Ranitidine hydro­chloride, a polymorphic crystal form

In the title compound, di­methyl­({5-[2-(1-methyl­amino-2-nitro­eth­enyl­amino)­ethyl­thio­methyl]-2-furyl}­methyl)­ammon­ium chloride, C₁₃H₂₃N₄O₃S⁺·­Cl^-, protonation occurs at the di­methyl­amino N atom. The ranitidine mol­ecule adopts an eclipsed conformation. Bond lengths indicate extensive electron delocalization in the N,N'-di­methyl-2-nitro-1,1-ethenedi­amine system of the mol­ecule. The nitro and methyl­amino groups are trans across the side chain C=C double bond, while the ethyl­amino and nitro groups are cis. The Cl^- ions link mol­ecules through hydrogen bonds.

S1. Comment

Ranitidine, an H₂ receptor antagonist, is a high potency inhibitor of gastric acid secretion, and is used in the treatment of peptic ulcers and related gastro-intestinal disorders (Brogden et al., 1982). The crystal structure of ranitidine hydrogen oxalate (Kojić-Prodić et al., 1982) and ranitidine hydrochloride (Ishida et al., 1990) have previously been reported. Here we report the crystal structure of ranitidine hydrochloride, (I), in a different and as yet unpublished crystal form, and compare it with the published structures. \sch

The molecular structure is presented in Fig. 1. The enamine portion of the molecule can exist in two possible configurations with respect to the C15═C18 double bond: E and Z arrangements, in which the methylamino and nitro substituents are cis and trans to each other, respectively. The Z configuration is adopted in this structure, as opposed to the E arrangement in the crystal structure of ranitidine hydrogen oxalate, and both forms, disordered, in the previous structure of ranitidine hydrochloride. An equimolar mixture of E/Z enamine isomers has been reported in solution (Cholerton et al., 1984); interconversion presumably is facilitated by Π-electron delocalization over the enamine system. Thus the C15═C18 bond in this structure is lengthened to 1.425 (3) Å, and the single bonds C15—N14, C15—N16 and C18—N19 are shortened to 1.335 (3), 1.332 (3) and 1.349 (3) Å, respectively. Similarly, the two N—O distances in the nitro group, 1.270 (2) and 1.284 (2) Å, indicate electron delocalization, even though O20 takes part in a strong hydrogen bond and O21 is involved in a weak C—H···O interaction. The same phenomena were observed in ranitidine hydrogen oxalate, whereas in the other crystal form of ranitidine hydrohloride the disordered structure was interpreted in terms of electronically localized E and Z forms with distinct double and single bond lengths. Bond distances and angles in the rest of the molecule agree well with commonly accepted values. The least-squares plane through the nine atoms involved in the enamine moiety (C13 to O21) indicate they are planar, the r.m.s. deviation of the atoms being 0.035 (2) Å with maximum of 0.069 (2) Å for O20 and minimum of 0.001 (1) Å for C13. The ranitidine molecule, as a whole, adopts an eclipsed conformation (i.e. neither fully folded nor fully extended) similar to that of disordered ranitidine hydrochloride. Rotation of the group of atoms C13 through O21 by 114° about the C12—C13 bond results in conformational coincidence of this structure with the Z isomer in the disordered ranitidine HCl structure (Fig. 2) (primed set of atoms in Ishida et al. (1990)]. In contrast, ranitidine hydrogen oxalate was found to have a folded conformation. An open conformation is reportedly the one that is most likely to exist in solution (Sega et al., 1982; Gaggelli et al., 1988).

An intramolecular hydrogen bond from N14 to O20 (see Table 1) helps to stabilize the planarity of the 2-ethylamino-2-methylamino-1-nitroethylene moiety. Such an interaction is present in all of the ranitidine crystal structures and is the reason for E/Z configurations being favored in the solid state; in aqueous solution, with water available as a hydrogen-bond donor, rotation about the C15—C18 bond occurs readily (Cholerton et al., 1984). Rotation also occurs in other solvents: attempted crystallization of the present material in acetonitrile, the crystallization solvent used in the previous ranitidine hydrochloride structure determination, resulted in our getting crystals of that crystal form.

