Utilization of Surface Equilibria for Controlling Heterogeneous

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The utilization of surface equilibria for controlling heterogeneous nucleation: Making the "disappeared" polymorph of 3-aminobenzensulfonic acid “reappear” Mitulkumar A Patel, Kyle Kaplan, Simseok A Yuk, Sugandha Saboo, Kassandra Melkey, and Keith Chadwick Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b01116 • Publication Date (Web): 24 Oct 2016 Downloaded from http://pubs.acs.org on October 28, 2016

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Crystal Growth & Design

The utilization of surface equilibria for controlling heterogeneous nucleation: Making the "disappeared" polymorph of 3−aminobenzensulfonic acid “reappear”. Mitulkumar A. Patel, Kyle Kaplan, Simseok A. Yuk, Sugandha Saboo, Kassandra Melkey, and Keith Chadwick1* 1

Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana, United States.

ACS Paragon Plus Environment

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ABSTRACT The ability to control crystal form is essential for the development of materials with desired properties. The rational design of hetero-surfaces to control nucleation is one such approach. Hetero-surfaces are commonly selected based on their chemistry and/or crystallography and/or morphology. However, the hetero-surface is almost always considered to be in equilibrium with the crystallization medium during nucleation. This may lead to an inaccurate description of the epitaxial mechanisms responsible for controlling nucleation. Herein, we discuss controlling the surface equilibria of sparingly soluble crystals to control heterogeneous nucleation and crystal form. The heterogeneous crystallization of 3aminobenzensulfonic acid (3-ABSA) on seeds of 1,5-diaminonaphthalene (DAN) was investigated. The DAN crystal faces were determined to be in a non-equilibrium state upon suspension in an aqueous solution of 3-ABSA, resulting in significant changes in surface morphology. Controlling the kinetics of surface equilibration resulted in DAN seeds with differing surface morphologies. Seeding with these different surface morphologies led to the nucleation of different crystal forms of 3-ABSA, including the so-called “disappeared” polymorph, Form I. Utilizing surface equilibria to control heterogeneous nucleation represents a highly novel approach to controlling crystal form.


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INTRODUCTION

The use of hetero-surfaces has become a popular approach for the discovery of crystal forms and controlling crystallization.1-7 Heterogeneous crystallization has many potential applications: (1) controlling crystal morphology and size, polymorphism and nucleation kinetics, (2) improving physical stability and crystal purity/quality, and (3) chiral separation.6,

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In

particular, controlling polymorphism using this approach is of significant interest due to differing physicochemical properties polymorphs can exhibit. There are many different classes of heterosurface described in the literature for controlling polymorphism; inorganic and organic crystals, polymers, silanized glasses, and self-assembly monolayers.8,

11, 13-16

These different surfaces

control nucleation through a wide range of epitaxial mechanisms. Epitaxy is defined as the process by which a surface (generally crystalline) orientates pre-nucleation clusters into a structure that resembles a specific crystalline form.17, 18 Epitaxial mechanisms are governed by the chemistry and/or crystallography and/or morphology of the surface.19-21 There are numerous examples in the literature demonstrating the ability of a heterosurface to control polymorphism. For instance, the work of Matzger and co-workers showed that the polymorphism of various organic compounds such as tolfenamic acid and flufenamic acid could be controlled using polymers with varying chemistry.8,

22

Similarly, work from the

Myerson group showed that self-assembly monolayers (SAM) with different end terminal functional groups, are a useful tool for controlling polymorphism.23 Finally, crystalline heterogeneous surfaces have also been shown to direct molecular self-assembly through two or three dimensional epitaxial mechanisms. For example, Ward and co-workers successfully crystallized different polymorphs of various organic compounds by using lattice matching and ledge directed epitaxy.18, 24 However, in many cases the hetero-surfaces were selected without


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prior knowledge of how the surface properties would influence the epitaxial mechanism. Furthermore, studies that do utilize rational selection criteria for engineering hetero-surfaces almost always assume that the hetero-surface is in equilibrium with the crystallization media during nucleation.17, 19 However, if the surface were not to be in equilibrium during nucleation, ex-situ characterization of the surface prior to crystallization occurring would not be sufficient for predicting the epitaxial mechanism and the resulting crystal form. There are a limited number of studies that provide evidence to support the fact that a hetero-surface is not in equilibrium during crystallization and that changes in surface properties influence the epitaxial mechanism.25, 26

