. Glycine has three polymorphs (R, β, γ), which have different densities, shapes (morphologies), and space group symmetries.9-11 The γ-form is the most stable at around room temperature.12 The R-form is metastable, which usually crystallizes from aqueous solution, unless * To whom correspondence should be addressed. E-mail: doki@ iwate-u.ac.jp.
the solution is acidified or made alkaline.11 The β-form, which does not crystallize from aqueous solution at ordinary temperatures,13 is the least stable in aqueous solution at any temperature. The relative stability of the R- and γ-forms depends on temperature, with the γ-form being less soluble (more stable) at low temperatures but more soluble (less stable) at high temperatures, and at 165 °C, the γ-form to the R-form transformation is observed.11,12 According to Yu and Ng,14 the glycine solution at the natural pH (6.2) yielded R-glycine by spray drying, whereas the solutions adjusted to higher or lower pH yielded γ-glycine. Further, they concluded that this phenomenon could be explained by the pH effect on the formation of the cyclic dimer, the elemental growth unit R-glycine. Ferrari et al.15 reported that, for the transformation of the β- to R-form in ethanol/water solution, the rate-controlling step is the dissolution of the β-form crystals. According to our previous studies on seeding in batch crystallization of nonpolymorphic substances,16-21 a sufficient amount of seed crystals is effective for growing only seed crystals added with suppressed secondary nucleation. The only one condition for the suppression of secondary nucleation is to add sufficient seed crystals more than a critical amount. The critical seed amount, which can be determined by experiments, depends on the seed size. An empirical equation correlating the critical seed amount with seed size was proposed by Doki et al.21 for the potassium alum-water system. This equation can be conveniently used for designing a crystallizer and operation strategy.22 This seeding technique, which was successfully used for nonpolymorphic substances, was expected to be applied for polymorphic systems to grow selectively seed crystals of a required metastable polymorph without nucleation of either of the metastable and the stable polymorphs. In this paper, we report a reliable and reproducible crystallization technique to produce the metastable R-form of glycine crystals with controlled size. This seeding technique is expected to be widely applied in
10.1021/cg034123h CCC: $27.50 © 2004 American Chemical Society Published on Web 11/22/2003
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Figure 1. Temperature profiles examined for natural cooling crystallization.
Doki et al.
Figure 2. Photographs of seed crystals of the R-form glycine (average size ) 300 µm).
industry for a variety of polymorphic materials. This study does not intend to deal with the mechanism of phase transformation nor molecular aspects in polymorphic crystallization of glycine. 1. Experimental Section Batch cooling crystallization for the glycine-water system was performed in a similar way as that employed for crystallization of ordinary nonpolymorphic substances by Jagadesh et al.,16,17 Doki et al.,18,19 and Kubota et al.20 An aqueous solution of glycine, saturated at 50 °C for the R-form, was introduced at 60 °C into a crystallizer of 500 mL working capacity and kept at this temperature for 1 h under gentle agitation. Then the agitation speed was adjusted to 300 min-1, and the solution was cooled by circulating a cooling water of 40 °C through the jacket. The temperature of the content fell down naturally to 40 °C in an exponential manner as shown in Figure 1. Dry seed crystals of the R-form were added just at the moment when the solution temperature passed the saturation point (50 °C). After seeding, the crystallization operation was continued for 3 h (batch time). The produced crystals were separated by filtration from the final slurry under vacuum and dried overnight in the air at room temperature, and sieved to obtain the crystal size distribution. Powder XRDs of the product crystals were measured to ascertain their polymorphic forms. The impeller used was a four-bladed marine propeller. The crystals of the R-form, produced by a rapid cooling technique,3 were used as seeds after classified by sieving. Two fractions were used as seeds: one fraction that passes the 350 sieve and is retained on the 250 µm and the other fraction that is retained between the 180 and 150 µm sieves. The mean sizes of these classified crystals were calculated as arithmetic means of the two successive sieve openings, being 300 and 165 µm, respectively. A microscopic picture of the 300 µm seeds is shown in Figure 2. The polymorphic form of the seeds was confirmed by powder XRD to be the R-form (see Figure 4 below). As additional experiments, the transient supersaturation of the solution was measured throughout the batch. The solution concentration was determined by evaporating solvent from a given amount of the sample solution to dryness at 80 °C on a hot plate and weighing.
