Structural study of piracetam polymorphs and cocrystals: crystallography redetermination and quantum mechanics calculations

Pharmaceutical compounds are mostly developed as solid dosage forms containing a single-crystal form. It means that the selection of a particular crystal state for a given molecule is an important step for further clinical outlooks. In this context, piracetam, a pharmaceutical molecule known since the sixties for its nootropic properties, is considered in the present work. This molecule is analyzed using several experimental and theoretical approaches. First, the conformational space of the molecule has been systematically explored by performing a quantum mechanics scan of the two most relevant dihedral angles of the lateral chain. The predicted stable conformations have been compared to all the reported experimental geometries retrieved from the Cambridge Structural Database (CSD) covering polymorphs and cocrystals structures. In parallel, different batches of powders have been recrystallized. Under specific conditions, single crystals of polymorph (III) of piracetam have been obtained, an outcome confirmed by crystallographic analysis.

Computing details

Data collection: CrysAlis PRO, Oxford Diffraction Ltd., Version 1.171.33.55 (release 05-01-2010 CrysAlis171 .NET) (compiled Jan 5 2010,16:28:46); cell refinement: CrysAlis PRO, Oxford Diffraction Ltd., Version 1.171.33.55 (release 05-01-2010 CrysAlis171 .NET) (compiled Jan 5 2010,16:28:46); data reduction: CrysAlis PRO, Oxford Diffraction Ltd., Version 1.171.33.55 (release 05-01-2010 CrysAlis171 .NET) (compiled Jan 5 2010,16:28:46); program(s) used to solve structure: Sir92; program(s) used to refine structure: SHELXL97 (Sheldrick, 1997).

Figures

(I)

Crystal data

C6H10N2O2	F(000) = 304
Mr = 142.16	Dx = 1.379 Mg m^−3
Monoclinic, P21/n	Cu Kα radiation, λ = 1.54178 Å
Hall symbol: -P 2yn	Cell parameters from 240 reflections
a = 6.503 (1) Å	θ = 3.3–32.6°
b = 6.418 (1) Å	µ = 0.88 mm^−1
c = 16.416 (3) Å	T = 290 K
β = 92.087 (4)°	Prism, colorless
V = 684.7 (2) Å^3	0.20 × 0.20 × 0.10 mm
Z = 4

Data collection

Xcalibur, Ruby, Gemini ultra diffractometer	1202 independent reflections
Radiation source: fine-focus sealed tube	1132 reflections with I > 2σ(I)
Mirror monochromator	Rint = 0.011
Detector resolution: 10.3712 pixels mm^-1	θmax = 67.4°, θmin = 5.4°
ω scans	h = −7→7
Absorption correction: multi-scan CrysAlis PRO, Oxford Diffraction Ltd., Version 1.171.33.55 (release 05-01-2010 CrysAlis171 .NET) (compiled Jan 5 2010,16:28:46) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.	k = −6→7
Tmin = 0.844, Tmax = 0.918	l = −18→19
4113 measured reflections

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)] = 0.035	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.099	w = 1/[σ^2(Fo^2) + (0.0568P)^2 + 0.1732P] where P = (Fo^2 + 2Fc^2)/3
S = 1.06	(Δ/σ)max < 0.001
1202 reflections	Δρmax = 0.17 e Å^−3
100 parameters	Δρmin = −0.15 e Å^−3
0 restraints	Extinction correction: SHELXL, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0125 (19)

