Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270110009339/mx3027sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270110009339/mx3027Isup2.hkl |
CCDC reference: 779961
RWJ-416457 (75.4 mg; 0.20 mol) was added to DMSO (1 ml, 0.63 mol) in water at 353 K. Malonic acid (1.186 g, 11.39 mol) was added to the solution to increase the solubility of (I). The solution of (I) and malonic acid was passed through a 0.2 µm filter and the filtrate was left to cool in a glass vial at room temperature. Single crystals of the title compound appeared after 1 d.
Structure determination of (I) was initiated in space group P21 as indicated from the observed metric constants, intensity statistics and systematic absences. Subsequent structure solution and refinement confirmed this choice; however, least-squares refinement failed to improve R1 < 17% for F2 > 2σ(F2). Twinning was suspected, and close inspection of the frames for the full data collection revealed a number of extra reflections that did not overlap with the original unit cell. Domain searching analysis using ROTAX (Cooper et al., 2002) revealed a twin law [0.998 0 -0.005/0 -1 0/ -0.999 0 -0.998] as well as an optimized `twin tolerance' parameter of 0.022 Å-1, which identified the overlapping and separate reflections from the two domains (Cooper et al., 2002). The analysis and successful refinement demonstrated that the crystal was a twin lattice quasi-symmetry twin (Donnay & Donnay, 1974; Giacovazzo, 1992) with a rotation about [102] and small twin obliquity (Donnay & Donnay, 1972), ω = 0.46o. Scale factors for the two twin components were constrained to sum to 1.0, with the value of the major twin component scale refining to 0.8037 (17). Least-squares refinement of the data on F2 using this twin law led to significant improvement [R1 = 4.9% for F2 > 2σ(F2)]. In an attempt to improve the data, CELL_NOW (Sheldrick, 2003) was run on the original data, yielding a numerically identical twin law. The data were integrated using the two-domain .p4p file, and TWINABS (Sheldrick, 2002) was used to generate HKLF4 and HKLF5 files. The refinement using these files was not significantly different, with marginally higher R vales, from that using the ROTAX procedure described above, and thus the original refinement was retained. The molecules are ordered and closely packed (Kitaigorodskii packing index KPI = 71.4%) (Spek, 2009).
All non-H atoms were refined using anisotropic displacement parameters. After location on an electron density difference map, the H atoms were first regularized with the use of restraints and subsequently allowed to ride on the corresponding C or N atoms, with C—H distances in the range 0.93–0.98 Å and N—H distances of 0.86 Å [0.92–1.00 and 0.87 Å according to CIF].
Data collection: APEX2 (Bruker, 2006); cell refinement: APEX2 (Bruker, 2006); data reduction: APEX2 (Bruker, 2006); program(s) used to solve structure: SHELXS86 (Sheldrick, 2008); program(s) used to refine structure: CRYSTALS (Betteridge et al., 2003); molecular graphics: DIAMOND (Crystal Impact, 2009); software used to prepare material for publication: publCIF (Westrip, 2010).