For example, CaCO3 crystallization on SAMs with or without the presence of a dissolved

polyelectrolyte (poly(acrylic acid), Na salt) generated different crystal forms. Without the polyelectrolyte the SAMs nucleated calcite crystals. However, when the polyelectrolyte was added to the crystallization medium, changes to the orientation of the molecules comprising the SAM surface were observed which resulted in a favorable lattice match between the surface and the (001) crystal face of vaterite.26 These studies demonstrate the need to understand surface equilibria during heterogeneous crystallization, the potential impact on epitaxial mechanisms and potential to control crystal form by influencing surface equilibria. Developing such an understanding is necessary in order to rationally design surfaces for controlling crystal form. Herein, we demonstrate the first instance in which the surface equilibria of a poorly soluble crystalline material can be controlled in order to control nucleation and crystal form. In our study, we shall discuss the crystallization of 3-aminobenzensulfonic acid (3-ABSA) on crystals of 1,5-diaminonaphthalene (DAN). We will demonstrate that the crystal faces of DAN are in non-equilibrium state when suspended in aqueous solutions of 3-ABSA. Controlling the kinetics of equilibration of the DAN crystals in solution resulted in two different surface


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morphologies, micro-pyramids or micro-needles. Finally, it will be shown that crystallizing 3ABSA in the presence of DAN seeds with different surface morphologies resulted in the nucleation of different crystal forms, including the so-called “disappeared” Form I. In addition, for the first time the crystal structures of Form III and a newly observed hydrate shall be discussed. EXPERIMENTAL SECTION Materials. 3-aminobenzensulfonic acid (3-ABSA) and 1,5-diaminonaphthalene (DAN), with purities of >99% and >97% respectively, were purchased from Sigma-Aldrich (Saint Louis, MO). Absolute ethanol, purity >99.5%, was purchased from Fisher Scientific Inc. (Pittsburgh, PA). Ultrapure water was obtained using a Millipore ultrapure water system (Billerica, MA). Solubility determination of Form II 3-ABSA. Form II of 3-ABSA was added to 10g of water at 10 and 50 °C. The resulting slurries were stirred for 2 days in order to reach equilibrium. After which ~500 µL of solution was then decanted using a syringe (maintained at about the same temperature as that of the sample) and filtered using a 0.22 µm cellulose acetate filter. The filtrate was then analyzed by UV spectroscopy (λmax 204 nm) to determine the concentration. The solubilities of 3-ABSA in water were found to be 12.5 ± 0.3 and 32.5 ± 0.5 mg/g at 10 and 50 °C, respectively. Crystallization of DAN. Crystals of DAN were obtained by cooling crystallization. First, an ethanolic solution of DAN (10 mg/g) was prepared at 55 °C. The solution was then cooled to 10 °C and maintained at this temperature for 24 hr. After which dark purple crystals were observed. The crystals were then filtered and air dried. X-ray powdered diffraction (XRPD). Diffraction patterns were recorded using a Rigaku SmartLab (XRD 6000) diﬀractometer (The Woodlands, TX) using Bragg−Brentano


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mode. A target material made of copper was used in the X-ray tube which emits Kα radiation (λ = 0.15405 nm). Samples (~40 mg) were placed onto a glass sample holder. Diffraction data were recorded at room temperature between 5° to 40° 2θ (step size - 0.02°). Aqueous solution of 3-ABSA for crystallization and DAN treatment. A stock solution of 3-ABSA in water (32.5 mg/g – saturated at 50 °C) was prepared. For all crystallization ore treatment conditions, 5mL aliquots of the solution were syringe filtered into scintillation vials using a 0.22 µm cellulose acetate membrane filter. Solubility determination of DAN. DAN was added to 10g of 3-ABSA solution at 10 and 50 °C. The resulting slurry was stirred for 2 days in order to reach equilibrium. After which ~500 µL of solution was then decanted using a syringe (maintained at about the same temperature as that of the sample) and filtered using a 0.22 µm cellulose acetate filter. The filtrate was then analyzed by UV spectroscopy (λmax 230 nm) to determine the concentration. The thermodynamic solubilities of DAN in stirred aqueous solution of 3-ABSA were found to be 0.19 ± 0.02 and 0.73 ± 0.03 mg/g at 10 and 50 °C, respectively. Generation of different DAN surface morphologies. DAN single crystals (7.5 mg), prepared using the method outlined above, were placed into 5 mL of pure water and aqueous solutions of 3-ABSA (32.5 mg/g) at 10 and 50 °C for 5 min without stirring. The crystals were then filtered, washed with cold water to remove any residual mother liquor and air dried. In addition, the concentration of DAN dissolved in the mother liquor after 5 min was monitored by UV spectrometer and were found to be 0.07 ± 0.01 and 0.20 ± 0.03 mg/g at 10 and 50 °C, respectively. Solution composition monitoring by UV spectrometry. DAN single crystals (7.5 mg), prepared using the method outlined above, were placed into 5 mL of pure water and aqueous


