Article pubs.acs.org/crystal
Functionalized Silica Nanoparticles as Additives for Polymorphic Control in Emulsion-Based Crystallization of Glycine Abu Zayed Md. Badruddoza,† Arpad I. Toldy,‡ T. Alan Hatton,‡,§ and Saif A. Khan*,†,‡ †
Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117576, Singapore ‡ Chemical and Pharmaceutical Engineering Program, Singapore-MIT Alliance, National University of Singapore, 4 Engineering Drive 3, E4-04-10, Singapore 117576, Singapore § Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 66-309, Cambridge, MA 02139, United States S Supporting Information *
ABSTRACT: Emulsion-based crystallization to produce spherical crystalline agglomerates is an attractive route to control the size and morphology of active pharmaceutical ingredient (API) crystals, which in turn improves downstream processability. Here, we demonstrate the use of silica nanoparticles modified with different surface functional groups (hydroxyl, amino, carboxylic, imidazolim chloride, and chloride) as additives in water-in-oil emulsion-based crystallization of glycine, a model API molecule. Spherical agglomerates of glycine obtained under different experimental conditions are characterized by powder X-ray diffraction (XRD) and scanning electron microscopy. Our observations reveal the strong influence of particle functionalization on polymorphic outcome at near-neutral (pH ∼6) conditions, where we are able to selectively crystallize the least stable β-polymorph of glycine or tune the relative ratio of α- and β-polymorphs by selecting appropriate experimental conditions. Mixtures of α- and γ-glycine are typically obtained under acidic solutions (pH ∼3), irrespective of the functional groups used. We examine the influence of charge and immobilization density of surface functional groups and nanoparticle concentration on the polymorphic outcome and rationalize our results by analyzing molecular and functional group speciation.
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particles10,11 have been rationally designed and used for screening and controlling polymorphism in inorganic and molecular crystals. Aizenberg et al. studied the oriented growth of calcite controlled by self-assembled monolayers of functionalized alkane thiols supported on gold and silver and found that SAMs terminated in CO2−, SO3−, PO32‑, and OH groups were active in inducing nucleation, whereas SAMs terminated in N(CH3)3+ and CH3 inhibited nucleation.12 Toworfe and coworkers studied the nucleation and growth of calcium phosphate on amine-, carboxyl-, and hydroxyl-silane selfassembled monolayers and found that the variations in surface morphology, size, and growth rate of Ca−P precipitates depended on the functional groups.13 Molecular functionality at the surface of the substrate is known to play an important role in crystal nucleation; it can lead to specific favorable intermolecular interactions, such as hydrogen bonding, with the nucleating plane of crystals thereby controlling both polymorphism and crystallographic orientation.
INTRODUCTION Production of spherical agglomerates of active pharmaceutical ingredients (APIs) by the emulsion-based crystallization method, where crystallization and agglomeration can be carried out simultaneously in one step,1 is of great interest to the pharmaceutical industry. This technique has been utilized to improve downstream processability of crystalline APIs by improving flowability, compressibility, and compactibility2 and to enhance bioavailability,1 due to the small size of the individual crystals that constitute the spherical agglomerates. Emulsion-based crystallization is not only a method to control the size and shape of API crystal agglomerates, but it can also be used to achieve polymorphic selectivity. Control of polymorphism has received enormous attention as crystal polymorphs show different physical and chemical properties such as melting point and solubility.3 Several approaches have been reported in the literature to control the polymorphic outcome of crystallization processes, such as the use of “tailormade” additives,4 solvent selection,5 pH change,6 etc. However, understanding and control of polymorphic nucleation still remains a major challenge in polymorphism research. In recent years, several types of functionalized solid substrates such as self-assembled monolayers (SAMs)7−9 and polymeric micro© 2013 American Chemical Society
Received: January 26, 2013 Revised: April 12, 2013 Published: April 12, 2013 2455
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using a basic glycine solution (pH ∼10.0), possibly due to surfactant degradation, (see Figure S1 of the Supporting Information), and further experiments were not conducted at basic conditions. The pH of the aqueous glycine solution was adjusted by adding NaOH or HCl. The surfactant mixture chosen to stabilize the water-in-oil emulsions was a 10 wt % mixture of Span 20 and Span 80 (70:30 by weight, respectively) based on the total aqueous phase. Supersaturation was induced by the evaporation of water from the emulsion drops at 82 °C under ambient pressure. After the complete evaporation of water (which took almost 4 h), the crystal samples were collected, separated, and dried under vacuum at room temperature. Use of Silica Nanoparticles As Additives. SiO2 NPs (diameter ∼250 nm) with different surface functional groups (hydroxyl, amino, carboxylic, imidazolim