Microfluidic Continuous Seeded Crystallization: Extraction of Growth

Nov 5, 2012 - ... microchannels to avoid the signal from PDMS; 784.8 nm excitation from a solid-state Invictus laser (Kaiser Optical Systems, Inc.) wa...
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Microfluidic Continuous Seeded Crystallization: Extraction of Growth Kinetics and Impact of Impurity on Morphology Mahmooda Sultana† and Klavs F. Jensen* Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States S Supporting Information *

ABSTRACT: We describe a continuous microfluidic system for seeded crystallization of small organic molecules, such as active pharmaceuticals, and demonstrate integration with in situ detection tools for determining the size and polymorphic form of the crystals. This integrated device is used to extract growth kinetics, as a screening platform for process parameter effects and optimization, and to gain insight into the fundamentals of the crystallization process. In addition, the microfluidic system also allows studies of additive effects on the crystal habit. The method is demonstrated with growth kinetics for α-, β-, and γ-forms of glycine along with the effects upon the morphology of adding glutamic acid and methionine.

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INTRODUCTION Crystallization is an important process in the pharmaceutical industry. Almost all low-molecular weight active pharmaceutical ingredients are isolated in crystalline form, and more than 90% of all products are formulated in particulate, generally crystalline form.1 However, the sensitivity of crystallization to process conditions can give rise to serious reproducibility issues.2,3 The traditional batch crystallizers suffer from variations in local conditions across the reactor. Moreover, chaotic, poorly controlled mixing of the reagents often results in polydisperse crystal size distributions and impure polymorphs. Variations in conditions further complicate fundamental studies and the collection of kinetic data for crystallization.3 Microfluidic systems offer a unique platform for crystallization because of well-defined laminar flow profiles, enhanced heat and mass transfer, sealed systems with protection from particles that can give rise to undesired nucleation, and optical access for in situ characterization.4 In addition, low levels of consumption of reagents make it an attractive research tool for expensive pharmaceutical compounds as demonstrated for batch crystallization in several studies, including protein crystallization in a microfluidic device using free interface diffusion5−7 and batch microfluidic evaporation-driven crystallization of glycine.8 Many investigators have used droplet microfluidics to generate a variety of conditions in nanoliter volumes, which then served as individual batch reactors for crystallization of proteins and small molecules,9−15 and as a method to develop phase diagrams for protein crystallization.16 Thus, microfluidics has been used mostly for crystallization in microbatches, but so far not for continuous crystallization of small organic molecules such as active pharmaceutical ingredients (APIs). © 2012 American Chemical Society

Continuous crystallization of small organic crystals is difficult to achieve in microfluidic devices as wall interactions, uncontrolled nucleation, agglomeration, and sedimentation of crystals easily clog the micrometer-sized channels. In this work, we demonstrate continuous crystallization of small organic molecules in a microfluidics-based crystallizer (Figure 1). We

Figure 1. Schematic of the crystallization setup (not drawn to scale). Pressure-driven flow was used for seed inlet.

used seeded crystallization and reactor design to decouple the nucleation phenomenon from the growth process, as well as to control secondary nucleation, agglomeration, and sedimentation of crystals. In addition, we eliminated any significant interaction of crystals with channel walls by modifying channel surfaces when necessary. As a result, we were able to avoid channel plugging and run crystallization continuously. To Received: October 19, 2012 Published: November 5, 2012 6260

