Article pubs.acs.org/crystal
Transformation and Growth of Polymorphic Nuclei through Evaporative Deposition of Thin Films John D. Yeager,*,† Kyle J. Ramos,† Nathan H. Mack,‡ Hsing-Lin Wang,‡ and Daniel E. Hooks† †
Shock and Detonation Physics, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, United States Physical Chemistry and Applied Spectroscopy, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, United States
‡
S Supporting Information *
ABSTRACT: Rapidly dip-coating a silicon substrate in an acetaminophen solution creates a thin film of polymorphic nuclei, and the relative amounts of each polymorph vary with the type of solvent. Polarized light microscopy (PLM) revealed that all films were initially amorphous and gradually crystallized over time scales of minutes to hours. Fourier transform infrared spectroscopy (FTIR) was used to identify the polymorphic form during crystallization and weeks after apparent stabilization of growth. Crystallites that initially nucleated from the amorphous films were found to be the metastable orthorhombic form. Over time, the orthorhombic crystallites stopped growing and the remaining amorphous regions transformed to the stable monoclinic form. The choice of solvent determined how fast the orthorhombic crystallites grew and thus controlled the polymorphic character of the film. For example, dip-coating from an ethanol solution produced a largely orthorhombic film, while water yielded a film with mixed character. Kinetic arguments are made to discuss these results in terms of relative nucleation rates, supersaturation, and evaporation rate of the solvent. We demonstrate that PLM and FTIR are suitable tools for exploring phase space with these thin films. This methodology might be applied broadly to polymorph screening and selection in evaluating pharmaceutical materials.
1. INTRODUCTION Polymorph screening and selection is of great importance to the pharmaceutical industry. The crystal structure of a drug can affect the ease or quality of manufacturability as well as the medicinal properties.1 Density, optical behavior, dissolution rate, and compaction are all examples of properties that vary by polymorph for many organic molecular crystals. Occasionally unexpected and harmful consequences result from previously undiscovered polymorphism. Perhaps the most well-known recent case was that of Ritonavir, in which a previously unknown polymorph with poor oral dissolution was accidentally manufactured and distributed and eventually resulted in a complete market withdrawal.2 A comprehensive screening procedure could have detected the existence of this new polymorph, and later screening studies have shown a further three potential phases for this drug.3 There is no current standard screening method, but most organizations follow similar procedures and solvent-based techniques are usually desirable.2 Solvent-based screening approaches rely on sampling a diverse set of crystallization conditions by varying parameters such as strength of solvent−solute interactions, solubilities, and kinetics to increase the likelihood of observing different polymorphic forms. The probability that a particular form will appear is a function of free energy and the kinetic rate associated with crystal formation.4 Less stable polymorphs can nucleate in solution as a result of higher nucleation rates. The persistence of the less stable forms during subsequent growth is © 2012 American Chemical Society
determined by several factors though transformation to the stable form usually occurs over time. A solvent-mediated phase transformation can accelerate the process as solubility becomes size dependent: the metastable phase dissolves while the stable phase grows in its place in order to minimize the surface area and volume contribution to free energy.5 This complex crystallization process, involving nucleation followed by growth and/or transformation, and metastable phases can make it difficult to interpret screening results and isolate less stable polymorphic forms.6 Investigations of polymorph crystallization have utilized methods ranging from microanalytic techniques to sophisticated in situ techniques.1 One common method for studying metastable forms involves melting a starting powder to an amorphous form, then combining spectroscopy with microscopy and thermal analysis to observe and characterize polymorphic nuclei (e.g., Wu and Yu7). However, solutionbased techniques often have more applicability to pharmaceutical processes (i.e., wet formulation) and allow for a broad study of liquid−drug interactions.6 In this work we study polymorphic nuclei through evaporative thin film deposition from solution. The evaporation of the solution takes place at room temperature in one to three seconds, rapid enough that the resulting solid film is in a Received: July 31, 2012 Revised: September 14, 2012 Published: September 26, 2012 5513
