Crystal Habit Modification of Metronidazole by Supramolecular Gels with Complementary Functionality

Article abstract of DOI:10.1021/acs.cgd.1c00659

A series of bis(urea) compounds with complementary functional groups similar to the pharmaceutical drug metronidazole and a structural isomer isometronidazole have been synthesized. The gelation properties of these compounds were studied in various solvent/solvent mixtures. The mechanical strength of the isomeric gelators was compared using rheology, and the morphologies of the xerogels were analyzed by scanning electron microscopy. These gels were used as media for metronidazole crystallization resulting in a marked habit modification of the metronidazole crystals in the drug-mimicking gels. However, crystallization in the nonmimetic isomeric gel resulted in morphologies similar to the solution state. These results indicate that the drug-mimetic gels interact with the surface of the drug crystal giving rise to new morphologies.

Full text of DOI:10.1021/acs.cgd.1c00659

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Article
Crystal Habit Modification of Metronidazole by Supramolecular Gels
with Complementary Functionality
Published as part of a Crystal Growth and Design virtual special issue on Nonclassical Crystallization in
Synthetic and Natural Systems
Sreejith Sudhakaran Jayabhavan, Jonathan W. Steed,* and Krishna K. Damodaran*
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ABSTRACT: A series of bis(urea) compounds with complementary
functional groups similar to the pharmaceutical drug metronidazole and a
structural isomer isometronidazole have been synthesized. The gelation
properties of these compounds were studied in various solvent/solvent
mixtures. The mechanical strength of the isomeric gelators was compared
using rheology, and the morphologies of the xerogels were analyzed by
scanning electron microscopy. These gels were used as media for
metronidazole crystallization resulting in a marked habit modification of
the metronidazole crystals in the drug-mimicking gels. However,
crystallization in the nonmimetic isomeric gel resulted in morphologies
similar to the solution state. These results indicate that the drug-mimetic gels interact with the surface of the drug crystal giving rise
to new morphologies.
can enable the gelator molecules to interact with the substrate,
offering the possibility of epitaxial crystal growth and hence
favoring metastable or hard-to-nucleate solid forms of
molecular crystals including pharmaceutically relevant com-
pounds.9−11,19−27
INTRODUCTION
■
Supramolecular gels based on low molecular weight gelators
(LMWGs)1−7 have become highly topical in the last two
decades owing to their intriguing potential applications in drug
delivery, separation techniques, as templates for inorganic and
polymer materials, and as media for crystallization. Crystal-
lization in gel media dates back at least as far as the discovery
of the well-known “Liesegang rings”, which represent periodic
precipitation in gels.8 Gel phase crystallization represents an
example of orthogonal self-assembly of the crystals and gel
network.9 The gel medium limits convection and prevents
sedimentation by providing continuous, diffusion-limited
growth,10,11 as well as influencing the nucleation behavior of
the crystals.12 LMWGs have been used to crystallize inorganic
substances, proteins, and active pharmaceutical ingre-
dients,13−18 and the gel environment can influence factors
such as crystal habit and polymorphism.9 LMWGs can provide
various advantages as media for crystal growth, such as facile
synthesis, long shelf life, and easy modification of functional
groups. There have been a few recent reports of crystallization
within LMWG,9 for example, calcite crystallization in a
bis(urea) gel19 and crystallization of aspirin, caffeine,
indomethacin and carbamazepine in toluene-based tetraamide
organogels.20 We have shown that LMWGs can be used as a
medium for crystallizing inorganic complexes and reported the
selective crystallization of one particular form (form I) of a
copper(II) isonicotinate-N-oxide complex.21 We have shown
that designing gelators that mimic the crystallization substrate
Previous work on gel phase crystallization using crystal-
lization substrate-mimicking gelators has resulted in the crystal
habit modification of isoniazid28 and cisplatin.29 Crystallization
in bis(urea) LMWGs tagged with functional groups (Scheme
1) similar to a highly polymorphic drug precursor, ROY,
resulted in the selective crystallization of the metastable R
polymorph in contrast to the Y form obtained in solution.10
Recently, drug-mimicking LMWGs have been used to prevent
concomitant crystallization.30 Thus, structural similarity
between the crystallization substrate and the gelator is
potentially significant in gel phase crystallization. In the
present work, we have designed bis(urea) compounds that
mimic the antibiotic metronidazole as well as isomeric control
gelators in order to study the outcome of the drug-mimetic gel
phase crystallization of this drug substance.
Received: June 8, 2021
Revised: July 8, 2021
https://doi.org/10.1021/acs.cgd.1c00659
Cryst. Growth Des. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

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the role of the position of functional groups on gelation and gel
phase crystallization in LMWGs.
Scheme 1. Gel Phase Crystallization in Drug-Mimetic and
Nonmimetic Gels
a
EXPERIMENTAL SECTION
■
Materials and Methods. All the starting materials and reagents
were commercially available (Sigma-Aldrich and TCI Europe) and
used as supplied except for metronidazole, which was purchased from
1
Accel Pharmtech, USA. H and 13C NMR spectra (Figures S1−S12,
see Supporting Information) were recorded on a Bruker AVANCE
400 spectrometer, and scanning electron microscopy (SEM) was
performed on a Leo Supra 25 microscope. Single-crystal X-ray
diffraction (SCXRD) and powder X-ray diffraction (PXRD) were
carried out using a Bruker D8 venture and PANalytical instrument.
Synthesis. The bis(urea) compounds of metronidazole (1−3) and
isometronidazole (4−6) were synthesized following a general
procedure by reacting the amine precursors with the corresponding
diisocyanates. The amine precursors of metronidazole and isome-
tronidazole were synthesized as described below.
Synthesis of 1-(2-Bromoethyl)-2-methyl-5-nitro-1H-imidazole
(7). Compound 7 was synthesized by slightly modifying the reported
procedure.43 Bromine solution (1.6 mL, 32.2 mmol) was added to a
stirred solution of triphenylphosphine (8.4 g, 32.1 mmol) in DCM
(100 mL) at 0 °C, followed by the dropwise addition of triethylamine
(4.5 mL, 32.0 mmol). Metronidazole (5.0 g, 29.2 mmol) was added in
portion to the above solution and was equilibrated to room
temperature after 10 min. The mixture was stirred for 30 min, and
the excess bromine was quenched with a saturated solution of
aqueous sodium thiosulfate (10.0 mL). Water (50.0 mL) was added
to the mixture, and the organic phase was separated and treated with
40.0 mL of 1.0 M HCl. The organic phase was discarded, and the
aqueous layer was extracted with DCM (3 × 30 mL) to remove the
excess triphenylphosphine oxide impurities. The solution was treated
with 2.0 M sodium hydroxide solution to precipitate the product,
which was extracted with DCM (3 × 40 mL), dried over sodium
sulfate, and evaporated in a rotary vapor to yield the product as a
yellow solid. Yield: 78.0%. 1H NMR (400 MHz, chloroform-d) δ 7.97
(s, 1H), 4.67 (t, J = 6.2 Hz, 2H), 3.69 (t, J = 6.2 Hz, 2H), 2.57 (s,
3H). 13C{1H} NMR (100 MHz, chloroform-d) δ 151.12, 138.24,
133.51, 47.40, 29.53, 14.81. HRMS (APCI): calcd for C6H9N3O2BrN
[M + H]+, 233.9873; found, 233.9862.
a
Red lines represent drug-mimicking functional groups, and the green
lines indicate random functional groups. Specific interactions between
the gel fiber and the drug in the mimetic case can give rise to changes
in morphology and polymorphic form.
