Exploring solid states of atovaquone: crystal or glass?

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.

Computing details

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)

Crystal data

C22H19ClO3	F(000) = 768
Mr = 366.82	Dx = 1.355 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
a = 12.448 (13) Å	Cell parameters from 982 reflections
b = 5.231 (5) Å	θ = 3.0–17.2°
c = 27.64 (3) Å	µ = 0.23 mm^−1
β = 92.597 (15)°	T = 296 K
V = 1798 (3) Å^3	Plate, yellow
Z = 4	0.50 × 0.09 × 0.06 mm

Data collection

Bruker APEXII CCD diffractometer	Rint = 0.114
φ and ω scans	θmax = 25.0°, θmin = 1.5°
21205 measured reflections	h = −14→14
3159 independent reflections	k = −6→6
1327 reflections with I > 2σ(I)	l = −32→32

Refinement

Refinement on F^2	0 restraints
Least-squares matrix: full	Hydrogen site location: mixed
R[F^2 > 2σ(F^2)] = 0.062	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.196	w = 1/[σ^2(Fo^2) + (0.0443P)^2 + 1.4655P] where P = (Fo^2 + 2Fc^2)/3
S = 1.01	(Δ/σ)max < 0.001
3159 reflections	Δρmax = 0.31 e Å^−3
239 parameters	Δρmin = −0.22 e Å^−3

Special details

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 (Ų)