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were created per solution. The samples appeared dry visually after several seconds but were allowed to dry for a minimum of 1 h before analyzing. A schematic of the dip-coating process is given in the Supporting Information. Film thicknesses were measured by a variable angle spectroscopic ellipsometer (VASE) (J.A. Woolam Co., Inc., Lincoln, NE). A general review of the thin film ellipsometry technique is given by Theeten and Aspnes.14 Table 1 summarizes the acetaminophen solutions used and the resulting film thicknesses. The weight percents of solution were chosen to yield thin films of approximately the same thickness for each solvent. Three film thicknesses were created from one solvent (ethanol) in order to verify that thickness changes between films did not affect the infrared spectroscopic measurement. Acetaminophen has a relatively low solubility in room temperature water and so the deionized water was filtered through a 0.44 μm sieve to ensure no solid powder remained in solution. Fourier transform infrared (FTIR) spectra were first collected with a commercial benchtop spectrometer (Thermo-Nicolet Nexus 670 FTIR). Reference spectra of bulk powder and solvents were measured with the use of an attenuated total internal reflection (ATR) module. Spectra of films were measured by IR transmission through the dip coated samples, subtracting the transmission of the plain Si wafer as background. Transmission spectra of liquid solvents transferred by pipet onto the wafer were compared to literature reports to ensure that the silicon wafer did not attenuate the film measurements. Later, spatially resolved FTIR measurements to identify the polymorphic form of specific crystallites were performed with a Thermo-Nicolet Continuum FTIR microscope in reflection mode. The spectrometer was purged with nitrogen gas and background spectra of a gold mirror were taken immediately before every sample measurement to minimize the presence of water vapor peaks.
vitreous state and slowly transforms to metastable and stable forms over time. We have chosen acetaminophen (paracetamol) as a model system to demonstrate the technique. Acetaminophen is a monotropic, polymorphic system that has received considerable attention due to the better compaction behavior of the metastable orthorhombic Form II.8 It is also ideal for demonstration purposes as the orthorhombic form is characteristically difficult to nucleate in solution and current techniques to preferentially produce this metastable form are not fully understood. For example, various reports emphasize the importance of contact-line evaporation,9 heteronucleation with polymers,10 boiling and slow cooling of saturated solutions,11 or crystallizing at subambient temperatures.8 We have had only limited success in reproducing some of these techniques. Our study utilizes evaporative thin-film deposition of acetaminophen from a variety of solvents in order to determine the effect of the solvent on both the nucleation and solventassisted transformation. Films deposited from ethanol and water were observed over time to monitor the transformation and growth of both metastable and stable forms. We find that this approach is suitable for exploring phase space and structure homogeneity in polymorph screening. The additional variables of the dip-coating process (substrate, solvent, concentration, rate) added controls to enable nucleation of difficult-to-obtain metastable forms. As a result, this technique may be ideal to reveal previously unknown forms of other materials.
2. EXPERIMENTAL SECTION 3. RESULTS 3.1. Nucleation and Growth of Metastable Form II Acetaminophen Films. Polarized light microscopy (PLM) was initially used to observe the crystallization of the acetaminophen films dip-coated from ethanol solutions. Acetaminophen is optically active so crystallization was assessed by viewing the film surface through cross-polarizers on the microscope. 8,15 Extinction was observed in amorphous regions.16 This was verified later with FTIR microscopy. Crystallites nucleated both at the edge of the substrate and in the interior, Figure 1. The transmission FTIR spectrum of a fully crystallized acetaminophen film on a silicon wafer is shown in Figure 2 along with a reference spectrum of the original acetaminophen powder, taken 1 week after dip-coating. This film is a representative sample of the films coated from the 7.5 wt % ethanol solution. The film signal, though clear, was weak due to small sample thickness. In Figure 2, the spectrum of the acetaminophen film on silicon was scaled 10-fold for better comparison with the bulk spectrum. Comparison of the acetaminophen spectra with those in the literature, such as Al-Zoubi et al.17 and Burgina et al.,18 confirms that the as-received bulk powder is the Form I monoclinic phase. However, the film exhibits significant changes in relative intensity and peak width of features in the 1000−1300 cm−1 range. There are also some apparent shifts to higher frequency for three prominent peaks in the 1300−1500 cm−1 range, and splitting of two peaks in the 1600−1700 cm−1 range. Table 2 shows a comparison of the peak locations for the perturbed spectral features of the acetaminophen film on Si, listing corresponding features in bulk powder and the measured values for each phase as given by Burgina et al.18 The experimental peak frequencies in Table 2 confirm that the perturbed regions in the FTIR spectrum of the film are
