Crystal Growth & Design
Article
refined by the full-matrix least-squares method on F2. All non-
hydrogen atoms were refined with anisotropic displacement
parameters. The 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. Crystallographic data and details of refinements of 1−3
are listed in Table 1, and the hydrogen bonding distances and angles
are given in Table 2.
made to maintain absorbance readings within the standard curve. After
the dissolution experiment, the remaining solid was collected by
filtration, dried, and analyzed by XRPD, and the pH value of the
resulting solution was also measured.
Intrinsic Dissolution Measurement. The intrinsic dissolution
rate (IDR) experiments of solid materials were carried out on a ZQY-2
Dissolution Tester (Shanghai Huanghai Yaojian instrument distribu-
tion Co., Ltd.). Approximate 80 mg of each solid was compressed in a
hydraulic press at 0.5 t for 2 s in a die of 5 mm diameter disk. The disk
was coated using paraffin wax, leaving only the surface under
investigation free for dissolution. Then the disk was dipped into 900
mL of 0.02 M phosphate buffer (pH 6.8) at 37 °C, with the paddle
rotating at 100 rpm. At each time interval, 2 mL of the dissolution
medium was withdrawn and replaced by an equal volume of fresh
medium to maintain a constant volume. After filtration through a 0.22
μm nylon filter, solutions were injected into the HPLC system for
analysis.
Dynamic Vapor Sorption (DVS). DVS study was performed on a
DVS Intrinsic instrument (Surface Measurement Systems, UK). All
samples were initially dried for several hours under a stream of
nitrogen to establish the equilibrium dry mass under 25 °C. Then the
relative humidity (RH) was increased in 10% RH steps to 95% RH.
Finally, the RH was decreased in a similar fashion for the desorption
phase. The temperature was maintained at a constant of 25 0.1 °C.
The sorption/desorption isotherms were calculated from the
equilibrium mass values.
Table 2. Hydrogen Bonding Distances and Angles for 1−3
D−H···A
D···A (Å)
D−H···A (deg)
a
1
N3−H3···O5
2.832(2)
2.949(3)
3.167(3)
2.877(2)
2.937(3)
3.032(3)
3.361(3)
177(2)
167(2)
148(3)
172(2)
178(3)
167(2)
148(3)
N1−H2···O1#1
N1−H1···O2#2
N5−H7···O1#3
N5−H6···O5#4
N4−H4···O2
N4−H5···N1#5
b
2
N3−H3···O4#1
N1−H1A···O5#2
N1−H1B···O1#3
N1−H1B···O2#4
O6−H6···O7#5
O4−H4···O3
2.949(3)
3.324(3)
2.788(3)
3.251(3)
2.601(2)
2.749(3)
2.809(3)
166(3)
150(3)
116(3)
152(3)
176.7
RESULTS AND DISCUSSION
172.9
■
O5−H5···N1#6
166.7
Crystal Structures. The asymmetric unit of 1 contains one
urea and one Rev molecules, in which the urea molecules
alternately link the Rev molecules through N3−H3···O5 and
N4−H4···O2 (synthon I), and N5−H7···O1#3 intermolecular
hydrogen bonds to form a wave-shaped chain along the a axis
(Figure 1a). The adjacent chains are further connected via two
interchain hydrogen bonds to generate a two-dimensional (2D)
sheet along the b axis (Figure 1b), in which two hydrogen
bonds are formed between the adjacent two Rev molecules
(N1−H2···O1#1). The 2D sheets are further held together
through three hydrogen bonds (N1−H1···O2#2, N5−H6···
O5#4 and N4−H5···N1#5) and π···π interactions to form a
three-dimensional (3D) structure of 1, with the centroid···
centroid distance of 3.671 Å (Figure 1c).