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Figure 2. Continuous seeded crystallization in microfluidic devices. (a) Seeds of α-, β-, and γ-glycine used for the process (left column) and crystals of the corresponding forms grown inside the microchannels (right column). The arrow shows the direction of flow. (b) Self-alignment of different high-aspect ratio crystal systems under laminar flow: plates of modified α-glycine (left) and needles of lovastatin (right). The scale bar is 50 μm for the growth of β-glycine and 10 μm in rest of the images. of the material allows one to use microscopy tools to obtain highresolution images of the crystals, as well as to integrate spectroscopy tools such as Raman for in situ polymorph detection. The antisolvent and undersaturated glycine solutions were loaded in separate syringes (GasTight, Hamilton) and were delivered with Syringe pumps (Harvard Apparatus). The experiments were designed on the basis of literature data about the solubility of glycine polymorphs with different solvent−antisolvent compositions.18−21 The residence time of the reactor used ranged from 30 s to 12 min, and the flow rates used for each of the inlets ranged from 2 to 10 μL min−1; 70−100% ethanol in water was used as the antisolvent, and an aqueous solution of glycine with a concentration of 2−12 g of glycine /100 mL of water was used as the undersaturated solution. Diluted seeds of the following size were carefully prepared: 7−10 μm for α- and γ-glycine and 10−20 μm for βglycine (details of the seed preparation technique given below). The polymorphic form and the size distribution of seeds were characterized with X-ray diffraction and microscopy, respectively, before the crystallization experiments were performed (Figures S1−S3 of the

illustrate the use of the system, we extracted growth kinetics data for crystals of various shapes, including high-aspect ratio crystals such as that with acicular or platelike habits. We also demonstrated the unique advantage these microfluidics-based microcrystallizers offer over the current state-of-the-art technology in more accurately measuring the size, size distribution, and growth kinetics for high-aspect ratio crystals. Furthermore, we illustrated the use of microfluidic devices for screening effects of impurity or additive effects on crystal habits.

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EXPERIMENTAL METHODS

Microfluidic devices were fabricated in poly(dimethylsiloxane) (PDMS) with 300 μm wide and 250−300 μm deep main channels and 50 μm wide and 250−300 μm deep mixing channels by using standard soft lithographic techniques.17 The device designs were based on the growth calculations of the glycine polymorphs. PDMS was chosen as the device material because realizing complicated reactor designs in PDMS is fast, easy, and inexpensive. Also, the transparency 6261

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Supporting Information). The seed solution was purely aqueous for the stable forms (α and γ). The β-form is unstable and readily converts to the α-form, with the conversion time depending on the moisture and solvent composition, among other factors.18,22 An aqueous mixture of 70 wt % ethanol provided the best balance of these factors and was used as the seed solution for the β-form. The supersaturation achieved in the main channel was between 1 and 1.6 with respect to the α-form. The experiments were performed at room temperature. The interaction of the hydrophilic glycine crystals with the channel walls was minimized through hydrophobic surface modification when necessary. Glycine (≥99% pure), anhydrous ethanol, L-glutamic acid (≥99% pure), lovastatin (≥98% pure), and D,L-methionine (≥99% pure) were purchased from Sigma-Aldrich. Spectroscopy grade water was purchased from VWR. X-ray diffraction showed that the commercial glycine purchased was usually a mixture of α- and γ-crystals, with varied percentages of each in different batches. As a result, seeds of each of the three polymorphs were carefully prepared to avoid mixtures of different polymorphic forms. α-Glycine seeds were prepared from an aqueous solution. As purchased glycine was dissolved in water (0.3 g of glycine/g of water) by being heated. The solution was filtered with a hot 0.2 μm filter and brought to room temperature while being stirred. As soon as nucleation was detected, an equal volume of a saturated glycine solution (with respect to the α-form) was added to dilute out the seeds and prevent agglomeration. γ-Glycine was prepared by suspending excess glycine in a solvent composed of water and acetic acid in a 2:1 ratio for 1 week. The crystals were filtered through a 0.2 μm filter with vacuum suction, followed by a wash with a small amount of filtered deionized water. The crystals were dried in a vacuum oven at 50 °C for a few hours, and the polymorphic form was confirmed via X-ray diffraction. γ-Glycine made this way was used to make additional γglycine by suspending it with excess glycine in deionized water for at least 7 days. γ-Crystals were then ground, filtered with 5−7 μm sieves (Gilson Co., Inc.), and added to pure water to give the desired seed density. Seeds were handled in a laminar flow hood to avoid contamination. α- and γ-seeds were allowed to mature for 24 h and checked with X-ray diffraction before being used. β-Seeds were prepared in the following way. A solvent composed of water and acetic acid in a 2:1 ratio was saturated with glycine and aged for at least 3 days. The solution was then filtered with a 0.2 μm filter. Acetone and the filtered solution were simultaneously added to a new vial at a 2:1 ratio, which led to the precipitation of β-glycine. The precipitated solution was immediately vacuum filtered with a 0.2 μm filter. Plenty of acetone (filtered with a 0.2 μm filter) was used to thoroughly wash the precipitate. The crystals were subsequently dried at 50 °C in a vacuum oven for a few hours and stored in the glovebox until they were used. X-ray diffraction was used to confirm the polymorphic form before using it for experiments. Right before the experiment, β-glycine was ground, sieved with a 5−7 μm filter (Gilson Co., Inc.), and added to ethanol in the glovebox. The solution was then taken out of the glovebox; water was added to it to reach the desired solvent composition, and the seeds were used immediately. The final seed size was analyzed by optical microscopy using glass bottom culture dishes (Mat Tek Corp.) before use. We roughly estimated the seed density by drawing a measured amount of the seed solution with a pipet, dispensing the solution into the covered glass bottom culture dishes, and counting the number. A Nikon TE2000-E inverted microscope was used with Nikon CF DL 5×, 10×, and 20× objectives and a Plan Neofluar 100×/1.30 oil immersion objective. A high-resolution camera from Sensicam was used to capture images. Images of many crystals were taken at different residence times of the reactor; the sampling volume was kept the same to eliminate errors from a large range of seed sizes. For α- and γglycine, data were collected downstream of the reactor such that seeds were able to grow for a few minutes (approximately half of the residence time) before data collection was started. However, for the βform, data collection was started immediately because of its high growth rate. The size of the crystals was analyzed from the images to extract growth kinetics. The residence time of the crystals was

