New solid forms of the anti-HIV drug etravirine: Salts, cocrystals, and solubility

Article abstract of DOI:10.1021/cg4007058

Thirteen new solid forms of etravirine were realized in the process of polymorph and cocrystal/salt screening to improve the solubility of this anti-HIV drug. One anhydrous form, five salts (hydrochloride, mesylate, sulfate, besylate, and tosylate), two cocrystals (with adipic acid and 1,3,5-benzenetricarboxylic acid), and five solvates (formic acid, acetic acid, acetonitrile, and 2:1 and 1:1 methanolates) were obtained. The conformational flexibility of etravirine suggests that it can adopt four different conformations, and among these, two are sterically favorable. However, in all 13 solid forms, the active pharmaceutical ingredient (API) was found to adopt just one conformation. Due to the poor aqueous solubility of the API, the solubilities of the salts and cocrystals were measured in a 50% ethanol-water mixture at neutral pH. Compared to the salts, the cocrystals were found to be stable and showed an improvement in solubility with time. All the salts were dissociated within an hour, except the tosylate, which showed 50% phase transformation after 1 h of the slurry experiment. A structure property relationship was examined to analyze the solubility behavior of the solid forms.

Full text of DOI:10.1021/cg4007058

Article
pubs.acs.org/crystal
New Solid Forms of the Anti-HIV Drug Etravirine: Salts, Cocrystals,
and Solubility
Lalit Rajput, Palash Sanphui, and Gautam R. Desiraju*
Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India
S
* Supporting Information
ABSTRACT: Thirteen new solid forms of etravirine were realized in the process
of polymorph and cocrystal/salt screening to improve the solubility of this anti-
HIV drug. One anhydrous form, five salts (hydrochloride, mesylate, sulfate,
besylate, and tosylate), two cocrystals (with adipic acid and 1,3,5-benzene-
tricarboxylic acid), and five solvates (formic acid, acetic acid, acetonitrile, and 2:1
and 1:1 methanolates) were obtained. The conformational flexibility of etravirine
suggests that it can adopt four different conformations, and among these, two are
sterically favorable. However, in all 13 solid forms, the active pharmaceutical
ingredient (API) was found to adopt just one conformation. Due to the poor
aqueous solubility of the API, the solubilities of the salts and cocrystals were
measured in a 50% ethanol−water mixture at neutral pH. Compared to the salts,
the cocrystals were found to be stable and showed an improvement in solubility
with time. All the salts were dissociated within an hour, except the tosylate, which
showed 50% phase transformation after 1 h of the slurry experiment. A structure property relationship was examined to analyze
the solubility behavior of the solid forms.
In continuation of our efforts to improve the physiochemical
properties of APIs with the crystal engineering approach, we
have selected an anti-HIV drug, etravirine (ETR).9 Etravirine,
4-[[6-amino-5-bromo-2-[(4-cyanophenyl)-amino]-4-
pyrimidinyl]oxy]-3,5-dimethylbenzonitrile, is a non-nucleoside
reverse transcriptase inhibitor (NNRTI), which binds to HIV-1
reverse transcriptase and blocks the DNA polymerase activities
by disrupting the enzyme’s catalytic site.10 It is believed that it
binds in at least two conformationally distinct modes, due to its
flexibility. There is a report on the polymorph screening (forms
A to M) of etravirine characterized by PXRD, DSC, and solid-
state NMR.10c Further, a cocrystal of etravirine-nicotinamide
characterized by PXRD is reported.10d Etravirine (brand name
Intelence, formerly known as TMC125, is marketed by
Tibotec) is a BCS class IV drug and exhibits low solubility
and permeability.11 It is almost insoluble in water over a wide
range of pH and is stable at room temperature nearly
indefinitely. It is a flexible molecule which has a central
pyrimidine ring with two arm phenyls bridged via an ether
linkage (Ar−phenyl) and a secondary amine linkage (Ph−
phenyl). Both the phenyl arms have terminal cyano
functionality in the para position (Scheme 1). Since the
molecule has multiple hydrogen bond donor and acceptor sites,
there is a high probability for the formation of cocrystals or salts
(Scheme 2). Molecular modeling studies suggest that there is a
possibility of polymorphism due to different possible
INTRODUCTION
■
Crystal engineering with the synthon-based approach for the
formation of multicomponent molecular crystals of active
pharmaceutical ingredients (APIs) has received major attention
from chemists because of its fundamental importance and
potential for direct applications in the pharmaceutical industry.1
This approach has shown that major variations in terms of
properties of a drug can be achieved by using a GRAS
(generally regarded as safe)2 coformer, especially in obtaining
advantageous stability, solubility, bioavailability, and tableting
attributes.3 Almost 40% of the APIs in the market today face a
major problem of poor aqueous solubility.4 Poor aqueous
solubility can be improved by making an amorphous phase
through solid dispersion or by using a polymer, additive,
excipient, or cyclodextrin.5 However, salt or cocrystal formation
is still one of the best approaches for solubility improvement
without disturbing the inherent properties of the API. Cocrystal
formation can improve solubility by 4−160 times, whereas salts
can modulate solubility 100−1000 fold.6 Due to their superior
solubilities, more than 50% of the APIs are marketed as salts.