The furanyl ring is almost perfectly planar and forms an angle of 69.5 (1)° with the plane through the 2-ethylamino-2-methylamino-1-nitroethylene moiety atoms (C13 through O21), close to the value 63.4 (1)° in disordered ranitidine hydrochloride, and 75.2 (1)° in ranitidine hydrogen oxalate. In the crystal structure, the molecules are held together through hydrogen bonds from N atoms N7 and N16 to two different Cl anions (Table 1) forming one-dimensional infinite chains of molecules running perpendicular to the b axis along the base vector (101), in a head-to-tail fashion. The chains of molecules are held together by van der Waals interactions and weak hydrogen bonds of the type C—H···O (Steiner, 1997; Desiraju, 1996). The existence of this type of carbon-hydrogen bonds is facilitated by the presence of the adjacent activating groups NO₂ and N⁺, and Cl⁻ ions. The chloride ion is coordinated by four hydrogen atoms (H7, H16, H6B and H8A) forming a tetrahedron with almost perfect geometry.

S2. Experimental

The crystals were obtained as colourless prisms by solvent evaporation from a methanol-ethyl acetate mixture.

S3. Refinement

Ranitidine HCl crystallized in the monoclinic system; space group P2₁/n from the systematic absences. Hydrogen atoms, except for H7 at N7 which was found from a difference map, were calculated geometrically. During the refinement H atoms were treated isotropically and were riding on parent atoms (at distances 0.93 to 0.98 Å) except for H7 which had its positional and isotropic temperature parameters refined independently.

Computing details

Data collection: Nonius KappaCCD Server Software; cell refinement: DENZO-SMN (Otwinowski & Minor, 1997); data reduction: DENZO-SMN; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 for Windows (Farrugia, 1998); software used to prepare material for publication: SHELXL97.

Figures

	Fig. 1. ORTEP-3 (Farrugia, 1997) view of the molecule showing 50% probability displacement elipsoids. H atoms are drawn as small circles of arbitrary radius.
	Fig. 2. Superposition of the ranitidine hydrochloride (small circles) and the Z isomer in the disordered structure of ranitidine hydrochloride (large circles) after 114° rotation of the present structure about the C12—C13 bond.

N-(2-{[5-(Dimethylaminomethyl)-2-furanyl]methylthio}ethyl)-N' -methyl-2-nitro-1,1-ethanediamine hydrochloride

Crystal data

C13H23N4O3S^+·Cl^−	F(000) = 744
Mr = 350.86	Dx = 1.331 Mg m^−3
Monoclinic, P21/n	Mo Kα radiation, λ = 0.71073 Å
a = 12.1918 (6) Å	Cell parameters from all reflections reflections
b = 6.5318 (3) Å	µ = 0.35 mm^−1
c = 22.0382 (8) Å	T = 100 K
β = 93.985 (3)°	Prism, colourless
V = 1750.76 (13) Å^3	0.45 × 0.25 × 0.23 mm
Z = 4

Data collection

Nonius Kappa CCD diffractometer	2680 reflections with I > 2σ(I)
Radiation source: rotating-anode	Rint = 0.000
Graphite monochromator	θmax = 27.5°, θmin = 3.1°
ω rotation scans	h = 0→15
3994 measured reflections	k = 0→8
3994 independent reflections	l = −28→28

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.042	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.130	H atoms treated by a mixture of independent and constrained refinement
S = 0.80	w = 1/[σ^2(Fo^2) + (0.0488P)^2] where P = (Fo^2 + 2Fc^2)/3
3994 reflections	(Δ/σ)max < 0.001
210 parameters	Δρmax = 0.29 e Å^−3
0 restraints	Δρmin = −0.27 e Å^−3