calculated by averaging the residence time of many crystals for each of the polymorphs. A PANalytical X-pert Pro Multipurpose Diffractometer with Cu Kα radiation (λ = 1.5418 Å), a high-speed high-resolution X’Celerator detector, and divergence optics was used for the detection of the polymorphic form of the seeds. We prepared dispersion samples by uniformly transferring a thin layer of sample on a zero background plate [(510) silicon plate]. Samples of the β-form were prepared inside the glovebox and analyzed in an air-sensitive sample holder. We conducted in situ Raman spectroscopy on the crystals grown inside microreactors by carefully focusing the laser in the center of microchannels to avoid the signal from PDMS; 784.8 nm excitation from a solid-state Invictus laser (Kaiser Optical Systems, Inc.) was coupled to a backscattered setup via a 15 μm optical fiber. Scattered photons were collected with a microprobe and transferred to a transmission grating (HoloPlex, Kaiser Optical Systems, Inc.) with a liquid nitrogen-cooled CCD through a 15 μm optical fiber. The wavelength and intensity were calibrated using a mercury lamp and a white lamp, respectively, and were checked with cyclohexane (tolerance of 0.02 cm−1). Figure 2b represents the average of 20 exposures of 60 s each. Each spectrum was obtained by subtracting the glass and blank signal from the original signal.

