Pseudopolymorph Control of l-Phenylalanine Achieved by Laser

Article Cite This: Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Pseudopolymorph Control of L‑Phenylalanine Achieved by Laser Trapping Chi-Shiun Wu,† Pei-Yun Hsieh,† Ken-ichi Yuyama,†,‡ Hiroshi Masuhara,†,§ and Teruki Sugiyama*,†,§,#

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†

Department of Applied Chemistry and §Center for Emergent Functional Matter Science, National Chiao Tung University, Hsinchu 30010, Taiwan ‡ Research Institute for Electronic Science, Hokkaido University, Sapporo 001-0020, Japan # Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma 630-0192, Japan S Supporting Information *

ABSTRACT: We demonstrate pseudopolymorph control of L-phenylalanine (L-Phe) with laser trapping method by tuning laser power, polarization, and initial solution concentration. When a continuous-wave near-infrared laser beam of 1064 nm was focused at an air/solution interface of L-Phe D2O solutions with different saturation, L-Phe crystallization was always observed within 30 min-irradiation, even from unsaturated solution. Either whisker- or plate-like crystals were generated depending on given conditions, and identified by Raman spectroscopy to be two L-Phe pseudopolymorphs of monohydrate and anhydrous forms, respectively. The absolute control of L-Phe pseudopolymorphism was achieved by changing the initial solution concentration. In unsaturated solution, laser trapping always produced only one anhydrous crystal at the focus, which can never be produced on spontaneous nucleation at ordinary temperatures and pressures, while in supersaturated solution, a number of monohydrate crystals were densely distributed in an area ranging from 500 μm to 1 mm away from the focus. Moreover, in saturated solution, laser power and polarization contributed to the pseudopolymorphism. As laser power was increased, linearly and circularly polarized laser irradiation increased the formation probability of the anhydrous and monohydrate crystals, respectively. The dynamics and mechanism of laser trapping-induced pseudopolymorphism of L-Phe are discussed in view of the formation of a highly concentrated domain consisting of the liquid-like clusters and the stability of the clusters in the domain under electromagnetic field of trapping laser. dependent polymorphism for amino acids.12,13 For instance, α- and γ-forms of glycine, the simplest amino acid, can be selectively formed by switching the polarization of the input laser in a specific concentration region,12 although recent results have suggested that polarization control for the polymorphism is not as strong as that reported by them.8,13−17 They interpreted the mechanism of polymorph control in terms of optical Kerr effect: realignment of solute molecules due to the polarization of the input laser. In this method, nonphotochemical light-induced nucleation (NPLIN), supersaturation must be needed for triggering nucleation. Nanosecond laser pulses are illuminated directly to supersaturated solution in a sample tube, and resultant crystals are identified on the tube bottom at a certain time after laser irradiation. However, direct observation for the crystallization is not available in real time.

1. INTRODUCTION Polymorphism is a phenomenon in which molecules crystallize into more than one form without any chemical structural change, and solvent molecules are sometimes included as a part of the crystal structure, which is known as pseudopolymorphism.1 Polymorph control has been one of the most promising topics in crystal engineering and pharmaceutical research fields, since different polymorphs show different physical and chemical properties such as density, solubility, melting point, shape, bioavailability, and so on.1−5 Polymorphism has been controlled so far by optimizing experimental conditions such as solvent, temperature, supersaturation, and additives, along which many research efforts have systematically investigated various compounds.6,7 Polymorph control using laser has received much attention of many researchers as an optical approach, because of lack of contact, lack of additives, and high controllability with the unique mechanism.8−10 A pioneering work on laser-induced polymorphism was reported in 2001 by Garetz, Myerson, and coworkers,11 who reported laser power and polarization© XXXX American Chemical Society

Received: May 25, 2018 Revised: July 26, 2018 Published: July 27, 2018 A

DOI: 10.1021/acs.cgd.8b00796 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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Figure 1. Optical setup for pseudopolymorph control in laser trapping crystallization of L-Phe in D2O.

