Download Cocrystal and Salt Forms of Furosemide: Solubility and Diffusion

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Cocrystal and Salt Forms of Furosemide: Solubility and Diffusion
Variations
Manas Banik, Shanmukha Prasad Gopi, Somnath Ganguly, and Gautam R. Desiraju*
Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India
S Supporting Information
*
ABSTRACT: Multicomponent solid forms of the BCS class IV
drug furosemide (FSM) were obtained upon liquid assisted
grinding with coformers anthranilamide (ANT), 4-toluamide
(TOL), 2-picolinamide (PCM), piperazine (PPZ), 2,3,5,6tetramethylpyrazine (TMPZ), pyrazine (PYZ), 2-picolinic acid
(PIC), isoniazid (INZ), and theophylline (THP), and identified
with powder X-ray diffraction. Solid forms FSM−TMPZ (2:1),
FSM−ANT (1:1), FSM−PPZ (1:1), and FSM−TOL ethanol
solvate (1:1:1) were further characterized with single crystal Xray diffraction and differential scanning calorimetry; a
sesquihydrate structure for FSM−PCM (1:1:1.5) was additionally confirmed with thermogravimetric analysis. The
thermodynamically stable form I of FSM contains O−H···O acid···acid and N−H···O sulfonamide dimer synthons and chains.
These synthons are modified in the cocrystals/salts sometimes leading to changes in physicochemical properties. The FSM−PPZ
(1:1) salt converted to a thermodynamically more stable form FSM−PPZ (2:1) within 1 h. The apparent solubility of FSM−PPZ
(1:1) salt is ∼3 times higher than the equilibrium solubility of the thermodynamically stable FSM−PPZ (2:1) salt. The
solubilities of FSM−TMPZ and FSM−ANT are comparable to FSM, and this could be linked to coformer solubility. The
metastable FSM−PCM sesquihydrate exhibited unusually high FSM concentration in solution as a function of time and as
monitored in a slurry experiment. This prolonged presence of FSM in solution is rationalized by a synthon-extended-spring-andparachute model. Our rationale starts with Nangia’s explanation of the apparently high solubility of pharmaceutical cocrystals
based on the simple spring-and-parachute model of Guzman et al. and later detailed by Brouwers et al. We go on to suggest that
certain heteromolecular aggregates might well persist in soluble amorphous forms leading to a higher persistence of the drug in
solution. Cocrystals/salts with higher solubility show higher values of initial diffusion/flux. A few bases when used as coformers
render stable salt/cocrystals that resulted in low solubility/diffusion. In the new solid forms of FSM studied here, solubility and
flux are seen to go hand in handan observation of import in drug absorption.
■
INTRODUCTION
A significant number of pharmaceutical leads being synthesized
today tend to have high lipophilicity, and this reduces drug
absorption leading to a high rate of failure.1−3 To increase
solubility of such compounds, formulations have been used, but
these show a drop in membrane permeability.4,5 Permeability
through the GI tract is an important parameter in absorption,
and low permeability causes poor absorption.6 Modification of
the physical properties of pharmaceutical substances has been a
subject of considerable interest, and the design of new solid
forms using suitable and accepted modifiers known as
coformers is an active area of research.7 The solubility and
release rates of these solid forms have been studied
extensively.8−15 However, only a few of these have been
studied for permeability/diffusion behavior.11,16,17 Sanphui et
al. reported simultaneous enhancements in both solubility and
permeability for a few cocrystals of BCS class IV hydrochlorothiazide.11 These authors indicated that the physical
properties of the coformers and drug−coformer interactions of
the cocrystal have an important bearing on the solubility and
permeability/diffusion of the cocrystal.
© 2016 American Chemical Society
To investigate this further, another BCS class IV drug
furosemide (FSM) was chosen for the present study.18,19 FSM
is a loop diuretic and acts on the ascending loop of Henle in the
kidney inhibiting the reabsorption of NaCl.20,21 Oral
formulations of FSM are commonly used in the treatment of
edema, congestive heart failure, renal failure, and hypertension.22 It exhibits poor solubility (7.31 mg/L) and
permeability (Caco2 permeability = −6.5).21,23 FSM is a
conformationally flexible molecule with −SO2NH2 groups and
a dangling furan moiety and also has three hydrogen bond
donating groups: −COOH, −SO2NH2, and −NH−. Lack of
hydration/solvation potential arising from strong intra- and
intermolecular H-bonding interactions and the presence of
furan rings causes poor solubility. Nangia et al. used
cocrystallization methods to improve solubility and dissolution
of FSM relative to the parent FSM (10% ethanol−water) but
encountered stability problems in the cocrystals.24 FSM has
Received: June 14, 2016
Revised: July 19, 2016
Published: July 21, 2016
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FSM−ANT (1:1). 0.30 mmol of FSM and 0.30 mmol of ANT were
ground together with a few drops of MeOH and dissolved in a variety
of solvents. Colorless plate-like crystals were harvested from MeOH/
MeCN solvent mixture after 3−4 days.
FSM−TOL Solvate (1:1:1). 0.30 mmol of FSM and 0.30 mmol of
TOL were ground with a few drops of MeOH. Colorless needle
crystals of 1:1:1 MeOH, EtOH, and MeNO2 solvates of FSM-TOL
were obtained from MeOH, EtOH, and MeNO2 respectively after 3−5
days. Bulk FSM−TOL−EtOH was also synthesized from both slurry
crystallization and liquid assisted grinding with EtOH. FSM-toluene
solvate single crystals were obtained when the above powder cocrystal
was crystallized from a MeOH/toluene solvent mixture.
FSM−PCM Sesquihydrate (1:1:1.5). 0.30 mmol of FSM and 0.30
mmol of PCM were ground together with a few drops of acetone and
dissolved in a variety of solvents. Colorless needle-like crystals were
harvested from acetone after 2−3 days.