2. Results and Discussion 2.1. Product Crystals - Appearance and Polymorphism. Microscopic pictures of the product crystals are shown in Figure 3a,c and the corresponding powder XRD patterns are shown in Figure 4. In Figure 4, the theoretical XRD patterns calculated by using literature crystallographic data (Marsh9 for the R-form, Iitaka11 for the γ-form) and the XRD pattern of the 300 µm seed
Figure 3. Photographs of product crystals obtained. (a) Product A: Cs ) 0 (no seeds); (b) product B: Cs ) 0.10; (c) product C: Cs ) 0.33.
crystals are also indicated. Figure 3a shows a picture of the crystals (product A) obtained from a nonseeded run. The crystals exhibit a four-faced polyhedron shape with opaque white color, and some broken pieces are included. These crystals were all the γ-form according to the powder XRD pattern (see Figure 4). Figure 3b shows a picture of the product B obtained from a seeded run when the seed loading ratio was relatively low at Cs ) 0.10, where Cs is defined by Cs ) Ws/Wth as the mass ratio of the seed amount added, Ws, to the maximum theoretical yield, Wth, of the R-form crystals calculated from solubility.12 The product B is a mixture of the opaque four-faced polyhedron crystals and transparent prismatic ones. The XRD pattern of the mixture proves that these crystals are a mixture of the R- and γ-glycine crystals. At a high seed loading ratio of Cs ) 0.33, the crystals obtained were all transparent prismatic ones (product C), which are of the R-form (see the XRD pattern of the product C in Figure 4). Similarly, for the small seed crystals of 165 µm, the R-form crystals were obtained at high seed loadings. These results lead to the conclusion that the R-form glycine crystals are
Crystallization of the Metastable R-Form Glycine
Figure 4. Powder X-ray diffraction patterns of glycine crystals (Powder XRD patterns were obtained and indexed by using a powder X-ray diffractometer (RIGAKU, Japan) with Cu KR radiation of λ ) 1.5418 Å. The sample was scanned in the 2θ values from 10° to 50° at a rate of 2°/min.).
Crystal Growth & Design, Vol. 4, No. 1, 2004 105
Figure 6. Seed chart showing normalized mean mass size of product crystals of glycine as a function of the seed loading ratio. (Data of the potassium alum-water system are shown for comparison.)
(Jagadesh et al.16).
(
)
Lp 1 + Cs ) Ls Cs
Figure 5. Effect of seed loading ratio Cs on product crystal size distribution of glycine.