In 2007, we reported for the first time a novel crystallization method based on laser trapping,18 and have called this phenomenon “laser trapping crystallization”. In this method, laser trapping of clusters in solution increases local concentration at the laser focus, where crystallization is observed in real time due to its spatiotemporal controllability. The first demonstration of the laser trapping crystallization was conducted for glycine supersaturated D2O solution,18 and then we confirmed that crystallization can be induced even from unsaturated solution. It was also found that the generated crystal showed the repetitive manner of crystallization and dissolution during laser irradiation due to unsaturation.19 Following these successes, we also controlled polymorph of glycine by optimizing laser power, polarization, and initial solution concentration.20,21 At a certain laser power, α- and γforms were selectively generated on circularly and linearly polarized laser irradiation, respectively. The polymorph control mechanism was discussed based on the arrangement of the liquid-like clusters22−24 (prenucleation clusters) at the laser focus reflected by laser polarization. In 2014, we demonstrated laser trapping crystallization of Lphenylalanine (L-Phe) in its supersaturated H2O and D2O solutions,25 and reported that two pseudopolymorphs of L-Phe, anhydrous and monohydrate forms, were selectively generated in H2O and D2O, respectively. According to previous papers related to spontaneous nucleation of L-Phe in H2O,26−29 either whisker-like monohydrate or plate-like anhydrous crystal is precipitated from H2O solution by spontaneous evaporation depending on a given temperature. The most thermodynamically stable form at 25 °C is the monohydrate crystal, while the stability reverses above a temperature of ∼36 °C.29,30 Taking this fact into consideration, we concluded that laser heating in a supersaturated H2O solution exceeded the transition temperature, which triggered the anhydrous crystal.25 Indeed, the local temperature elevation at laser focus is estimated to be approximately 20 and 3 K in H2O and D2O solutions, respectively (Supporting Information (SI) 1).

In order to demonstrate the high potential of laser trappingcontrolled polymorphism without the laser heating effect, we use D2O as a solvent and systematically and thoroughly investigate laser trapping-controlled pseudopolymorphism of LPhe as functions of laser power, polarization, and initial solution concentration. In particular, pseudopolymorphism in unsaturated solution is quite intriguing, because crystallization in unsaturated solution is made possible only by this laser trapping crystallization method. The entire dynamics and mechanism are discussed in view of the formation of a highly concentrated domain consisting of the liquid-like clusters and the stability of the clusters in the domain under the strong electromagnetic field of trapping laser.

2. EXPERIMENTAL SECTION 2.1. Sample Preparation. L-Phe (Sigma, >98.5%) and D2O (Aldrich, 99.9%) were used as solute and solvent, respectively. L-Phe D2O solutions with three different concentrations were prepared by dissolving 20.0, 25.0, or 30.0 mg of L-Phe powders into 1.0 g of pure D2O. These solutions were heated to 60 °C for 12 h with vigorous shaking in order to completely dissolve the powder into D2O, and then the solution was slowly cooled down to room temperature (25 °C) in 7 h. All of the experiments were carried out at room temperature. As far as we know, the solubility of L-Phe in D2O has not been measured yet, so the degree of saturation for each solution was roughly checked by the following experiment. An extremely small amount of monohydrate crystals generated spontaneously was added into three kinds of solutions, each solution was completely sealed, and the change of crystal size was traced for a few days. Consequently, the crystal dissolution or growth was obviously observed in the most diluted (20 mg) or concentrated solutions (30 mg), respectively, while no apparent change of the size was confirmed in the middle concentrated solution (25 mg). Therefore, it was confirmed that each solution was under unsaturation, saturation, and supersaturation, respectively. 2.2. Optical Setup. Figure 1 shows an optical setup used in this study, which was newly equipped with a 532 nm excitation laser for Raman measurement based on our previous one.25 A continuouswave (CW) near-infrared (NIR) laser beam of Nd3+:YVO4 laser B



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Figure 2. CCD images just after laser irradiation (a), and of crystallization behavior of plate-like (b and c) and whisker-like crystals (d and e) generated by laser trapping.

