Structural characterization of polymorphs and molecular complexes of finasteride

Journal

of

MOLECULAR STRUCTURE Journal of Molecular Structure 474 (1999) I57- I66

Structural characterization of polymorphs and molecular complexes of finasteride Irena Wawrzycka”,

Krystyna Stqpniak”, Slawomir Matyjaszczyk”, Tadeusz Lisb, Khalil A. Abboud”

Anna E. Koziol”,“,

“Faculty of Chemistry, Maria Curie-Sktodowska University. 20-031 Luhlin. Poland bFaculty of Chemistry. Universit.y of Wroctaw, 50.383 Wt-ocraw, Poland ‘Department of Chemistry, University of Floridcr, Gainesville, FL 32611, USA Received

IO March 1998; received in revised form 17 August 1998; accepted

I7 August I998

Abstract The molecular structure of finasteride, 17~-(N-tert-butylcarbamoyl)-4-aza-5a-andros~-l-en-3-one, and structures of three related crystalline forms have been determined by X-ray analysis. The rigid steroid skeleton of the molecule adopts a half-chair/ chair/chair/half-chair conformation. Two peptide groups, one cyclic (lactam) in the ring A and a second being a part of the substituent at C17, are the main factors influencing intermolecular contacts. Different hydrogen-bond interactions of these hydrophilic groups are observed in the crystal structures. An infinite ribbon of finasteride molecules is formed between lactam groups in the orthorhombic homomolecular crystal (1) obtained from an ethanol solution. The linear molecular complex finasteride-acetic acid (la) is connected by hydrogen bonds between the lactam of finasteride and the carboxyl group of acetic acid. The crystallization from an ethyl acetate solution gives a complex structure of bis-finasteride monohydrate ethyl acetate clathrate (lb) with guest molecule disordered in channels. Crystals of a second (monoclinic) finasteride polymorph (2) were obtained during thermal decomposition of la, and sublimation of 1, la and lb. Two polymorphic forms show different IR spectra. 0 1998 Elsevier Science B.V. All rights reserved. Keywords: Azaandrosten Steroids; Polymorphs

derivative;

Bis-finasteride

ethyl acetate clathrate; Finasteride-acetic

1. Introduction The role of specific fragments of steroids in molecular recognition (i.e. steroid-receptor and steroidenzyme interactions) has been discussed by Diederich et al. [ 11. Hydrophilic groups, e.g. hydroxyl, carboxyl and carbonyl, at the steroid skeletons are factors influencing abilities to form molecular complexes by hydrogen

bonding.

Finasteride

acid complex;

X-ray analysis;

carbamoyl)-4-aza-5ol-androst1-en-3-one], modified steroid derivative with two peptide the ring A contains a lactam group while butylamide residue is the substituent at Cl7 CONHC(CH,), CH3

CH3

[ 17P-(N-tert-butyl-

/ A

* Corresponding author. Tel.: 00 48 8 I 537 5662; Fax: 00 48 81 533 3348: e-mail: [email protected]. 0022-2860/98/$ - see front matter 0 1998 Elsevier Science B.V. All rights reserved. PII: SOO22-2860(98)00569-9

D

C

&

B

N k

1

1, is a groups; the tert[2].

I58 Table I Crystal data and experimental

Empirical formula Formula weight Crystal system Space group Unit cell dimensions: (I (A) h (A) (’(A) p (A) v (A?) Z D, (g cm-‘) D, (g cm -‘) Crystal habit Crystal size (mm) Diffractometer Wavelength (A) p (mm-‘) F(OOO) I3 range (“) Index ranges:

Reflections collected Data/restraints/ parameters in refinement Goodness-of-fit on F’ Final R indices [I >

1. Wawyycka

er al. / Jourwl

of Molecular

Structure 474 (1999)

157-166

parameters 1

la

lb

Czdz&Q 312.54 Orthorhombic

C23Hi~NzOZCHzCOOH 432.59 Monoclinic

2 CziHihN202.H~0.C4Hx02 851.20 Orthorhombic

p2,2,2,

P?,

p2,2,2,

6.451 l(1) I2.7406(3) 25.9789(6) 2135.2(l) 4 I.159 1.145 Prism 0.11 x 0.14 x 0.23 SMART 0.7 1073 0.073 816 I .6-29.0 -8GhG8 - I7 G k s I6 - 28 G 1 G 34 14143 5 158/O/389

