Physicochemical Properties of Crystalline Forms of
Ethynylestradiol Solvates: Comparison of Thermal
Behavior with X-ray Crystal Structure
TOSHIMASA
ISHIDA', M~TSUNOBUDoi, MARISHIMAMOTO,
NAOKO MINAMINO,KATSUMINONAKA,
AND MASATOW INOUE
Received January 26, 1988, from the LaboraWY of Physical Chemistty, Osaka University of Pharmaceutical Sciences, 2-10-65Kawai, Matsubara,
Osaka 580, Japan. Accepted for publication May 5, 1988.
Abstract 0 Four crystalline forms of ethynylestradiol solvates were
obtained from three solvents [acetonitrile(Form A), methanol (Form B),
and chloroform saturated with water (Forms C and D)], and were
characterized by X-ray powder patterns and thermal analyses. The
crystal structures of Forms A, B, and C were further analyzed using the
X-ray diffraction method, and the results are discussed in comparison
with the thermal behavior of the crystalline forms. The steroid conforma-
tion of ethynylestradiol was rigid and no noticeable difference was
observed among the solvated crystal structures; the molecular structure
differed only in the orientation of the ethynyl group with respect to the
steroid skeleton. The difference in the interaction mode between
ethynylestradiol and the solvent molecules primarily discriminates the
physicochemical properties.
Estrogens such as estradiol are the essential hormones for
the development of primary and secondary female sex char-
acteristics and h a v e a common steroid ring skeleton, as
shown below. Since the molecular conformation of steroids is
intimately related to their biological activity, structural
investigations have been performed o n various estrogen
analogues.l-ll These s t e r o i d c o m p o u n d s h a v e been
shown t o have several polymorphic crystals when they are
crystallized under different conditions.12 Therefore, the de-
termination a n d characterization of the solid-state conforma-
tions a r e of practical importance to provide insight into the
extent of conformational change which the molecule c a n
adopt. This, in turn, sheds light o n the molecular conforma-
tion-activity relationship and also clarifies t h e differences
between the physicochemical properties of polymorphic crys-
tals, because the polymorph of the drug exerts a significant
effect on its dissolution rate and bioavailability.
Ethynylestradiol, a potent synthetic estrogen, has been
used in replacement therapy for cases of estrogen deficiency.
This paper deals with the physicochemical properties of four
ethynylestradiol crystalline forms obtained from the solvents
acetonitrile (Form A), methanol (Form B), a n d chloroform
saturated w i t h water (Forms C and D).These crystalline
forms were characterized b y measuring the melting points,
IR spectra, thermal reactions, and X-ray powder patterns.
Furthermore, the crystal structures of Forms A, B, a n d C
/ H
A B
H '
Estradiol Ethynylestradiol
274 / Journal of Pharmaceutical Sciences
Vol. 78, No. 4,April 1989
were analyzed using the X-ray diffraction method; to our
knowledge, this i s the first X-ray study of the ethynylestra-
diol molecule.
Experimental Section
Preparation of Four Different Crystalline Forms of Ethynyles-
tradiol-Four different crystals of ethynylestradiol were obtained
from the following solvents: Form A (thin needles) was grown slowly
from acetonitrile (2 weeks); Form B (needles) was grown from
methanol (2-3 d); and Forms C (plates) and D (thin needles) were
grown from chloroform saturated with water (1 week). The crystals
of Forms C and D were obtained in the same beaker and then
separated under a microscope. The ethynylestradiol concentrations
used for crystallization were all 10 mglmL. The solution was placed
inside covered beakers and allowed to evaporate slowly at room
temperature (15-20 "C).
Infrared Spectra-The IR spectra were measured with an Hitachi
infrared spectrometer (model 260-12, Japan) using the KBr disk
method.
Thermal Analyses-Gravimetric and calorimetric changes accom-
panying thermal decomposition were measured by thermogravi-
metry (TG) and differential scanning calorimetry (DSC) instruments
(Rigaku model M8075, Japan). The TG and DSC profiles were
measured using 15 mg of well-powdered samples; A1203was used as
a standard, and the heating rate was 1.25 "Clmin.