chloride, and chloride) were used as additives. An FESEM image of bare SiO2 NPs is provided in Figure S2 of the Supporting Information. Different quantities of SiO2 NPs ranging from 25 to 125 mg [0.1−0.5% (v/v) of total volume] were dispersed in 9 mL of dodecane-surfactant solution by sonication. After stirring at 800 rpm and 82 °C for 2−3 min, 1 mL of preheated glycine solution was added to the dodecane−surfactant−particle mixture and underwent evaporation at 82 °C. SiO2 NPs were dispersed into the dodecane phase rather than into the aqueous glycine solution to avoid premature glycine precipitation. Details of synthesis and characterization of SiO2 NPs are provided in the Supporting Information. The reaction schemes to synthesize all the functionalized SiO2 NPs and their X-ray photoelectron spectroscopy (XPS) spectra are provided in Figures S3 and S4 of the Supporting Information, respectively. Partitioning experiments of SiO2 NPs in dodecane/water mixtures of the same volume ratio used in the above emulsion-based crystallization experiments revealed that >80% NPs partitioned to and dispersed in the water phase. In a typical partitioning experiment, about 100 mg of each type of SiO2 NPs was added and dispersed in the dodecane/water solution (9:1 v/v) followed by sonication (∼1 min) and vortex mixing. After equilibration (when we observed the two immiscible phases separated by a clear and stable interface), 0.5 mL of water or dodecane phase was collected and weighed. Partitioning of SiO2 NPs in the dodecane−water system was thus calculated by gravimetric analysis. Characterization of Spherical Agglomerates. The size and morphology of the spherical agglomerates were characterized with a field-emission scanning electron microscope (JEOL JSM-6700F) at 5 kV accelerating voltage and at various magnifications. Samples were collected on conventional SEM stubs with carbon tape and were coated with ∼10 nm of platinum by sputter coating. A powder X-ray diffractometer (model: XRD-6000, Shimadzu) was used for polymorphic characterization of crystal agglomerates. Crystalline powders collected were analyzed without grinding to avoid polymorph transformation during this process. The X-ray diffractometer was operated at 40 kV, 30 mA, and at a scanning rate of 2°/min over the range of 2θ = 10 − 40°, using Cu Kα radiation wavelength of 1.54 Å. Quantification of the Polymorph Composition. The polymorphic compositions of glycine agglomerates were quantified to evaluate the effects of the SiO2 NP concentration and functionalization on the polymorphic outcome. All samples analyzed from emulsionbased crystallization experiments were mixtures of either forms α and β (pH 4.0 − 8.0) or α and γ (pH ∼3.0). The mass fraction of the α form, ηα1, in an (α + β) mixture and the mass fraction of the same form, ηα2, in an α + γ mixture were calculated from the following two equations:
Several studies have been carried out to understand pharmaceutical emulsion-based crystallization processes,2,14−18 in which API crystallization occurs in the dispersed phase of water-in-oil (or oil-in-water) emulsions, and supersaturation is achieved by evaporation, cooling, or antisolvent addition. Espitalier et al. investigated the role of operating conditions in evaporative crystallization of oil-in-water emulsions for the preparation of poorly soluble steroids.15 More recently, Allen et al. studied the effect of the dimensions of the two-phase system (microemulsion, macroemulsion, and lamellar phases) on the outcome of glycine crystallization.17 Chadwick et al. examined the roles of operating conditions and additives in the emulsionbased crystallization of three water-soluble molecules (ephedrine, glutamic acid−HCl, and glycine) and achieved limited polymorphic control in some cases.16 Toldy et al. recently demonstrated the controllable production of uniformly sized spherical agglomerates of α-glycine by using a capillary microfluidic emulsion generator in conjunction with evaporative crystallization.18 In general, there are relatively few studies on selective polymorphic crystallization in emulsionbased systems. In this paper, we demonstrate the use of hydrophilic silica nanoparticles (hereafter abbreviated as SiO2 NPs) with different surface functional groups as additives in the emulsion-based crystallization of APIs. The use of functionalized SiO2 NPs is inspired by previous studies on the use of functionalized solid substrates as templates for controlling nucleation and crystal growth of biominerals and inorganic and organic crystals, as noted above.12,13 SiO2 NPs are nontoxic and biocompatible, and the Food and Drug Administration (FDA) has approved their usage for molecular imaging for cancer treatment. Glycine, with three known polymorphs (α, β, and γ), was employed here as a model compound as it is widely used in polymorphic crystallization studies.4,19,20 In this study, SiO2 NPs not only act as fillers or excipients but also influence the polymorphic outcome within the confined environment of the emulsion droplets. We find that the chemical nature and speciation of the functional groups on the silica NPs and their surface densities affect the polymorphic outcome in evaporative emulsion-based crystallization. To the best of our knowledge, this is the first demonstration of the use of functionalized solids (nanoparticles) in an emulsion-based crystallization system to achieve polymorphic control.