Form I acetaminophen powder (Acros, Morris Plains, NJ) was dissolved into the solvents shown in Table 1 at 21 °C. These solvents
Table 1. Acetaminophen Solutions and Their Resulting Film Thicknesses solvent
group12
weight %
film thickness (nm)
Ethanol (absolute, Pharmco-AAPER)
3
7.5 2.2 1.0 2.6 3.6 2.6 2.3
107 47 17 29 34 54 20
Methanol (ACS, Fisher Chemical) 3 Acetone (ACS, Fisher Chemical) 5 Cyclohexanone (99+%, Alfa Aesar) 5 Acetonitrile (Spectral grade, Fisher 9 Chemical) Deionized water, 18.1 MΩ 15 0.5 68 Dimethylsulfoxidea, glycerola, ethyl acetateb, chloroformb, tolueneb, cyclohexaneb a
Acetaminophen dissolved in the solvent but the solution was too viscous to dip coat effectively. bAcetaminophen solubility was too low to deposit films. were chosen by considering the polymorphic screening technique suggested by Gu et al,12 wherein 96 common screening solvents were divided into 15 groups by considering parameters such as dipole moment, surface tension, hydrogen bond propensity, etc. Following these general guidelines, solvents spanning several such groups were chosen, and included some group repetition as a control. Thin films of acetaminophen were created by a controlled dip coating process.13 Silicon wafers (Silicon Sense, Inc., Neshua, NH) were used as substrates for the films and were cleaned with acetone and atmospheric plasma etching immediately prior to coating. They were then dipped into the acetaminophen solutions and removed in a humidity-regulated room-temperature environment at a constant speed of 50 mm/min (humidity was 20−25%). At least three samples 5514
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Figure 1. Acetaminophen crystallization at the substrate (a) edge and (b) interior. The edge of the silicon substrate can faintly be seen in (a) just below and paralleling the scale bar.
diffraction (XRD) using a Rigaku Ultima III diffractometer with an in-house stage. The stage and diffraction parameters had previously been successfully optimized for thin films,20 but unfortunately the signal obtained from the film was too weak to definitively determine the polymorphic phase. 3.2. Evolution of Polymorphic Structures over Time. To ascertain the nature and stability of mixed phase structure from the films, new samples were fabricated from ethanol and water for further characterization by polarized light microscopy (PLM),7,8 transmission FTIR and FTIR microscopy.21 Given the difference in spot size between the two FTIR instruments, comparison of time-elapsed data from both would contrast the “bulk” vs “local” structure changes. Films were deposited as described earlier and then stored under identical temperature and humidity conditions (20 °C, ∼25% relative humidity). Figure 3a is a polarized light micrograph taken from a section of the water-deposited film remote from the substrate edge, 1.5 h after coating, and Figure 3b is a micrograph of the same section after 16 h. In the PLM figures, regions of crystallinity are observable by their interaction with the polarized light, while the amorphous regions between the crystallites do not alter the polarization of the light. Figure 3 shows that nucleation is not restricted to the contact line of the solution as the film is pulled, as might be suggested by the work of Capes et al.9 Figure 4 shows micrographs taken over time from the 47 nm film deposited from ethanol. Timeelapsed PLM revealed that several stages of crystallization were occurring in the films; the ethanol film crystallization was similar to water films but happened much faster and with fewer, larger crystallites. First, nucleation and growth of small round or oval-shaped crystallites began over several hours from dipcoating. Crystallite growth was arrested after approximately 4 h. The amorphous region between the crystallites then was observed to crystallize, apparently nucleating at the edges of the large crystallites but with an optically distinguishable appearance. Films did not optically appear to change further even over several months of storage. Crystallization was not noticeably different for the other ethanol films of various thickness. Because the crystallization of the film appeared to happen in stages, FTIR microscopy was performed to yield local FTIR data taken from individual crystallites as well as the regions between them. Figure 5 is a PLM micrograph of the sample in Figure 4 along with FTIR spectra taken from the indicated
Figure 2. Partial FTIR spectra of acetaminophen dip-coated from ethanol [1] and Form I acetaminophen powder [2]. The silicon wafer spectrum [3] was subtracted as background from [1] and has no specific spectral features in this range. Annotations highlight the notable perturbations in the spectrum as described in the text and in Table 2. [1] is scaled up 10-fold.
