Synthon polymorphs of 1: 1 co-crystal of 5-fluorouracil and 4-hydroxybenzoic acid: Their relative stability and solvent polarity dependence of grinding outcomes

Article abstract of DOI:10.1039/c4ce00221k

Although polymorphism is a common phenomenon, the polymorphism of co-crystals is not studied extensively as compared to single-component molecules. Herein we report polymorphism in a co-crystal system comprising 5-fluorouracil, and 4-hydroxybenzoic acid with a 1: 1 stoichiometry. The polymorphs were characterized by single-crystal and powder X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis. Crystal structure analysis revealed different synthons of 5-fluorouracil and 4-hydroxybenzoic acid in two forms. The solvent-drop grinding experiments show a high degree of solvent polarity specificity. The theoretical and experimental methods suggest an enantiotropic relationship between the polymorphs.

Full text of DOI:10.1039/c4ce00221k

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Synthon polymorphs of 1 : 1 co-crystal of
5-fluorouracil and 4-hydroxybenzoic acid:
their relative stability and solvent polarity
dependence of grinding outcomes†
Cite this: CrystEngComm, 2014, 16,
6450
a
ac
Song Li,ab Jia-Mei Chen and Tong-Bu Lu
*
*
Although polymorphism is a common phenomenon, the polymorphism of co-crystals is not studied
extensively as compared to single-component molecules. Herein we report polymorphism in a co-crystal
system comprising 5-fluorouracil, and 4-hydroxybenzoic acid with a 1 : 1 stoichiometry. The polymorphs
were characterized by single-crystal and powder X-ray diffraction, differential scanning calorimetry and
thermogravimetric analysis. Crystal structure analysis revealed different synthons of 5-fluorouracil and
4-hydroxybenzoic acid in two forms. The solvent-drop grinding experiments show a high degree of solvent
polarity specificity. The theoretical and experimental methods suggest an enantiotropic relationship between
the polymorphs.
Received 28th January 2014,
Accepted 9th April 2014
DOI: 10.1039/c4ce00221k
www.rsc.org/crystengcomm
Synthon polymorphism occurs when the primary synthons in
the forms are different.14,19
Introduction
Polymorphism is the ability of a solid material to be crystal-
lized in at least two crystal structures.1 This phenomenon is
common in drugs, agrochemicals, pigments, dyes and explo-
sives, etc.2–5 Polymorphism has gained considerable interest
since different polymorphs exhibit different physical and chemical
properties such as melting point, solubility, chemical stability,
moisture sorption tendency, compressibility, and processability.6–11
The origin of polymorphism can be classified into four catego-
ries: packing polymorphism, conformational polymorphism,
tautomeric polymorphism, and synthon polymorphism. Packing
polymorphism refers to identical molecular moieties packing
into different periodic crystal structures.12–14 Conformational
polymorphism is defined as molecular moieties with rotational
degrees of freedom which adopt different conformations in
the crystal.14,15 Tautomeric polymorphism appears when tau-
tomers crystallize from the solution, in which the tautomers
coexist and equilibrate at the crystallization temperature.16–18
Polymorphism has been studied widely in single-component
molecules but its occurrence in multi-component systems
such as co-crystals has not been extensively addressed.20–42
A
co-crystal is built up by at least two components that are solids
under ambient conditions coexisting through non-covalent
interactions.43 The study of co-crystals is currently of interest
since they are exploited to yield new crystalline forms of mate-
rials with desirable physical and chemical properties.44–49
Herein we report supramolecular synthon polymorphism in
a 1 : 1 co-crystal of 5-fluorouracil (5FU) and 4-hydroxybenzoic
acid (4HBA) (see Scheme 1). 5FU, a chemotherapeutic agent,
is a pyrimidine analogue with multiple N–H donors and CO
acceptors and exhibits the diversity of hydrogen bonding
motifs from a crystal engineering viewpoint.50 4HBA is one of
the most commonly used co-formers for co-crystallization of
a School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006,
China. E-mail: chenjm37@mail.sysu.edu.cn, lutongbu@mail.sysu.edu.cn;
Fax: +86 20 84112921
b School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China
c MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry
and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China
† Electronic supplementary information (ESI) available: IR spectra, DSC and
TG curves of Form
I and Form II, PXRD date with regard to grinding
experiments and slurry experiments, VT-PXRD of Form II, CCDC 983683 and
983684 for Form II and Form I, respectively. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c4ce00221k
Scheme 1 Structures of 5-fluorouracil (5FU) and 4-hydroxybenzoic
acid (4HBA).
