Article

pubs.acs.org/crystal

Geometric Design of Heterogeneous Nucleation Sites on

Biocompatible Surfaces
Vilmalí López-Mejías, Allan S. Myerson, and Bernhardt L. Trout*
Department of Chemical Engineering, Massachusetts Institute of Technology, 50 Ames Street, Cambridge, Massachusetts 02139,
United States
*
S Supporting Information

ABSTRACT: Biocompatible polymer surfaces imprinted with nanopores of

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various geometries were utilized as heteronucleants during crystallizations of

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mefenamic acid (MA). MA, a nonsteroidal anti-inflammatory drug (NSAID) that

possesses two structurally characterized polymorphs, is utilized as a model
compound. By combining geometric nanoconfinement and favorable surface−
solute interactions, it was possible to influence the nucleation kinetics of this system
and harvest the metastable form of MA, MA form II, on the square nanopores. An
exploration of the relationship between the preferred orientation found by powder
X-ray diffraction (PXRD) and the angular matching based on the intrinsic angles,
determined by the predicted morphology, was used to provide insights into the
mechanism for the observed nucleation enhancement and polymorph selection.
The results presented here might lead to a rational design strategy of surfaces to
control nucleation and, therefore, polymorphism.

T here are many challenges that arise during the

manufacturing of crystalline materials; one of these is
controlling the product quality. Since crystallization is often
used as the last step in the production of the final product as a
solid form, it is of considerable importance to design
crystallization processes that control not only purity but other
properties of the solid, such as size distribution, morphology,
and polymorphism, to ensure the product quality and therefore
its performance. The latter task is complicated by the fact that
there are many compounds exhibiting multiple crystalline
phases that differ in the arrangement and/or conformations of
molecules within a crystal lattice. In recent years, hetero-
nucleation, the process by which molecules aggregate to form a
crystal nuclei at a solid−liquid interface, has emerged as a
valuable method to control nucleation and therefore poly-
morphism. However, the current fundamental understanding of
this process does not provide a rational design of hetero-
nucleants. Previous reports have implied the role of the surface
in liquid−solid phase transformations, as well as the impact of
the surface morphology on the crystallization outcome.1−5
Recent investigations have shown that crystal nucleation under
porous confinement can alter nucleation kinetics, phase
stabilization, polymorphism, and crystal orientation.6−17 On
smooth polymer surfaces, polymer-induced heteronucleation
has allowed access to an unprecedented number of structurally
characterized polymorphs based on complementary interac-
tions at the polymer−crystal interface.18−21 At the computa-
tional level, there have been studies which relate crystal
nucleation to the geometry of the surface.16 Moreover, at the
experimental level, the presence of a nanoimprinted polymer
surface has been demonstrated to alter nucleation kinetics in a
solution.22 These investigations provided the first insights into a
rational design of a surface to control nuclei formation and,
therefore, polymorphism. By combining geometric nano-
confinement and favorable surface-solute interactions, it should
be possible to influence not only nucleation but also crystal size
distribution, crystallization yield, and morphology.
In the present investigation, a range of nanopore geometries
were employed as heteronucleants, choosing pore geometries
which contain angles that were encountered most often among
the major faces of the calculated morphology in structurally
similar compounds. The geometries explored here are
imprinted on a biocompatible polymer surface, presenting a
high degree of hydrophilicity. This strategy aims to facilitate
nuclei formation by providing favorable molecular interactions,
as well as angular matching between the surface and the
crystallizing molecules in solution. By providing kinetic
resolution at the corners of the nucleating nanopore, it might
be possible to provide access to specific polymorphs of a given
compound if the crystal structures are known. Similarly, it
might be possible to produce a never observed solid form for a
compound by screening different angles or shapes, choosing
either from a general library or from targeted guesses based on
structural resemblance. The first possibility is explored in this
investigation, and the second one would be the focus of future
experiments.
Mefenamic acid (MA, Figure 1) is a potent nonsteroidal anti-
inflammatory drug (NSAID), which possesses two structurally
characterized polymorphs by single crystal X-ray diffraction.
Elucidation of the first crystal structure (form I) occurred in
Received: June 28, 2013
Published: July 3, 2013

© 2013 American Chemical Society 3835 dx.doi.org/10.1021/cg400975b | Cryst. Growth Des. 2013, 13, 3835−3841
Crystal Growth & Design Article

Figure 1. Molecular structures of NSAIDs mefenamic acid (MA), tolfenamic acid (TA), flufenamic acid (FFA), and other structural analogues
employed in the morphology prediction calculation and determination of the most common intrinsic angles among these structurally similar
molecules. The numbers of structurally characterized forms for each molecular structure presenting polymorphism are in parentheses.