However, salt formation can sometimes lead to lower stabilities
and, hence, low solubility.7 The physical properties of
crystalline solids are a reflection of the molecular arrangement
and can be tuned by altering the intermolecular interactions
between molecules. For this, structure−property relationship
studies are helpful to understand the nature of the multi-
component molecular crystals; this further helps in an
understanding of the fundamentals of crystallization and
molecular recognition.8
Received: May 7, 2013
Revised: June 4, 2013
© XXXX American Chemical Society
A
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Scheme 1. Schematic Representation of Etravirine and Its New Solid Forms
publication suggesting some operational guidelines.14 The U.S.
FDA guidelines state that if the difference in pka between the
proton donor and acceptor is less than 1.0, the substance
should be considered as being a cocrystal. If this difference is
greater than 1.0, the substance is assumed to be a salt, but more
spectroscopic confirmation has been deemed necessary.13
Single crystal X-ray analysis will provide definitive answers in
almost all cases. We feel that the so-called “rule of three” is still
a fairly reliable measure to judge a compound as a salt or a
cocrystal.
In this report, we discuss our efforts to improve the solubility
of etravirine by preparing its crystalline salts and cocrystals and
by studying their structural aspects and structure−property
relationships. The new solid forms are characterized by FT-IR,
DSC, powder and single crystal X-ray diffraction.
Scheme 2. Synthons Observed in the Crystal Structures of
Etravirine Solid Forms
conformations of this flexible molecule (Scheme 3). Although
extensive studies are in progress on the biological/clinical
activity of the drug, it is surprising that there is no report to
date on the crystal structure of etravirine or its cocrystals/
salts.12
It may be useful to comment on some general nomenclature
issues pertaining to terms like “salt”, “cocrystal”, “solvates”, and
so on because these terms are widely used in the crystal
engineering literature. It is not the intention to provide a
detailed review here. It may suffice to say that the United States
Food and Drug Administration (U.S. FDA) has recently come
up with some guidelines for the nomenclature of cocrystals13
and also that a large group of authors have coauthored a
RESULTS AND DISCUSSION
■
Etravirine was screened for new solid phases (single component
and multicomponent systems) using high-throughput crystal-
lization. It is observed that due to the imbalance of donor
(three) and acceptor (five) sites, the API has a tendency to
Scheme 3. Different Possible Conformations of Etravirine
B
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Table 1. Crystallographic Parameters of Compounds 1−13
compound
1
2
3
4
5
6
7
empirical formula
formula wt
crystal system
space group
T (K)
C20 H15N6OBr
435.29
C20H16N6OClBr
471.75
C21H19N6O4SBr
531.39
C21H20N6O6SBr
564.40
C26H21N6O4SBr
593.46
C27H23N6O4SBr
607.48
C23H20N6O3Br
508.35
orthorhombic
Pna21
monoclinic
P21/c
triclinic
triclinic
monoclinic
P21
monoclinic
P21/c
triclinic
P1
̅
150
P1
̅
150
P1
̅
150
150
150
150
293
a (Å)
19.885(5)
10.789(3)
8.712(2)
90
8.897(4)
16.622(4)
14.378(6)
90
8.225(9)
8.668(10)
15.857(18)
88.56(2)
87.00(2)
88.85 (2)
1131(2)
1.561
8.460(16)
8.627(17)
16.65(3)
97.44(3)
90.58(3)
90.90(3)
1205(4)
1.556
8.988(2)
12.801(2)
22.956(8)
90
8.769(14)
13.86(2)
22.91(4)
90
8.124(1)
11.984(1)
13.515(1)
64.231(12)
83.606(15)
87.777(14)
1177.49(13)
1.434
b (Å)
c (Å)
α (deg)
β (deg)
90
106.923(16)
90
95.655(15)
90
97.058(12)
90
γ (deg)
90
volume (Å3)
1869(8)
1.547
2034.1(13)
1.540
2628.4(12)
1.500
2763(7)
1.460
Dcalcd (g cm−3
)
Z
4
4
2
2
4
4
2
2θ range
2.1 to 27.5
0.0449, 0.1379
1.144
2.4 to 27.5
0.0606, 0.1860
1.053
2.3 to 27.5
0.0468, 0.1352
1.038
2.4 to 27.5
0.0752, 0.2381
1.065
1.8 to 27.5
0.0718, 0.2047
1.064
1.8 to 27.5
0.0911, 0.2196
