Improving the solubility of 6-mercaptopurine via cocrystals and salts

Article abstract of DOI:10.1021/cg3010745

An antitumor drug, 6-mercaptopurine monohydrate, has a low oral bioavailability (about 16%) due to its poor aqueous solubility. To improve its solubility, two cocrystals of 6-mercaptopurine with 4-hydroxybenzoic acid (1) and 2,4-dihydroxybenzoic acid (2), as well as two salts with piperazine in 1:1 (3) and 2:1 (4) stoichiometry, respectively, were obtained and characterized by infrared spectra, powder and single crystal X-ray diffraction. The structures of 1-4 are assembled via N-H(pyrimidine)?O(carboxyl), N-H(pyrimidine) ?N(imidazole), O-H(carboxyl)?S, O-H(hydroxyl)?N(imidazole), N-H(pyrimidine)?S, O-H(carboxyl)?O(carboxyl) and N-H(piperazine) ?N(imidazole) hydrogen bonds. After the formation of cocrystals and salts, the solubility of 6-mercaptopurine monohydrate is much improved, and the apparent solubility values of 1-4 in the phosphate buffer of pH 6.8 are approximately 1.6, 2.0, 14.0, and 4.2 times as large as that of 6-mercaptopurine monohydrate. Interestingly, 3 transformed to 4 at 40 °C/75% RH within one month.

Full text of DOI:10.1021/cg3010745

Article
pubs.acs.org/crystal
Improving the Solubility of 6‑Mercaptopurine via Cocrystals and Salts
Lin-Lin Xu,† Jia-Mei Chen,*,† Yan Yan,‡ and Tong-Bu Lu*,†,‡
†School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
‡MOE Key Laboratory of Bioinorganic and Synthetic Chemistry/State Key Laboratory of Optoelectronic Materials and
Technologies/School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China
S
* Supporting Information
ABSTRACT: An antitumor drug, 6-mercaptopurine mono-
hydrate, has a low oral bioavailability (about 16%) due to its
poor aqueous solubility. To improve its solubility, two cocrystals
of 6-mercaptopurine with 4-hydroxybenzoic acid (1) and 2,4-
dihydroxybenzoic acid (2), as well as two salts with piperazine
in 1:1 (3) and 2:1 (4) stoichiometry, respectively, were ob-
tained and characterized by infrared spectra, powder and single
crystal X-ray diffraction. The structures of 1−4 are assembled
via N−H(pyrimidine)···O(carboxyl), N−H(pyrimidine)···
N(imidazole), O−H(carboxyl)···S, O−H(hydroxyl)···N(imidazole), N−H(pyrimidine)···S, O−H(carboxyl)···O(carboxyl) and
N−H(piperazine)···N(imidazole) hydrogen bonds. After the formation of cocrystals and salts, the solubility of 6-mercaptopurine
monohydrate is much improved, and the apparent solubility values of 1−4 in the phosphate buffer of pH 6.8 are approximately
1.6, 2.0, 14.0, and 4.2 times as large as that of 6-mercaptopurine monohydrate. Interestingly, 3 transformed to 4 at 40 °C/75%
RH within one month.
INTRODUCTION
Scheme 1. Structures of 6-Mercaptopurine,
4-Hydroxybenzoic Acid, 2,4-Dihydroxybenzoic Acid, and
Piperazine (left to right)
■
Most drug development candidates fail to reach market due
to deficient physicochemical properties, and poor aqueous sol-
ubility is recognized as the single largest physicochemical prob-
lem hindering oral drug delivery.1 Thus solubilization of poorly
soluble drugs is a very formidable task for pharmacetical scientists.
Salt formation is the most common method for improving solu-
bility and dissolution rates of acidic and basic drugs.2 Recently,
cocrystals have been identified as viable solid forms for improving
the solubility of the active pharmaceutical ingredients (APIs), es-
pecially for nonionizable APIs.3 A pharmaceutical cocrystal is
defined as a stoichiometric multiple component substance formed
by an API and one or more coformers, in which the API and
coformers are connected by noncovalent intermolecular
interactions, typically hydrogen bonds.4−6 Therefore, the
presence of hydrogen bond donors and acceptors in API and
coformers is usually a precondition for cocrystal formation.4,7
Moreover, cocrystals have been documented to be effective for
modifying the physicochemical properties of an API, such as
mechanical properties, melting point, hygroscopic properties,
photosensitivity, dissolution behavior and bioavailability.8−15
The versatility of cocrystals arises from the wide array of coformers.