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RESULTS AND DISCUSSION Amino acids are widely used as model systems because of their well-established physicochemical properties and their ability to crystallize in multiple polymorphic forms23 (crystalline phases with identical chemical compositions but different molecular packing and/or conformation).24 Glycine is a common pharmaceutical excipient25 and has three polymorphic forms at atmospheric pressure: α, β, and γ.26−29 The α-form is the metastable form30,31 and usually crystallizes as centrosymmetric bipyramids in a monoclinic space group (P21).32−34 The β-form is the unstable form and often crystallizes as noncentrosymmetric, high-aspect ratio habits such as needles in a monoclinic space group (P21/n).35,36 The most stable form is the γform,30,31 which crystallizes as noncentrosymmetric pyramids in a polar space group (P31/P32).37−39 Each of the three polymorphs has its own set of challenges, in terms of rheological properties, stabilities, and surface properties that make them excellent examples of the versatility of continuous seeded crystallization in microfluidic devices. One of the difficulties with seeded crystallization is the fact that seeds of high-density polymorphic forms such as α-glycine tend to settle at the bottom of the seed container over time, resulting in an inconsistent density of seeds fed to the reactor. We use pressure-driven flow to deliver seeds into the device, which allows us to continuously stir the seed solution over the duration of experiments and, thus, to maintain a consistent seed density over time (Figure 1). An undersaturated solution of a solvent and the precursor was mixed with an antisolvent to generate a supersaturated solution on chip. On chip supersaturation generation in these closed systems prevented undesired and uncontrolled nucleation at the air−solution interface present in batch systems and provided a tool for studying seeded crystallization. The supersaturated solution was then added to the seed solution in the main channel such that the concentration was always below the metastable limit but above the solubility limit. This approach prevented nucleation that could otherwise have occurred when the antisolvent was added directly to the seed solution because of the high level of supersaturation at their interface. Varying the ratios of flow rates in the three inlets allowed precise control of the supersaturation achieved in the reactor. The seed density was controlled such that the precursor concentration remained 6262

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Table 2. Growth Rates of β- and γ-Glycine

constant over the desired residence time. Multiple side channels for adding a supersaturated solution to the main channel allowed us either to keep the level of supersaturation constant in the main channel during growth experiments with long residence times40 or to change the level of supersaturation in the main channel between each consecutive side channel. The former allowed the crystals with a slow growth rate to grow to a detectable size. Simulation with COMSOL of the transport of the solvent, antisolvent, and crystal precursor, as well as their intermixing in the device, shows that substantially uniform supersaturation (>95%) was achieved within 5% of the residence growth time. This dispersion was much smaller than the typical dispersion inherent in the growth process of organic crystals such as glycine (∼30%).41 Figure 2a shows seeds of each of the polymorphic forms introduced into the microreactor, as well as the crystals grown inside the reactor. Under flow conditions, crystals orient themselves to minimize shear and the largest facets lie on the visual planes. Most of the time, α-glycine crystals were oriented to display faces perpendicular to the ±a direction. The centrosymmetric nature of the α-form made it possible to calculate the growth rate along the {011} and {010} faces by measuring lengths in the b and c directions (Figure S5a of the Supporting Information). The growth rates obtained for these faces compared well with the literature values at the same level of supersaturation, as shown in Table 1,41 even though we

β-glycine

0.56 0.33 0.28 0.17 0.08

G{011},exp (μm/min) 3.34 2.22 2.02 1.21 0.73

± ± ± ± ±

0.43 0.91 0.39 0.22 0.22

G{011},refb (μm/min)41 3.74 2.17 1.83 1.03 0.42

± ± ± ± ±

1.29 0.75 0.63 0.36 0.15

G{010},exp (μm/min) 0.74 0.40 0.23 0.31 −

± ± ± ±

0.16 0.25 0.09 0.14

± ± ± ± ±

0.30 0.39 0.47

194 ± 55 235 ± 43 250 ± 52

ln(C/Cs,γ)a

G(00−1) (μm/min)

0.319 0.389

3.2 ± 1.6 5.5 ± 1.6

4.4 ± 1.8 −

Cs,γ is the solubility of γ-glycine (grams of glycine per 100 g of solvent).