1976,23 and nearly thirty years later the structure of a second

metastable form (form II) showing disorder was reported.24
The study of the crystallization behavior in this compound is of
particular interest since many members of the femanic acid
series present polymorphism, including flufenamic acid (FFA,
Figure 1), the most polymorphic compound known with eight
structurally characterized forms,21 and tolfenamic acid (TA,
Figure 1),18 another highly polymorphic compound that
possesses five structurally characterized forms.
In order to design the nanopore geometries investigated
here, the predicted morphology based on the crystal structures
of MA, its analogues, and polymorphs thereof was calculated
using BFDH prediction methods.25 In this investigation, we
have assumed that structurally similar molecules will give rise to
isostructural or structurally similar crystal forms, therefore the Figure 2. Histogram of number count of intrinsic angles (deg) in MA
intrinsic angles among these should be similar. The single and its structural analogues that fall within a ± 5° range.
crystals structures were retrieved from the Cambridge
Crystallographic Database (CSD). The reference codes for hypothesize that for a given crystal, some of the major faces for
the structures used in the morphology prediction can be found the predicted morphology will be manifested, even as a minor
in the Supporting Information. The major facets of these face experimentally. Therefore, even a coarse morphology
predicted morphologies were identified and used in the prediction method such as BFDH can be used to determine the
determination of the intrinsic angle between (adjacent) major most common intrinsic angles in a predictive way and guide the
crystal facets. It was observed that 60°, 70°, 80°, and 90° were design of the geometric nanopores.
the most commonly observed intrinsic angles among these In order to imprint nanopores on a surface containing the
structurally similar compounds (Figure 2 and the Supporting 60° and 80° angles, it was necessary to form parallelograms
Information). Given the assumptions of BFDH, the predicted with complementary angles of 120° and 100°, respectively.
angles are only at best a guide and should not be taken as Since these complementary angles were not observed in the
quantitative predictions of actual experimental morphologies. investigation of the most commonly observed intrinsic angles
Nevertheless, the intrinsic angles among major faces (Figure 2 and the Supporting Information), they should have
determined via BFDH prediction methods, will not vary minimal effect on the nucleation kinetics of this system. Three
significantly based on morphology. As long as at least two of different nanopatterns were developed for this investigation:
the adjacent major facets appear, even as minor faces, these the type A pattern containing nanopores with 60° and 120°
angles will be present in the observed morphology. We angles, the type B pattern containing nanopores with 80° and
3836 dx.doi.org/10.1021/cg400975b | Cryst. Growth Des. 2013, 13, 3835−3841
Crystal Growth & Design Article

Figure 3. AFM images of (a) type A, (b) type B, (c) type C, and (d) spherical patterns imprinted on hydroxylpropylmethyl cellulose (HPMC), as
well as (e) a smooth HPMC surface.

Figure 4. AFM images of type C (square nanopores) on a HPMC surface: (a) 5 × 5 μm area prior to exposure to crystallization solvent and heat,
(b) 1 × 1 μm and (c) 5 × 5 μm areas after exposure to anisole at 65 °C in the absence of solute, and (d) 1 × 1 μm and (e) 5 × 5 μm areas
containing MA form II crystals deposited by cooling crystallization method using anisole as a solvent.