All the compounds appear on the generally regarded as safe (GRAS)
or everything added to the food in the United States (EAFUS) list
are potential coformers.16
(0.135 mg/mL).19 Therefore, increasing the solubility of
6-MP·H2O and consequently improving its bioavailability through
preparing novel cocrystals or salts is of interest for the develop-
ment of new dosage forms of 6-MP.
In this paper, two cocrystals of 6-MP with 4-hydroxybenzoic
acid and 2,4-dihydroxybenzoic acid, and two salts of 6-MP with
piperazine were obtained. 4-Hydroxybenzoic acid is listed in the
GRAS substances,20 2,4-dihydroxybenzoic acid is enlisted in
EAFUS list,21,22 and piperazine is a pharmaceutically accepted
basic salt former and has pharmacological activity as an anthel-
mintic.11 All of the cocrystals and salts were characterized by
infrared spectra, powder and single crystal X-ray diffraction, and
their powder dissolution and stability were also investigated.
EXPERIMENTAL SECTION
Materials and General Methods. 6-MP·H2O was purchased from
Suizhou Hongqi Chemical Co., Ltd. All the coformers were purchased
■
6-Mercaptopurine (6-MP) is known as a clinically important
antimetabolite and antineoplastic drug in the treatment of human
leukemia, systemic lupus erythematosus, rheumatoid arthritis and
inflammatory bowel disease.17,18 The commercially available form,
6-mercaptopurine monohydrate (6-MP·H2O), has low oral bio-
availability (about 16%) due to its poor solubility in water
Received: July 27, 2012
Revised: October 12, 2012
Published: October 31, 2012
© 2012 American Chemical Society
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Table 1. Crystallographic Data and Refinement Parameters for 1−4
1
2
3
4
formula
formula weight
temperature/K
crystal system
space group
a/Å
C12H10N4O3S
290.30
C12H10N4O4S
306.30
C9H14N6S
238.32
C14H17N10S2
390.50
150(2)
orthorhombic
Pna21
150(2)
293(2)
130(2)
monoclinic
P21/c
monoclinic
P21/c
orthorhombic
Pbca
12.3806(8)
8.0655(6)
12.5124(8)
90
14.3545(8)
7.5483(4)
12.3239(6)
90
11.0569(3)
13.1725(3)
15.5061(4)
90
11.4885(7)
12.1759(6)
12.0078(7)
90
b/Å
c/Å
α/deg
β/deg
90.292(6)
90
102.860(5)
90
90
90
γ/deg
90
90
V
cell/Å3
1249.42(15)
4
1301.83(12)
4
2258.42(10)
8
1678.59(16)
4
Z
Dc/g cm−3
F(000)
1.543
1.563
1.402
1.545
600
632
1008
816
crystal size/mm
index ranges
0.10 × 0.10 × 0.05
−14 ≤ h ≤ 13
−9 ≤ k ≤ 8
−14 ≤ l ≤ 14
0.0291
0.20 × 0.10 × 0.10
−16 ≤ h ≤ 17
−8 ≤ k ≤ 7
−14 ≤ l ≤ 14
0.0353
0.30 × 0.30 × 0.03
−11 ≤ h ≤ 12
−15 ≤ k ≤ 13
−17 ≤ l ≤ 18
0.0199
0.10 × 0.05 × 0.05
−8 ≤ h ≤ 13
