Structure of a monoclinic polymorph of N-[4-(acetyloxy)-phenyl]acetamide, a prodrug of acetaminophen

Article abstract of DOI:10.1023/A:1009565926282

The preparation, single crystal x-ray structure and the computed powder XRD pattern of a monoclinic polymorph of N-[4-(acetyloxy)phenyl]acetamide, a prodrug of acetaminophen, are reported. The polymorph crystallizes in the space group P2₁/n with Z = 4 and unit cell dimensions a = 7.219(2), b = 8.015(2), c = 16.575(2) A, β = 92.07(1)°, and V = 958.4(4) A³. Infinite spiral molecular arrays result from intermolecular head-to-tail hydrogen bonding between the amidic H atom of one molecule and the acetoxy carbonyl oxygen atom of a 2₁-related molecule.

Full text of DOI:10.1023/A:1009565926282

Journal of Chemical Crystallography, Vol. 29, No. 2, 1999
Structure of a monoclinic polymorph of N-[4-(acetyloxy)-
phenyl]acetamide, a prodrug of acetaminophen
M. R. Caira,(1)* F. N. de Wet,(2) and J. J. Gerber(2)
Received January 4, 1999
The preparation, single crystal x-ray structure and the computed powder XRD pattern
of a monoclinic polymorph of N-[4-(acetyloxy)phenyl]acetamide, a prodrug of acetamino-
phen, are reported. The polymorph crystallizes in the space group P21/n with Z ϭ 4 and
˚
unit cell dimensions a ϭ 7.219(2), b ϭ 8.015(2), c ϭ 16.575(2) A, ͱ ϭ 92.07(1)Њ, and V ϭ
3
˚
958.4(4) A . Infinite spiral molecular arrays result from intermolecular head-to-tail hydrogen
bonding between the amidic H atom of one molecule and the acetoxy carbonyl oxygen atom
of a 21-related molecule.
KEY WORDS: Acetaminophen prodrug; drug polymorphism; x-ray analysis.
Introduction
of N-[4-(acetyloxy)phenyl]acetamide. Three poly-
morphic forms of the compound have been identified
Acetaminophen (N-[4-hydroxyphenyl]acetamide,
by X-ray, thermal and infrared analyses.4 For drugs
with low aqueous solubility, the dissolution rate and
bioavailability may depend critically on the polymor-
phic form used in a formulation.6 It is therefore neces-
sary to identify and characterize such polymorphs
thoroughly with respect to their relative stabilities,
crystal structures, possible interconversions and dis-
solution rates in order to ensure optimum choice of
a polymorph for a specific formulation. There are no
previous reports of crystallographic analyses of the
title compound.7 In this report, we describe the crystal
and molecular structure of a monoclinic polymorph
of N-[4-(acetyloxy)phenyl] acetamide. We are at-
tempting to crystallize the other polymorphic forms
for x-ray analysis and further physicochemical char-
acterization.
or paracetamol) is a very widely used drug possessing
analgesic and antipyretic properties but little anti-
inflammatory activity.1 Its undesirable characteristics
include poor compaction properties and an acrid
taste. The former problem has been overcome by a
solvation/desolvation process which produces pure
acetaminophen with a fine, sintered texture suitable
for tableting.2 Improvement in taste, stability, and
solubility have been effected by addition of cyclodex-
trins, owing to the formation of an inclusion complex
in solution.3 Another approach to the problem of
undesirable taste is derivatization. The title com-
pound is derived by acetylation of the hydroxyl group
of the parent compound. It is a prodrug of acetamino-
phen and has recently been identified as a good candi-
date for incorporation into a chewable tablet.4 The
compound possesses low aqueous solubility and
nearly similar bioavailability to acetaminophen.5
The present study relates to the polymorphism
Experimental
Acetaminophen was added to a glacial acetic
acid/PEG-400 solution (4 : 1 by volume) at 45ЊC until
a saturated solution was obtained. The solution was
heated to 70ЊC and the temperature maintained for
60 min. After cooling to ambient temperature and
storage for 7 days, the title compound crystallized in
(1) Department of Chemistry, University of Cape Town, Ronde-
bosch 7701, South Africa.
(2) Research Institute for Industrial Pharmacy, Potchefstroom Uni-
versity for CHE, Potchefstroom 2520, South Africa.
* To whom all correspondence should be addressed.
175
1074-1542/99/0200-0175$16.00/0 1999 Plenum Publishing Corporation