Metronidazole, a nitroimidazole antibiotic, is used to treat
periodontal disease and shows activity against anaerobic
protozoa and bacteria.31−34 There are two polymorphs
reported for this drug in the Cambridge Structural Database35
(form I, CSD refcode MNIMET)36 and (form II, CSD refcode
MNIMET01). The solid forms of metronidazole are an area of
interest as a result of its poor tableting properties. Di Martino
et al. have demonstrated that the crystal habit of metronidazole
is influenced by both the solvent polarity index and the
crystallization method.37 This prompted us to study gel phase
crystallization of metronidazole using drug-mimicking com-
pounds as gelators. However, designing LMWGs with specified
properties and structure is challenging, and LMWGs are often
discovered by serendipity. This is because the structure and
properties of the supramolecular gels rely primarily on the
geometry and spatial arrangement of the building blocks and
also the nature of intermolecular interactions.38,39 The gel−
solute interactions can potentially affect both nucleation and
crystal growth rates in a supramolecular gel phase crystal-
lization.40 Thus, the spatial arrangement of the functional
groups and gelator aggregation mode are both of interest in
supramolecular gel phase crystallization. We have designed
gelators based on the bis(urea) backbone with a comple-
mentary functional group similar to metronidazole and
isometronidazole. The urea motif chosen is well-known to
form α-tapes resulting in fibrils that could align the drug-
derived functional groups as a locally ordered array on the
surface of the gel fibers (Scheme 1).3,41,42 The resulting
LMWGs are anticipated to have a fibrous surface that
chemically matches the crystallization substrate,10 which offers
the possibility of epitaxial crystal growth.9 We have selected
structural isomers as the complementary functional groups to
analyze the effect of positional isomers on gelation in LMWGs.
In this work, we report the gelation and gel phase
crystallization in LMWGs based on derivatives of both
metronidazole and its structural isomer isometronidazole.
Comparison of the gelation abilities of metronidazole and
isometronidazole bis(urea) compounds will enable us to study
Synthesis of 1-(2-Azidoethyl)-2-methyl-5-nitro-1H-imidazole43
(8). Sodium azide (1.25 g, 19.8 mmol) was added in portions to a
solution of compound 7 (3.0 g, 12.8 mmol) in 40.0 mL of DMF, and
the mixture was stirred at 60 °C for 22 h. The solvent DMF was
evaporated, and 40 mL of water was added. The mixture was extracted
with DCM (3 × 40 mL), and the organic parts were combined, dried
over sodium sulfate, and evaporated to obtain the product as a
yellowish powder. Yield: 99.0%. 1H NMR (400 MHz, chloroform-d) δ
7.98 (s, 1H), 4.44 (dd, J = 6.0, 5.0 Hz, 2H), 3.78 (t, J = 6.1 Hz, 2H),
2.54 (s, 3H). 13C{1H} NMR (100 MHz, chloroform-d) δ 151.33,
138.29, 133.42, 50.98, 45.57, 14.57. HRMS (APCI): calcd. for
C6H9N6O2 [M + H]+, 197.0781; found, 197.0776.
Synthesis of 2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethan-1-
amine44 (9). Compound 8 (5.8 g, 29.6 mmol) was dissolved in a
mixture of 60.0 mL of THF and 7.5 mL of water and was treated with
triphenylphosphine (16.3 g, 62.2 mmol). The mixture was stirred at
room temperature for 15 h and was concentrated (∼10.0 mL). The
mixture was treated with 2.0 M HCl (20.0 mL) and was washed with
DCM (3 × 30 mL) to remove the impurities. The aqueous layer was
evaporated to obtain a white powder, which was washed with a
methanol/DCM mixture (1:9, v/v) to yield amine dihydrochloride
(9·2HCl). The crude product was recrystallized from acidic DMF
1
solution. Yield: 73.0%. H NMR (400 MHz, DMSO-d6) δ 8.57 (s,
3H), 8.37 (s, 1H), 4.62 (t, J = 6.6 Hz, 2H), 3.30−3.17 (m, 2H), 2.61
(s, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 150.43, 137.79,
129.16, 42.98, 37.28, 12.93. HRMS (APCI): calcd for C6H10N4O2Na
[M + H]+, 171.0877; found, 171.0876.
Synthesis of 1-(2-Bromoethyl)-2-methyl-4-nitro-1H-imidazole45
(10). A solution of 2-methyl-4-nitro-1H-imidazole (5.0 g, 39.3 mmol),
potassium carbonate (13.5 g, 97.6 mmol), and 1,2-dibromoethane
B
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(17.0 mL, 196.5 mmol) was prepared in 50.0 mL of DMF, and the
mixture was stirred overnight at room temperature. The solution was
evaporated, and 40.0 mL of water was added and extracted with DCM
(3 × 30 mL). The organic layers were combined and evaporated to
dryness. The crude product was obtained as a yellow-white solid,
which was purified by column chromatography (eluent: DCM with
133.06, 132.24, 126.11, 46.52, 40.81, 38.72, 24.29, 14.65, 14.00.
HRMS (APCI): calcd for C35H46N10O6Na [M + Na] +, 725.3494;
found, 725.3473.
Synthesis of 1,1′-(Hexane-1,6-diyl)bis(3-(2-(2-methyl-4-nitro-1H-
imidazol-1-yl)ethyl)urea) (4). The precipitate was then washed with
ethyl acetate to obtain the pure product as a white powder. Yield:
1
1
79.0%. H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 2H), 5.94 (t, J =
methanol gradient, 0−0.5%). Yield: 65.0%. H NMR (chloroform-d,
5.8 Hz, 4H), 4.01 (t, J = 5.7 Hz, 4H), 3.37−3.29 (m, 4H), 2.92 (q, J =
6.5 Hz, 4H), 2.31 (s, 6H), 1.30 (m, 4H), 1.18 (m, 4H). 13C{1H}
NMR (100 MHz, DMSO-d6) δ 157.85, 145.34, 145.30, 122.27, 46.78,
39.50, 39.08, 29.88, 26.03, 12.45. HRMS (APCI): calcd for
C20H32N10O6Na [M + Na]+, 531.2398; found, 531.2400.
