Preparation and characterisation of solid state forms of paracetamol-O-glucuronide

Article abstract of DOI:10.1016/j.carres.2011.12.018

The synthesis and crystallisation of the pharmaceutically important metabolite, paracetamol-O-glucuronide, is described. Hydrated and anhydrous forms of the target molecule have been characterised by PXRD, DSC and TGA. In addition, a methanol solvate has

Full text of DOI:10.1016/j.carres.2011.12.018

Carbohydrate Research 349 (2012) 108–112
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Preparation and characterisation of solid state forms of
paracetamol-O-glucuronide
⇑
John A. Hayes, Kevin S. Eccles, Simon E. Lawrence, Humphrey A. Moynihan
Department of Chemistry/Analytical and Biological Chemistry Research Facility, University College Cork, College Road, Cork, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 October 2011
Received in revised form 16 December 2011
Accepted 20 December 2011
Available online 29 December 2011
The synthesis and crystallisation of the pharmaceutically important metabolite, paracetamol-O-glucuro-
nide, is described. Hydrated and anhydrous forms of the target molecule have been characterised by
PXRD, DSC and TGA. In addition, a methanol solvate has been analysed, including single crystal analysis,
which represents the first structure solution for this system.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Paracetamol-O-glucuronide
Solvates
Hydrates
X-ray diffraction
Glucuronides are a group of biologically active molecules formed
in vivo as a result of phase II metabolism. This metabolic pathway is
formation of hydrates and solvates is based on the concept of mul-
1
9
ti-point recognition. Hydrate forms of both the parent acid and so-
1
0,11
primarily concerned with the bioconjugation of non-polar xenobiot-
ics to glucuronic acid resulting in more water soluble forms of the
parent compound which then can be readily excreted. For example,
paracetamol, one of the world’s most widely used analgesic and
antipyretics, is metabolised extensively in the body, mainly in the
liver. The main metabolites from this pathway are paracetamol-O-
sulfate, N-acetyl-p-benzoquinone imine and paracetamol-O-glucu-
ronide 5. Formation of paracetamol-O-glucuronide accounts for up
to two thirds of this metabolic pathway.2
dium salt of paracetamol-O-glucuronide 5 have been reported
1
2
as well as an anhydrous form. To date no solid state forms of this
biologically important molecule have been fully elucidated. Herein
we report the preparation, crystallisation and crystal forms of
4-acetomidophenyl-b-D-glucopyranosiduronic acid 5 (Scheme 1)
and for the first time the crystal structure of a methanol solvate of
the target compound. The only reported crystal structure of a glucu-
1
3
14
ronide is that of estrone glucuronide (CSD ref. code RESKAB).
10,12,15
A number of syntheses of compound 5 have been reported.
1
5
Glucuronides are highly polar molecules which have tradition-
ally been synthesised on milligram scales for the purposes of phar-
macological testing, testing for drug substances of abuse and
investigation of possible metabolites of new APIs during clinical
Brown et al. used a tri-O-isobutyryl protected trichloroacetimi-
date as glucuronidating agent. However, we found that use of the
1
6
tri-O-acetyltrichloroacetimidate 3 provided the most practical
route to useful quantities of compound 5 (Scheme 1). Treatment of
3
trials. Many synthetic methods exist for the synthesis of O-linked
methyl tetra-O-acetyl-b-
methoxide in dichloromethane yielded the hemiacetal 2 as a mix-
ture of diastereoisomers (approximately 75:25 /b) in 87% yield.
Coupling 2 to trichloroacetonitrile with DBU resulted in the exclu-
sive formation of the -imidate 3. Methyl (4-acetamidophenyl-
2,3,4-tri-O-acetyl-b- -glucopyranosid)uronate was obtained
using the glucuronide donor 3, paracetamol and BF in dichlo-
ÁOEt
romethane. Base hydrolysis of 4 was achieved using 2 equiv of K CO
O. Following neutralisation with a strongly
acidic ion-exchange resin and column chromatography, 4-aceto-
midophenyl-b- -glucopyranosiduronic acid 5 was isolated in 47%
D-glucopyranuronate 1 with tributyltin
1
7
glucuronides and their various derivatives. Acyl protected interme-
diates such as methyl tetra-O-acetyl-b-
D
-glucopyranuronate 1 seem
a
to be the most prevalent intermediates for the synthesis of the glu-
curonide series, although higher priority alkyl and aryl protecting
a
4
5
6
groups such as the iso-butyryl, pivaloyl and benzyl groups have
also been employed.