	x	y	z	Uiso*/Ueq
Cl1	1.07437 (12)	0.7095 (4)	0.88139 (5)	0.1172 (7)
O1	0.5696 (3)	0.1973 (7)	0.56443 (12)	0.0821 (10)
O2	0.4058 (3)	0.2031 (6)	0.50106 (11)	0.0882 (11)
O3	0.4069 (3)	0.8642 (7)	0.64582 (13)	0.0945 (11)
C1	0.8056 (4)	0.8678 (9)	0.80720 (18)	0.0814 (14)
H1A	0.7519	0.9909	0.8088	0.098*
C2	0.8905 (5)	0.8737 (10)	0.84108 (18)	0.0899 (16)
H2A	0.8936	0.9982	0.8651	0.108*
C3	0.9684 (4)	0.6972 (11)	0.83885 (17)	0.0770 (14)
C4	0.9653 (4)	0.5161 (10)	0.80444 (19)	0.0862 (15)
H4A	1.0199	0.3953	0.8033	0.103*
C5	0.8804 (4)	0.5107 (9)	0.77082 (17)	0.0797 (14)
H5A	0.8785	0.3849	0.7470	0.096*
C6	0.7975 (4)	0.6878 (9)	0.77140 (16)	0.0629 (11)
C7	0.7076 (4)	0.6872 (8)	0.73439 (15)	0.0688 (12)
H7A	0.6578	0.8227	0.7432	0.083*
C8	0.7444 (3)	0.7495 (9)	0.68373 (16)	0.0755 (13)
H8A	0.7809	0.9134	0.6845	0.091*
H8B	0.7954	0.6209	0.6742	0.091*
C9	0.6519 (4)	0.7592 (9)	0.64663 (17)	0.0804 (14)
H9A	0.6062	0.9037	0.6536	0.097*
H9B	0.6798	0.7858	0.6148	0.097*
C10	0.5855 (4)	0.5191 (8)	0.64593 (15)	0.0702 (13)
H10A	0.6335	0.3817	0.6362	0.084*
C11	0.5513 (4)	0.4491 (9)	0.69603 (15)	0.0717 (13)
H11A	0.4992	0.5733	0.7064	0.086*
H11B	0.5166	0.2831	0.6948	0.086*
C12	0.6447 (4)	0.4409 (8)	0.73259 (15)	0.0733 (13)
H12A	0.6923	0.3018	0.7245	0.088*
H12B	0.6181	0.4065	0.7644	0.088*
C13	0.4943 (4)	0.5236 (8)	0.60875 (15)	0.0643 (12)
C14	0.4907 (4)	0.3631 (9)	0.57091 (15)	0.0650 (12)
C15	0.4017 (4)	0.3550 (9)	0.53425 (16)	0.0680 (12)
C16	0.3126 (4)	0.5309 (9)	0.53922 (16)	0.0689 (13)
C17	0.2270 (5)	0.5268 (11)	0.50559 (18)	0.0920 (16)
H17A	0.2253	0.4109	0.4800	0.110*
C18	0.1439 (5)	0.6988 (13)	0.5107 (2)	0.1067 (19)
H18A	0.0859	0.6995	0.4883	0.128*
C19	0.1465 (5)	0.8677 (12)	0.5485 (2)	0.1039 (19)
H19A	0.0898	0.9815	0.5517	0.125*
C20	0.2316 (4)	0.8713 (10)	0.58182 (18)	0.0874 (15)
H20A	0.2326	0.9858	0.6076	0.105*
C21	0.3157 (4)	0.7034 (8)	0.57674 (16)	0.0670 (12)
C22	0.4073 (4)	0.7072 (9)	0.61334 (17)	0.0687 (12)
H1O1	0.555 (5)	0.118 (12)	0.536 (2)	0.17 (3)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1	0.0958 (11)	0.1687 (16)	0.0865 (10)	−0.0157 (10)	−0.0050 (8)	−0.0063 (10)
O1	0.094 (3)	0.088 (2)	0.064 (2)	0.026 (2)	0.0025 (18)	−0.0110 (19)
O2	0.105 (3)	0.094 (3)	0.064 (2)	0.024 (2)	0.0005 (18)	−0.0170 (19)
O3	0.098 (3)	0.090 (3)	0.097 (3)	0.012 (2)	0.012 (2)	−0.029 (2)
C1	0.093 (4)	0.069 (3)	0.083 (3)	0.014 (3)	0.019 (3)	−0.005 (3)
C2	0.109 (4)	0.091 (4)	0.070 (3)	−0.009 (4)	0.007 (3)	−0.017 (3)
C3	0.071 (3)	0.090 (4)	0.071 (3)	−0.002 (3)	0.016 (3)	0.005 (3)
C4	0.073 (4)	0.089 (4)	0.096 (4)	0.011 (3)	0.007 (3)	−0.013 (3)
C5	0.077 (4)	0.075 (3)	0.086 (4)	0.004 (3)	0.000 (3)	−0.017 (3)
C6	0.063 (3)	0.058 (3)	0.068 (3)	0.001 (3)	0.010 (2)	0.008 (2)
C7	0.072 (3)	0.061 (3)	0.074 (3)	−0.004 (3)	0.011 (2)	0.004 (2)
C8	0.069 (3)	0.078 (3)	0.081 (3)	−0.006 (3)	0.014 (3)	0.015 (3)
C9	0.082 (3)	0.083 (4)	0.077 (3)	−0.005 (3)	0.011 (3)	0.017 (3)
C10	0.088 (3)	0.062 (3)	0.062 (3)	0.005 (3)	0.014 (3)	−0.004 (2)
C11	0.081 (3)	0.065 (3)	0.069 (3)	−0.011 (3)	0.014 (3)	0.004 (2)
C12	0.087 (3)	0.073 (3)	0.061 (3)	−0.009 (3)	0.009 (3)	0.000 (2)
C13	0.079 (3)	0.063 (3)	0.053 (3)	0.002 (3)	0.015 (2)	−0.001 (2)
C14	0.077 (3)	0.065 (3)	0.054 (3)	0.012 (3)	0.014 (2)	0.002 (2)
C15	0.082 (3)	0.070 (3)	0.053 (3)	0.006 (3)	0.015 (3)	0.005 (2)
C16	0.075 (3)	0.081 (3)	0.051 (3)	0.015 (3)	0.008 (3)	0.009 (3)
C17	0.103 (4)	0.103 (4)	0.071 (3)	0.020 (4)	0.003 (3)	0.007 (3)
C18	0.096 (4)	0.144 (6)	0.079 (4)	0.029 (4)	−0.010 (3)	0.014 (4)
C19	0.100 (5)	0.120 (5)	0.092 (4)	0.040 (4)	0.010 (4)	0.013 (4)
C20	0.099 (4)	0.088 (4)	0.077 (4)	0.022 (3)	0.022 (3)	0.008 (3)
C21	0.081 (3)	0.058 (3)	0.064 (3)	0.008 (3)	0.021 (3)	0.004 (2)
C22	0.077 (3)	0.063 (3)	0.067 (3)	0.000 (3)	0.017 (3)	0.002 (3)