Table 2. Peak Frequencies (in cm−1) of Spectral Features Exhibiting Differences in Bulk Acetaminophen and the Acetaminophen Film from Ethanola mode
powder
film
Form I18
Form II18
CO (stretch) + CNH (bend) Phenyl(stretch) CNH (bend) + Phenyl(stretch) Methyl(bend) + Phenyl(stretch) Methyl(bend) Phenyl (bend) + C− N(stretch) Ph-H(bend) + C−C(stretch)
1651
1668, 1655
1653
1667, 1655
1610 1504
1624, 1610 1514
1610 1506
1622, 1610 1513
1435
1454
1442
1454
1371 1259
1375 1244
1371 1260
1375 1280, 1243
1225
1221
1227
1220
a
Values of the experimental peak positions for the monoclinic and orthorhombic phases as well as mode assignments are taken from Burgina et al.18
indeed consistent with the orthorhombic phase. While infrared allows positive identification of the polymorph for acetaminophen,19 we endeavored to confirm the results with X-ray 5515
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Figure 3. Acetaminophen thin films dip-coated from water after (a) 1.5 h and (b) 16 h. Note amorphous regions in between small oval-shaped crystallites in the 1.5 h image.
Figure 4. Acetaminophen thin films dip-coated from ethanol after (a) 3 h, (b) 4.5 h, (c) 5 h, and (d) 5.5 h. The crystallites grow into or from the amorphous region to a certain point, after which an apparently different type of crystal grows in the center of the image.
regions. The large crystallites were found to be the orthorhombic form, while the region between them slowly transformed from amorphous to the monoclinic form. While several studies have shown spectral differences between amorphous or “glassy” acetaminophen and the monoclinic form,19,22 our spectra look largely similar. However, as in Qi et al.,23 we observe a shift in the three peaks between 780 and 850 cm−1 to indicate the amorphous form. Figure 5b highlights the amorphous frequencies with dashed lines, confirming PLM identification of amorphous acetaminophen located between crystallites.
The exact reason for the spectral differences between our amorphous films and bulk glasses is unknown, though several possible explanations can be offered. First, our films are thin and second, their structure may be affected by proximity to crystalline monoclinic regions and the degree to which they have transformed toward a more stable form. Thin films can exhibit spectral shifts as a function of thickness,24 and there may be some variability in thickness of our films. However, we did not observe spectral shifts when measuring random areas of the film, so this explanation is unlikely. The degree of structure can also influence the spectrum. A glassy sample with a completely random structure could exhibit different or shifted features 5516
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Figure 5. PLM micrograph (Figure 4b) showing two types of crystallite and amorphous region between them (a), with partial FTIR spectra from indicated areas in (b). The large crystallites [1] are orthorhombic Form II, while the dark region [3] is verified as amorphous (dashed lines indicating frequencies of interest) but is transforming to monoclinic Form I [2].
film from cyclohexane solution displayed features somewhere in between the cases of water and ethanol. We attempted to quantify the relative amounts of polymorphic nuclei following the method of Al-Zoubi et al.,17 but the results were complicated by the changing size of nuclei over time in relation to the spot size of the beam on the sample. Additionally, various ratios of Form I to Form II could be found by taking measurements in different areas of the sample. The combination of PLM and FTIR microscopy proved useful in answering questions raised by the bulk transmission FTIR. FTIR microscopy of the samples from Figure 6 revealed identical crystallization pathways for films from all solvents, though the duration of each crystallization step was not uniform. In every case, the circular crystallites which nucleated minutes to hours after coating were Form II, while the surrounding matrix initially was amorphous and gradually transformed to Form I. Note that the films from water usually deposited nonuniformly across the silicon substrate due to the hydrophobicity of Si. However, the crystallization of the film was not affected, as each of the small deposited regions exhibited the same nucleation and growth behavior. Taking the representative samples shown in Figure 6, we can estimate that the films ranged from 5% orthorhombic to 95% orthorhombic, depending on the solvent. The month-old films can be ranked from exhibiting the most Form II characteristics to the least as follows: ethanol, methanol, cylcohexanone, acetone, water, and acetonitrile.