FSM−PPZ (1:1). 0.30 mmol of FSM and 0.30 mmol of PPZ were
ground together with a few drops of MeOH (or acetone) and
dissolved in a variety of solvents. Yellow block-shaped crystals were
harvested from MeOH/EtOH solvent mixture after 4−5 days.
FSM−PPZ (2:1). FSM-PPZ (II) was prepared stirring 200 mg of
FSM−PPZ (1:1) in 5−6 mL of pH 7.4 buffer; the residue was filtered,
dried, and dissolved in a variety of solvents. Alternatively 0.30 mmol of
FSM and 0.15 mmol of PPZ were ground together with a few drops of
MeOH and dissolved in a variety of solvents. White needle-shaped
crystals were harvested from MeOH after 2−3 days.
FSM−THP (1:1). 0.30 mmol of FSM and 0.30 mmol of THP were
ground for 2 min in the presence of a few drops of acetone then 15
min in presence MeCN. No single crystals could be grown. Formation
of a new solid phase was confirmed by PXRD.
FSM−PIC. 0.30 mmol of FSM and 0.30 mmol of PIC were ground
together with a few drops of MeOH (or acetone). Formations of new
solid phases were confirmed by PXRD.
FSM−PYZ. 0.30 mmol of FSM and 0.30 mmol of PYZ were ground
together with a few drops of MeOH. Formation of a new solid phase
was confirmed by PXRD.
FSM−INZ. 0.30 mmol of FSM and 0.30 mmol of INZ were ground
together with a few drops of MeOH (or acetone). Formations of new
solid phases were confirmed by PXRD.
Bulk samples and batches were prepared following the abovementioned procedures (solvent drop grinding). Phase purity of these
samples was confirmed by comparison of experimental powder pattern
with the calculated powder pattern from the single crystal X-ray
structure. Recrystallization was performed in the case of slightly
impure samples.
Solubility Measurements. The absorption coefficient of each
solid phase was measured from the slope of the absorbance vs
concentration curve of more than five known concentrated solutions
in pH 7.4 buffer phosphate medium and measured at 330 nm in a
PerkinElmer UV−vis spectrometer (for ANT, the 277 nm peak was
chosen as both API and coformer show UV peaks at ∼330 nm). The
solubility of each solid was measured at an interval of 1 h, 4 h, and 24 h
using the shake-flask method at room temperature (27 ± 2 °C).34 The
experiments were repeated twice or thrice.
Diffusion Measurements. Diffusion studies of FSM and its
cocrystals/salts were carried out according to the literature using the
modified Franz diffusion cell apparatus through a cellulose nitrate
membrane (0.45 μm, 11306, Sartorius, Germany).11 The effective
surface area of the dialysis membrane was 4.5 cm2. A 100 mg finely
powdered sample (average particle size ∼2−10 μm, measured using
FESEM) was taken in the donor compartment in all experiments. The
receptor compartment was filled with 20 mL of phosphate buffer (pH
7.4) and stirred at 60 ± 5 rpm. The diffusion samples were analyzed in
a UV−visible spectrophotometer at a λmax of 330 nm (for FSM−ANT
277 nm) after suitable dilution. The concentrations of cocrystals and
API were measured, in pH 7.4 buffer at room temperature (27 ± 2
°C), at 1 h intervals until 8 h of the diffusion experiment. No
significant change of pH was noticed in the receptor compartment
solution after diffusion experiments. All diffusion measurements were
repeated twice.
been investigated heavily in the context of solid forms, and a
number of reports on salts, cocrystals and solvates of FSM have
appeared recently.25−30 However, none of these papers throw
much light on flux/diffusion behavior.
In our search for new solid forms of FSM, the acid···amide
and acid···Nheterocyclic supramolecular synthons were targeted
using crystal engineering with coformers containing basic
nitrogen and −CONH2 groups, which would be complementary to the −COOH group of FSM.31−33 New solid forms of
FSM were found with the coformers piperazine (PPZ), 2,3,5,6tetramethylpyrazine (TMPZ), 2-picolinamide (PCM), anthranilamide (ANT), 4-toluamide (TOL), theophylline (THP),
pyrazine (PYZ), 2-picolinic acid (PIC), and isoniazid (INZ).
These solids were characterized using single-crystal X-ray
diffraction (SCXRD), powder X-ray diffraction (PXRD),
differental scanning calorimetry (DSC), Fourier transform
infrared (FTIR) spectroscopy, and thermogravimetric analysis
(TGA); then the solubility (pH 7.4 buffer) and diffusion
behavior were studied. An interpretation of the physicochemical properties was finally attempted through an analysis of
structural and thermal data.
Scheme 1. Furosemide (FSM) and Coformers in the Present
Study
■
EXPERIMENTAL SECTION
FSM was obtained from Yarrow Chem Products, Mumbai, India and
used as such. Melting points were measured on a Büchi melting point
apparatus (Sigma-Aldrich, Bangalore, India). Water filtered through a
double distilled water purification system (Siemens, Ultra Clear,
Germany) was used in all experiments. FTIR spectra were recorded
using an ATR accessory on a PerkinElmer (Frontier) spectrophotometer (4000−600 cm−1). PXRD data were recorded using a
PANalytical X-ray powder diffractometer equipped with a X’cellerator
detector at room temperature with the scan range 2θ = 5 to 35° and
step size 0.026°. X’Pert HighScore Plus were used to compare the
experimental PXRD pattern with the calculated lines from the crystal
structure. Solid state grinding, solution crystallization, and slurry
methods in polar solvents such MeOH, EtOH, acetone, and MeCN
were used to obtain the cocrystals.
Preparation of Furosemide Salt/Cocrystals. FSM−TMPZ (2:1).
0.30 mmol of FSM and 0.15 mmol of TMPZ were ground together
with a few drops of MeOH and dissolved in a variety of solvents.
Colorless needle-like crystals were harvested from MeOH after 3−4
days.