D
4
3
2
7
Based on Etter’s rules, the ratio of hydrogen bond donors: accep-
2
3
1
8
tors for a typical glucuronide suggests that it is possible to incorpo-
rate one or more hydrate or solvate molecule within the hydrogen
in 5:5:1 MeOH/THF/H
2
8,9
bonding framework in the solid state.
This guideline for the
D
yield. A coupling constant of 7.5 Hz for the 1H doublet was assigned
to the hydrogen on C-1 of the glucopyranose, indicative of b stereo-
chemistry, which was also confirmed by single crystal analysis (see
below).
⇑
Corresponding author. Tel.: +353 21 4902488; fax: +353 21 4274097.
E-mail address: h.moynihan@ucc.ie (H.A. Moynihan).
0
008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.12.018

J. A. Hayes et al. / Carbohydrate Research 349 (2012) 108–112
109
MeO C
MeO C
MeO C
2
2
2
O
O
O
AcO
AcO
AcO
a
b
AcO
OAc
AcO
OH
AcO
OAc
OAc
OAc
OC(NH)CCl3
1
2
3
MeO C
HO C
2
2
O
O
c
AcO
HO
d
AcO
O
HO
O
OAc
OH
NHAc
NHAc
4
5
Scheme 1. Reagents and conditions: (a) Bu
3
SnOMe, CH
2
Cl
2
, 87%; (b) CCl
3
CN, DBU, CH
2
Cl
2
, 65%; (c) paracetamol, BF
3
ÁEt
2
O, CH
2 2 2 3
Cl , 76%; (d) 2 equiv K CO in 5:5:1 MeOH–THF–
Ò
+
Ò
+
H
2
O, followed by Amberlyst 15 H ion-exchange resin, 47% (for sodium salt, Amberlyst 15 H resin, then aq NaHCO
3
soln, MeOH, 85%).
In our hands, complete evaporation to dryness of solutions of 5
particular form or another, but not both simultaneously, as ob-
served in this case, is more unusual but still would not be a partic-
ularly surprising crystallisation phenomenon. It is likely that sub-
critical nuclei of both forms are present in solution but that once
one form nucleates, growth of that form is exclusive at least on
the occasions these crystallisation have been carried out by us.
There was no obvious difference in how these crystallisations were
carried out which would lend a bias towards one form or the other.
The crystalline sodium salt of 5 was achieved by reaction of the
free acid with aqueous sodium bicarbonate in ethanol. However,
recrystallisation of the sodium salt from aqueous ethanol yields
microcrystalline 5 sodium salt as an agglomerated solid which
was not suitable for structural analysis.
The only form observed in our studies suitable for single crystal
analysis was a methanol solvate of 5 which was crystallised from
methanol–dichloromethane. This form was found to be ortho-
1 1 1
rhombic, crystallising in the P2 2 2 space group (see Table 1).
Comparison of the PXRD pattern of the bulk material with the the-
oretically generated pattern based on the crystal structure we have
gave amorphous material, displaying typical amorphous halos in
their powder X-ray diffraction (PXRD) patterns. Attempts to crys-
tallise these batches from solvents also gave amorphous material.
Crystalline material could be obtained by clarifying the product
solution with charcoal, reducing to approximately half volume
and cooling to between 0 and 5 °C. This resulted in the formation
of two distinct crystalline forms of target compound 5, an anhy-
drous form and a hydrated form. The anhydrous form of 5 was char-
acterised by PXRD (Supplementary data) and shows no significant
weight loss in the corresponding TGA traces (Supplementary data).
The other crystalline form of 5 was isolated as a monohydrate with
a needle-like habit (Supplementary data). The TGA traces (Fig. 1) re-
vealed two events, the first in the region of 20–60 °C which is due to
residual solvent tightly held on the crystal surfaces, the second in
the region of 100–120 °C, being due to the hydrate. On no occasion
were both of these forms observed together. Concomitant polymor-
phism, in which two or more crystal forms are observed to be pres-
ent simultaneously, is well reported.19 Formation of either one
1
1
10
00
6
.388%
5
.321%
9
8
7
6
0
0
0
0
2
5
75
125
175
Universal V3.9A TA Instruments
Temperature (ºC)
Figure 1. TGA trace 5ÁH
2
O.