X-ray Powder P a t t e r n s X - r a y powder patterns were measured
on a Rigaku GAB-RZ diffractometer using CuKa radiation. The
powder patterns of each crystalline form were measured three times
and then averaged.
X-ray Single Crystal Analyses of Forms A, B, and C-Cell
constants and the orientation matrix for intensity data collection
were obtained from the least-squares refinement of the scattering
angles of 25 reflections. The crystallographic data are listed in Table
I. The crystal density was measured by the flotation method using an
aqueous KI solution. A single crystal (Form A, 0.1 x 0.2 x 0.7 mm;
Form B, 0.2 x 0.2 X 0.8 mm; Form C, 0.2 x 0.5 x 0.6 mm) was
mounted on a computer-controlled Rigaku AFC-5 diffractometer.
Intensity data in the range 2" < 28 < 130" were measured using
graphite-monochromated CuKa radiation (A = 1.5415 A); the (u20
scanning mode was used for data collection with a scan speed of
4"lmin. Peak counts were corrected with background counts for 5 s
measured a t both ends of each reflection. Intensities were also
corrected for the Lorentz and polarization effects, but not for the
extinction or absorption effect. The crystals were all stable and
showed no deterioration during data collection.
The structure was solved by the direct method using the MUL-
TAN78 program.13 Nonhydrogen atoms were refined by the block-
diagonal least-squares method with anisotropic temperature factors.
The positional parameters of the hydrogen atoms, except for the
water molecules of Form C, were all located on a difference Fourier
map and were refined with an overall isotropic temperature factor.
The ideal hydrogen atomic positions of water solvent in Form C were
calculated and used for refinement. The quantity minimized was
OO22-3~9/89/O400-0274$01.00/0
0 1989, American Pharmaceutical Association
Table I-Crystal Characteristics of Ethynylestradiol Solvates

Parameter Form A Form B Form C

Chemical formula C20HZ4O2.l/2CH,CN C20H2402CH30H
Molecular weight 316.93 328.45
Crystal system Orthorhombic Monoclinic Monoclinic
Space group P212121 P21 c2
Cell constant
a,A 20.531(9) 6.685(2) 21.009(9)
b, A 7.283(2) 16.631(6) 6.646(9)
c, A 23.815(9) 8.665(3) 12.122(1)
i39 a 90.0 106.27(5) 90.51(5)
V,a3 3561(2) 924.8(6) 1692.5(8)
Z 8 2 4
D,,,, g . ~ m - ~ 1.182(1) 1.178(5) 1.173(1)
Dx,g m r 3 1.182 1.179 1.199
p(CuKa)-' 5.51 5.76 5.75
F(0 0 0) 1368 356 660
No. of obsd data 3458 1559 1269
No. of data with F, > 0.0 3250 1544 1240
No. of variables 425 218 209
R 0.084 0.082 0.057
RbV 0.076 0.096 0.097
S 1.849 2.125 0.856

Iw(lF,I -lFcl)', and the following weighting scheme was used in the
final refinement:
Form A: w = 0.1682 for F, = 0.0
w = ~.O/[CT(F,)~ - 1.19671FOl+ 0.05511F,121 forF, > 0.0 (1)
Form B: w = 0.2531 for F, = 0.0
w = l.0/[(+(F,)2 - 1.2129/F01+ 0.0987~0121 for F, > 0.0 (2)
Form C: w = 0.4293 for F, = 0.0
w = ~.O/[CT(F,)~ + 0.0576 lFol + 0.0012~F,~21 for F, > 0.0 (3)
where cr(FJ2 is the standard deviation of the intensity based on
counting statistics, and F, and F, are the observed and calculated
structure factors, respectively. Final R ~ ~ ~ ~ F , , - ~ RF, c ~ ic
~~~.w~~~o~-~F andc S([Cw(lFoI-~Fc1)2/(M
~~2~~~~Fo~ 2 1 1 where
- N)1"2, ' 2 ~ , consist of the chemical formulae C20H2402.1/2CH3CN,
M and N are the numbers of reflections and variables, respectively)
are also tabulated in Table I. In the final refinement, none of the
positional parameters shifted more than one third of the estimated
standard deviation. The residual fluctuations in the final difference curves of Forms A, C, and D, a n exothermic peak always
map were within the range -0.4-+0.3 e k 3 . The positional parame-
ters of the nonhydrogen atoms and the isotropic temperature factors