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Table 1. Crystallographic Parameters of FSM Salt, Solvate, and Cocrystals
compound
emp formula
formula wt
crystal system
space group
T/K
a/Å
b/Å
c/Å
α/°
β/°
γ/°
volume/Å3
Z
Dcalcd (g cm−3)
μ (mm−1)
F(000)
total ref
unique ref
observed ref (I > 2σ(I))
Rint
R1 (I > 2σ(I))
wR2
completeness (%)
goodness-of-fit
2θ range
CCDC No.
compound
emp formula
formula wt
crystal system
space group
T/K
a/Å
b/Å
c/Å
α/°
β/°
γ/°
volume/Å3
Z
Dcalcd (g cm−3)
μ (mm−1)
F(000)
total ref
unique ref
observed ref (I > 2σ(I))
Rint
R1 (I > 2σ(I))
wR2
completeness (%)
goodness-of-fit
2θ range
CCDC No.
FSM−TMPZ
FSM−ANT
FSM−PPZ
FSM−PCM hydrate
C16H17ClN3O5S
C19H19ClN4O6S
C16H21ClN4O5S
398.84
466.89
416.88
monoclinic
monoclinic
monoclinic
P21/c
C2/c
P21/n
150
150
150
13.624(3)
10.3022(14)
13.339(6)
5.4540(13)
15.721(2)
8.792(4)
24.623(6)
26.101(5)
16.202(7)
90
90
90
98.232(7)
91.402(9)
98.941(6)
90
90
90
1810.8(7)
4226.1(11)
1877.0(14)
4
8
4
1.463
1.468
1.475
0.359
0.324
0.351
828
1936
872
13460
19189
16556
3560
4151
3686
2067
3426
3464
0.102
0.072
0.133
0.0699
0.0555
0.0520
0.1951
0.1834
0.1579
99.9
99.8
99.9
1.03
1.17
1.15
3.02−26
1.56−26
1.84−25.99
1470973
1470970
1470971
FSM−TOL−EtOH
FSM−TOL−MeOH
FSM−TOL−MeNO2
FSM−toluene
C22H26ClN3O7S
511.97
monoclinic
P21/c
150
11.2753(17)
9.3387(10)
22.881(4)
90
101.364(6)
90
2362.1(6)
4
1.440
0.299
1072
20795
4629
4192
0.055
0.0435
0.1531
99.9
1.12
1.82−26
1470974
C21H24ClN3O7S
497.94
monoclinic
P21/c
150
11.0827(16)
9.0114(11)
23.460(4)
90
99.520(6)
90
2310.7(6)
4
1.431
0.303
1040
20951
4533
4171
0.093
0.0454
0.1485
99.9
1.14
1.76−26
1470976
Dissolution. Intrinsic dissolution rate (IDR) and was measured in
an Electrolab dissolution tester. A 200 mg portion of the solid was
taken in the intrinsic attachment and compressed to a 0.5 cm2 pellet
using a hydraulic press at a pressure of 2.5 ton/in for 3 min. The pellet
was compressed to provide a flat surface on one side, and the other
side was sealed. Then the pellet was dipped into 500 mL of pH 7.4
buffer medium at 37 °C with the disk rotating at 150 rpm. At regular
C21H23ClN4O8S
526.94
monoclinic
P21/c
150
11.673(3)
8.8845(19)
23.058(5)
90
99.784(7)
90
2356.5(9)
4
1.485
0.306
1096
20134
4617
2414
0.154
0.0732
0.1771
99.8
1.00
1.76−26
1470975
C31H29Cl2N4O10S2
752.63
triclinic
P1̅
150
8.133(8)
10.449(9)
10.926(9)
63.91(4)
78.79(4)
80.82(4)
815.1(13)
1
1.533
0.392
389
7567
3189
2612
0.117
0.0597
0.1918
99.9
1.13
2.10−25.99
1470977
C18H15ClN4O7.68S
477.73
triclinic
P1̅
150
5.117(2)
14.475(6)
14.859(6)
76.363(7)
82.502(8)
87.226(8)
1440.0(2)
2
1.497
0.331
491
8489
4103
1614
0.163
0.1077
0.2694
98.0
1.00
3.48−25.99
1470972
FSM−PPZ (2:1)
C14H16ClN3O5S
373.81
monoclinic
P21/n
293
6.4623(9)
19.983(3)
13.1428(17)
90
98.376(7)
90
1679.1(4)
4
1.479
0.382
776
15435
3284
2496
0.044
0.0473
0.1176
99.8
1.07
3.1−26
1483447
intervals of specified time (30 min for FSM, FSM−ANT, FSM−PPZ
(2:1), 3 min for FSM−PCM sesquihydrate, FSM−TOL−EtOH,
FSM−THP and 5 min for FSM−PPZ (1:1)), 5 mL of the dissolution
medium was withdrawn and replaced by an equal volume of fresh
medium to maintain a constant volume. Samples were filtered through
nylon filters and spectrophotometrically assayed for drug content at
330 nm (for FSM−ANT 277 nm) on a Thermo scientific EV201 UV−
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Figure 1. Crystal structure of FSM−TMPZ: (a) 2D corrugated layer view along the b-axis (b) 1D catemer-like chain via N−H···O hydrogen bonds
along the b-axis.
Figure 2. Crystal structure of FSM−ANT: (a) acid···amide heterodimer synthons form 1D chain via N−H···O hydrogen bonds along the b-axis (b)
1D stacked chains: view along the b-axis.