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active pharmaceutical ingredients because of its carboxyl and
hydroxyl functional groups as well as its low toxicity.51–53 We
now reveal two polymorphs of the title co-crystal and report
our observations dealing with phase transformations and rela-
tive stability of the forms. The two polymorphs were charac-
terized by various analytical techniques, such as single-crystal
and powder X-ray diffraction, differential scanning calorimetry,
and thermogravimetric analysis.
added to the reactants prior to grinding. The resulting solids
were analyzed by PXRD to identify the polymorph.
Slurry experiments
Excess amounts (approximately 100 mg) of Form I and Form II
in a 1 : 1 ratio were added to 1 mL of aqueous solution, which
was saturated with 5FU (0.09 mmol) and 4HBA (0.05 mmol) in
advance. The resulting slurries were allowed to stir at ambient
conditions for 1 day. The solids were collected by vacuum
filtration and analyzed by PXRD.
Experimental
Reagents
5FU (Form I) was purchased from Melon Pharmaceutical Co.,
Ltd, and 4HBA was purchased from Aladdin reagent Inc. They
were used without any further purification. All other reagents
and solvents obtained from commercial suppliers were used
as received.
Single-crystal X-ray diffraction (SXRD)
SXRD data of Form I and Form II were collected at 150 K on
an Agilent Xcalibur Nova CCD diffractometer, with graphite
monochromated Cu Kα radiation (λ = 1.5418 Å). Cell refine-
ment and data reduction were applied using the program
package CrysAlis PRO. The structures were solved by direct
methods and refined by the full-matrix least-squares method
on F2. All the non-hydrogen atoms were refined anisotropically.
All hydrogen atoms were refined at geometrically constrained
riding positions. All the calculations were performed using the
SHELX-97 program. The crystallographic data are summarized
in Table 1, and selected hydrogen bonding distances and angles
are given in Table 2.
Preparation of polymorphs
Form I was prepared via the following two methods: (i) a mix-
ture of 5FU (130 mg, 1 mmol) and 4HBA (138 mg, 1 mmol)
was added to 1 mL of water and allowed to stir at 50 °C or
room temperature (RT) for 24 h. The suspension was filtered
and the isolated solid of Form I was dried under vacuum
for 24 h. Yield: 220.8 mg, 82.4%. The filtrate was left to eva-
porate slowly at RT. After two weeks, rod-shaped crystals
of Form I were obtained. Anal. (%) calcd for C11H9FN2O5:
C, 49.26; H, 3.38; N, 10.45. Found: C, 49.28; H, 3.40; N, 10.41.
IR (KBr, νCO): 1710 (s), 1649 (s) cm−1. (ii) A 1 : 1 mixture of
5FU (130 mg, 1 mmol) and 4HBA (138 mg, 1 mmol) was
added to a stainless steel grinding jar. Approximately two
drops of water was added, and the mixture was ground for
30 min at a frequency of 25 Hz.
Form II was obtained via the following two methods: (i) a
mixture of 5FU (130 mg, 1 mmol) and 4HBA (138 mg, 1 mmol)
was dissolved in 2 mL of water with stirring at 65 °C, then the
resulting solution was filtered immediately. Upon rapid cooling
to RT and standing for 24 h, block-shaped crystals of Form II
were harvested. Yield: 201.5 mg, 75.2%. Anal. (%) calcd for
C11H9FN2O5: C, 49.26; H, 3.38; N, 10.45. Found: C, 49.24; H, 3.36;
N, 10.43. IR (KBr, νCO): 1715 (s), 1676 (s) cm−1. (ii) A 1 : 1 mix-
ture of 5FU (130 mg, 1 mmol) and 4HBA (138 mg, 1 mmol)
was added to stainless steel grinding jar. Approximately two
drops of THF was added, and the mixture was ground for
30 min at a frequency of 25 Hz.
Powder X-ray diffraction (PXRD)
Room temperature PXRD analysis was performed on a Bruker
D2 Advanced diffractometer (Bruker, PHASER) operated with
Cu Kα radiation (λ = 1.5418 Å) at 30 kV and 10 mA. The data
were collected over an angular range of 5°–40° (2θ) value in
continuous scan mode using a step size of 0.014° (2θ) and a
step time of 0.1 s. Typically, 30 mg of solid was used for analy-
sis and pressed gently on a silicon slide to give a level surface.