c
3
O4−H13···O9
2.574(2)
2.722(2)
2.827(3)
2.623(2)
2.692(2)
2.794(2)
2.775(3)
2.990(3)
3.103(3)
3.028(3)
3.119(3)
2.975(3)
174.9
O6−H16···O3#1
O7−H18···N1#2
O10−H24···O12#3
O8−H19···O5
O11−H21···O5#4
O12−H25···O1#5
O12−H26···O7
O12−H26···O10#6
N1−H1···O2#2
N1−H2···O10#7
N3−H3···O6
172.8
170.6
174.4
178.5
158.5
167(4)
136(3)
121(3)
156(2)
152(3)
179(3)
a
Symmetry codes. #1 x−1/2,−y+3/2,z; #2 −x+3/2,y+1/2,−z+2; #3
Similar to 1, the asymmetric unit of 2 contains one 35DHBA
and one Rev molecules, in which the 35DHBA molecules
alternately link the Rev molecules through O4−H4···O3
(synthon III) and O5−H5···N1#6 intermolecular hydrogen
bonds to form a chain along the c axis (Figure 2a). Two
adjacent chains are connected with each other through N3−
H3···O4#1 hydrogen bonds (synthon IV) and interchain
hydrogen bonds (O6−H6···O7#5) to generate a 2D sheet
along the b axis (Figure 2b). The 2D sheets are further held
together through three hydrogen bonds (N1−H1A···O5#2,
N1−H1B···O1#3 and N1−H1B···O2#4) to form a 3D
structure (Figure 2c).
In contrast to 1 and 2, the asymmetric unit of 3 contains one
Rev, two 35DHBA and one water molecules, in which two
35DHBA molecules form a dimer through O4−H13···O9 and
O8−H19···O5 intermolecular hydrogen bonds. Two dimers
and one Rev molecule are linked by a water molecule through
O12−H26···O7, O12−H26···O10#6 and O12−H25···O1#5
intermolecular hydrogen bonds to form a chain along the c
axis. The adjacent chains are further connected via interchain
hydrogen bonds (N3−H3···O6, synthon IV) to generate a 2D
sheet along the b axis (Figure 3b). The 2D sheets are further
held together through additional hydrogen bonds (O6−H16···
b
x−1/2,−y+1/2,z; #4 −x+1,−y,−z+1; #5 x,y−1,z. #1 −x+1,−y+1,−z
+1; #2 −x+1,−y+2,−z+1; #3 x+1,y,z; #4 −x+2,−y+1,−z+2; #5 −x,−y
c
+3,−z+1; #6 x−1,y,z−1. #1 −x,−y+2,−z+1; #2 −x−1,−y+1,−z; #3 x
+1,y,z+1; #4 −x+1,−y,−z+1; #5 x,y−1,z; #6 −x+1,−y+1,−z+1; #7
−x,−y+1,−z+1 (D and A are hydrogen bond donors and acceptors).
High Performance Liquid Chromatography (HPLC) Analysis.
The contents of Rev were analyzed by a Shimadzu LC-20A HPLC
system, with a C18 column (Inertsil ODS-3, 5 μm × 4.6 mm × 150
mm column, GL Sciences Inc., Japan) and a UV detection wavelength
of 304 nm. The mobile phase consisted of acetonitrile/H2O (90/10,
v/v) for 1 and acetonitrile/0.1% phosphoric acid (88/12, v/v) for 2
and 3, with a flow rate of 1.0 mL/min.
Powder Dissolution Experiments. Concentrations of 1−3 and
Rev·0.5H2O in 0.2 M phosphate buffer of pH 6.8 were determined by
HPLC analysis, and peak area 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
experiment, 50 mL of phosphate buffer was added to a flask containing
134 mg of Rev·0.5H2O (or corresponding to, for cocrystals 1−3), and
the resulting mixture was stirred at 37 °C and 500 rpm. At each time
interval, an aliquot of the slurry was withdrawn from the flask and
filtered through a 0.22 μm nylon filter. Appropriate dilutions were
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dx.doi.org/10.1021/cg500327s | Cryst. Growth Des. 2014, 14, 3069−3077