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Formulation design is necessary to improve drug solubility, particularly for drugs in Biopharmaceutics Classification System (BCS) classes II and IV. The formulating decision is often affected by the drug's physicochemical properties. To complement the available knowledge, the thermal and structural properties of atovaquone have been investigated. Heat was applied to raw atovaquone to observe the effect of temperature on crystalline polymorphic changes and physical state conversion. Physicochemical properties were assessed through drug content assay, differential scanning calorimetry, X-ray powder diffraction, single-crystal X-ray diffraction and attenuated total reflectance Fourier transform infrared spectroscopy. The surface morphology was observed under a scanning electron microscope. Thermal degradation of atovaquone was confirmed through drug recovery and the sublimating behaviour was observed during the heating process. Understanding the fundamental thermal and structural characteristics of atovaquone plays an important role in designing a stable product of high bioavailability.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S1600576722007865/iu5020sup1.cif
Contains datablock I

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S1600576722007865/iu5020Isup2.hkl
Contains datablock I

pdf

Portable Document Format (PDF) file https://doi.org/10.1107/S1600576722007865/iu5020sup3.pdf
Additional experimental details

CCDC reference: 2094320

Computing details top

Data collection: Bruker APEX2; cell refinement: Bruker SAINT; data reduction: Bruker SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014/7 (Sheldrick, 2014); molecular graphics: Bruker SHELXTL; software used to prepare material for publication: Bruker SHELXTL.

(I) top
Crystal data top
C22H19ClO3F(000) = 768
Mr = 366.82Dx = 1.355 Mg m3
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
a = 12.448 (13) ÅCell parameters from 982 reflections
b = 5.231 (5) Åθ = 3.0–17.2°
c = 27.64 (3) ŵ = 0.23 mm1
β = 92.597 (15)°T = 296 K
V = 1798 (3) Å3Plate, yellow
Z = 40.50 × 0.09 × 0.06 mm
Data collection top
Bruker APEXII CCD
diffractometer
Rint = 0.114
φ and ω scansθmax = 25.0°, θmin = 1.5°
21205 measured reflectionsh = 1414
3159 independent reflectionsk = 66
1327 reflections with I > 2σ(I)l = 3232
Refinement top
Refinement on F20 restraints
Least-squares matrix: fullHydrogen site location: mixed
R[F2 > 2σ(F2)] = 0.062H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.196 w = 1/[σ2(Fo2) + (0.0443P)2 + 1.4655P]
where P = (Fo2 + 2Fc2)/3
S = 1.01(Δ/σ)max < 0.001
3159 reflectionsΔρmax = 0.31 e Å3
239 parametersΔρmin = 0.22 e Å3
Special details top