growing dimension, the length of needles (Figure S5b of the Supporting Information). Weissbuch et al. have shown that the growth rate at the (010) face, the +b end, of β-needles is much higher than that at the opposite end.36 Therefore, the growth in length was attributed to the growth of the (010) face (Table 2). Because of the fast growth in the +b direction, the residence time for the β-form was designed to be short, ranging from 30 to 90 s. As a result, significant growth in the smaller dimensions was not observed. Most of the time, γ-glycine crystals were oriented to display faces perpendicular to either the a or b axis, allowing measurement along the c axis (Figure S5c of the Supporting Information). Because the γ-form is known to have a much higher growth rate at the flat end in the −c direction, compared to the pyramidal end in the +c direction,42 growth along the c axis was attributed to the (00−1) facet. The growth mechanism of the γ-form is known to be complex and to vary depending on the experimental conditions.43 It was observed that uncontrolled supersaturation gave rise to very fast growth rates of the γ-form, possibly because of a change in mechanism. Such a fast growth rate almost always caused the crystals to potentially sediment and/or bridge with microchannel surfaces, clogging the reactor. The increasing level of control over supersaturation in our devices allowed for operation at lower levels of supersaturation, thus preventing the “very fast growth” regime, and allowed us to successfully extract growth kinetic data for the γ-form. The polymorphic form of the grown crystals was verified using in situ Raman spectroscopy for the α- and γ-forms. Raman spectra of the α- and γ-forms in the range of 0−1600 cm−1 (Figure 3) were found to be consistent with the literature.44,45 In this study, CH2 rocking, CH2 twisting, CH2 wagging, and CH2 bending modes were compared in the region of 900−1500 cm−1 to distinguish between the two polymorphs. CH2 rocking and twisting modes are present at 915 and 1323 cm−1, respectively, in the γ-form, but are absent in the α-form. The CH2 wagging mode appears at 1326 cm−1 in the α-form, but at 1337 cm−1 in the γ-form. There are two CH2 bending modes at 1440 and 1456 cm−1 in the α-form, but only one at 1439 cm−1 in the γ-form. It was difficult to obtain the spectrum of the β-form in situ as the thin needles constituted a small fraction of the sampling volume. Using microfluidic devices to measure growth kinetics combines the advantages of single-crystal studies and ensemble studies. It not only provides laminar flow profiles and a wellcontrolled environment as in single-crystal studies but also allows one to study flow effects for continuous crystallizers, as well as to look at many crystals in the same environment, which is necessary to obtain meaningful data for processes with statistical phenomena such as crystal growth. Moreover, it provides a platform for easily varying process parameters such as temperature, supersaturation level, and solvent composition

G{011},refb (μm/min)41 0.47 0.28 0.23 0.14 0.07

ln(C/Cs,α)

G{100,010} (μm/min)

a

Table 1. Growth Rates of the {011} and {010} Faces of αGlycine ln(C/Cs,α)a

γ-glycine

G(010) (μm/min)

0.53 0.32 0.26 0.16 0.07

a

C is the concentration of glycine (grams of glycine per 100 g of solvent); Cs,α is the solubility of α-glycine (grams of glycine per 100 g of solvent). bThe reference values were calculated from the kinetic parameters presented in ref 41. The errors in the reference growth rates were calculated by propagating the errors of the kinetic parameters.

generated supersaturation with ethanol rather than water, which was used in the original experiments. The ethanol was between 15 and 20 wt % of the final solvent composition for the α-form. However, we did not notice any detectable change in growth rates either as a result of ethanol addition or when the ethanol content in the final solvent composition was varied to a small extent. This is probably because the growth rate dispersion in these systems was higher than the change in growth rate due to the small change in solvent composition. Growing large crystals of the α-form was avoided because of sedimentation problems, which ultimately clogged the channels, and also because larger crystals tended to have significantly higher growth rates with a larger standard deviation, as also observed by Li et al.,41 presumably because of the larger surface area and correspondingly more defects. The growth rate of β-glycine is presented with respect to the supersaturation of the α-form (Table 2), as the solubility of the β-form is difficult to measure accurately for stability reasons.18 For β-glycine, the growth rate was obtained for the fastest 6263

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Figure 3. In situ Raman spectra of α- and γ-glycine (after subtracting background spectra).

