Polymorphs of the antiviral drug ganciclovir

Ganciclovir (GCV; systematic name: 2-amino-9-{[(1,3-di­hydroxy­propan-2-yl)­oxy]meth­yl}-6,9-di­hydro-1H-purin-6-one), C₉H₁₃N₅O₄, an anti­viral drug for treating cytomegalovirus infections, has two known polymorphs (Forms I and II), but only the structure of the metastable Form II has been reported [Kawamura & Hirayama (2009). X-ray Struct. Anal. Online, 25, 51–52]. We describe a successful preparation of GCV Form I and its crystal structure. GCV is an achiral mol­ecule in the sense that its individual conformers, which are generally chiral objects, undergo fast inter­conversion in the liquid state and cannot be isolated. In the crystalline state, GCV exists as two inversion-related conformers in Form I and as a single chiral conformer in Form II. This situation is similar to that observed for glycine, also an achiral mol­ecule, whose α-polymorph contains two inversion-related conformers, while the γ-polymorph contains a single conformer that is chiral. The hydrogen bonds are exclusively inter­molecular in Form I, but both inter- and intra­molecular in Form II, which accounts for the different mol­ecular conformations in the two polymorphs.

Computing details

Data collection: APEX3 (Bruker, 2015); cell refinement: SAINT-Plus (Bruker, 2015); data reduction: SAINT-Plus (Bruker, 2015); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009) and Gn (Guzei (2013).

2-Amino-9-{[(1,3-dihydroxypropan-2-yl)oxy]methyl}-6,9-dihydro-1H-purin-6-one

Crystal data

C9H13N5O4	F(000) = 536
Mr = 255.24	Dx = 1.653 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
a = 4.6448 (10) Å	Cell parameters from 5037 reflections
b = 15.632 (3) Å	θ = 2.9–30.5°
c = 14.130 (3) Å	µ = 0.13 mm^−1
β = 91.632 (10)°	T = 100 K
V = 1025.5 (4) Å^3	Needle, colourless
Z = 4	0.58 × 0.1 × 0.1 mm

Data collection

Bruker SMART APEXII area detector diffractometer	45424 independent reflections
Radiation source: microfocus sealed X-ray tube, Incoatec Iµs	38287 reflections with I > 2σ(I)
Mirror optics monochromator	Rint = 0.060
Detector resolution: 7.9 pixels mm^-1	θmax = 30.6°, θmin = 1.9°
0.5° ω and 0.5° φ scans	h = −6→6
Absorption correction: multi-scan (TWINABS; Bruker, 2012)	k = −22→22
Tmin = 0.54, Tmax = 0.99	l = −20→19
45424 measured reflections

Refinement

Refinement on F^2	Primary atom site location: dual
Least-squares matrix: full	Hydrogen site location: mixed
R[F^2 > 2σ(F^2)] = 0.054	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.151	w = 1/[σ^2(Fo^2) + 0.6622P] where P = (Fo^2 + 2Fc^2)/3
S = 1.02	(Δ/σ)max < 0.001
45424 reflections	Δρmax = 0.45 e Å^−3
184 parameters	Δρmin = −0.29 e Å^−3
0 restraints