100° angles, and the type C pattern containing nanopores of
only 90° angles (Figure 3, panels a−c). For each pattern, a 4”
silicon master comprised of pillars in the shape of the
parallelogram was developed through interference lithography
(made in collaboration with the Nanostructures Laboratory at
MIT). A silicon master containing angles of 70° and 110° was
not fabricated. The fabrication of the silicon masters is time-
consuming and expensive. At the onset of this investigation, it
was decided to work only with three masters. Silicon masters
containing the 60°, 80°, and 90° angles were chosen because
we hypothesize that these were the most effective for our
system of interest, MA, according to our preliminary angle-
matching analysis. An additional control surface with spherical
pores of 100 nm was produced by patterning a 2” quartz disk
(Figure 3d). The disk was treated with O2 plasma to enrich the
surface with hydroxyl groups, then 200 μL of a 5% (w/w)
colloidal silica particles in water were spread and allowed to
self-assemble by slow evaporation. The self-assembled SiO2 and
the quartz slide were then sintered at 800 °C in a high
temperature oven. The absence of nanopores (a smooth
surface, Figure 3e) and the absence of a polymer surface were
also tested as controls.
3837
The nanopatterned surfaces were then imprinted onto a
biocompatible polymer film by solvent casting a 10% (w/w)
solution of hydroxylpropylmethyl cellulose (HPMC) in a 1:1
mixture of EtOH:H2O on top of the mold. Since it was
observed that the majority of the faces covering the largest
percent (%) area in the predicted morphology presented
hydrogen bonding opportunities, this highly hydrophilic
polymer was chosen for the study (Supporting Information).
The films were peeled off the mold and utilized as
heteronucleants after drying at 70 °C for 2 h in a vacuum
oven. The smooth polymer surface was developed by following
a similar solvent casting and drying procedure in the presence
of an unpatterned 4” silicon wafer.
Biocompatible organic solvents were screened in order to
find an appropriate crystallization solvent. Ethanol, acetonitrile,
ethyl acetate, heptane, anisole, and cumene were tested. When
heated to 65 °C in the absence of solute, only films exposed to
anisole and cumene retained the imprinted pattern on the
surface as confirmed by AFM imaging (Figure 4, panels a−c
and the Supporting Information). The solubility at equilibrium
of MA in both anisole and cumene was determined at three
different temperatures (30, 45, and 65 °C). The solubility of
MA in anisole was determined to be 4.6 mg/mL at 30 °C, 5.8
dx.doi.org/10.1021/cg400975b | Cryst. Growth Des. 2013, 13, 3835−3841
Crystal Growth & Design
mg/mL at 45 °C, and 29.5 mg/mL at 65 °C. The solubility of
MA in cumene was determined to be 0.6 mg/mL at 30 °C,
which is not high enough to proceed with experiments using
this solvent. Therefore, only anisole was utilized as a solvent in
this investigation because it does not dissolve the patterns
imprinted on these films and provides reasonable solubility
under the experimental conditions utilized. A supersaturation of
1.5× was determined to be the optimal supersaturation level in
order to minimize homogeneous/bulk nucleation while
maintaining reasonable induction times. It is at this low
supersaturation that heterogeneous nucleation can be truly
explored; at higher supersaturation homogeneous/bulk nucle-
ation dominates the crystallization events with little effect from
the surface. At this supersaturation level, relatively large spatial
fluctuations are likely needed for nucleation to occur. It was
assumed that these fluctuations occur at a scale larger than the
>5 nm radius of curvature resulting after the polymer
imprinting process. A 7 mg/mL solution of MA in anisole
was delivered (750 μL) into 78 (1 mL) vials and crashed cooled
from 65 to 30 °C to achieve a supersaturation of 1.5×.
The crystal nucleation induction time for the vials was
monitored continuously with an inverted microscope in order
to determine the average induction time of nucleation. Six
different samples were prepared: bulk samples without polymer
films, samples with polymer films imprinted with types A−C,
and spheres, as well as polymer films without any pattern. For
each type of samples, 13 vials were prepared and loaded onto
the temperature controlled block. The heating and cooling
procedures were repeated to provide statistically significant data
for 78 samples. The samples were crash-cooled from 65 to 30
°C to achieve a 1.5× supersaturated solution. The onset of each
crystallization event was detected optically; when the first
crystal was observed, the frame number was recorded. Frames
were taken at 5 min intervals. The average nucleation induction
time, τ, was determined from a statistical analysis of the
induction time data based on the knowledge that nucleation
follows a Poisson distribution, P(t) = e(‑t/τ), where P is the