1.334
3.0 to 27.5
0.0509, 0.1629
0.947
R1 [I > 2 σ(I)], wR2
GOF
diffractometer
compound
Rigaku-CCD
8
Rigaku-CCD
9
Rigaku-CCD
10
Rigaku-CCD
Rigaku-CCD
Rigaku-CCD
Rigaku-CCD
13
11
12
empirical formula
formula wt
crystal system
space group
T (K)
C29H23N6O8Br
663.44
C21H17N6O3Br
C22H19N6O3Br
C41H34N12O3Br2
902.62
C21H19N6O2Br
467.32
C42H32N13O2Br2
481.32
495.34
910.63
triclinic
orthorhombic
Pna21
monoclinic
P21/n
triclinic
monoclinic
P21/c
monoclinic
P21/n
P1
̅
150
P1
̅
150
150
150
150
150
a (Å)
8.0836(16)
8.9850(15)
19.589(4)
93.209(9)
91.009(12)
99.211(8)
1401.7(4)
1.572
22.244(5)
10.857(3)
8.7559(16)
90
8.5277(13)
22.639(3)
11.345(2)
90
8.587(9)
16.131(15)
16.241(15)
64.59(3)
82.83(4)
80.35(4)
2000(3)
1.499
16.337(3)
13.845(2)
20.240(4)
90
8.6128(2)
20.9616(7)
11.2537(4)
90
b (Å)
c (Å)
α (deg)
β (deg)
90
92.995(9)
90
112.841(6)
90
90.511(2)
90
γ (deg)
90
volume (Å3)
2114.6(8)
1.512
2187.2(6)
1.504
4218.9(13)
1.472
2031.64(11)
1.489
Dcalcd (g cm−3
)
Z
2
4
4
2
8
2
2θ range
2.1 to 27.5
0.0563, 0.1667
1.079
2.6 to 27.5
0.0529, 0.1525
1.088
2.0 to 27.5
0.0561, 0.1810
1.161
2.4 to 27.5
0.0517, 0.1674
1.065
2.0 to 27.5
0.0564, 0.1632
1.128
2.66 to 26.99
0.0378, 0.0922
1.029
R1 [I > 2σ(I)], wR2
GOF
diffractometer
Rigaku-CCD
Rigaku-CCD
Rigaku-CCD
Rigaku-CCD
Rigaku-CCD
Bruker APEX-II CCD
Figure 1. Crystal structure of anhydrous form, 1: (a) 1D Chain via N−H···N hydrogen bonds and (b) corrugated 2D layer assembled exclusively via
N−H···N hydrogen bonds viewed along the a-axis (one of the 1D chains is shown in green).
form solvates/hydrates, while the weak basicity of the API
makes it prone to form salts with strong acids. Thirteen new
solid forms were obtained from different solvent and solvent
combinations: anhydrous form (1), five salts: hydrochloride
(2), mesylate (3), sulfate (4), besylate (5), and tosylate (6),
two cocrystals: with adipic acid (ADP) (7) and 1,3,5-
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Figure 2. Crystal structure of hydrochloride salt, 2: (a) dimeric unit of protonated etravirine bridged by Cl− ions and (b) the 2D layer involving the
dimeric units linked via N−H···N hydrogen bonds.
Figure 3. Dimeric units of protonated etravirine bridged by corresponding sulfate anions in compound (a) 3 and (b) 4. 2D layers are present in
compounds (c) 3 and (d) 4. (Notice synthon I and hydrophilic chains).
Figure 4. Dimeric units of protonated etravirine bridged by corresponding sulfate anions in compound (a) 5 and (b) 6. 2D layers present in
compounds (c) 5 and (d) 6. (Notice the sliding of dimeric units as well as hydrophobic interactions).
benzenetricarboxylic acid (H3BTC) (8) and five solvates:
formic acid (9), acetic acid (10), 2:1 ETR:MeOH (11), 1:1
ETR:MeOH (12), and acetonitrile (13). Despite several
cocrystallization attempts with mono- and dicarboxylic acids,
we failed to obtain single crystals of cocrystals, except with ADP
and H3BTC. The crystallographic parameters and solubility
results are summarized in Tables 1 and 2, respectively. We now
discuss the structural aspects of these new multicomponent
crystals of etravirine.
Anhydrous Form (1). The molecule crystallizes in the
orthorhombic crystal system with the Pna21 space group (Z =
4). The molecule adopts a V-shaped geometry (conformation
A, Scheme 3), and both the arm phenyls are oriented on the
same side of the central pyrimidine ring, as shown in Figure 1a.
Within the molecule, the phenyl rings interact with each other
via edge-to-face π···π interactions with a closest C···C distance
of 3.699 Å. The molecule assembles into one-dimensional (1D)
chains via N−H···N hydrogen bonds between the primary
amine and cyano groups of the Ph-ring. The 1D chain is further
D
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Figure 5. Crystal structure of cocrystal 7: (a) synthon II between etravirine and adipic acid forming a ladder network. 3D packing of the ladders (b)
top view and (c) side view (one of the ladder is shown in dark yellow).