Figure 3. Definition of pseudopolymorph based on crystallization behavior. (Coherent, Matrix 1064-10-CW) of 1064 nm was used as a trapping light source and introduced into an inverted microscope (Olympus IX 71). The output laser power throughout an objective lens (60× magnification, 0.90 NA, Olympus) was tuned ranging from 0.7 to 1.5 W by adjusting the angle of a half-wave plate coupled with a polarizing beam splitter. The laser polarization was changed by the angle of a quarter-wave plate (Sigma, WPQ-10640-4M) to generate linearly polarized (LP), right- (RCP) and left-handed circularly polarized (LCP) light. A small amount of each sample solution (15 μL) was poured into a handmade sample glass bottle as shown in the upper right of Figure 1, when the solution height was measured to be in the range from 120 to 160 μm. The sample bottle was immediately and completely sealed by a lid to avoid solution evaporation, and then set on the microscope stage. After confirming that a visible HeNe laser (Thorlabs, HNL020L), with the same optical path as the trapping laser, was focused at an air/solution interface of the liquid thin-film, the HeNe laser was turned off, and the trapping laser was then turned on. In order to correct the chromatic aberration of both lasers, immediately after starting the trapping laser irradiation, we slightly readjusted the laser focus by checking the reflection light at the air/solution interface. The crystallization behavior was always monitored and captured in real time by a charge-couple device (CCD) video camera (Watec Co., Ltd., WAT-231S2) under halogen lamp illumination. In situ Raman measurements under the microscope were carried out in order to characterize pseudopolymorph of L-Phe. The 532-nmlaser (Spectra-Physics, Excelslor-532−200-CDRH) at 30 mW was introduced into the microscope along the same optical path as that of the trapping laser, and focused to the resultant crystal through the objective lens. Before starting the measurement, a halogen lamp was turned off and the mirrors were switched to guide Raman scattering signals into a spectrometer through the side port of a microscope. Raman scattered light was collected by the same objective lens, and its measurement was performed using a Concave Holographic Grating

Spectrograph (Andor tech. SR-303i-A) equipped with an EMCCD camera (Andor Newton, DU920P−BV). Raman spectra of two pseudopolymorphs were obtained in a frequency ranging from 200 to 1700 cm−1 by a 10 s integration time, and were analyzed using spectroscopic software (Andor Newton).

3. RESULTS 3.1. Crystallization Behavior in Laser Trapping Crystallization. L-Phe crystallization was always realized within 30 min irradiation, and either whisker- or plate-like crystal was generated under all given conditions (Figure 2). Immediately after starting the laser irradiation, only a single bright spot, which is ascribed to the reflection of the trapping laser from the solution surface, was observed (Figure 2a). The subsequent irradiation led to crystallization. Only one platelike crystal was always generated at the laser focus (Figure 2b and c), while a number of whisker-like crystals were generated not at the focus, but at the surroundings of the focus (Figure 2d and e). It is noteworthy that the whisker-like crystal formation has never observed in the field of view of 110 × 80 μm2. Furthermore, the whisker-like crystals always grew from the outside of the CCD image to the inside, and we have never observed the floating of the whisker-like crystals to the outside. Therefore, we concluded that the generation position of each crystal was different depending on the crystal shape. We also measured the required time of the irradiation for observing the plate-like crystal formation, which are generated at the laser focus. As a result, the time became shorter as the laser power and concentration become higher. The detailed results in saturated solution can be seen in SI 2. C



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Figure 4. Formation probability of L-Phe pseudopolymorphs produced by laser trapping in supersaturated solution (a) and in unsaturated solution (b) under different laser power and polarization.