calculated from the anisotropic ones are given in Table 11, in which
solvent molecules of acetonitrile, methanol, and water are represent- becoming more stable thermally. In form A, the second
ed by suffix letters of a, m, and w, re~pective1y.l~ All numerical
calculations were carried out on a n Micro VaxII computer at the
Computation Center of Osaka University of Pharmaceutical Sci-
ences using the UNICS program.l5 Atomic scattering factors and the
terms of anomalous dispersion corrections were taken from Znterna-
tional Tables for X-ray Crystallography.16
Results and Discussion
Physicochemical Properties of Crystalline Forms A, B,
C, and D-The structural differences between these crystal-
line forms are clearly evidenced by their X-ray powder
pattern measurements, as shown in Figure 1.The diffraction
intensities of Form D crystals are very weak, probably due to
the poor quality of crystallinity; this crystal is very fragile
and quickly becomes opaque from exposure to air. On the
other hand, the remaining crystalline forms show well-
resolved X-ray diffraction patterns. The 20 values of the
three strong diffraction peaks for each form are as follows:
14.6, 16.8, and 22.5" for Form A; 14.9, 15.6, and 24.2" for
Form B; and 16.7, 18.2, and 13.7" for Form C. The IR spectra
were also different from one another, and the characteristic
bands for Forms B and C are in agreement with the pub-
lished ones,12 within their acceptable experimental errors.
Although ethynylestradiol was reported to have several
kinds of polymorphic crystal^,^^^^^ it is obvious from their
thermal behavior that Forms A-D are not polymorphic
crystals of ethynylestradiol molecule. Rather, they are com-
plex crystals with solvent molecules, which can be classified
as solvate crystals; the same conclusion has been reported by
Kuhnert-Brandstaetter and Winkler.I2
The TG and DSC profiles of Forms A-D are shown in
Figure 2; the deviations of DSC and TG curves from their
base lines represent the thermal (exo- or endothermic)
change and the weight loss, respectively. The thermodynam-
~ ~data
~ F given
o ~ ~ in
, Table I11 clearly show that Forms A-D
C20H2402CH30H, C20H2402.1/2H20,and C20H2402.1/2-
CHC13, respectively. It is of interest to note that in the DSC
accompanies the first appearance of an endothermic one near
90 "C. This implies the rearrangement of molecular packing
in the crystal lattice; consequently, their packing states are
endothermic change is revealed without the temperature lag,
and is accompanied by a large weight loss. It can be consid-
ered from these TG and DSC profiles that the first broad
endothermic peak in Form A reflects the breaking of interac-
tions such as the hydrogen bonds between the ethynyl-
estradiol and acetonitrile molecules, and the second one
corresponds to the release of the solvent from the crystal. In
the crystals of Forms C and D, however, the solvent mole-
cules are released during the first endothermic change.
Comparison of thermal profiles for Form C with those of
Form D suggests that their molecular packing modes are
very similar. However, the interaction force between the
ethynylestradiol and solvent molecules or the compactness of
the crystal packing is much stronger in Form C than D. The
chloroform solvent in Form D begins to release from the
crystal at -50 "C, which reflects the instability of the crystal
structure of Form D. The bulkiness of the chloroform solvent
may be disadvantageous to the formation of compact crystal
packing with the ethynylestradiol molecule.
On the other hand, Form B shows very different thermal
profiles; there are two endothermic peaks near 90 and 120 "C.