1.025

12.170(l) 8.165217) 13.577(l) 111.630(1) 1254. I(2) I.146 I.139 Plate 0.08 x 0.23 x 0.27 SMART 0.7 I073 0.077 472 I .6-2X.9 - I6 G h G I5 -1lskSX - 16 s 1 s I7 8436 470211 I44 I

I.096

8.173(3) I8.364(6) 35.65(2) 5350(4) 4 I.057 Not measured Needle 0.2 x 0.25 x 0.6 KM4 I .54178 0.55 I I864 2.5-69.9 OGhG9 - 20 c k s 22 - 39 G I =s43 7554 4610/19/530

0.968

2a(0l: RI wR2

Extinction coefficient Max. and min. Ap(e A-‘)

0.05 10

0.0924 0.0096( I I ) 0.19 and - 0.13

The presence of these two groups can affect strength and pattern of intermolecular contacts between the neighboring molecules in the solid state. Finasteride is a competitive and specific inhibitor of testosterone So-reductase, and does not show any steroid-hormone related property [3]. It had been reported [4] that finasteride itself forms two polymorphs, depending on the solvent used for crystallization and the mode of crystal treatment, but structural details were not discussed.

0.0529 0.1158 0.033(5) 0.36 and - 0.20

0.0765 0.1143 0.0014(3) 0.38 and - 0.22

2. Experimental Crystals of the first polymorphic form of finasteride 1 (m.p. 253-256°C) were obtained from an ethanol/ water (1:lO) solution. The crystallization of finasteride from an acetic acid/water mixture (about 2:l) by slow evaporation of solvents gave fine crystals of the chemical formula finasteride:acetic acid = I:1 (la). Solid la decomposes, losing acetic acid, and recrystallizes in the range 170-174°C (m-p. 255 257°C).

I. Wawycka

et (11. / Joumul

Fig. I. Perspective

of Molec~ulur Structure

view of finasteride

During the evaporation of ethyl acetate from the third finasteride solution (containing traces of H20), unstable crystals of lb are formed (m.p. 252-255°C). The stoichiometric ratio of the three-component phase lb is finasteride:water:ethyl acetate = 2:l: 1. The densities of 1 and la were measured by flotation in KI solution. The single-crystal X-ray diffraction data for 1, la and lb were collected at room temperature. Crystals of la and lb were sealed in glass capillaries. The crystallographic data and experimental details are collected in Table 1, and the atom-numbering scheme of the finasteride molecule is shown in Fig. 1. All crystal structures were solved by direct methods [5] and refined by full-matrix least-squares on F* [6]. Positions of hydrogen atoms of 1 and la were located in difference electron density maps. Parameters refined for these structures were coordinates of all atoms, anisotropic displacement parameters of nonhydrogen atoms and isotropic displacement parameters of hydrogen atoms. For lb, the hydrogen atoms of finasteride molecule were positioned from geometry while the water molecule H-atoms were found in a AF map, and their coordinates were kept fixed. The isotropic displacement parameters of Hatoms were UiSO= 1.2 U,, of the atom to which they

Fig. 2. The disordered

474 (I 999)

157-

159

166

molecule with atom numbering.

are attached. The ethyl acetate molecule, a guest molecule in lb, is disordered over two positions (Fig. 2). Therefore, only positional and isotropic displacement parameters of the ethyl acetate nonhydrogen atoms were refined, with bond-length restraints applied. Atomic parameters for 1, la and lb are given in Tables 2, 3 and 4, respectively. The absolute configuration of the steroid nucleus used in all calculations was consistent with that of androstane [71. The second polymorphic form of finasteride 2 was obtained both by thermal decomposition of la ( 175°C 30 min) and sublimation of 1, la and lb (about 235°C 30 min), using hot stage microscopy. Unit cell parameters for poor quality crystals of 2 were determined on a KM4 diffractometer. The FTIR spectra were recorded for pellets in KBr on a Perkin-Elmer 1725X spectrometer.