−14 ≤ k ≤ 11
−14 ≤ l ≤ 10
0.0317
Rint
goodness-of-fit on F2
1.042
1.101
1.051
1.014
a
R1 [I > 2σ(I)]
0.0602
0.0479
0.0330
0.0459
b
wR2 [all data]
0.1566
0.1501
0.0912
0.1162
c
Flack parameter
0.19(4)
a
b
c
2
R1 = Σ|| Fo| − | Fc||/Σ Fo. wR2 = [Σ[w(Fo2 − Fc2)2]/Σw(Fo )2]1/2, w = 1/[σ2 (Fo)2 + (aP)2 + bP ],where P = [(Fo 2) +2Fc2]/3. Absolute structure
parameter.36−38
Table 2. Hydrogen Bonding Distances and Angles for 1−4
compound
H bond
D−H/Å
H···A/Å
D···A/ Å
∠D−H···A/°
a
1
N4−H4A···O1#1
O2#1−H2A#1···S1
N1#2−H1A#2···N3
N1−H1A···N3#3
O3−H3A···N2
N1#1−H1N#1···S1
N1−H1N···S1#1
N4−H4N···N2#2
N4#3−H4N#3···N2
O1−H1A···O2#4
O1#4−H1A#4···O2
O3−H3A···O2
0.94(5)
0.83(4)
0.84(5)
0.84(5)
0.83(4)
0.91(4)
0.91(4)
0.86(4)
0.86(4)
0.85(4)
0.85(4)
0.97(4)
0.86(4)
0.91(2)
0.81(2)
0.95(2)
0.88
1.78(6)
2.38(4)
2.04(5)
2.04(5)
1.95(4)
2.36(4)
2.36(4)
2.17(4)
2.17(4)
1.81(4)
1.81(4)
1.78(4)
1.89(4)
1.90(2)
2.16(2)
1.85(2)
2.040
2.708(4)
3.202(3)
2.846(5)
2.846(5)
2.768(4)
3.256(2)
3.256(2)
3.026(3)
3.026(3)
2.658(3)
2.658(3)
2.629(2)
2.740(3)
2.807(2)
2.958(2)
2.790(2)
2.908(4)
2.782(5)
2.829
170(5)
169(4)
160(5)
160(5)
170(4)
169(3)
169(3)
172(3)
172(3)
175(4)
175(4)
145(3)
173(4)
174(2)
169(2)
170(2)
168.6
b
2
O4−H4A···N3
c
3
N1#1−H1#1···N4
N5+#2−H5B#2···N6
N5+−H5A···N3−
N5#1−H5#1···N8
N9+#2−H9A#2···N7−
N10+#2−H10B#2···N2−
N1#3−H1A#3···N4#4
d
4
0.92
1.900
159.8
0.92
1.917
170.7
0.88
2.000
2.841
159.4
a
b
Symmetry codes: #1 1 + x, −1 + y, z; #2 x, 5/2 − y; #3 x, 5/2 − y, z +1/2. #1 1 − x, −y, 1 − z; #2 x, 1/2 − y, 1/2 + z; #3 x, 1/2 − y, −1/2 + z;
#4 −1 − x, −y, −z. #1 1/2 + x, 3/2 − y, −z + 1; #2 1/2 + x, y, 3/2 − z. #1 −1/2 + x, 1/2 − y, z; #2 1 − x, 1 − y, −1/2 + z; #3 1/2 + x, 3/2 − y, z;
#4 x, 1 + y, z. (D and A are hydrogen bond donors and acceptors).
c
d
from Aladdin reagent Inc. All of the other chemicals and solvents were
commercially available and used as received. Elemental analyses (EA) were
carried out by Elementar Vario EL elemental analyzer. The infrared spectra
(IR) were recorded in the 4000 to 400 cm−1 region using KBr pellets and a
Bruker EQUINOX 55 spectrometer. Thermogravimetric analyses (TGA)
were recorded on a Netzsch TG-209 instrument and platinum crucible in
nitrogen atmosphere, with a heating rate of 10 °C/min.
6-MP/4-Hydroxybenzoic Acid Cocrystal (1:1), 1. This cocrystal
was prepared via the following two methods: (i) A mixture of 6-MP·H2O
(34.0 mg, 0.2 mmol) and 4-hydroxybenzoic acid (27.6 mg, 0.2 mmol) was
added to 2 mL of methyl acetate and allowed to stir for 2 days at 50 °C.
