A new γ-polymorph of chlor­prop­amide: 4-chloro-N-(propyl­amino­carbon­yl)benzene­sulfonamide

The structure of a new polymorph of the title compound, C₁₀H₁₃ClN₂O₃S, known as the anti­diabetic drug chlor­prop­amide, is monoclinic, in contrast with the two previously described ortho­rhom­bic α- and β-forms. The mol­ecules in the γ-polymorph are linked into bands by hydrogen bonds similar to those in the α-polymorph. The conformation of the mol­ecules in the γ-form is close to that in the β-polymorph.

S1. Comment

The existence of several polymorphs of chlorpropamide (an antidiabetic drug) has been reported (Simmons et al., 1973; Burger, 1975; Al-Saieq & Riley, 1982; Ueda et al., 1984; De Villiers & Wurster, 1999; Vemavarapu et al., 2002), but the crystal structures of only two polymorphs have been reported so far, namely the α-form (Koo et al., 1980) and the β-form (Drebushchak et al., 2006). These two polymorphs differ in the conformations and packing of the molecules in the crystal structure. In the present communication, we report the structure of the third polymorph, which we have termed the γ-polymorph, (I).

The powder diffraction pattern calculated from the single-crystal structural data of (I) using POWDERCELL (Version 2.4; Kraus & Nolze, 1999) has shown that this form may be present as one of the phases in the mixture, corresponding to the records 35–1969, 34–1879 and 34–1882 (not indexed) in the Powder Diffraction File (PDF-2, set 50; ICDD, Year?).

The γ-polymorph crystallized from a heptane–ethyl acetate solution on slow cooling, growing concomitantly with the α-form. The previously described β-polymorph (Drebushchak et al., 2006) was also obtained from a heptane–ethyl acetate solution, but under different crystallization conditions. In general, our numerous crystallization experiments have shown that various polymorphs can be obtained from solutions of chlorpropamide in heptane–ethylacetate mixtures depending on the conditions.

The crystal structure of the γ-polymorph is monoclinic (space group P2₁, Z = 2), whereas the two other previously described (α- and β-) polymorphs are orthorhombic. The γ-form is non-centrosymmetric, as is the α-form (space group P2₁2₁2₁); the β-form is centrosymmetric (space group Pbcn).

The asymmetric unit of the γ-polymorph contains one chlorpropamide molecule (Fig. 1). The intramolecular bond lengths and angles are in a good agreement with the statistically averaged values for organic crystal structures in general [Cambridge Structural Database, Version 5.28 (Allen, 2002) and Mogul, Version 1.1.1 (Bruno et al., 2004)]. The C═O bond in the γ-polymorph is longer than that in the β-polymorph, and this observation is also supported by the IR spectroscopic data on the polymorphs of chlorpropamide (Drebushchak et al., 2007). The torsion angles are summarized in Table 1.

The molecule of chlorpropamide is flexible, and all the three forms (α, β and γ) can be classified as conformational polymorphs (Bernstein, 2002). In all three polymorphs, the atoms of the central part of the molecule (N1, C7, O3, N2 and C8) are practically in the same plane (Fig. 2), and atoms S1 and O1 are close to this plane (within 0.25 Å). The conformation of the molecule in the γ-form resembles that in the β-form: the phenyl ring and the alkyl `tail' are on the same side of the N1/C7/O3/N2/C8 plane (Fig. 2 b,c), whereas in the α-form they are on opposite sides (Fig. 2a). At the same time, the orientation of the phenyl ring with respect to the urea group is similar in the α- and γ-forms, but it differs noticeably from that in the β-form (Fig. 2). The angle between the plane of the phenyl ring and the N1/C7/O3/N2/C8 plane is 80° in the α-form (Koo et al., 1980), 81.1 (2)° in the γ-form (present study) and 89.7 (2)° in the β-form (Drebushchak et al., 2006).