Synthesis of 1,1′-(1,3-Phenylenebis(propane-2,2-diyl))bis(3-(2-
(2-methyl-4-nitro-1H-imidazol-1-yl)ethyl)urea) (5). The crude com-
pound was purified by washing with diethyl ether and ethyl acetate.
Yield: 79.0%. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 2H), 7.27 (s,
1H), 7.22−7.09 (m, 1H), 7.11−6.89 (m, 2H), 6.28 (s, 2H), 5.91 (t, J
= 6.0 Hz, 2H), 3.98 (t, J = 5.8 Hz, 4H), 3.34−3.27 (m, 4H), 2.32 (s,
6H), 1.47 (s, 12H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 156.84,
148.16, 145.33, 145.30, 127.22, 122.30, 122.23, 121.19, 54.23, 46.81,
39.08, 29.85, 12.52. HRMS (APCI): calcd for C26H36N10O6Na [M +
Na]+, 607.2711; found, 607.2711.
Synthesis of 1,1′-(Methylenebis(2,6-diethyl-4,1-phenylene))bis(3-
(2-(2-methyl-4-nitro-1H-imidazol-1-yl)ethyl)-urea) (6). Purification
was performed by washing the crude compound with dichloro-
methane to yield a white powder. Yield: 80.0%. 1H NMR (400 MHz,
DMSO-d6) δ 8.18 (s, 2H), 7.39 (s, 2H), 6.92 (s, 4H), 6.26 (m, 2H),
4.04 (t, J = 5.8 Hz, 4H), 3.78 (s, 2H), 3.48−3.37 (m, 4H), 2.44−2.36
(m, 8H), 2.35 (s, 6H), 1.02 (t, J = 7.5 Hz, 12H). 13C{1H} NMR (100
MHz, DMSO-d6) δ 157.07, 145.75, 145.68, 142.46, 139.50, 132.91,
126.63, 122.98, 47.35, 41.28, 24.76, 24.30, 15.05, 13.10. HRMS
(APCI): calcd for C35H46N10O6Na [M + Na]+, 725.3494; found,
725.3459.
Synthesis of Isometronidazole (2-(2-Methyl-4-nitro-1H-imidazol-
1-yl)ethan-1-ol) (14). A solution of 2-methyl-4-nitro-1H-imidazole
(0.30 g, 2.4 mmol), potassium carbonate (0.97 g, 7.9 mmol),
bromoethanol (830 μL, 11.8 mmol), and potassium iodide (0.39 g,
2.4 mmol) was added to DMF (20.0 mL) in a round bottomed flask,
and the mixture was stirred overnight at room temperature. The
solvent was evaporated and dried, the mixture was purified by column
chromatography in DCM using a methanol gradient (0.0−0.5%), and
the product was recrystallized from ethanol/diethyl ether. Yield:
81.0%. 1H NMR (400 MHz, methanol-d4) δ 8.08 (s, 1H), 4.15−4.08
(m, 2H), 3.87−3.80 (m, 2H), 2.45 (s, 3H). 13C{1H} NMR (100
MHz, methanol-d4) δ 145.96, 145.48, 121.00, 60.32, 49.17, 11.48.
HRMS (APCI): calcd for C6H9N3O3Na [M + H]+, 194.0536; found,
194.0537.
400 MHz) δ 7.77 (s, 1H), 4.36 (t, J = 6.1 Hz, 2H, 3.64 (t, J = 6.1 Hz,
2H), 2.47 (s, 3H). 13C{1H} NMR (100 MHz, chloroform-d) δ
146.83, 144.97, 119.62, 48.32, 29.21, 13.33. HRMS (APCI): calcd for
C6H8N3O2BrNa [M + Na]+, 255.9692; found, 255.9693.
Synthesis of 1-(2-Azidoethyl)-2-methyl-4-nitro-1H-imidazole
(11). The reaction procedure was similar to compound 8. Compound
10 (3.2 g, 13.7 mmol), sodium azide (1.3 g, 20.5 mmol), and 40.0 mL
of DMF. Yield: 98.0%. 1H NMR (400 MHz, chloroform-d) δ 7.76 (s,
1H), 4.08 (t, J = 6.1 Hz, 2H), 3.73 (t, J = 6.1 Hz, 2H), 2.45 (s, 3H).
13C{1H} NMR (100 MHz, chloroform-d) δ 146.75, 145.04, 119.80,
50.86, 46.12, 13.16. HRMS (APCI): calcd for C6H8N6O2Na [M +
Na]+, 219.0601; found, 219.0598.
Synthesis of 2-(2-Methyl-4-nitro-1H-imidazol-1-yl)ethan-1-
amine44 (12). The reaction procedure was similar to compound 9.
Compound 11 (2.25 g, 11.5 mmol), triphenylphosphine (6.17 g, 23.6
mmol), and THF/water (20/2.5 mL). The amine was recrystallized as
a hydrochloride salt in acidic ethanol solution (12·HCl). Yield: 73.0%.
1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.37 (s, 3H), 4.32 (t,
J = 6.1 Hz, 2H), 3.25 (t, J = 6.1 Hz, 2H), 2.40 (s, 3H). 13C{1H} NMR
(100 MHz, DMSO-d6) δ 145.59, 145.50, 122.36, 43.69, 38.28, 12.76.
HRMS (APCI): calcd for C6H10N4O2Na [M + Na]+, 193.0696;
found, 193.0692.
Synthesis of Bis(3,5-diethyl-4-isocyanatophenyl)methane (13).
The bis(isocyanate) was synthesized according to a reported
procedure.46 Yield: 95.0%. 1H NMR (400 MHz, chloroform-d) δ
6.87 (s, 4H), 3.85 (s, 2H), 2.65 (q, J = 7.6 Hz, 8H), 1.22 (t, J = 7.6
Hz, 12H). 13C{1H} NMR (100 MHz, chloroform-d) δ 138.91,
138.49, 127.96, 126.94, 41.12, 25.70, 14.24.
General Procedure for the Synthesis of Bis(urea) Compounds.
The amine hydrochloride (2.1 equiv) was dissolved in chloroform by
adding triethylamine (4.0 equiv) at room temperature. A solution of
the corresponding diisocyanate (1.0 equiv) was added dropwise to the
above mixture and was refluxed overnight under a nitrogen
atmosphere. The precipitate formed was filtered and stirred with
saturated sodium bicarbonate solution for 24 h. The mixture was
filtered, and the residue was washed with a copious amount of water
and dried to isolate the product.