The suspension was filtered and the isolated solid of 1 was dried under a
vacuum for 24 h at ambient temperature. Yield: 50.8 mg, 82.5%. The
filtrate was left to evaporate slowly at room temperature in a sealed glass
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Scheme 2. Hydrogen Bonds in the Structure of 6-MP·H2O (left), and Possible Hydrogen Bonding Synthons (I−IV) of 6-MP with
Coformers (right)
desiccator containing P2O5. After 4 days, block-shaped crystals of 1 were
obtained. (ii) A 1:1 mixture of 6-MP·H2O (170.2 mg, 1.0 mmol) and
4-hydroxybenzoic acid (138.1 mg, 1.0 mmol) was added to stainless
steel grinding jar. Approximately two drops of ethanol was added, and
the mixture was ground for 30 min at a frequency of 20 Hz. Anal. (%)
Calcd for C12H10N4O3S: C, 49.47; H, 3.47; N, 19.30; S, 11.05. Found: C,
49.45; H, 3.58; N, 19.30; S, 11.03. IR data (KBr, cm−1): 3015, 2813,
1669, 1618, 1589, 1382, 1256, 1166, 1156, 881, 772, 614, 528.
6-MP/2,4-Dihydroxybenzoic Acid Cocrystal (1:1), 2. This
cocrystal was prepared via the following two methods: (i) A mixture
of 6-MP·H2O (34.0 mg, 0.2 mmol) and 2,4-dihydroxybenzoic acid
(30.8 mg, 0.2 mmol) was added to 2 mL of methanol and allowed to stir
for 2 days at 50 °C. The suspension was filtered and the isolated solid of
2 was dried under a vacuum for 24 h at ambient temperature. Yield:
56.5 mg, 87.2%. The filtrate was left to evaporate slowly at room tem-
perature in a sealed glass desiccator containing P2O5. After 2 days, block-
shaped crystals of 2 were obtained. (ii) A 1:1 mixture of 6-MP·H2O
(170.2 mg, 1.0 mmol) and 2,4-dihydroxybenzoic acid (154.1 mg, 1.0 mmol)
was added to stainless steel grinding jar. Approximately two drops of
ethanol was added, and the mixture was ground for 30 min at a fre-
quency of 20 Hz. Anal. (%) Calcd for C12H10N4O4S: C, 47.05; H, 3.29;
N, 18.29; S, 10.47. Found: C, 46.88; H,3.39; N, 18.22; S, 10.41. IR data
(KBr, cm−1): 3047, 2914, 1643, 1623, 1566, 1351, 1255, 1179, 1017,
981, 847, 793, 621, 591, 481.
6-MP/Piperazinium Salt (1:1), 3. This salt was prepared via the
following two methods: (i) 6-MP·H2O (50.0 mg, 0.3 mmol) was added
to a nearly saturated solution of piperazine (100.0 mg, 1.2 mmol) in
methanol (1 mL) and allowed to stir for 2 days at 50 °C. The suspension
was filtered and the isolated solid of 3 was dried under a vacuum for 24 h
at ambient temperature. Yield: 53.2 mg, 35.5%. The filtrate was left to
evaporate slowly at room temperature in a sealed glass desiccator con-
taining P2O5. After 5 days, rod-shaped crystals of 3 were obtained.
(ii) A 1:1 mixture of 6-MP·H2O (170.2 mg, 1.0 mmol) and piper-
azine (86.1 mg, 1.0 mmol) was added to stainless steel grinding jar.
Approximately two drops of ethanol was added, and the mixture was
ground for 30 min at a frequency of 20 Hz. Anal. (%) Calcd for
C9H14N6S: C, 45.36; H, 5.92; N, 35.26; S, 13.46. Found: C, 45.41;
H, 5.80; N, 34.94; S, 13.34. IR data (KBr, cm−1): 3230, 1587, 1374,
1180, 1113, 1011, 852, 666, 573, 462, 416.