Geometric parameters (Å, º)

Cl1—C3	1.728 (5)	C9—H9B	0.9700
O1—C14	1.328 (5)	C10—C13	1.497 (6)
O1—H1O1	0.89 (6)	C10—C11	1.512 (6)
O2—C15	1.216 (5)	C10—H10A	0.9800
O3—C22	1.217 (5)	C11—C12	1.506 (6)
C1—C6	1.366 (6)	C11—H11A	0.9700
C1—C2	1.380 (6)	C11—H11B	0.9700
C1—H1A	0.9300	C12—H12A	0.9700
C2—C3	1.343 (6)	C12—H12B	0.9700
C2—H2A	0.9300	C13—C14	1.340 (6)
C3—C4	1.342 (6)	C13—C22	1.457 (6)
C4—C5	1.376 (6)	C14—C15	1.468 (6)
C4—H4A	0.9300	C15—C16	1.453 (6)
C5—C6	1.387 (6)	C16—C21	1.374 (6)
C5—H5A	0.9300	C16—C17	1.382 (6)
C6—C7	1.481 (6)	C17—C18	1.383 (7)
C7—C12	1.507 (6)	C17—H17A	0.9300
C7—C8	1.528 (6)	C18—C19	1.367 (7)
C7—H7A	0.9800	C18—H18A	0.9300
C8—C9	1.508 (6)	C19—C20	1.372 (7)
C8—H8A	0.9700	C19—H19A	0.9300
C8—H8B	0.9700	C20—C21	1.378 (6)
C9—C10	1.503 (6)	C20—H20A	0.9300
C9—H9A	0.9700	C21—C22	1.490 (6)
C14—O1—H1O1	107 (4)	C12—C11—C10	112.4 (4)
C6—C1—C2	122.4 (5)	C12—C11—H11A	109.1
C6—C1—H1A	118.8	C10—C11—H11A	109.1
C2—C1—H1A	118.8	C12—C11—H11B	109.1
C3—C2—C1	119.1 (5)	C10—C11—H11B	109.1
C3—C2—H2A	120.5	H11A—C11—H11B	107.9
C1—C2—H2A	120.5	C11—C12—C7	112.4 (4)
C4—C3—C2	121.3 (5)	C11—C12—H12A	109.1
C4—C3—Cl1	120.4 (5)	C7—C12—H12A	109.1
C2—C3—Cl1	118.3 (5)	C11—C12—H12B	109.1
C3—C4—C5	119.3 (5)	C7—C12—H12B	109.1
C3—C4—H4A	120.3	H12A—C12—H12B	107.8
C5—C4—H4A	120.3	C14—C13—C22	118.9 (4)
C4—C5—C6	121.9 (5)	C14—C13—C10	121.5 (4)
C4—C5—H5A	119.1	C22—C13—C10	119.6 (4)
C6—C5—H5A	119.1	O1—C14—C13	121.1 (5)
C1—C6—C5	116.0 (4)	O1—C14—C15	115.3 (4)
C1—C6—C7	122.0 (5)	C13—C14—C15	123.6 (5)
C5—C6—C7	122.0 (4)	O2—C15—C16	122.9 (4)
C6—C7—C12	113.5 (4)	O2—C15—C14	118.9 (4)
C6—C7—C8	112.6 (4)	C16—C15—C14	118.2 (4)
C12—C7—C8	109.2 (4)	C21—C16—C17	120.8 (5)
C6—C7—H7A	107.0	C21—C16—C15	119.4 (4)
C12—C7—H7A	107.0	C17—C16—C15	119.7 (5)
C8—C7—H7A	107.0	C16—C17—C18	118.5 (5)
C9—C8—C7	112.3 (4)	C16—C17—H17A	120.7
C9—C8—H8A	109.1	C18—C17—H17A	120.7
C7—C8—H8A	109.1	C19—C18—C17	120.5 (5)
C9—C8—H8B	109.1	C19—C18—H18A	119.7