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EXPERIMENTAL SECTION
Materials. Glycine (≥99%), dodecane (≥99%), sorbitan monolaurate (Span 20) and sorbitan monooleate (Span 80), 3-aminopropyltriethoxysilane (APTS, 98%), 3-chlorpropyltrimethoxysilane (97%), and 1-methylimidazole (99%) were purchased from SigmaAldrich. Ammonium hydroxide (25%) was purchased from Merck and tetraethyl orthosilicate (TEOS, 99%) was purchased from Fluka. All chemicals were used as received with no further purification. Deionized water (18.3 MΩ) obtained using a Millipore Milli-Q purification system was used in all experiments. Methods. Spherical agglomerates of glycine were prepared from water-in-oil macroemulsions coupled with evaporative crystallization using a batch technique. Macroemulsions were prepared at 82 °C by dissolving the desired surfactants into the oil phase (dodecane) and adding the aqueous phase with overhead stirring at 800 rpm. In our experiments, a single-neck round-bottom flask (50 mL volume) was used, and the solution was stirred with a paddle-type stirrer. For all experiments, the concentration of glycine was 0.308 g per gram of water and the ratio of oil to aqueous phase used was 90:10 by volume. Glycine solutions with pH ranging from 3.0 to ∼8.0 were used in this study. Spherical agglomerates of glycine crystals were not obtained
ηα1 = k1
I(θα) I(θα) + I(θβ)
(1)
ηα 2 = k 2
I(θα) I(θα) + I(θγ )
(2)
where I denotes relative peak intensity, and θα, θβ, and θγ are the characteristic peak positions (2θ in all figures of XRD patterns) for forms α, β, and γ, respectively. In an α + β mixture, θα = 29.8° and θβ = 17.9°, while in an α + γ mixture, θα = 29.8° and θγ = 25.3°, all being the most intense among the characteristic peaks of their respective 2456
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phases. The coefficient k, which converts the peak intensity fraction to the polymorph mass fraction, was determined experimentally. A calibration curve was constructed to determine k1 and k2 using glycine crystal mixtures of known mass fractions of forms α + β and α + γ, respectively. For this purpose, pure form α + β and form α + γ mixtures were prepared. α- and γ-glycine were purchased from SigmaAldrich, whereas β-glycine crystals were prepared following the procedure described in the literature.5 The relevant XRD patterns are provided in Figure S5 of the Supporting Information. The linear regression results following eqs 1 and 2 yielded k1 = 1.02 (R2 = 0.99) and k2 = 1.04 (R2 = 0.99), respectively. Variations in polymorphic composition measured by this procedure across multiple experiments were typically less than 12%.
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RESULTS AND DISCUSSION Figure 1 (panels a−d) shows SEM images of typical agglomerates produced from near-neutral glycine solutions Figure 2. FESEM images of glycine spherical agglomerates crystallized from acidic glycine solutions (pH ∼3) in the absence or presence of additives: (a) without SiO2 NPs and with (b) bare SiO2 NPs, (c) SiO2NH2 NPs, and (d) SiO2COOH NPs. In each experiment, 7.5 mg mL−1 of NPs were used.
Figure 1. FESEM images of glycine spherical agglomerates crystallized from a neutral glycine solution (pH ∼6.1) (a) without SiO2 NPs, and with (b) bare SiO2 NPs, (c) SiO2NH2 NPs and (d) SiO2COOH NPs; FESEM images of cross sections of agglomerates obtained using (e) bare SiO2 NPs and (f) SiO2NH2 NPs. 10.0 mg mL−1 of NPs were used in all experiments.