Nova CCD diffractometer, with Cu Kα radiation (λ = 1.5418 Å). Data
reduction and cell refinement were performed with the program of
CrysAlis PRO.23 The structures were solved by the direct method using
the SHELXS-97 programs24 and refined by the full-matrix least-squares
method on F2. All non-hydrogen atoms were refined with anisotropic
displacement parameters. One 6-MP anion in 4 is disordered, which was
refined with an occupancy ratio of 70:30. The positions of hydrogen
atoms on nitrogen and oxygen atoms in 1−3 were located in Fourier-
difference electron density maps; all the other hydrogen atoms were
placed in calculated positions with fixed isotropic thermal parameters
and included in the structure factor calculations in the final stage of full-
matrix least-squares refinement. Crystal data and details of refinements
of 1−4 are listed in Table 1, and the hydrogen bonding distances and
angles are given in Table 2.
X-ray Powder Diffraction (XRPD). Room and variable temper-
ature XRPD 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/step scan speed. Experimental
XRPD patterns were compared to XRPD patterns simulated from the
single crystal data of 1−4.
Powder Dissolution Experiments. Concentrations of 1−4 and
6-MP·H2O in the phosphate buffer of pH 6.8 were determined by a Cary
50 UV spectrophotometry, and the absorbance values were related to
solution concentrations using a calibration curve. The solids were milled
to powders and sieved using standard mesh sieves to provide samples
with approximate particle size ranges of 75−150 μm. In a typical experi-
ment, 100 mL of phosphate buffer (pH 6.8) was added to a flask con-
taining 300 mg of sample, and the resulting mixture was stirred at 25 °C
and 500 rpm. At each time interval an aliquot of the slurry was with-
drawn from the flask and filtered through a 0.22 μm nylon filter. And
appropriate dilutions were made to maintain absorbance readings
within the standard curve. The resulting solution was measured with a
UV/vis spectrophotometer. After the dissolution experiment, the
remaining solids were collected by filtration, dried and analyzed by
XRPD, and the pH values of the resulting solutions were also
measured.
Stability Test. Stability was evaluated at 40 °C/75% RH. Vial of each
sample was subjected to the condition for one month. Then the samples
were immediately analyzed by XRPD.
6-MP/Piperazinium Salt (2:1), 4. Amixtureof6-MP·H2O (170.2 mg,
1.0 mmol) and piperazine (43.0 mg, 0.5 mmol) was added to 6 mL of
ethanol and allowed to stir for 2 days at 50 °C. The suspension was
filtered and the isolated solid of 4 was dried under a vacuum for 24 h at
ambient temperature. Yield: 181.9 mg, 85.3%. The filtrate was left to
evaporate slowly at room temperature within a sealed glass desiccator
containing P2O5. After about 15 days, block-shaped crystals of 4 were
obtained. Anal. (%) Calcd for C14H17N10S2: C, 43.17; H, 4.40; N,
35.96; S, 16.47. Found: C, 43.11; H, 4.44; N, 35.94; S, 16.45. IR data
(KBr, cm−1): 3143, 1595, 1457, 1408, 1376, 1325, 1196, 1118, 995,
854, 654, 516, 424.
RESULTS AND DISCUSSION
■
To evaluate the potential for cocrystallization, the structure of
6-MP·H2O was analyzed in terms of the available hydrogen
bond donors and acceptors. In the structure of 6-MP·H2O,25
6-mercaptopurine molecules are connected by water molecules
via two hydrogen bonds of N−H(pyrimidine)···O(water) and
O−H(water)···N(imidazole) to form a 1D chain, and the adjacent
chains are further linked by N−H(imidazole)···N(pyrimidine)
hydrogen bonds to generate a 2D structure (Scheme 2). So
6-mercaptopurine has potential to form hydrogen bonds
(Scheme 2) with compounds containing carboxylic, hydroxyl
and amino groups, etc. Therefore, a series of coformers
Single Crystal X-ray Diffraction. Diffraction data for crystals 1, 2,
and 4 were collected using an Agilent Technologies Gemini A Ultra
system, and diffraction data for 3 were collected on an Agilent Xcalubur
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Figure 1. (a) 1D chain, (b) a crossover mode among 1D chains, (c) 3D framework with 1D channels, and (d) four-folded interpenetrating in 1.
containing such groups were used to screen cocrystals with
6-mercaptopurine monohydrate, and two cocrystals and two
salts were obtained.