Synthesis of 1,1′-(Hexane-1,6-diyl)bis(3-(2-(2-methyl-5-nitro-1H-
imidazol-1-yl)ethyl)urea) (1). The crude compound was recrystal-
1
lized from ethanol. Yield: 75.0%. H NMR (400 MHz, DMSO-d6) δ
Gelation Details. Gelation Test. In a standard 7.0 mL vial (ID =
15.0 mm), an appropriate amount of the gelator and 1.0 mL of
suitable solvent were added, and the vial was sealed. The mixture was
then sonicated and heated until a clear solution was obtained. The
solution was left undisturbed for gelation, and a vial-inversion test was
performed to confirm gelation.
8.00 (s, 2H), 6.01−5.90 (m, 4H), 4.29 (t, J = 5.7 Hz, 4H), 3.37−3.28
(m, 4H), 2.90 (q, J = 6.4 Hz, 4H), 2.38 (s, 6H), 1.29 (m, 4H), 1.24−
1.15 (m, 4H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 157.23,
150.88, 137.82, 132.50, 45.73, 38.55, 38.21, 29.31, 25.46, 13.12.
HRMS (APCI): calcd for C20H32N10O6Na [M + Na]+, 531.2398;
found, 531.2403.
Minimum Gel Concentration (MGC). The gel was prepared
following the above procedure by dissolving the compounds in 1.0
mL of solvent. An additional amount of the solvent was added in
portions, and the gelation process was repeated until a trace amount
of the solvent was observed on the top of the gel. The excess solvent
was removed, and MGC of the gelator was determined by calculating
the weight percent of the compound.
Tgel Experiment. The appropriate amount of the gelator was taken
in a standard 7.0 mL vial, and 1.0 mL of solvent was added. The
mixture was sonicated and heated to dissolve and left undisturbed. A
tiny spherical glass ball was carefully put on the top of the gel after 24
h and was heated in an oil bath fitted with a thermosensor and
magnetic stirrer. The temperature of the oil bath was steadily raised
by 10.0 °C per minute. The temperature at which the glass ball
touched the bottom of the vial was recorded as Tgel.
Synthesis of 1,1′-(1,3-Phenylenebis(propane-2,2-diyl))bis(3-(2-
(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)urea) (2). The crude ma-
terial was recrystallized from isopropanol. Yield: 72.0%. 1H NMR
(400 MHz, DMSO-d6) δ 8.00 (s, 2H), 7.27 (s, 1H), 7.24−7.14 (m,
1H), 7.08 (d, J = 7.7 Hz, 2H), 6.28 (s, 2H), 5.91 (t, J = 6.0 Hz, 2H),
4.27 (t, J = 5.4 Hz, 4H), 3.37−3.28 (m, 4H), 2.41 (s, 6H), 1.47 (s,
12H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 156.22, 150.91,
147.51, 137.84, 132.52, 126.69, 121.80, 120.63, 53.65, 45.84, 37.84,
29.26, 13.25. HRMS (APCI): calcd for C26H36N10O6Na [M + Na]+,
607.2711; found, 607.2712.
Synthesis of 1,1′-(Methylenebis(2,6-diethyl-4,1-phenylene))bis(3-
(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)urea) (3). The crude
compound was recrystallized in ethanol. Yield: 75.0%. 1H NMR
(400 MHz, DMSO-d6) δ 7.98 (s, 2H), 7.39 (s, 2H), 6.91 (s, 4H),
6.26 (s, 2H), 4.32 (t, J = 5.7 Hz, 4H), 3.78 (s, 2H), 3.45 (s, 4H), 2.44
(s, 6H), 2.39−2.32 (m, 8H), 1.03 (t, J = 7.5 Hz, 12H). 13C{1H} NMR
(100 MHz, DMSO-d6) δ 156.62, 151.47, 141.99, 139.28, 138.55,
Rheology. Rheological experiments were performed in nitro-
benzene. The mechanical strength of the gelators was measured using
C
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an MCR 102 Anton Paar modular compact rheometer with a 2.5 cm
stainless steel parallel plate geometry. Gels were prepared by
dissolving 30.0 mg of the corresponding gelator in 1.0 mL of
nitrobenzene. Experiments were carried out carefully by scooping a
∼1.0 mL portion of gel on the plate. A Peltier temperature control
hood was used to avoid the solvent evaporation and to maintain a
temperature of 25.0 °C for frequency and amplitude sweeps.
Amplitude sweeps were performed with a constant frequency of 1.0
Hz and log ramp strain (γ) = 0.01−100%, while the frequency sweeps
were carried out between 0.1 and 10.0 Hz within the linear
viscoelasticity domain (0.02% strain).
RESULTS AND DISCUSSION
■
Metronidazole and isometronidazole-mimicking bis(urea)
compounds (Scheme 2) were synthesized by reacting the
corresponding amine precursors of these compounds with
different diisocyanates (Scheme 3).
Scheme 2. Metronidazole and Isometronidazole-Mimicking
Bis(urea) Compounds
Scanning Electron Microscopy (SEM). The surface morpholo-
gies of the xerogels were examined using SEM. Gels of compounds
(1−6) were prepared in nitrobenzene at 3.0 wt/v %, and the gel was
filtered after 24 h and dried in air to obtain the xerogel. A small
portion of the xerogel was placed on a pin mount with the carbon tab
on top, which was coated with gold for 5−6 min and was loaded on a
Leo Supra 25 microscope at an operating voltage of 3.0 kV and a
working distance 3−4 mm. An in-lens detector was used to record the
SEM images. We have also performed the SEM of dried gel of gelator
3 from DMSO/water (7:3, v/v, 3.0 wt/v %), ethanol (0.3 wt/v %),
and 1,4-dioxane (0.5 wt/v %). The SEM of gelators 2 and 4 was
performed on the xerogels from DMSO/water (1:1, v/v) at 5.0 wt/v
%.
Crystallography. Single-Crystal X-ray Diffraction. Single crystals
of metronidazole and isometronidazole amine hydrochlorides were
obtained by the slow evaporation of the acidic solution of the
compounds in DMF/water (1:1 v/v) and ethanol/water (1:1 v/v),
respectively. X-ray quality crystals of compound 2 were obtained by
the slow evaporation of a nitromethane solution of the compound. X-
ray analysis was performed on a Bruker D8 Venture (Photon100
CMOS detector) diffractometer equipped with Cryostream (Oxford
Cryosystems) open-flow nitrogen cryostats. The data for the crystals
of metronidazole (9·2HCl) and isometronidazole (12·HCl)-based
amines were collected using CuKα radiation (λ = 1.542 Å) at 295(2)
K, and MoKα radiation (λ = 0.71073 Å) at 150(2) K was used for
gelator 2. Apex-III software (Bruker AXS: Madison, WI, 2015) was
used for the unit cell determination, data collection, data reduction,
structure solution/refinement, and empirical absorption correction.