Figure 3. XRD patterns of glycine agglomerates obtained at neutral pH condition using different functionalized SiO2 NPs. Group A: SiO2NH2 NPs (functional amine density: 0.89 μmol m−2) of three different concentrations 7, 10, and 13 mg mL−1 were used. Group B: SiO2NH2 NPs (functional amine density: 2.4 μmol m−2) of three different concentrations 2.5, 5.0, and 7.5 mg mL−1 were used. Group C: SiO2COOH NPs of three different concentrations 3.0, 5.0, and 10.0 mg mL−1 were used. Bare SiO2 NPs used here: 13.0 mg mL−1. In the above experiments, either the β-polymorph or a mixture of α- and β-forms was obtained, and the percentage of the β-polymorph is represented.
(pH ∼6.1) with and without functionalized SiO2 NPs. Spherical agglomerates were obtained in all experiments, with sizes in the ∼10 μm range in all cases. Size distribution histograms of all samples are provided in Figure S6 of the Supporting Information; these measurements revealed that SiO2 NP additives had no apparent effect on agglomerate sizes. SiO2 NPs were observed both on the surfaces and within the agglomerates, as shown in typical cross-sectional SEM images presented in Figure 1 (panels e and f), consistent with partitioning experiments that indicated >80% partitioning of SiO2 NPs into the aqueous phase (details provided in Experimental Section). Figure 2 shows spherical agglomerates obtained from acidic glycine solutions (pH ∼3.0) using different types of functionalized NPs. Although the agglomer-
ates produced were in the same size range (see Figure S7 of the Supporting Information for histograms) as those obtained from the near-neutral glycine solution, they differed in their surface morphologies and had significantly rougher external surface texture. Polymorphic characterization revealed that crystallization of near-neutral glycine solutions (pH = 6.1) in the absence of SiO2 NPs yielded, as expected, a mixture of α and β-glycine, 2457
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was obtained with bare SiO2 NPs at slightly basic conditions, with pH ∼7.9 after addition of particles (see Figure 5 and further discussion below). Next, we used two types of SiO2 NH2 NPs, denoted by “Group A” and “Group B” in Figure 3, with different surface functional group densities at near-neutral conditions. Details of immobilization density assays are provided as Supporting Information. When 7 mg mL−1 SiO2NH2 NPs with functional −NH2 group density of ∼0.89 μmol m−2 were used, spherical agglomerates comprised of a mixture of α- and β-polymorphs (Group A, Figure 3) were obtained, with the α-form as the dominant polymorph. Interestingly, when higher concentrations (10 and 13 mg mL−1) of SiO2NH2 NPs of the same functional group density were used, the β-form of glycine was produced almost exclusively. Now, when SiO2NH2 NPs (Group B, Figure 3) with higher functional group density (2.4 μmol m−2) were used, even a low concentration of NPs (2.5 mg mL−1) was sufficient to completely preclude the crystallization of α-glycine. It has been reported that β-glycine crystallized by rapid cooling of aqueous solutions21 or by precipitation from water−ethanol solutions5 readily transforms to the α-form at ambient conditions usually within minutes. In contrast, the spherical agglomerates produced via the emulsion route were stable for hours, as also reported by Allen and co-workers;17 the low solubility of glycine in dodecane likely inhibits its solventmediated transformation to the α-form. SiO2 NPs containing −COOH terminated groups (denoted by Group C in Figure 3) were also used in this study to assess their effects on the polymorphic outcomes. Three different concentrations of SiO2COOH NPs ranging from 3 to 10 mg mL−1 were used; in each case, the process yielded more than 90% of the βpolymorph. These observations collectively point to the strong influence of nanoparticle additives, particularly the presence, density, and overall concentration of functional groups, on the polymorphic outcome in the spherical crystallization of glycine at near-neutral conditions. In order to interpret these results, we examine the surface chemistry of SiO2 NPs in glycine solution. The speciation curves of glycine and functionalized SiO2 NPs as a function of pH are provided in Figure 4. In the pH region 4−8, it is clear that glycine exists predominantly as zwitterions. With the addition of SiO2NH2 NPs (pKa = 9.0)22 to glycine solution, the pH increases from ∼6.1 to ∼6.5, whereas the pH drops to ∼5.9 with the addition of SiO2COOH NPs (pKa = 4.2).23 At these pH values, the functional groups on SiO2 NPs exist as cationic (SiO2NH3+) and anionic (SiO2COO−) species, respectively. On the other hand, with the addition of bare SiO2 NPs (pKa = 7.0)22 to glycine solution, the pH increases from ∼6.1 to ∼7.0, and the SiO2 NPs have both neutral and anionic hydroxyl groups on their surfaces; the relative concentration of anionic (SiO2O−) species rapidly increases at pH above 7. Further, order-of-magnitude estimates reveal that the molar ratio of glycine to the functional groups presented by silica surfaces within the emulsion drops in our experiments is ∼800−4000. These estimates are based on the various experiments with SiO2−NH2, where we have estimated immobilization density, and compare reasonably well with typical amounts of molecular additives used in previous studies, where the molar ratio of glycine to additive is typically ∼50− 2500.4,16,24−26 Therefore, based on prior literature on the effect of molecular additives on glycine polymorphism, we hypothesize that functionalized and charged nanoparticle surfaces can influence glycine polymorphism by affecting glycine−glycine
Figure 4. Speciation diagrams of (a) glycine, (b) bare SiO2 NPs, (c) SiO2NH2 NPs, and (d) SiO2COOH NPs at different pH values.