In all the three polymorphs, intermolecular N—H···O hydrogen bonds link the molecules into infinite bands, which stretch along the b axis (Fig. 3). The geometric parameters of the hydrogen bonds in the γ-form are summarized in Table 2. The polymorphs differ in the orientations of the alkyl tails and the phenyl rings with respect to each other and to the plane of the hydrogen-bonded bands. In the γ-form, the phenyl rings in neighbouring molecules in a chain are on opposite sides of this plane, so that a zigzag pattern is seen when the chain is viewed along its axis (the b axis) or projected on the (010) plane (Fig. 4). The same pattern is observed in the α-polymorph (Fig. 5). In the β-polymorph, the phenyl rings of all the molecules in a band are on the same side of the plane of the hydrogen-bonded `band core', so that a `tweezers' pattern is seen along the b axis/projected on the (010) plane (Fig. 6). The different packing of the molecules within a band also manifests itself in the geometric parameters of the intermolecular hydrogen bonds: they are similar in the α- and γ-forms, but differ noticeably in the β-form, in which one of the N—H···O hydrogen bonds is shorter than in the α- and γ-forms, while the other two bifurcated hydrogen bonds are, in contrast, much longer.

The calculated density of the γ-form is larger than that of the β-form but smaller than that of the α-polymorph. These differences must be related to the different efficiency in the packing of the alkyl tails, depending on the molecular conformation and the mutual orientation of neighbouring molecules.

The structure quality for all three structures (α-, β- and γ-forms) is not the best, as seen by the consistently elevated R-factors. This can result from poor quality crystals grown under non-equilibrium conditions. As all three polymorphs give poorish structures, and all three come out of the same crystallization solvent, one might also suspect that the crystals are not actually 100% pure single polymorphs, but may contain some domains of the other polymorph(s). This parallels the situation reported recently for aspirin (Bond et al., 2007a,b), or postulated for the high-pressure polymorphs of L-serine (Boldyreva et al., 2006), ζ-glycine (Goryainov et al., 2006) or L-cysteine (Moggach et al., 2006). This hypothesis is indirectly supported by the fact that the powder diffraction patterns measured for several crystallites from the same crystallization batch often indicated the presence of the α-form as an admixture to the γ-form of chlorpropamide. Although there was no difficulty indexing the reflections or initially determining the unit cell in collecting data for the β- and γ-polymorphs, we cannot exclude the presence of the domains of another form, as the data were collected with a point detector only. Further experiments using a CCD or area detector would be helpful.

Related literature

For related literature, see: Al-Saieq & Riley (1982); Allen (2002); Bernstein (2002); Boldyreva et al. (2006); Bond et al. (2007a, 2007b); Bruno et al. (2004); Burger (1975); De Villiers & Wurster (1999); Drebushchak et al. (2006, 2007); Goryainov et al. (2006); Koo et al. (1980); Kraus & Nolze (1999); Moggach et al. (2006); Simmons et al. (1973); Ueda et al. (1984); Vemavarapu et al. (2002).

S2. Experimental

Chlorpropamide (280 mg; Sigma Chemical Co., batch No. 31H0722) was dissolved in a boiling mixture of heptane (2 ml) and ethyl acetate (3 ml). The hot solution was filtered on a glass filter. On slow cooling, crystals suitable for X-ray crystallographic analysis were obtained. A kinetic phase transition and melting was observed in the range 383–403 K (Drebushchak et al., 2007).

S3. Refinement

All H atoms were positioned geometrically and refined using a riding model, with C—H distances of 0.93 (aromatic), 0.96 (CH₃) or 0.97 Å (CH₂) and with N—H distances of 0.86 Å, and with U_iso(H) = 1.2U_eq(C, N), or 1.5U_eq(C) for the methyl group.

Computing details

Data collection: STADI4 (Stoe & Cie, 1997); cell refinement: STADI4; data reduction: X-RED (Stoe & Cie, 1997); 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, 1997) and POWDERCELL (Kraus & Nolze, 1999); software used to prepare material for publication: SHELXL97, X-RED, WinGX (Farrugia, 1999) and publCIF (Westrip, 2007).