Variable temperature PXRD (VT-PXRD) data were obtained on
a Bruker D8 Advance with Cu Kα radiation (40 kV, 40 mA).
Each sample was scanned between 5° and 40° (2θ) with 0.02°
(2θ) step size and 0.12 s per step scan speed. Calculated PXRD
patterns were generated from the single-crystal structure data
using Mercury CSD 3.1 (Cambridge crystallographic data cen-
ter, UK).
Infrared (IR) spectroscopy
IR (KBr pellet) spectra were recorded on a Bruker EQUINOX
55 FT-IR spectrometer. A total of 64 scans were collected over
a range of 4000 to 400 cm−1 with a resolution of 0.2 cm−1 for
each sample.
Grinding experiments
Grinding was performed using a Retsch Mixer Mill model
MM200 with two 25 ml stainless steel grinding jars and two
15 mm stainless steel grinding balls at a rate of 25 Hz for
30 min. All the experiments were carried out with a 1 : 1 stoi-
chiometric ratio of 5FU (130 mg, 1 mmol) and 4HBA (138 mg,
1 mmol). For solvent-drop grinding experiments, two drops of
a selected solvent with different dielectric constant were
Differential scanning calorimetry (DSC)
DSC was recorded in a nitrogen atmosphere using a Netzsch
DSC-204 Instrument. The sample was placed in an alumin-
ium pan and scanned from 30 °C to a final temperature of
180 °C at a heating rate of 10 °C min−1.
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Table 1 Crystallographic data and refinement parameters for Form I and Form II
Form I
Form II
Formula
Mr
C11H9FN2O5
268.20
C11H9FN2O5
268.20
Temperature/K
150.02(11)
0.20 × 0.1 × 0.1
1.5418
150.00(10)
0.20 × 0.20 × 0.10
1.5418
Crystal size/mm3
Wavelength/Å
Crystal system
Space group
Monoclinic
P21/c
Triclinic
P1
¯
a/Å
7.0356(3)
6.8225(6)
b/Å
c/Å
α (°)
β (°)
14.9022(13)
10.2665(4)
90
8.6115(9)
10.7203(12)
67.906(10)
86.057(8)
99.418(4)
γ (°)
90
78.308(8)
571.46(10)
2
1.559
1.176
Vcell/Å3
1061.90(11)
4
1.678
Z
ρ(calcd)/g cm−3
μ/mm−1
1.265
F(000)
552
276
θ range (°)
5.28–62.95
−7, 7; −17, 16; −10, 11
3520
1690 [R(int) = 0.0413]
98.5%
1690/0/185
1.055
R1 = 0.0617, wR2 = 0.1490
R1 = 0.1014, wR2 = 0.1844
0.269, −0.436
4.45–62.94
−7, 5; −9, 9; −10, 12
3293
1808 [R(int) = 0.0329]
98.1%
1808/0/182
1.054
R1 = 0.0456, wR2 = 0.1106
R1 = 0.0630, wR2 = 0.1266
0.208, −0.275
Index ranges
Reflections collected
Independent reflections
Completeness
Data/restraints/parameters
GOF
Final R indices [I > 2σ(I)]a
R indices (all data)a
Largest diff. peak, hole (e Å−3
)
P
P
P
P
a
2
R1 = ‖Fo| − Fc‖/ |Fo|. wR2 = [ [w(Fo − Fc2)2]/ w(Fo2)2]1/2, w = 1/[σ2(Fo)2 + (aP)2 + bP], where P = [(Fo2) + 2Fc2]/3.