from a sample with short-range but no long-range order. Marentette and Brown found this to be the case in polyethyelene oxide,25 and a similar effect may be happening here. In our samples, for practical purposes the spectra are different enough to confirm the PLM results and distinguish amorphous from crystalline structures. The limitation to this argument is that our amorphous film may contain crystalline nuclei too small to affect the polarized light microscopy. The combination of time-elapsed PLM and FTIR microscopy reveals the stages of polymorphic nucleation and growth in the acetaminophen film. The film is initially deposited as amorphous. After minutes to hours, orthorhombic crystallites nucleate within the film and grow for hours to days. At some point, the large crystallites stop growing and the amorphous region between them transforms to the more stable monoclinic Form I. The stability of the metastable polymorph was evaluated for the films with both benchtop FTIR spectrometer and the FTIR microscope. Little to no changes in spectral features were observed over the period of several months, other than a small increase in signal-to-noise ratio, indicating stability of the fully crystallized films. Comparison of time-elapsed FTIR spectra collected by the benchtop spectrometer is shown in the Supporting Information. 3.3. Effect of Various Solvents on Polymorphic Character. Comparison of films dipped from various solvents provided insight into the nucleation behavior of acetaminophen. Figure 6 shows representative optical micrographs from each of the films from Table 1, 1 month after dip-coating, revealing in all cases some amount of circular crystallites in a largely featureless yet crystalline matrix. The extent of crystallization varied depending on the solvent but each of the films contained crystallites similar to those seen in Figure 4. Benchtop FTIR measurements were taken for each film. Spectra for three films are shown in Figure 7 for simplicity, while a figure containing spectra from films dip-coated from all solutions is given in the Supporting Information. In Figure 7, the largely orthorhombic film from ethanol is compared with films from cyclohexanone and deionized water. Most of the asprepared thin films reveal spectral features identical to the orthorhombic phase but some show varying degrees of similarity to the monoclinic phase. For example, the ethanol solution produced films that exactly matched Form II. The water solution produced films that had a mixed character, and
4. DISCUSSION The elucidation of the transformation and growth process in these acetaminophen films sheds some light both on apparent polymorphic evolution and the effect of the solvent. The dipcoating technique creates an unstable amorphous layer which transforms to the metastable orthorhombic Form II. The Form II crystallites grow for some time and then arrest, and then the remaining amorphous portions of the film to transform to the stable Form I. FTIR measurements taken after a week or more will thus sample entirely transformed polymorphic films. The mixed Form I/Form II character of the films measured by the benchtop spectrometer is therefore a function of the beam spot size (∼1 mm diameter) sampling multiple crystallites and regions between them. As noted earlier, samples showed some variability in apparent relative amounts of Form II to Form I 5517
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Figure 6. Optical micrographs of acetaminophen films dip-coated on silicon substrates from various solvents: (a) acetone, (b) acetonitrile, (c) cyclohexanone, (d) ethanol, (e) methanol, and (f) water. Bright, usually circular crystallites are seen in all cases but are much smaller and rarer in (b) and (f).
Beyond that simple observation, correlation between Form II nucleation and solvent properties is difficult. There are no clear trends that would indicate that the process of dip-coating inherently promotes the formation of one polymorph over the other. There is no obvious correlation between polymorphic form and film thickness or evaporation rate of the solvent. For example, acetone evaporates more quickly than ethanol or water but yields a film having apparent polymorphic content intermediate between the two, and cyclohexanone has the slowest evaporation rate of all the solvents but has more Form II character than water or acetonitrile. None of the other solvent parameters considered by Gu et al. (e.g., dipole moment, viscosity) completely correlate with the experimental data. A large-scale investigation of acetaminophen film
when different areas were measured with the benchtop spectrometer. The FTIR microscope had a much smaller beam size (∼150 μm diameter), which resolved the structure of individual crystallites. Practically, the larger spot size instrument is sufficient to at least identify the presence of multiple polymorphs in a given film sample, but a full description of the microstructure requires the higher resolution of the FTIR microscope. The role played by the solvent in structure evolution is less clear. The solvent appears to influence the rate of nucleation and growth of the Form II crystallites. Samples with few large crystallites (e.g., films from acetonitrile and water) are identified as “mostly” Form I, while samples with many large crystallites (e.g., films from ethanol and methanol) are mostly Form II. 5518
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films. Further experiments to answer remaining questions regarding processing parameters, final supersaturation, quantitative determination of relative amounts of polymorphic nuclei, and nucleation mechanisms are currently being designed.
