Polarization Switching of Crystal Structure in the Nonphotochemical Laser-Induced Nucleation of Supersaturated Aqueous L-Histidine† Xiaoying Sun,‡ Bruce A. Garetz,*,‡ and Allan S. Myerson§
CRYSTAL GROWTH & DESIGN 2008 VOL. 8, NO. 5 1720–1722
Department of Chemical and Biological Sciences, Polytechnic UniVersity, Brooklyn, New York 11201, and Department of Chemical and EnVironmental Engineering, Illinois Institute of Technology, Chicago, Illinois 60616 ReceiVed September 7, 2007; ReVised Manuscript ReceiVed February 4, 2008
ABSTRACT: Polarization switching of polymorphs has been observed in the nonphotochemical laser-induced nucleation of aqueous 2 L-histidine in the supersaturation range 1.40–1.60. Exposure of solutions to 0.24 GW/cm , 7 ns pulses of 532 nm light induced the nucleation of different polymorphs of L-histidine depending on polarization state of the light. Circularly polarized laser pulses tended to nucleate the orthorhombic A polymorph, whereas linearly polarized pulses tended to nucleate a mixture of the orthorhombic A and monoclinic B polymorphs. Higher supersaturation also favors the formation of mixed polymorphs. These observations support the hypothesis that the laser is organizing hydrogen-bonded groups of histidine molecules through an optical Kerr alignment. 1. Introduction (A) Polymorphism. Understanding and controlling polymorphism, the ability of a molecule to crystallize into different lattice structures, remains a subject of broad interest and active research.1 Different polymorphs of a substance can exhibit different physical properties, such as solubility, dissolution rate, melting point, hygroscopicity, and crystal habit, which can have a great influence on bioavailability and manufacturing processes of pharmaceuticals and other specialty materials.2 For example, R-L-glutamic acid polymorph precipitation is preferred over the β polymorph in industry because of its advantage in solid–liquid separation efficiency.3 Traditionally, polymorph formation has been controlled through the choice of solvents and temperature.4 or the use of additives that inhibit or promote the growth of particular crystal faces.5 It can also be controlled through polymer or selfassembled monolayer (SAM) interactions,6 or through protein interactions as in biomineralization.7 (B) NPLIN. Nonphotochemical laser-induced nucleation (NPLIN), a phenomenon in which intense laser pulses induce supersaturated solutions to nucleate, was discovered by Garetz et al.8,9 NPLIN has also been demonstrated to control polymorphism through “polarization switching”, in which the polymorph formed depends on the polarization state of the laser light used.10–12 In those experiments, it was shown that in aqueous glycine solutions with supersaturation (SS) in the range 1.45–1.54 (SS ) c/c0, where c is the molal concentration of the solution and c0 is the molal concentration of a saturated solution), linearly polarized near-infrared light with a wavelength of 1064 nm produced γ-glycine, whereas circularly polarized light produced R-glycine. Outside of this supersaturation window, different polarizations yield the same polymorph. Because NPLIN appears to be independent of wavelength and occurs at wavelengths where neither the solvent nor the solute absorbs light, it is not likely to be a photochemical † This paper was intended to be published as part of the Special Issue “Facets of Polymorphism in Crystals” (Cryst. Growth Des. 2008, Vol. 8, issue 1). * Corresponding author. E-mail:
[email protected]. ‡ Polytechnic University. § Illinois Institute of Technology.
process. There is growing evidence that nucleation from liquid solutions is often a two-step process: the formation of liquidlike solute clusters followed by the organization of such clusters into a crystalline structure.13 We have hypothesized that NPLIN involves the electric-field induced alignment of molecules or groups of molecules in a prenucleating solute cluster, aiding the cluster to organize into a crystal-like entity, through optical Kerr alignment.14 Linear and circular polarizations induce linear and planar alignment, respectively,10,12 and thus can induce the nucleation of different polymorphs. NPLIN offers a nonchemical way to control polymorph formation that does not require the addition of solvents or impurities, making the method an attractive alternative for the pharmaceutical industry. To further our understanding of NPLIN, specifically the relationship between polymorph structure and laser polarization, we have investigated polarization switching in aqueous L-histidine, a system that includes a chiral amino acid, adding a level of complexity not found in aqueous glycine. (C) L-Histidine. L-(+)-Histidine (C6N3O2H9) has two known polymorphs, designated A and B. A is orthorhombic (P212121), with unit cell dimensions of a ) 5.177 Å, b ) 7.322 Å, c ) 18.87 Å, and Z ) 4. B is monoclinic (P21) and crystallizes from ethanol, with unit cell of dimensions a ) 5.172 Å, b ) 7.384 Å, c ) 9.474 Å, β ) 97.162°, and Z ) 2.15,16 The difference in the crystallographic structures between the polymorphs of L-histidine is much smaller than that of the polymorphs of L-glutamic acid or glycine; for this reason, they tend to crystallize together. A is the lowest energy polymorph and B is a metastable polymorph. A can be obtained from the transformation from B f A in aqueous solutions. The solubility of A is lower than that of B by 4–8% in the temperature range 283–333 K.17 Both polymorphs precipitate in almost equal amounts from aqueous solution over a wide concentration range. The mole fraction of A that initially crystallizes from solution is between 0.4 and 0.6 and increases very slightly with increasing temperature. Transformation from B to A is solution-mediated, and the rate is very slow. Pure A was obtained after 3 days at 293