The whisker- and plate-like crystals generated by laser irradiation were characterized by in situ Raman spectroscopy. Since L-Phe pseudopolymorphism in D2O has not been reported as far as we know, first we confirmed the pseudopolymorphism on spontaneous nucleation at different temperatures of 25 and 40 °C, referring that in H2O.29,30 The whisker- and plate-like crystals were selectively precipitated at respective temperature, strongly supporting that the thermodynamic property of two pseudopolymorphs of L-Phe in D2O should be similar to that in H2O. Furthermore, the whiskerand plate-like crystals obviously showed different Raman spectra. These results imply that they are ascribed to be anhydrous and monohydrate crystals of L-Phe, respectively. Raman spectra of each crystal generated by laser irradiation were totally consistent with those generated on spontaneous nucleation (SI 3). This result enabled us to judge instantly which pseudopolymorph was generated by laser irradiation just from crystal shape and generation position. After the first crystal was generated, further irradiation sometimes produced another pseudopolymorph. In this paper, we defined pseudopolymorphism by pseudopolymorph observed at first, and second generated pseudopolymorph were not considered here. Figure 3 summarizes our definition of pseudopolymorphism based on two kinds of crystallization behaviors; cases (a) and (b). For case (a), a number of monohydrate crystals are densely distributed at the outside of the laser focus. This case can be simply classified into “Monohydrate”. For case (b), only one plate-like crystal is observed at the focus with no whisker-like crystal formation in the field of view. This case can be classified to be “Anhydrous”; however, this classification needs special attention, because the monohydrate crystals might be generated at a position away

from the laser focus prior to the anhydrous crystal formation. In order to check it, the following experiment was carried out. Immediately after confirming the anhydrous crystal formation at the focus, we always scanned a whole solution quickly using a relatively low magnification objective lens. Actually, the monohydrate crystals were hardly found by the scan (less than 3%). Furthermore, there is also a possibility that the monohydrate crystals are generated during the scan. Therefore, we can simply classify the case (b) into “Anhydrous”. 3.2. Pseudopolymorphism Depending on Initial Solution Concentration. In supersaturated and unsaturated solutions, the experiments on laser trapping crystallization were repetitively carried out for 10 samples under each laser power and polarization to evaluate the formation probability of two pseudopolymorphs based on our definition as shown in Figure 3. Figure 4 shows the formation probability against laser power and polarization. In supersaturated solution, independent of laser power and polarization, a number of monohydrate crystals were always generated at the outside of the laser focus, ranging from 500 μm to 1 mm away from the focus.25 Therefore, pseudopolymorph in supersaturated solution was simply classified into “Monohydrate” as shown in Figure 4a. While, in unsaturated solution, only one anhydrous crystal was constantly generated at the laser focus, also independent of laser power and polarization as shown in Figure 4b. Based on this result, we classified pseudopolymorph in unsaturated solution to “Anhydrous”. We should refer here to two unusual phenomena observed in unsaturated solution. The first is that crystallization is realized in unsaturated solution. The second is that anhydrous crystal, which cannot be precipitated by spontaneous nucleation at ordinary temperatures and pressures,29,30 D



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Figure 5. Formation probability of two pseudopolymorphs in saturated solution, depending on laser power and polarization.

Figure 6. Photographs and illustrations of the distribution of monohydrate crystals prepared by laser trapping (a) and by spontaneous evaporation (b).

4. DISCUSSION First, we should discuss the unique phenomenon in which a number of monohydrate crystals were generated not at the laser focus, but at an area ranging from 500 μm to 1 mm away from the focus. The two conditions, Condition (1) and Condition (2), must be simultaneously satisfied for this phenomenon. Condition (1) is that in which concentration reaches high enough to produce monohydrate crystal at the area away from the focus. Condition (2) is that crystal nucleation is inhibited at/near the laser focus. Condition (1) can be interpreted by the formation of a millimeter-sized highly concentrated cluster domain, which we have proposed in our previous papers.25,31,32 The increase in local concentration at the laser focus is achieved by laser trapping, leading to the formation of a highly concentrated domain consisting of the liquid-like clusters. The clusters in the domain are stabilized by a strong electromagnetic field of trapping laser, by which the cluster domain is grown and extended to the outside of the laser focus in a millimeter-order distance. The formation of such a large cluster domain was here confirmed experimentally as follows. Figure 6a shows a