All structures were solved by direct method and refined by the full-
matrix least-squares on F2 for all data using SHELXTL.47 The
disordered imidazole moieties and the solvent molecule of gelator 2
were modeled using free variable (FVAR) instructions and were
refined isotropically. All other nondisordered non-hydrogen atoms
were refined anisotropically. All the hydrogen atoms were placed in
the calculated positions and refined using a riding model. Crystallo-
graphic data for the structures have been deposited to Cambridge
Crystallographic Data Centre as supplementary publication (CCDC
nos. 2088742−2088744).
Scheme 3. Synthesis of Metronidazole and
Isometronidazole Bis(urea) Compounds
We selected diisocyanates with different linkers, namely,
hexylene, sterically hindered m-dipropylenephenylene and
tetraethyl diphenylmethane derivatives, which have been
previously used as effective linkers for LMWGs.10 The
preparation of the amine precursors of metronidazole and
isometronidazole is outlined in Scheme 4.
Scheme 4. Synthesis of Metronidazole and
Isometronidazole-Based Amine Precursors
Powder X-ray Diffraction (PXRD). The PXRD of the isolated
metronidazole crystals from gel phase crystallization and the solution
phase were recorded on a PANalytical instrument with 2θ ranging
from 4.0−60.0°. The crystals were isolated from the crystallizing
medium, washed with hexane, dried, and ground to fine powder, and
PXRD was recorded. We have also performed the PXRD of the
synthesized metronidazole and isometronidazole-based amine hydro-
chlorides to ensure the purity of bulk products. Xerogels of 2 were
prepared by filtering the gels from the corresponding solvents, and the
PXRD was performed after drying the xerogels in the fume hood for
16 h.
Gel Phase Crystallization. The gel phase crystallization was
performed in nitrobenzene and aqueous solution (1:1, v/v) of DMSO
and DMF. The experiments were performed in a standard 7.0 mL vial
with the gelator and the drug molecule in 1.0 mL of the solvent.
Experiments were performed at various concentrations of the gelator
and the drug moiety to study the effect on the gel phase
crystallization. The gels were removed after 24 h and analyzed
under a Leica MC190 HD digital microscope. We have repeated
several batches of gel phase crystallization experiments, and the gels
were analyzed at different time intervals (up to 3 weeks).
The hydroxyl group of metronidazole was converted to the
bromo derivative via bromination, while the bromo derivative
of isometronidazole was synthesized from 2-methyl-4(5)-
nitroimidazole via substitution reaction with 1,2-diethyl
bromide (Scheme S2, see Supporting Information).10,48 The
bromo derivatives were converted to azide and then reduced to
the corresponding amines in the presence of triphenylphos-
phine (Scheme 4). The products were then converted to the
hydrochloride salts by treatment with dilute HCl.
The molecular structure of these two isomeric amine
hydrochloride salts was confirmed by single-crystal X-ray
diffraction (Tables S1 and S2 and Figure S13, see Supporting
Information). The reaction of the metronidazole amine
derivative in the presence of Et3N with the diisocyanates
outlined in Scheme 3 in chloroform yielded compounds 1, 2,
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and 3, respectively. Similarly, the reaction of the isometroni-
dazole amine derivative with these diisocyanates yielded 4, 5,
and 6.
Gelation Studies. The gelation properties of the bis(urea)
compounds were tested in a wide range of solvents (Table S3,
see Supporting Information). The gelation tests were carried
out by heating the gelator (10 mg) in a suitable solvent (1.0
mL) in a sealed vial (1.0 wt/v %) to give a transparent
solution. The vial was left undisturbed, and the gel formation
was confirmed by a vial inversion test.
Table 1. Minimum Gel Concentration and Tgel at 3.0 wt/v %
of the Gelators in Nitrobenzene
compound
MGC (wt/v %)
Tgel (°C)
1
2
3
4
5
6
0.8
0.9
0.5
2.8
2.5
2.8
103.7
84.3
151.4
145.4
118.8
153.8
Metronidazole-mimicking compounds (1−3) formed gels in
nitrobenzene at 1.0 wt/v % (Figure 1), and gel formation was
wt/v % (Table S4, see Supporting Information). The MGC in
DMSO/water for gelator 2 (1:1, v/v) and 3 (7:3, v/v) is 2.5
wt/v % and 3.0 wt/v %, respectively.
Thermal Stability. The thermal stability of the gels was
evaluated by recording the transition temperature (Tgel) at
which the gel converts to the solution phase. Tgel experiments
were performed for all gels at 3.0 wt/v % in nitrobenzene, and
the results indicate that gelator 2 has the lowest Tgel value
(Table 1). The Tgel experiments performed at a lower
concentration (1.0 wt/v %) for compounds 1−3 in nitro-
benzene revealed the highest thermal stability for gels of 3
(Table S5, see Supporting Information), and the thermal
stability increases with concentration. The thermal stability of
the diphenylmethane-derived gelator is higher than the other
gelators in most cases (Table S5, see Supporting Information).
The Tgel of the mimetic and the nonmimetic gelators in
nitrobenzene were compared to see the effect of the spatial
arrangement of the functional groups, which indicates that the
thermal stability of the mimetic gels (1−3) is lower than
nonmimetic gelators (4−6).
Mechanical Strength. Rheology has been used to evaluate
the solid-like properties and the stiffness of the gels.49,50
Rheology is used to quantify the deformation and flow
characteristics of supramolecular gels, and rheological experi-
ments provide information about the gel structural character-
istics.51−53 The mechanical properties of the bis(urea) gelators
were measured at 3.0 wt/v % in nitrobenzene. A strain sweep
was performed to determine the linear viscoelastic region
(LVR), at a constant frequency of 1.0 Hz, and the elastic
modulus (G′) was independent of the applied strain. Most of
the gelators displayed a constant G′ up to 0.1% strain, except
for compound 1, where the G′ value decreased after 0.02%
(Figure 2). The cross-over point for gelators 2 and 5 was found
to be around 0.5−3.0% strain, while the cross-over point for
gelators 1, 3, 4, and 6 is around 5.0−15.0% strain.
Frequency sweep experiments were performed within a
range of 0.1−10 Hz at a constant strain of 0.02%. A constant
elastic (G′) and viscous (G″) moduli under varying frequency
establish that these materials are true gels (Figure S14).