Special details

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

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

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

	x	y	z	Uiso*/Ueq
Cl1	0.40889 (4)	0.24606 (8)	−0.03956 (2)	0.02621 (16)
O1	0.49639 (13)	−0.0598 (2)	0.20041 (6)	0.0242 (3)
C2	0.48856 (19)	−0.0926 (3)	0.26160 (9)	0.0248 (5)
C3	0.3902 (2)	−0.0294 (4)	0.27828 (11)	0.0324 (6)
H3	0.3651	−0.0348	0.3172	0.0330 (15)*
C4	0.3312 (2)	0.0481 (4)	0.22433 (11)	0.0316 (5)
H4	0.2603	0.1015	0.2215	0.0330 (15)*
C5	0.39872 (19)	0.0284 (3)	0.17855 (10)	0.0248 (5)
C6	0.38943 (18)	0.0802 (3)	0.11325 (10)	0.0253 (5)
H6A	0.3122	0.0867	0.0994	0.0330 (15)*
H6B	0.4230	−0.0280	0.0908	0.0330 (15)*
N7	0.44348 (15)	0.2813 (3)	0.09936 (9)	0.0249 (4)
H7	0.438 (3)	0.281 (5)	0.0564 (15)	0.062 (10)*
C8	0.56184 (19)	0.2861 (4)	0.12042 (11)	0.0311 (5)
H8A	0.5960 (6)	0.409 (2)	0.1044 (6)	0.0330 (15)*
H8B	0.5983 (6)	0.164 (2)	0.1058 (6)	0.0330 (15)*
H8C	0.5692 (2)	0.289 (2)	0.1650 (6)	0.0330 (15)*
C9	0.3838 (2)	0.4605 (4)	0.12235 (11)	0.0310 (5)
H9A	0.3851 (10)	0.4542 (12)	0.1660 (7)	0.0330 (15)*
H9B	0.3089 (12)	0.4586 (13)	0.1055 (6)	0.0330 (15)*
H9C	0.4188 (9)	0.5846 (19)	0.1104 (6)	0.0330 (15)*
C10	0.58691 (19)	−0.1792 (4)	0.29512 (10)	0.0277 (5)
H10A	0.6065	−0.3058	0.2755	0.0330 (15)*
H10B	0.5686	−0.2127	0.3361	0.0330 (15)*
S11	0.70691 (5)	−0.00941 (9)	0.29966 (3)	0.02977 (17)
C12	0.6502 (2)	0.2250 (3)	0.32782 (10)	0.0261 (5)
H12A	0.7046	0.3327	0.3261	0.0330 (15)*
H12B	0.5869	0.2639	0.3012	0.0330 (15)*
C13	0.61514 (19)	0.2095 (3)	0.39289 (9)	0.0255 (5)
H13A	0.5670	0.0924	0.3962	0.0330 (15)*
H13B	0.6795	0.1888	0.4206	0.0330 (15)*
N14	0.55837 (15)	0.3938 (3)	0.40989 (8)	0.0238 (4)
H14	0.4899	0.4021	0.3978	0.0330 (15)*
C15	0.60016 (18)	0.5520 (3)	0.44215 (9)	0.0218 (5)
N16	0.70553 (15)	0.5547 (3)	0.46272 (8)	0.0245 (4)
H16	0.7461	0.4522	0.4543	0.0330 (15)*
C17	0.75598 (19)	0.7213 (3)	0.49855 (10)	0.0265 (5)
H17A	0.7435 (10)	0.8480 (19)	0.4773 (4)	0.0330 (15)*