Figure 6. Crystal structure of cocrystal 8: (a) synthon II between etravirine and H3BTC in a 2D layer and (b) 3D packing of the layers through
water bridging and the C−H···N hydrogen bond.
propagated to corrugated two-dimensional (2D) layers via N−
H···N hydrogen bonds between the secondary amine and cyano
group of the Ar ring (Figure 1b).
not stable at room temperature and rapidly lose crystallinity
after exposure to air.
Besylate (5) and Tosylate (6) Salt. Both the salts
crystallize in the monoclinic system with space group P21 for
5 and P21/c for 6. As in the mesylate anion, the besylate and
tosylate anions also form the same synthon as shown in Figure
4 (panels a and b). However, the overall packing of 5 and 6
differs significantly from 3 and 4 due to the presence of the
bulky phenyl ring compared to the methyl group in the
mesylate salt. Along the crystallographic a-axis, dimer units slide
over adjacent units and interact with each other through
dipole−dipole interactions, forming a 1D chain. The 1D chain
in both the salts is assembled into 2D layers in the ab-plane via
hydrophobic interactions. In 5, the 1D chain is exclusively
assembled through edge-to-edge aromatic interactions (closest
C···C distances: 3.47 Å and 3.56 Å) between the besylate
anions (Figure 4c). However, in 6, it is assembled via edge-to-
edge aromatic interactions (closest C···C distances: 3.86 Å) as
well as the dimeric C−H···π (C···C distance: 3.68 Å)
interactions between the tosylate anions (Figure 4d).
Hydrochloride Salt (2). The salt crystallizes in the
monoclinic crystal system with the P21/c space group (Z =
4). Protonated etravirine adopts a V-shaped geometry and two
such inversion related molecules form dimeric units bridged by
two Cl− anions (Figure 2a). The Cl− anion is trifurcated in the
molecular plane and is hydrogen bonded to the secondary
amine NH group of one molecule and the primary amine NH2
and a protonated pyrimidine NH group of another. Each
dimeric unit is hydrogen bonded with four adjacent dimeric
units through N−H···N hydrogen bonds, forming a 2D layer
(Figure 2b).
Mesylate (3) and Sulfate (4) Salt. The mesylate salt (3)
crystallizes in the triclinic system with the P1 space group (Z =
̅
2). Protonated etravirine adopts a V-shaped geometry and two
such molecules form dimeric units bridged by two mesylate
anions (Figure 3a). In the molecular plane, the mesylate anion
is strongly hydrogen bonded to the primary amine NH2 group
of one molecule and the secondary amine NH, protonated
pyrimidine NH, and the phenyl CH of another molecule. Each
dimeric unit is hydrogen bonded to two adjacent dimeric units
via synthon I, forming a 1D chain. The 1D chain is assembled
into a 2D layer through dimeric C−H···O hydrogen bonds
between the mesylate anions and dimeric weak Br···π (closest
C···Br distance: 3.54 Å) interactions (Figure 3c). Interestingly,
alternate hydrophilic chains of mesylate anions and hydro-
phobic chain of phenyl rings are present within the 2D layer.
Compound 4 also exhibits similar features as the mesylate
salt (Figure 3, panels b and d). To compensate for the methyl
group of the mesylate fragment, compound 4 includes a
methanol molecule in the unit cell. The crystals of the salt 4 are
Adipic Acid Cocrystal (7). The cocrystal 7 crystallizes in
triclinic (P1), Z = 2. Etravirine adopts a V-shaped geometry and
̅
forms synthon II with the acid. The structure is a ladder
network where the adipic acid units join the 1D chains of the
API (as observed in 1) (Figure 5a). The ladders are packed in
an offset fashion. The 1D chains of the ladders involving the
API overlap over each other (Figure 5b). In the ladder plane,
the adjacent ladders are linked with C−H···π interactions
between the Ar-ring and the methyl group CH (closest C···C
distances: 3.56 Å). The butyl spacer of the adipic acid adopts a
gauche-anti-gauche conformation which subsequently holds the
1D chains of the API at different planes (Figure 5c). The
overall 3D packing of the ladders is in an ABAB manner.
E
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Figure 7. 1D chain of molecular complex of the acid−API involving synthon II in (a) 9 and (b) 10. (c) 2D layer of 9 (dipole−dipole interactions are
shown in pink, one of the 1D chain in dark yellow and formic acid molecules in green color). (d) 2D layer of 10, involving acetic acid hydrogen
bonded dimers and halogen bond.