Figure 4. Modifying the habit of α-glycine.46−48 (a) Packing arrangement of α-glycine with the methyl groups of molecules 1 and 3 oriented toward the + b direction and those of molecules 2 and 4 oriented toward the −b direction. (b) Habits of α-glycine when it was nucleated and grown from a pure glycine solution (1) or in the presence of (S)-amino acid (2), (R)-amino acid (3), and (R,S)-amino acid (4) additives.

and scanning their effects. Furthermore, microfluidic devices offer an interesting advantage for high-aspect ratio crystals. We note that high-aspect ratio crystals align themselves parallel to the streamlines to minimize the shear created by continuous laminar flow (Figure 2b). This phenomenon was observed for all high-aspect ratio crystal systems, including β-glycine (Figure 2a, center right), lovastatin (Figure 2b, right), and the modified habit of α-glycine (e.g., platelike in Figure 2b, left). The selfalignment of high-aspect ratio crystals facilitates more accurate measurement of the crystal size, size distribution, and growth kinetics versus what can be achieved with the existing techniques. Microfluidic devices can also be used for screening additive effects caused by high spatiotemporal resolution, as well as for single-crystal studies to provide insights into the mechanism of habit modification. We used α-glycine as the model system because habit modification of α-glycine with tailor-made additives has been well-established.36,46−48 The packing arrangement of α-glycine, presented in Figure 4a, shows that the molecules have methyl groups exposed at both (010) and (0−10) faces. However, substituting the exposed methyl group of nonchiral glycine with a side chain at the (010) face leads to molecules with the (R)-configuration, and a similar substitution at the (0−10) face leads to the (S)-configuration. Consequently, only (R)-amino acid additives can replace a glycine molecule at the (010) face, and only (S)-amino acid additives can replace a glycine molecule at the (0−10) face because of the steric requirement that the additive molecule be recognized at the crystal surface as a substrate molecule, glycine, with the amino acid side chain emerging out of the crystal face.47 Figure 4b shows modified α-glycine habits when they are crystallized from a pure solution (1) or in the presence of an (S)-amino acid (2), an (R)-amino acid (3), and a racemic amino acid (4).48 The top row of Figure 5a presents a series of images captured every minute following the growth of the same crystal in the presence of (S)-glutamic acid. We observed that one of the {010} faces, (0−10) according to the argument above, was inhibited, while the (010) face grew at a rate 2−4 times higher than that in the absence of impurities. Faces adjacent to the (0−10) face, namely, (−1−11) and (1−1−1), grew out over time. However, it was interesting to note that some of the faces

adjacent to the inhibited face grew at a rate faster than those of the corresponding faces adjacent to the uninhibited {010} face (Figure 3c). Therefore, it was found that (S)-glutamic acid not only inhibited one of the {010} faces but also resulted in a change in the relative growth rate of the remaining faces, which made it difficult to accurately measure the growth rate of the individual faces. The bottom row of Figure 5a presents a series of images that were captured following the habit modification in the presence of (R,S)-methionine. As racemic methionine inhibited growth at both the {010} faces, the crystals were seen to reorient themselves displaying their larger faces, {010}. As observed in the presence of (S)-glutamic acid, the relative growth rates of the remaining faces appeared to change with a few faces completely growing out in the ±c direction. The period of time for these faces to completely grow out was very short, on the order of seconds. Figure 5b shows two-dimensional schematics (perpendicular to the c direction) of the modified habit in the presence of (S)-amino acid (1), (R)-amino acid (2), and (R,S)amino acid (3) additives. Li et al. also reported an enhancement of the rate of growth of uninhibited faces of α-glycine in the presence of L-leucine, up to 3 times depending on the impurity concentration.49 They suggested that the growth rate increase resulted from a change in the interfacial tension and an increase in the extent of dimer formation in the presence of impurities.49 We propose that the growth rate increase could also result from an increase in the level of supersaturation because of the lack of growth unit consumption at the neighboring, inhibited faces.