1
10
J. A. Hayes et al. / Carbohydrate Research 349 (2012) 108–112
Table 1
Crystal data for 5ÁMeOH
coated silica plates (Merck Silica Gel 60, F24). Column chromatog-
raphy was conducted using Merck Silica Gel 60, typically with a
30:1 ratio of silica to sample. TLC plates were visualised either un-
der ultraviolet (UV) light or an anisaldehyde stain. Infrared spectra
were recorded on a Perkin-Elmer Paragon 1000 FT-IR spectrome-
Chemical formula
Formula mass
Crystal system
a (Å)
b (Å)
c (Å)
Unit cell volume (Å )
Temperature (K)
Space group
No. of formula units per unit cell, Z
C
15
H
21NO
9
359.33
Orthorhombic
8.3590(4)
1
ter. The H NMR spectra were recorded on a Bruker AVANCE 300
8.4792(4)
or 400 MHz spectrometers. Spectra were recorded using either
22.8663(10)
1620.71(13)
296(2)
P2
4
3
deuterated chloroform (CDCl
DMSO-d ) or deuterated water (D
the internal standard. Chemical shift values (d
3
), deuterated dimethyl sulfoxide
O) using tetramethylsilane as
and d ) are ex-
(
6
2
1 1 1
2 2
H
C
pressed as parts per million (ppm). Elemental analyses were per-
formed by the Microanalysis Laboratory, University College Cork,
using a Perkin-Elmer 240 and an Exeter Analytical CE440 elemen-
tal analyser.
Radiation type
Absorption coefficient,
No. of reflections measured
No. of independent reflections
a
Cu K (1.5418 Å)
À1
l
(mm
)
1.054
12,824
2699
0.032
0.033
0.085
0.038
0.088
1.03
R
int
Final R
Final wR(F ) values (I > 2
Final R values (all data)
1
values (I > 2r(I))
2
1.2. Synthesis
r(I))
1
2
Final wR(F ) values (all data)
Goodness of fit on F2
Flack parameter
1
.2.1. Methyl 2,3,4-triacetyl-
Methyl tetra-O-acetyl-b- -glucopryranuronate (1) (15.0 g, 39
mmol) was dissolved in dry CH Cl (120 mL) and tributyltin meth-
a,b-glucopyranuronate (2)
D
0.3(2)
2
2
oxide (12.6 mL, 43.8 mmol) was added. The solution was refluxed
for 4 h until TLC indicated consumption of the starting material.
The solution was cooled to room temperature and then washed with
1
0% aq HCl (2 Â 20 mL), water (20 mL), dried and concentrated in
vacuo. The resulting syrup was triturated with hexane (3 Â 40 mL)
to yield a solid which was recrystallised from EtOAc–hexane to give
1
a white crystalline solid (11.6 g, 87%) ratio of
a
to b anomers (by H
2
1
NMR) = 75:25 (
H), 2958 (C–H), 1752 (C@O) cm ; m/z (ESI): 357 (M +Na, 15%). H
NMR (CDCl ) ( anomer) d 5.57 (t, 1H, J 9.5 Hz, H-3), 5.54 (d, 1H, d,
a:b) mp 89–90 °C, lit. 91–92 °C; IR (KBr) m3469 (O–
À1
+
1
3
a
J 3.6 Hz, H-1), 5.17 (t, 1H, J 9.5 Hz, H-4), 4.90 (dd, 1H, J 3.6, 9.5 Hz,
H-2), 4.59 (d, 1H, J 9.5 Hz, H-5), 4.24 (br d, 1H, J 3.6 Hz, OH) 3.75 (s,
1
H, CO
2
Me), 2.09 (s, 3H, OAc), 2.04 (s, 3H, OAc), 2.03(s, 3H, OAc).
C NMR (CDCl ) ( anomer) d 170.2 (C@O), 170.1 (C@O), 168.5
C@O), 166.7 (C@O), 90.2 (C-1), 70.78 (C–H), 69.6 (C–H), 69.2 (C–
1
3
3
a
(
1
H), 67.99 (C–H), 52.90 (CO
b anomer) d 5.29 (t, 1H, J 9.5 Hz), 5.21 (t, 1H, J 9.5 Hz), 4.95 (d, 1H,
J 7.8 Hz, H-1), 4.82 (t, 1H, J 9.3 Hz), 4.36 (br d, 1H, J 7.8 Hz, OH),
2
CH
3
), 20.6 (3 Â OAc). H NMR (CDCl
3
)
(
4
.12 (d, 1H, J 9.6 Hz, H-5), 3.76 (s, 3H, CO
2
Me), 2.09 (s, 3H, OAc),
1
3
2
.04 (s, 3H, OAc), 2.03 (s, 3H, OAc). C NMR (b anomer) d 170.52
Figure 2. Lattice orientation of 5ÁMeOH showing preferential growth along the
crystallographic b axis.