3. Results and disscussion 3. I. Molecular

structure offinasteride

In general, considering the lower accuracy of structure determination of the two symmetrically

ethyl acetate molecule as a guest in the clathrate

structure

lb

I. Wawrzycka et al. /Jourrrrrl of Molecular Structure 474 (1999) 157-166

160

Table 2 Atomic coordinates ( x IO’) and equivalent parameters (A’ x IO’) for finasteride 1

C(l) C(2) C(3) O(3) N(4) C(5) C(6) C(7) C(8) C(9) C(l0) C(l1) C(12) C(13) C(14) C(15) C(l6) C(17) C(18) C(19) C(20) (x20) N(20) C(21) C(22) C(23) c(24)

isotropic displacement

Table 3 Atomic coordinates ( X 101) and equivalent parameters (A’ X IO’) for finasteride-acetic

x

Y

;

u’q

11993(4) 12811(5) 11664(4) I2 184(3) 9986(4) 9578(4) 7514(6) 7205(7) 7445(4) 9567(4) 9848(4) 9908(5) 9505(4) 7349(4) 7 192(4) 5213(7) 5 148(6) 688 l(5) 5685(5) 8331(5) 6239(4) 4410(3) 7812(4) 7663(5) 6725(9) 9883(g) 6340(7)

8579(2) 85 16(3) 8074(2) 8247(2) 751 l(2) 7213(2) 6670(3 ) 6309(2) 7229(2) 7784(2) 8171(2) 8650(2) 8283(3) 7803(2) 6888(2) 63 13(3) 6423(3) 7223(2) X640(3) 9061(2) 7958(2) 8 180(2) 8370(2) 9193(2) 10176(3) 9365(4) 8804(3)

6455( 1) 5986(l) 5547( I ) 5098( I) 5675(l) 6210(l) 6263( I) 6818(l) 7199(l) 7130(l) 6566( 1) 7535( 1) 8091(l) 8141(l) 7757( I) 7919(l) 8508(l) 8656( 1) 8050( 1) 6434( I) 9087( 1) 9169(l) 9361(l) 9760( 1) 9526(2) 9945(2) 10210(1)

57(l)

C(I)

65(l) 56(l) 74( 1) 55(l)

cm

-

49(l) 62(l) 64(l) 43(l) 43(l) 41(I) 52(l) 50(l) 42( 1) 47(l) 68(l) 68(l) 49(l) 54(l) 52(l) 50(l) 68(l) 52(l) 60(l) 92(l) 94(l) 76(l)

independent molecules in lb, the geometry of finasteride molecules observed in the crystal structures 1, la and lb is very similar. Configuration of the ring junctions of the azaandrosten skeleton is truns-untitram-anti-tram. The central six-membered rings B and C adopt a chair conformation, while conformations of the six-membered ring A and five-membered ring D are distorted half-chair. Selected parameters describing the molecular geometry of finasteride are given in Tables 5 and 6. The least-squares fit of four finasteride conformations observed in the three crystal structures (Fig. 3) showed that the steroid nucleus of the molecule is rigid while relative differences in positions of the lactam 03 atom and the quaternary C21 atom of the tert-butyl group are up to 0.40 and 0.97 A, respectively. In all structures, the lactam group generates different hydrogen-bond interactions, depending on

C(3) O(3) N(4) C(5) C(6) C(7) C(8) C(9) C(10) C(l1) C(l2) C(l3) C(14) C(l5) C(l6) C(17) C(l8) C(19) C(20) O(20) N(20) C(21) C(22) C(23) C(24) O(lA) O(2A) C(1A) C(2A)

isotropic displacement acid complex la

*

Y

z

8382(3) 8979(4) 9287(3) 9625(2) 9 168(3) 8973(3) 8707(4) 8615(4) 7754(3) 8026(3) 8021(3) 7233(4) 7290(4) 696 l(3) 7794(3) 7566(4) 7306(4) 7254(3) 564613) 6795(3) 6400(3) 5519(2) 6670(3) 5965(3) 4741(6) 6647(7) 5847(6) 10095(5) 9606(3) 10304(5) 11379(6)

12781(5) 13329(S) 12256(4) 12794( 3) 10650(4) 100 13(4) 8193(4) 7584(S) 8555(4) 1041 l(4) 11018(4) 11409(5) 10784(5) 8973(4) 8019(4) 6212(5) 627 l(5) 8085(5) 8728(6) 10867(6) 8463(5) 7649(4) 9815(4) 10572(6) 11006(13) 12078(9) 9365(9) 13264(5) 10765(5) I 1844(6) 11219(9)