is prepared. These phenomena are characteristic of a laser trapping crystallization method, which has been reported by us.19−21,25 Thus, absolute control of L-Phe pseudopolymorph was realized just by changing initial solution concentration, which was made possible by laser trapping method. On the other hand, in saturated solution, pseudopolymorph was determined by laser power and polarization, different from the cases in supersaturated and unsaturated solutions. We repetitively performed a series of the experiment for 20 samples under each laser power and polarization in order to evaluate more accurately the formation probability of two pseudopolymorphs. The results are summarized in Figure 5. Intriguingly, as the laser power was increased, the anhydrous crystal formation became dominant upon LP laser irradiation, while it was recessive upon CP laser irradiation. It is noteworthy that the results on CP laser irradiation completely deny pseudopolymorphism depending on temperature elevation by laser heating, because local temperature by laser heating should be increased with laser power. Incidentally, we did not observe clear dependence of LCP and RCP on pseudopolymorphism. E



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Figure 7. Schematic illustrations of proposed mechanism of laser polarization-dependent pseudopolymorphism in saturated solution upon CP (a) or LP (b) laser irradiation.

concentration leading to the anhydrous crystal formation is achieved at the focus by continuous laser trapping. Therefore, a pseudopolymorph can be determined by whether or not monohydrate crystals are generated prior to the achievement of critical nucleation. In other words, during laser irradiation, the cluster domain is grown and extended sufficiently to the outside of laser focus before anhydrous crystal is formed at the focus. As it is considered that the stable and large liquid-like clusters originally exist in supersaturated solution, the cluster domain is efficiently extended to the outside of the focus by the adsorption of the clusters. On the contrary, in unsaturated solution, as the existence of such large and stable liquid-like clusters cannot be expected, the extension of the cluster domain is too slow or its final size is too small for monohydrate crystals to be generated. Consequently, the critical concentration is attained at the laser focus, and the anhydrous crystal is generated at the laser focus prior to the monohydrate crystal formation. These phenomena observed in supersaturated and unsaturated solutions occur independent of laser power and polarization. Different from the cases in supersaturated and unsaturated solutions, we confirmed laser power- and polarization-dependent pseudopolymorphism in saturated solution. First, we try to discuss the mechanism of pseudopolymorph according to the conventional theory of nucleation rate. The nucleation rate is generally determined by surface energy of pseudopolymorphs and saturation value of solution (SI 5),34 and the less thermodynamically stable form preferentially generates as solution concentration is increased. This is obviously inconsistent with the results in Figure 5, meaning that the pseudopolymorph in laser trapping crystallization cannot be explained just by the increase in local concentration at laser focus. Simultaneously, the results in Figure 5 also indicate that laser trapping in saturated solution does not achieve critical concentration at the focus. Therefore, we should consider alternative factors for controlling pseudopolymorphism in the laser trapping crystallization. The dynamics and mechanism of laser trapping-controlled pseudopolymorphism in saturated solution are summarized schematically in Figure 7. We propose here that pseudopolymorph can be determined by cluster arrangement in the domain which is reflected by laser polarization. In other words, the inhibition of the anhydrous crystal formation at laser focus depends on laser polarization, which determines the pseudopolymorphism. Myerson et al. reported helpful results