(C@O), 170.10 (C@O), 169.59 (C@O), 167.61 (C@O), 95.45 (C-1),
72.85 (C–H), 72.53 (C–H), 71.6 (C–H), 69.43 (C–H), 53.10 (CO CH ),
0.51 (3 Â OAc). Anal. Calcd forC13 10: C, 46.71; H, 5.43. Found:
C, 46.36; H, 5.70.
2
3
2
18
H O
obtained shows that the structure is representative of the bulk
material (Supplementary data).
Face indexing experiments of the needle-like crystals observed
for the methanol solvate indicate that the preferred growth direc-
tion is along the b axis of the unit cell (Fig. 2).
1
.2.2. Methyl 2,3,4-triacetyl-1-O-(trichloroacetimidoyl)-a-D-
glucopyranouronate (3)
Methyl 2,3,4-triacetyl-a,b-glucopyranuronate (2) (12.0 g, 36
This can be rationalised by inspection of the single crystal data
mmol) and trichloroacetonitrile (18 mL, 180 mmol) was stirred in
dry CH Cl at 0 °C for 30 min. DBU (1.5 mL, 10 mmol) was added
dropwise and the solution was allowed warm to room temperature
and stirred overnight. The solvent was removed in vacuo and the
residue was subjected to flash chromatography (40:59:1 EtOAc–
7
which show C(5) chains along the crystallographic b axis (Fig. 3).
2
2
These C(5) chains are made by the diol functionality on C-2 and C-3
1
of the glucopyranose ring, and are related by a 2 screw axis as rep-
7
resented in Figure 3. Unitary graph set analysis along this crystal-
lographic axis shows a discrete (capping) HÁ Á ÁO–Me hydrogen
bond between the OH group on C-4 of the glucopyranose ring
and the interstitial MeOH molecule is also observed (Fig. 3).
3
hexane–Et N). Appropriate fractions were pooled and the solvent
removed under reduced pressure to yield a syrup which was tritu-
rated with diethyl ether. Following recrystallisation with EtOAc–
hexane (50:50) to yield 8.5 g (65%) of an off white solid. mp
2
2
1
1
. Experimental
108–109 °C, lit. 109–110 °C; IR (KBr)
m
3320 (N–H), 2958 (C–H),
) d 8.73 (s, 1H, NH), 6.64 (d, 1H, J
3.6 Hz, H-1), 5.63 (t, 1H, J 10 Hz, H-3), 5.27 (t, 1H, J 10 Hz, H-4),
.16 (dd, 1H, J 3.6 Hz, 10 Hz, H-2), 4.49 (d, 1H, J 10 Hz, H-5), 3.75
(s, 3H, CO Me), 2.05 (s, 3H, OAc), 2.04 (s, 3H, OAc), 2.02 (s, 3H,
À1
1
1
755 (C@O) cm . H NMR (CDCl
3
.1. General
5
All commercial reagents were purchased from Sigma-Aldrich
and were used without further purification. All solvents were
2
1
3
OAc). C NMR (CDCl ) d 169.78 (C@O), 169.72 (C@O), 169.47
3
either of a HPLC grade or distilled prior to use. Methyl tetra-O-acet-
(C@O), 167.14 (C@O), 160.58 (C@N), 92.64 (C–H), 70.49 (C–H),
yl-b-
D
-glucopryranuronate 1 was prepared as described by Bollen-
69.47 (C–H), 69.10 (C–H), 68.96 (C–H), 53.04 (CO Me), 21.04,
20.66, 20.48, 20.39 (3 Â OAc and 1 Â CCl3).
2
2
0
back et al. Thin layer chromatography (TLC) was conducted on

J. A. Hayes et al. / Carbohydrate Research 349 (2012) 108–112
111
a
HO C
b
2
HO C
2
O
O
HO
O
O
HO
C(5) chain
O
O
OAr
O
OAr
H
H
H
H
H
H
H
O
H
O
O
OAr
OAr
HO
HO
O
O
HO C
HO C
2
2
Ar = 4-AcNHC H -
6
4
Figure 3. (a) Unit cell of 5ÁMeOH along the crystallographic b axis, showing C(5) chains and interstitial MeOH molecules, along the preferential growth axis (some molecules
have been removed for clarity). (b) Graphical representation of the C(5) chains along the b axis of the unit cell.