3291(3) 2708(3) 1989(3) 1286(2) 21 lO(2) 3042(3) 2944(3) 397 I(3) 4323(3) 4359(3) 3273(2) 4793(3) 5874(3) 5822(2) 5409(3) 5595(3) 6632(3) 6901(3) 5121(3) 2384(3) 7449(3) 7316(2) 8066(2) 8622(3) 7822(6) 9184(7) 9442(4) -899(4) - 1330(3) -738(4)

“e,

94(6)

55(l) 59(l) 54(l) 68(l) 54(l) 47(l) 57(l) 59(l) 45(l) 43(l) 44(l) 54(l) 53(l) 44(l) 46(l) 55(l) 61(l) 51(l) 58(l) 57(l) 56(l) 83( 1) 60(l) 69(l) 114(2) 118(2) 95(2) 144(2) 108(l) 79(l) 102(2)

the molecular environment. It acts both as a donor and an acceptor of intermolecular hydrogen bonds. In contrast, access to the peptide group at Cl7 is shielded by tert-butyl, and only weak interactions of this fragment are observed. In two cases, the 020 atom is an acceptor in a weak C-H...0 hydrogen bonds, and in one case the N20-H is a donor to the water molecule.

3.2. Orthorhombic

form ofjinasteride

Finasteride crystallizes from an ethanol solution in the orthorhombic space group P2,2,2,. In the homomolecular crystal structure 1, molecules are arranged in a ‘head-to-head and tail-to-tail’ network type. They

I. Wawrqcka

et al. /Journal

of Molecular

Table 4 Atomic coordinates ( x 10”) and isotropic displacement parameters (A’ X 10’) for bis-finasteride monohydrate ethyl acetate clathrate lb

Molecule

1

C(1) C(2) C(3) O(3) N(4) C(5) C(6) C(7) C(8) C(9) C(l0) C(l1) C(12) C(l3) C(l4) C(15) C(16) C(17) C(l8) C(19) C(20) O(20) N(20) C(21) C(22) C(23) C(24)

3103(17) 2476( 17) 3605( 19) 2961(10) 5164(13) 5774( 13) 7583( 13) 8191(14) 7222( 16) 541 l(13) 4834( 15) 4461(14) 5108(16) 6929(15) 7811(16) 9636( 15) 9643( 17) 7865( 19) 7255(15) 4995( 16) 7553(23) 8491(14) 6036( 19) 5385(24) 5206(21) 3845(27) 6383(26)

6334(g) 6475(g) 6455(8) 6397(6) 64 16(6) 6575(7) 6453(7) 6673(7) 6327(7) 6444(6) 6165(7) 6138(7) 6424(7) 6294(6) 6646(6) 6579(9) 6724(g) 6718(7) 5469(6) 5330(6) 6390(8) 6000(6) 6586(6) 6325(g) 5515(g) 6690( 12) 6554(9)

7620(3) 7276(3) 695 l(4) 6625(2) 7015(2) 7393(3) 7415(3) 7794(3) 8122(3) 8075(2) 7689(3) 8407(2) 8782(3) 8836(3) 8503(3) 8607(3) 9033(3) 9149(3) 8874(3) 7653(3) 955 l(4) 9702(3) 9692(3 ) 10054(3) 10063(4) 10129(5) 10390(3)

86(4) lOO(5) 87(4) 97(3) 75(3) 67(4) 69(4) 75(4) 70(4) 57(3) 62(3) 74(4) 80(4) 61(3) 66(3) 90(4) 98(5) 91(5) 72(4) 80(4) 89(4) 122(4) IO4(4) 102(5) 123(6) 234( 14) 164(8)

Molecule 2 C(lA) C(2A) C(3A) O(3A) N(4A) C(5A) C(6A) C(7A) C(8A) C(9A) C(IOA) C(llA) C(l2A) C(l3A) C(l4A) C(15A) C( 16A) C( 17A) C(l8A) C(19A) C(20A)

7077( 15) 7647( 15) 6617(17) 7210(10) 5015(14) 4329( 12) 2490( 14) 1845(13) 2765( 14) 4638(13) 5300(16) 5569( 14) 4925( 14) 3152(15) 2236(13) 401(14) 388( 16) 2226( 16) 2853( 17) 5121(16) 2558(24)

6224(7) 6387(7) 6345(7) 6324(5) 6328(5) 6479(7) 6326(7) 6553(7) 6167(6) 63 13(6) 6041(6) 6008(6) 6288(7) 6128(6) 6469(6) 6405(7) 6529(7) 65 I7(7) 5293(6) 5221(6) 6195(7)