photograph and its schematic illustration of the monohydrate crystals produced by spontaneous evaporation. Immediately after the spontaneous crystallization took place, a whole solution was instantly filled up with the monohydrate crystals, and we observed its homogeneous distribution. On the other hand, monohydrate crystals generated by laser irradiation in saturated solution were not distributed homogeneously as shown in Figure 6b. The photograph was taken at 1 h after monohydrate crystals were generated by applying laser trapping at the center of a handmade glass bottle. Obviously, the monohydrate crystals were densely distributed around the bottle center. It is noteworthy that L-Phe solution still remained around the crystals as shown in the illustration, and that the monohydrate crystals gradually dissolved into solution again over a long time. These results strongly support that the millimeter-sized highly concentrated cluster domain is formed around the laser focus although the highly concentrated cluster domain has been never observed directly as a CCD image. This cluster domain plays a very important role for determining L-Phe pseudopolymorph in laser trapping crystallization, the details of which will be presented later. For the condition (2), we might need to consider the temperature distribution around the laser focus due to laser heating, although the temperature elevation in D2O is strongly suppressed and estimated to only about 3 K/W as described above (SI 1). According to the results reported by Catalá et al.,33 the temperature elevation at the laser focus is logarithmically decreased with the distance from the focus and decreases to 10% at 40 μm away from the focus (SI 4). This cannot explain the inhibition of crystal nucleation up to 500 μm away from the laser focus, so that we conclude that the temperature elevation at laser focus should be a minor factor for the inhibition of crystal nucleation. Alternatively, we here propose that the inhibition is due to the high stability of the cluster in the domain at the laser focus under a strong electromagnetic field of trapping laser, and its effect propagates to the outside of the laser focus. The stability becomes lower with the distance from the focus, eventually forming monohydrate crystals at a position away from the laser focus. We here discuss pseudopolymorphism in supersaturated and unsaturated solutions based on this cluster domain. One of the most important phenomena is that continuous laser irradiation frequently induced anhydrous crystal at laser focus, even in supersaturated solution when the whisker-like crystals were first observed. This is possibly the reason why critical F



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to consider the structure of liquid-like clusters in the domain as follows.12 Without any external perturbation, the structure in solution resembles the local regions of a given crystal structure. This suggests that L-Phe liquid-like clusters resemble the local regions of the monohydrate crystal, since spontaneous nucleation always provides this form. Unfortunately, single X-ray crystallographic analysis for L-Phe pseudopolymorphs has never been successful as far as we know; however, their crystal structure has been solved by the diffraction data from the powder X-ray crystallographic analysis.35,36 According to their results, both the monohydrate and the anhydrous crystals consist of hydrogen-bonded bilayer structures similar to the crystal structure of α-glycine.5,37 For glycine polymorphs, αform crystal has hydrogen-bonded bilayer structures consisting of cyclic dimer structures with disk-like polarizability, which interacts with CP laser light, while the γ-form crystal has a column-like structure with rod-like polarizability, which interacts with LP laser light. Therefore, it is considered that the liquid-like cluster of L-Phe has a disk-like polarizability, which interacts more strongly with CP laser light, the same as that of α-glycine. Therefore, it is considered that the molecules/clusters in the domain are more stabilized by CP laser irradiation, which inhibits anhydrous crystal formation at laser focus. As shown in Figure 7a, during the strong inhibition on CP laser irradiation, the cluster domain is extended to the outside of the focus, where the monohydrate crystal is first generated. It is reasonable to consider that the cluster domain can be more stabilized as laser power is increased, so that the anhydrous crystal formation is more inhibited. Consequently, the probability of formation of the anhydrous crystal upon CP laser irradiation is decreased as laser power is increased (Figure 5). Contrarily, the molecules/clusters in the domain are less stabilized on LP laser irradiation, compared to the case upon CP laser irradiation. The lower stability suppresses the extension of the cluster domain, and makes the anhydrous crystal formation at laser focus dominant since the energy barrier in the transition process from the clusters to the crystal at laser focus becomes comparatively low (Figure 7b). As the trapping effect of the clusters becomes high as laser power is increased, the probability of formation of the anhydrous crystal is increased with laser power (Figure 5). Thus, the inhibition of crystallization at laser focus depends on how clusters in the domain are stabilized by interacting with trapping laser, which determines pseudopolymorphism in saturated solution. Here we discuss that the control mechanism of polymorphism described above is different from the glycine case that we reported previously.20,21 In the glycine case, we explained the mechanism in view of the stabilization of critical nuclei depending on laser polarization. In this work, we discuss the mechanism in view of the stabilization of the highly concentrated cluster domain, which is recognized as the intermediate stable liquid state formed by laser trapping. The stabilization of critical nuclei or intermediate state accelerates or inhibits the crystal nucleation, respectively. Therefore, both mechanisms of polymorph control seem to be mutually inconsistent; however, both mechanisms are reasonable.