5. CONCLUSION We have created nanometer-scale thin films of acetaminophen with different crystal forms through a controlled dip-coating and evaporation process. The fast evaporation of the solvent slowed growth and transformation, allowing observation of these phenomena for polymorphic nuclei. In all cases, the films were initially amorphous and partially transformed over several hours as Form II crystallites nucleated and grew. At a certain point the Form II crystallites stopped growing and the remaining amorphous regions transformed to Form I, leaving the films with a mixture of Form I and II. A range of mixtures of Form I and II were found for several solvents, though films from ethanol consistently showed the most Form II character. Characterization of the films after several months showed that the Form II crystallites do not transform to the stable Form I, indicating that this technique might be used to create seed nuclei for crystal growth. The fabrication and characterization methodology presented here reveals varied nucleation behavior and evolution of phases from solution and could prove useful for screening of polymorphs in other materials, specifically in finding difficult-to-crystallize metastable forms.
Figure 7. Partial FTIR spectra of acetaminophen dip-coated from deionized water [1], cyclohexanone [2], and ethanol [3]. Dashed lines indicate peaks of interest from Table 2.
crystallization with even more solvents might yield statistically valid correlations between solvent characteristics and Form II nucleation, and preliminary research into this area is underway. While thermodynamic or energetic influences on polymorph selection are uncertain, kinetic factors clearly play an important role with this technique. Dip-coating is a rapid method of evaporative thin film deposition in which very little crystal growth occurs immediately following deposition, and at least in the case of acetaminophen the deposited film begins as amorphous material. This allows for the study of polymorphic nucleation and growth without the complication of solvent mediations and phase transformations. The amount of each polymorph formed is likely proportional to their respective nucleation rates, because the time duration for nucleation is short (∼1−3 s for evaporation) and can be assumed to be approximately the same for each polymorph in a given dip coating experiment. However, nucleation and solubility parameters such as metastable zone widths, supersaturation as the solvent evaporates, and nucleation rates for the polymorphs require further experimentation to fully understand. Additionally, an understanding of heterogeneous versus homogeneous nucleation in these systems may be important. For example, if the nucleation happens at the film-silicon interface, the solvent is less likely to have an effect than if the nucleation begins in the bulk or at the film−air interface (e.g., Wu and Yu7). Multiple processing variables could have an effect on both film deposition and polymorph selection, perhaps even concurrently. The dip-coating process itself relies on surface interactions between the depositing material and the substrate, and those interactions are a function of solvent and substrate surface energies as well as substrate roughness. Solution viscosity and acetaminophen concentration affect the final film thickness. Film thickness was not found to have a significant effect on polymorphic character for the ethanol samples studied here but larger ranges of thicknesses should be tested in order to verify these initial findings. Another issue, perhaps critically important, is whether there is residual solvent in the film and, if so, what role it plays. Certainly the amount of residual solvent for our samples is less than the detectable amount using a benchtop spectrometer, but even minute amounts of residual solvent could be enough to alter polymorph nucleation or cause a solvent-mediated phase transformation (e.g., Kachrimanis et al.26) in these very thin
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ASSOCIATED CONTENT
S Supporting Information *
Photographs and micrographs of the acetaminophen films from various solutions along with a schematic illustration of the dipcoating procedure. Full FTIR spectra collected by the benchtop instrument from films shown in Figure 6 is given. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*John D. Yeager, Shock and Detonation Physics, MS P952 Los Alamos National Laboratory, Los Alamos, NM 87545. E-mail:
[email protected]. Tel: (505) 665-0879. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
Funding for this work was provided by the National Nuclear Security Administration Science Campaign 2 and the Department of Energy/Department of Defense Joint Munitions Technology Development Program. J.D.Y. is supported by an Agnew National Security Fellowship. This work was performed, in part, at the Center for Integrated Nanotechnologies, a U.S. Department of Energy, Office of Basic Energy Sciences user facility. Los Alamos National Laboratory, an affirmative action equal opportunity employer, is operated by Los Alamos National Security, LLC, for the National Nuclear Security Administration of the U.S. Department of Energy under contract DE-AC52-06NA25396. We thank D.F. Bahr (Purdue University) and D. S. Moore (LANL) for helpful discussions regarding technical content, D. Williams (LANL) for XRD measurements, and M. Wolverton (LANL) for assistance with some FTIR measurements. 5519
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