5361(3) 5699(3) 6049(4) 6358(2) 5972(2) 5593(3) 5582(3) 5 194(3) 4872(3) 491 l(3) 5296(3) 4569(3) 4205(3) 4156(3) 4501(3) 4391(3) 3962(3) 3838(3) 4129(3) 5348(3) 3461(3)

72(4) 75(4) 77(4) 93(3) 77(3) 61(3) 75(4) 70(4) 60(3) 59(3) 64(4) 72(4) 69(4) 62(3) 61(3) 77(4) 84(4) 73(4) 90(4) 84(4) 89(5)

161

Structure 474 (1999) 157-166

Table 4 (continued) 1608(13) O(20A) 3910(15) N(20A) 4682(26) C(2lA) 4885(21) C(22A) C(23A) 6 182(24) 3309(28) C(24A)

5728(5) 6424(6) 6142(9) 5332(g) 6552(13) 6302(9)

3322(2) 3277(3) 2934(4) 2966(4) 2874(5) 2615(4)

lOO(3) 85(3) lO6(5) 129(6) 214(12) I75(9)

7105(5)

6461(2)

107(3)

3889(32) 4578(16) 4339( 17) 4101(54) 4592(49) 4382(36) 3764(30) 4031(19) 3576(49) 4308(36)

6570(24) 6473(17) 6376(g) 5972( IO) 6503(28) 6503( 14) 6197(18) 6510(11) 6736(30) 6575(40)

Water molecule 46(11)

O(lW) Ethyl acetate molecule O( 1 /)” O( 1 II)” C(l0 C(2 /)u C(2 lI)O O(2 I)” O(2 II)” C(4 0 C(5 I)” C(5 II)”

3422(36) 3879(40) 2238(34) 2343(56) 316(64) 845(36) 2061(46) 5 149(33) 6449(50) 6965(44)

a Site occupancy

579(22)h 579(22)h 600(40j’ 579(22)h 579(22)” 579(22)’ 579(22)h 4 I O(25)’ 579(22)’ 579(22)h

factor = 0.5

b u,,,.

Table 5 Selected bond lengths (A) 1

la

lb (mol. I)

lb (mol. 2)

c(2)-o(3) C(3)-N(4) N(4)-C(5) C(5)-C( 10) C(I)-C(l0)

I .330(4) 1.47 l(4) 1.235(3) I .339(4) I .466(3) I .541(3) I .506(4)

I .324(5) I .466(5) 1.250(4) 1.336(5) 1.467(5) I .542(4) I .503(5)

I .36(2) 1.48(2) 1.28(l) I .30(2) 1.47(l) 1.51(l) 1.47(2)

I .33(2) I .50(2) 1.21(l) 1.34(l) 1.49(l) 1.55(l) 1.51(2)

Ring D C(13)-C(14) C(l4)-C(l5) C(15)-C(16) C(16)-C(l7) C(13)-C(l7) C( 17)-C(20) C(20)-O(20) C(20)-N(20)

1.538(3) 1.531(4) I .539(4) 1.561(4) I .558(3) 1.5 I7(4) 1.232(3) I .346(3)

1.539(5) 1.539(5) I .554(5) I .532(5) I .554(5) 1.517(5) 1.218(4) 1.350(5)

1.53(l) 1.54(2) 1.54(l) 1.51(2) I .56(2) I .58(2) 1.18(2) 1.38(2)

1.57(l) 1.55(l) 1.55(l) I .57(2) I .54(2) I .49(2) I .26(2) 1.35(2)

Ring A C(l)-C(2) C(2)-C(3)

162

1. Wawrzycku et al. / Journul of Molecular Structure 474 (I 999) 157-166

Table 6 Selected torsion angles (“) la

1

Ring A ClO-Cl-C2-C3 Cl -C2-C3-N4 C2-C3-N4-C5 C3-N4-CS-Cl0 N4-CS-C 10-C 1 c2-Cl-ClO-c5

1S(5) - I H(4) - lOS(4) 47.3(3) -54.5(3) 33.5(3)

1.2(S) -13.1(S) ~ 12.1(S) 45X(4) -5 1I)(4) 30.7(4)

Ring D c17-c13-c14-Cl5 Cl3-Cl4-Cl5-Cl6 Cl4-Cl5-Cl6-Cl7 Cl5-Cl6-Cl7-Cl3 Cl4-Cl3-C17-Cl6