Interestingly, the mimetic gelator 2 displays higher G′ and G″
compared to all the other gelators, indicating a comparatively
stronger network in nitrobenzene. Gels of compounds 2 and 5
are stiffer (>200 kPa) compared to other bis(urea) gelators in
nitrobenzene and the elastic modulus (G′) is around 2-fold
higher than the other bis(urea) gels. Comparison of the
mimetic gelators (1−3) revealed that gelator 2 displayed
higher G′ and G″ values indicating a strong gel network. The
mechanical strength of the gel network in 3 was more robust
than gelator 1. For the nonmimetic gelators (4−6), the gel of 5
was found to be a stiffer gel, and the G′ and G″ values of gels of
4 and 6 were comparable and low, suggesting a weaker gel
network in these gels. The difference in mechanical strength
Figure 1. Gels of bis(urea) compounds (1−6) obtained from
nitrobenzene.
confirmed by a simple inversion test in all cases. Compound 2
formed gel in 1,2-dibromoethane, chlorobenzene, and 1,4-
dioxane at 2.0 wt/v %. The metronidazole-mimicking
diphenylmethane derivative (3) formed gel in cyclopentanone
and cyclohexanone at 1.0 wt/v % and in ethylene glycol at 2.0
wt/v %. The insolubility of compound 3 at 1.0 wt/v % in
alcohols and nonpolar solvents prompted us to check the
gelation properties at a lower concentration (≤0.5 wt/v %),
and gelation was observed in ethanol, n-propanol, n-butanol, n-
pentanol, 1,4-dioxane, and nitromethane. The gelation studies
of isometronidazole-mimicking compounds (4−6) revealed
that gelation was observed at a higher concentration (3.0 wt/v
%) in nitrobenzene compared to metronidazole derivatives 1−
3. In the case of compound 5, sonication was required to
induce gelation in nitrobenzene prior to cooling. The
diphenylmethane-derived isometronidazole analogue (6)
gelled ethylene glycol at 3.0 wt/v % and DMF at 4.0 wt/v
%. We have also studied the gelation properties of these
compounds in aqueous solution (1:1, v/v) of DMF and
DMSO. Compound 6 formed gel in DMF/water at 3.0 wt/v %,
and compound 4 formed gels in DMSO/water and DMF/
water at 4.0 and 5.0 wt/v %, respectively. Compound 3 formed
gels in DMF/water and DMSO/water mixture at 3.0 wt/v %
when the solvent combination was changed to 7:3 (v/v).
The minimum gel concentration (MGC) is the minimum
amount of the compound required to form a self-supporting
gel. The MGC of the gelators was evaluated in various solvents
(Table S4, see Supporting Information). The MGC measure-
ments of metronidazole-based gelators 1−3 in nitrobenzene
(Table 1) establish that compound 3 has lower MGC values.
Comparing the MGCs of mimetic and nonmimetic gels in
nitrobenzene indicated that the MGCs of the nonmimetic
compounds 4−6 are higher. Compound 3 can be considered as
a supergelator in 1-propanol, ethanol, 1-butanol, nitromethane,
1,4-dioxane, and 1-pentanol because the MGC is less than 0.5
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Figure 3. SEM images of the xerogel of (a) 1, (b) 2, (c) 4, and (d) 6
from nitrobenzene at 3.0 wt/v %.
Figure 4. SEM images of gelator 3: from (a) DMSO/water (7:3, v/v)
at 3.0 wt/v % and (b) 1,4-dioxane (0.5 wt/v %).
wt/v %, Figure 4b) and ethanol (0.33 wt/v %, Figure S18, see
Supporting Information), and the images displayed helical
fibrous aggregates with fiber thickness ranging from 20 to 40
nm.
Single-Crystal X-ray Diffraction. X-ray quality single
crystals of 2 were obtained via slow cooling of the
nitromethane solution and characterized by X-ray crystallog-
raphy (Figure S19 and Tables S1 and S2, see Supporting
Information). The compound displays the characteristic one-
dimensional (1-D) hydrogen-bonded urea α-tape motif
resulting from the complementary crisscross urea hydrogen
bonding from one of the urea moieties (Figure 5a). These 1-D
zigzag tapes interact with adjacent tapes via N−H···O
hydrogen-bonding interaction arising from the second urea
Figure 2. Amplitude sweep experiments of bis(urea) gels (3.0 wt/v
%) in nitrobenzene at 25.0 °C with a constant frequency of 1.0 Hz.
Color codes: (a) gelator-1 G′ (black solid square) and G′′ (black
open square), gelator-2 G′ (red solid circle) and G′′ (red open circle),
gelator-3 G′ (blue solid triangle) and G′′ (blue open triangle up), and
(b) gelator-4 G′ (pink solid diamond) and G′′ (pink open diamond),
gelator-5 G′ (green solid triangle right-facing) and G′′ (green open
triangle right-facing), gelator-6 G′ (orange solid star) and G′′ (orange
open star).
for 2 and 5 may be attributed to the favorable network
formation in nitrobenzene compared to others.
Gel Morphology. The morphology of the dried gel fibrils
was analyzed by SEM. SEM performed on the dried gels of all
the gelators from nitrobenzene (3.0 wt/v %) revealed a fibrous
network in most cases. Gelator 1 displayed needle-shaped
morphology (Figure 3a) with a thickness ranging from 1.0 to
3.0 μm. Gelator 2, 3, and 5 displayed an entangled fibrous
network (Figure 3b and Figures S15−S16, see Supporting
Information), and the diameter of the fibers ranged from 200
to 400 nm. The gelator 4 displayed a plate-shaped morphology
with a diameter of around 1.0−4.0 μm (Figure 3c). The
dibenzyl linker-based gelator 6 displayed long needle-shaped
morphology (Figure 3d).
SEM images recorded for gelator 3 at 3.0 wt/v % in DMSO/
water (7:3, v/v) displayed needle-shaped morphology (Figure
4a).54−56 Similarly, the SEM images of gelator 4 from DMSO/
water (1:1, v/v) at 4.0 wt/v % displayed thicker needles
(Figure S17, see Supporting Information). We also performed
the SEM of gelator 3 xerogel obtained from 1,4-dioxane (0.5
Figure 5. Illustration of crystal structure in 2 (a) 1-D hydrogen-
bonded zigzag chains via complementary urea hydrogen bonding (the
purple sphere represents the metronidazole mimetic fragment) and
(b) adjacent 1-D chains interact with each other (broken black lines)
to form a 2-D hydrogen-bonded network.
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motif to form a 2-D hydrogen-bonded sheet architecture
Figure 5b). The nitrogen and oxygen atoms of the imidazole
moiety of adjacent 2-D networks interact with each other to
form voids with entrapped nitromethane (Figure S19, see
Supporting Information). The comparison of the powder X-ray
diffraction pattern (PXRD) of the bulk crystal with the
simulated pattern obtained from the crystal structure21,56−58
confirmed the phase purity of the crystals (Figure S20, see
Supporting Information). The comparison of the powder
diffraction pattern of either the native gel or the dried gel with
the calculated pattern from the crystal structure can provide
information about the structure of xerogels.21,56−59 Although
the drying process can result in artifacts,60 this approach may
provide useful information about the self-assembly process in
LMWGs.1,7,21,56−59 The comparison of the PXRD pattern of
the dried gel from nitrobenzene with the crystal structure
indicated that the two materials are different solid forms.