Figures

	Fig. 1. The molecular structure of γ-chlorpropamide, with the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level and H atoms are shown as spheres of arbitrary radii.
	Fig. 2. Molecules of chlorpropamide viewed along the O3—C7 bond in (a) the α-form, (b) the β-form and (c) the γ-form.
	Fig. 3. A fragment of the crystal structure of the γ-polymorph of chlorpropamide, viewed along the a axis. Hydrogen bonds are shown as dashed lines.
	Fig. 4. Comparative views of the crystal packing of the three polymorphs of chlorpropamide: (a) the γ-polymorph viewed along the b axis, (b) the α-polymorph viewed along the a axis, and (c) the β-polymorph viewed along the b axis. Hydrogen bonds are shown as dashed lines.

4-chloro-N-(propylaminocarbonyl)benzenesulfonamide

Crystal data

C10H13ClN2O3S	F(000) = 288
Mr = 276.74	Dx = 1.416 Mg m^−3
Monoclinic, P21	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2yb	Cell parameters from 48 reflections
a = 6.126 (2) Å	θ = 10.0–12.2°
b = 8.941 (6) Å	µ = 0.45 mm^−1
c = 12.020 (4) Å	T = 295 K
β = 99.68 (3)°	Plate, colourless
V = 649.0 (5) Å^3	0.42 × 0.15 × 0.04 mm
Z = 2

Data collection

Stoe STADI4 four-circle D094 diffractometer	1674 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.050
Planar graphite monochromator	θmax = 27.5°, θmin = 1.7°
Scan width (ω) = 1.60–1.80, scan ratio 2θ:ω = 1.00 I(Net) and σ(I) calculated according to Blessing (1987) Blessing, R. H. (1987). Crystallogr. Rev. 1, 3–58.	h = −7→7
Absorption correction: ψ scan (X-RED; Stoe & Cie, 1997)	k = −11→11
Tmin = 0.833, Tmax = 0.978	l = −15→15
3354 measured reflections	2 standard reflections every 240 min
2961 independent reflections	intensity decay: 5.7%

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.075	H-atom parameters constrained
wR(F^2) = 0.163	w = 1/[σ^2(Fo^2) + (0.0473P)^2 + 0.1797P] where P = (Fo^2 + 2Fc^2)/3
S = 1.17	(Δ/σ)max < 0.001
2961 reflections	Δρmax = 0.22 e Å^−3
157 parameters	Δρmin = −0.28 e Å^−3
1 restraint	Absolute structure: Flack (1983), with 1385 Friedel pairs
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.11 (16)