45.X3) -34.5(3) 9.7(4) 1X.2(3) -38.6(3)

17f3-chain Cl4-Cl3-Cl7-C20 Cl5-C16-Cl7-C20 020-C20-N20-C2 1 Cl7-C20-N20-C21 C20-N20-C2 1-C22 C20-N20-C2 1-C23 C20-N20-C2 1-C24

-161.4(2) 141.1(3) -5.6(4) 172.6(2) -59.1(4) 180.0(3) 62.5(4)

lb (mol. 1)

O(2)

lb (mol. 2)

X2)

-l](2) - 1x2)

- 17(2) -l](2)

49(2) -53( 1)

48(2) -53( 1)

31(2)

310)

47.60) -34.0(4) 6.5(J) 22.9(J) -42.X(3)

49(l) -38(l)

47(l) -35(l)

lO(2) 21(2) -43(l)

10(l) 20(l) -40(l)

- 167.8(3) 147.8(3) -3.1(6) 174.4(3) -57.6(7) - 178.8(5) 62.9(S)

-168(l) 145(l) -O(2) 177(l) -61(2) I75(2) 63(2)

-168(l) 145(l) - lO(2) 170(l) -49(2) - 176(2) 65(2)

are connected by strong intermolecular N4-H...03 hydrogen bonds between the ring A lactam groups (‘heads’) to give ribbons along the 2, axis (Fig. 4). The packing mode of molecules of two other heterocyclic androsten derivatives, 17@-hydroxy-2-aza-Soandrost-4-en-3-one [8] and 17@-hydroxy-4-aza-5Pandrost- 1-en-3-one [9], is determined by similar intermolecular N-H...0 hydrogen bonds. In both crystals ribbons of molecules are formed along the two-fold screw axes. The lactam-lactam interactions in 1 are stronger (Table 7) than those in 17@-hydroxy-2-aza5o-androst-4-en-3-one [8] where the N...O distance is 2.935 A. The opposite part of the molecule, the Cl7 sidechain (‘tail’), is located around the second type of 2, axes, and C-H...0 hydrogen bonds are observed between neighboring methyl and peptide groups. 3.3. Finasteride-acetic

Fig. 3. Comparison offour finasteride conformations adopted in the solid state. Solid line-structure la; open line-structure 1.

acid complex

The infinite linear finasteride-acetic acid complex (1: 1) la is formed by two intermolecular hydrogen bonds, that is bonding between the alternating

I. Wawrzyeka et al. /Journal

Fig. 4. Projection

of Molecular

of the molecular

finasteride lactam fragment and carboxyl group of acetic acid: . ..O=C-NH...O=C-OH...O=C-NH.... The methyl groups of the host and solvate molecules are in nearly parallel orientation (Fig. 5). Molecules of cocrystallizing acetic acid are parallel to the two-fold

Table I Hydrogen-bond

Structure 474 (1999) 157-166

packing along a in the crystal 1

screw axis. The strong N-H...0 and O-H...0 bonds are accompanied by two weak C-H...0 interactions (Table 7). Both C-H...0 contacts are methyl...carbony1 interactions between: (i) the Cl9 methyl and 020 peptide atoms of finasteride, and (ii) the C2A

geometry

D-H...A

D...A (A)

H...A

(A,

ID-H..,A

. i(4)-H(4N).-.0(3)“’ 2.869(3) C(24)-H(243)...0(20)“’ 3.594(5) Symmetrycodes:(1)0.5+x,1.5-~,2-z;(2)x-0.5,1.5-~,1-z

I .95(3) 2.52(4)

169(2) l60(3)

d~A)-H(20H)...0(3)“’ N(4)-H(4).,.0( 1A)“’ C(19)-H(19C)~~.0(20)‘2’ C(2A)-H(2Al)...O( ]A)“’ Symmetry codes: (I) 2 - x, y - 0.5, z;

1.59(7) I .92(5) 2.36(5) 2.37(8) - z

l@(5) 167(4) l60(4) l59(5)

2.593(5) 2.893(5) 3.327(5) 3.419(9) (2) 1 - x, J + 0.5, 1

lb N(4)-H(4N)...0(3A) 2.89(l) N(4A)-H(4NA),..0(3) 2.87(l) 0( 1W)-H( I W),.,O(3) 2.78(I) O(lW)-H(2W),.,0(3A)’ 2.75( 1) N(20A)-H(20A)...O( I W)’ 3.01(l) Symmetry codes: (I) x - I, ?;. Z; (2) x + 0.5, 1.5 - y,