Figure 3. Crystal structure of FSM−PPZ: (a) PPZ···PPZ 1D zigzag chain extending along the b-axis (b) FSM tetramer 1D chain extending along the
b-axis (c) 2D layer view along the b-axis.
data were processed with the Rigaku Crystal clear software.35 Structure
solution and refinements were executed using SHELX-9736 using the
WinGX37 suite of programs. Refinement of coordinates and
anisotropic thermal parameters of non-hydrogen atoms were
performed with the full-matrix least-squares method. The differing
treatment of H atoms in D−H in any structure depends on data
quality. The H atom positions were located from difference Fourier
maps or calculated using a riding model. The PLATON38,39 software
was used to prepare material for publication, and Mercury 3.7 was
utilized for molecular representations and packing diagrams. Crystallo-
vis spectrometer. The amount of drug dissolved in each time interval
was calculated using a calibration curve. The linear region of the
dissolution profile was used to determine the intrinsic dissolution rate
(IDR) of the compound. Diffusion measurements were repeated twice.
Buffer Preparation. 50 mL of 0.2 M KH2PO4 was taken into a
200 mL volumetric flask followed by 39.1 mL of 0.2 M NaOH; water
was then added to fill the volume.
Single Crystal X-ray Diffraction. Single crystal X-ray data were
collected on a Rigaku Mercury 375/M CCD (XtaLAB mini)
diffractometer using graphite monochromated Mo Kα radiation. The
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Figure 4. Crystal structure of FSM−TOL−EtOH: (a) acid···amide heterodimer synthons give 1D chain via N−H···N hydrogen bonds along the baxis (b) FSM−ethanol 1D tape along the b-axis.
graphic cif files (CCDC Nos. 1470970−1470977 and 1483447) are
available at www.ccdc.cam.ac.uk/data_request/cif or as part of the
Supporting Information (SI).
■
RESULTS AND DISCUSSION
FSM−TMPZ (2:1), FSM−ANT (1:1), FSM−PPZ (1:1),
FSM−TOL−EtOH (1:1:1), and FSM−PCM sesquihydrate
Figure 5. Crystal structure of FSM−PCM sesquihydrate: amide···
pyridine homodimer synthons and sulfonamide···water interactions
along the a-axis.
Figure 7. Simple spring-and-parachute model for cocrystals (according
to Nangia).
were characterized by DSC and single crystal X-ray diffraction;
in addition, the stoichiometry of the FSM−PCM sesquihydrate
(1:1:1.5) was confirmed with TGA. Isomorphous FSM−TOL
cocrystal solvates of EtOH, MeOH, and MeNO2 were obtained
from the respective solvents. FSM−toluene solvate was
obtained serendipitously when a FSM−TOL mixture was
crystallized from an MeOH/toluene solvent mixture (Figure
S1). FSM−PPZ (1:1) transformed to FSM−PPZ (2:1) salt
when stirred in buffer. FSM−THP complex formation was
confirmed only with PXRD and DSC as no suitable single
crystal was obtained for SCXRD. For the rest of the
compounds, multiple endotherms were seen for an equimo-
lecular ground powder. Solution crystallization of these forms
led to disintegration, which can be attributed to a mismatch of
solubility between the FSM and coformers. The crystallographic parameters and normalized hydrogen bonds for the
crystal data are summarized in Table 1 and Table S1 in the SI.
Structural Studies. FSM−TMPZ (2:1). FSM−TMPZ
cocrystal crystallizes in the P21/c space group with Z = 4.
The TMPZ molecule lies on the inversion center. The cocrystal
adopts a 2D corrugated layer structure through the acid···
pyridine (d: 1.869 Å; θ: 160.28°) synthons which connect FSM
catemer-like 1D chains forming from SO2HN−H···OS (d:
2.131 Å; θ: 152.85°) hydrogen bonds between neighboring
Figure 6. Crystal structure of FSM−PPZ (2:1): (a) FSM···PPZ 1D zigzag chain extending along the a-axis (b) extended supramolecular structure
along the bc-plane.
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Figure 8. Proposed mechanism of synthon-extended-spring-and-parachute model.
Table 2. Solubility and Stability Profiles of FSM in pH 7.4 Buffer
compounds
first hour
(mg/mL)
fourth hour
(mg/mL)
24th hour
(mg/mL)
FSM
FSM−CAF
FSM−CYT
FSM−ADE
FSM−TMPZ
FSM−ANT
FSM−PPZ (1:1) salt
FSM−PPZ (2:1) salt
FSM−THP
FSM−TOL−EtOH
FSM−PCM sesquihydrate
6.81
3.03
3.01
5.80
7.78
6.02
15.07
7.12
7.80
8.83
11.28
7.38
3.29
3.15
5.98
8.16
6.31
7.28
2.70
2.35
4.96
7.31
7.15
7.61
FSM
FSM−PPZ (2:1) salt
FSM−PPZ (1:1) salt
FSM−ANT
FSM−PCM
sesquihydrate
FSM−TOL−EtOH
FSM−THP
IDR
(mg cm−2 min−1)
apparent solubility
(mg/mL)
1.003
0.807
2.425
0.882
1.416
7.28
7.61
22.86
6.40
10.28
1.200
1.074
8.71
7.80
FSM
FSM−CAF
FSM−CYT
FSM−ADN
FSM−TMPZ
FSM−ANT
FSM−PPZ (2:1)
FSM−PPZ (2:1)
FSM, THP hydrate
FSM, TOL
FSM
residue (fourth
hour)
residue (24th
hour)
FSM
FSM−CAF
FSM−CYT
FSM−ADN
FSM−TMPZ
FSM−ANT
FSM
FSM−CAF
FSM−CYT
FSM−ADN
FSM−TMPZ
FSM−ANT, FSM
FSM−PPZ (2:1)
FSM−PPZ (2:1)
interactions between alkyl C−H groups and Cl-atoms of
neighboring FSM molecules.
