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Toward Polymorph Control in an Inorganic Crystal System by Templated Nucleation at a Microdroplet Liquid Interface: Potassium Hexacyanoferrate(II) Trihydrate Loreta Geneviciute, Nick Florio, and Sunghee Lee* Department of Chemistry, Iona College, New Rochelle, New York 10801, United States ABSTRACT: Potassium hexacyanoferrate(II) trihydrate (KFCT) is known to manifest multiple structure types under practical conditions of crystal growth, including a monoclinic modification which is stable at room temperature and a metastable tetragonal form. Its rich polytypic nature renders it an ideal model inorganic crystal for studies of the influence of ordered structures upon the nucleation of differing crystal forms. We have utilized a microdroplet-based crystallization method to investigate the influence of self-assembled surfactant monolayers (octadecanol, stearic acid, and octadecylamine (ODA)) at a water-decanol interface upon the crystal nucleation behavior of KFCT at the isolated microdroplet level. Our results indicate that markedly different habits can be selectively nucleated, depending upon the choice of surfactant and temperature. The crystals of differing habits were analyzed by polarized light microscopy and micro-Raman spectroscopy. We have demonstrated that a droplet crystallization platform promises control of the nucleation outcome, even in a crystal system where the polymorphic crystal forms have only the most delicate energetic differences, since confinement to isolated droplets ensures single nucleation events and avoids interconversion of polymorphic forms.
’ INTRODUCTION Considerable attention has accrued to the understanding and control of crystallization, in an effort to design crystals with a predetermined function or structure. Such crystal engineering promises to be a core technology for future developments in materials chemistry in the field of pharmaceuticals, pigments, cosmetics, foods, and electronics.18 For example, much effort has been devoted to the synthesis of nanocrystals,9,10 in understanding the process of biomineralization1113 of inorganic materials and precise control of active pharmaceutical crystal forms.14 Crystalline materials of desired shape, size, and molecular structure may be prepared by a variety of means. For instance, methods for crystal shape control, resulting in particles, rods, wires, sheets, and more complex forms, have been explored in recent years.9 One leading means for exercising control over size, shape, and structure has been with soluble or insoluble monolayers assembled at interfaces adjacent to the sites of nucleation. Amphiphilic materials assembled as monolayers at an airwater interface have been particularly prominent in this endeavor.1518 Usually, the mechanism responsible for assisted crystal nucleation in the presence of a monolayer template at an airwater interface has been described as a molecular recognition between the monolayer and the nucleated crystal.11,15,17 Such recognition largely depends on the cooperative effects of structural, hydrogen bonding, and electrostatic interactions between the monolayer and the crystal nuclei. Importantly, emphasis has been increasingly placed upon the ability of the monolayer to adapt to its adjacent subphase,19,20 in order to orient itself to act as a template, and upon mutual influences of the monolayer with inorganic moieties of the crystallizable substance.21 r 2011 American Chemical Society
Of particular interest in the field of crystal engineering is the generation and control of materials which have various discrete polymorphic forms. Polymorphism is defined as the ability of a chemical substance to crystallize in two or more different crystal structures. Polymorphism can occur in both molecular and inorganic crystals. This phenomenon has come under intense study in the pharmaceutical field, since active pharmaceutical ingredients may have differing bioavailability, solubility, or other properties depending on polymorphic form. Various polymorphs have been selectively obtained via nucleation induced through heterogeneous interactions, often relying upon the interplay of surfaces with solutions. For example, polymer-induced heteronucleation,22 self-assembled monolayers (SAMs) at a solid/liquid interface,23 and Langmuir monolayer films at an air/liquid interface24 have been successfully used to control nucleation to preferred orientations, polymorphic outcome, and morphology (crystal shape). Materials which have been grown in a controlled way on SAMs include optically pure amino acids, biomaterials, and pharmaceuticals. Successful examples of the foregoing have included that of Sommerdijk, who has demonstrated polymorph selectivity in calcium carbonate system using specific interactions between a template or additive and the developing nucleus.16 Davey and co-workers have found that emulsion and microemulsion systems are convenient for interfacially directing the formation of glycine polymorphs.25 For many applications, the task of determining or isolating all possible polymorphs in a given crystalline system, or of controlling the polymorphic outcome of a nucleation event, has paramount Received: May 18, 2011 Revised: August 12, 2011 Published: August 22, 2011 4440