obtained at high seed loadings. The quantitative discussion on how much seed crystals of the R-form glycine will be made later in section 2.3 following the discussion on product crystal size. 2.2. Product Crystal Size. Figure 5 shows cumulative size distributions (mass basis) of the products A, B, and C, of which photographs are shown in Figure 3a-c, respectively. The crystal size of the product A, obtained from crystallization with no seeds, distributes widely. As seen in Figure 5, the size distribution of product becomes narrow by seeding, but this change depends on the amount of seeds added. The size distribution of the product B, obtained at the relatively low seed loading ratio of Cs ) 0.10, is bimodal and it is still wide, whereas, at the high seed loading ratio of Cs ) 0.33, the size distribution (product C) becomes unimodal with narrow width. The mean mass size of the product C was 472 µm, which agreed, with a relative difference of -1%, with the corresponding theoretical mean mass size of product (477 µm) calculated from eq 1 assuming no change in crystal number and shape
1/3
(1)
where Lp and Ls are the mean mass sizes of product and seed crystals, respectively. In addition, at a seed loading ratio of Cs ) 0.26 for the seeds of 300 µm, the experimental mean mass size of the product was 491 µm with the corresponding theoretical product size of 503 µm (relative difference: 3%). The experimental product size was 405 µm at a relatively high seed loading ratio of Cs ) 0.071 for the 165 µm seeds, and the corresponding theoretical value was 407 µm (relative difference: 0.5%). Thus, at high seed loadings, the mean mass size of product agreed with the theoretical mean mass size. Therefore, the addition of sufficient seeds is concluded to be effective in producing the product with the size calculated by eq 1 or even for the polymorphic substance glycine similarly as observed for nonpolymorphic substances.16-22 Therefore, we can produce the product crystals of glycine with a controlled size. 2.3. Seed Chart and Critical Seed Amount. The experimental mean mass size of the product crystals normalized with the mean mss size of seed crystals, Lp/ Ls, is plotted in Figure 6 for the seed crystals of Ls ) 165 and 300 µm as a function of seed loading ratio Cs. (The seed sizes of Ls ) 165 and 300 µm were actually arithmetic means of the two successive sieve openings between which seed crystals are retained, but these are good approximate values of the mean mass size because of the narrow width of size distributions.) As seen in Figure 6, the value of Lp/Ls approaches the ideal growth line of eq 1 with an increase in Cs both for the 165 and 300 µm seeds, finally coinciding with it. The point of coincidence, or the critical seed loading ratio,22 above which seed loading ratio no secondary nucleation is practically guaranteed, was determined on the seed chart and plotted in Figure 6. In Figure 6, curves of Lp/Ls versus Cs for the potassium alum-water system, which were obtained previously by Doki et al.21 for the seed sizes of 165 and 328
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correlation for the potassium alum-water system,22 which was a best fit to the data as
C/s ) 2.17 × 10-6 L2s (Ls: µm)
Figure 7. Critical seed loading ratio vs mean mass size of seed crystals. (Data of the glycine-water system are plotted over the data of the potassium alum-water system.)
Figure 8. Transient supersaturation over a wide range of seed loading ratios.
µm, are drawn for comparison as dotted lines with data points of closed circles. The location of the critical points for the glycine-water system is close to those of the potassium alum-water system. It does not seem to depend on the system. In addition, the value of Lp/Ls is nearly the same for the both systems in the range of high Cs. However, in the range of low Cs, it exhibits a large difference between the two systems. For the glycine-water system, it continuously increases with a decrease in Cs in the low range. This increase can be attributed to the growth of the stable γ-form crystals following their nucleation, i.e., the so-called solutionmediated phase transformation. Therefore, in this range of Cs, the products were the mixture of the R-and γ-form crystals as observed typically in the product B in Figure 3. On the other hand, for the potassium alum (nonpolymorhic)-water system, the value of Lp/Ls decreases with a decrease in C/s in the low range. This is because a large amount of secondary nuclei are produced due to large supersaturation established in the early stage during a batch.18 (see Figure 8). The values of the critical seed loading ratio C/s , determined graphically in Figure 6, are plotted as open circles in Figure 7 as a function of mean mass size of seeds Ls on a logarithmic paper. These values lie near the nonpolymorphic data (closed circles) obtained previously by Doki et al.22 for the potassium alum-water system. The solid line in the figure is the experimental
(2)