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	0.00810 (19)	0.0656 (2)	0.33350 (7)	0.0360 (3)
C2	−0.1112 (2)	−0.1109 (2)	0.36898 (9)	0.0475 (4)
H2A	−0.2024	−0.1731	0.3277	0.057*
H2B	−0.1928	−0.0618	0.4134	0.057*
C3	0.0476 (2)	−0.2675 (3)	0.39962 (11)	0.0549 (4)
H3A	0.0409	−0.3932	0.3668	0.066*
H3B	0.0247	−0.3042	0.4559	0.066*
C4	0.2551 (2)	−0.1614 (2)	0.39235 (9)	0.0448 (4)
H4A	0.3139	−0.1260	0.4457	0.054*
H4B	0.3504	−0.2508	0.3646	0.054*
C5	0.36723 (19)	0.1752 (2)	0.32861 (8)	0.0370 (3)
H5A	0.3172	0.2695	0.2862	0.044*
H5B	0.4867	0.1034	0.3088	0.044*
C6	0.43039 (18)	0.30059 (19)	0.40419 (8)	0.0347 (3)
N1	0.20996 (15)	0.02533 (16)	0.34489 (6)	0.0346 (3)
N2	0.61342 (18)	0.3920 (2)	0.40293 (8)	0.0439 (3)
O1	−0.06305 (14)	0.22136 (17)	0.29894 (6)	0.0490 (3)
O2	0.31260 (15)	0.31870 (17)	0.46039 (6)	0.0488 (3)
H2C	0.699 (3)	0.362 (3)	0.3646 (11)	0.052 (5)*
H2D	0.654 (3)	0.480 (3)	0.4443 (13)	0.063 (5)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0350 (7)	0.0411 (7)	0.0318 (6)	0.0047 (5)	0.0014 (5)	−0.0042 (5)
C2	0.0371 (7)	0.0512 (9)	0.0545 (8)	−0.0033 (6)	0.0038 (6)	0.0018 (7)
C3	0.0507 (9)	0.0451 (8)	0.0692 (11)	−0.0022 (7)	0.0047 (7)	0.0126 (7)
C4	0.0425 (8)	0.0399 (8)	0.0518 (8)	0.0040 (6)	−0.0029 (6)	0.0078 (6)
C5	0.0349 (7)	0.0417 (7)	0.0345 (7)	−0.0007 (5)	0.0047 (5)	0.0017 (5)
C6	0.0338 (6)	0.0325 (7)	0.0378 (7)	0.0019 (5)	0.0034 (5)	0.0029 (5)
N1	0.0322 (5)	0.0341 (6)	0.0373 (6)	0.0018 (4)	0.0000 (4)	−0.0002 (4)
N2	0.0378 (6)	0.0458 (7)	0.0485 (7)	−0.0071 (5)	0.0083 (5)	−0.0081 (5)
O1	0.0422 (6)	0.0523 (6)	0.0526 (6)	0.0122 (4)	0.0015 (4)	0.0097 (5)
O2	0.0458 (6)	0.0557 (7)	0.0459 (6)	−0.0102 (5)	0.0140 (4)	−0.0118 (5)

Geometric parameters (Å, º)

C1—O1	1.2315 (17)	C4—H4A	0.9700
C1—N1	1.3443 (16)	C4—H4B	0.9700
C1—C2	1.502 (2)	C5—N1	1.4361 (16)
C2—C3	1.514 (2)	C5—C6	1.5228 (18)
C2—H2A	0.9700	C5—H5A	0.9700
C2—H2B	0.9700	C5—H5B	0.9700
C3—C4	1.520 (2)	C6—O2	1.2259 (16)
C3—H3A	0.9700	C6—N2	1.3279 (17)
C3—H3B	0.9700	N2—H2C	0.878 (19)
C4—N1	1.4537 (17)	N2—H2D	0.91 (2)
O1—C1—N1	124.66 (12)	N1—C4—H4B	110.9
O1—C1—C2	126.88 (12)	C3—C4—H4B	110.9
N1—C1—C2	108.46 (11)	H4A—C4—H4B	108.9
C1—C2—C3	105.88 (11)	N1—C5—C6	112.03 (10)
C1—C2—H2A	110.6	N1—C5—H5A	109.2
C3—C2—H2A	110.6	C6—C5—H5A	109.2
C1—C2—H2B	110.6	N1—C5—H5B	109.2
C3—C2—H2B	110.6	C6—C5—H5B	109.2
H2A—C2—H2B	108.7	H5A—C5—H5B	107.9
C2—C3—C4	105.87 (12)	O2—C6—N2	123.70 (12)
C2—C3—H3A	110.6	O2—C6—C5	120.39 (11)
C4—C3—H3A	110.6	N2—C6—C5	115.86 (11)
C2—C3—H3B	110.6	C1—N1—C5	122.95 (11)
C4—C3—H3B	110.6	C1—N1—C4	114.20 (11)
H3A—C3—H3B	108.7	C5—N1—C4	121.39 (10)
N1—C4—C3	104.42 (11)	C6—N2—H2C	120.5 (11)
N1—C4—H4A	110.9	C6—N2—H2D	119.7 (11)
C3—C4—H4A	110.9	H2C—N2—H2D	119.7 (16)
O1—C1—C2—C3	176.77 (14)	C2—C1—N1—C5	−171.00 (12)
N1—C1—C2—C3	−2.66 (15)	O1—C1—N1—C4	175.91 (12)
C1—C2—C3—C4	8.34 (17)	C2—C1—N1—C4	−4.65 (15)
C2—C3—C4—N1	−10.69 (16)	C6—C5—N1—C1	93.02 (14)
N1—C5—C6—O2	−23.18 (17)	C6—C5—N1—C4	−72.38 (15)
N1—C5—C6—N2	159.25 (11)	C3—C4—N1—C1	9.85 (16)
O1—C1—N1—C5	9.56 (19)	C3—C4—N1—C5	176.44 (12)