Special details

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Refinement. Refined as a 2-component twin.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
O1	0.8794 (3)	0.29596 (9)	0.67663 (10)	0.0163 (3)
O2	0.4005 (3)	0.40726 (9)	0.25113 (9)	0.0144 (3)
O3	0.2212 (3)	0.38278 (9)	−0.00228 (9)	0.0156 (3)
H3	0.094 (7)	0.340 (2)	−0.007 (2)	0.047 (9)*
O4	0.5480 (3)	0.55219 (9)	0.16460 (10)	0.0158 (3)
H4	0.617 (6)	0.575 (2)	0.116 (2)	0.042 (9)*
N1	0.1570 (3)	0.49144 (11)	0.62555 (12)	0.0147 (3)
H1A	0.032 (5)	0.5186 (17)	0.591 (2)	0.024 (7)*
H1B	0.220 (6)	0.5137 (19)	0.680 (2)	0.029 (7)*
N2	0.5152 (3)	0.39079 (11)	0.64408 (12)	0.0127 (3)
H2	0.510 (5)	0.4037 (17)	0.699 (2)	0.024 (7)*
N3	0.8130 (3)	0.24735 (10)	0.46481 (11)	0.0132 (3)
N4	0.4703 (3)	0.31416 (10)	0.37787 (11)	0.0126 (3)
N5	0.2822 (3)	0.41260 (10)	0.49414 (11)	0.0119 (3)
C1	0.3186 (4)	0.43137 (12)	0.58517 (13)	0.0120 (3)
C2	0.7116 (4)	0.32817 (12)	0.61743 (13)	0.0126 (3)
C3	0.6763 (4)	0.30842 (12)	0.51948 (13)	0.0125 (3)
C4	0.6837 (4)	0.25277 (12)	0.38132 (13)	0.0136 (4)
H4A	0.7319	0.2181	0.3288	0.016*
C5	0.4636 (4)	0.34996 (12)	0.46676 (12)	0.0115 (3)
C6	0.2863 (4)	0.33450 (12)	0.29719 (13)	0.0138 (4)
H6A	0.2773	0.2854	0.2530	0.017*
H6B	0.0888	0.3468	0.3180	0.017*
C7	0.2467 (4)	0.42577 (12)	0.16349 (13)	0.0123 (3)
H7	0.0410	0.4081	0.1691	0.015*
C8	0.3819 (4)	0.37434 (13)	0.08467 (13)	0.0156 (4)
H8A	0.5815	0.3945	0.0758	0.019*
H8B	0.3904	0.3133	0.1030	0.019*
C9	0.2598 (4)	0.52153 (12)	0.14811 (13)	0.0141 (4)
H9A	0.1956	0.5352	0.0824	0.017*
H9B	0.1283	0.5505	0.1918	0.017*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0166 (7)	0.0192 (7)	0.0130 (6)	0.0023 (5)	−0.0019 (5)	0.0026 (5)
O2	0.0176 (7)	0.0142 (7)	0.0111 (6)	−0.0036 (5)	−0.0029 (5)	0.0031 (5)
O3	0.0196 (7)	0.0170 (7)	0.0102 (6)	−0.0032 (5)	−0.0022 (5)	0.0006 (5)
O4	0.0168 (7)	0.0174 (7)	0.0134 (7)	−0.0043 (5)	0.0001 (5)	0.0014 (5)
N1	0.0148 (8)	0.0163 (8)	0.0128 (7)	0.0023 (6)	−0.0018 (6)	−0.0019 (6)
N2	0.0134 (8)	0.0150 (8)	0.0096 (7)	0.0008 (5)	−0.0005 (5)	−0.0008 (6)
N3	0.0143 (8)	0.0126 (7)	0.0127 (7)	−0.0004 (5)	0.0025 (5)	0.0004 (6)
N4	0.0147 (8)	0.0124 (7)	0.0107 (7)	−0.0007 (5)	−0.0002 (5)	−0.0001 (6)
N5	0.0125 (7)	0.0121 (7)	0.0111 (7)	−0.0008 (5)	−0.0007 (5)	0.0000 (6)
C1	0.0112 (8)	0.0125 (8)	0.0124 (8)	−0.0020 (6)	0.0000 (6)	0.0010 (7)
C2	0.0126 (8)	0.0118 (8)	0.0134 (8)	−0.0015 (6)	0.0003 (6)	0.0017 (7)
C3	0.0127 (8)	0.0126 (8)	0.0121 (8)	−0.0006 (6)	0.0010 (6)	0.0008 (7)
C4	0.0160 (9)	0.0113 (8)	0.0134 (8)	−0.0005 (6)	0.0023 (6)	0.0005 (7)
C5	0.0129 (8)	0.0115 (8)	0.0102 (8)	−0.0028 (6)	0.0007 (6)	0.0004 (6)
C6	0.0157 (9)	0.0143 (9)	0.0114 (8)	−0.0036 (6)	−0.0015 (6)	0.0014 (7)
C7	0.0132 (9)	0.0132 (8)	0.0105 (7)	0.0005 (6)	−0.0019 (6)	0.0006 (6)
C8	0.0186 (9)	0.0173 (9)	0.0108 (8)	0.0035 (7)	−0.0025 (6)	−0.0013 (7)
C9	0.0141 (9)	0.0133 (8)	0.0148 (8)	0.0003 (6)	−0.0009 (6)	0.0002 (7)

Geometric parameters (Å, º)