Journal of Pharmaceutical Sciences / 275

Vol. 78, No. 4, April 1989
Table Il-Posltional and Isotropic Thermal Parameters ( x lo4) of Nonhydrogen Atoms with Their Standard Deviations in Parentheses

Atom X Y z Beqa Atom X Y z Be, a

Form A (MoleculeA1 )
-2375(1) 6350(5) 10274(1) 4.7(1)
-2854(2) 6857(5) 10650(1) 5.1(2) 6461(8) 5636(3) 631 l(5) 3.6(2)
-3386( 1) 571l(5) 10751(1) 4.7(1) 7378(7) 6062(3) 7715(5) 3.5(2)
-3865(1) 6274(3) 11 122(0) 4.7(1) 6166(7) 6593(2) 8274(5) 3.1(1)
-3425(1) 4066(5) 10481(1) 4.0(1) 7066(5) 6993(2) 9723(3) 3.6(1)
-2942(1) 3539(4) 10092(1) 3.7(1) 4102(7) 6726(3) 7417(5) 3.3(1)
-3014( 1) 1649(4) 9819( 1) 4.0(1) 3230(7) 6317(3) 5992(5) 3.0(1)
-2577(1) 1404(5) 9314(1) 4.2(1) 1022(8) 6536(3) 5051(6) 4.1(2)
-1 88911) 2084(4) 9433(1) 3.5( 1) 303(7) 616913) 3406(5) 3.6(2)
-1 897(1) 4165(4) 9552(1) 3.6(1) 1031(7) 5305(2) 3438(4) 2.7(1)
-24 15(1) 4669(4) 9985(1) 3.6(1) 3443(7) 5268(2) 3898(5) 2.9(1)
- 1216(1) 4923(5) 9668(1) 4.4(1) 4407(7) 5745(2) 5461(5) 2.8(1)
-734(1) 4466(5) 9191(1) 4.1(1) 4232 (7) 441 l(3) 3949(3) 3.0(1)
-724(1) 2383(4) 9077(1) 3.3(1) 3238(7) 3949(3) 2344(5) 3.3(1)
- 1418(1) 1726(4) 8951(1) 3.5(1) 890(6) 3988(2) 1906(4) 2.7(1)
- 1329(1) -21 6(5) 8731(1) 4.6(1) 172(6) 4860(2) 1847(5) 2.8(1)
-658(1) - 164(5) 8414(1) 4.9(1) -2173(7) 4831(3) 1118(5) 3.4(1)
-373(1) 1746(5) 8528(1) 3.7(1) -2496(6) 4133(3) - 102(5) 3.4(1)
328(1) 1602(3) 8586(1) 4.2(1) -312(7) 3718(3) 174(6) 3.1(1)
-424( 1) 1394(6) 9576(1) 5.3(2) -606(5) 2890(2) -71(4) 4.1(1)
-488(1) 3005(5) 8056(1) 4.6(1) 94(7) 3466(3) 3096(6) 3.9(2)
-570(2) 4029(8) 7681(1) 6.9(2) 719(8) 4053(3) -1018(5) 3.9(2)
1552(11) 4332(4) - 1921(7) 5.7(3)
4414(5) 7215(2) 1454(3) 4.4(1)
(MolecL A21 5255(11) 7523(5) 3039(8) 6.3(3)
-249541) 744(4) 7416(1) 4.2(1)
-1 971(1) 1091(4) 7045(1) 4.1(1)
- 1623(1) -351(4) 6842(1) 3.7(1) 5840(2) -601(8) 6404(3) 3.2(2)
-1116(1) -83(3) 6472(0) 4.8(1) 5707(2) -928(9) 7518(3) 3.7(2)
- 1758(1) -2 139(4) 7008(1) 4.2(1) 5883(2) 465(9) 8295(3) 3.9(2)
-2280(1) -2472(4) 7382(1) 3.7(1) 5731(2) 252(8) 9387(2) 5.1(2)
-2397( 2) -4425(4) 7562(1) 5.0(1) 6208(2) 2204(9) 7981(3) 3.7(2)
-2806( 1) -4542(5) 8088(1) 4.7(1) 6356(2) 2516(8) 6870(3) 3.1 (2)
-3409(1) -3371(4) 8034(1) 3.4(1) 6702(2) 4429(9) 6596(3) 3.6(2)
-3206(1) - 1340(4) 8010(1) 3.2(1) 6935(2) 4540(9) 5405(3) 3.6(2)
-2659(1) -1 015(4) 7589(1) 3.3(1) 6423(2) 3760(8) 4616(3) 2.8(2)
-3794(1) - 85(4) 7938(1) 4.2(1) 6295(2) 1518(8) 4847(3) 2.9(2)
-431 0(1) -386(4) 8397(1) 4.1(1) 6158(1) 1142(8) 6057(3) 3.0(2)
-4508( 1) -2431(4) 8426(1) 3.8(1) 5785(2) 683(9) 405963) 3.8(2)
-3896(1) -3583(4) 8508(1) 3.8(1) 5930(2) 1097(9) 2829(3) 3.6(2)
-4151(2) -5493(5) 8651(1) 5.4(2) 6071(2) 3278(8) 2631(3) 2.9(2)
-4787(2) - 5120(6) 8986(1) 7.3(2) 6603(2) 3988(8) 3408(3) 3.0(2)
-4903( 1) -301O(5) 8972(1) 5.1(2) 6809(2) 6018(10) 2979(3) 4.3(2)