176
Caira, de Wet, and Gerber
the form of colorless platelets. A melting range of
147–152ЊC was measured on a Linkam THMS600
hot stage equipped with a Linkam TP92 tempera-
ture controller.
Preliminary unit cell and space group data were
obtained from x-ray precession photographs. The
structure was solved by direct methods8 from mea-
sured intensities corrected for Lorentz-polarization
effects. Least-squares refinement9 proceeded rou-
tinely and all H atoms were located in a subsequent
difference electron density map. The position of the
amidic H atom was allowed to refine subject to the
˚
restraint N(7)UH(7) ϭ 1.00 A while all other H
atoms were inserted in a riding model with CUH
˚
1.00 A. Non-H-atoms were treated anisotropically
and H atoms were assigned common variable Uiso
parameters (one for aromatic, one for methyl H).
Atom H(7) was assigned an individual Uiso. Further
details of the data-collection and structure refinement
appear in Table 1.
Fig. 1. ZORTEP view of the molecule with thermal ellipsoids
drawn at the 50% probability level. H atoms are drawn as small
spheres of arbitrary size.
Table 1. Crystal Data and Summary of Intensity Data Collection
and Structure Refinement
Results and discussion
Compound
CCDC deposit no.
Color/shape
Formula weight
Temperature
Crystal system
Space group
C10H11NO3
CCDC-1003/5499
Colorless, plates
193.20
Crystal and molecular structure
The molecular conformation, atomic numbering,
and thermal ellipsoids10 are shown in Fig. 1. Atomic
coordinates and thermal parameters are listed in Ta-
ble 2. The acetamide residue, including atoms N(7),
294(1)K
Monoclinic
P21/n
˚
a ϭ 7.219(2) A, Ͱ ϭ 90Њ
Unit cell dimensions
(24 reflections, ␪ 16–17Њ)
˚
b ϭ 8.015(2) A, ͱ ϭ 92.07(1)Њ
˚
c ϭ 16.575(2) A, Ͳ ϭ 90Њ
958.4(4) A
3
˚
Volume
Z
Density (calculated)
Absorption coefficient
Diffractometer/scan
Radiation/wavelength
Table 2. Atomic Coordinates (ϫ 104) and Equivalent
4
3
3 a
˚
Isotropic Displacement Parameters (A ϫ 10 )
1.339 g/cm3
0.932 cmϪ1
Atom
x
y
z
Ueq
Enraf-Nonius CAD4/Ͷ-2␪
MoKͰ (graphite
monochrom.)/0.71069A
408
0.20 ϫ 0.25 ϫ 0.35 mm
1.00 to 25.0
h: Ϫ8 Յ 8, k: 0 Յ 9, l: 0 Յ 19
1891
1487 (Rint ϭ 0.021)/1196 [I Ͼ
2␴(I)]
Full-matrix least-squares on F
1196/1/139
˚
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
N(7)
C(8)
O(9)
C(10)
O(11)
C(12)
O(13)
C(14)
7373(3)
7220(3)
5600(3)
4150(3)
4283(3)
5896(3)
9044(3)
9442(3)
8387(2)
11330(3)
2456(2)
2304(3)
3510(2)
490(3)
2658(3)
1810(3)
1897(3)
2841(3)
3714(3)
3624(3)
2458(3)
2909(3)
3687(2)
2335(3)
2834(2)
3882(3)
4832(2)
3666(4)
3650(1)
2919(1)
2448(1)
2706(2)
3418(2)
3898(2)
4108(1)
4886(2)
5299(1)
5202(2)
2260(1)
1627(1)
1464(1)
1176(2)
44(1)
50(1)
52(1)
48(1)
52(1)
50(1)
48(1)
45(1)
55(1)
56(1)
58(1)
46(1)
60(1)
61(1)
F(000)
Crystal size
␪ range for data collection
Index ranges
Reflections collected
Independent/observed
reflections
Refinement method
Data/restraints/parameters
Goodness-of-fit
Weights
2.587
[␴2(Fo)]Ϫ1
Final R ϭ ⌺͉ ͉Fo͉ Ϫ ͉Fc͉ ͉/⌺͉Fo͉ 0.0443
Rw
Largest diff. peak and hole
0.0436
0.088 and Ϫ0.055 eA
Ϫ3
˚
a Ueq is defined as (1/3)⌺i⌺jUijaiaj a* и a*.
i
j