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

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
Cl11.07437 (12)0.7095 (4)0.88139 (5)0.1172 (7)
O10.5696 (3)0.1973 (7)0.56443 (12)0.0821 (10)
O20.4058 (3)0.2031 (6)0.50106 (11)0.0882 (11)
O30.4069 (3)0.8642 (7)0.64582 (13)0.0945 (11)
C10.8056 (4)0.8678 (9)0.80720 (18)0.0814 (14)
H1A0.75190.99090.80880.098*
C20.8905 (5)0.8737 (10)0.84108 (18)0.0899 (16)
H2A0.89360.99820.86510.108*
C30.9684 (4)0.6972 (11)0.83885 (17)0.0770 (14)
C40.9653 (4)0.5161 (10)0.80444 (19)0.0862 (15)
H4A1.01990.39530.80330.103*
C50.8804 (4)0.5107 (9)0.77082 (17)0.0797 (14)
H5A0.87850.38490.74700.096*
C60.7975 (4)0.6878 (9)0.77140 (16)0.0629 (11)
C70.7076 (4)0.6872 (8)0.73439 (15)0.0688 (12)
H7A0.65780.82270.74320.083*
C80.7444 (3)0.7495 (9)0.68373 (16)0.0755 (13)
H8A0.78090.91340.68450.091*
H8B0.79540.62090.67420.091*
C90.6519 (4)0.7592 (9)0.64663 (17)0.0804 (14)
H9A0.60620.90370.65360.097*
H9B0.67980.78580.61480.097*
C100.5855 (4)0.5191 (8)0.64593 (15)0.0702 (13)
H10A0.63350.38170.63620.084*
C110.5513 (4)0.4491 (9)0.69603 (15)0.0717 (13)
H11A0.49920.57330.70640.086*
H11B0.51660.28310.69480.086*
C120.6447 (4)0.4409 (8)0.73259 (15)0.0733 (13)
H12A0.69230.30180.72450.088*
H12B0.61810.40650.76440.088*
C130.4943 (4)0.5236 (8)0.60875 (15)0.0643 (12)
C140.4907 (4)0.3631 (9)0.57091 (15)0.0650 (12)
C150.4017 (4)0.3550 (9)0.53425 (16)0.0680 (12)
C160.3126 (4)0.5309 (9)0.53922 (16)0.0689 (13)
C170.2270 (5)0.5268 (11)0.50559 (18)0.0920 (16)
H17A0.22530.41090.48000.110*
C180.1439 (5)0.6988 (13)0.5107 (2)0.1067 (19)
H18A0.08590.69950.48830.128*
C190.1465 (5)0.8677 (12)0.5485 (2)0.1039 (19)
H19A0.08980.98150.55170.125*
C200.2316 (4)0.8713 (10)0.58182 (18)0.0874 (15)
H20A0.23260.98580.60760.105*
C210.3157 (4)0.7034 (8)0.57674 (16)0.0670 (12)
C220.4073 (4)0.7072 (9)0.61334 (17)0.0687 (12)
H1O10.555 (5)0.118 (12)0.536 (2)0.17 (3)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Cl10.0958 (11)0.1687 (16)0.0865 (10)0.0157 (10)0.0050 (8)0.0063 (10)
O10.094 (3)0.088 (2)0.064 (2)0.026 (2)0.0025 (18)0.0110 (19)
O20.105 (3)0.094 (3)0.064 (2)0.024 (2)0.0005 (18)0.0170 (19)
O30.098 (3)0.090 (3)0.097 (3)0.012 (2)0.012 (2)0.029 (2)
C10.093 (4)0.069 (3)0.083 (3)0.014 (3)0.019 (3)0.005 (3)
C20.109 (4)0.091 (4)0.070 (3)0.009 (4)0.007 (3)0.017 (3)
C30.071 (3)0.090 (4)0.071 (3)0.002 (3)0.016 (3)0.005 (3)