-5599(1) -271 7(4) 8920(1) 6.3(1) 6672(3) 5929(11) 1707(3) 5.0(3)
-4897(1) -2952(6) 7900(1) 5.7(2) 6373(2) 3844(9) 1497(3) 3.8(2)
-4668(2) -2174(6) 9481(1) 5.6(2) 5926(2) 3956(7) 598(2) 4.7(2)
-4451 (2) - 1592(7) 9899(1) 7.4(2) 5459(2) 4548(1 0) 2764(3) 4.5(2)
3927(2) 922(7) 8641(1) 9.9(2) 6873(2) 2387( 10) 1189(3) 4.3(2)
3642(2) 2213(6) 8746( 1) 6.3(2) 7266(3) 1232(13) 889(4) 6.4(3)
3270(2) 3868(7) 8871(1) 6.862) 4961(23) -31 65(14) 10004(32) 4.2(4)
~

'Be, = 413 ( B , , 2 + &,b + 8333 + acS,,cosp). bOccupancy = 0.5.

The temperature lag between both peaks and the nearly
same weight loss for each peak imply that there are two
pathways for the release of solvent molecule from the crystal.
As a possible releasing mechanism of methanol from the
crystal, the schematic shown in Figure 3 could be considered,
where the letters Est and Met represent ethynylestradiol and
methanol molecules, respectively. In contrast to Forms A, C,
and D, Form B shows no exothermic peak, which suggests
that the molecular packing of Form B is not essentially
affected by the loss of the solvent molecule.
These solvate crystals all become amorphous states by the
complete release of the solvent molecules; X-ray diffractions
of Forms A-D, which were heated a t 150°C and then
recooled at room temperature, all showed no noticeable peak
in the range 2" < 28 < 60".
Molecular Conformation and Crystal Packing of Forms
A, B, and C-The molecular structures of ethynylestradiol in
Forms A, B, and C are shown in Figure 4, in which two
crystallographically independent molecules in the crystal
structure of Form A are designated as A1 and A2. Bond
lengths, bond angles, and torsion angles are given in Figure
5. The averaged standard deviations for bond lengths, bond
angles, and torsion angles are, respectively, 0.006 A, 0.3",
and 0.4" for Form A, 0.007 A, 0.4",and 0.6"for Form B, and
0.008 A, 0 3 , and 0.7"for Form C. In general, the molecular
dimensions, except for the D-ring, are in good agreement
with those reported for estradiol analogues,l-lO within their
standard deviations. However, the addition of an ethynyl
group at the C(17) site appears to affect the molecular
dimensions of the D-ring; when the present data are com-

276 / Journal of Pharmaceutical Sciences

Vol. 78,No. 4, April 1989
 C
.......AT~..................... .-. I5
...................... 14
13
DSC -
Fj
X I F/
x I -
I

15
14
................
13
D

9
%
t
X
.......C...................... I
.................................. IS
3
14
13

20 40 110

28 28
15
Figure 1-X-ray powder patterns of Forms A, 6,C, and D at 20 "C. 14
13
............................
12

pared with published data for neutral e ~ t r a d i o l ,the

~ , ~bond /

length of C(13)-C(17) is significantly longer for the former

(1.57 A) than for the latter (1.53 A).
