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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.
Supporting information
CCDC references: 251387; 251388
For both compounds, program(s) used to refine structure: SHELXL97 (Sheldrick, 1997).
Crystal data top
C14H11Cl2NO2 | V = 2688.40 (8) Å3 |
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 top
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 top
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.034 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.094 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.02 | w = 1/[σ2(Fo2) + (0.0555P)2 + 1.2359P] where P = (Fo2 + 2Fc2)/3 |
2197 reflections | (Δ/σ)max = 0.038 |
216 parameters | Δρmax = 0.21 e Å−3 |
0 restraints | Δρmin = −0.28 e Å−3 |
Crystal data top
C14H11Cl2NO2 | γ = 90° |
Mr = 296.14 | V = 2688.40 (8) Å3 |
?, ? | Z = 8 |
a = 20.2906 (4) Å | Mo Kα radiation |
b = 6.9952 (1) Å | µ = 0.48 mm−1 |
c = 20.1137 (4) Å | T = 293 K |
α = 90° | × × mm |
β = 109.663 (1)° | |
Data collection top
6188 measured reflections | 1911 reflections with I > 2σ(I) |
2197 independent reflections | Rint = 0.019 |
Refinement top
R[F2 > 2σ(F2)] = 0.034 | 0 restraints |
wR(F2) = 0.094 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.02 | Δρmax = 0.21 e Å−3 |
2197 reflections | Δρmin = −0.28 e Å−3 |
216 parameters | |
Special details top
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 (Å2) top | 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 (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
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) top
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) | | |
Crystal data top
C14H11Cl2NO2 | V = 2688.9 (17) Å3 |
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 top
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 top
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.060 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.135 | w = 1/[σ2(Fo2) + (0.0388P)2] where P = (Fo2 + 2Fc2)/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+0.001xFc2λ3/sin(2θ)]-1/4 |
Primary atom site location: structure-invariant direct methods | Extinction coefficient: 172 (63) |
Crystal data top
C14H11Cl2NO2 | γ = 90.00 (2)° |
Mr = 296.14 | V = 2688.9 (17) Å3 |
?, ? | Z = 8 |
a = 20.298 (4) Å | Mo Kα radiation |
b = 6.993 (4) Å | µ = 0.48 mm−1 |
c = 20.107 (4) Å | T = 293 K |
α = 90.00 (2)° | × × mm |
β = 109.60 (2)° | |
Data collection top
1373 measured reflections | Rint = 0.000 |
1373 independent reflections | θmax = 20.7° |
606 reflections with I > 2σ(I) | |
Refinement top
R[F2 > 2σ(F2)] = 0.060 | 6 restraints |
wR(F2) = 0.135 | H atoms treated by a mixture of independent and constrained refinement |
S = 0.81 | (Δ/σ)max = 0.210 |
1373 reflections | Δρmax = 0.27 e Å−3 |
78 parameters | Δρmin = −0.19 e Å−3 |
Special details top
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 (Å2) top | 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) top
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) | | |
Experimental details
| (I) | (II) |
Crystal data |
Chemical formula | C14H11Cl2NO2 | C14H11Cl2NO2 |
Mr | 296.14 | 296.14 |
Crystal system, space group | ?, ? | ?, ? |
Temperature (K) | 293 | 293 |
a, b, c (Å) | 20.2906 (4), 6.9952 (1), 20.1137 (4) | 20.298 (4), 6.993 (4), 20.107 (4) |
α, β, γ (°) | 90, 109.663 (1), 90 | 90.00 (2), 109.60 (2), 90.00 (2) |
V (Å3) | 2688.40 (8) | 2688.9 (17) |
Z | 8 | 8 |
Radiation type | Mo Kα | Mo Kα |
µ (mm−1) | 0.48 | 0.48 |
Crystal size (mm) | × × | × × |
|
Data collection |
Diffractometer | ? | ? |
Absorption correction | – | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 6188, 2197, 1911 | 1373, 1373, 606 |
Rint | 0.019 | 0.000 |
θmax (°) | 24.7 | 20.7 |
(sin θ/λ)max (Å−1) | 0.588 | 0.497 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.034, 0.094, 1.02 | 0.060, 0.135, 0.81 |
No. of reflections | 2197 | 1373 |
No. of parameters | 216 | 78 |
No. of restraints | 0 | 6 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement | H atoms treated by a mixture of independent and constrained refinement |
(Δ/σ)max | 0.038 | 0.210 |
Δρmax, Δρmin (e Å−3) | 0.21, −0.28 | 0.27, −0.19 |
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