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CONCLUSION We have designed a continuous microfluidic system for seeded crystallization of small organic molecules such as active pharmaceuticals and integrated in situ detection tools for determining the size and polymorphic form of the crystals. This integrated device can be used as a tool to study growth kinetics, as well as a platform for fast screening of process parameter 6264

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Figure 5. (a) Habit evolution of α-glycine over time when bipyramidal seeds were grown in the presence of 1% (S)-glutamic acid (top row) and 2% (R,S)-methionine (bottom row). Scale bars are 10 μm. (b) Two-dimensional cross sections of modified habits when bipyramidal seeds of α-glycine were grown in the presence of (S)-amino acid (1), (R)-amino acid (2), and (R,S)-amino acid (3) additives.

Notes

effects and optimization, to gain insight into the fundamentals of the crystallization process. We have demonstrated its use for extracting growth kinetics for α-, β-, and γ-forms of glycine. The applicability of this technique to the three polymorphs, each with a distinct habit and a different set of challenges, shows the versatility of this method. Moreover, we have demonstrated that continuous laminar flow in microfluidic devices causes selfalignment of high-aspect ratio crystals, leading to accurate measurement of their size, size distribution, and growth kinetics. Moreover, this work has also shown how microfluidic devices can be used to screen additive effects on the crystal habit because of the high spatiotemporal resolution.

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the financial support from Merck, AlcatelLucent Fellowship (MS), and the National Science Foundation (CHE-0714189). We thank the staff of MIT-MTL and MITCMSE (DMR-0819762) for technical assistance.

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(1) Valder, C.; Merrifield, D. SmithKline Beecham R&D News 1996, 32, 1. (2) Goho, A. Sci. News (Washington, D.C.) 2004, 166. (3) Nyvlt, J. Industrial Crystallization, 2nd ed.; Verlag Chemie: Weinheim, Germany, 1982. (4) Leng, J.; Salmon, J. B. Lab Chip 2009, 9, 24. (5) Anderson, M. J.; Hansen, C. L.; Quake, S. R. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 16746. (6) Hansen, C. L.; Sommer, M. O. A.; Quake, S. R. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 14431. (7) Hansen, C. L.; Skordalakes, E.; Berger, J. M.; Quake, S. R. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 16531. (8) He, G. W.; Bhamidi, V.; Wilson, S. R.; Tan, R. B. H.; Kenis, P. J. A.; Zukoski, C. F. Cryst. Growth Des. 2006, 6, 1746. (9) Gerdts, C. J.; Tereshko, V.; Yadav, M. K.; Dementieva, I.; Collart, F.; Joachimiak, A.; Stevens, R. C.; Kuhn, P.; Kossiakoff, A.; Ismagilov, R. F. Angew. Chem., Int. Ed. 2006, 45, 8156. (10) Li, L.; Du, W. B.; Ismagilov, R. F. J. Am. Chem. Soc. 2010, 132, 112. (11) Li, L.; Mustafi, D.; Fu, Q.; Tereshko, V.; Chen, D. L. L.; Tice, J. D.; Ismagilov, R. F. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 19243. (12) Perry, S. L.; Roberts, G. W.; Tice, J. D.; Gennis, R. B.; Kenis, P. J. A. Cryst. Growth Des. 2009, 9, 2566.

ASSOCIATED CONTENT

S Supporting Information *

Figures S1−S5 and seed synthesis. This material is available free of charge via the Internet at http://pubs.acs.org.

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: (617) 253-4589. Fax: (617) 258-8992. Present Address

† Detector Systems Branch, NASA Goddard Space Flight Center, 8800 Greenbelt Rd., Greenbelt, MD 20904.

Author Contributions

M.S. and K.F.J. designed the research. M.S. performed the research. M.S. and K.F.J. analyzed data and wrote the manuscript. 6265

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dx.doi.org/10.1021/cg301538y | Cryst. Growth Des. 2012, 12, 6260−6266