Structure determination of diclofenac in a diclofenac-containing chitosan matrix using conventional X-ray powder diffraction data

The structure determination of diclofenac embedded in a diclofenac-containing chitosan matrix using conventional X-ray powder diffraction data is demonstrated. It reveals that sodium diclofenac, the starting material in the preparation of a controlled-release diclofenac-containing chitosan matrix, changes to diclofenac acid in space group C2/c in the matrix. Simple methods were employed for handling the sample to obtain X-ray powder diffraction data of sufficiently high quality for the determination of the crystal structure of diclofenac embedded in chitosan. These involved grinding and sieving several times through a micro-mesh sieve to obtain a suitable particle size and a uniformly spherical particle shape. A traditional technique for structure solution from X-ray powder diffraction data was applied. The X-ray diffraction intensities were extracted using Le Bail's method. The structure was solved by direct methods from the extracted powder data and refined using the Rietveld method. For comparison, the single-crystal structure of the same drug was also determined. The result shows that the crystal structure solved from conventional X-ray powder diffraction data is in good agreement with that of the single crystal. The deviations of the differences in bond lengths and angles are of the order of 0.030 Å and 0.639°, respectively.

Computing details

For both compounds, program(s) used to refine structure: SHELXL97 (Sheldrick, 1997).

Figures

(I)

Crystal data

C14H11Cl2NO2	V = 2688.40 (8) Å^3
Mr = 296.14	Z = 8
?, ?	F(000) = 1216
a = 20.2906 (4) Å	Dx = 1.463 Mg m^−3
b = 6.9952 (1) Å	Mo Kα radiation, λ = 0.71073 Å
c = 20.1137 (4) Å	µ = 0.48 mm^−1
α = 90°	T = 293 K
β = 109.663 (1)°	× × mm
γ = 90°

Data collection

Radiation source: fine-focus sealed tube	Rint = 0.019
Graphite monochromator	θmax = 24.7°, θmin = 8.2°
6188 measured reflections	h = −23→23
2197 independent reflections	k = −8→6
1911 reflections with I > 2σ(I)	l = −23→18