FSM−PPZ (1:1). The FSM−PPZ salt crystallizes in the P21/n
space group with Z = 4. The electron density map showed that
the acidic H atom of the FSM carboxyl group is transferred to
one of the basic N atoms of PPZ resulting in an N+−H···O− (d:
1.793 Å; θ: 166.61°) ionic interaction. Protonated PPZ
molecules are linked through N−H···N (d: 1.842; θ:
163.54°) hydrogen bonds to give PPZ···PPZ zigzag chains
along the b-axis (Figure 3a). FSM molecules are connected with
SO2HN−H···O (d: 2.004 Å, 2.195 Å; θ: 171.65°, 136.63°)
hydrogen bonds forming a tetramer synthon chain also along
the b-axis (Figure 3b). These adjacent FSM-tetramer chains
and PPZ chains are connected to each other through ionic
interactions to form a 2D layer structure (Figure 3c). Finally,
sulfonamide oxygens of neighboring layers form bifurcated C−
H···O hydrogen bonds with furan ring hydrogens and alkyl
hydrogens (d: 2.632 Å, 2.503 Å; θ: 129.34°, 151.09°).
FSM−TOL−EtOH (1:1:1). The cocrystal solvate takes the
P21/c space group with Z = 4. FSM forms robust acid···amide
(d: 1.585 Å, 2.406 Å; θ: 171.50°, 162.06°) heterodimer synthon
with TOL. These heterodimer aggregates form 1D chain via
N−H···N (d: 2.386 Å; θ: 151.16°) hydrogen bonds along the caxis (Figure 4a). Sulfonamide groups of FSM molecules are
assembled together with EtOH and form tapes along the b-axis
Table 3. IDR and Apparent Solubility in pH 7.4 Buffer
compound
residue (first hour)
FSM molecules (Figure 1). Finally, weak C−H···Ofuran (d:
2.747 Å; θ: 139.78°) hydrogen bonds connect these layers to
form the 3D structure.
FSM−ANT (1:1). The FSM−ANT cocrystal takes the C2/c
space group with Z = 8. FSM forms the robust acid···amide (d:
1.443 Å, 2.237 Å; θ: 164.44°, 166.46°) heterodimer synthon
with ANT. These heterodimers make 1D chains via HN−H···
OS (d: 2.221 Å; θ: 141.48°) hydrogen bonds (Figure 2a).
Such chains are stacked through SO2HN−H···NH2 (d: 2.222 Å,
θ: 172.95°), >N−H···OS (d: 2.449 Å, θ: 129.34°) hydrogen
bonds, slip-stacked π···π (closest C···C distance: 3.385 Å)
interactions and weak N−H···πfuran (closest C···H distance:
2.788 Å) interactions to give the 2D structure (Figure 2b). The
structure is additionally stabilized by weak C−H···Cl (2.958 Å)
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Figure 9. Intrinsic dissolution curves of (a) FSM−PPZ (1:1), (b) FSM−PCM sesquihydrate, FSM−TOL−EtOH, FSM−THP, (c) FSM, FSM−
ANT, and FSM−PPZ (2:1) in pH 7.4 buffer at 37 °C.
Figure 10. (a) Cumulative amounts of salts/cocrystals diffused vs time. (b) Flux/permeability of salts/cocrystals vs time.
FSM forms a robust acid···amide heterodimer synthon (d:
1.452 Å, 2.075 Å; θ: 172.30°, 153.55°) with PCM. The
−SONH2 group was also found to be disordered, and no
sulfonamide H atoms could be obtained from the difference
map. FSM molecules form 1D chain pairs along the a-axis via
sulfonamide···sulfonamide interactions. The structure is stabilized with amide···pyridine (d: 2.309 Å, θ: 149.69°) homodimer
synthons and sulfonamide···water interactions (Figure 5). The
water molecules are found in a continuous chain; whether or
(Figure 4b). The structure is additionally stabilized by weak C−
H···πfuran (closest C···H distance: 2.719 Å) interactions.
FSM−PCM Sesquihydrate (1:1:1.5). The cocrystal hydrate
takes the P1̅ space group with one FSM molecule, one PCM
molecule, and disordered water molecule(s) in the asymmetric
unit. The ratio of components (1:1:1.5) of the molecular
complex was confirmed with TGA and the calculated PXRD
pattern was found to be in good agreement with the
experimental microcrystalline sample (Figures S2 and S3).
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corresponding to loss of crystalline water molecules, followed
by melting at 120 °C. Multiple endotherms were observed for
FSM−TOL−EtOH and a broad endotherm was seen in the
range 115−135 °C corresponding to loss of lattice solvent.
Multiple endotherms were also seen for FSM−PIC, FSM−
PYZ, and FSM−INZ. TGA confirms the presence of crystalline
solvate/hydrate molecules in the cocrystals (Figure S3).
Solubility and Stability Studies. Solubility is a
preformulation property that has immense impact on the
bioavailability of an active pharmaceutical ingredient (API).
FSM is a weak acid and its solubility increases with increase
with pH.22,40 The solubility value obtained for FSM at pH 7.4 is
7.3 mg/mL, and this is in good agreement with the reported
solubility of 6.9 mg/mL at pH 7.5.22 Solubility experiments of
the new solid forms were carried out in pH 7.4 phosphate
buffer, and their phase stability was studied at intervals of 1, 4
and 24 h by checking the PXRD of the residues (Figure S2).
The pH values of the slurried solutions were also measured
after the experiments and are given in Table S3. The pH
variations are around ±1 and so the solubility values in the
different experiments may be meaningfully compared, especially
because the pH decreases upon slurrying in all cases excepting
FSM−PPZ (1:1) where a small increase of 0.8 pH units was
observed.
