A 1:1 cocrystal of baicalein with nicotinamide

Article abstract of DOI:10.1107/S0108270112024456

Cocrystallization of baicalein with nicotinamide yields a 1:1 cocrystal [systematic name: pyridine-3-carboxamide-5,6,7-trihy-droxy-2-phenyl-4H-chromen- 4-one (1/1)], C₆H₆N₂O·C ₁₅H₁₀O₅. The asymmetric unit contains one baicalein and one nicotinamide mol-ecule, both in neutral forms. Mol-ecules in the cocrystal form column motifs stabilized by an array of inter-molecular hydrogen bonds.

Full text of DOI:10.1107/S0108270112024456

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
have been determined, and their solubility and oral bioavail-
ability have been shown to be improved over that of quercetin
(Smith et al., 2011).
ISSN 0108-2701
Nicotinamide (NA) belongs to the vitamin B group (vitamin
B3) and is classified as a GRAS substance. Therefore, this
molecule is widely used in the cocrystallization of carboxylic
acid functionalized APIs (Berry et al., 2008). Recently, two
cocrystals of orcinol (3,5-dihydroxytoluene) with NA were
reported (CSD refcodes EWAQEZ and EWAQAV; Muk-
herjee et al., 2011), showing that NA can be successfully
applied to the cocrystallization of hydroxy-functionalized
APIs.
A 1:1 cocrystal of baicalein with
nicotinamide
a
b
´
Michał Sowa, Katarzyna Slepokura and Ewa Matczak-
Jona*
Herein, the 1:1 cocrystal of baicalein with nicotinamide, (I),
is reported. The asymmetric unit of (I) comprises one baica-
lein and one nicotinamide molecule, both in their neutral
forms (Fig. 1).
.
aDepartment of Chemistry, Wrocław University of Technology, Wybrzeze
Wyspianskiego 27, 50-370 Wrocław, Poland, and bFaculty of Chemistry, University
´
of Wrocław, 14 F. Joliot-Curie Street, 50-383 Wrocław, Poland
Correspondence e-mail: ewa.matczak-jon@pwr.wroc.pl
Received 30 April 2012
Accepted 29 May 2012
Online 15 June 2012
Cocrystallization of baicalein with nicotinamide yields a 1:1
cocrystal [systematic name: pyridine-3-carboxamide–5,6,7-
trihydroxy-2-phenyl-4H-chromen-4-one (1/1)], C6H6N2Oꢀ-
C15H10O5. The asymmetric unit contains one baicalein and
one nicotinamide molecule, both in neutral forms. Molecules
in the cocrystal form column motifs stabilized by an array of
intermolecular hydrogen bonds.
It is common among flavones that two rings of the phenyl-
benzopyran entity, referred to as A/C (benzopyran), are
conjugated and coplanar, while the third one, B (phenyl), is
usually out of this plane. In (I), the mean planes defined by the
A/C and B rings of baicalein are inclined to each other with a
dihedral angle of 20.0 (2)ꢁ. This is higher than the values of 8.6
and 9.7ꢁ determined for baicalein crystals grown from,
respectively, a methanol–water mixture (CSD refcode RAM-
GOB; Rossi et al., 2001) and ethyl acetate (CSD refcode
RAMGOB01; Hibbs et al., 2003). Typically, the cocrystalliza-
tion of flavonoids leads to a change in the angle between the
A/C and B ring planes. This can be illustrated by comparing
the values of these angles in quercetin–caffeine methanol
solvate (Smith et al., 2011) and quercetin–isonicotinamide
(Smith et al., 2011) cocrystals (0.2 and 24.0ꢁ, respectively) with
the values of 8.1 and 22.0ꢁ, respectively, for quercetin dihy-
drate (CSD refcode FEFBEX01; Jin et al., 1990) and quercetin
pyridine solvate (CSD refcode NIXLUC; O’Mahony et al.,
2006).
Comment
Flavones, members of the flavonoid family, are low molecular
weight plant polyphenolic compounds with a wide range of
biological activities (Verma & Pratap, 2010). Baicalein (5,6,7-
trihydroxyflavone) is one of the main bioactive compounds
found in roots of the traditional Chinese herb Scutellaria
baicalensis (Olennikov et al., 2010). It has been shown to
inhibit iron-induced lipid peroxidation (Perez et al., 2009) and
induce apoptosis in HIV-infected cells in vitro (Ono et al.,
1989), and research into its anticancer (Miocinovic et al.,
2005), antioxidant (Shao et al., 2002) and anti-inflammatory
(Chou et al., 2003) properties has shown good results.
By virtue of the fact that flavonoids (including baicalein)
have low solubility in water and therefore low bioavailability
(Zhang et al., 2005, 2007), the discovery and identification of
new solid forms of them is highly desirable. A convenient way
of modifying the physicochemical properties and pharmaco-
kinetic parameters of active compounds of pharmaceutical
interest (active pharmaceutical ingredients, APIs) is cocrys-
tallization with a substance generally regarded as safe
(GRAS) (Schultheiss & Newman, 2009, and references
therein). This gives rise to novel supramolecular complexes
which generally exhibit enhanced solubility and dissolution
rates compared with their constituent components. Recently,
the structures of quercetin cocrystals with caffeine (MeOH
solvate; Smith et al., 2011), isonicotinamide (Smith et al., 2011)
and theobromine [dihydrate; Cambridge Structural Database
(CSD; Allen, 2002) refcode MUPPOD (Clarke et al., 2010)]
Figure 1
The molecular complex of (I), showing the atom-numbering scheme and
the symmetry-independent hydrogen bonds (dashed lines). Displacement
ellipsoids are drawn at the 50% probability level.
o262 # 2012 International Union of Crystallography
doi:10.1107/S0108270112024456
Acta Cryst. (2012). C68, o262–o265