N-[4-(acetyloxy)phenyl]acetamide
177
˚
Table 3. Bond Lengths (A) and Bond
Angles (Њ)
C(1)UC(2)
C(1)UC(6)
C(1)UN(7)
C(2)UC(3)
C(3)UC(4)
C(4)UC(5)
C(4)UO(11)
C(5)UC(6)
N(7)UC(8)
C(8)UO(9)
C(8)UC(10)
O(11)UC(12)
C(12)UO(13)
C(12)UC(14)
1.391(3)
1.391(3)
1.411(3)
1.384(3)
1.372(3)
1.372(4)
1.406(3)
1.388(4)
1.360(4)
1.216(3)
1.514(3)
1.345(3)
1.195(3)
1.494(3)
C(6)UC(1)UN(7)
C(2)UC(1)UN(7)
C(2)UC(1)UC(6)
C(1)UC(2)UC(3)
C(2)UC(3)UC(4)
C(3)UC(4)UO(11)
C(3)UC(4)UC(5)
C(5)UC(4)UO(11)
C(4)UC(5)UC(6)
C(1)UC(6)UC(5)
C(1)UN(7)UC(8)
N(7)UC(8)UC(10)
N(7)UC(8)UO(9)
O(9)UC(8)UC(10)
C(4)UO(11)UC(12)
O(11)UC(12)UC(14)
O(11)UC(12)UO(13)
O(13)UC(12)UC(14)
123.6(2)
116.9(2)
119.5(2)
120.4(2)
119.4(2)
119.5(2)
121.2(2)
119.1(2)
119.8(2)
119.7(2)
128.8(2)
113.8(2)
123.8(3)
122.4(3)
116.9(2)
111.3(2)
122.3(2)
126.4(2)
Fig. 2. Stereoview of the packing arrangement showing hydrogen
bonds (dotted lines).
Figure 2is a stereoviewshowing the crystal packing
and hydrogen bonding. The molecules are linked head-
to-tail by a hydrogen bond N(7)UH(7)иииO(13I)uC(12I)
(I ϭ symmetry equivalent 1.5 Ϫ x, Ϫ0.5 ϩ y, 0.5 Ϫ
z) between the amido group of one molecule and the
acetoxy carbonyl oxygen of a 21-related molecule.
Parameters for this hydrogen bond are NиииO ϭ
˚
2.927(3) A and angle NUHиииO ϭ 164(2)Њ. Repeti-
tion of the hydrogen bonded motif by translation
along the b-axis generates an infinite spiral of mole-
cules. The phenyl rings of two molecules related by
the 21-axis are approximately orthogonal.
C(8), O(9), and C(10) is planar (max. deviation from
the least squares plane, 0.004(3) A for C(8)) as is the
˚
Figure 3 is the computer-generated XRD
pattern13 for this polymorph (CuKͰ radiation, ␭ ϭ
phenyl ring (max. deviation from the least squares
˚
˚
plane, 0.007(3) A for C(4)). The dihedral angle be-
1.5418 A). Except for minor intensity differences
tween these residues is 10.2(1)Њ. Bond distances and
angles (Table 3) for the acetamide residue are in
close agreement with those observed in the mono-
clinic11 and orthorhombic12 polymorphs of the parent
compound acetaminophen, but in these molecules,
the acetamide moiety is more steeply inclined to the
phenyl ring (dihedral angles 21.1 and 17.7Њ, respec-
tively). The maximum deviation from the least
which can be attributed to preferred orientation ef-
fects, the experimental pattern is in excellent
agreement with that of Fig. 3, indicating that the
˚
squares plane of the acetoxy group is 0.004(2) A
(for C(12)) and this plane is inclined at 96.4(1)Њ
to the phenyl ring. The overall conformation of
the molecule may be described by the torsion
angles C(6)UC(1)UN(7)UC(8) ϭ 10.7(4)Њ and
C(5)UC(4)UO(11)UC(12) ϭ 99.9(3)Њ. Acetylation
of the UOH group of acetaminophen leads to a sig-
nificant lengthening of the C(4)UO(11) distance,
˚
from 1.377(3) and 1.389(5) A in the two poly-
morphs11,12 to 1.406(3) A in the title compound.
Fig. 3. Computer-generated XRD pattern for the title compound.
˚