Table 2 The hydrogen bonding distances and angles for Form I and Form II
Compound
H bond
D–H/Åg
H⋯A/Åg
D⋯A/Åg
∠D–H⋯A/Åg
Form I
O(4)–H(4)⋯O(2)a
N(1)–H(1)⋯O(1)b
N(2)–H(2)⋯O(5)c
O(3)–H(3)⋯O(1)
N(2)–H(2)⋯O(2)d
N(1)–H(1)⋯O(2)e
O(4)–H(4)⋯O(5)f
O(3)–H(3)⋯O(1)
0.82
1.84
2.640(5)
3.028(4)
2.784(6)
3.019(5)
2.847(2)
2.805(2)
2.615(2)
2.645(2)
164.4
172(5)
168(3)
167(6)
164(2)
176(2)
176.1
144.3
0.82(5)
0.89(4)
0.86(7)
0.93(3)
0.92(3)
0.82
2.21(5)
1.90(4)
2.17(7)
1.94(3)
1.89(3)
1.80
Form II
0.82
1.94
a
b
c
d
e
f
Symmetry codes: [x, y + 1, z]. [−x + 1, −y + 1, −z + 2]. [−x + 1, −y, −z]. [−x + 2, −y + 1, −z + 2]. [−x + 1, −y + 1, −z + 2]. [−x + 1, −y, −z].
g
D and A are hydrogen bond donors and acceptors.
Thermogravimetric analysis (TGA)
Results and discussion
TGA was performed using a Netzsch TG-209 instrument. The
sample was placed in an aluminium sample pan and heated
over the temperature range of 30–500 °C at a heating rate of
10 °C min−1.
To evaluate the potential for co-crystallization behavior of
5FU and 4HBA as co-formers, the structures of pure 5FU and
4HBA were analyzed from a crystal engineering perspective.
Form I of 5FU (refcode FURACL14) adopts a hydrogen-bonded
sheet structure exploiting all of the available uracil donors and
acceptors (including double hydrogen bond homosynthon A,
Scheme 3) and exhibiting regions where the fluorine atoms
are in close proximity, approaching within 3.2 Å (Scheme 2).
The crystal structure of 4HBA (refcode JOZZIH) shows that
two 4HBA molecules form a dimer through the acid–acid
Stability test
The stability of Form I and Form II was evaluated at 40 °C/
75% relative humidity (RH). A vial of each sample was
subjected to the conditions for one month. Then the samples
were immediately analyzed by PXRD.
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molecules are connected through a doubly hydrogen bonded
R22(8) homosynthon (synthon A) to form a dimer, and two
5FU-dimers are further connected with two 4HBA molecules
through two amide–acid R22(8) heterosynthons (synthon E)
and two O3–H3⋯O1 hydrogen bonds (synthon F) to form a
one-dimensional (1D) chain (Fig. 1b). The 1D chains are
packed to form a two-dimensional (2D) sheet via F⋯F (2.850 Å)
interactions55 and van der Waals force (Fig. 1b). The 2D
sheets further stack along the c-axis through the interlayer
π⋯π interactions (3.58 Å) between the rings of 5FU and 4HBA
to form the three-dimensional (3D) structure (Fig. 1c, d).
In Form I, each 5FU molecule generates two hydrogen
bonds with adjacent 5FU molecules and three hydrogen
bonds with adjacent 4HBA molecules, and each 4HBA mole-
cule forms three hydrogen bonds with two adjacent 5FU mole-
cules (Fig. 1b).
The crystal structure of Form II was solved in a triclinic,
¯
P1 space group (Table 1). The asymmetric unit also contains
one 5FU molecule and one 4HBA molecule (Fig. 2a). 5FU mole-
cules are connected through two doubly hydrogen bonded
R22(8) homosynthons (synthon B and C) to generate a 1D chain.
4HBA molecule links another 4HBA molecule through an
acid–acid R22(8) homosynthon (synthon D) to form a carboxylic
dimer. The 5FU 1D chains are further connected by 4HBA
dimers through O3–H3⋯O1 hydrogen bonds (synthon F) to
generate a 2D sheet (Fig. 2b). The 2D sheets are packed along
the b-axis via interlayer π⋯π interactions (3.49 Å) between the
rings of 5FU and 4HBA to form the 3D structure (Fig. 2c, d).
In Form II, each 5FU molecule forms four hydrogen bonds
with adjacent 5FU molecules and one hydrogen bond with
adjacent 4HBA molecules, and each 4HBA molecule generates
one hydrogen bond with adjacent 5FU molecules and two
hydrogen bonds with adjacent 4HBA molecules (Fig. 2b).
From the crystal structure analysis, we can see that these
two forms are synthon polymorphs since their primary synthons
are different. The acid–acid homosynthon (synthon D) of 4HBA
Scheme 2 Hydrogen-bonded sheet structure of Form I of 5FU (a) and
acid–acid dimer structure of 4HBA (b).