Crystal Structures. The asymmetric unit of 1 contains one
6-MP and one 4-hydroxybenzoic acid molecules. As shown in
Figure 1a, 4-hydroxybenzoic acid molecules alternately connect
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Figure 2. (a) 1D zigzag chain, and (b) 3D structure in 2.
Figure 3. (a) 1D chain, (b) side view (left) and front view (right) of 2D sheet, (c) 3D structure in 3.
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Figure 4. (a) Two 1D anion chains of 6-MP connected by piperazinium cations in 4. (b) The 2D sheet. (c) A two-folded interpenetrating 2D bilayer.
(d) The 3D structure of 4.
6-MP molecules with three hydrogen bonds of N4−H4A···O1,
S1···H2A-O2 and O3−H3A···N2 to form a one-dimensional
(1D) chain. The 1D chains are further connected in a crossover
mode through N1−H1A···N3 hydrogen bonds (Figure 1b) to
generate a three-dimensional (3D) framework (Figure 1c) with
1D channels; the sizes of the channels are 16.13 × 24.76 Å.
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Because of the large void of the 1D channels in 1, the 3D
frameworks are four-folded interpenetrating26 to generate the
structure of 1 (Figure 1d).
Similar to 1, the asymmetric unit of 2 also contains one
6-MP and one 2,4-dihydroxybenzoic acid molecule. As shown in
Figure 2a, two 2,4-dihydroxybenzoic acid molecules form a dimer
through two O2···H1A-O1 intermolecular hydrogen bonds.
Two 6-MP molecules in 2 also form a dimer through two
S1···H1N−N1 intermolecular hydrogen bonds. Two dimers are
alternately linked through N3···H4A-O4 intermolecular hydro-
gen bonds to generate a 1D zigzag chain (Figure 2a). The 1D
chains are held together by N4−H4N···N2 hydrogen bonds to
generate the 3D structure of 2 (Figure 2b).
The asymmetric unit of 3 contains one 6-MP anion and one
piperazinium cation, in which a proton is transferred from
the imidazole group of 6-MP to the nitrogen atom of piperazine.
As shown in Figure 3a, all the 6-MP anions form a 1D anion
chain through intermolecular N4···H1−N1 hydrogen bonds, all
the piperazinium cations also form a 1D cation chain through
N6···H5B−N5+ hydrogen bonds. The 6-MP anion chains alter-
nately connect the piperazinium cation chains through charged-
assisted hydrogen bonds27−30 of N3−···H5A−N5+ to form a 2D
wave-like sheet (Figure 3b). The 2D wave-like sheets are further
held together through intersheet π···π interactions to form the
3D structure of 3 (Figure 3c), with the centroid···centroid
distance31 of 4.23 Å.
In contrast to 3, the asymmetric unit of 4 contains two 6-MP
anions and one piperazinium cation, in which two protons are
transferred from two imidazole groups of two 6-MP molecules
to two nitrogen atoms of one piperazine molecule. As shown
in Figure 4a, the 6-MP anions are separately linked by inter-
molecular hydrogen bonds of N8···H5−N5 and N4···H1A−N1
to form two 1D chains. The adjacent 1D chains are further
connected by piperazinium cations through two charged-assisted
hydrogen bonds27−30 N9+−H9A···N7− and N10+−H10B···N2−
to generate a 2D sheet (Figure 4b). The 2D sheets are two-folded
interpenetrating26 to form a 2D bilayer (Figure 4c), and the 2D
bilayers are further connected by the interlayer π···π interactions
to generate the 3D structure of 4 (Figure 4d), with a centroid···
centroid distance31 of 4.267 Å.
XRPD Analyses and Powder Dissolution Studies. XRPD
was used to check the crystalline phase purity of 1−4. The results
show that the patterns of the products are different from either
that of 6-MP·H2O or those of corresponding coformers (Figure
S1), indicating the formation of new crystalline phases, and all
the peaks displayed in the measured patterns for 1−4 closely
match those in the simulated patterns generated from single-
crystal diffraction data (Figure S1), confirming the single phases
of 1−4 were formed, and the isolated solids 1−4 are the same
forms as the single crystals.