power, polarization, and initial solution concentration. The crystallization was realized even in unsaturated solution, when laser trapping always produced only one anhydrous crystal which can never been precipitated on spontaneous nucleation. Contrarily, in supersaturated solution, laser trapping always provided monohydrate crystals, independent of laser power and polarization. Thus, we succeeded in the absolute control of the pseudopolymorphism just by changing the initial solution concentration. In saturated solution, the dependence of laser power and polarization on pseudopolymorphism became obvious. CP laser strongly interacts with L-Phe liquid-like clusters in the domain, which inhibits the crystallization at laser focus due to the high stability. During the inhibition, the cluster domain is extended to the outside of the laser focus, where monohydrate crystals are first generated. In contrast, LP laser irradiation stabilized the clusters less, forming anhydrous crystal at laser focus before the cluster domain is extended. Thus, the dynamics and mechanism of pseudopolymorphism were discussed in view of the formation of a millimeter-sized highly concentrated cluster domain and the stability of liquid-like clusters depending on laser polarization. There are several advantages of our trapping method for polymorphism control, which has never been realized by conventional methods. The first is that crystallization can be attained even from unsaturated solution. Under unsaturation, the arrangement of the clusters is caused by laser polarization, different from the case in supersaturated solution. Actually, the anhydrous crystal, which is a metastable phase and is different from that by spontaneous evaporation, is always formed in unsaturated solution. Thus, the investigation of polymorph control in unsaturated solution is made possible only by our method. The systematic investigation in unsaturated solution will be performed for various kinds of compounds, and a new polymorph characteristic of the laser trapping method will be hopefully realized. The second is that crystallization is spatiotemporally controlled. This feature enables us to elucidate spectroscopically the mechanisms of crystallization and polymorphism. We believe that our laser trapping crystallization method will give a high impact to studies on polymorph control and crystal engineering.

5. CONCLUSION We studied pseudopolymorphism of L-Phe in D2O by laser trapping of a focused continuous-wave laser of 1064 nm. The pseudopolymorphism was systematically and thoroughly investigated under various experimental conditions of laser

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.8b00796. Movie of L-Phe anhydrous crystal formation by laser trapping (AVI) Movie of L-Phe monohydrate crystal by laser trapping (AVI) Estimation of local temperature elevation at laser focus by laser irradiation; Crystallization time for anhydrous crystal formation in saturated solution; Characterization of monohydrate and anhydrous crystals of L-Phe by in situ Raman spectroscopy; Temperature distribution around laser focus under laser trapping condition; Nucleation rate theory for pseudopolymorphism (PDF)

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Ken-ichi Yuyama: 0000-0002-6998-6942 Hiroshi Masuhara: 0000-0002-4183-5835 Teruki Sugiyama: 0000-0001-9571-4388 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The present work is partly supported by the Center for Emergent Functional Matter Science of National Chiao Tung University from the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan, Ministry of Science and Technology, Taiwan to T.S. (MOST 106-2113-M009-017-) and to H.M. (MOST 107-3017-F-009-003), and JSPS KAKENHI Grant Number JP16H06507 in Scientific Research on Innovative Areas “Nano-Material OpticalManipulation” to T.S., and JP17K14427 for Young Scientists (B) to K.Y.

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Pseudopolymorph Control of l-Phenylalanine Achieved by Laser

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