probability that no nucleation event occurs within time, t2. The
total number of vials as a function of time was also monitored
during the experiment.
Nucleation induction time experiments revealed that at the
same supersaturation level, the presence of type C or square
nanopores are able to enhance the nucleation kinetics 5× faster
than in the absence of the polymer (Table 1 and the
Table 1. Summary of Average Nucleation Induction Times
for MA Crystals Nucleated on the Various Nano-Imprinted
Polymer Surfaces
heteronucleant type induction time (τ, h) error (h) linearity (h)
type A (60° and 120°) 9.6 0.1
type B (80° and 100°) 13.6 0.3
type C (90°) 8.8 0.1
no polymer 42.7 0.8
no pattern 15.8 0.3
spheres 36.5 0.7
Supporting Information). The patterns of types A and B
provide nucleation induction enhancement but to a lesser
extent when compared to the type C pattern. An even lesser
effect was observed for the samples in which crystals grew in
the absence of a pattern (smooth surface). The presence of
spherical pores seems to have minimal effect on the average
Article
induction time when compared to the results observed in the
absence of the polymer. Additionally, a higher percentage of
vials crystallized in the presence of a polymer surface (95−
65%), with the exception of the spherical pattern, in which the
number of vials crystallized as a function of time is slightly less
(40%) than in the absence of a polymer (55%) (Supporting
Information).
The surface of each polymer film after crystallization
occurred was studied through atomic force microscopy
(AFM). It was observed that on the surfaces patterned with
geometrical nanopores, the pores contained a significant
number of the crystals that nucleated on the surface (Figure
4, panels d−e, and the Supporting Information). Specifically, it
was observed that the crystals mostly form at the corners of the
nanopores (Figure 4, panels d−e, and the Supporting
Information). Generally, for the surfaces used as controls, the
spherical nanopores and the smooth polymer surfaces, the
number of crystals covering the examined area were fewer than
those of the experimental nanopatterned surfaces.
Further examination of each polymer surface was performed
using powder X-ray diffraction (PXRD). Diffractograms for
each of the surfaces examined during this investigation present
different and highly discernible preferred orientation (PO); this
is indicative of different intermolecular interactions occurring at
the polymer−crystal interface during nucleation (Figure 5). A
high density of crystals aligned along a specific crystallographic
plane (or face) will produce a high intensity peak or a preferred
orientation peak in the resulting PXRD, which indicates that
the majority of the molecules aggregate and further nucleate
from this specific face and allow for Bragg’s Law to be satisfied.
When crystals that grew in the absence of a surface were
examined through PXRD, the resulting diffractogram presented
only a small degree of PO along the (100) face of MA form I
(Figure 5a). For the type A pattern, only one single major
reflection was observed, corresponding to crystals of MA form I
nucleating along the (100) face with a high degree of PO
(Figure 5b). For the type B pattern, two major reflections were
observed, corresponding also to MA form I crystals nucleating
from the (100) and the (02-2) faces (Figure 5c). When the
type C pattern was utilized during this crystallization
experiment, the presence of MA form II was established by
examination of the diffractogram, which indicated the presence
of three major reflections corresponding to PO along the (01-
1), (02-1), and (012) faces (Figure 5d). On the other hand,
when the crystals nucleated in the absence of nanopores, the
crystals examined display a high degree of PO along the slow
growing (100) face of form I MA (Figure 5b). The molecular
arrangement for all of the PO faces found by PXRD when the
different nanopores were utilized as heteronucleants is shown
in Figure 6. Examination of these PO faces indicate that each of
0.99
these faces provides hydrogen bonding between the hetero-
0.98
nucleant and the molecules in contact with the PO face. This
0.99
finding supports the notion that favorable surface−solute
0.99
interactions are required to effectively enhance the nucleation
0.96
induction time.
0.95
The dimensions of the crystals nucleated on the nanopores
are on the nanometer range, therefore, the use of optical
microscopy (hot-stage microscopy) or differential scanning
calorimetry (DSC) to determine phase purity were unsuccess-
ful, due to the limit of detection of these techniques. When the
samples were examined by Raman spectroscopy, three major
regions (1605−1570, 1250−1035, and 1000−770 cm−1) aided
the identification of the polymorphs (see the Supporting
3838 dx.doi.org/10.1021/cg400975b | Cryst. Growth Des. 2013, 13, 3835−3841
Crystal Growth & Design Article