However, the PXRD pattern of the xerogel of 2 from
nitrobenzene and chlorobenzene matched with the pattern of
bulk crystals of a second solid form of 2 obtained from
isopropanol. The PXRD pattern of the DMSO/water (1:1, v/
v) xerogels proved to be more similar to the pattern calculated
from the single-crystal structure (Figure S21, see Supporting
Information). These results indicate that there are at least two
types of gelator structure obtained depending on the
crystallizing or gelling solvent.
Gel Phase Crystallization. The ability of the gelators to
gel nitrobenzene prompted us to select nitrobenzene as a
solvent for gel phase crystallization of the target drug material.
The metronidazole was purified by recrystallization from
DMSO/water (1:1, v/v) prior to crystallization studies.
Initially, we performed the solution phase crystallization of
metronidazole from nitrobenzene to optimize the crystalliza-
tion conditions. Plate-shaped crystals of metronidazole in a
herringbone fashion (Figure 6a) were observed in nitro-
benzene (30 mg/mL) after a day (Table S6, see Supporting
Information). Experiments performed at higher concentrations
also resulted in crystals with a similar morphology after 2−3 h.
Gel phase crystallization was performed by dissolving
metronidazole and the gelators in 1.0 mL of nitrobenzene,
and the mixture was sonicated and heated to yield a
transparent solution. The solution was left undisturbed at
ambient temperature, and gelation was observed in 5−10 min.
The gels were analyzed by polarized light microscopy after 24
h, which indicated the formation of crystals within the gels in
most cases (Table S7, see Supporting Information). The
optimized concentration of metronidazole was found to be 50
mg/mL, and the experiments performed with 30 mg/mL did
not result in any crystals after 2−3 weeks. The experiments
were performed at 2.0 wt/v % for gelator 1 because the gels
were not stable at lower concentrations in the presence of
crystallization substrate. Analysis of the crystals obtained from
gelator 1 indicated that needle-shaped crystals were formed
(Figure 6b). The experiments performed in gelators 2 at 1.0
wt/v % yielded transparent gels, and crystal growth was
observed after 24 h (Figure S22, see Supporting Information).
The morphology of the crystals was found to be similar to the
crystals from gelator 1 (Figure 6c).
Figure 6. Comparison of crystals of metronidazole from solution and
gel phase crystallization (GPC) in nitrobenzene. (a) Solution phase
and (b) gel phase crystallization in 1, (c) 2, (d) 3, (e) 4, (f) 5, (g) 6,
and (h) alanine gelator, respectively.
indicated that the morphologies of the crystals were consistent
batch-to-batch and over time. The crystallization experiments
were repeated with increasing concentrations of metronidazole
(75 and 100 mg/mL), and the morphologies were similar to
the 50 mg/mL experiments. The experiments performed at 3.0
wt/v % of the gelators 1−3 also resulted in morphologies
similar to 1.0 wt/v % of the corresponding gelators.
For comparison, gel phase crystallization was also carried out
with the isometronidazole-mimetic gelators 4−6. A gelator
concentration of 6.0 wt/v % (Table S8, see Supporting
Information) was used to avoid dissolution of gels in the
presence of crystallization substrate. The experimental
procedure was similar to the mimetic gels, and partial gels
were observed for gelator 5 in the presence of metronidazole.
Plate-shaped crystals in a herringbone morphology were
observed for gels of gelator 4, and similar results were
observed at higher concentrations of metronidazole (Figure
6e). Gel phase crystallization experiments in gelator 5 were
achieved by sonicating the mixture prior to cooling, but
crystals were not formed even at a higher concentration of
metronidazole after a month. Analysis of the partial gels of
gelator 5 obtained by a normal gel phase crystallization
procedure indicated the formation of microneedle crystals of
metronidazole (Figure 6f). The experiments performed with
gelator 6 resulted in clusters of crystals arranged in a
herringbone fashion (Figure 6g). Crystallization of metroni-
dazole was also undertaken in an unrelated (non-metronida-
Gel phase crystallization in gelator 3 at 1.0 wt/v % resulted
in a herringbone pattern of needle-shaped crystals clumped
together (Figure 6d). Gel phase crystallization experiments
were performed in several batches, and the crystals were
analyzed at different time intervals over 2−3 weeks, which
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zole-mimetic) bis(urea) gelator based on L-phenyl alanine
methyl ester at 2.0 wt/v % (Figure S23, see Supporting
Information), which resulted in plate-shaped crystals clumped
in a herringbone pattern (Figure 6h). The needle-shape
morphology obtained in the case of the mimetic gels may be
attributed to the epitaxial growth of metronidazole crystals on
gel fibers due to their favorable interactions with structurally
similar functional groups of the LMWGs.
Face indexing of representative crystals grown from solution
and from gels of compounds 1−6 revealed a complex and
varied influence of all the gels on morphology. The solution-
grown crystals have a relatively simple morphology and express
faces with mainly low indices, namely, (100), (010), and
(001), as well as a large (115) face. The morphology of gel-
grown crystals proved much more complex and unique to each
gel with multiple high-index faces being expressed. For
example, crystals obtained from nitrobenzene gels of 3 exhibit
a wedge shape expressing a large (097) face, Figure 7. Other
(Tables S9−S11). The enhanced mechanical properties of the
mimicking gelators (1−3) in the presence of crystallization
substrate indicate a favorable interaction of the gelator
molecules with the substrates presumably due to the similarity
in the functional group. However, a reverse phenomenon was
observed for the nonmimetic gelators (4−6), which clearly
indicates the importance of structural similar functional groups
in LMWGs and the crystallization substrates.
In contrast to nitrobenzene, solution phase crystallization of
metronidazole in aqueous DMF and DMSO (1:1 and 7:3, v/v)
resulted in long, needle-shaped crystals (Figure S24, see
Supporting Information). The gel phase crystallization with
gelator 2 in DMSO/water (1:1, v/v) resulted in needle-shaped
crystals, while microneedle-shaped crystals were obtained with
gelator 3 in DMSO/water (7:3, v/v) and gelator 4 in DMSO/
water (1:1, v/v), (Figure S25, see Supporting Information).
The gel phase crystallization in DMF/water (1:1, v/v) with
gelator 4 and 6 resulted in microneedle crystals, respectively.