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Crystal Growth & Design importance. However, at least one form in any given polymorphic system must be thermodynamically metastable relative to the stable form, and this fact may create complications in attempts to isolate all possible forms. For example, in many systems where a mixture of crystal nuclei forms simultaneously, the nuclei of a more stable polymorph will eventually grow at the expense of a less stable polymorph via a mechanism analogous to Ostwald ripening. Ultimately, then, only the most stable form will exist. Thus, in order to isolate a metastable polymorph, it often becomes necessary to achieve high supersaturation (to encourage the energetic, metastable form to nucleate), while segregating the incipient metastable crystal from other forms. Therefore, in order to ensure that a nucleated polymorph can be isolated and characterized, many groups have employed confinement crystallization methods. By ensuring that crystal nucleation occurs in a small space, such as a droplet, nanoporous solid, or self-assembled nanoparticle, the probability that only a single nucleation event will occur is maximized. This has proven useful in isolating a metastable polymorph, in systems which achieve high supersaturation rate in a microfluidic device26 or on patterned metallic gold islands.2729 Confinement can also beneficially result in isolation of metastable forms since there is usually insufficient solvent present in a small space to promote redissolution once a metastable form is nucleated.30,31 In view of the foregoing, we propose a platform that is capable of simultaneously (1) driving the formation of high energy crystalline forms; (2) directing the nucleation process; and (3) isolating the initially appearing form once nucleated. All three of these desired conditions can be achieved by a droplet crystallization platform, in which isolated aqueous microdroplets of a solution of a crystallizable solute are brought to high supersaturation levels while surrounded by a surfactant monolayer selfassembled at an oilwater interface. Such a platform has important antecedents in the work of Popovitz-Biro et al., who provide evidence that long-chain amphiphilic alcohols aggregate at the oilwater interface to form structured clusters which can induce varying levels of ice nucleation.32 Our system also bears a notable resemblance to several known techniques for protein crystallization which employ droplets to screen crystallization conditions. Some of these techniques employ arrays of static droplets for rapid screening of precipitants, while many newer fluidic methods are being developed for continuous flow crystallizations. The microbatch-under-oil method, developed by Chayen et al., is a static protein crystallization method which uses oil to encapsulate an aqueous drop to prevent rapid dehydration.33 Separate microdroplets of a protein solution and a precipitant (each ∼200 nL) are merged under oil, the merged droplet generally resides on a solid substrate, and crystals form in the resultant droplet, protected by the oil from evaporation.33 Ismagilov et al. has reviewed numerous microfluidic microdroplet methods for protein crystallization which are capable of carrying out many experiments simultaneously, using small quantities of samples to carry out these experiments, with precise control of mixing, interfaces, and time of contact between solutions.34 Roach et al. has successfully influenced protein adsorption at the wateroil interface with a fluorous surfactant that self-assembles at droplets in a microfluidic system, which was found to have implications for protein crystallization, but again, a precipitant was needed.35 There are a number of differentiating features between droplet protein crystallization methods and our techniques. To drive the crystallization event, supersaturation is usually achieved in the prior methods through mixing of a
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precipitant with the protein solution to be crystallized, whereas we rely upon a surrounding dehydrating solvent to concentrate solutes without adding extraneous substances. In fact, droplet microfluidic methods frequently ensure that the conveying fluid surrounding the droplet is completely inert to the droplet, which is best ensured by choosing a fluorinated liquid. Finally, it appears that there has not been extensive reported work on the influence of oil-soluble surfactants or lipids on crystal nucleation (protein or otherwise) in aqueous droplets. Our system takes advantage of some of the features of these systems, but notably is employed on an isolated, single droplet level in the absence of contact with solid walls; uses a solvent (oil) selected for its dehydration ability to promote high supersaturation levels; does not have significant mechanical disturbances which could promote untoward nucleation; and presents a surfactant monolayer at a liquidliquid interface to potentially accelerate nucleation. Compared to the use of a monolayer at an airwater interface, far less study has been reported on the use of amphiphiles at a liquidliquid interface to control crystallization.25,32,3639 In our recent studies, we successfully demonstrated the controlled crystallization of inorganic salts by the use of a template at the liquidliquid interface in a single droplet level.40,41 We used a highly controllable crystallization platform where an isolated aqueous microdroplet in an immiscible phase is isothermally driven to crystallization. An aqueous microdroplet bound by a liquidliquid interface (manipulated by micropipets under digital video microscopy) provides a level of control of many important parameters in crystallization study. In addition, an aqueous microdroplet allows us to easily modulate the molecular packing of the surrounding monolayer via varying surfactant characteristics. In this work, we extend our earlier studies to a system having a known polymorphic behavior. Using our microdroplet-based crystallization platform outlined above, we herein report the habit control of a model inorganic system exhibiting multiple concomitant polytypes, namely, potassium hexacyanoferrate(II) trihydrate (K4Fe(CN)6 3 3H2O, KFCT). As is known from prior studies, KFCT manifests multiple structural types under practical conditions of crystal growth, including a room temperature monoclinic modification M (C2/c), a metastable tetragonal form T, a low-temperature ferroelectric Cc monoclinic modification,4244 and optically anomalous intermediate forms.42,45 The low temperature monoclinic Cc form is well-known for its ferroelectric characteristic, having a Curie temperature of 248.5 K. It can be formed when the room temperature modifications are brought to temperatures below 60 °C. The ferroelectric Cc form is said to revert to C2/c upon warming to room temperature.4244 For this intricate polymorphic system, we report the influence of varying surfactant templates and differing conditions upon its crystallization behavior, which points the way to new possibilities in the control of inorganic crystalline forms.