Figure 8. Dimeric units involving MeOH molecules in (a) 11 and (b) 12. (c) Interactions of one of the dimers with the adjacent dimers in 11 (one
of the dimers is shown in dark yellow color and MeOH in green) and (d) a 2D layer of 12 involving synthon I.
Benzenetricarboxylic Acid Cocrystal Hydrate (8). In
the cocrystal 8, etravirine adopts a V-shaped geometry and
forms synthon II with the acid (Figure 6a). The etravirine−acid
aggregate forms a 1D chain via strong O−H···N hydrogen
bonds between the OH group of the acid and the CN group of
the aromatic ring. The 1D chain is further propagated to a 2D
layer in the bc-plane through N−H···O hydrogen bonds
between the primary NH2 and carbonyl of H3BTC, as well as
water bridging between two H3BTC units. The 2D layer has a
planar geometry and is packed in 3D with an ABAB pattern.
The AB layers interact with each other via hydrogen bonds
involving water molecules, while the BA are held together via
C−H···N hydrogen bonds (Figure 6b).
Formic Acid (9) and Acetic Acid (10) Molecular
Complexes. Compound 9 crystallizes in the orthorhombic
crystal system (Pna21), while 10 is monoclinic (P21/n). In both
cases, etravirine and the acid form synthon II. The API forms
1D chains via N−H···N hydrogen bonds between the primary
amine and the cyano group of the Ph-ring, as observed in 1
(Figure 7, panels a and b). However, the 2D and 3D packing
differs significantly from 1.
hydrogen bonds between the acetic acid molecules, halogen
bonds between Br···N (3.48 Å), and face-to-face π···π
interactions between the Ar rings (closest C···C distance:
3.50 Å) (Figure 7d).
Methanol Solvates (11 and 12). 2:1 (11) and 1:1 (12)
methanolates of the API were obtained concomitantly from
MeOH. Compound 11 crystallizes in the triclinic system with a
P1 space group and 12 takes the monoclinic P2 /c space group.
̅
1
In both cases, etravirine interacts with each other through
synthon III (Figure 8, panels a and b), forming a dimer. This
dimer is hydrogen bonded to one MeOH molecule in 11 and
symmetrically to two MeOH molecules in 12.
In 11, the dimers interact with the adjacent units via N−
H···N hydrogen bonds between the cyano group and the
primary amine NH2 and secondary amine NH functionalities
forming a corrugated 2D layer in the ab-plane (Figure 8c). The
dimeric units in 12 are assembled into a 2D layer in the ac-
plane via synthon I (Figure 8d). The adjacent 2D layers are
interdigitated and form a bilayer, involving face-to-face π···π
(the closest C···C distance of 3.48 Å) interactions between the
Ar rings of the layers.
The 1D chain of 9 is packed in the bc-plane via π···π
interactions with a closest C···C distance of 3.40 Å and dipole−
dipole interactions between the CN group and the pyrimidine
CN bond (NCN···CPYM distance: 3.31 Å and CCN···NPYM
distance: 3.32 Å) (Figure 7c). However, in 10, the 1D chain is
assembled into a 2D layer in the ab-plane with C−H···O
Acetonitrile Solvate (13). The acetonitrile solvate of
etravirine exhibits the same features as the anhydrous form.
They differ only in the 3D packing. For compound 13, the 2D
layers are held together by acetonitrile molecular chains for
further 3D packing, which involves C−H···N and C−H···Br
hydrogen bonds (Figure S1 of the Supporting Information).
F
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Powder X-ray Diffraction. Powder X-ray diffraction is a
crucial characterization method to know the bulk purity of the
sample.15 Here, the purity of the new solid bulk forms was
confirmed by comparing the calculated X-ray patterns with the
experimental ones obtained from crystallization or grinding
experiments (see the Supporting Information).
Thermal Analysis. Differential scanning calorimetry (DSC)
measures the exact melting point and/or decomposition
temperature for a solid compound. At the same time, it
shows phase transitions for polymorphs or dissociation of the
multicomponent system at a certain temperature. DSC can be
used to measure even a small amount of impurity in the new
solid. Etravirine exhibits a melt endotherm at 252 °C, followed
by immediate decomposition (exotherm). But, the hydro-
chloride and mesylate salts showed broad endotherms in the
range of 206−220 °C before dissociating into the API. The
besylate and tosylate salts showed higher exotherms in the
range of 264−271 °C, which is nothing but a direct
decomposition without transforming to API. Cocrystal 7 starts
melting at 212 °C and decomposes from 235 °C onward.
Cocrystal 8 is stable enough at ambient conditions and loses
lattice water in the temperature range of 110−140 °C followed
by melting onset at 153 °C. This phenomenon is further
confirmed by hot stage microscope images (see the Supporting
Information). Formic and acetic acid solvates lose the
corresponding solvent in the range of 100−140 °C and
transform to the API before final decomposition. Acetonitrile
solvates lose the solvent comparatively at higher temperature in
the range of 160−170 °C and transform to the API before final
decomposition, which is further confirmed by hot stage
microscope images (see the Supporting Information). Overall,
the new solid forms show distinct decomposition pathways.