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solutions of 3-ABSA (32.5 mg/g) at 10 and 50 °C for 5 min without stirring. A UV spectrometer (SI Photonics, Tuscon, AZ) was then used to determine the UV absorbance of both 3-ABSA (λmax 204 nm) and DAN (λmax 230 nm) at t = 0, 1, 3, and 5 mins. DAN surface analysis by Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR). ATR-FTIR spectra of the various DAN samples were collected using a Bruker Vertex 70 instrument (Bruker Co., Billerica, MA). The instrument was equipped with an Attenuated Total Reflectance (ATR) sampling accessory with diamond crystal and the instrument was operated using OPUS software (Bruker Co., Billerica, MA). To obtain the FTIR spectra, crystals of DAN (with or without treatment) were placed on the ATR accessory and 64 scans between 650 cm−1 and 3900 cm−1 (resolution 4 cm−1) were collected and then averaged to generate the final sample spectrum. Crystallization of Form III of 3-ABSA. The vials containing aqueous solution of 3ABSA (prepared as mentioned above, 32.5 mg/g in water) were quench cooled to 10 °C (solubility at 10 °C = 12.5 mg/g and supersaturation, σ = (C-Csat)/Csat, σ = 1.6) and held at this temperature until crystallization was observed. The crystals were then filtered and air dried. Crystallization of hydrate of 3-ABSA. The vials containing 5 mL of aqueous solution of 3-ABSA (prepared as mentioned above) were quench cooled to 10 °C and held isothermally for 7 mins (σ = 1.6), after which 7.5 mg of untreated DAN or micro-pyramid surface DAN seeds were added and the vials maintained at 10 °C until crystallization was observed. The crystals were then filtered and air dried. Crystallization of Form I of 3-ABSA. 7.5 mg of untreated DAN seeds were added to the vials containing 5 mL of aqueous solution of 3-ABSA (prepared as mentioned above held at 50 °C) prior to cooling. After which the vials were quench cooled (σ = 1.6) and held 10 °C until


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crystallization was observed. Alternatively, 7.5 mg of micro-needle surface DAN seeds were added after the final supersaturation was achieved. The crystals from all vials were filtered and air dried. Scanning Electron Microscopy (SEM). Images of the crystals were collected using a Nova NanoSEM (FEI Co., Hillsboro, OR) scanning electron microscope. The samples were coated with Platinum (~2 nm thickness) using a Cressington sputter coater (208HR, Cressington Scientific Instruments, Watford, United Kingdom) and images taken at an accelerating voltage of 5 kV. Optical Surface Profiling (OSP). Samples were coated with Platinum (~2 nm thickness) using a Cressington sputter coater. Crystal surfaces were analyzed using a Contour GT-K profilometer (Bruker, Berlin, Germany). Images were collected at a magnification of 50x and processed using the Vision64 software (Bruker, Billerica, MA, USA).

RESULTS AND DISCUSSION 3-ABSA is commonly referred as metanilic acid and is a precursor in the manufacturing of various azo dyes and sulfa-drugs.27, 28 To date there are three known polymorphs referred to as Forms I, II, III. In 1965, Hall and Maslen crystallized Form I from water and determined the full crystal structure.29 It was later determined to be a metastable form. In 2005, Bernstein et al. repeated the Hall and Maslen experiments, however, they were only able to crystallize a new polymorph which they denoted as Form II. This was determined to be the stable polymorph.30 To confirm this observation, we slurried Form II in water at 10 and 50 °C for 2 days and then analyzed the crystals using XRPD (Figure S1). The results showed that the 3-ABSA crystals remained Form II, indicating that Form II is the thermodynamically stable form over this


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temperature range. In addition, Bernstein et al. were also able to crystallize a third polymorph, Form III, from water using the structurally similar additive m-toluenesulfonic acid. After performing a large set of experiments they noted that they were unable to crystallize Form I and declared it to be a so-called “disappeared” polymorph.30 The objective of this study was to design a surface which would result in the heterogeneous nucleation of Form I. Unseeded crystallization of 3-ABSA from Water First it was necessary to verify that Form I could not be easily obtained from aqueous solutions using a similar approach to that of Hall and Maslen.29 Cooling crystallizations were performed from supersaturated aqueous solutions (σ = 1.6). Crystallization was observed to occur within 1 – 2 hours after supersaturation was achieved. The crystals exhibited a needle-like morphology (Figure 1). The XRPD data were identical to the diffraction data of Form III provided by Bernstein et al. in their 2005 study (Figure S2).30 We hypothesize that Bernstein et al. required an additive to crystallize Form III from water whereas in our study it was possible to obtain it from pure water because of differences in the crystallization methods. They utilized slow cooling versus the quench cooling approach in this study. To our knowledge the full crystal structure of Form III has not been previously determined. Therefore, we performed single crystal X-ray diffraction on appropriate single crystals. The data collected was that of a unique crystal structure of 3-ABSA and confirms that diffraction data collected by Bernstein and co-workers is that of a third polymorph. Analysis of the crystal structure of Form III showed that 3-ABSA is present as a zwitterionic form. In both Forms I and II 3-ABSA is also present in zwitterionic form. In Form III, the 3-ABSA molecules pack into a sheet like structure. In each sheet the neighboring molecules interact through two hydrogen bonds between the amine (N-H) and sulfonic acid (S=O) groups, as shown in Figure