The molecular conformations of ethynylestradiol in respec-
tive crystals are similar; the torsion angles listed in Figure
5c show no significant differences from one another. As is
obvious from Figure 4,ring A is essentially planar with a
slight fluctuation (c0.02 A) from the best-fit plane, and rings
B and C are all in the chair conformation with the junctions
B/C and C/D being trans. Ring D shows the slightly deformed
P-envelope form. These conformational characteristics are
also found in the neutral estradiol hormone. Only one differ-
ence among these four molecular conformations is found in
the orientation of the ethynyl group with respect to the
steroid skeleton. T h e t o r s i o n a n g l e s of C(13)--
C(17)-C(19)-C(20) and C(16)-C(17)-C~19)-C~20) are,
respectively, 94(3)" and -150(3)" for A1 of Form A, -93(3Y
and 21(3)" for A2 of Form A, -23(2)' and 90(1)" for Form B,
and 147(1)"and -98(1)" for Form C. Comparison of these four
molecular structures leads to the conclusion that the steroid
moiety of ethynylestradiol is rigid and is not likely to show
conformational variability.
Molecular packings in the crystal structures are shown in
Figure 6. The characteristics of molecular packings can be
briefly described as follows. In Form A, molecule A1 (marked
50 100 150 200
OC
Flgure 2-Differential scanning calorimetric (DSC) and thermogravime-
tric (TG) curves of Forms A, 6,C,and D.
by oblique lines in Figure 6) is linked to the neighboring
same molecules in a head-to-tail fashion by hydrogen bonds
(see Table IV) and forms a n infinite waved chain along the a-
axis. Two molecules each of A2 and acetonitrile, which are
related by a diad screw symmetry, occupy each swollen part
built by the waved chain alignments of A1 molecules. Judg-
ing from the difference between the molecular packings of A1
and A2, it is obvious that two crystallographically indepen-
dent molecules are necessary for the crystallization of Form
A. On the other hand, a common characteristic can be seen in
the molecular packings of Forms B and C. A waved (Form B)
or linear (Form C) infinite chain linked by hydrogen bonds to
the neighboring molecules in a head-to-tail fashion runs
along the b- (Form B) or c-(Form C) axis, and the solvent
molecules lie among these chains and stabilize the molecular

Table Ill-Thermodynamic Data for Ethynylestradiol Solvate Crystals

TG a
DSC *
Crystal Weight Loss from
Temperature, "C Starting Sample Temperature, "C AH, kcal/mol Comment
(15mg), Yo

Form A 83-1 11 2.8(5) 92-1 12 1.2(2) endothermic

113-1 26 6.6(5) 112-1 16 0.4(2) exothermic
116-129 2.7(1) endothermic
177-1 89 10.5(2) melting
Form B 93-1 04 4.8(5) 85-1 06 6.3(1) endothermic
1 18-1 37 10.0(5) 117-133 5.5(2) endothermic
179-1 86 10.6(2) melting
Form C 97-1 11 3.1 (5) 91-107 4.4(1) endothermic
107-114 0.5(2) exothermic
181-193 9.6(2) melting
Form D 48-1 06 17.0(5) 93-1 05 1.7(2) endothermic
105-113 0.6(2) exothermic
179-1 87 11.2(2) melting
'Thermogravimetry. Differential scanning calorimetry.

Journal of Pharmaceutical Sciences / 277

Vol. 78, No. 4,April 1989
 ".€st.. .Met...Est....Yet...Est...Met...

85 - 93°C 85 - 93°C

- Est.-.Met ESt...Met ESt-..Met - - Met-..Est Mrt...Est Met..-Est -

this packing is thermally this packing is thermally

unstable, and releases Met stable, and releases Met
at 93 - 104°C at 118 -
137'c

- Est Est
1 Est - - Est
1 Est ESt -

Figure 3-A releasing scheme of methanol solvents from Form B

crystals: Est and Met represent ethynylestradiol and methanol mole-
cules, respectively. a

A1

' 116.4
116.1
115.2
117.1
1a4.3
114.1
1as.z
A2 105.9
113.6
113.2
116.2

017

C
Figure 4-Perspective views of ethynylestradiolmolecules observed in
Forms A (A 1 and A2), B, and C.

packings along the c- (Form B) or a-(Form C ) axis.