Dissolution rate and apparent solubility of solids are of
paramount importance in pharmaceutical development and
quality control, and shorter dissolution times and higher
apparent solubility may result in more absorption. Powder
dissolution profiles for 6-MP·H2O and 1−4 in phosphate
buffer of pH 6.8 are shown in Figure 5. It can be found that
1−4 show an increase in the dissolution rate and solubility
values. Compounds 1 and 2 reach a maximum solubility
(Smax) within 15−20 min, while 3 and 4 reach Smax after 5 min,
and then decrease over the time. This specific type of profile
is a product of the “spring and parachute effect” which has
been exhibited by many pharmaceutical cocrystals.32−35 The
maximum solubility values for 1, 2, 3 and 4 are approximately
Figure 5. Powder dissolution profiles for 6-MP·H2O and 1−4 in the
phosphate buffer of pH 6.8.
1.6, 2.0, 14.0, and 4.2 times as large as that of 6-MP·H2O. The
pH values of the resulting solutions for 1−4 and 6-MP·H2O
after the powder dissolution experiments were measured,
and no significant pH change was observed. The undissolved
solids were filtered and dried under a vacuum, and the results
of XRPD analyses indicate 1−4 transformed to 6-MP·H2O
(Figure S2).
Stability. Since 1−4 transformed to 6-MP·H2O during the
powder dissolution experiments, the cocrystals and salts may also
give rise to solid-state physical stability concerns. Consequently,
the stability of 1−4 at 40 °C/75% RH was also monitored for
one month. The results of XRPD measurements indicate that 1, 2
and 4 remained their initial crystal form, while 3 converted to
4 (Figure S3). This means that 4 is more stable than 3 at 40 °C/
75% RH. The strong volatility of piperazine is a major reason for
the transformation from 3 to 4.
The results of TGA also demonstrate that 4 is more stable
than 3. The TGA curves of 3 and 4 show a weight loss starting
at 142 and 173 °C, respectively (Figure S4); the weight loss of
33.0% between 142 and 181 °C for 3 is consistent with the
loss of one piperazine molecule (calcd 33.1%), and the weight
loss of 22.0% between 173 and 207 °C for 4 is consistent with
the loss of half piperazine molecule (calcd 22.1%). Variable
temperature XRPD was used to monitor the transition from 3
to 4 (Figure 6). The XRPD patterns of 3 show that 3 maintains
its crystallinity up to 140 °C, and then it transforms to the
mixture of 4 and 6-MP at 145 °C and completely transforms to
6-MP at 155 °C.
6010
dx.doi.org/10.1021/cg3010745 | Cryst. Growth Des. 2012, 12, 6004−6011

Crystal Growth & Design
Article
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Two cocrystals of 6-MP with 4-hydroxybenzoic acid (1) and
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piperazine in 1:1 (3) and 2:1 (4) stoichiometry, were syn-
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X-ray diffraction. The structures of 1−4 are assembled via inter-
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been increased after the formation of 1−4, indicating the sol-
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ASSOCIATED CONTENT
* Supporting Information
The XPRD patterns for 1−4 and TGA curves for 1 and 2. This
material is available free of charge via the Internet at http://pubs.
acs.org.
■
S
(27) Drask
̌
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AUTHOR INFORMATION
Corresponding Author
*Fax: +86-20-84112921. E-mail: chenjm37@mail.sysu.edu.cn
(J.-M.C.); lutongbu@mail.sysu.edu.cn (T.-B.L.).
■
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Notes
The authors declare no competing financial interest.
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Des. 2009, 9, 1344−1352.
(34) Takata, N.; Takano, R.; Uekusa, H.; Hayashi, Y.; Terada, K. Cryst.
Growth Des. 2008, 8, 3856−3862.
ACKNOWLEDGMENTS
■
This work was supported by 973 Program of China
(2012CB821705), NSFC (91127002, 21121061, 20831005
and 21101173).
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