Figure 5. XRD patterns of glycine agglomerates obtained at different pH (pH: 4.0−8.0), using bare SiO2 NPs as additives. The reported pH values are those obtained after the addition of SiO2 NPs. In each experiment, 13.0 mg mL−1 of NPs were used; a mixture of α- and βforms was obtained, and the percentage amount of the α-polymorph is presented.
with the α form as the dominant polymorph (∼62%) (Figure 3); Chadwick et al. reported a similar outcome under similar experimental conditions.16 Spherical agglomerates obtained in the presence of various surface-functionalized SiO2 NPs at nearneutral conditions were also characterized by XRD (Figure 3). First, bare SiO2 NPs with hydroxyl groups on their surfaces were observed to induce crystallization of both α- and β-glycine from near-neutral glycine solution (pH = 6.1) but with the βform as the dominant polymorph (∼63%) (Figure 3). We note here that the pH increased to ∼7 after the addition of bare SiO2 NPs to the glycine solution. A similar result (β-form ∼62%) 2458
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Figure 6. FESEM images of spherical agglomerates of glycine crystallized from near-neutral glycine solution (pH of ∼6.1) in the presence of (a−b) SiO2ImCl NPs and (c) SiO2Cl NPs. Insets of Figure 6 (panels a and c): chemical structures of SiO2ImCl and SiO2Cl NPs. (d) XRD patterns of glycine crystals of β-polymorph constituting these spherical agglomerates. In all experiments, 10 mg mL−1 NPs was used.
electrostatically interact with glycine zwitterions and reduce the concentration of molecular clusters of glycine, which in turn affects the polymorphic behavior by retarding the nucleation and growth of α-glycine. Second, several molecular additives that can stabilize metastable polymorphs have been reported in the literature.28 For example, methanol can act as an additive that selectively crystallizes β-glycine.5 In this case, it has been proposed that methanol selectively interacts with and inhibits both {010} and {01̅0} faces of α-glycine but only one {010} face of the β-form, thus leading to the crystallization of the latter form. In analogous fashion, hydrogen-bonding interactions between charged NP surfaces (with exposed NH3+, −COO−, or −O− groups) and embryonic crystallites of αglycine can potentially retard the growth of α-glycine and lead to kinetic precipitation of the β-form. To test the hypothesis that particle surface charge plays a role in polymorph selection, we conducted crystallization experiments with bare SiO2 NPs in the pH range of 4.0−4.6 (under otherwise identical conditions), where SiO2 NP surfaces are nominally uncharged, while glycine remains zwitterionic. The polymorphic characterization results from these experiments are provided in Figure 5. Interestingly, these conditions yielded crystals with α-glycine as the dominant polymorph, in marked contrast to the situation at or slightly above pH ∼7, where βglycine is the dominant polymorph. As a further striking demonstration of the role of particle surface charge in polymorph selectivity, we used two other classes of SiO2 NPs, positively charged imidazolium-modified SiO2 NPs (SiO2ImCl NPs) and negatively charged 3-chloropropyltrimethoxysilane-modified SiO2 NPs (SiO2Cl NPs), as
Figure 7. XRD patterns of glycine agglomerates obtained at an acidic pH condition (pH ∼3.0), using different types of functionalized SiO2 NPs as additives. In each experiment, 10 mg mL−1 of NPs were used, and the percentage compositions of the polymorphs (α and γ) obtained are represented.