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
C1	0.2453 (12)	0.4143 (10)	0.9369 (6)	0.068 (2)
C2	0.3620 (14)	0.5433 (9)	0.9404 (6)	0.073 (2)
H2	0.3425	0.6178	0.9919	0.088*
C3	0.5111 (13)	0.5631 (7)	0.8666 (5)	0.0638 (19)
H3	0.5896	0.6522	0.8669	0.077*
C4	0.5422 (10)	0.4493 (6)	0.7924 (5)	0.0480 (16)
C5	0.4236 (12)	0.3165 (7)	0.7918 (6)	0.0649 (19)
H5	0.4451	0.2395	0.7428	0.078*
C6	0.2738 (13)	0.3005 (8)	0.8647 (6)	0.069 (2)
H6	0.1925	0.2127	0.8648	0.083*
C7	0.4298 (9)	0.4609 (7)	0.5081 (5)	0.0436 (13)
C8	0.1444 (8)	0.4746 (7)	0.3404 (4)	0.0474 (13)
H8A	0.1914	0.3748	0.3234	0.057*
H8B	0.1336	0.5337	0.2721	0.057*
C9	−0.0778 (10)	0.4651 (9)	0.3733 (6)	0.0684 (18)
H9A	−0.1288	0.5650	0.3870	0.082*
H9B	−0.0673	0.4088	0.4429	0.082*
C10	−0.2454 (11)	0.3902 (9)	0.2824 (7)	0.082 (2)
H10A	−0.1865	0.2968	0.2613	0.124*
H10B	−0.2753	0.4543	0.2175	0.124*
H10C	−0.3802	0.3722	0.3110	0.124*
Cl1	0.0547 (4)	0.3897 (3)	1.02808 (17)	0.1007 (8)
N1	0.5816 (8)	0.5414 (5)	0.5830 (4)	0.0483 (13)
H1A	0.5993	0.6341	0.5675	0.058*
N2	0.3131 (8)	0.5406 (5)	0.4268 (4)	0.0488 (13)
H2A	0.3372	0.6352	0.4246	0.059*
O1	0.8762 (7)	0.5968 (5)	0.7395 (4)	0.0644 (13)
O2	0.8199 (7)	0.3328 (4)	0.6764 (4)	0.0601 (12)
O3	0.4104 (7)	0.3225 (4)	0.5182 (3)	0.0513 (10)
S1	0.7310 (3)	0.47569 (16)	0.69880 (13)	0.0509 (4)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.071 (5)	0.082 (5)	0.046 (4)	0.010 (5)	0.000 (3)	0.000 (4)
C2	0.092 (6)	0.067 (5)	0.059 (5)	0.008 (5)	0.012 (5)	−0.018 (4)
C3	0.084 (5)	0.045 (4)	0.058 (4)	0.003 (4)	−0.003 (4)	−0.009 (3)
C4	0.062 (4)	0.037 (4)	0.038 (3)	0.005 (3)	−0.010 (3)	0.001 (2)
C5	0.090 (5)	0.043 (4)	0.059 (4)	−0.011 (4)	0.002 (4)	−0.005 (3)
C6	0.082 (5)	0.061 (5)	0.063 (5)	−0.014 (4)	0.005 (4)	0.011 (4)
C7	0.051 (3)	0.036 (3)	0.042 (3)	−0.003 (3)	0.003 (3)	−0.006 (3)
C8	0.055 (3)	0.036 (3)	0.048 (3)	0.008 (4)	0.002 (3)	0.001 (3)
C9	0.065 (4)	0.069 (4)	0.072 (4)	0.003 (5)	0.015 (3)	−0.009 (4)
C10	0.050 (4)	0.083 (5)	0.112 (6)	−0.002 (4)	0.009 (4)	−0.018 (5)
Cl1	0.1024 (17)	0.1271 (18)	0.0769 (13)	0.0077 (15)	0.0275 (12)	0.0083 (14)
N1	0.072 (4)	0.025 (2)	0.044 (3)	−0.003 (2)	−0.003 (2)	0.002 (2)
N2	0.065 (3)	0.026 (2)	0.050 (3)	0.000 (2)	−0.005 (3)	0.004 (2)
O1	0.067 (3)	0.043 (2)	0.075 (3)	−0.016 (2)	−0.012 (2)	−0.004 (2)
O2	0.063 (3)	0.036 (2)	0.076 (3)	0.010 (2)	−0.003 (2)	−0.001 (2)
O3	0.068 (3)	0.0247 (18)	0.057 (2)	−0.0017 (19)	−0.003 (2)	−0.0009 (18)
S1	0.0599 (9)	0.0320 (6)	0.0551 (9)	−0.0001 (9)	−0.0069 (7)	0.0005 (8)

Geometric parameters (Å, º)