The solubility of multicomponent systems like cocrystals and
salts depends on a number of factors such as drug···coformer
interactions, and the individual concentrations of the coformer
and the un-ionized drug in solvent.12,41 The thermodynamically
stable solid form I of FSM contains O−H···O acid···acid and
N−H···O sulfonamide dimer synthons and chains; these are
modified in the cocrystals and salts.42 The spring-and-parachute
model of Guzman et al. seeks to explain the enhanced (kinetic)
solubility of selected solid forms of an API relative to a pure
drug compound.43 These authors proposed that the existence
of high energy crystal forms (spring) transiently increases the
solubility in water relative to the pure API. Excipients that
function as precipitation inhibitors (parachute) provide
enhanced dissolution and increased bioavailability. Brouwers
et al. continued with the idea of API supersaturation through
high energy solid forms and specifically mentioned amorphous
forms and cocrystals as solid forms that could show enhanced
solubility.44 They noted that that “the term ‘apparent solubility’
describes the apparent equilibrium between drug in solution
and a solid whose structure is not in the most stable state”. The
breakthrough paper in the application of the spring-andparachute model to pharmaceutical cocrystals is, however, the
2011 review of Nangia, where the connection between a cocrystal
and an amorphous form was clearly stated.45 A more recent
review from Nangia further expands the point.46 This model is
schematically illustrated in Figure 7, and its essence is that
when the solubility of the coformer is in excess of that of the
API, it is leached out of the solid cocrystal by the solvent
leaving an “amorphous” API structure, which being amorphous,
may be temporarily held in solution. This manifests itself as an
apparent increase in (kinetic) solubility. This amorphous form
is the spring (high energy form), and it leads to enhanced
solubility. The amorphous assembly may then transform either
to a metastable crystalline form, the parachute, which gradually
converts into the low solubility thermodynamic form, or it may
collapse quickly to the thermodynamic form (dotted line in
scheme) showing just a spike in the solubility of the API.
However, the parachute effect is not clearly explained in the
literature. Guzman et al. ascribe it to excipients. Brouwers et al.
Figure 11. Solubility (mg/mL) and initial flux (mg cm−2 h−1) values
for FSM solid forms.
not the term “channel hydrate” can be applied is a matter of
discussion because there is hydrogen bonding between the
water and the sulfonamide groups.
FSM−PPZ (2:1). The FSM−PPZ salt crystallizes in the P21/n
(Z = 4) with one molecule of FSM and half molecule of
protonated PPZ in the asymmetric unit. Accordingly, the
protonated PPZ ring lies on the inversion center. FSM ions are
bridged by protonated PPZ ions via N+−H···O− (d: 1.879 Å,
1.812 Å; θ: 58.57, 167.80°) ionic interactions forming a 1D
chain along the crystallographic a-axis (Figure 6a). These 1D
chains are then extended along the bc-plane through SO2HN−
H···O (d: 2.091 Å, θ: 148.80°) hydrogen bonds to form a 3D
supramolecular structure (Figure 6b). The structure is
additionally stabilized by two weak C−H···O (d: 2.594 Å,
2.371 Å) hydrogen bonds formed from two sulfonamide
oxygen atoms with furan and piperazine fragments. Moreover,
auxiliary interactions such as N−H···π and C−H···π (closest
C···H distance: 2.579, 2.606 Å) also augment the packing.
A molecular overlay diagram (Figure S5) shows that the
molecular conformations in all these solids differ in the
orientations of the furanylmethylamino fragments of FSM. This
fragment is almost perpendicularly (C−N−C−C = 70.67°)
oriented to the central benzene ring in FSM−ANT. However,
in other cases smaller torsions (C−N−C−C = 163−178°) are
observed; both PPZ salts possess similar FSM conformations
with an angle of 19.7° between the furan planes.
Formation of an equimolecular complex of FSM−THP was
evident from PXRD (Figure S2), but crystallization from
different solvents gave separate crystals of FSM and THP. IR
spectra of the complex shows three carbonyl peaks at 1704
cm−1, 1669 and 1642 cm−1 (Figure S4). The PXRD pattern of
FSM−THP neither matches with the FSM−CAF nor with the
FSM−pentoxyphylline.24,29 The instability of the complex in
different solvents could be indicative of cocrystal formation.
Thermal Analysis. The thermal behavior of these
compounds was investigated by DSC. FSM exhibits a small
endothermic peak at 136 °C followed by a sharp exothermic
peak at 213 °C (the melting endotherm was not clearly seen).
FSM−PPZ shows a melting endotherm at 225 °C followed by
decomposition, the higher melting point being due to the salt
form. FSM−ANT and FSM−TMPZ cocrystals exhibit melting
endotherms at 144 °C (sharp) and 150−170 °C (broad)
respectively. FSM−THP shows a sharp melting endotherm
differentiable from FSM and observed at 201 °C (lower than
that of coformer as well as FSM). FSM−PCM sesquihydrate
shows a broad endotherm in the range 95−105 °C,
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We are also able to rule out the possibility that the enhanced
solubility of the sesquihydrate over a sustained time period is
due to conversion of the cocrystal to amorphous FSM, which
then shows enhanced solubility. Perusal of the literature shows
that amorphous FSM exists only up to 20−30 min in solution,
whereas in our case the high concentration of the susbstance in
solution persists even after 24 h.50 Further, it is mentioned
quite clearly that the solubility of crystalline and amorphous
FSM is nearly the same (and moderate) at 25−27 °C, which is
close enough to the ambient temperature of the experiment
here. Therefore, the sustained presence in solution of FSM
cannot arise from the contribution of amorphous FSM (even if
the latter does exist in solution, for which there is no particular
indication).
Entropic considerations are also undoubtedly important in
extending the lifetime of the API in solution. The presence of
an amorphous cocrystal assembly surely decreases the entropy
of transformation in each of the stages solid cocrystal →
amorphous cocrystal in solution → amorphous API in solution
→ metastable API → stable API effectively increasing the
(kinetic) solubility of the API. We emphasize that each of these
transients serves to extend the lifespan of the API in solution,
and the cumulative effect is that it is still held in significant
amounts in solution after 24 h. This is surely long enough for
the drug to be absorbed by the body, and therefore it suffices to
render a cocrystal an effective solid form for drug absorption
and delivery.