Solubility Study. Solubility is one of the important
preformulation properties that has a significant effect on
dissolution as well as on the bioavailability of an API. There are
several methods to improve the solubility of poorly aqueous
soluble APIs; these include formation of nanoparticles, solid
dispersions, cyclodextrin complexes, the inclusion of additives
(excipients), amorphous phases, cocrystals, and salts.5 Among
these, salt formation is the most commonly used technique in
the pharmaceutical industry because of the high solubility and
purity of most salts.
Figure 9. Molecular overlay of etravirine. 1: blue, 2: pink, 3: red, 4:
orange, 5X: yellow, 5Y: light green, 6: dark green, 7: light blue, 8:
cyan, 9: purple, 10: violet, 11X: magenta, 11Y: dark gray, 12X: black,
12Y: brown, and 13: green. (X and Y are the two molecules from the
asymmetric unit for a particular compound).
Conformation of Etravirine. Etravirine is a conformation-
ally flexible molecule and, in principle, can adopt different
conformations in its crystals (Scheme 3). However, in all 13
solid forms, it is observed that the molecule adopts only
conformation (A) (i.e., a V-shaped geometry). Molecular
overlay (Figure 9) indicates that there is a little torsion in the
phenyl rings. This geometry is stabilized by edge-to-face π···π
interactions between the arm phenyl rings, which is not
possible in the other conformations (B, C, or D). Further, the
ortho hydrogen of the Ph ring of conformer A is engaged in
intramolecular hydrogen bonding with the pyrimidine nitrogen
in this robust geometry. Conformations C and D are
energetically not favored because the Ar ring has to rotate
along the C−O bond to avoid steric repulsion between the Br
and two ortho-methyl substitutions on the Ar ring. However,
conformation B is energetically favorable, and there is a
possibility (so far not realized) of a polymorph for etravirine
with this conformation.10
There is no report on the solubility study of etravirine in the
literature. However, there are reports on formulation of the API
as a solid dispersion.10 The compound is almost insoluble in
water over a wide range of pH. Hence, there is a need to
improve the solubility which can increase the poor bioavail-
ability of the compound. In search of alternative solid forms
with better solubility, salts and cocrystals were prepared. A 50%
During the preparation of the nitrate salt of etravirine, the Br
group on the central pyrimidine ring was substituted by a NO2
group. However, the point to be noticed here is that the
molecule adopts the same V-shaped geometry as observed for
etravirine in all the solid forms (Figure S2 of the Supporting
Information).
Table 2. Solubility Profiles of Etravirine and Its New Solid Forms in 50% EtOH at 25°C
apparent solubility
residue obtained in solubility
experiment after
(mg/L)
solubility (mg/L)
24 h
crystalline forms
1: ETR
absorption coefficient (mM−1 cm−1
)
1 h
4 h
1 h
ETR
4 h
24 h
41.33
35.73
59.70
35.18
48.83
39.34
11.37
74.3
114.7
56.6
−
−
−
−
−
−
−
−
−
456.0
−
−
−
−
−
−
−
8
2: HETR·Cl
ETR
ETR
ETR
ETR + 6
ETR
8
−
−
−
ETR
3: HETR·CH3SO3
5: HETR·C6H5SO3
6: HETR·MeC6H4SO3
7: ETR·ADP
118.1
116.6
118.7
110.1
−
99.0
−
396.8
−
8
8: ETR·H3BTC·H2O
G
dx.doi.org/10.1021/cg4007058 | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
EtOH−water solvent mixture was chosen for solubility
experiments, as etravirine shows better solubility in 74 mg/L
at 1 h of dissolution.16 The solubility experiments of the solid
forms (salts and cocrystals) were carried out in 50% aqueous
EtOH, and the phase stability was studied at the interval of 1 h,
4 h, and 24 h. It was observed that in the case of salts and the
adipic acid cocrystal (7), the apparent solubility is improved
only 1.5 times compared to the parent API, whereas cocrystal 8
shows solubility enhancements up to 5-fold within a 4 h time
interval (Table 2). The hydrochloride, mesylate, besylate salts,
and cocrystal 7 were found to be less stable and within 1 h were
dissociated into the API. However, the tosylate salt is
comparatively stable with half (52%) the salt remaining intact
after 1 h; complete dissociation was observed after 4 h.
Interestingly, cocrystal 8 did not show any change in its powder
pattern and was found to be stable even after a 24 h slurry
experiment (see the PXRD comparison in the Supporting
Information). The difference in the stability of cocrystals is
reflected in the calculated density from the single crystal data.