2 2
Cl
), lit.15
1
.2.3. Methyl (4-acetamidophenyl-2,3,4-tri-O-acetyl-b-
D
-
(47%) of crystalline material. Mp 135 °C (MeOH–CH
134–137 °C; IR (KBr) 3347 (O–H), 2925 (C–H), 1728 (C@O), 1663
glucopyranosid)uronate (4)
m
À1
+
À
Methyl2,3,4-triacetyl-1-O-(trichloroacetimidoyl)-a-D-glucopyra-
(C@C), 1510 (C@C) cm . m/z (ESI): 328 (M , 10%), 326 (M , 20%).
1
nouronate (3) (10.0 g, 21.0 mmol), paracetamol (3.5 g, 23 mmol) and
Å molecular sieves were stirred in dry CH Cl for 30 min. BF
ÁEt
4 mL, 23 mmol) was added dropwise at 0 °C and the solution was al-
lowed to stir overnight. The solvent volume was reduced, washed
with satd aq Na CO
(2 Â 30 ml), water (2 Â 30 ml) dried with MgSO
and concentrated in vacuo to yield a pale white solid. Column chro-
matography (40:1 CHCl –MeOH) followed by recrystallisation from
IPA gave a white crystalline solid (7.5 g, 76%). mp 214–216 °C, lit.
6
H NMR (DMSO-d ) d 9.89 (s, 1H, NH), 7.52 (d, 2H, J 8.8 Hz, Ar-H),
4
(
2
2
3
2
O
7.02 (d, 2H, J 8.8 Hz, Ar-H), 5.41 (br s, 1H, OH) 5.22 (br s, 1H, OH),
4.92 (d, 1H, J 7.5 Hz, H-1), 4.42 (br s, 1H, OH), 4.17(br s, 1H, OH),
H 2
2.06 (s, 3H, NAc). d (D O shake) 7.25 (d, 2H, J 9 Hz, Ar-H), 7.03 (d,
2
3
4
2H, J 9 Hz, Ar-H), 5.06 (d, 1H, J 7.5 Hz, H-1), 4.06 (d, 1H, J 9 Hz, H-
1
3
2
5), 3.64–3.53 (m, 3H, H-2, 3, 4), 2.04 (s, 3H, NAc). C NMR (D O) d
3
172.7 (C@O), 171.9 (C@O), 153.8 (Cq), 132.18 (Cq), 123.7, 117.2,
100.4 (C–H), 75.0 (C–H), 74.5 (C–H), 72.5 (C–H), 71.1 (C–H), 23.7
2
3
2
13.5–214.5 °C; IR (KBr)
m
3300 (N–H), 3146–2969 (C–H), 1758
3
(NHCOCH ).
À1
+
1
(
C@O), 1509 (Ar-H) cm . m/z (ESI): 468 (M , 100%) H NMR (CDCl
3
)
d 7.42 (d, 2H, J 9 Hz, Ar-H), 7.2 (br s, 1H, NH), 6.96 (d, 2H, J 9 Hz, Ar-
H), 5.35–5.23 (m, 3H, H-2, 3, 4), 5.07 (d, 1H, J 7.2 Hz, H-1), 4.14 (d,
1
.2.5. 4-Acetomidophenyl-b-
sodium salt
Methyl (4-acetamidophenyl 2,3,4-tri-O-acetyl-b-
sid)uronate (4) (1.00 g, 2.15 mmol) was dissolved in a solution of
MeOH–THF–H O (5:5:1, 40–50 mL) and the solution stirred under
an N atmosphere at 0 °C. K CO (0.6 g, 4.3 mmol) was added and
D-glucopyranosiduronic acid (5)
1
H, J 9.6 Hz, H-5), 3.74 (s, 3H, CO
2
Me), 2.16 (s, 3H, NAc), 2.06 (s, 3H,
13
D
-glucopyrano-
OAc), 2.05 (s, 3H, OAc), 2.04 (s, 3H, OAc). C NMR (CDCl
3
) d 170.08
C@O), 169.35 (C@O), 169.25 (C@O), 168.29 (C@O), 166.91 (C@O),
(
1
9
5
53.28 (Cq, Ar) 133.28 (Cq, Ar), 121.66 (C–H, Ar), 117.82 (C–H, Ar),
9.64 (C –H), 72.62 (C–H), 71.91 (C–H), 71.1 (C–H), 69.16 (C–H),
2
1
2
2
3
the reaction mixture was heated to 40 °C for 5 h. The reaction mix-
ture was cooled to room temperature and neutralised with strongly
acidic ion-exchange resin (AmberlystÒ 15 H Form). The exchange
resin was removed and the solution was clarified with charcoal.