R22(8)54 doubly hydrogen bonded homosynthon D (Schemes 2
and 3). When 5FU co-crystallizes with 4HBA, all their
hydrogen bond donors and acceptors adjust to achieve a
balance of all parts of the two molecules. Some supramo-
lecular homosynthons motifs in pure 5FU and 4HBA must
be interrupted, whereas some new heterosynthons must
be generated.
Crystal structures of Form I and Form II
The crystal structure of Form I belongs to the monoclinic,
P21/c space group (Table 1). The asymmetric unit contains
one 5FU molecule and one 4HBA molecule (Fig. 1a). Two 5FU
Scheme 3 Homo- and heterosynthons exhibited by 5FU-4HBA co-crystal polymorphs.
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Fig. 1 (a) The molecular structure, (b) 2D sheet, (c) side view and (d) top view of 3D structure (the blue, red and teal color are the first,
second and third layer, respectively) of Form I.
is interrupted and new heterosynthons (synthons E and F) are
generated in Form I, while synthon D of 4HBA is preserved
and only heterosynthon F is generated in Form II. As a result,
all hydrogen-bonding sites in 5FU and 4HBA molecules are
effectively utilized in Form I and Form II.
PXRD and thermal analyses
The PXRD patterns of the bulk batch of Form I and Form II
are different from either that of 5FU or 4HBA (Fig. 3a and b),
indicating the formation of new crystalline phases. In addi-
tion, all the peaks displayed in the measured patterns closely
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Fig. 2 (a) The molecular structure, (b) 2D sheet, (c) side view and (d) top view of 3D structure (the blue, red and teal colors are the first,
second and third layers, respectively) of Form II.
match those in the simulated patterns generated from single-
crystal diffraction data (Fig. 3a and b), confirming the formation
of the corresponding polymorphic forms. The displacement
of the peaks at the high angle regions between the measured
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can be classified into two categories: solvent-drop grinding
(SDG) and neat grinding (NG), which differ in adding or not
adding solvent when grinding.58,59
NG and SDG were conducted using a 1 : 1 molar ratio of
5FU and 4HBA. The resulting solids were analyzed by PXRD
to identify the crystal form. Dry grinding of 5FU with 4HBA
for 30 minutes resulted in generation of Form II. SDG was
performed using each of the solvents selected with different
dielectric constants (Table 3). The results of the SDG experi-
ment revealed that Form II was produced when low polar sol-
vents were used. As the polarity of solvent increased, a mixture
of Form I and Form II was generated. Pure Form I can
be obtained when the polarity of solvents increases further
(Fig. S3†). These observations suggest a high degree of solvent
polarity specificity for the grinding experiments. Low polar
solvents have a higher tendency to generate Form II, while
high polar solvents tend to generate Form I. Similar polarity
dependent polymorphic outcomes of grinding experiments
have been reported before.61–64
A kinetically reasoned hypothesis can account for the
different outcome of grinding experiments with high polar
solvents (Form I) and low polar solvents (Form II). In the
presence of high polar solvents, the carboxyl group of 4HBA,
the highest polar group in two molecules, is tightly solvated,
resulting in the disruption of the doubly hydrogen-bonded
acid–acid dimers (synthon D) in 4HBA during grinding. In
contrast, this group is much less strongly solvated in low
polar solvents and leaves synthon D in 4HBA intact during
grinding. Thus the strong solvation of the carboxyl group of
4HBA with high polar solvents provides a barrier to the pres-
ervation of the acid–acid R22(8) motif in Form I, suggesting
such kinetic effects may play a major role in determining the
polymorphic outcome.
Relative stability of Form I and Form II
Relative polymorph stabilities can usually be determined by
theoretical and experimental approaches. From a theoretical
aspect, typically, the higher the density of a polymorph the higher
Fig. 3 PXRD patterns of 5FU, 4HBA, as-synthesized by the solution
crystallization method, and simulated from the single-crystal data for
(a) Form I and (b) Form II.
its stability.65 The calculated density of Form I (1.678 g cm−3
)
is higher than that of Form II (1.559 g cm−3), indicating that
Form I will be the stable form at low temperatures.
and simulated patterns is mainly caused by the different mea-
suring temperature between the powder patterns (room tem-
perature) and the single-crystal data (150 K).
From the DSC and TGA curves it can be found that both
Form I and Form II decompose on heating (about 179 °C)
before melting. There is no evidence of a phase transformation
in a DSC curve of either form before decomposition (Fig. S2†).