Thus, unlike nitrobenzene, gel phase crystallization in aqueous
DMF and DMSO does not show crystal habit modification
with any gelator, presumably due to the interaction of LMWGs
with hydrogen-bonding solvents, which prevents the drug from
interacting with the complementary sites in the gelators.
The role of LMWGs in tuning crystallization was analyzed
by performing solution phase crystallization in the presence of
dissolved gelators 3, 4, 5, and 6, which resulted in plate-shaped
crystals clumped in a herringbone pattern similar to the
solution phase crystal morphology (Figure S26, see Supporting
Information). However, the experiments with 1 and 2
displayed a mixture of plate-shaped crystals with herringbone
patterns and needle-shaped crystals. These results suggest that
the gel medium plays a vital role in inducing crystal habit
modification rather than just the gelator molecule itself in
solution. The solution/gel phase crystallization of isometroni-
dazole did not yield any crystals.
X-ray analysis performed on all the crystals revealed no
difference in polymorphic form with the known form I36
produced in all cases. The phase purity of the bulk crystal was
analyzed by comparing the PXRD of the bulk crystal with the
simulated pattern obtained from the crystal structure
reported.21,56−58 These data were obtained using bulk crystals
isolated from the gel phase and solution phase crystallization
experiments. The comparison of the PXRD pattern of the
metronidazole crystals from the solution and gel phase
crystallization with the simulated pattern of the crystal
structure revealed superimposable patterns (Figure 8 and
Figure S41, see Supporting Information), indicating phase
purity of the bulk solid.
Figure 7. Face-indexed morphology of metronidazole crystals (a)
grown from nitrobenzene solution, (b) wedge-shaped crystal from a
nitrobenzene gel of metronidazole-mimetic gelator 3 expressing
higher-order faces.
gel-grown samples all expressed a wide variety of faces and
asymmetric morphology (Supporting Information Figures
S27−S33, see Supporting Information). This implies a variety
of specific adsorption modes of the gel fibers to the growing
crystals.
We performed the rheology experiments of the gels in the
presence of metronidazole (50 mg/mL) in nitrobenzene at 3.0
wt/v %, and isometronidazole-mimicking gels formed partial
gels. The mechanical strength of the mimetic gels (1−3) was
increased in the presence of the drug additive (Figure S34, see
Supporting Information). At higher gelator concentration (6.0
wt/v %), gels were observed in all cases with increased
mechanical strength compared to the corresponding gels
without drug additives, expect for 4 and 5 (Figures S35−S36,
see Supporting Information). This prompted us to check
whether the discrepancy in the stabilities is related to the
kinetic trapping of the self-assembled structures by annealing
the gels.61,62 This was achieved by performing a gel-to-sol
transition by heating the gels after 12 h, and the solution thus
obtained was left undisturbed for gelation. The mechanical
strength of mimetic and nonmimetic gels did not show any
drastic change compared to the corresponding nonannealed
gels (Figures S37−S40, see Supporting Information). The
mechanical strength of the mimetic gels (1−5) in the presence
of the metronidazole displayed similar results compared to the
corresponding nonannealed gels, but the mechanical strength
of 6 decreased after annealing (Figures S38 and S40, see
Supporting Information). However, the thermal stabilities of
the gels were found to be lower in the presence of the additives
CONCLUSIONS
■
We have synthesized six bis(urea) compounds with functional
groups mimicking either metronidazole (1−3) or its isomer
isometronidazole (4−6). The gelation studies revealed that
metronidazole-mimetic compound 3 gels various solvents
compared to the isomeric gelator 6. The Tgel experiments
suggested that gels based on the isometronidazole gelators 4−6
have a higher thermal stability than the mimetic gels 1−3. The
comparison of the mechanical strength of the gelators in
nitrobenzene revealed that the metronidazole-mimetic gelators
2 and 3 are more mechanically robust compared to the
isomeric analogues 5 and 6, but the hexylene-linker based
gelator 4 forms a stronger gel compared with that of gelator 1.
The morphologies of the dried gels were analyzed by SEM,
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AUTHOR INFORMATION
■
Corresponding Authors
Krishna K. Damodaran − Department of Chemistry, Science
Institute, University of Iceland, Dunhagi 3 107 Reykjavík,
Iceland; orcid.org/0000-0002-9741-2997; Phone: +354
525 4846; Email: krishna@hi.is; Fax: +354 552 8911
Jonathan W. Steed − Department of Chemistry, Durham
University, Durham DH1 3LE, U.K.; orcid.org/0000-
0002-7466-7794; Email: jon.steed@durham.ac.uk
Author
Sreejith Sudhakaran Jayabhavan − Department of Chemistry,
Science Institute, University of Iceland, Dunhagi 3 107
Reykjavík, Iceland
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.cgd.1c00659
Notes
The authors declare no competing financial interest.
Figure 8. Comparison of PXRD pattern of metronidazole: simulated
from single-crystal data, bulk crystals obtained from DMSO/water,
crystals from solution phase and gel phase crystallization from gelator
1 in nitrobenzene.
ACKNOWLEDGMENTS
■
We thank University of Iceland Research Fund and Science
Institute for funding. S.S.J. thanks the University of Iceland for
the doctoral research grant. We thankfully acknowledge Dr.
Dmitry S. Yufit, Department of Chemistry, Durham University,
U.K., for face indexing the crystals from different gelators. We
also acknowledge Dr. Sigríđur Jónsdóttir and Dr. Friđrik
Magnus, University of Iceland, for NMR/mass spectroscopy
and powder X-ray diffraction analysis, respectively. We thank
Rannís Iceland for infrastructure grants (150998-0031 and
191763-0031) for a single-crystal X-ray diffractometer and
rheometer.
which showed the presence of the entangled networks in most
cases. Gel phase crystallization was performed in nitrobenzene
since all the compounds formed gels in this solvent. The
morphology of metronidazole crystals obtained from solution
phase and gel phase crystallization was analyzed by polarized
light microscopy. Plate-shaped crystals aggregated in a
herringbone fashion were observed from solution phase
crystallization. Crystallization from the isometronidazole-
based gels displayed different morphologies such as plate-
shaped (4), microcrystals (5), and thicker needles (6). The
morphologies of the crystals obtained from the mimetic
metronidazole gel (1−3) were consistent, displaying needle-
shaped crystals, and the needle-shaped crystals in 3 were
clumped together in a herringbone fashion. The results
indicate that crystal habit modification (plate to needle
morphology) arises selectively from gels based on the mimetic
gelators. This crystal habit modification can be attributed to
adsorption of the growing crystals onto the surface of the gel
fibers and potentially epitaxial crystal growth in the case of the
mimetic gels.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.cgd.1c00659.
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sı
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Accession Codes
CCDC 2088742−2088744 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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