C40.073 (4)0.089 (4)0.096 (4)0.011 (3)0.007 (3)0.013 (3)
C50.077 (4)0.075 (3)0.086 (4)0.004 (3)0.000 (3)0.017 (3)
C60.063 (3)0.058 (3)0.068 (3)0.001 (3)0.010 (2)0.008 (2)
C70.072 (3)0.061 (3)0.074 (3)0.004 (3)0.011 (2)0.004 (2)
C80.069 (3)0.078 (3)0.081 (3)0.006 (3)0.014 (3)0.015 (3)
C90.082 (3)0.083 (4)0.077 (3)0.005 (3)0.011 (3)0.017 (3)
C100.088 (3)0.062 (3)0.062 (3)0.005 (3)0.014 (3)0.004 (2)
C110.081 (3)0.065 (3)0.069 (3)0.011 (3)0.014 (3)0.004 (2)
C120.087 (3)0.073 (3)0.061 (3)0.009 (3)0.009 (3)0.000 (2)
C130.079 (3)0.063 (3)0.053 (3)0.002 (3)0.015 (2)0.001 (2)
C140.077 (3)0.065 (3)0.054 (3)0.012 (3)0.014 (2)0.002 (2)
C150.082 (3)0.070 (3)0.053 (3)0.006 (3)0.015 (3)0.005 (2)
C160.075 (3)0.081 (3)0.051 (3)0.015 (3)0.008 (3)0.009 (3)
C170.103 (4)0.103 (4)0.071 (3)0.020 (4)0.003 (3)0.007 (3)
C180.096 (4)0.144 (6)0.079 (4)0.029 (4)0.010 (3)0.014 (4)
C190.100 (5)0.120 (5)0.092 (4)0.040 (4)0.010 (4)0.013 (4)
C200.099 (4)0.088 (4)0.077 (4)0.022 (3)0.022 (3)0.008 (3)
C210.081 (3)0.058 (3)0.064 (3)0.008 (3)0.021 (3)0.004 (2)
C220.077 (3)0.063 (3)0.067 (3)0.000 (3)0.017 (3)0.002 (3)
Geometric parameters (Å, º) top
Cl1—C31.728 (5)C9—H9B0.9700
O1—C141.328 (5)C10—C131.497 (6)
O1—H1O10.89 (6)C10—C111.512 (6)
O2—C151.216 (5)C10—H10A0.9800
O3—C221.217 (5)C11—C121.506 (6)
C1—C61.366 (6)C11—H11A0.9700
C1—C21.380 (6)C11—H11B0.9700
C1—H1A0.9300C12—H12A0.9700
C2—C31.343 (6)C12—H12B0.9700
C2—H2A0.9300C13—C141.340 (6)
C3—C41.342 (6)C13—C221.457 (6)
C4—C51.376 (6)C14—C151.468 (6)
C4—H4A0.9300C15—C161.453 (6)
C5—C61.387 (6)C16—C211.374 (6)
C5—H5A0.9300C16—C171.382 (6)
C6—C71.481 (6)C17—C181.383 (7)
C7—C121.507 (6)C17—H17A0.9300
C7—C81.528 (6)C18—C191.367 (7)
C7—H7A0.9800C18—H18A0.9300
C8—C91.508 (6)C19—C201.372 (7)
C8—H8A0.9700C19—H19A0.9300
C8—H8B0.9700C20—C211.378 (6)
C9—C101.503 (6)C20—H20A0.9300
C9—H9A0.9700C21—C221.490 (6)
C14—O1—H1O1107 (4)C12—C11—C10112.4 (4)
C6—C1—C2122.4 (5)C12—C11—H11A109.1
C6—C1—H1A118.8C10—C11—H11A109.1
C2—C1—H1A118.8C12—C11—H11B109.1
C3—C2—C1119.1 (5)C10—C11—H11B109.1
C3—C2—H2A120.5H11A—C11—H11B107.9
C1—C2—H2A120.5C11—C12—C7112.4 (4)
C4—C3—C2121.3 (5)C11—C12—H12A109.1
C4—C3—Cl1120.4 (5)C7—C12—H12A109.1
C2—C3—Cl1118.3 (5)C11—C12—H12B109.1
C3—C4—C5119.3 (5)C7—C12—H12B109.1
C3—C4—H4A120.3H12A—C12—H12B107.8
C5—C4—H4A120.3C14—C13—C22118.9 (4)
C4—C5—C6121.9 (5)C14—C13—C10121.5 (4)
C4—C5—H5A119.1C22—C13—C10119.6 (4)