C1—C2	1.353 (10)	C8—N2	1.461 (7)
C1—C6	1.367 (10)	C8—C9	1.482 (8)
C1—Cl1	1.745 (8)	C8—H8A	0.9700
C2—C3	1.387 (10)	C8—H8B	0.9700
C2—H2	0.9300	C9—C10	1.523 (9)
C3—C4	1.388 (8)	C9—H9A	0.9700
C3—H3	0.9300	C9—H9B	0.9700
C4—C5	1.391 (8)	C10—H10A	0.9600
C4—S1	1.759 (7)	C10—H10B	0.9600
C5—C6	1.379 (10)	C10—H10C	0.9600
C5—H5	0.9300	N1—S1	1.641 (5)
C6—H6	0.9300	N1—H1A	0.8600
C7—O3	1.251 (7)	N2—H2A	0.8600
C7—N2	1.318 (7)	O1—S1	1.434 (4)
C7—N1	1.382 (7)	O2—S1	1.432 (4)
C2—C1—C6	122.1 (7)	H8A—C8—H8B	107.7
C2—C1—Cl1	119.6 (6)	C8—C9—C10	111.9 (6)
C6—C1—Cl1	118.3 (7)	C8—C9—H9A	109.2
C1—C2—C3	119.3 (7)	C10—C9—H9A	109.2
C1—C2—H2	120.3	C8—C9—H9B	109.2
C3—C2—H2	120.3	C10—C9—H9B	109.2
C2—C3—C4	119.6 (7)	H9A—C9—H9B	107.9
C2—C3—H3	120.2	C9—C10—H10A	109.5
C4—C3—H3	120.2	C9—C10—H10B	109.5
C3—C4—C5	120.0 (6)	H10A—C10—H10B	109.5
C3—C4—S1	119.3 (5)	C9—C10—H10C	109.5
C5—C4—S1	120.7 (5)	H10A—C10—H10C	109.5
C6—C5—C4	119.2 (6)	H10B—C10—H10C	109.5
C6—C5—H5	120.4	C7—N1—S1	125.7 (4)
C4—C5—H5	120.4	C7—N1—H1A	117.1
C1—C6—C5	119.7 (7)	S1—N1—H1A	117.1
C1—C6—H6	120.2	C7—N2—C8	122.6 (5)
C5—C6—H6	120.2	C7—N2—H2A	118.7
O3—C7—N2	123.9 (5)	C8—N2—H2A	118.7
O3—C7—N1	121.1 (5)	O2—S1—O1	120.3 (3)
N2—C7—N1	115.0 (5)	O2—S1—N1	109.6 (3)
N2—C8—C9	113.9 (5)	O1—S1—N1	104.1 (3)
N2—C8—H8A	108.8	O2—S1—C4	108.2 (3)
C9—C8—H8A	108.8	O1—S1—C4	108.7 (3)
N2—C8—H8B	108.8	N1—S1—C4	104.9 (3)
C9—C8—H8B	108.8
C6—C1—C2—C3	1.9 (11)	O3—C7—N2—C8	1.1 (9)
Cl1—C1—C2—C3	−179.1 (5)	N1—C7—N2—C8	−179.7 (5)
C1—C2—C3—C4	−1.6 (10)	C9—C8—N2—C7	87.1 (7)
C2—C3—C4—C5	0.3 (9)	C7—N1—S1—O2	44.3 (5)
C2—C3—C4—S1	179.8 (5)	C7—N1—S1—O1	174.2 (5)
C3—C4—C5—C6	0.7 (9)	C7—N1—S1—C4	−71.7 (5)
S1—C4—C5—C6	−178.8 (5)	C3—C4—S1—O2	150.4 (5)
C2—C1—C6—C5	−0.8 (11)	C5—C4—S1—O2	−30.1 (5)
Cl1—C1—C6—C5	−179.9 (5)	C3—C4—S1—O1	18.2 (5)
C4—C5—C6—C1	−0.5 (10)	C5—C4—S1—O1	−162.3 (5)
N2—C8—C9—C10	−177.8 (5)	C3—C4—S1—N1	−92.7 (5)
O3—C7—N1—S1	−7.3 (8)	C5—C4—S1—N1	86.8 (5)
N2—C7—N1—S1	173.5 (4)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1A···O3^i	0.86	1.97	2.796 (6)	161
N2—H2A···O2^i	0.86	2.26	2.948 (6)	136
N2—H2A···O3^i	0.86	2.30	3.047 (6)	145

Symmetry code: (i) −x+1, y+1/2, −z+1.