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)] = 0.034	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.094	H atoms treated by a mixture of independent and constrained refinement
S = 1.02	w = 1/[σ^2(Fo^2) + (0.0555P)^2 + 1.2359P] where P = (Fo^2 + 2Fc^2)/3
2197 reflections	(Δ/σ)max = 0.038
216 parameters	Δρmax = 0.21 e Å^−3
0 restraints	Δρmin = −0.28 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
C1	0.22591 (8)	0.3689 (2)	0.33540 (9)	0.0390 (4)
C2	0.23892 (10)	0.4480 (2)	0.27761 (10)	0.0461 (4)
C3	0.18921 (11)	0.4454 (3)	0.21117 (10)	0.0522 (5)
C4	0.12472 (11)	0.3628 (3)	0.20170 (10)	0.0508 (5)
C5	0.11032 (10)	0.2842 (3)	0.25842 (9)	0.0442 (4)
C6	0.16006 (8)	0.2874 (2)	0.32571 (8)	0.0369 (4)
C7	0.09028 (8)	0.0932 (2)	0.38114 (8)	0.0380 (4)
C8	0.08254 (9)	−0.0869 (3)	0.34864 (9)	0.0437 (4)
C9	0.02680 (11)	−0.2069 (3)	0.34521 (11)	0.0548 (5)
C10	−0.02120 (12)	−0.1530 (3)	0.37617 (11)	0.0586 (5)
C11	−0.01392 (10)	0.0186 (3)	0.41116 (10)	0.0521 (5)
C12	0.04097 (9)	0.1392 (2)	0.41314 (9)	0.0416 (4)
C13	0.28201 (10)	0.3714 (3)	0.40770 (11)	0.0505 (5)
C14	0.27049 (9)	0.5347 (3)	0.45099 (9)	0.0469 (4)
N1	0.14675 (8)	0.2131 (2)	0.38561 (8)	0.0439 (4)
O1	0.22098 (8)	0.5375 (2)	0.47297 (7)	0.0607 (4)
O2	0.31588 (8)	0.6732 (2)	0.46169 (9)	0.0640 (4)
Cl1	0.04921 (3)	0.35561 (7)	0.45803 (3)	0.0600 (2)
Cl2	0.14508 (3)	−0.16736 (7)	0.31430 (3)	0.0620 (2)
H1	0.3026 (16)	0.775 (5)	0.4823 (17)	0.099 (10)*
H1N	0.1553 (11)	0.281 (3)	0.4167 (11)	0.050 (6)*
H2	0.2816 (12)	0.503 (3)	0.2848 (10)	0.054 (5)*
H3	0.1970 (11)	0.498 (3)	0.1708 (12)	0.062 (6)*
H4	0.0887 (12)	0.364 (3)	0.1572 (13)	0.064 (6)*
H5	0.0673 (12)	0.230 (3)	0.2518 (11)	0.056 (5)*
H9	0.0251 (12)	−0.328 (4)	0.3222 (12)	0.068 (6)*
H10	−0.0606 (14)	−0.232 (4)	0.3711 (12)	0.074 (7)*
H11	−0.0457 (12)	0.054 (3)	0.4328 (11)	0.056 (5)*
H13A	0.2803 (11)	0.253 (4)	0.4329 (11)	0.060 (6)*
H13B	0.3251 (13)	0.381 (3)	0.4015 (11)	0.061 (6)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0373 (8)	0.0317 (8)	0.0505 (9)	−0.0001 (6)	0.0183 (7)	−0.0081 (7)
C2	0.0484 (10)	0.0341 (9)	0.0657 (12)	−0.0077 (8)	0.0324 (9)	−0.0083 (8)
C3	0.0719 (13)	0.0389 (10)	0.0552 (11)	−0.0066 (9)	0.0338 (10)	−0.0002 (8)
C4	0.0614 (12)	0.0425 (10)	0.0454 (10)	−0.0035 (8)	0.0139 (9)	0.0030 (8)
C5	0.0405 (9)	0.0415 (9)	0.0487 (9)	−0.0063 (7)	0.0127 (7)	0.0003 (7)
C6	0.0385 (8)	0.0303 (8)	0.0457 (9)	−0.0018 (6)	0.0189 (7)	−0.0032 (6)
C7	0.0400 (8)	0.0380 (9)	0.0367 (8)	−0.0010 (7)	0.0138 (7)	0.0043 (7)
C8	0.0500 (9)	0.0390 (9)	0.0467 (9)	0.0023 (8)	0.0225 (8)	0.0043 (7)
C9	0.0697 (12)	0.0396 (10)	0.0581 (11)	−0.0115 (9)	0.0255 (10)	0.0006 (9)
C10	0.0585 (12)	0.0571 (12)	0.0646 (12)	−0.0163 (10)	0.0265 (10)	0.0075 (9)
C11	0.0480 (10)	0.0624 (12)	0.0536 (10)	−0.0003 (9)	0.0272 (9)	0.0118 (9)
C12	0.0457 (9)	0.0413 (9)	0.0387 (8)	0.0048 (7)	0.0155 (7)	0.0058 (7)
C13	0.0366 (9)	0.0493 (11)	0.0627 (12)	−0.0029 (8)	0.0129 (8)	−0.0078 (9)
C14	0.0423 (9)	0.0500 (11)	0.0422 (9)	−0.0101 (8)	0.0059 (7)	−0.0054 (8)
N1	0.0456 (8)	0.0468 (9)	0.0415 (8)	−0.0110 (7)	0.0177 (6)	−0.0065 (7)
O1	0.0655 (8)	0.0605 (9)	0.0640 (8)	−0.0227 (7)	0.0321 (7)	−0.0213 (7)
O2	0.0580 (8)	0.0611 (9)	0.0770 (10)	−0.0227 (7)	0.0280 (7)	−0.0236 (7)
Cl1	0.0714 (4)	0.0545 (3)	0.0610 (3)	0.0040 (2)	0.0314 (3)	−0.0103 (2)
Cl2	0.0725 (4)	0.0480 (3)	0.0793 (4)	0.0092 (2)	0.0437 (3)	−0.0030 (2)

Geometric parameters (Å, º)

C1—C2	1.391 (3)	C7—C8	1.404 (2)
C1—C6	1.404 (2)	C8—C9	1.391 (3)
C1—C13	1.515 (3)	C8—Cl2	1.7301 (18)
C2—C3	1.377 (3)	C9—C10	1.374 (3)
C3—C4	1.384 (3)	C10—C11	1.374 (3)
C4—C5	1.383 (3)	C11—C12	1.387 (3)
C5—C6	1.390 (2)	C12—Cl1	1.7414 (18)
C6—N1	1.419 (2)	C13—C14	1.501 (3)
C7—N1	1.398 (2)	C14—O1	1.226 (2)
C7—C12	1.397 (2)	C14—O2	1.304 (2)
C2—C1—C6	118.99 (16)	C9—C8—Cl2	118.49 (15)
C2—C1—C13	120.32 (16)	C7—C8—Cl2	119.71 (13)
C6—C1—C13	120.68 (16)	C10—C9—C8	120.03 (19)
C3—C2—C1	121.52 (17)	C9—C10—C11	120.11 (19)
C2—C3—C4	119.28 (18)	C10—C11—C12	119.55 (18)
C3—C4—C5	120.32 (19)	C11—C12—C7	122.61 (17)
C4—C5—C6	120.73 (17)	C11—C12—Cl1	118.67 (14)
C5—C6—C1	119.14 (15)	C7—C12—Cl1	118.72 (13)
C5—C6—N1	122.51 (15)	C14—C13—C1	110.63 (15)
C1—C6—N1	118.35 (15)	O1—C14—O2	123.16 (18)
N1—C7—C12	122.04 (15)	O1—C14—C13	121.87 (16)
N1—C7—C8	121.94 (15)	O2—C14—C13	114.95 (17)
C12—C7—C8	115.86 (15)	C7—N1—C6	123.45 (14)
C9—C8—C7	121.76 (17)

(II)