’ EXPERIMENTAL SECTION Materials. All chemicals were purchased at the highest purity available and used without further purification. Aqueous solutions were prepared from purified, deionized water by a Millipore water purification system (Direct Q-3) with 18.2 MΩ 3 cm. Preparations of Surfactant Solutions. Homogeneous surfactant solutions were prepared by directly dissolving various surfactants (e.g, 1-octadecylamine (CH3(CH2)17NH2; ODA), stearic acid, (CH3(CH2)16COOH; SA) or 1-octadecanol, CH3(CH2)17OH) into oil 4441
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Figure 1. The essential components of the system consist of (a) inverted microscope, (b) crystallization chamber with micropipet set up, and (c) in situ monitoring and recording capability. medium (e.g., 1-decanol), followed by ∼510 min of bath sonication. All solutions were prepared immediately prior to use and filtered through a 0.2 μm Millipore syringe filter. Preparations of Micropipets and Hydrophobic Coating. A micropipet used for manipulation of aqueous microdroplets was prepared using a commercially available micropipet puller (Narishige PB-7) and subsequently fashioned to a desired diameter using a microforge (Narishige MF-900) when necessary. Once a micropipet with desired diameter was achieved, the micropipet was coated to render it hydrophobic to ensure that the aqueous droplets in the pipet remained spherical throughout the experiments without wetting of the glass surface by the aqueous solution. The hydrophobic coating was applied by exposing a freshly pulled pipet to vapors of hexamethyldisilazane [(CH3)3SiNHSi(CH3)3)] in an enclosed container for about 30 min. Temperature Control. All experiments were carried out at an ambient temperature of 24 ( 1 °C (RT), unless specified otherwise. As a check, the temperature within the chamber solution is always monitored with a thermocouple at the beginning and the ending of the use of a given chamber. Other temperatures were achieved by a custom-made temperature-controlled microchamber, which was thermostatted via an external circulating water bath. System. We used a droplet-based crystallization system where isolated aqueous microdroplets are manipulated individually by micropipet under digital video microscopy, in order to monitor in real-time the effect of various parameters (surfactants, temperature, additives, etc.) upon nucleation of crystallizable solutes. The system consists of (a) inverted microscope (Olympus IX51), (b) crystallization chamber with hydraulic micropipet set up (Narishige), and (c) a high resolution digital camera (Olympus DP70) with PC connection for in situ monitoring, recording, and analysis, as shown in Figure 1. The preparation of the crystallization “chamber” (in actuality, a pool of decanol held between glass slides), and other general experimental details have been described in our recent publication.40 In brief, once a pipet was introduced into the chamber it was cleaned by pressurization to release a few water droplets. Then, a microdroplet with a desired initial size was produced by applying slight positive pressure through a syringe connected to the micropipet, which is capable of providing a controlled diameter droplet within the range of 100 ( 10 μm. Once a microdroplet is isolated from the column of solution in the pipet, it is held by small suction pressure at the end of the micropipet tip during the entire crystallization experiment. Successive crystallization experiments were performed only after changing the relative position of the pipet in the chamber to ensure that the droplet is in contact with a new region of chamber solvent. Both the pipet and the solvent in the solvent chamber were freshly provided after about every 10 droplet experiments.
Figure 2. A plot of diameter as a function of time (with corresponding images) during KFCT crystallization process. Each of image frames 16 is taken at the time indicated by arrow. The time span between frames 4 and 6 is less than 1 s.
Refractive Index Measurement. The measurement of the refractive index of solutions is accomplished by an Abbe refractometer. This refractometer has an accuracy of (0.0001 units and is calibrated with water at room temperature (25 °C) according to accepted literature values.46 Raman Spectroscopy. Raman spectrum of crystalline samples was obtained using a Raman microscope (Horiba Jobin Yvon LabRAM) with laser HeNe source in the wavelength range of 1004000 cm1 at room temperature. General Method of Microdroplet Crystallization and Analysis. All microdroplet crystallization experiments were performed using 1-decanol (“decanol”) as the immiscible medium for aqueous microdroplets, unless specified otherwise. In our system, a water droplet, having an average size of 100 μm diameter (∼0.5 nL), is formed in an immiscible medium having a volume of ∼200 μL. The chamber volume is thus at least ∼5 orders of magnitude larger than the droplet which means that the water droplet is in effectively “infinite” dilution. Owing to an appreciable solubility of water in decanol (3.35 wt % at 29.6 °C)47 microdroplet shrinkage is readily observable on a laboratory time scale. The converse solubility of decanol in water is 0.021 wt % at 29.6 °C.47 When an aqueous droplet containing a solute of interest becomes dewatered by a dehydrating oil medium, the droplet undergoes dissolution and shrinks, and solute is thereby concentrated to eventually reach an effective saturation level for crystallization. During this isothermal crystallization process, digital video microscopy is used to monitor the waiting time for nucleation and growth of individual crystals and their shape. Figure 2 shows a typical example of 20% KFCT aqueous droplet of ∼100 μm diameter undergoing shrinkage and arriving at crystallization within ∼5 min. For each crystallization event, we determined Conset, which is the calculated concentration of the KFCT solute in the microdroplet at the onset of crystallization, that is, at the first perceptible microscopic appearance of a solid phase. By taking into account the initial concentration of solute and measuring the diameter of the shrinking, spherical droplet, the solute concentration C could be calculated at any given time while droplet shrinkage progressed, according to eq 1: Cµ
3 4πr 3
ð1Þ
wherein r is radius of the droplet. In this paper, Conset concentrations are reported as “%”, which refers to mass of solute (g) per volume (mL) of solution (w/v), unless otherwise specified. 4442
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Figure 4. Videomicrographs of KFCT microdroplet passing through condition of refractive index match with surrounding decanol phase during shrinkage process. Image 2 is at the matching point where droplet is invisible, while images 1 and 3 are immediately before and after the matching. Bar represents 100 μm.
Figure 3. (A) Sequence of videomicrographs of crystallization process, with two different crystal outcomes. Bar represents 100 μm. (B) The relative frequency of hexagonal habit and octagonal habit is found to be 88% vs 12%, respectively, for multiple (>100) crystallization events.