Interaction Mode between Ethynylestradiol and Solvent
Molecules and Comparison with Thermal AnalysesThe
interaction mode between ethynylestradiol and solvent mole-
cules is shown in Figure 7. Possible hydrogen bonds are given
in Table IV.In Form A, the hydrogen bonds between the
O(17) and O(3) atoms of neighboring A1 molecules form
infinite waved chains, as was already stated. Molecule A2 is
linked with A1 by two hydrogen bonds: the O(3) atom of A2,
as a donor, is hydrogen bonded to the O(17) atom of A l , and
this O(3) atom, as an acceptor, is further linked to an O(3)
atom of another A1 molecule. Acetonitrile solvent is fixed by
a hydrogen bond with the A2 molecule [0(17) . . . N(1)l. As is
obvious from Figure 7a, a swollen space formed by molecular
alignments of A 1 is large enough to accommodate two
molecules each of A2 and acetonitrile. Therefore, a possible
explanation of the thermal behavior of Form A (see Figure 2)
is as follows. The exothermic peak following the endothermic
C
Figure 5-Bond lengths (a), bond angles (b), and torsion angles (c) of
ethynylestradiol in Forms A (A 1 : top number; A2: second number), B
(third number), and C [fourth number).
peak may reflect the molecular rearrangement of A2 by the
breaking of either or both of two hydrogen bonds between A1
and A2 molecules. The consequent endothermic peak may be
due to the release of the solvent molecule due to breaking the
hydrogen bonds with A2. The many van der Waals contacts
of this molecule with molecules A1 and A2 may be why the
solvent molecule is not released first.
Three kinds of hydrogen bonds are formed in the crystal
structure of Form B. The hydrogen bonds among neighboring
O(3)and O(17) atoms form infinite waved chains. The metha-
nol solvent is held by two hydrogen bonds with neighboring

276 /Journal of Pharmaceutical Sciences

Vol. 78, No. 4, April 1989

- w c +
-%%-%a
. Ips+
C
Figure 6-Molecular packing views of Forms A (a), 5 (b), and C (c).
e t h y n y l e s t r a d i o l molecules [ 0 ( 3 ) . . . O ( l ) m a n d
O(1jm.. . 0(17)]. The Est . . . Met and Met. . . Est interac-
tions shown in Figure 3 may correspond to O(1)m. . . O(17)
and O ( 3 ) . . . O(1)m hydrogen bonds, respectively. No exo-
thermic peak in Form B (see Figure 2) reveals that the waved
infinite chain shown in Figure 7b has a thermally stable
crystal structure.
In the crystal structure of Form C, the O(3) atom of
ethynylestradiol is hydrogen bonded to the O(171 atom of a
neighboring molecule, consequently forming an infinite lin-
ear chain. This chain is further stacked antiparallel to the
one related by a diad screw symmetry. The water molecules
lie among these layered structures and stabilize the molecu-
lar packing by hydrogen bond formations with O(3) and
O(17) atoms. The water solvent near the 112,y,O position is
disordered. This disorder results from the special position of
a
C
Figure 7-Hydrogen bonding scheme observed in the crystal structures
of Forms A (a), B (b), and C (c).
the water molecule for the C2 space group and the nonlinear
angle of H-0-H. The crevice between the layered structure is
relatively wide (the average separating distance is 4.5fi) and
can account for the structural change which is interpreted
based on the exothermic appearance in the DSC curve of
Form C (see Figure 2). This figure further shows the com-
plete, not separated, release of the disordered water mole-
cules. The nearly identical DSC patterns of Forms C and D
imply that the chloroform molecules in Form D probably
interact with ethynylestradiol molecules in the same manner
as with water molecules.
Journal of Pharmaceutical Sciences / 279
Vol. 78, No. 4, April 1989
Table IV-Hydrogen Bond Distances the conformational deformation of the ethynylestradiol mole-
Donor at At Symmetry cule itself.
Acceptor Distance, r$
x, y, z Operation
References and Notes
-0.5 - X, 1 - y,0.5 + 2.897(5)
0.5 + X, 0.5 - y, 2 - z 1. Brown, J. N.; Trefonas, L. M. J . Am. Chem. SOC.1972,94,4311.