C6—C5—H5A119.1O1—C14—C13121.1 (5)
C1—C6—C5116.0 (4)O1—C14—C15115.3 (4)
C1—C6—C7122.0 (5)C13—C14—C15123.6 (5)
C5—C6—C7122.0 (4)O2—C15—C16122.9 (4)
C6—C7—C12113.5 (4)O2—C15—C14118.9 (4)
C6—C7—C8112.6 (4)C16—C15—C14118.2 (4)
C12—C7—C8109.2 (4)C21—C16—C17120.8 (5)
C6—C7—H7A107.0C21—C16—C15119.4 (4)
C12—C7—H7A107.0C17—C16—C15119.7 (5)
C8—C7—H7A107.0C16—C17—C18118.5 (5)
C9—C8—C7112.3 (4)C16—C17—H17A120.7
C9—C8—H8A109.1C18—C17—H17A120.7
C7—C8—H8A109.1C19—C18—C17120.5 (5)
C9—C8—H8B109.1C19—C18—H18A119.7
C7—C8—H8B109.1C17—C18—H18A119.7
H8A—C8—H8B107.9C18—C19—C20120.8 (5)
C10—C9—C8112.5 (4)C18—C19—H19A119.6
C10—C9—H9A109.1C20—C19—H19A119.6
C8—C9—H9A109.1C19—C20—C21119.3 (5)
C10—C9—H9B109.1C19—C20—H20A120.3
C8—C9—H9B109.1C21—C20—H20A120.3
H9A—C9—H9B107.8C16—C21—C20120.0 (5)
C13—C10—C9113.3 (4)C16—C21—C22121.1 (4)
C13—C10—C11113.4 (4)C20—C21—C22118.9 (5)
C9—C10—C11111.6 (4)O3—C22—C13122.5 (5)
C13—C10—H10A106.0O3—C22—C21118.8 (5)
C9—C10—H10A106.0C13—C22—C21118.7 (4)
C11—C10—H10A106.0
C6—C1—C2—C30.3 (8)C22—C13—C14—C152.2 (6)
C1—C2—C3—C40.0 (8)C10—C13—C14—C15178.2 (4)
C1—C2—C3—Cl1179.6 (4)O1—C14—C15—O20.5 (6)
C2—C3—C4—C50.1 (8)C13—C14—C15—O2179.8 (4)
Cl1—C3—C4—C5179.7 (4)O1—C14—C15—C16179.8 (4)
C3—C4—C5—C60.0 (8)C13—C14—C15—C160.1 (6)
C2—C1—C6—C50.4 (7)O2—C15—C16—C21177.6 (4)
C2—C1—C6—C7178.3 (4)C14—C15—C16—C212.1 (6)
C4—C5—C6—C10.3 (7)O2—C15—C16—C170.9 (7)
C4—C5—C6—C7178.2 (4)C14—C15—C16—C17179.4 (4)
C1—C6—C7—C12122.9 (5)C21—C16—C17—C180.6 (7)
C5—C6—C7—C1259.3 (5)C15—C16—C17—C18179.0 (4)
C1—C6—C7—C8112.3 (5)C16—C17—C18—C190.4 (8)
C5—C6—C7—C865.4 (6)C17—C18—C19—C200.4 (9)
C6—C7—C8—C9177.6 (4)C18—C19—C20—C210.5 (8)
C12—C7—C8—C955.3 (5)C17—C16—C21—C201.5 (7)
C7—C8—C9—C1054.3 (5)C15—C16—C21—C20180.0 (4)
C8—C9—C10—C13179.1 (4)C17—C16—C21—C22179.5 (4)
C8—C9—C10—C1151.6 (5)C15—C16—C21—C222.1 (6)
C13—C10—C11—C12178.9 (4)C19—C20—C21—C161.5 (7)
C9—C10—C11—C1251.8 (5)C19—C20—C21—C22179.5 (5)
C10—C11—C12—C755.1 (5)C14—C13—C22—O3177.5 (4)
C6—C7—C12—C11177.8 (4)C10—C13—C22—O32.1 (7)
C8—C7—C12—C1155.7 (5)C14—C13—C22—C212.2 (6)
C9—C10—C13—C14114.6 (5)C10—C13—C22—C21178.2 (4)
C11—C10—C13—C14117.0 (5)C16—C21—C22—O3179.7 (4)
C9—C10—C13—C2265.0 (5)C20—C21—C22—O32.4 (6)
C11—C10—C13—C2263.4 (5)C16—C21—C22—C130.0 (6)
C22—C13—C14—O1178.1 (4)C20—C21—C22—C13177.9 (4)
C10—C13—C14—O11.5 (6)
 

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