H17B	0.8334 (11)	0.6976 (12)	0.5049 (6)	0.0330 (15)*
H17C	0.7242 (10)	0.7281 (14)	0.5370 (6)	0.0330 (15)*
C18	0.53295 (17)	0.7231 (3)	0.45492 (9)	0.0219 (5)
H18	0.5637	0.8259	0.4799	0.0330 (15)*
N19	0.42754 (16)	0.7450 (3)	0.43301 (8)	0.0245 (4)
O20	0.37837 (13)	0.6112 (3)	0.39817 (7)	0.0304 (4)
O21	0.37558 (14)	0.9062 (3)	0.44580 (8)	0.0344 (4)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1	0.0270 (3)	0.0248 (3)	0.0266 (3)	−0.0053 (2)	0.0002 (2)	0.0041 (2)
O1	0.0268 (9)	0.0239 (8)	0.0216 (7)	0.0027 (6)	0.0006 (6)	0.0020 (6)
C2	0.0321 (13)	0.0204 (11)	0.0220 (11)	−0.0016 (10)	0.0017 (9)	0.0028 (9)
C3	0.0306 (14)	0.0376 (14)	0.0301 (12)	−0.0005 (11)	0.0088 (10)	0.0073 (10)
C4	0.0214 (12)	0.0365 (14)	0.0369 (13)	0.0018 (10)	0.0031 (10)	0.0073 (11)
C5	0.0218 (12)	0.0219 (11)	0.0302 (11)	−0.0012 (9)	−0.0015 (9)	0.0045 (9)
C6	0.0225 (12)	0.0244 (11)	0.0285 (11)	−0.0038 (9)	−0.0018 (9)	0.0028 (9)
N7	0.0224 (10)	0.0273 (10)	0.0247 (10)	−0.0026 (8)	−0.0004 (7)	0.0046 (8)
C8	0.0224 (12)	0.0379 (14)	0.0324 (12)	−0.0065 (10)	−0.0020 (9)	0.0111 (10)
C9	0.0311 (14)	0.0274 (12)	0.0346 (12)	0.0006 (10)	0.0038 (10)	0.0058 (10)
C10	0.0352 (14)	0.0231 (11)	0.0248 (11)	0.0052 (10)	0.0014 (9)	0.0030 (9)
S11	0.0258 (3)	0.0331 (3)	0.0304 (3)	0.0063 (2)	0.0020 (2)	−0.0058 (2)
C12	0.0281 (12)	0.0245 (12)	0.0261 (11)	0.0020 (9)	0.0043 (9)	−0.0007 (9)
C13	0.0318 (13)	0.0205 (11)	0.0242 (11)	0.0019 (9)	0.0020 (9)	−0.0023 (9)
N14	0.0221 (10)	0.0223 (9)	0.0271 (9)	−0.0001 (8)	0.0023 (7)	−0.0014 (7)
C15	0.0257 (12)	0.0224 (11)	0.0177 (10)	0.0002 (9)	0.0046 (8)	0.0043 (8)
N16	0.0247 (10)	0.0208 (9)	0.0279 (9)	0.0051 (8)	0.0010 (8)	−0.0020 (7)
C17	0.0209 (12)	0.0263 (12)	0.0315 (12)	0.0032 (9)	−0.0027 (9)	−0.0040 (9)
C18	0.0230 (12)	0.0227 (11)	0.0201 (10)	0.0012 (9)	0.0017 (8)	0.0017 (8)
N19	0.0236 (10)	0.0256 (10)	0.0246 (9)	0.0027 (8)	0.0032 (7)	−0.0005 (8)
O20	0.0250 (9)	0.0331 (9)	0.0326 (9)	−0.0011 (7)	−0.0009 (7)	−0.0056 (7)
O21	0.0284 (9)	0.0310 (9)	0.0437 (10)	0.0111 (8)	0.0007 (7)	−0.0067 (8)