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2A. The N–H⋯O hydrogen bond distances were found to be 2.037, 1.958, 1.949 and 2.146 Å as shown in the Figure 2A. As the molecules exist as zwitterions there are also electrostatic interactions between the amine and sulfonic acid groups. These 2D sheets interact with each other through a hydrogen bond also between the amine (N-H) and sulfonic acid (S=O) from each sheet (Figure 2B). The N–H⋯O hydrogen bond distance between the sheets was found to be 2.146 Å. Effect of surface equilibria on DAN surface morphology Having established that Form I could not be crystallized from pure water under the crystallization conditions utilized in this study, the next step was to select a hetero-surface that would template its nucleation. Previous research has shown that metastable polymorphs may be crystallized on hetero-surfaces with similar functional groups to those on the compound undergoing crystallization.2,

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The metastable polymorph (Form II) of acetaminophen was

successfully crystallized using 4-aminophenylacetic acid as the surface, which has the same amine group as acetaminophen.19 Similarly, metastable Form II of vanillin was crystallized by using polymers with the same functional groups as vanillin.2 In these studies it was hypothesized that the similarity in chemistry allows for strong intermolecular interactions between the solute and the surface which increases adsorption, creating a high interfacial supersaturation which may favor nucleation of a metastable polymorph. In addition, another selection criteria was that the hetero-surface needed to be either insoluble or sparingly soluble in water. Based on these criteria DAN was selected as the hetero-surface (Figure 3). Before performing any crystallization experiments, it was first necessary to understand the effect, in any, of surface equilibria on the morphology of DAN in aqueous solutions of 3ABSA. Any change would influence the epitaxial mechanism by which 3-ABSA nucleates on


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DAN. First, single crystals of DAN were obtained by cooling crystallization from ethanol (Figure S3). After which they were then added to aqueous solutions of 3-ABSA, at 10 and 50 °C, for 5 min. The 10 °C condition represented a supersaturated Form II 3-ABSA solution, while the 50 °C condition represented a saturated Form II 3-ABSA solution. The crystals were then collected and the crystal faces of DAN analyzed by SEM and 3D surface morphology profiler to determine if any changes to the surface morphology had occurred. Figures 4A and B are representative images of the surface morphology of the DAN crystal faces obtained from pure ethanol. The DAN crystal faces exhibited minimal surface roughness at the µm scale. However, when the DAN crystals were suspended in the 3-ABSA solution at 10 °C for 5 minutes, “micropyramids” were observed on the surface of the crystals (Figures 4C and D). Finally, suspending the DAN crystals in the 3-ABSA solution at 50 °C for 5 minutes resulted in the formation of “micro-needles” on the surface of the crystals (Figures 4E and F). To determine if the observed changes in surface morphology were due to the 3-ABSA or water, the experiments were repeated in pure water at 10 and 50 °C. In both case, the DAN crystals did not show either “micropyramid” or “micro-needle” morphologies (Figure S4A-D). To confirm the composition of these micro-structures on the DAN crystal surfaces at both temperatures was DAN and not 3-ABSA we utilized several analytical approaches. First, we monitored the concentration of 3-ABSA and DAN in solution as a function of time. Figures 5A and B show that at both 10 and 50 °C there is no change in the absorbance for 3-ABSA at the λmax, indicating no change in 3-ABSA concentration over the course of the experiment. However, for DAN, at both 10 and 50 °C, there is an increase in absorbance at λmax after 1 min indicating the partial dissolution of DAN (Figure 5A and B).