10.1021/cg800028v CCC: $40.75 2008 American Chemical Society Published on Web 04/18/2008
Polarization of Crystal Structure in Nucleation of L-Histidine
Crystal Growth & Design, Vol. 8, No. 5, 2008 1721
K in solutions. Seeding of solutions with A or B crystals has no effect on the precipitation behavior.17 2. Experimental Procedures (A) Sample Preparation. The L-histidine was obtained from Fluka Biochemika and was used without further purification; the water was obtained from Fisher (Environmental grade). At least 40 identical L-histidine solutions were prepared at each of four concentrations ranging from 0.35 to 0.5 mol/kg. The solute was dissolved by placing test tubes containing solvent and solute in an ultrasonic heating bath at 49 °C for 8–10 h, after which the solutions were allowed to cool slowly to room temperature overnight. Solutions that did not nucleate during the cooling period typically lasted longer than 2 weeks without spontaneously nucleating. Solutions exposed to laser pulses were aged from 1 to 4 days. (B) Optical Setup. Solutions were exposed to 10 pps trains of 7 ns pulses from a frequency-doubled Quanta-Ray DCR-1A Q-switched Nd: YAG laser with a wavelength of 532 nm, and an intensity of 0.24 GW/ cm2 for 1 min. The doughnut-shaped beam was passed through a 1.85 mm diameter circular aperture to select a small portion of the beam with approximately constant intensity. For each concentration, supersaturated solutions were exposed to either linearly or circularly polarized laser pulses at 532 nm. The linearly polarized light is produced by sending the laser pulses through a GlanThompson prism polarizer. The circularly polarized (CP) light is generated by sending the linearly polarized light through a quartz zerothorder quarter-wave retardation plate, cut for 532 nm. By measuring and minimizing the intensity of a laser beam reflected back through the wave plate and the polarizer,18 we were able to produce CP light with a purity of 100:1. The laser power was measured with a Coherent LM30-V power meter, designed for high intensity use. The test tubes used have curved walls, and therefore each behaves as a cylindrical lens for the incident laser beam. Based on ray tracing calculations, we estimate that the focusing caused by this curvature increases the laser intensity in the solution by a factor of 2 at 532 nm. (C) Polymorph Analysis. Solutions were examined several hours after exposure to the laser to see if crystals had formed. If they had, the crystals were separated from the solution by filtration, dried, and ground for polymorph analysis. All crystals were analyzed by powder X-ray diffraction (XRD) using a Philips model XRG 3100 powder diffractometer and Traces software. X-ray Cu KR radiation (λ ) 1.5406 Å), a current of 20 mA, a voltage of 40 kV and a temperature of 20–25 °C were used to determine the polymorph composition. Data were collected from 15 to 25° 2θ in steps of 0.01° or 0.02°, and a scan rate of 0.004°/s.
3. Results and Discussion (A) Polymorph analysis. Figure 1 shows two X-ray powder diffraction patterns obtained from the NPLIN of aqueous L-histidine. A characteristic powder diffraction peak of polymorph A is present at 2θ ) 17.6° and a characteristic peak of polymorph B appears at 2θ ) 17.2°.17 XRD analysis of crystals obtained as a result of NPLIN of supersaturated aqueous L-histidine yields the two different XRD patterns shown in Figure 1, and the relative occurrence of these two patterns depends on concentration and whether the solutions were exposed to linearly or circularly polarized light. The blue pattern, obtained with circularly polarized light, shows the absence or near absence of the polymorph B peak (which we refer to as “pure A”), whereas the red pattern, obtained with linearly polarized light, exhibits both A and B peaks, indicating a mixture of the two polymorphs. Another feature of the XRD patterns shown in Figure 1 concerns the two intense peaks with 2θ values between 21 and 22°. For “pure A” samples, the two peaks have comparable amplitudes, whereas for a mixture of A and B, the peak at higher angle has lower amplitude. On the basis of the relative areas of the characteristic peaks of polymorphs A and B, the A/B mixtures have mole fractions of A between 0.4 and 0.6, whereas the “pure A” samples have mole fractions of A of ∼0.95.
Figure 1. Powder X-ray diffraction patterns of crystals obtained from the NPLIN of aqueous L-histidine solutions with a supersaturation of 1.60. Blue pattern is induced by circularly polarized light; red pattern is induced by linearly polarized light. Characteristic peaks of the A and B polymorphs are indicated by the two arrows. Table 1. Polymorph Distribution Due to Polarization Switching in the NPLIN of Aqueous L-Histidine percent of samples composed of pure polymorph Ab a
supersaturation
spontaneous linear polarization circular polarization
1.40 1.50 1.60
50 ( 15 (8) 40 ( 15 (8) 29 ( 15 (7)
60 ( 15 (10) 33 ( 14 (9) 18 ( 11 (11)
1.80
0c (8)
0 (7)
80 ( 13 (10) 75 ( 14 (8) LCP: 45 ( 9 (13) RCP: 50 ( 9 (14) 0 (7)
a
Supersaturations are calculated on the basis of the solubility of the stable A polymorph, c0 ) 0.270 mol/kg at 25 °C.19 b Percent of pure A represents the percentage of samples containing “pure A” out of the total number crystallized samples. The number in parentheses is the number of samples that nucleated. LCP ) left circular polarization; RCP ) right circular polarization. Standard deviations are calculated on the basis of a binomial distribution.9 c The zero means that 100% of the nucleated samples contained a mixture of A and B.