Cocrystal 7 has the lowest density (1.434 g/cm3) among the
solid forms, whereas 8 has the highest (1.572 g/cm3), indicating
a better packing.
The salt coformers (hydrochloric acid, methanesulfonic acid,
benzenesulfonic acid, and p-toluenesulfonic acid) used here are
highly soluble/miscible in water and form an incongruent
system with the API.17 Hence, there is a greater probability of
dissociation of the salt; this is indeed observed here in the
slurry experiment of a 1 h interval. Comparatively speaking,
benzenetricarboxylic acid is less soluble and might be forming a
better congruent system (less solubility difference between API
and coformer) of comparable solubility in cocrystal 8, which
would exhibit better stability even after the 24 h slurry
experiment. Among the cocrystals, 7 shows poor stability and,
hence, poor solubility. From the structural point of view, 7
exhibits an API:coformer ratio 1:0.5 and involves a strong
interaction through synthon II in 1D only. However, 8 exhibits
the API:coformer ratio 1:1 and involves a strong interaction in
2D, as well as 3D, due to the inclusion of water, which
ultimately improves the stability. Further, in the packing of 7,
one molecule of API is surrounded by five API molecules
except from the synthon II side; it also has the same 1D chain
as seen in the anhydrous form. This arrangement helps to
increase the rate of dissociation of the cocrystal to API. In 8,
however, there is no direct API−API interaction, and the API is
mostly surrounded by H3BTC, which helps in improving
solubility. In summary, cocrystal 8 shows the best solubility
(456 mg/L) among the new multicomponent systems of
etravirine isolated in this study.
interaction and the C−H···N hydrogen bond. The strong
intermolecular hydrogen bonding involved in etravirine leads to
its poor aqueous solubility. The cocrystal approach was found
to be a better option for improving the solubility of etravirine
compared to salt formation. Cocrystals have shown up to a 6-
fold increase in solubility with respect to the parent API,
whereas only 1.5 times improvement was shown by salts and
that too with poor attendant stability.
EXPERIMENTAL SECTION
■
General Procedures. Etravirine was obtained from Mylan
laboratories, Hyderabad, India. All other reagents were purchased
from commercial sources and were used without further purification.
Fourier Transform-infrared (FT-IR) spectra were recorded as KBr
pellets with a Perkin-Elmer spectrophotometer (4000−400 cm−1).
Powder X-ray diffraction (PXRD) data were recorded using a Philips
X’pert Pro X-ray powder diffractometer equipped with an X’cellerator
detector at room temperature with the scan range 2θ = 3 to 40° and
step size 0.017°. X’Pert HighScore Plus was used to stack the
experimental PXRD pattern with the calculated lines from the crystal
structure. DSC was performed on a Mettler Toledo DSC 822e module
with the heating rate of 5 °C/min between the temperature range of
30−300 °C under nitrogen atmosphere.
Preparation of Solid Forms. (1) ETR: crystallized from CHCl3.
(2) HETR·Cl: Salt 2 was crystallized by dissolving 15 mg of etravirine
in 4 mL of a solvent mixture of EtOH: CH3NO2 (1:1) with 4 drops of
concentrated HCl. (3) (HETR·CH3SO3): Salt 3 was crystallized by
dissolving 15 mg of etravirine in 4 mL of a solvent mixture of
EtOH:CH3NO2 (1:1) with 4 drops of CH3SO3H. (4) (HETR·H-
SO4·CH3OH): Salt 4 was crystallized by dissolving 15 mg of etravirine
in 4 mL of a solvent mixture of MeOH:CH3NO2 (1:1) with 4 drops of
a concentrated H2SO4. (5) (HETR·C6H5SO3): 15 mg (0.035 mmol)
of etravirine and 11 mg (0.070 mmol) of benzenesulfonic acid were
ground together and dissolved in 4 mL of an EtOH:CH3NO2 (1:1)
solvent mixture. Block-shaped crystals were obtained within a week.
(6) (HETR·MeC6H4SO3): 15 mg (0.035 mmol) of etravirine and 14
mg (0.074 mmol) of p-toluenesulfonic acid hydrate were ground
together and dissolved in 4 mL of an EtOH:CH3NO2 (1:1) solvent
mixture. Block-shaped crystals were crystallized within a week. (7)
(2ETR·ADP): 30 mg (0.069 mmol) of etravirine and 6 mg (0.041
mmol) of adipic acid were ground together and dissolved in a
minimum amount of CH3NO2 (3 mL). Rectangular block-shaped
crystals were crystallized within 3 days. (8) (ETR·H3BTC·H2O): 15
mg (0.035 mmol) of etravirine and 15 mg (0.071 mmol) of 1,3,5-
benzenetricarboxylic acid were ground together and dissolved in 4 mL
of MeOH. Block-shaped crystals were obtained in a week. (9)
(ETR·HCOOH), compound 9, was crystallized by dissolving 25 mg of
etravirine in 5 mL of a solvent mixture of HCOOH:EtOH:CH3NO2
(1:2:2). (10) (ETR·CH3COOH), compound 10, was crystallized by
dissolving 25 mg of Etravirine in 5 mL of a solvent mixture of
CH3COOH:EtOH:CH3NO2 (1:2:2). (11) (2ETR·MeOH) and (12),
(ETR·MeOH), were crystallized from MeOH and obtained in the
same vial as a block- and plate-shaped crystals, respectively. (13)
(ETR·CH3CN): Crystallized from CH3CN.