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Additionally, we performed an ATR-FTIR study of the “micro-pyramid” and “microneedle” DAN surface morphologies to further confirm that these surface modifications are as a result of changes in DAN surface equilibrium and not deposition of 3-ABSA. The penetrative depth of the ATR-FTIR beam is ~0.5 - 2 µm31, 32 and while the thickness of the crystals used in this study were at least 50 µm. This ensured only the chemical composition at the surface of the DAN crystals was being analyzed. The ATR-FTIR spectra of both “micro-pyramid” and “microneedle” DAN surfaces are identical to the spectrum of the untreated DAN crystals (Figure 6). Finally, XRPD analysis of the both the “micro-pyramid” and “micro-needle” DAN crystals, as well as untreated DAN crystals were performed. For all samples all diffraction peaks corresponded with diffraction peaks of the only known crystal form of DAN (Figure S5). Based on these analyses, it was clear that the composition of “micro-pyramid” and “micro-needle” morphologies are DAN and not 3-ABSA. These results suggest that the DAN crystal faces were in a non-equilibrium state when suspended in the 3SBSA solutions and that the changes in surface morphology occurred due to the DAN crystals attempting to minimize their interfacial free energy. These surface modifications were made possible as DAN is sparingly soluble when placed in aqueous solutions of 3-ABSA (0.07 ± 0.01 mg/g at 10 °C and 0.20 ± 0.03 mg/g at 50 °C). We hypothesize that the difference in temperature between the two solutions alters the kinetics of the DAN crystals reaching an equilibrium morphology leading to the formation of “micro-pyramids” or “microneedles” on the DAN crystal faces. After obtaining DAN seeds with different surface morphologies, we wanted to see if these differences could be used to control which crystal form of 3-ABSA heterogeneously crystallized. Previous research has shown that epitaxial mechanisms can be altered by the


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morphology of the surface.33 Vilmali et al. studied the nucleation of mefenamic acid crystallization, the surface with square nanopores allowed the nucleation of metastable Form II, while the surface with spherical nanopores led to nucleation of stable Form I. Based on this notion, we hypothesized that the epitaxial mechanism by which 3-ABSA nucleated on DAN would be different depending on whether seeds with surface “micro-pyramids” or “microneedles” were used and lead to a change in crystal form. Crystallization of 3-ABSA with “micro-pyramid” DAN surfaces When 3-ABSA was crystallized in the presence of “micro-pyramid” DAN seeds large needle-like crystals (~90 mg from 5 mL crystallization medium) were obtained (Figure 7). Comparing the XRPD data of these crystals with the diffraction patterns of the known three polymorphs suggested that a new crystal form had nucleated. Single crystal X-ray structure determination of these crystals revealed that a previously unreported hydrate of 3-ABSA had heterogeneous crystallized. The stoichiometry of the hydrate is 1.5:1 water to 3-ABSA molecules. Analysis of the structure shows that the 3-ABSA molecules pack in such a way as to form 2D sheets. In each sheet neighboring molecules interact through two hydrogen bonds between the amine (N-H) and sulfonic acid (S=O) groups as shown in Figure 6A. The N–H⋯O hydrogen bond distances were found to be 1.895 and 1.958 Å (Figure 8A). The sheets interact with each other through four types of hydrogen bond: (1) two between the sulfonic acid (S=O) and water (O-H) molecules, with hydrogen bond distances of 1.972 and 1.930 Å, (2) N–H⋯O between the amine and water (1.813 Å), and (3) between two water molecules (1.895 Å) (Figure 8B). The water molecules occupy positions in the channels that run between the sheets of 3ABSA molecules (Figure 8B). Crystallization of 3-ABSA with “micro-needle” DAN surfaces


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When 3-ABSA was crystallized in the presence of “micro-needles” DAN seeds, it also resulted in large needle-like crystals (~90 mg from 5 mL crystallization medium) as shown in Figure 9. XRPD analysis of these crystals showed that the elusive Form I had crystallized (Figure S6). In order to ensure that any DAN dissolved into the 3-ABSA solution has no impact on nucleation and the crystal form selection was as a result of the difference in surface morphology of the DAN seeds, we performed 3-ABSA crystallizations in presence of dissolved DAN. Based on the thermodynamic solubility data, aqueous solutions of 3-ABSA containing 0.19 and 0.73 mg/g of DAN were prepared and cooling crystallization were then performed. The results of the crystallizations showed that at both these concentrations, 3-ABSA crystallizes as Form III (Figure S7). These results suggested that the “micro-pyramid” surface morphology of DAN resulted in an epitaxial mechanism leading to the nucleation of the hydrate. On the other hand, the “micro-needle” surface morphology of DAN gave an epitaxial mechanism which led to nucleation of Form I. We hypothesize that the two different DAN surface morphologies result in two different ledge-directed epitaxial mechanisms. The angle between the crystal faces comprising the ledge and the step has been shown to have a significant impact on the heterogeneous nucleation mechanism.17,

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The ledge orders the pre-nucleation cluster into a

structure that resembles two crystal faces of a particular crystal form that share an angular match with the ledge and step. The ledges created by the “micro-needles” and ‘micro-pyramids” may provide a better angular match with pre-nucleation clusters that resemble Form I and the hydrate respectively. However, as both the micro-pyramids and micro-needles are densely populated on the DAN surface, verification and/or determination of the exact epitaxial mechanisms has not