’ RESULTS Crystallization of KFCT in Pure Decanol at Room Temperature. We performed crystallizations of KFCT by introdu-
cing microdroplets having an initial solute concentration of 20% into the decanolcontaining chamber, at room temperature. Droplet shrinkage was observed due to the appreciable solubility of water into decanol (3.35%),47 and then an initial crystal would nucleate, which would rapidly grow to fill the droplet and substantially consume the remainder of the solution. We observed that each droplet shrinkage would, in the overwhelming majority of cases, give rise to only one crystal (Figure 3); in the rare other instances, a polycrystalline/nonregular mass appears. When repetitive crystallizations were performed in pure decanol at room temperature, we typically found two different shapes of crystals were formed. We observed crystals of hexagonal habit and crystals of octagonal habit. The sequence of video micrographs for the last few seconds of the crystallization is shown in Figure 3A. Typical examples of each crystal shape are shown as insets of Figure 3B. Hexagonal habit crystals evidenced a sixsectored appearance, whereas octagonal habit crystals, although the sides are not always equal in length, had the appearance of a clover-shaped inclusion within the eight-sided crystal. It is thus apparent that we can visually distinguish two different shapes of crystals which form at early stages of the crystallization process. The crystals of hexagonal habit were observed most frequently, while octagonal habit was observed on less frequent occasions. The relative frequency of the two habits was found to be 88% vs 12%, for hexagonal and octagonal habit, respectively, over multiple (>100) individual crystallization events (Figure 3B). The relative frequency values (e.g., 88%) which we report in this paper are based simply upon the raw observed occurrences of each habit. It is clear that the number of crystallization events which we have employed to ascertain the statistical occurrence of the separate habits has certain limitations. In a study of concomitant crystallization in the polymorphic ROY system, Myerson et al.29 achieved statistical accuracy for polymorph distribution by analyzing a large number (∼10 000) of SAM islands upon which this organic crystal can be nucleated. In our case, the use of
∼100 trials permits an estimated standard deviation of ∼10% ((Ntrial)1/2), since only two habits are ever observed across trials, and only one habit is formed in any given trial. In this system, we are capable of determining the relative level of supersaturation at which a crystal appears, by measurement of Conset. For our recent studies in the potassium ferricyanide (potassium hexacyanoferrate(III)) system40 and the potassium sulfate system,41 significant changes in Conset were observed under different crystallization conditions. However, in this study, we did not discern a significant difference in Conset for the respective habits of KFCT. The mean Conset values were 90 ( 10% and 83 ( 10%, respectively, for hexagonal habit and octagonal habit. This could indicate that the two habits represent energetically comparable forms; that is, comparable levels of supersaturation are required to drive the formation of each. Such energetic similarity would be consistent with the concomitant formation of T and M as observed by Punin and others.42,43,48 Our finding regarding the relative frequency for the occurrence of two different habits would be consistent with the literature finding in which two polytypic modifications of KFCT have always been found concomitantly in spontaneous crystallization from solution at ambient temperature.42,48 Conset Verification by Refractive Index Matching. Interestingly, during the crystallization process, we have noticed that an aqueous microdroplet containing KFCT in decanol medium goes through a transition where the refractive index of the shrinking droplet passes through a matching point with that of the surrounding decanol phase. The microdroplet thus disappears and then reappears over the interval of a few seconds. This is depicted in image 3 of Figure 2 and the series of images in Figure 4. We realized that this refractive index matching point phenomenon could be exploited to serve as an independent check of the solute concentration values (e.g., Conset) derived from droplet diameter measurements. The size of the droplet was measured immediately before (image 1 in Figure 4) and after (image 3 in Figure 4) its refractive index matching point (image frame 2 in Figure 4), and the sizes averaged to form an estimate for the point at which exact matching happens. The mean concentration of KFCT solute determined this way was found to be 67 ( 2% for an analysis of 10 microdroplets in decanol medium. A similar matching point was found for shrinkage of KFCT droplets in DMS oil (polydimethylsiloxane, trimethylsiloxy terminated, Hampton Research) (see Figure 5). Then, solutions of known concentration of KFCT were prepared, and Figure 5 shows a plot of their refractive index (RI) as a function of KFCT % at 25 °C. The region marked * was determined by an Abbe refractometer. A relationship was obtained from the experimental measurement: refractive index = 0.0015(KFCT concentration) + 1.3329. Assuming validity for a linear extrapolation, we determined the 4443
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Figure 5. Plot of RI as a function of KFCT aqueous solution concentration at 25 °C. The region marked * was determined by Abbe refractometer. Two oil media, decanol and DMS oil, have been tested. The large circles indicate the RI match point between droplet and media.