C18H20FN5O3 | F(000) = 392 |
Mr = 373.39 | Dx = 1.444 Mg m−3 |
Monoclinic, P21 | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: P 2yb | Cell parameters from 1377 reflections |
a = 4.8358 (17) Å | θ = 2–22° |
b = 10.293 (4) Å | µ = 0.11 mm−1 |
c = 17.403 (6) Å | T = 150 K |
β = 97.524 (10)° | Acicular, colourless |
V = 858.7 (5) Å3 | 0.31 × 0.04 × 0.01 mm |
Z = 2 |
Area diffractometer | 1180 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.041 |
ϕ & ω scans | θmax = 26.0°, θmin = 2.3° |
Absorption correction: multi-scan (APEX2; Bruker, 2006) | h = −6→5 |
Tmin = 1.00, Tmax = 1.00 | k = −12→11 |
5186 measured reflections | l = −22→21 |
1725 independent reflections |
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.049 | H-atom parameters constrained |
wR(F2) = 0.087 | Method = Modified Sheldrick
w = 1/[σ2(F2) + (0.02P)2 + 0.59P], where P = [max(Fo2,0) + 2Fc2]/3 |
S = 0.96 | (Δ/σ)max = 0.001 |
1725 reflections | Δρmax = 0.52 e Å−3 |
245 parameters | Δρmin = −0.49 e Å−3 |
1 restraint |
C18H20FN5O3 | V = 858.7 (5) Å3 |
Mr = 373.39 | Z = 2 |
Monoclinic, P21 | Mo Kα radiation |
a = 4.8358 (17) Å | µ = 0.11 mm−1 |
b = 10.293 (4) Å | T = 150 K |
c = 17.403 (6) Å | 0.31 × 0.04 × 0.01 mm |
β = 97.524 (10)° |
Area diffractometer | 1725 independent reflections |
Absorption correction: multi-scan (APEX2; Bruker, 2006) | 1180 reflections with I > 2σ(I) |
Tmin = 1.00, Tmax = 1.00 | Rint = 0.041 |
5186 measured reflections |
R[F2 > 2σ(F2)] = 0.049 | 1 restraint |
wR(F2) = 0.087 | H-atom parameters constrained |
S = 0.96 | Δρmax = 0.52 e Å−3 |
1725 reflections | Δρmin = −0.49 e Å−3 |
245 parameters |
Experimental. Data collection: Data collection, integration, scaling, and absorption corrections were carried out using the Bruker Apex2 software (Bruker AXS, 2006). Refinement (full-matrix-least squares) was performed using the Oxford University Crystals for Windows software (Betteridge et al., 2003). |
x | y | z | Uiso*/Ueq | ||
F1 | 0.6810 (8) | 0.4098 (4) | 0.6734 (2) | 0.0489 | |
O1 | 0.1398 (9) | 0.4902 (4) | 0.8753 (2) | 0.0366 | |
O2 | 0.0443 (8) | 0.6627 (4) | 0.9470 (2) | 0.0306 | |
O3 | 0.2756 (9) | 0.5529 (4) | 1.1278 (2) | 0.0415 | |
N1 | 1.0014 (11) | 0.6160 (5) | 0.6173 (3) | 0.0263 | |
N2 | 1.3050 (11) | 0.4938 (5) | 0.4523 (3) | 0.0358 | |
N3 | 1.4481 (11) | 0.5937 (5) | 0.4255 (3) | 0.0299 | |
N4 | 0.3617 (9) | 0.6869 (5) | 0.8651 (3) | 0.0249 | |
N5 | 0.1920 (10) | 0.7670 (5) | 1.1065 (3) | 0.0283 | |