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been possible to date. We are currently trying to develop new techniques for studying epitaxial mechanisms on morphologically complex surfaces. Controlling surface equilibria during crystallization Finally, we investigated that whether the surface equilibria of the DAN seeds could be controlled in-situ during the crystallization process, rather than by pretreating them, and still retain the same control over crystal form. Untreated DAN seeds were added to the supersaturated 3-ABSA solution (at 10 °C) and maintained at the same temperature until it crystallized. The XRPD data confirmed that the hydrated form nucleated (Figure S8). If the untreated DAN seeds were added to the 3-ABSA solution (at 50 °C) and then the solution was quench cooled to 10 °C, Form I crystallized (Figure S8). We confirmed that the same changes in DAN surface morphology occurred in-situ by SEM analysis of the seeds after the crystallizations were complete (Figure S9). The results showed the formation of “micro-pyramids” when the seeds were added to the crystallizer after supersaturation was generated and “micro-needles” when the seeds were added to the crystallizer prior to supersaturating the solution. These experiments demonstrated that controlling the crystal form of 3-ABSA using DAN did not require the need to generate the different DAN surface morphologies ex-situ. That the changes in DAN surface morphology necessary to template the nucleation of the different crystal forms occurred on a shorter time scale than the crystallization process. CONCLUSIONS In conclusion, this study showed the first instance where controlling the surface equilibria of a poorly soluble crystalline hetero-surface can be used to control crystal form. DAN crystal surfaces were found to be in a non-equilibrium state when suspended in 3-ABSA aqueous solutions. The surface undergoes rearrangement in order to minimize the interfacial free energy.


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By controlling the temperature at which equilibration of the DAN surfaces occurred it was possible to produce seeds with distinct surface morphologies. Seeding supersaturated solutions of 3-ABSA with these different DAN surface morphologies led to the selective crystallization of either a previously unreported hydrate or the so-called ‘disappeared’ polymorph, Form I. We are currently developing new methods to study the exact epitaxial mechanisms leading to the observed crystallization behavior. This study demonstrates the importance of understanding the surface equilibria of hetero-surfaces in a crystallization medium and the impact it may have on epitaxial mechanisms and the ability to rationally design surfaces for controlling nucleation and crystal form. The concept of controlling the kinetics of surface equilibration in order to produce different surface properties represents a new approach to designing surfaces for crystal form selection. ASSOCIATED CONTENT Supporting Information It covers materials and methods along with additional data. This material is available free of charge via the Internet at http://pubs.acs.org. Accession Codes CCDC 1486374 and 1486375 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. AUTHOR INFORMATION Corresponding Author


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*To whom correspondence should be addressed: Keith Chadwick, Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana-47906, USA. Phone: 765-496-2775, Fax: 765-494-6545. E-mail: [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ACKNOWLEDGMENT This research is support in part by pharma foundation (PhRMA) grant. In addition, we are thankful to Dr. Zeller, department of chemistry, at Purdue University, for his kind help in single crystal structure determination. REFERENCES (1) Shah, U. V.; Amberg, C.; Diao, Y.; Yang, Z.; Heng, J. Y., Heterogeneous nucleants for crystallogenesis and bioseparation. Curr. Opin. Chem. Eng. 2015, 8, 69-75. (2) Kavuru, P.; Grebinoski, S. J.; Patel, M. A.; Wojtas, L.; Chadwick, K., Polymorphism of vanillin revisited: the discovery and selective crystallization of a rare crystal structure. CrystEngComm 2016, 18, 1118-1122. (3) Sakamoto, T.; Nishimura, Y.; Kato, T., Tuning of morphology and polymorphs of carbonate/polymer hybrids using photoreactive polymer templates. CrystEngComm 2015, 17, 6947-6954. (4) Pfund, L. Y.; Price, C. P.; Frick, J. J.; Matzger, A. J., Controlling Pharmaceutical Crystallization with Designed Polymeric Heteronuclei. J. Am. Chem. Soc. 2015, 137, 871-875. (5) Tan, L.; Davis, R. M.; Myerson, A. S.; Trout, B. L., Control of heterogeneous nucleation via rationally designed biocompatible polymer surfaces with nanoscale features. Cryst. Growth Des. 2015, 15, 2176-2186. (6) Quon, J. L.; Chadwick, K.; Wood, G. P.; Sheu, I.; Brettmann, B. K.; Myerson, A. S.; Trout, B. L., Templated nucleation of acetaminophen on spherical excipient agglomerates. Langmuir 2013, 29, 3292-3300. (7) Giri, G.; Li, R.; Smilgies, D.-M.; Li, E. Q.; Diao, Y.; Lenn, K. M.; Chiu, M.; Lin, D. W.; Allen, R.; Reinspach, J.; Mannsfeld, S. C. B.; Thoroddsen, S. T.; Clancy, P.; Bao, Z.; Amassian, A., One-dimensional self-confinement promotes polymorph selection in large-area organic semiconductor thin films. Nat. Commun. 2014, 5, 3573. (8) López-Mejías, V.; Kampf, J. W.; Matzger, A. J., Nonamorphism in flufenamic acid and a new record for a polymorphic compound with solved structures. J. Am. Chem. Soc. 2012, 134, 9872-9875.