concentration of KFCT solution to be 68.3% at the matching point. For this, we used the RI of decanol 1.4354, measured using our system. Two values obtained from two different methods are fairly consistent with each other: 68.3% from the extrapolation using RI measurement vs 67 ( 2% from diameter measurement of the shrinking droplet. (Had the decanol been saturated with water, it would have exhibited an RI of n = 1.4325, which would give a concentration of 66.4%.) Similarly in DMS media (RI of DMS 1.390), we obtained 38.1% from the extrapolation using RI measurement vs 39 ( 2% from diameter measurement. This result can be employed to lend corroborating weight to our belief that there is no significant mass transport of KFCT to the surrounding decanol during the time scale of our crystallization experiments. The Effect of Surfactant. The region surrounding the microdroplet offers opportunities for modulating the interfacial environment of the aqueous phase, owing to a high ratio of surface area to volume. Various oil-soluble surfactants were thus investigated to ascertain the effect of self-assembled surfactant monolayers on the outcome of nucleation. Surfactants of three different classes (anionic, neutral, cationic) were employed in the decanol chamber medium, each at a concentration of 3.7 mM in oil. Figure 6A depicts the resultant average Conset values for an ensemble of crystallization events in the presence of no surfactant, stearic acid, octadecanol, and octadecylamine, respectively; the corresponding dominant habit for KFCT is also indicated. Little significant distinction was observed in the values for Conset, regardless of surfactant type. The values for concentration at the onset of crystallization were not markedly changed relative to the absence of surfactant. However, in the case of octadecylamine (ODA), a high predominance of octagonal habit crystals was seen. As shown in Figure 6B, stearic acid and octadecanol produced the two habits of crystals in the same relative proportion as with absence of surfactant: nearly 90% of hexagonal habit. In contrast, the population of crystals of hexagonal habit formed in the presence of ODA monolayer was merely about 20%, with a predominance (80%) of octagonal habit. It is difficult to conclusively determine which factors are the dominant ones that account for the preponderance of octagonal habit crystals in the ODA system. However, certain factors are readily apparent. ODA is known to be a weakly basic surfactant. It is characterized by undergoing hydrolysis to form a cationic headgroup at the aqueous interface. It is possible that electrostatic attraction of the highly charged [Fe(CN)6]4 anion to the
Figure 6. (A) The Conset values for KFCT crystallization events in the presence of no surfactant, stearic acid, octadecanol, and octadecylamine along with the corresponding image for dominant habit. (B) Our results indicate that the relative frequency of hexagonal habit and octagonal habit sharply depends on the surfactant used.
cationic interface can lead to accumulation of these solute moieties in the vicinity of the interface, which would allow this kind of monolayer system to perturb the nucleation event.40 Also, studies in a Langmuir monolayer system, using ODA as surfactant and the analogous hexacyanoferrate(III) anion in the subphase, demonstrated a strong interaction between [Fe(CN)6]3 and the ODA molecule.49 In order to further verify whether it is the primarily the cationic nature of the ODA surfactant which drives the result, or another factor, we extended our studies to include other cationic surfactants, viz., cetyl trimethylammonium bromide (CTAB) and dioctadecyl dimethylammonium bromide (DODAB). Crystallizations performed under the same conditions as noted above for ODA, but with these alternative cationic surfactants, resulted in the substantially same distribution of crystal habits as with no surfactant present, and as with anionic or nonionic surfactant: nearly 90% hexagonal habit. This would support a conclusion that electrostatic attraction is likely not the only responsible factor. Rather, there is undoubtedly a complex interplay between the surfactant monolayer and incipient crystal nucleus that involves the relative structural characteristics of each. However, as will be discussed in greater depth below, ascertaining the structure of surfactant monolayers at a liquidliquid interface is itself a challenge, one which motivates us to study of the subtleties of this system. Polarized Micrograph. We have taken steps to assign both of the observed crystal habits to known forms, using optical microscopy. We have found that both of the KFCT crystal habits which we have observed are readily distinguished under polarized light microscopy, as shown in Figure 7. Hexagonal habit crystals were formed as sectored hexagonal tablets; when observed under 4444
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Figure 7. Crystals of hexagonal habit and octagonal habit, each observed by polarized light microscopy. Figure 9. Comparison of supersaturation rate for KFCT in octanol, decanol, and dodecanol at 24 °C. In all cases, hexagonal habit is the dominant habit observed.
Figure 8. The habit of the crystal formed for KFCT in pure decanol depends on the temperature.
cross-polarizers, alternate sectors exhibited extinction. Octagonal habit crystals appeared uniformly dark under polarized light, behavior consistent with what is expected for a uniaxial tetragonal crystal. The extinction pattern of the hexagonal habit crystals is generally consistent with the biaxial nature of a monoclinic crystal, while the behavior of the octagonal habit crystals is that which is expected for a uniaxial tetragonal crystal. However, in the literature, the KFCT crystal system exhibits numerous forms which are optically anomalous.45 Thus, we cannot rule out the hexagonal crystals being twins (2- or 3-way) of monoclinic crystals. Effect of Temperature. We have found that changing the temperature of the crystallization process also affects the proportion of one habit forming over the other, just as does the use of the ODA surfactant. The effect of temperature has been reported in earlier studies for the crystallization of KFCT in the bulk from aqueous solutions.43,48,50 Figure 8 shows the distribution of various habits of KFCT which crystallized at a specified temperature, in the absence of any added surfactant; the oil medium was pure decanol. We have seen that as the temperature is increased, the relative proportion of octagonal habit crystals greatly increases. At a temperature of 55 °C, nearly 90% of the crystallization events result in the octagonal habit crystals (inset (c), Figure 8), compared with a similar proportion of hexagonal habit (inset (a), Figure 8) forming at room temperature. Interestingly, for crystallizations of KFCT performed at intermediate temperatures (e.g., 42 °C, 50 °C), a habit having a hybrid appearance (denoted hybrid habit) was formed, with a somewhat six-sided shape of the hexagonal habit but with the cloverleaf