178
Caira, de Wet, and Gerber
2. Fachaux, J.M.; Guyot-Hermann, A.-M.; Guyot, J.-C.; Con-
flant, P.; Drache, M.; Huvenne, J.P.; Bouche´, R. Congr. Int.
Technol. Pharm. 6th. 1992, 5, 213.
3. Lin, S.Y.; Yang, J.C.; Kawashima, Y. J. Taiwan Pharm. Assoc.
1984, 36, 24.
4. Bhalla, D.V.; Lalla, J.K. Drug Dev. Ind. Pharm. 1990, 16, 115.
5. Baugess, C.T.; Fincher, J.H.; Sadik, F.; Hartman, C.W.
J. Pharm. Sci. 1975, 64, 1489.
6. Laird, T. In Comprehensive Medicinal Chemistry; Kennewell,
P.D., Ed.; Pergamon Press: Oxford, 1990; Vol. 1, p 321.
7. Cambridge Structural Database and Cambridge Structural
Database System, (Version 5.15), Cambridge Crystallo-
graphic Data Centre, University Chemical Laboratory: Cam-
bridge, England, April 1998.
manual grinding involved in sample preparation
caused no polymorphic transformation in the starting
material. As noted earlier,14 the computed XRD pat-
tern serves as the best reference pattern for a specific
crystalline phase and is therefore provided here. It
is particularly useful for unequivocal future identifi-
cation of the drug polymorph in question as well as
for quantitative assessment of the polymorphic purity
of a recrystallized sample of the drug.
8. Sheldrick, G.M. Acta Crystallogr. 1990, A46, 467.
9. Sheldrick, G.M. SHELX76. A System of Computer Programs
for X-ray Structure Determination; University of Cambridge:
England; 1976.
Acknowledgments
We thank the University of Cape Town and the
FRD (Pretoria) for financial support.
10. Zsolnai, L. ZORTEP. An Interactive Version of ORTEP; Uni-
versity of Heidelberg: Germany, 1994.
11. Haisa, M.; Kashino, S.; Kawai, R.; Maeda, H. Acta Crystallogr.
1976, B32, 1283.
12. Haisa, M.; Kashino, R.; Maeda, H. Acta Crystallogr. 1974,
B30, 2510.
References
13. Yvon, K.; Jeitschko, W.; Parthe´, E.J. J. Appl. Crystallogr.
1977, 10, 73.
14. Bar, I.; Bernstein, J. J. Pharm. Sci. 1985, 74, 255.
1. Shearn, M.A. In Basic & Clinical Pharmacology, Katzung,
B.G., Ed.; Lange Medical Publications: California, 1984,
Chapter 34, p 412.