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(9) Chen, J.; Myerson, A. S., Pasteur revisited: chiral separation by crystallization on selfassembled monolayers. CrystEngComm 2012, 14, 8326-8329. (10) Ehmann, H. M.; Werzer, O., Surface mediated structures: stabilization of metastable polymorphs on the example of paracetamol. Cryst. Growth Des. 2014, 14, 3680–3684. (11) Kim, K.; Lee, I. s.; Centrone, A.; Hatton, T. A.; Myerson, A. S., Formation of nanosized organic molecular crystals on engineered surfaces. J. Am. Chem. Soc. 2009, 131, 18212-18213. (12) Krattiger, P.; Nassif, N.; Völkel, A.; Mastai, Y.; Wennemers, H.; Cölfen, H., Investigation of active crystal morphogenesis peptide sequences from peptide libraries by crystallization on peptide functionalized beads. Colloids Surf. Physicochem. Eng. Aspects 2010, 354, 218-225. (13) Diao, Y.; Myerson, A. S.; Hatton, T. A.; Trout, B. L., Surface design for controlled crystallization: The role of surface chemistry and nanoscale pores in heterogeneous nucleation. Langmuir 2011, 27, 5324-5334. (14) Tsekova, D. S.; Williams, D. R.; Heng, J. Y., Effect of surface chemistry of novel templates on crystallization of proteins. Chem. Eng. Sci. 2012, 77, 201-206. (15) Diao, Y.; Helgeson, M. E.; Siam, Z. A.; Doyle, P. S.; Myerson, A. S.; Hatton, T. A.; Trout, B. L., Nucleation under Soft Confinement: Role of Polymer–Solute Interactions. Cryst. Growth Des. 2011, 12, 508-517. (16) Cantor, B., Heterogeneous nucleation and adsorption. Phil. Trans. R. Soc. Lond. A 2003, 361, 409-417. (17) Chadwick, K.; Chen, J.; Myerson, A. S.; Trout, B. L., Toward the rational design of crystalline surfaces for heteroepitaxy: role of molecular functionality. Cryst. Growth Des. 2012, 12, 1159-1166. (18) Bonafede, S. J.; Ward, M. D., Selective nucleation and growth of an organic polymorph by ledge-directed epitaxy on a molecular crystal substrate. J. Am. Chem. Soc. 1995, 117, 78537861. (19) Chadwick, K.; Myerson, A.; Trout, B., Polymorphic control by heterogeneous nucleation-A new method for selecting crystalline substrates. CrystEngComm 2011, 13, 66256627. (20) Diao, Y.; Harada, T.; Myerson, A. S.; Hatton, T. A.; Trout, B. L., The role of nanopore shape in surface-induced crystallization. Nat. Mater. 2011, 10, 867-871. (21) Arlin, J.-B.; Price, L. S.; Price, S. L.; Florence, A. J., A strategy for producing predicted polymorphs: catemeric carbamazepine form V. Chem. Commun. 2011, 47, 7074-7076. (22) López-Mejías, V.; Kampf, J. W.; Matzger, A. J., Polymer-induced heteronucleation of tolfenamic acid: structural investigation of a pentamorph. J. Am. Chem. Soc. 2009, 131, 45544555. (23) Kim, K.; Centrone, A.; Hatton, T. A.; Myerson, A. S., Polymorphism control of nanosized glycine crystals on engineered surfaces. CrystEngComm 2011, 13, 1127-1131. (24) Carter, P. W.; Ward, M. D., Directing polymorph selectivity during nucleation of anthranilic acid on molecular substrates. J. Am. Chem. Soc. 1994, 116, 769-770. (25) Du, X.; Fan, R.; Wang, X.; Yu, G.; Qiang, L.; Wang, P.; Gao, S.; Yang, Y., Cooperative Crystallization of Chiral Heterometallic Indium(III)–Potassium(I) Metal–Organic Frameworks as Photosensitizers in Luminescence Sensors and Dye-Sensitized Solar Cells. Cryst. Growth Des. 2016, 16, 1737-1745.