inclusion of the octagonal habit (see inset (b), Figure 8). These variable temperature results are consistent with earlier bulk studies which have shown that C2/c monoclinic KFCT is formed in an amount of 90% in crystallizations conducted at ambient temperatures, as ascertained by 13C NMR.42 In contrast, a high temperature crystallization was conducted at 55 °C by antisolvent precipitation of KFCT by ethanol, resulting in predominantly the tetragonal form, with only about 20% monoclinic present.42 Punin48 quantifies the occurrence of the different types based on the optic axial angle 2V; the higher the angle, the greater the proportion of monoclinic KFCT in the sample. The frequency at which we see hexagonal crystals at room temperature is the same as the frequency at which Punin detects high values of 2V at room temperature; and the frequency at which we see octagonal crystals at 55 °C is the same at which Punin sees low values of 2V at 55 °C. These results further corroborate an assignment of the hexagonal habit to the M polymorph, generally, and the octagonal habit to the T form. Supersaturation Rate. It is generally known that the rate at which supersaturation is increased in a solution (supersaturation rate) can sometimes have a strong effect upon the outcome of a nucleation process.51 Aqueous droplet solutions held in an oil medium at high temperature have a tendency to shrink at greatly increased rates relative to room temperature droplets; thus, their supersaturation rate is enhanced relative to room-temperature shrinkage. In order to determine whether the temperature dependency noted above was a function of supersaturation rate, we sought to change the dehydrating oil solvent in order to change the rate of shrinkage. Longer chain alcohols, having a lesser solubility for water, tend to dehydrate and thus make aqueous droplets shrink more slowly than shorter chain alcohols (the relative solubility of water in 1-octanol, 1-decanol, and 1-dodecanol is about 4.4 wt %, 3.35 wt %, and 2.9 wt %, respectively).47,52 We studied the crystallization of 20% aqueous KFCT in droplets held in 1-octanol, 1-decanol, and 1-dodecanol, respectively, at room temperature. As shown in Figure 9, the supersaturation rate in 1-octanol was markedly higher than in 1-dodecanol, and yet in each case, the dominant (i.e., > 80%) formation of hexagonal habit was seen. For comparison, we note that the shrinkage rate for a droplet in 1-octanol at room temperature is nearly equal to that occurring in decanol at 55 °C. These data tend to indicate that changes in supersaturation rate engendered by a temperature increase from 25 to 55 °C are not the major factors in controlling the observed crystal habit. Effect of K2CrO4 Additive. KFCT crystallization is known to be strongly affected by the presence of certain additives. 4445
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Figure 10. Comparison of the statistical outcome of crystallizations under different conditions.
In general, the relative amounts of the various polytypes of KFCT that can be obtained from a bulk crystallization are influenced by the addition of K2CrO4 or KOH.42,48 For example, the addition of potassium chromate to KFCT solutions is said to stabilize the monoclinic form, even in a temperature regime where T predominates. We can employ this phenomenon to further validate our assignments of the two crystal habits. Figure 10 compares the statistical outcome of crystallizations under different conditions. System A denotes the use of an ODA interfacial template at room temperature, which, as previously noted, gives rise to crystals of octagonal habit in nearly 80% of instances. Addition of a small amount of K2CrO4 additive (0.5% by weight relative to weight of KFCT) shifts the distribution to 60% of hexagonal habit and only 40% octagonal habit. Similarly, crystallization performed at high temperature but without ODA (55 °C; denoted system B) also results in the predominant formation of octagonal habit. Addition of a small amount of K2CrO4 additive (0.5% by weight relative to weight of KFCT) to system B also shifts its distribution to ∼70% of hexagonal habit. Because of the consistency between our results and that of the precedent studies, we are thus confident at this point that crystals of hexagonal habit can be attributed to a form in the monoclinic system, whereas octagonal habit crystals are a form in the tetragonal system. Raman Studies. We investigated the Raman spectral parameters for hexagonal habit crystals by micro-Raman spectroscopy (Horiba LabRAM). The Raman spectrum in the wavelength range of 18004000 cm1 (room temperature) for hexagonal habit crystals is shown in Figure 11. The spectrum is highlighted by the characteristic region between 2000 and 2200 cm1, in which modes for CtN stretching are expected to be found. We observed a set of four prominent sharp peaks in this region: at 2093, 2073, 2062, and 2024 cm1. A peak of lesser intensity is seen at 2041 cm1. Prior Raman studies of the KFCT crystal system have been limited to investigation of the monoclinic form; no Raman spectra of the tetragonal form appear to be available in the literature. Savatinova et al.53 have obtained the room-temperature solid-state Raman spectrum of monoclinic KFCT and made assignments for the vibrations attributable to CtN stretch in the Fe(CN)64- moiety. In the characteristic CN region, they observed the following stretches: 2095 cm1 [ν1(Ag)], 2064 cm1 and 2056 cm1 [ν3(Eg)] and 2038 cm1 [ν6(F1u)]. At the present time, it is unclear whether our observed peak at 2024 cm1 represents the ν6 peak shifted somewhat owing to crystal stresses, or whether it may be attributable to a decomposed or dehydrated state of the KFCT. Although we have
Figure 11. Raman spectrum of potassium ferrocyanide trihydrate (KFCT) crystal of hexagonal habit.
not been able to conclusively assign hexagonal habit crystals to the monoclinic system via Raman, we believe that our observed spectrum is not inconsistent with the results of Savatinova. Raman studies of crystals of octagonal habit are planned in order to ascertain whether putative polymorphs can be distinguished spectroscopically. X-ray Investigation. We have made attempts to obtain X-ray diffraction from crystals of each habit. Microcrystals generally in the form of flat plates with the longest dimension of no greater than 50 μm (typically about 30 20 5 μm) were mounted on a loop at room temperature and exposed to Beamline X25 at the National Synchrotron Light Source, Brookhaven, NY. No diffraction data could be obtained. Optical examination of the crystals after exposure to the beam showed evidence of crystal decomposition. We believe that the observed decomposition is likely due to at least one or more of the following factors: radiation damage to the crystals by the synchrotron light; dissociation of waters of crystallization; loss of stabilizing quantities of mother liquor; and photo-oxidation of the reductive hexacyanoferrate(II) moiety.