Figure 5. PXRD of MA crystals nucleated in the presence and absence of a heteronucleant. (a) Crystals that grew in the absence of a surface do not
express a high degree of preferred orientation (black ●) relative to the simulated PXRD of MA form I (red star). (b) MA form I crystals grown on a
type A nanopore and smooth surface (both represented by the PXRD under the black ●) align along the (100) face with a high degree of preferred
orientation. (c) MA form I crystals grown on type B nanopore (black ●) align along the (100) and the (02-2) faces with a high degree of preferred
orientation, and (d) MA form II crystals selectively grown on a type C nanopore (dark circle) align along the (01-1), (02-1), and (012) faces with a
high degree of preferred orientation relative to the simulated PXRD of MA form II (orange hexagon).

Figure 6. Observed molecular arrangement of MA crystals as determined by the PO faces on the diffractogram for each heteronucleant type. (a) MA
form I crystals aligned along the (100) face, possibly forming hydrogen bonds with the HPMC polymer surface in both the absence of pores (a
smooth surface) and the presence of the type A pattern. (b) MA form I crystals aligned along the (100) and (02-2) faces possibly forming hydrogen
bonds with the HPMC polymer surface imprinted with the type B pattern. (c) MA form II crystals aligned along the (01-1), (02-1), and (012) faces,
possibly forming hydrogen bonds with the HPMC polymer surface imprinted with the type C pattern.

Information). Crystals that grew in the absence of a polymer, in types A and B correspond to those of the thermodynamically
the presence of a smooth polymer surface, a spherical polymer stable form, MA form I, whereas crystals that grew in the
surface, or an imprinted polymer surface with the patterns of presence of an imprinted polymer surface with the type C
3839 dx.doi.org/10.1021/cg400975b | Cryst. Growth Des. 2013, 13, 3835−3841
Crystal Growth & Design
Figure 7. Illustrations of the relationship between the PO face found by PXRD and the angular matching based on the angles present on the (a−c)
type A, (d) type B, and (e−f) type C patterns.
pattern correspond to those of the metastable form, MA form
II. It is worth mentioning that the quality of the Raman spectra
is not good, due to the presence of the polymer film and the
size of the nanocrystals. Nevertheless, unique Raman shifts
corresponding to either MA form I or MA form II are observed,
in addition to large and broad Raman shifts that correspond to
the polymer heteronucleant. The determination of the phase
purity by Raman spectroscopy rules out the possibility that
some crystals might be oriented in directions that do not
diffract (aligned along space-group defined systematic absen-
ces) and supports our observation that only polymers
imprinted with the type C pattern provide phase selectivity
for MA form II, in contrast to the other crystallization
conditions used in this investigation, which only provide access
to the MA form I.
In order to determine the role of the pores during nucleation
and phase selection of MA crystal forms, a possible relationship
between the PO found by PXRD and the angular matching
based on the intrinsic angles determined by the predicted
morphology was investigated. The PO faces found by PXRD
were modeled, and faces that were perpendicular to the PO face
were determined from these; faces that formed intrinsic angles
that match the nanopore geometry utilized during the
crystallization experiment were identified. To facilitate the
search, only those faces that contributed significant area to the
predicted morphology were examined. For the type A pattern,
there are three possible combinations of faces laying almost
perpendicular to the PO face, the (100) face, and containing an
angle that closely matches that of the nanopore imprinted on
this surface (Figure 7, panels a−c). The first intrinsic angle of
56.0° is formed between the (0-11) face and the (0-10) face
(Figure 7a). The second intrinsic angle of 56.1° is formed
between the (010) face and the (01-1) face (Figure 7b). The
third intrinsic angle of 63.2° is formed between the (010) face
and the (−101) face (Figure 7c). The angular matching
between the nanopore and the intrinsic angle explain the
decrease in the nucleation induction time when this type of
nanopore is utilized relative to crystallizations happening in the
3840
Article
absence of a heteronucleant. For the type B pattern, there is just
one possible combination of faces laying almost perpendicular
to the PO face, the (02-2) face, and containing an angle that
closely matches that of the nanopore imprinted on this surface.
This combination is that of the (100) face and the (0-10) face
which forms an intrinsic angle of 80.4° (Figure 7d). A second
PO face is presented in the diffractogram of MA crystals
nucleated on the type B pattern (Figure 5c). This corresponds
to the (100) face, which is one of the slow-growing faces in MA
form I (49.7% of the total facet area in the predicted
morphology); therefore, it is possible that the crystals might
present this orientation regardless of the imprinted nanopore
present on the surface. This might also explain the greater
number of possible combinations of faces that would lead to
the PO along the (100) face when a type A pattern is utilized.
For this reason, only the combination between the (100) face
and the (0-10) face providing an intrinsic angle of 80.4° should
be responsible for the decrease in the nucleation induction time
observed when the type B pattern is used as a heteronucleant.
For the type C pattern, there are two possible combinations of
faces laying almost perpendicular to the PO faces observed in
the diffractogram of MA form II and containing an angle that
matches that of the square nanopore (Figure 7, panels e−f).
The first combination involves PO along the (02-1) face to
which the (001) and the (100) faces are almost perpendicular
and make an intrinsic angle of 84.5° (Figure 7e). The second
combination presents PO along the (012) face to which the
(01-1) and the (100) faces are almost perpendicular and make
an intrinsic angle of 83.6° (Figure 7f). The third PO face
present in the diffractogram of MA form II crystals grown on a
type C pattern, the (01−1) face, is one of the slow-growing
faces in the predicted morphology (13.4% of the total facet
area). Therefore, it is also possible that MA form II crystals
might present this orientation regardless of the imprinted
nanopore present on the surface. This would explain the
absence of an intrinsic angle matching this PO face. Although
these possible combinations do not provide an intrinsic angle
that exactly matches the 90° angle present in the square
dx.doi.org/10.1021/cg400975b | Cryst. Growth Des. 2013, 13, 3835−3841
Crystal Growth & Design Article