organic compounds
The overall geometry of baicalein and NA in (I) is similar to
that determined for the parent components. A twist of the
amide group of NA relative to its pyridine ring plane is
reflected in the value of the O1A—C7A—C3A—C4A torsion
angle [ꢂ28.2 (5)ꢁ, Table 1] and reveals a similar conformation
to that of the pure nicotinamide crystal (CSD refcode
NICOAM01; Miwa et al., 1999).
with angles significantly below 140ꢁ are regarded as structu-
rally insignificant (Wood et al., 2009).
It should be noted here that the O—Hꢀ ꢀ ꢀNar interaction is
one of the most competitive heterosynthons (Bis et al., 2007)
and has also been observed in quercetin–isonicotinamide
(Smith et al., 2011), hesperetin–isonicotinamide (Kavuru,
2008) and quercetin–caffeine methanol solvate (Smith et al.,
The supramolecular arrangement in flavonoid cocrystals
depends on the number of hydroxy substituents on the
flavonoid backbone, as well as on the crystallization conditions
(Timmons et al., 2008). Quercetin, hesperetin and apigenin
exhibit hydroxy substitution on both benzopyran and phenyl
rings, which facilitates the formation of O—Hꢀ ꢀ ꢀO and N—
Hꢀ ꢀ ꢀO hydrogen-bonded two- or three-dimensional struc-
tures. Accordingly, quercetin cocrystals with caffeine (MeOH
solvate; Smith et al., 2011), isonicotinamide (Smith et al., 2011),
theobromine (dihydrate; CSD refcode MUPPOD; Clarke et
al., 2010) and triethylenediamine (CSD refcode COLHIV;
Timmons et al., 2008) reveal two-dimensional hydrogen-
bonded networks, and a three-dimensional network has been
observed in the quercetin–isonicotinic acid zwitterion hydrate
cocrystal (CSD refcode RUWHUN; Kavuru et al., 2010).
Similarly, the hesperetin–isonicotinamide cocrystal (Kavuru,
2008) comprises molecules arranged into a two-dimensional
sheet, while hesperetin–nicotinic acid zwitterion cocrystals
(CSD refcodes RUWHEX and RUWHIB; Kavuru et al., 2010)
and the apigein triethyelenediamine cocrystal (Timmons et al.,
2008) reveal the formation of one-dimensional extended
structures.
Baicalein contains a trihydroxy-substituted benzopyran
ring, therefore having three potential hydrogen-bond donor
atoms (O5, O6 and O7). In the crystal structure of (I), hydroxy
atom O5 of each baicalein molecule acts as an H-atom donor
in an intramolecular O5—H5ꢀ ꢀ ꢀO4 hydrogen bond, which is
common to all 5-hydroxyflavone derivatives known so far. The
remaining atoms O6 and O7 act as H-atom donors in inter-
molecular interactions (Table 2). Each baicalein molecule is
also joined to two adjacent inversion-related nicotinamide
molecules, leaving no possibility for further extension into a
two-dimensional structure. Similarly, 3,6-dihydroxyflavone
possesses two potential hydrogen-bond donor atoms on the
benzopyran ring (O3 and O6), facilitating the formation of
one-dimensional helices or ribbons with a bidentate cocrystal
former (CSD refcodes COLHAN and COLHIV, respectively;
Timmons et al., 2008).
An intermolecular O7—H7ꢀ ꢀ ꢀO1A hydrogen bond forms a
baicalein–NA heterodimer (Figs. 1 and 2a, and Table 2), in
which the planes defined by the A/C rings of baicalein and the
N1A/C6A atoms of NA are inclined to each other at a dihedral
angle of 27.3 (2)ꢁ. The heterodimers are further extended
Figure 2
A packing diagram for (I), showing (a) ribbons of (I) along the a axis and
(b) the inter-ribbon hydrogen-bond network resulting in the column
motif along the a axis. (In the electronic version of the journal, hydrogen
bonds between molecules forming the heteromolecular dimer are
indicated by blue dashed lines, and red and green dashed lines,
respectively, represent hydrogen bonds involved in forming the ribbon
and column motifs.) Some H atoms and intramolecular hydrogen bonds
have been omitted for clarity. [Symmetry codes: (i) ꢂx + 2, ꢂy + 2, ꢂz + 1;
(ii) x + 1, y, z; (iv) x ꢂ 1, y, z.]
along the
a direction into ribbons through N2A—
H2A2ꢀ ꢀ ꢀO1Aii hydrogen bonds (Fig. 2a). Two inversion-
related ribbons are assembled into a one-dimensional column
in the a direction by means of O6—H6ꢀ ꢀ ꢀN1Ai hydrogen
bonds (Fig. 2b). C4A—H4Aꢀ ꢀ ꢀO4iii interactions join adjacent
columns into sheets parallel to (001) (all symmetry codes as in
Table 2). Other possible N—Hꢀ ꢀ ꢀO and C—Hꢀ ꢀ ꢀO contacts
ꢃ
Acta Cryst. (2012). C68, o262–o265
Sowa et al. C6H6N2ꢀC15H10O5 o263