’ DISCUSSION The KFCT crystal system has long been known to have a rich and complex polymorphous nature.42,43,48,50,54 A careful study by Punin et al.48 indicates that two polytypes have been reliably established: two-layer monoclinic and metastable, four-layer tetragonal. There is a region of stability for each polytype, with monoclinic being stable below about 40 °C and tetragonal which is stable at temperatures above this. Still, these investigators note that crystals of pure phases are rarely observed. The various forms nucleate concomitantly, or grow together as interpenetrated crystals, a result of syntactic concretion. Only in the earliest stages of crystallization are pure phases observed. Punin et al. conclude that the various forms are related by polytypism, which is regarded as a one-dimensional polymorphism. Significantly, they note that the energy difference between these polytypes is very small. Similarly, Toyoda43 has noted that grown crystals of KFCT show extraordinary polytypic variation due to twinning and oriented overgrowth; five different polytypic varieties were observed. In consonance with the foregoing, Willans et al. have also found,42 via solid-state 13C NMR, that room temperature crystallization yields a mixture comprised of 90% M, whereas 4446
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Table 1. Crystallizations in the Absence of Surfactant, in Comparison to the Literature monoclinic/tetragonal ratio hexagonal/octagonal ratio literature(ref) room temperature
our result
42
88:12
20:8042
14:86
stabilize monoclinic48
68:27
biaxial/uniaxial48,43
biaxial/uniaxial
90:10
ratio (25 °C) high temperature ratio (55 °C) K2CrO4 additive effect at 55 °C polarized light behavior
crystallization at 55 °C gave rise to only 20% M. The fact that we almost exclusively only observe two habits could be an indication that our approach in fact can capture individual polytypes, which at minimum can be reliably assigned to different crystal systems, based on our results as summarized in Table 1. The KFCT crystal system has therefore been established in these prior studies to be a complex system having only very slight energetic differences between polytypes. This complexity has interesting implications for the mechanism of crystal nucleation induced by a surfactant monolayer at the liquidliquid interface. As already noted, the fact that only ODA has been shown to perturb the crystallization outcome is an indication that an electrostatic attraction between the monolayer (presumably comprising octadecylammonium headgroups) and highly charged solute moieties [Fe(CN)64] is likely at play here. However, this cannot be the sole mechanism which is operating. While this mechanism can explain the perturbation of the crystallization outcome, it cannot explain the discrimination between the two observed habits, since they both are potentially nucleated from identical supersaturated solutions. The fact that the ODA monolayer appears to preferentially induce a metastable tetragonal form to be nucleated, and yet other cationic surfactants (viz., CTAB and DODAB) do not, implies that the ODA monolayer may also have a favored structural match with KFCT nuclei of the tetragonal form. To fully determine the mechanism through which an interfacial assembly fosters nucleation would require detailed knowledge of a number of factors. Assisted crystal nucleation in the presence of a monolayer template has been ascribed to molecular recognition between the monolayer and the nucleated crystal, which largely depends upon cooperative effects of electrostatic, geometric, stereochemical, hydrogen bonding and other interactions between the monolayer and the nucleated crystal.11,15,17,55 Any of these can come into play in a discussion of polymorph control as well. However, there are major impediments to a thorough discussion of any matching between the ODA surfactant monolayer and an incipient crystal nucleus of the presumably T form KFCT. While single-crystal X-ray diffraction data for the T form KFCT appears to be absent from the literature, it is more significant to note that the structure of the liquidliquid interface at the molecular level has only relatively recently begun to come into focus. Recent advances in the understanding of adsorption at the liquidliquid interface has now clearly established that this interface cannot be treated as a simple extension or approximation of the airwater interface.58,59 The vast majority of studies which have heretofore correlated monolayer structure with the orientation/form of nucleated
crystals have been concerned with the airwater interface. Indeed, many insoluble organic monolayers assembled at an airwater interface often possess sufficient crystalline character to permit structural characterization by methods such as synchrotron grazing-incidence X-ray diffraction (GIXD). Similar knowledge pertaining to the lattice spacing and 2D/3D arrangement of octadecylamine assembled at an oilwater interface would be invaluable for establishing the existence of any geometric matching or registry between the ODA monolayer and a preferentially induced habit. However, the oilwater interface provides a very different environment for surfactant adsorption relative to the air water interface. The molecular level understanding has thus far been limited to the changes in chain tail conformation upon adsorption.56,57 More recent studies have explored the nature and bonding environment of the headgroup upon adsorption to the interface. A broad variety of headgroup orientations have been reported for carboxylic acid surfactants at a waterCCl4 interface, each of which act to solvate the headgroups. The surfactant takes on more degrees of freedom at this interface, allowing for the variety. This has been found to contrast sharply with the highly defined orientation for the same surfactant at the airwater interface. At the airwater interface, oil solvent molecules are not present which would screen alkyl tail groups from each other as occurs at the liquidliquid interface. Thus, surfactants at an airwater interface benefit from stronger van der Waals forces, leading to more ordered monolayers.58,59 Despite its relative disorder relative to the airwater interface, a surfactant monolayer at a liquidliquid interface may nevertheless be anticipated to have a certain ordered character. Any level of ordering at that interface can have implications for the promotion of nucleation of solutes in one of the phases. Although the precise details of the forces responsible for this preferential induction of habit await further detailed studies, it is clear that a liquidliquid interfacial system opens interesting new possibilities for the control of inorganic as well as organic crystal nucleation. We have provided evidence for a droplet crystallization platform which holds promise in controlling the nucleation outcome, even in a polymorphic crystal system where the crystal forms have only the most delicate energetic differences. Furthermore, since the droplet method allows us to separate nucleation events from any appreciable crystal growth or redissolution (since the crystal grows so quickly to consume the droplet and then stops), any initially formed polymorph can be trapped, without any possible intergrowth with other phases and without the possibility of any solvent-mediated conversion to other forms.