The removal of solvent from the lattice in both cocrystal
solvate and hydrate could be the cause of their instability in
slurry conditions. Poorly soluble FSM and TOL precipitate out
within 1 h. In the case of FSM−THP, the thermodynamically
stable form 1 of FSM and the poorly soluble THP hydrate were
detected after 1 h. It was also observed that FSM−PPZ (1:1)
salt transformed to a thermodynamically more stable form
FSM−PPZ (2:1) within 1 h. The concentration of FSM−PPZ
(1:1) is more than twice that of FSM after 1 h and must be due
to the ionic nature of the salt and the pH (8.2) of the
medium.51 However, the solubility of FSM−PPZ (2:1) is
reduced to 7.61 mg/mL, which could be explained from the
crystal structures. In FSM−PPZ (2:1), the carboxylate group of
FSM symmetrically interacts with two neighboring PPZ ions,
which is reflected in C−O bond distances of 1.252 and 1.257 Å,
leading to strong ionic interaction. In FSM−PPZ (1:1), the
FSM carboxylate interacts unsymmetrically with the PPZ ion
and a sulfonamide hydrogen with C−O bond distances 1.251
and 1.267 Å. Such a structural difference leads to a more stable
structure for FSM−PPZ (2:1) with a ≈ 10° increase in melting
point. The driving force in this transformation could be the
charge distribution in the carboxylate moiety. Cocrystal FSM−
ANT was found to be stable after a 4 h slurry experiment
(solubility at 4 h is 6.31 mg/mL). However, thermodynamically
stable forms of FSM and FSM−ANT were detected after a 24 h
slurry experiment. The solubility of FSM−TMPZ at room
temperature is 7.31 mg/mL after 24 h. The solubilities of
FSM−TMPZ and FSM−ANT are not high enough compared
to FSM, and this may be linked to coformer solubility. The
stability difference of these two complexes could be attributed
to the presence of strong −SO2HNN−H···OS interactions
forming a 1D chain in FSM−TMPZ, absent in FSM−ANT.
To understand the solubility dependence of cocrystals on
coformer structure, three more stable solid forms of FSM were
prepared with bases (studied earlier in 10% EtOH-water):
furosemide−cytosine salt (FSM−CYT), furosemide−caffeine
identify the parachutes as precipitation inhibitors, which are
possibly introduced in the formulation steps. Nangia equates
the parachute with metastable polymorphs. The essence of
Nangia’s model is that dissolution of a cocrystal can lead to an
amorphous API structure in solution, while a slow dissolving
crystalline metastable polymorph acts as the parachute.
The results observed in the FSM−PCM sesquihydrate
cocrystal system in this study suggest an elaboration of the
Nangia model. The concentration of FSM−PCM sesquihydrate
after 1 h is 11.28 mg/mL. We note that the solubility of pure
FSM under similar conditions, namely, in pH 7.4 buffer, is 7.28
mg/mL; the effect of pH can be ignoredin both pure API
and cocrystal, similar pH changes are observed upon
dissolution. One needs, in effect, to account for the increase
of 4.00 mg/mL of FSM concentration in solution. Further, the
concentration of FSM−PCM sesquihydrate is well maintained
even after 24 h in a supersaturated solution (it falls only to 9.47
mg/mL). We ascribe this retention of high solubility over
prolonged duration to the formation of a loosely bound,
amorphous cocrystal structure in solution through a supramolecular synthon effect. This is depicted in Figure 8. The
origin of this extended kinetic solubility effect could be owing
to the intermediate solubility of the PCM coformer. It is not so
high that it is leached out rapidly as in the simple spring-andparachute model, and yet it is not so low that the cocrystal itself
has poor solubility (TMPZ, ANT). A coformer of intermediate
solubility gets leached out of the cocrystal by the solvent but
only gradually, and there is time for a loosely associated
amorphous cocrystal to form and be held in solution. The
presence of such an aggregate effectively extends the lifetime of
the API in solution. Whether it is a delayed action spring or the
early beginnings of the parachute is a matter for further
discussion. In summary, this uniquely bonded drug−coformer
system in solution may be visualized as a disordered/
amorphous drug assembly obtained through the slow leaching
out of the coformer.
We believe that after rearrangement in saturated solution the
FSM−PCM sesquihydrate system would resemble an amorphous cocrystal phase wherein the weak acid···amide synthon
would sustain a drug−coformer bonding which in turn would
cause the increase in concentration of FSM in solution. This
situation resembles the model of Nangia in that we are
proposing the existence of an amorphous aggregate in solution,
but it differs in that we are suggesting that it is an amorphous
cocrystal rather than an amorphous single phase material.
Whether this goes to a metastable cocrystal or a metastable API
polymorph (which collapses to the low solubility thermodynamic form of the API) is still a matter of conjecture. However,
what seems to suggest itself is that the synthon structure is an
effective precipitation inhibitor. We propose the term synthonextended-spring-and-parachute to describe our model for
cocrystal solubility. Basically, our model proposes the existence
of supramolecular synthons in solution. This is not new.47,48
Recently, we have provided NMR data in selected (nonpharmaceutical) systems that show the presence of discrete
molecular aggregates in solution that are closely related to the
synthons in the final crystal structure.49 The present work
touches upon this idea in a different and interesting way: the
presence of amorphous heteromolecular clusters in solution are
the precipitation inhibitors of Guzman and Brouwers and
constitute the parachute in the spring-and-parachute model of
Nangia.
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diffusion behavior as FSM, and this may be due to their similar
solubility nature, but it shows higher diffusion behavior later,
which likely is linked to the hydrophobic nature of the salt
former.
The salt and cocrystal of bases CYT and CAF exhibit the
lowest flux and mass of drug diffused per unit time. This
appears to be lower due to lesser amount of dissolved solids at
the membrane. FSM−ADE has a higher flux than CYT and
CAF cocrystals in line with its higher solubility. Overall, we
suggest that coformers causing higher solubility of cocrystal/salt
lead to higher diffusion. Solubility and flux/diffusion are seen to
go hand in hand: higher solubilities give higher flux/diffusion
(Figure 11). These results on salts and cocrystals of FSM are
extremely positive for the improvement of physicochemical
properties of poorly soluble and poorly permeable drug
candidates.
cocrystal (FSM-CAF) and furosemide−adenine cocrystal
(FSM−ADE).24 The FSM−CYT salt showed lower solubility
in pH 7.4 buffer and the reasons could be 2-fold: (a) low
solubility of CYT; (b) a robust two-point carboxylate···
aminopyridine synthon. The higher solubility of FSM−ADE
compared to FSM−CAF and FSM−CYT may be linked to
lower lattice energy.