After removal of the charcoal on a bed of CeliteÒ the solvent was re-
2
2.97 (CO Me), 24.37 (NHAc), 20.75, 20.6, 20.49 (3 Â OAc).
+
1
.2.4. Acetamidophenyl-b- -glucopyranosiduronic acid (5)
D
Methyl (4-acetamidophenyl-2,3,4-tri-O-acetyl-b- -gluco-
pyranosid)uronate (4) (1.00 g, 2.15 mmol) was dissolved in a
solution of MeOH–THF–H O (5:5:1, 40–50 mL) and allowed to stir
under a nitrogen atmosphere at 0 °C. K CO (0.6 g, 4.3 mmol) was
D
moved and the residue was dissolved in MeOH (50 mL). aq NaHCO
3
2
solution (20 ml) was added and the solution heated to boiling. After
heating for 10 min the solution was allowed to cool to room temper-
ature and left to stir for 1 h. The resulting solid was isolated and
recrystallised from aq EtOH to give the product as a white crystalline
2
3
added and the reaction mixture was heated to 40 °C for 5 h. The reac-
tion mixture was cooled to room temperature and neutralised with
strongly acidic ion-exchange resin (AmberlystÒ 15 H Form). The
exchange resin was removed and the solution clarified with
charcoal. The solvent volume was removed in vacuo and the residue
+
solid 0.63 g (85% yield). Mp 220–230 °C, (decomp.). IR (KBr)
m
3298
(
O–H), 2935 (C–H), 1578 (C@O), 1510 (C@C), 1414 (C@C), 1043
À1
1
(
C–O) cm
H, J 9.2 Hz, Ar-H), 5.10 (d, 1H, J 6.8 Hz, H-1), 3.89 (d, 1H, J 9.6 Hz,
H-5), 3.64–3.55 (m, 3H, H-2, 3, 4), 2.16 (s, 3H, NAc).
2
; H NMR (D O) d 7.36 (d, 2H, J 9.2 Hz, Ar-H), 7.14 (d,
subjected to column chromatography using EtOAc–MeOH–H
60:30:10). Appropriate fractions were pooled and the solvent
removed in vacuo. Recrystallisation of the residue yielded 0.34 g
2
O
2
(

1
12
J. A. Hayes et al. / Carbohydrate Research 349 (2012) 108–112
1
1
.3. Crystal growth
Acknowledgments
.3.1. Hydrated and anhydrous forms
Crystalline 5 was obtained as follows. Following neutralisation
This publication has emanated from research conducted with
the financial support of Science Foundation Ireland under Grant
Numbers 07/SRC/B1158 and 05/PICA/B802/EC07.
of the reaction mixture with acidic ion-exchange resin, removal
of the resin and clarification of the solution with charcoal, the fil-
tered solution was reduced to approximately half volume and
cooled to between 0 and 5 °C. This procedure provided either the
hydrate or the anhydrous form of compound 5 with no obvious
bias towards either. Mixtures of the two forms were not observed
on any occasion.
Supplementary data
Complete crystallographic data for the structural analysis have
been deposited with the Cambridge Crystallographic Data Centre,
CCDC number 841974. Copies of this information may be obtained
free of charge from the Director, Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: +44 1223
1
.3.2. Amorphous form
Amorphous 5 was obtained by allowing a saturated solution of
3
36033, e-mail: deposit@ccdc.cam.ac.uk or via: www.ccdc.cam.a-
c.uk). PXRD data on the crystalline forms and TGA data on the
anhydrous forms are also provided. Supplementary data associated
with this article can be found, in the online version, at doi:10.1016/
j.carres.2011.12.018.
paracetamol-O-glucuronide, from a variety of solvents, including
MeOH, EtOH and H O, to slowly evaporate at room temperature.
2
1
.3.3. MeOH solvate
Compound 5 (100 mg) was suspended in a minimum of dichlo-
romethane (approx 10 mL), a minimum of hot methanol (approx
–6 mL) was added to affect dissolution, and following cooling
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