O1—C2	1.234 (2)	N4—C5	1.376 (2)
O2—C6	1.421 (2)	N4—C6	1.440 (2)
O2—C7	1.441 (2)	N5—C1	1.326 (2)
O3—H3	0.89 (3)	N5—C5	1.355 (2)
O3—C8	1.425 (2)	C2—C3	1.423 (3)
O4—H4	0.85 (3)	C3—C5	1.382 (2)
O4—C9	1.435 (2)	C4—H4A	0.9500
N1—H1A	0.86 (3)	C6—H6A	0.9900
N1—H1B	0.88 (3)	C6—H6B	0.9900
N1—C1	1.340 (2)	C7—H7	1.0000
N2—H2	0.80 (3)	C7—C8	1.523 (3)
N2—C1	1.373 (2)	C7—C9	1.514 (3)
N2—C2	1.397 (2)	C8—H8A	0.9900
N3—C3	1.393 (2)	C8—H8B	0.9900
N3—C4	1.311 (2)	C9—H9A	0.9900
N4—C4	1.380 (2)	C9—H9B	0.9900
C6—O2—C7	111.84 (13)	N5—C5—N4	125.76 (16)
C8—O3—H3	109 (2)	N5—C5—C3	128.77 (17)
C9—O4—H4	112 (2)	O2—C6—N4	108.58 (14)
H1A—N1—H1B	120 (3)	O2—C6—H6A	110.0
C1—N1—H1A	118.8 (19)	O2—C6—H6B	110.0
C1—N1—H1B	117.9 (18)	N4—C6—H6A	110.0
C1—N2—H2	115.7 (19)	N4—C6—H6B	110.0
C1—N2—C2	126.04 (16)	H6A—C6—H6B	108.4
C2—N2—H2	118.3 (19)	O2—C7—H7	109.1
C4—N3—C3	104.51 (15)	O2—C7—C8	108.53 (15)
C4—N4—C6	126.23 (16)	O2—C7—C9	107.51 (14)
C5—N4—C4	106.57 (15)	C8—C7—H7	109.1
C5—N4—C6	127.18 (16)	C9—C7—H7	109.1
C1—N5—C5	111.93 (15)	C9—C7—C8	113.43 (16)
N1—C1—N2	115.89 (16)	O3—C8—C7	111.39 (15)
N5—C1—N1	120.71 (17)	O3—C8—H8A	109.4
N5—C1—N2	123.39 (17)	O3—C8—H8B	109.4
O1—C2—N2	120.52 (17)	C7—C8—H8A	109.4
O1—C2—C3	128.58 (18)	C7—C8—H8B	109.4
N2—C2—C3	110.86 (16)	H8A—C8—H8B	108.0
N3—C3—C2	130.29 (17)	O4—C9—C7	110.37 (15)
C5—C3—N3	110.68 (16)	O4—C9—H9A	109.6
C5—C3—C2	118.89 (17)	O4—C9—H9B	109.6
N3—C4—N4	112.77 (17)	C7—C9—H9A	109.6
N3—C4—H4A	123.6	C7—C9—H9B	109.6
N4—C4—H4A	123.6	H9A—C9—H9B	108.1
N4—C5—C3	105.47 (16)
O1—C2—C3—N3	1.7 (3)	C4—N3—C3—C2	175.54 (19)
O1—C2—C3—C5	176.87 (18)	C4—N3—C3—C5	0.1 (2)
O2—C7—C8—O3	173.90 (14)	C4—N4—C5—N5	−179.39 (17)
O2—C7—C9—O4	46.58 (19)	C4—N4—C5—C3	0.39 (19)
N2—C2—C3—N3	−176.04 (18)	C4—N4—C6—O2	−98.1 (2)
N2—C2—C3—C5	−0.9 (2)	C5—N4—C4—N3	−0.4 (2)
N3—C3—C5—N4	−0.3 (2)	C5—N4—C6—O2	83.8 (2)
N3—C3—C5—N5	179.48 (17)	C5—N5—C1—N1	−179.50 (17)
C1—N2—C2—O1	179.91 (17)	C5—N5—C1—N2	−0.8 (2)
C1—N2—C2—C3	−2.1 (3)	C6—O2—C7—C8	−87.48 (18)
C1—N5—C5—N4	177.25 (17)	C6—O2—C7—C9	149.46 (15)
C1—N5—C5—C3	−2.5 (3)	C6—N4—C4—N3	−178.82 (17)
C2—N2—C1—N1	−178.02 (17)	C6—N4—C5—N5	−1.0 (3)
C2—N2—C1—N5	3.2 (3)	C6—N4—C5—C3	178.81 (17)
C2—C3—C5—N4	−176.35 (16)	C7—O2—C6—N4	173.40 (14)
C2—C3—C5—N5	3.4 (3)	C8—C7—C9—O4	−73.42 (19)
C3—N3—C4—N4	0.2 (2)	C9—C7—C8—O3	−66.7 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···N3^i	0.89 (3)	1.93 (3)	2.811 (2)	172 (3)
O4—H4···O3^ii	0.85 (3)	1.91 (4)	2.754 (2)	176 (3)
N1—H1A···N5^iii	0.86 (3)	2.15 (3)	3.012 (2)	179 (3)
N1—H1B···O2^iv	0.88 (3)	2.34 (3)	3.093 (2)	143 (2)
N2—H2···O4^iv	0.80 (3)	2.07 (3)	2.869 (2)	172 (3)

Symmetry codes: (i) x−1, −y+1/2, z−1/2; (ii) −x+1, −y+1, −z; (iii) −x, −y+1, −z+1; (iv) −x+1, −y+1, −z+1.