Dissolution Studies. Intrinsic dissolution rate (IDR) is a
kinetic parameter, the rate at which the equilibrium solubility is
reached. For metastable drugs, which undergo phase transformation during slurry experiments, the IDR and apparent
solubility are the relevant parameters. Kanke et al. derived the
equation of apparent solubility, Cm = Cs(Jm/Js), applying the
Noyes−Whitney equation,52,53 where Cm is the apparent
solubility of the metastable solid, Cs is the solubility of the
thermodynamically stable form, while Jm and Js are the
dissolution rates of metastable and stable solids. Dissolution
rate measurements at 30 min intervals over 4 h were carried out
for FSM, FSM−ANT, and FSM−PPZ (2:1). However, for
FSM−PPZ (1:1) the measurement was carried out for 40 min
(5 min interval), and dissolution rate measurements of FSM−
PCM sesquihydrate, FSM−TOF−EtOH, and FSM−THP were
carried out for 21 min (3 min interval). The apparent solubility
of FSM−PPZ (1:1) salt is ∼3 times higher as compared to the
thermodynamically stable FSM−PPZ (2:1) salt (Table 3).
Generally, the apparent solubility of cocrystals follows their
coformer solubility behavior.
Diffusion/Flux of Salts and Cocrystals. Drug absorption
is dependent on solubility and membrane permeability. The
diffusion behavior of the solid forms of FSM was studied using
a simple Franz diffusion cell which gives a relative idea of
permeation behavior when solids of the same series are studied.
Any compound applied to either tissue or an artificial
membrane will have a lag time, the time it takes to permeate
through the membrane and diffuse into the receptor fluid and
then finally to reach a steady state of diffusion. The lag time is
also the period during which the rate of permeation across the
membrane is increasing. A steady state is reached when there is
a consistent, unchanging movement of the permeant through
the membrane. During the lag period there is rapid diffusion/
flux which is reflected by a sharp peak which drops off when the
steady state is attained. Diffusion of all the solids was measured
in buffer pH 7.4 at 1 h intervals over 8 h (Figure 10). No
significant change of pH was noticed in the receptor
compartment solution after diffusion experiments. The plots
of cumulative drug diffused and flux indicate that except for
FSM−CYT and FSM−CAF all the cocrystals/salt exhibit better
diffusion behavior compared to FSM; this may be explained by
structural interactions. None of these salts/cocrystals contain
the O−H···O acid···acid and N−H···O sulfonamide dimer
synthons and chains which are seen in form I of FSM.41 FSM−
TMPZ and FSM−ANT exhibit similar diffusion behavior with
an initial rise in cumulative drug, which levels off after 3 h.
FSM−PPZ (2:1) salt also exhibits initial slow increase in
diffusion, which reaches a steady state after 6 h. The rest of the
compounds show a steady increase in diffusion with time. The
higher initial diffusion/flux of FSM−TMPZ and FSM−ANT
compared to FSM could be due to the higher concentration
gradient across the membrane resulting from higher dissolved
solids.3 In addition to solubility of FSM−TMPZ, the
hydrophobic nature of the TMPZ could be a reason for its
higher diffusion behavior when compared with the FSM−ANT
cocrystal. FSM−PPZ (2:1) salt shows similar first hour flux/
■
CONCLUSIONS
The thermodynamically stable form I of FSM contains O−H···
O acid···acid and N−H···O sulfonamide dimer synthons and
chains which are modified in the cocrystals/salts. Two salts, one
solvate and six cocrystals (including cocrystal solvates) were
obtained and characterized by single crystal X-ray diffraction.
Studies conducted on cocrystals/salts indicate a general
dependence of kinetic solubilities on intrinsic coformer
solubilities. FSM−PPZ (1:1) salt shows the highest drug
concentration in saturated solution but transformed to a less
soluble and more stable FSM−PPZ (2:1) salt form within an
hour, and the driving force of the transformation is symmetric
charge distribution in the carboxylate moiety. FSM−PCM
sesquihydrate shows a higher concentration of FSM in solution
with time. Such a result is interpreted with a synthon-extendedspring-and-parachute model, wherein it is suggested that the
acid···amide synthon prolongs the drug concentration in
solution via an amorphous cocrystal. It would need to be
seen in the future whether such effects are seen in cocrystals
that are not solvated/hydrated. We have also observed that the
initial flux/diffusion and the solubility of these FSM solid forms
go hand-in-hand. Drug···coformer and cocrystal/salt···solvent
interactions are seen to play an important role in solubilitydiffusivity/flux variations in FSM cocrystals/salts. It is
anticipated that our studies here of salts/cocrystals of FSM
will be useful for the further development of physicochemical
properties of poorly soluble and permeable drug candidates.
■
ASSOCIATED CONTENT
S Supporting Information
*
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.cgd.6b00902.
Neutron normalized hydrogen bonding parameters,
PXRD, DSC, TGA, and FT-IR plots of the furosemide
solvate, salt and cocrystals (PDF)
Accession Codes
CCDC 1470970−1470977 and 1483447 contain the supplementary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing [email protected], or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*Fax: +91 80 23602306. Tel.: +91 80 22933311. E-mail:
[email protected].
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
■
REFERENCES
M.B. and S.P.G. thank the UGC for a Dr. D. S. Kothari
fellowship. S.G. thanks IISc for a fellowship. G.R.D. thanks
DST for a J. C. Bose fellowship. We thank S. Chakraborty and
S. Saha for their assistance in the crystal structure analysis.
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