C7—C8—H8B	109.1	C17—C18—H18A	119.7
H8A—C8—H8B	107.9	C18—C19—C20	120.8 (5)
C10—C9—C8	112.5 (4)	C18—C19—H19A	119.6
C10—C9—H9A	109.1	C20—C19—H19A	119.6
C8—C9—H9A	109.1	C19—C20—C21	119.3 (5)
C10—C9—H9B	109.1	C19—C20—H20A	120.3
C8—C9—H9B	109.1	C21—C20—H20A	120.3
H9A—C9—H9B	107.8	C16—C21—C20	120.0 (5)
C13—C10—C9	113.3 (4)	C16—C21—C22	121.1 (4)
C13—C10—C11	113.4 (4)	C20—C21—C22	118.9 (5)
C9—C10—C11	111.6 (4)	O3—C22—C13	122.5 (5)
C13—C10—H10A	106.0	O3—C22—C21	118.8 (5)
C9—C10—H10A	106.0	C13—C22—C21	118.7 (4)
C11—C10—H10A	106.0
C6—C1—C2—C3	0.3 (8)	C22—C13—C14—C15	−2.2 (6)
C1—C2—C3—C4	0.0 (8)	C10—C13—C14—C15	178.2 (4)
C1—C2—C3—Cl1	179.6 (4)	O1—C14—C15—O2	−0.5 (6)
C2—C3—C4—C5	−0.1 (8)	C13—C14—C15—O2	179.8 (4)
Cl1—C3—C4—C5	−179.7 (4)	O1—C14—C15—C16	179.8 (4)
C3—C4—C5—C6	0.0 (8)	C13—C14—C15—C16	0.1 (6)
C2—C1—C6—C5	−0.4 (7)	O2—C15—C16—C21	−177.6 (4)
C2—C1—C6—C7	−178.3 (4)	C14—C15—C16—C21	2.1 (6)
C4—C5—C6—C1	0.3 (7)	O2—C15—C16—C17	0.9 (7)
C4—C5—C6—C7	178.2 (4)	C14—C15—C16—C17	−179.4 (4)
C1—C6—C7—C12	−122.9 (5)	C21—C16—C17—C18	−0.6 (7)
C5—C6—C7—C12	59.3 (5)	C15—C16—C17—C18	−179.0 (4)
C1—C6—C7—C8	112.3 (5)	C16—C17—C18—C19	−0.4 (8)
C5—C6—C7—C8	−65.4 (6)	C17—C18—C19—C20	0.4 (9)
C6—C7—C8—C9	−177.6 (4)	C18—C19—C20—C21	0.5 (8)
C12—C7—C8—C9	55.3 (5)	C17—C16—C21—C20	1.5 (7)
C7—C8—C9—C10	−54.3 (5)	C15—C16—C21—C20	180.0 (4)
C8—C9—C10—C13	−179.1 (4)	C17—C16—C21—C22	179.5 (4)
C8—C9—C10—C11	51.6 (5)	C15—C16—C21—C22	−2.1 (6)
C13—C10—C11—C12	178.9 (4)	C19—C20—C21—C16	−1.5 (7)
C9—C10—C11—C12	−51.8 (5)	C19—C20—C21—C22	−179.5 (5)
C10—C11—C12—C7	55.1 (5)	C14—C13—C22—O3	−177.5 (4)
C6—C7—C12—C11	177.8 (4)	C10—C13—C22—O3	2.1 (7)
C8—C7—C12—C11	−55.7 (5)	C14—C13—C22—C21	2.2 (6)
C9—C10—C13—C14	114.6 (5)	C10—C13—C22—C21	−178.2 (4)
C11—C10—C13—C14	−117.0 (5)	C16—C21—C22—O3	179.7 (4)
C9—C10—C13—C22	−65.0 (5)	C20—C21—C22—O3	−2.4 (6)
C11—C10—C13—C22	63.4 (5)	C16—C21—C22—C13	0.0 (6)
C22—C13—C14—O1	178.1 (4)	C20—C21—C22—C13	177.9 (4)
C10—C13—C14—O1	−1.5 (6)