organic compounds
Table 2
Hydrogen-bond geometry (A, ).
2011) cocrystals, as well as in the cocrystal of orcinol (3,5-
dihydroxytoluene) with nicotinamide (CSD refcodes
EWAQEZ and EWAQAV; Mukherjee et al., 2011).
ꢁ
˚
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
In summary, this report provides an insight into the
previously unexplored field of baicalein cocrystallization and
is a further example of the successful application of nicotin-
amide as a coocrystal former for hydroxy-substituted mol-
ecules. The crystal structure of (I) comprises one-dimensional
ribbons, which are assembled into columns and held together
by weak intermolecular C—Hꢀ ꢀ ꢀO interactions. In contrast
with the quercetin, hesperetin and apigenin cocrystals known
so far, the crystal structure of (I) does not exhibit homo-
molecular hydrogen-bonded dimers.
O5—H5ꢀ ꢀ ꢀO4
0.84
0.84
0.84
0.88
0.95
1.81
1.91
1.94
2.23
2.32
2.563 (3)
2.694 (4)
2.720 (3)
2.996 (4)
3.200 (4)
148
155
154
145
154
O6—H6ꢀ ꢀ ꢀN1Ai
O7—H7ꢀ ꢀ ꢀO1A
N2A—H2A2ꢀ ꢀ ꢀO1Aii
C4A—H4Aꢀ ꢀ ꢀO4iii
Symmetry codes: (i) ꢂx þ 2; ꢂy þ 2; ꢂz þ 1; (ii) x þ 1; y; z; (iii) x ꢂ 1; y þ 1; z.
tion: CrysAlis RED; program(s) used to solve structure: SHELXS97
(Sheldrick, 2008); program(s) used to refine structure: SHELXL97
(Sheldrick, 2008); molecular graphics: DIAMOND (Brandenburg,
2005); software used to prepare material for publication:
SHELXL97.
Experimental
Baicalein was obtained from Sino-Future Bio-Tech Co. Ltd,
nicotinamide was obtained from Sigma–Aldrich and both were used
without further purification. Baicalein (0.025 g, 0.181 mmol) was
dissolved in a close-to-saturated solution of nicotinamide in ethyl
acetate (10 ml). Slow evaporation of the resulting solution yielded
amorphous material and crystals of (I), which were separated
manually and used for X-ray analysis.
Financial support from the Chemistry Department,
Wrocław University of Technology (grant No S10064/Z0304),
is gratefully acknowledged.
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: FG3251). Services for accessing these data are
described at the back of the journal.
Crystal data
C6H6N2ꢀC15H10O5
ꢂ = 79.83 (3)ꢁ
3
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Acta Cryst. (2012). C68, o262–o265
Sowa et al. C6H6N2ꢀC15H10O5 o265