’ CONCLUSIONS In this study, the complexity of the KFCT crystal system has been exploited as a uniquely sensitive probe for differences at a liquidliquid interface. We have demonstrated that a microdroplet crystallization system is capable of trapping a first-formed habit, a manifestation of confinement engendered by a droplet. The relative percentage of the two different habits crystallized depended on the crystallization conditions, such as the nature of surfactant template used, the temperature at which the crystals are formed, and the presence of additive. On the basis of optical properties and literature precedent, we can assign the two habits to different crystal systems. This work opens a promising future in application of this method to the study of the effect of a 4447
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’ AUTHOR INFORMATION Corresponding Author
*Tel: 914-633-2638. Fax: 914-633-2240. E-mail:
[email protected].
’ ACKNOWLEDGMENT The author would like to acknowledge the financial support for this research from National Science Foundation (NSF-CHE0909978); The Patrick J. Martin Foundation; and Iona College. Dr. Fran Adar of Horiba Jobin Yvon is thanked and acknowledged for kind collection of Raman spectral data. Dr. Peter W.R. Corfield and Dr. Peter T. DiMauro are thanked for helpful discussions. We are indebted to Dr. Annie Heroux at the National Synchrotron Light Source (Brookhaven National Laboratories) for beamline access. ’ REFERENCES (1) Lovette, M. A.; Browning, A. R.; Griffin, D. W.; Sizemore, J. P.; Snyder, R. C.; Doherty, M. F. Ind. Eng. Chem. Res. 2008, 47, 9812–9833. (2) Polymorphism: in the Pharmaceutical Industry; WILEY-VCH Verlag GmbH & Co. KGaA: Weinheim, 2006. (3) Bernstein, J. Polymorphism in Molecular Crystals; Oxford Science Publications: New York, 2002. (4) Hartel, R. W. Crystallization in Foods; Aspen Publishers, Inc.: Gaithersburg, MD, 2001. (5) Llinas, A.; Goodman, J. Drug. Discovery Today 2008, 13, 198– 210. (6) Crystallization Processes in Fats and Lipid Systems; Marcel Dekker: New York, 2001. (7) Davey, R. J.; Garside, J. From Molecules to Crystallizers; Oxford University Press: New York, 2000. (8) Mangin, D.; Puel, F.; Veesler, S. Org. Process Res. Dev. 2009, 13, 1241–1253. (9) Pileni, M. P. Nature 2003, 2, 145–150. (10) Rao, C. N. R.; Kalyanikutty, K. P. Acc. Chem. Res. 2008, 41, 489–499. (11) Mann, S. Biomineralization, Principles and Concepts in Bioinorganic Materials Chemistry; Oxford University Press: New York, NY, 2001. (12) Handbook of Biomineralization; Wiley-VCH: New York, 2007. (13) Meldrum, F. C.; CoIfen, H. Chem. Rev. 2008, 108, 4332–4432. (14) Chen, J.; Sarma, B.; Evans, J. M. B.; Myerson, A. S. Cryst. Growth Des. 2011, 11, 887–895. (15) Weissbuch, I.; Lahav, M.; Leiserowitz, L. Cryst. Growth Des. 2003, 3, 125–150. (16) Sommerdijk, N. A. J. M.; de With, G. Chem. Rev. 2008, 108, 4499–4550. (17) Rapaport, H.; Kuzmenko, I.; Berfeld, M.; Kjaer, K.; Als-Nielsen, J.; Popovitz-Biro, R.; Weissbuch, I.; Lahav, M.; Leiserowitz, L. J. Phys. Chem. B 2000, 104, 1399–1428. (18) Lendrum, C.; McGrath, K. M. Cryst. Growth Des. 2009, 9, 4391–4400. (19) Popescu, D. C.; Smulders, M. M. J.; Pichon, B. P.; Chebotareva, N.; Kwak, S.-Y.; van Asselen, O. L. J.; Sijbesma, R. P.; DiMasi, E.; Sommerdijk, N. A. J. M. J. Am. Chem. Soc. 2007, 129, 14058–14067. (20) DiMasi, E.; Kwak, S.-Y.; Pichon, B. P.; Sommerdijk, N. A. J. M. CrystEngComm 2007, 9, 1192–1204. (21) Lendrum, C.; McGrath, K. M. J. Colloid Interface Sci. 2009, 331, 206–213. (22) McClelland, A. A.; Lopez-Mejias, V.; Matzger, A. J.; Chen, Z. Langmuir 2011, 27, 2162–2165.
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