nanopores imprinted on this surface, they provide a close
enough match to the pore geometry. Moreover, the faster
crystallization kinetics provided by the type C pattern when
compared to any of the other crystallization conditions might
also be responsible for the appearance of the metastable form,
form II, of MA.
The use of geometrically imprinted biocompatible surfaces as
heteronucleants has successfully established that nanopores can
alter the nucleation kinetics, depending on the angle. It was
observed that in the presence of type C or square nanopores,
nucleation occurred faster than during any of the other
crystallization conditions utilized in this investigation, possibly
due to the angle matching between the intrinsic angle present
in the growing crystals and the angle at the corners of the
nanopore. Furthermore, the appearance of the metastable form,
MA form II, was observed only in the presence of the square
nanopores, which indicated that, under this crystallization
condition, the type C pore is able to provide kinetic control
over the formation of this polymorph versus the thermody-
namically more stable form, MA form I. Additionally, all of the
PO faces determined by PXRD show hydrogen-bonding
interactions demonstrating that favorable surface−solute
interactions are required to promote crystal nucleation. Finally,
this investigation revealed that a relationship exists between the
pore angle and the PO faces found in the crystals grown on this
nanopore; this relationship might be responsible for affecting
the nucleation kinetics and the phase selection through the
alteration of the orientation order at the nanometer scale in the
corners of the nanoindentation.
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■
*
ASSOCIATED CONTENT
S Supporting Information
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Experimental details, morphology prediction, nucleation
induction time measurement, Raman spectroscopy, powder
X-ray diffraction analysis, atomic force microscopy images, and
angular-matching analysis. This material is available free of
charge via the Internet at http://pubs.acs.org.

■ AUTHOR INFORMATION
Corresponding Author
*E-mail: trout@mit.edu.
Notes
The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS
We thank the Novartis-MIT Center for Continuous Manu-
facturing for the continuous funding of the research presented
here. We also thank Dow Chemical Company and Dow Wolff
Cellulosic for kindly providing Methocel LV free of charge and,
finally, Dr. Tim Savas and the Nanostructures Laboratory at
MIT for the fabrication of the types A−C silicon masters.

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