Crystal data

C14H11Cl2NO2	V = 2688.9 (17) Å^3
Mr = 296.14	Z = 8
?, ?	F(000) = 1216
a = 20.298 (4) Å	Dx = 1.463 Mg m^−3
b = 6.993 (4) Å	Mo Kα radiation, λ = 0.71073 Å
c = 20.107 (4) Å	µ = 0.48 mm^−1
α = 90.00 (2)°	T = 293 K
β = 109.60 (2)°	× × mm
γ = 90.00 (2)°

Data collection

Radiation source: fine-focus sealed tube	Rint = 0.000
Graphite monochromator	θmax = 20.7°, θmin = 3.1°
1373 measured reflections	h = 0→20
1373 independent reflections	k = 0→6
606 reflections with I > 2σ(I)	l = −19→18

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)] = 0.060	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.135	w = 1/[σ^2(Fo^2) + (0.0388P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 0.81	(Δ/σ)max = 0.210
1373 reflections	Δρmax = 0.27 e Å^−3
78 parameters	Δρmin = −0.19 e Å^−3
6 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: 172 (63)

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	0.2290 (9)	0.352 (2)	0.3411 (9)	0.060 (6)*
C2	0.2376 (13)	0.443 (3)	0.2806 (14)	0.126 (9)*
H2	0.2800	0.5037	0.2869	0.151*
C3	0.1883 (9)	0.447 (2)	0.2140 (9)	0.058 (5)*
H3	0.1975	0.5076	0.1769	0.070*
C4	0.1305 (8)	0.366 (2)	0.2047 (9)	0.044 (5)*
H4	0.0969	0.3619	0.1598	0.053*
C5	0.1168 (13)	0.284 (4)	0.2614 (14)	0.128 (9)*
H5	0.0741	0.2239	0.2546	0.154*
C6	0.1650 (9)	0.290 (2)	0.3262 (10)	0.053 (5)*
C7	0.0957 (19)	0.110 (5)	0.3792 (19)	0.187 (14)*
C8	0.0826 (11)	−0.087 (4)	0.3448 (12)	0.112 (9)*
C9	0.0288 (9)	−0.211 (3)	0.3417 (9)	0.065 (6)*
H9	0.0240	−0.3291	0.3197	0.078*
C10	−0.0180 (11)	−0.145 (3)	0.3740 (11)	0.099 (8)*
H10	−0.0572	−0.2192	0.3699	0.119*
C11	−0.0100 (9)	0.021 (3)	0.4112 (9)	0.064 (6)*
H11	−0.0404	0.0561	0.4349	0.076*
C12	0.0438 (11)	0.131 (3)	0.4118 (10)	0.081 (7)*
C13	0.2910 (9)	0.379 (3)	0.4074 (9)	0.065 (6)*
C14	0.2821 (11)	0.551 (3)	0.4498 (12)	0.117 (9)*
N1	0.1466 (10)	0.221 (3)	0.3833 (10)	0.098 (6)*
O1	0.3221 (6)	0.7044 (18)	0.4599 (7)	0.080 (4)*
O2	0.2292 (6)	0.5318 (15)	0.4682 (6)	0.057 (4)*
Cl1	0.0478 (3)	0.3467 (7)	0.4583 (3)	0.085 (2)*
Cl2	0.1440 (3)	−0.1576 (7)	0.3082 (3)	0.083 (2)*

Geometric parameters (Å, º)

C1—C6	1.31 (2)	C7—C8	1.53 (4)
C1—C2	1.43 (3)	C8—C9	1.38 (2)
C1—C13	1.507 (18)	C8—Cl2	1.718 (18)
C2—C3	1.38 (3)	C9—C10	1.40 (2)
C3—C4	1.259 (18)	C10—C11	1.36 (2)
C4—C5	1.39 (2)	C11—C12	1.33 (2)
C5—C6	1.34 (3)	C12—Cl1	1.760 (17)
C6—N1	1.40 (2)	C13—C14	1.52 (2)
C7—N1	1.27 (3)	C14—O2	1.255 (18)
C7—C12	1.42 (3)	C14—O1	1.318 (18)
C6—C1—C2	110.3 (19)	C9—C8—Cl2	118.5 (19)
C6—C1—C13	135.7 (18)	C7—C8—Cl2	114 (2)
C2—C1—C13	113.0 (18)	C8—C9—C10	115.2 (19)
C3—C2—C1	125 (2)	C11—C10—C9	124 (2)
C4—C3—C2	118 (2)	C12—C11—C10	116.4 (19)
C3—C4—C5	120 (2)	C11—C12—C7	132 (2)
C6—C5—C4	120 (2)	C11—C12—Cl1	113.0 (16)
C1—C6—C5	125 (2)	C7—C12—Cl1	115 (2)
C1—C6—N1	116.2 (19)	C1—C13—C14	112.1 (16)
C5—C6—N1	118.4 (19)	O2—C14—O1	126 (2)
N1—C7—C12	128 (3)	O2—C14—C13	110.8 (17)
N1—C7—C8	126 (3)	O1—C14—C13	123.1 (18)
C12—C7—C8	105 (3)	C7—N1—C6	126 (3)
C9—C8—C7	127 (2)