C1 | 0.6851 (13) | 0.5326 (6) | 0.7062 (3) | 0.0272 | |
C2 | 0.8437 (11) | 0.6298 (6) | 0.6780 (3) | 0.0250 | |
C3 | 0.8335 (12) | 0.7489 (6) | 0.7177 (3) | 0.0268 | |
C4 | 0.6748 (11) | 0.7675 (6) | 0.7777 (3) | 0.0260 | |
C5 | 0.5189 (11) | 0.6654 (6) | 0.8024 (3) | 0.0215 | |
C6 | 0.5250 (12) | 0.5458 (6) | 0.7654 (4) | 0.0268 | |
C7 | 1.0134 (13) | 0.4999 (6) | 0.5695 (3) | 0.0295 | |
C8 | 1.2000 (12) | 0.5472 (6) | 0.5127 (4) | 0.0248 | |
C9 | 1.2786 (11) | 0.6748 (6) | 0.5253 (3) | 0.0267 | |
C10 | 1.1540 (13) | 0.7292 (6) | 0.5928 (3) | 0.0316 | |
C11 | 1.4414 (13) | 0.7028 (6) | 0.4682 (3) | 0.0318 | |
C12 | 1.6037 (13) | 0.5757 (7) | 0.3594 (4) | 0.0404 | |
C13 | 0.3350 (13) | 0.8157 (6) | 0.8974 (3) | 0.0295 | |
C14 | 0.1706 (12) | 0.7899 (6) | 0.9653 (4) | 0.0296 | |
C15 | 0.3518 (12) | 0.7833 (6) | 1.0429 (3) | 0.0305 | |
C16 | 0.1579 (12) | 0.6533 (6) | 1.1425 (3) | 0.0264 | |
C17 | −0.0372 (12) | 0.6606 (7) | 1.2047 (3) | 0.0370 | |
C25 | 0.1838 (12) | 0.6025 (7) | 0.8928 (3) | 0.0267 | |
H31 | 0.9483 | 0.8223 | 0.7036 | 0.0330* | |
H41 | 0.6719 | 0.8457 | 0.8025 | 0.0325* | |
H51 | 0.0992 | 0.8340 | 1.1188 | 0.0338* | |
H61 | 0.4256 | 0.4746 | 0.7814 | 0.0317* | |
H71 | 0.8279 | 0.4752 | 0.5435 | 0.0363* | |
H72 | 1.0940 | 0.4284 | 0.6015 | 0.0355* | |
H101 | 1.2955 | 0.7595 | 0.6349 | 0.0364* | |
H102 | 1.0268 | 0.8006 | 0.5778 | 0.0359* | |
H111 | 1.5284 | 0.7808 | 0.4596 | 0.0396* | |
H121 | 1.5274 | 0.5040 | 0.3291 | 0.0618* | |
H122 | 1.5910 | 0.6543 | 0.3286 | 0.0611* | |
H123 | 1.7939 | 0.5540 | 0.3783 | 0.0615* | |
H131 | 0.2347 | 0.8730 | 0.8588 | 0.0370* | |
H132 | 0.5157 | 0.8533 | 0.9137 | 0.0368* | |
H141 | 0.0236 | 0.8563 | 0.9675 | 0.0343* | |
H151 | 0.4811 | 0.7077 | 1.0433 | 0.0367* | |
H152 | 0.4587 | 0.8644 | 1.0512 | 0.0361* | |
H171 | −0.0631 | 0.7493 | 1.2200 | 0.0570* | |
H172 | −0.2160 | 0.6253 | 1.1848 | 0.0575* | |
H173 | 0.0451 | 0.6122 | 1.2500 | 0.0571* |
U11 | U22 | U33 | U12 | U13 | U23 | |
F1 | 0.071 (3) | 0.023 (2) | 0.055 (3) | −0.0084 (19) | 0.018 (2) | −0.0093 (19) |
O1 | 0.038 (3) | 0.022 (3) | 0.048 (3) | −0.014 (2) | −0.002 (2) | 0.002 (2) |
O2 | 0.028 (2) | 0.031 (3) | 0.033 (2) | −0.011 (2) | 0.003 (2) | 0.000 (2) |
O3 | 0.052 (3) | 0.019 (3) | 0.055 (3) | 0.015 (2) | 0.016 (3) | 0.008 (2) |
N1 | 0.032 (3) | 0.018 (3) | 0.029 (3) | −0.004 (2) | 0.004 (3) | −0.004 (2) |
N2 | 0.042 (3) | 0.032 (4) | 0.035 (3) | −0.008 (3) | 0.010 (3) | −0.005 (3) |