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(26) Balz, M.; Therese, H. A.; Li, J.; Gutmann, J. S.; Kappl, M.; Nasdala, L.; Hofmeister, W.; Butt, H. J.; Tremel, W., Crystallization of Vaterite Nanowires by the Cooperative Interaction of Tailor‐Made Nucleation Surfaces and Polyelectrolytes. Adv. Funct. Mater. 2005, 15, 683-688. (27) Entry 5927. Merck Index. Merck Whitehouse Station, NJ 2006, 1023. (28) Monograph ID-M7268, Metanilic Acid. Merck Index (2013). https://www.rsc.org/MerckIndex/monograph/m7268/metanilic%20acid?q=authorize (29) Hall, S.; Maslen, E., The crystal structure of metanilic acid. Acta Crystallogr. 1965, 18, 301-306. (30) Rubin-Preminger, J.; Bernstein, J., 3-Aminobenzenesulfonic acid: a disappearing polymorph. Cryst. Growth Des. 2005, 5, 1343-1349. (31) Thermo Fisher Scientific Inc., Thermo Scientific Smart iTR™ Attenuated Total Reflectance (ATR) sampling accessory. In ed.; Thermo Fisher Scientific Inc: https://static.thermoscientific.com/images/D10775~.pdf, 2008. (32) Patel, M. A.; AbouGhaly, M. H. H.; Schryer-Praga, J. V.; Chadwick, K., The effect of ionotropic gelation residence time on alginate cross-linking and properties. Carbohydr. Polym. 2016, 155, 362-371. (33) López-Mejías, V.; Myerson, A. S.; Trout, B. L., Geometric Design of Heterogeneous Nucleation Sites on Biocompatible Surfaces. Cryst. Growth Des. 2013, 13, 3835-3841.


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“For Table of Contents Use Only”

Manuscript title The utilization of surface equilibria for controlling heterogeneous nucleation: Making the "disappeared" polymorph of 3−aminobenzensulfonic acid “reappear”. Author list Mitulkumar A. Patel, Kyle Kaplan, Simseok A. Yuk, Sugandha Saboo, Kassandra Melkey, and Keith Chadwick TOC graphic

Synopsis This work describes the application of controlling surface equilibria to control heterogeneous nucleation and crystal form. The utilzation of hetero-surfaces in a non-equilibrium state with the crystallization media allows for control of their surface morphology. Using this approach we have been successful in crystallizing the so called ‘disappeared’ polymorph of 3aminobenzenesulfonic acid.


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Figure 1. Optical images of 3-ABSA crystals obtained from homogeneous solution in absence of DAN from pure water. 104x79mm (300 x 300 DPI)



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Figure 2. Crystal structures of 3-ABSA Form III. (A) Showing interaction within a sheet of molecules, and (B) showing the interactions between the sheets of molecules. 322x113mm (300 x 300 DPI)


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Figure 3. Chemical structures of (A) 3-ABSA and (B) DAN. Circled area shows the presence of aromatic amine groups in both the structures. 108x45mm (300 x 300 DPI)



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Figure 4. (A) and (B) are SEM image and Surface morphology profile of DAN crystals surface without any treatment, respectively. (C) and (D) are SEM image and Surface morphology profile of DAN crystal surface after treatment with 3-ABSA solution at 10 °C, respectively. (E) and (F) are SEM image and Surface morphology profile of DAN crystal surface after treatment with 3-ABSA solution at 50 °C, respectively. Colour variations in images were due to minor tilt on the sample holder. 139x162mm (300 x 300 DPI)


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Figure 5. UV absorbance measurements of 3-ABSA (λmax 204 nm) and DAN (λmax 230 nm) at t = 0, 1, 3, and 5 mins, DAN crystals were added at t = 0 mins. (A) 10 °C and (B) 50 °C. 233x109mm (96 x 96 DPI)



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Figure 6. ATR-FTIR spectra of (A) DAN without and treatment, (B) DAN crystals with “micro-pyramid” like surfaces obtained by treatment with 3-ABSA solution at 10 °C, and (C) DAN crystals with “micro-needle” like surfaces obtained by treatment with 3-ABSA solution at 50 °C. 228x124mm (300 x 300 DPI)


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Figure 7. Optical images of 3-ABSA crystals obtained heterogeneously in the presence of DAN seeds having micro-pyramid like surface morphology. 103x77mm (300 x 300 DPI)



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Figure 8. Crystal structures of 3-ABSA hydrate. (A) Showing interaction within a sheet of molecules, and (B) showing the interactions between the sheets of molecules. 262x165mm (300 x 300 DPI)


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Figure 9. Optical images of 3-ABSA crystals obtained heterogeneously in the presence of DAN seeds pretreated with 3-ABSA at 50 °C. 103x78mm (300 x 300 DPI)


Utilization of Surface Equilibria for Controlling Heterogeneous

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