Geometric parameters (Å, º)

O1—C2	1.375 (2)	C10—H10A	0.9700
O1—C5	1.379 (3)	C10—H10B	0.9700
C2—C3	1.344 (3)	S11—C12	1.807 (2)
C2—C10	1.477 (3)	C12—C13	1.528 (3)
C3—C4	1.438 (3)	C12—H12A	0.9700
C3—H3	0.9300	C12—H12B	0.9700
C4—C5	1.352 (3)	C13—N14	1.451 (3)
C4—H4	0.9300	C13—H13A	0.9700
C5—C6	1.475 (3)	C13—H13B	0.9700
C6—N7	1.511 (3)	N14—C15	1.335 (3)
C6—H6A	0.9700	N14—H14	0.8600
C6—H6B	0.9700	C15—N16	1.332 (3)
N7—C9	1.485 (3)	C15—C18	1.425 (3)
N7—C8	1.485 (3)	N16—C17	1.456 (3)
N7—H7	0.95 (3)	N16—H16	0.8600
C8—H8A	0.9797	C17—H17A	0.9574
C8—H8B	0.9797	C17—H17B	0.9574
C8—H8C	0.9797	C17—H17C	0.9574
C9—H9A	0.9614	C18—N19	1.349 (3)
C9—H9B	0.9614	C18—H18	0.9300
C9—H9C	0.9614	N19—O21	1.270 (2)
C10—S11	1.833 (2)	N19—O20	1.284 (2)
C2—O1—C5	106.88 (16)	S11—C10—H10A	108.7
C3—C2—O1	110.16 (19)	C2—C10—H10B	108.7
C3—C2—C10	133.6 (2)	S11—C10—H10B	108.7
O1—C2—C10	116.16 (19)	H10A—C10—H10B	107.6
C2—C3—C4	106.6 (2)	C12—S11—C10	102.03 (11)
C2—C3—H3	126.7	C13—C12—S11	113.89 (15)
C4—C3—H3	126.7	C13—C12—H12A	108.8
C5—C4—C3	106.7 (2)	S11—C12—H12A	108.8
C5—C4—H4	126.6	C13—C12—H12B	108.8
C3—C4—H4	126.6	S11—C12—H12B	108.8
C4—C5—O1	109.57 (19)	H12A—C12—H12B	107.7
C4—C5—C6	134.2 (2)	N14—C13—C12	110.92 (17)
O1—C5—C6	116.26 (19)	N14—C13—H13A	109.5
C5—C6—N7	113.09 (18)	C12—C13—H13A	109.5
C5—C6—H6A	109.0	N14—C13—H13B	109.5
N7—C6—H6A	109.0	C12—C13—H13B	109.5
C5—C6—H6B	109.0	H13A—C13—H13B	108.0
N7—C6—H6B	109.0	C15—N14—C13	127.48 (19)
H6A—C6—H6B	107.8	C15—N14—H14	116.3
C9—N7—C8	111.42 (19)	C13—N14—H14	116.3
C9—N7—C6	112.65 (17)	N16—C15—N14	121.0 (2)
C8—N7—C6	112.52 (18)	N16—C15—C18	118.4 (2)
C9—N7—H7	110 (2)	N14—C15—C18	120.6 (2)
C8—N7—H7	108 (2)	C15—N16—C17	123.76 (19)
C6—N7—H7	101.5 (19)	C15—N16—H16	118.1
N7—C8—H8A	109.5	C17—N16—H16	118.1
N7—C8—H8B	109.5	N16—C17—H17A	109.5
H8A—C8—H8B	109.5	N16—C17—H17B	109.5
N7—C8—H8C	109.5	H17A—C17—H17B	109.5
H8A—C8—H8C	109.5	N16—C17—H17C	109.5
H8B—C8—H8C	109.5	H17A—C17—H17C	109.5
N7—C9—H9A	109.5	H17B—C17—H17C	109.5
N7—C9—H9B	109.5	N19—C18—C15	124.0 (2)
H9A—C9—H9B	109.5	N19—C18—H18	118.0
N7—C9—H9C	109.5	C15—C18—H18	118.0
H9A—C9—H9C	109.5	O21—N19—O20	118.51 (18)
H9B—C9—H9C	109.5	O21—N19—C18	119.08 (19)
C2—C10—S11	114.36 (16)	O20—N19—C18	122.38 (18)
C2—C10—H10A	108.7
C5—O1—C2—C3	0.3 (2)	O1—C2—C10—S11	66.0 (2)
C5—O1—C2—C10	−177.59 (18)	C2—C10—S11—C12	51.41 (18)
O1—C2—C3—C4	0.2 (3)	C10—S11—C12—C13	67.15 (18)
C10—C2—C3—C4	177.6 (2)	S11—C12—C13—N14	−173.02 (15)
C2—C3—C4—C5	−0.6 (3)	C12—C13—N14—C15	−98.5 (2)
C3—C4—C5—O1	0.8 (3)	C13—N14—C15—N16	0.4 (3)
C3—C4—C5—C6	−179.0 (2)	C13—N14—C15—C18	179.86 (19)
C2—O1—C5—C4	−0.7 (2)	N14—C15—N16—C17	−179.44 (19)
C2—O1—C5—C6	179.14 (18)	C18—C15—N16—C17	1.1 (3)
C4—C5—C6—N7	98.0 (3)	N16—C15—C18—N19	175.1 (2)
O1—C5—C6—N7	−81.8 (2)	N14—C15—C18—N19	−4.4 (3)
C5—C6—N7—C9	−69.5 (2)	C15—C18—N19—O21	−178.11 (18)
C5—C6—N7—C8	57.4 (3)	C15—C18—N19—O20	−0.1 (3)
C3—C2—C10—S11	−111.2 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N7—H7···Cl1	0.94 (3)	2.13 (3)	3.070 (2)	172 (3)
N14—H14···O20	0.86	1.93	2.612 (3)	135
N16—H16···Cl1^i	0.86	2.37	3.166 (2)	155
C6—H6A···O20^ii	0.97	2.33	3.263 (3)	160
C6—H6B···Cl1^iii	0.97	2.80	3.712 (2)	158
C8—H8A···Cl1^iv	0.98	2.66	3.568 (3)	153
C9—H9B···O21^ii	0.96	2.47	3.424 (3)	171
C18—H18···O21^v	0.93	2.47	3.399 (3)	173

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