eq 2 can be expected to be used to predict the critical seed loading ratio for the glycine-water system. According to the XRD patterns measured, no characteristic peaks of the γ-form glycine were observed for the product crystals obtained in the vicinity of C/s or Cs > C/s . The above discussion leads to the conclusion that the sufficient seeding satisfying the condition of Cs g C/s ensures the production of the metastable R-form glycine crystals with a controlled size in batch cooling crystallization. From the point of view of design and operation of a crystallizer, the scale-up effect on the value of C/s is important. According to Doki et al.,18 the value of it does not depend on the size of a crystallizer for the potassium alum-water system with respect to product size. In general, secondary nucleation becomes unlikely to occur as the scale of a crystallizer is increased.23 This effect on secondary nucleation favors in a large-scale crystallizer the prevention of an unstable crystalline phase from the solution-mediated transformation to a stable form. In addition, Ferrari et al.15 revealed that time needed for the solution-mediated transformation from the metastable β-glycine to the stable R-glycine in ethanol/water increased in a large crystallizer. It is suggested, therefore, that the criterion of Cs g C/s determined from a laboratory scale crystallizer can be applied for a large scale industrial crystallizer to produce metastable form crystals with controlled size. 2.4. Transient Supersaturation and SolutionMediated Phase Transformation. Figure 8 shows transient supersaturation profiles obtained. The supersaturation has a peak at an early stage of crystallization. This peak becomes lower with increasing the seed loading ratio. This is because the rate of consumption of supersaturation by the growth of the seed crystals is increased as the seed amount is increased. The supersaturation changes differently with time after the peak depending on the seed amount. The supersaturation at a sufficient seed loading ratio of Cs ) 0.33 (> C/s ) decreases slowly, finally approaching ∆cR ) 0, where ∆cR is supersaturation with respect to the R-form glycine, defined by ∆cR ) c - cR (c: concentration of glycine, cR: solubility of the R-form glycine). In this case, the final product was confirmed by XRD to be the R-form glycine as mentioned above. Whereas, at an insufficient seed loading ratio of Cs ) 0.10 (< C/s ), the supersaturation ∆cR decreases quickly, once exhibiting a plateau of ∆cR ) 0, and then it begins to decrease further to a point in the range of ∆cR < 0 but ∆cγ > 0, where ∆cγ is supersaturation based on the γ-phase, defined by ∆cγ ) c - cγ. XRD data and observation of the sampled crystals revealed that the stable γ-phase crystals grow with an expense of the metastable R-phase crystals. At a minimum seed loading ratio of Cs ) 0.026 and with no seeding, the supersaturation decreased monotonically directly from the peak, without showing a plateau, to a point in the range of ∆cR < 0. These observations at insufficient seed loadings and with no seeding are typical supersaturation changes seen in the
Crystallization of the Metastable R-Form Glycine
solution-mediated phase transformation. Contrary to this, supersaturation change at the sufficient seed loading ratio of Cs ) 0.33 corroborate that transformation did not occur. Conclusion Seeded batch cooling crystallization of a polymorphic substance glycine from aqueous solution was performed in a wide range of seed loadings of the R-phase crystals. From the experimental results, the following conclusion was drawn: (i) The seeding condition of Cs g C/s guarantees that the seed crystals of the metastable R-form glycine are grown with suppressed secondary nucleation. Therefore, the mean mass size of the product crystals (grown seeds) is estimated by eq 1, the equation of simple mass balance. (ii) The seeding condition of Cs g C/s also guarantees that the seed crystals of the metastable R-form glycine crystals are prevented from the so-called solutionmediated phase transformation to the stable γ-form glycine. (iii) The critical seed loading ratio C/s for the glycine-water system were nearly the same as that of the potassium alum-water system, which is given by eq 2 as a function of seed size. This suggests that the value of C/s does not depend on the system examined. (iv) The seeding technique proposed in this paper is expected to be a general method applied for a variety of polymorphic systems. 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). Note Added After ASAP Posting An earlier version of this paper posted on the ASAP website on November 20, 2003 had errors to Figure 8 axes labels and ref 8. These have been corrected in this new version posted December 2, 2003. Nomenclature Cs C/s cR
seed loading ratio () Ws/Wth) [-] critical seed loading ratio [-] solubility of the R-form glycine [kg/100 kg-water]
Crystal Growth & Design, Vol. 4, No. 1, 2004 107 cγ ∆cR ∆cγ L Ls Lp Ws Wth
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] mass of the seeds added [kg] theoretical crystal yield calculated using solubilities [kg]
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CG034123H