2.758(6)
-x, -0.5 + y, 1.5 - Z 2. Norton, D. A,; Kartha, G.; Lu, C. T. Acta Crystallogr. 1964, 17,
2.908(6) 77.
- 1 + x, y, z 2.900(6) 3. Cody, V.; Ddarnette, F.; Duax, W.; Norton, D. A. Acta Crystal-
logr., Sect. B 1971, B27, 2458.
4. Tsukuda, Y . ;Sato, T.; Shiro, M.; Koyama, H. J . Chem. Soc. (B)
x, y, 1 + z 2.649(5) 1969,336.
1 - x, -0.5 + y, 1 - z 2.742(5) 5 . Tsukuda, Y.; Sato, T.; Shiro, M.; Koyama, H. J . Chem. SOC.(B)
-x, 0.5 + y, - z 2.732(6) 19RR
- _- _ 1387
7

6. Busetta, B.; Courseille, C.; Geoffre, S.; Hospital, M. Acta Crystul-

x, y, z + 1 2.893(7)
x, 1 + y, -1 + 2 2.89(4)
1 -x,l +y,l - z 2.77(4)
x, y, 2 2.89(4)
1 -x,y,2-z 2.80(4)
‘The suffix letters, a, rn, and w, represent solvent molecules of
acetonitrile, methanol, and water, respectively.
It is of great interest to consider why ethynylestradiol
shows no polymorph, while the other related estradiol com-
pounds have been reported to exhibit several polymorphic
structures.12The present results show that the steroid skele-
ton of ethynylestradiol is rigid, and no detectable conforma-
tional fluctuation is observed. This may be an important
reason for the molecule not taking a polymorphic form. Since
the structure characterizing this molecule from the other
related compounds is only the existence of an ethynyl group,
this group may be responsible for making the steroid confor-
mation rigid. It is interesting to note that the electron-
donation ability of 0(17), determined from CNDO/P calcula-
tion, is meaningfully affected by the addition of ethynyl
group at the C(17) site. This may reflect the ease of the
complex formation with various solvent molecules without
logr., Sect. B 1972, B28, 1349.
7. Busetta, B.; Hospital, M. Acta Crystallogr., Sect. B 1972, B28,
560.
8. Courseille, C.; Busetta, B.; Preci oux, G.; Hospital, M. Acta
Crvstallom..Sect. B 1973. B29. 24g2.
9. B;rrans,-Y:; Courseille, ‘C.; Busetta, B.; Precigoux, G. Acta
Crystallogr., Sect. B 1976, B32, 1296.
10. Hadd, H. E.; Slikker, W., Jr.; Miller, D. W.; Helton, E.; Duax,
W. L.; Strong, P. D.; Swenson, D. C. J. SteroLd Bzochem. 1983,
18, 81.
11. Duax, W. L.; Griffi, J. F.; Rohrer, D. C.; Swenson, D. C.; Weeks,
C. M. J . Steroid Biochem. 1981,15, 41.
12. Kuhnert-Brandstaetter, M.; Winkler, H. Sci. Pharm. 1976, 44,
191.
13. Main, P.; Hull, S. E.; Lessinger, L.; Germain, G.; Declerq, J . P.;
Woolfson, M. M. A System of Computer Programs for the Auto-
matic Solution of Crystal Structures from X-ray DiffractionData,
MULTAN78; University of York U.K., 1978.
14. Tables of the observed and calculated structure factors, anisotro-
pic temperature factors of nonhydrogen atoms, and atomic
coordinates of hydrogen atoms are available from one of the
authors (T.I.) on request.
15. The Universal Crystallographic Computing System-Osaka; The
computation Center, Osaka University, 1979.
16. International Tables for X-ray Crystkllography; Kynoch: Bir-
mingham, U.K., 1974; Vol. IV.
17. Mesley, R. J.; Johnson, C. A. J . Pharrn. Pharmacol. 1965, 17,
329.
18. Phesant, R. J . Am. Chem. Soc. 1950, 72,4303.

280 /Journal of Pharmaceutical Sciences

Vol. 78, No. 4,April 1989