From an experimental aspect, a slurry experiment, also
referred to as a solvent-mediated phase transformation experi-
ment, was conducted to estimate the relative thermodynamic
stability of Form I and Form II at RT. A powdered 1 : 1 mixture
of these two forms was stirred in water for 24 h. Then the
resulting solid was filtered off, dried under vacuum and mea-
sured by PXRD. The results of the PXRD analysis revealed
that the mixture completely converted to Form I, suggesting
that Form I is more stable than Form II in aqueous solution
at RT (Fig. S4†). Besides, the results of the stability test at
40 °C/75% RH for one month also indicates that Form II can
be slowly converted into Form I at 40 °C/75% RH.
Solid-state grinding experiments
Solid-state grinding is a green approach for co-crystal screening,
which can avoid excessive use of crystallization solvent.56,57
This method can also offer a high yield of co-crystal, without
any waste by being dissolved in solutions. Solid-state grinding
VT-PXRD was conducted to further evaluate the relative
stability of Form I and Form II at higher temperature (Fig. 4).
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Table 3 The outcome of SDG of a 1 : 1 molar ratio of 5FU and 4HBA from 22 different solvents
Solvent
Dielectric constant (20 °C)60
Crystal forms identified by PXRD
n-Heptane
1.92
Form II
1,4-Dioxane
Benzene
2.21 (25 °C)
2.28
Form II
Form II
o-Xylene
2.27
Form II
p-Xylene
2.27
Form II
m-Xylene
2.37
Form II
Chloroform
Ethyl acetate
Methyl acetate
Tetrahydrofuran
Methylene chloride
sec-Butyl alcohol
n-Butyl alcohol
Isopropyl alcohol
Butanone
Acetone
Propanol
Ethanol
Methanol
4.90
6.02
6.68 (25 °C)
7.58 (25 °C)
9.10
Form II
Form II
Form II
Form II
Form II
Form II
Form II
Form II
Form I + Form II
Form I + Form II
Form I + Form II
Form I + Form II
Form I
15.50
17.10
18.30 (25 °C)
18.51
20.70 (25 °C)
22.20 (25 °C)
23.80
33.10
Acetonitrile
Ethylene glycol
Water
37.50
38.66
78.30
Form I
Form I
Form I
The samples were held for five minutes at each temperature
to equilibrate prior to PXRD measurement. The results of the
PXRD analysis indicate that Form I maintains its crystallinity
up to 150 °C, and then it transforms to a mixture of Form I
and Form II in the temperature range of 160–170 °C. Further
heating resulted in partial decomposition before complete
transformation of Form I to Form II (Fig. 4). The VT-PXRD
data of Form II was also obtained, and no evidence of a
phase transformation was observed (Fig. S5†). These results
normally suggest that the two forms are enantiotropically
related. Form I is more stable than Form II below 150 °C and
begins to convert to Form II at 160 °C. The thermodynamic
transition point lies in the temperature range of 150–160 °C.
Conclusions
Two polymorphs of 5FU-4HBA (1 : 1) co-crystals have been iso-
lated by both solid-state grinding and solution crystallization
methods. The SDG experiments show a high degree of sol-
vent polarity specificity. High polar solvents tend to favor the
generation of Form I, while low polar solvents tend to gener-
ate Form II. Single crystal structure analysis revealed the
synthon differences between the molecules of 5FU and 4HBA
in two polymorphs, which can also be classified as synthon
polymorphs. The crystal structure of Form I features an acid–
amide heterosynthon, whereas that of Form II features an
acid–acid homosynthon. A combination of theoretical and
experimental methods suggested an enantiotropic relationship
between the two polymorphs. Form I is more stable at lower
temperature while Form II is more stable at higher temperature.
The thermodynamic transition point for these two enantiotropic
forms was found to exist between 150 and 160 °C.
Acknowledgements
This work was financially supported by NSFC (grant no. 21101173,
91127002 and 21331007), NSF of Guangdong Province
(S2012030006240), and Guangzhou Pearl River New Star Fund
Science and Technology Planning Project (2013J2200054).
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Fig. 4 VT-PXRD analysis of a sample which was initially Form I of the
5FU-4HBA co-crystal. A phase transition from Form I to Form II
occurred between 150 and 160 °C.
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