interactions in solution, which have been shown to be crucial factors in directing polymorphic behavior and by affecting the relative growth rates of nucleated crystal interfaces. We elaborate on these hypotheses below. First, as mentioned above, glycine molecules are zwitterions at near-neutral conditions and are known to form hydrogenbonded dimers in solution.27 These hydrogen-bonded dimers are also crucial growth units in the crystal structure of α-glycine, which is composed of centrosymmetric bilayers formed by strong NH···O hydrogen-bonding interactions between cyclic hydrogen-bonded zwitterionic molecular pairs.5 Charged SiO2 NP surfaces with NH3+, O−, or −COO− groups can 2459
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it is possible to envision selective polymorphic crystallization in the confined environments of emulsions by appropriately designing the surface chemistry of nanoparticle additives.
additives for emulsion-based crystallization at near-neutral conditions (particle surface charge measurements are provided in Table S2 of the Supporting Information). As seen in Figure 6, the use of both these NPs yielded the β-form almost exclusively. As shown above, the polymorphic outcome for glycine crystals can depend on the starting pH of the aqueous glycine solutions through its influence on particle surface charge. We now show that pH can profoundly influence polymorphic outcome through its influence on the charge state of glycine, in agreement with previous literature reports. It has been suggested that in glycine solutions of high and low pH values (less than 3.8 or greater than 8.9), charged glycine species adopting the role of “self-poisoning” impurities may inhibit the growth of α-glycine, thus producing the kinetically lessfavorable γ-form of glycine whose growth is not disturbed by charged species.29 To examine this scenario, we conducted experiments at a pH of ∼3.0 with bare SiO2, SiO2NH2 and SiO2COOH NPs, and indeed obtained crystals with >70% γglycine in all cases (Figure 7). γ-Glycine exhibits a polar c axis with a fast-growing carboxylate rich (−) end and a slowgrowing amino rich (+) end in water.30 SiO2NH2 and SiO2COOH NPs which exist as cations (∼100%) and anions (6%), respectively (Figure 4), may interact with the fastgrowing carboxylate rich and slow-growing amine rich ends. However, the growth of γ-glycine along the c axis is not entirely inhibited, as at least one end of the c axis is always available for growth in either case. On the other hand, these particle additives can inhibit the growth of the α form by interacting with all four {011} faces at the c ends of α-glycine, which are locally polar, due to the exposure of both amino NH3+ and the carboxylate COO− polar groups at these faces.31 Interestingly, bare SiO2 NPs led to a modest increase in the percentage of γglycine (from 74% to 85%) (Figure 7). As these particles are charge-neutral at acidic pH (see Figue 4), they do not interact electrostatically with the polar +c or −c axis of the γ-form and, hence, cannot inhibit the growth of γ-glycine. The marginal increase in γ-glycine content could be attributed to an alternative route for suppression of α-glycine crystallization: bare SiO2 NPs may interact with C−H bonds exposed at {010} and {01̅0} faces of α-glycine through hydrogen (C−H···O) bonding, thereby inhibiting the growth of α-glycine along the b direction.5,32
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ASSOCIATED CONTENT
S Supporting Information *
Emulsion-based crystallization experiments at a pH of ∼10; detailed synthesis procedures for functionalized SiO2 NPs and their characterization; XPS; zeta potentials of as-prepared SiO2 NPs; colorimetric assay of amine density; XRD patterns of pure α, β, and γ-glycine; and size distribution of spherical agglomerates of glycine obtained under different experimental conditions. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors gratefully acknowledge research funding from the GSK-EDB Fund for Sustainable Manufacturing in Singapore and the Chemical and Pharmaceutical Engineering Programme of the Singapore−MIT Alliance. The authors also gratefully acknowledge Yuan Chuan Kee for assistance with initial experiments and numerous scientific discussions.
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REFERENCES
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CONCLUSIONS We have demonstrated the use of functionalized SiO2 NPs having various pendant functional groups as additives in emulsion-based crystallization. Spherical agglomerates are obtained from both neutral and acidic glycine solutions. Our observations reveal a strong influence of particle functionalization on polymorphic outcome at near-neutral conditions; in general, we observe that SiO2 NPs with either cationic or anionic functional groups promote the crystallization of βpolymorph from near-neutral glycine solutions. On the basis of an analysis of functional group and glycine speciation, we infer that surface charge plays an important role in influencing glycine−surface and glycine−glycine interactions and present validations of this hypothesis with nominally uncharged bare SiO2 particles, positively charged imidazolium- and negatively charged chloride-modified nanoparticles. From acidic glycine solutions with a pH of ∼3.0, agglomerates consisting of a mixture of α- and γ-glycine (with a predominance of the later) are obtained, regardless of the additives used. With this insight, 2460
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