2.04 2.05 1.81 1.74 2.16

I - z

163

157 151 161 179 156

(“)

164

Fig. 5. Packing of molecules

in the tinateride-acetic

methyl and OlA carboxyl atoms of acetic acid. So, weak bonds link the same molecular species. The distance between the finasteride peptide group and the acetic acid carboxyl group, N20...02A, is 3.447(6) A which is longer than values accepted for this type of hydrogen bond [lo]. Molecules in pure acetic acid crystals [l l] are linked by an intermolecular O-H...0 hydrogen bond forming chains along the pseudo-twofold screw axis; centrosymmetric dimers, commonly occurring for many carboxylic acids, are not observed here. The search for the CSD 1121 revealed that acetic acid is able to form several types of molecular complexes (solvates) through hydrogen bonds of the carboxyl group. Only two of them have a simple .. .host.. . CH$OOH...host.. CH$OOH. .. arrangement, similar to that observed in the finasteride-acetic acid complex,

Fig. 6. Hydrogen-bond

acid complex la. View along h.

with the carboxyl ‘bridging’ group. Such a heteromeric structure is formed with 8-fluoro-5-(4-fluorophenyl)2-[N-(3-bromophenyl)-carbamoyl]-hexahydro1Hpyridoindole 1131 and 6-phenyl-3(2H)-pyridazinone 1141. 3.4. Bis-jinasteride clathrute

monohydrate

ethyl acetate

Two symmetrically independent finasteride molecules in lb form dimers around the pseudo-twofold axis. This alignment is stabilized by two N-H...0 hydrogen bonds between the lactam groups of the ring A. The hydrogen-bonded water molecule is a ‘bridging’ unit connecting three finasteride dimers (Fig. 6). The water molecule is a double donor of H atoms to the lactam 0 atoms, and an acceptor from the

pattern in lb

165

Fig. 7. View of the (I axis channel in the clathrate

crystal structure

peptide N atom. The double-layer arrangement of the complexed host molecules enables formation of channels along the crystal axis a (Fig. 7). The channel of the clathrate crystal is filled in with disordered ethyl acetate molecules. The review of the CSD showed 70 crystal structures in which ethyl acetate is a guest molecule. The molecule of ethyl acetate cocrystallizes with organic host molecules of complicated three-dimensional structure which excludes undisturbed close packing in the crystalline lattice. In those solids, two types of host/guest interactions are observed: (i) the oxygen atoms of ethyl acetate are hydrogen-bond acceptors-molecular complexes are formed; (ii) only hydrophobic weak contacts are present-typical clathrates are formed with guest molecules, often disordered, located in structural cages or channels. Among them are six host molecules of steroid derivatives with substituents of variable size. 18-Methylestradiol [ 151, gitoxigenin bisdigitoxoside 1161 and digitoxigenin bisdigitoxoside (in orthorhombic form) [ 16) are hydrogen-bonded to ethyl acetate, while a characteristic feature of digoxigenin bisdigitoxoside (in triclinic form) [ 161, cholic acid [ 171 and dihydroiochromolide [ 181 is formation of channels of dimensions suitable for ethyl acetate hydrophobic inclusion. 3.5. Monoclinic form ofjnasteride The metastable form of finasteride 2, which is formed at higher temperatures (above 175°C) crystallizes in the monoclinic system with unit cell

lb. Large circles represent

ethyl acetate molecules

parameters: oa = 10.236(g), b = 7.948(g), c = 13.896( 1.5) A, l3 = 9584(g)“. Solid state IR in the region 1600-3500 cm-’ is diagnostic for the identification of polymorphs. Characteristic bands for 1 (v = 3429, 3348, 3238, 3115, 2969, 2937, 2904, 2837, 2661, 1689, 1669, 1601 cm-‘), and for 2 (u = 3439, 3336, 3213, 3110, 3048, 2964, 2944, 2872, 2843, 1680, 1657, 1599 cm-‘), indicate differences in the C=O, N-H and C-H intermolecular contacts.

Acknowledgements The authors wish to thank the Pharmaceutical Institute, Warsaw for gift of the compound. AEK thanks the Committee on International Activities of the American Chemical Society for partial financial support of this research.

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