The XRD pattern obtained from each single sample was always similar to the two cases shown in Figure 1, i.e., either “pure A” or a mixture of A and B. However, for a series of 20 solutions of a given concentration, exposed to the same polarization, some samples yielded “pure A” and others yielded a mixture of A and B. Table 1 summarizes the distributions obtained in each case. From the table, we can see that circular polarization and low supersaturation tend to favor the formation of “pure A”, whereas a mixture of A and B is favored with linear polarization and high supersaturation. At a supersaturation of 1.80, all samples contain a mixture of A and B, independent of polarization. Because L-histidine is chiral, it is conceivable, but unlikely, that it would interact differently with left and right circular polarization. Therefore, at a supersaturation of 1.60, we exposed samples to both RCP and LCP, as shown in Table 1. No significant differences were observed between samples exposed to RCP vs LCP. (B) Relationship between Polarization Switching and Crystal Structure. The results described in the previous section show clearly the existence of polarization switching in Lhistidine, with circular polarization preferentially forming the A polymorph, and linear polarization preferentially forming a mixture of A and B. This represents the second reported case of polarization switching in NPLIN, the first being aqueous glycine. In the case of glycine, we argued, based on optical Kerr alignment, that circular polarization favors the alignment of disklike groups of molecules, which matched the building
1722 Crystal Growth & Design, Vol. 8, No. 5, 2008
Sun et al.
is good at aligning rods, while circular polarization is good at aligning disks. Applying this analysis to L-histidine, we would expect linear polarization to tend to induce the formation of B (whose building blocks are rods of head-to-tail packed histidine molecules), while circular polarization would tend to induce the formation of A (whose building blocks are disks of twodimensionally packed rings of histidine molecules. This is consistent with our experimental observations that circular polarization tends to produce A, whereas linear polarization shifts the outcome to a mixture of A and B. 4. Concluding Remarks The nonphotochemical laser-induced nucleation of aqueous solutions was studied with linearly polarized light and circularly polarized light. Polarization switching was observed in the supersaturation range 1.40–1.60. Within this range, circularly polarized light favors the formation of polymorph A, whereas linearly polarized light favors the formation of a mixture of polymorphs A and B. An analysis of the molecular packing in the two polymorphs indicates that the building blocks of B are rodlike, whereas the building blocks of A are disklike. The observed polarization switching is thus consistent with the hypothesis that nucleation is the result of optical Kerr alignment of hydrogen-bonded groups of molecules in a prenucleating cluster. The supersaturation window for polarization switching observed in aqueous L-histidine is similar to that seen in aqueous glycine. L-histidine
Acknowledgment. The authors gratefully acknowledge the National Science Foundation (Grant CTS-0210065) and the American Chemical Society Petroleum Research Fund (Grant 45023-AC10) for their generous support of this work. Figure 2. Hydrogen-bonded molecular clusters that constitute the two polymorphs of L-histidine. (a) Orthorhombic A polymorph and (b) monoclinic B polymorph.
blocks of R-glycine, whereas linear polarization favors rodlike groups, matching the building blocks of γ-glycine. The crystal structures of the A and B polymorphs of L-histidine are quite similar. In both cases, the molecules take on an extended conformation in the c direction, and pack head to tail into columns in the c direction, linked by intermolecular hydrogen bonds between the carboxyl and imidazole groups. Another intermolecular hydrogen bond between the carboxyl and amino groups laterally links molecules in neighboring antiparallel columns, whereas a third, weak intramolecular hydrogen bond links the amino and imidazole groups, further stabilizing the structures. The lateral hydrogen bond lengths are very similar for the two polymorphs (2.77 and 2.85 Å for A; 2.76 and 2.85 Å for B), whereas there is a substantial difference in head-to-tail hydrogen bond lengths (2.78 Å for A, 2.73 Å for B). Thus, the head-to-tail packing is considerably stronger than the lateral packing in B, whereas the head-to-tail and lateral packing are comparable in A. Thus if we were to characterize the nature of the strongly bound clusters of molecules in the structure of polymorph B, they would consist of columns of histidine molecules packed one-dimensionally along the c-direction. Conversely, the strongly bound clusters in the structure of polymorph A would consist of planes of histidine molecules packed two-dimensionally, both longitudinally and laterally. Figure 2 shows the structures of such clusters, which appear to be rodlike columns in the B polymorph and disklike rings for the A polymorph. On the basis of our previous hypothesis concerning polarization switching in glycine, we proposed that linear polarization
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CG800028V