Single Crystal X-ray Diffraction. Except for 13, single crystal X-
ray data for all crystals were collected on a Rigaku Mercury 375/M
CCD (XtaLAB mini) diffractometer using graphite monochromated
Mo Kα radiation. The data were processed with Rigaku CrystalClear.18
For the crystals of 13, the data was collected on a Bruker APEX-II
CCD diffractometer using graphite monochromated Mo Kα radiation
and was processed using SMART (Bruker 2004). Structure solution
and refinements were executed using SHELX-97,19a using the
WinGX19b 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 the data
quality. The hydrogen atoms position was located from difference
Fourier map or calculated using a riding model. PLATON20 was used
to prepare material for publication, and Material Studio, version 6.0,21
CONCLUSIONS
■
To improve the solubility of etravirine, multicomponent
screening was carried out. Thirteen new solid forms of
etravirine were obtained in the form of salt, cocrystal, and
solvates. Etravirine was found to be capable of forming salts
only with the strong acids because of its low basicity. The
tendency to form solvates can be attributed to the imbalance of
the donor−acceptor ratio within the molecule. Polymorph
screening resulted in only one anhydrous form in a different
solvent and solvent combinations. A conformational study on
etravirine reveals that it can adopt four major possible
geometries. However, in all the 13 solid forms, it was found
to adopt only one conformation. This can be attributed to the
stability provided by the intramolecular edge-to-face π···π
H
dx.doi.org/10.1021/cg4007058 | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
was utilized for molecular representations and packing diagrams.
Crystallographic cif files (CCDC nos. 933645−933657) are available
at www.ccdc.cam.ac.uk/data_request/cif or as part of the Supporting
Information.
Solubility Study. The absorption coefficient of each solid form
and API were measured from the slope of the absorbance versus
concentration of the five known concentration solutions in a water−
EtOH (1:1) solvent mixture. The absorbance was measured at 317 nm
to avoid coformer interference (in the 250−280 nm region) on a
Perkin-Elmer UV−vis spectrometer. The solubility of each solid was
measured at 1 h, 4 h, and 24 h time intervals, using the shake-flask
method.22
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ASSOCIATED CONTENT
■
(c) Aakeroy, C. B.; Forbes, J.; Desper, J. J. Am. Chem. Soc. 2009, 131,
̈
S
* Supporting Information
17048−17049. (d) Bolla, G.; Sanphui, P.; Nangia, A. Cryst. Growth
Hydrogen bonding parameters, FT-IR, PXRD, and DSC of
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Des. 2013, 13, 1988−2003.
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State Chemistry; Desiraju, G. R., Ed.; Elsevier: Amsterdam, 1987; pp
471−518. (b) Dunitz, J. D. Pure and Applied Chemistry 1991, 63, 177−
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G. R. Angew. Chem., Int. Ed. 2007, 46, 8342−8356. (e) Griesser, U. J.;
Jetti, R. K. R.; Haddow, M. F.; Brehmer, T.; Apperley, D. C.; King, A.;
Harris, R. K. Cryst. Growth Des. 2008, 8, 44−56. (f) Castro, R. A. E.;
Maria, T. M. R.; Evora, A. O. L.; Feiteira, J. C.; Silva, M. R.; Beja, A.
M.; Canotilho, J.; Eusbio, M. E. S. Cryst. Growth Des. 2010, 10, 274−
282.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: desiraju@sscu.iisc.ernet.in. Fax: +91 80 23602306.
Tel: +91 80 22933311.
Notes
The authors declare no competing financial interest.
(9) (a) Bhatt, P. M.; Azim, Y.; Thakur, T. S.; Desiraju, G. R. Cryst.
Growth Des. 2009, 9, 951−957. (b) Mahapatra, S.; Thakur, T. S.;
Joseph, S.; Varughese, S.; Desiraju, G. R. Cryst. Growth Des. 2010, 10,
3191−3202.
ACKNOWLEDGMENTS
■
We are thankful to Dr. Ram Jetti (Mylan Laboratories,
Hyderabad) for providing the sample of the API. L.R. thanks
the DST for a Young Scientist Fellowship. P.S. thanks Ranbaxy
Pharmaceuticals for a Fellowship. G.R.D. thanks the DST for a
J. C. Bose Fellowship.
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