N3 | 0.034 (3) | 0.030 (4) | 0.028 (3) | 0.005 (3) | 0.008 (3) | 0.000 (3) |
N4 | 0.025 (3) | 0.019 (3) | 0.029 (3) | −0.002 (3) | 0.000 (3) | 0.001 (2) |
N5 | 0.036 (3) | 0.018 (3) | 0.032 (3) | 0.009 (2) | 0.010 (3) | 0.001 (3) |
C1 | 0.032 (4) | 0.016 (4) | 0.033 (4) | 0.003 (3) | −0.002 (3) | −0.003 (3) |
C2 | 0.018 (3) | 0.026 (4) | 0.029 (4) | 0.002 (3) | −0.004 (3) | 0.002 (3) |
C3 | 0.026 (3) | 0.022 (4) | 0.031 (3) | −0.001 (3) | −0.002 (3) | 0.002 (3) |
C4 | 0.027 (3) | 0.018 (4) | 0.033 (4) | −0.001 (3) | 0.001 (3) | −0.004 (3) |
C5 | 0.022 (3) | 0.020 (3) | 0.022 (3) | −0.002 (3) | −0.001 (3) | 0.003 (3) |
C6 | 0.023 (3) | 0.018 (3) | 0.037 (4) | 0.001 (3) | −0.007 (3) | 0.006 (3) |
C7 | 0.032 (4) | 0.016 (3) | 0.040 (4) | 0.004 (3) | 0.005 (3) | 0.002 (3) |
C8 | 0.023 (3) | 0.020 (4) | 0.030 (4) | 0.003 (3) | 0.001 (3) | 0.003 (3) |
C9 | 0.023 (3) | 0.023 (4) | 0.034 (4) | 0.006 (3) | 0.002 (3) | −0.002 (3) |
C10 | 0.026 (4) | 0.031 (4) | 0.037 (4) | 0.000 (3) | 0.003 (3) | −0.004 (3) |
C11 | 0.032 (4) | 0.023 (4) | 0.040 (4) | 0.008 (3) | 0.003 (4) | 0.004 (3) |
C12 | 0.039 (4) | 0.046 (5) | 0.037 (4) | 0.002 (4) | 0.009 (4) | 0.000 (3) |
C13 | 0.029 (4) | 0.026 (4) | 0.034 (4) | −0.003 (3) | 0.006 (3) | 0.002 (3) |
C14 | 0.027 (3) | 0.024 (4) | 0.038 (4) | −0.004 (3) | 0.005 (3) | 0.008 (3) |
C15 | 0.030 (3) | 0.029 (4) | 0.034 (4) | −0.003 (3) | 0.009 (3) | −0.004 (3) |
C16 | 0.020 (3) | 0.028 (4) | 0.030 (4) | 0.000 (3) | 0.000 (3) | 0.001 (3) |
C17 | 0.035 (4) | 0.044 (4) | 0.033 (4) | 0.005 (4) | 0.009 (3) | 0.008 (4) |
C25 | 0.018 (3) | 0.027 (4) | 0.033 (4) | −0.003 (3) | −0.007 (3) | 0.009 (3) |
F1—C1 | 1.386 (7) | C5—C6 | 1.392 (8) |
O1—C25 | 1.206 (7) | C6—H61 | 0.939 |
O2—C14 | 1.463 (7) | C7—C8 | 1.504 (8) |
O2—C25 | 1.377 (7) | C7—H71 | 0.984 |
O3—C16 | 1.224 (7) | C7—H72 | 0.973 |
N1—C2 | 1.388 (7) | C8—C9 | 1.378 (8) |
N1—C7 | 1.462 (7) | C9—C10 | 1.498 (8) |
N1—C10 | 1.472 (7) | C9—C11 | 1.376 (8) |
N2—N3 | 1.356 (7) | C10—H101 | 0.986 |
N2—C8 | 1.343 (7) | C10—H102 | 0.972 |
N3—C11 | 1.348 (7) | C11—H111 | 0.928 |
N3—C12 | 1.466 (7) | C12—H121 | 0.953 |
N4—C5 | 1.426 (7) | C12—H122 | 0.968 |
N4—C13 | 1.453 (7) | C12—H123 | 0.961 |
N4—C25 | 1.355 (7) | C13—C14 | 1.530 (8) |
N5—C15 | 1.440 (7) | C13—H131 | 0.975 |
N5—C16 | 1.347 (7) | C13—H132 | 0.963 |
N5—H51 | 0.865 | C14—C15 | 1.512 (7) |
C1—C2 | 1.388 (8) | C14—H141 | 0.991 |
C1—C6 | 1.374 (8) | C15—H151 | 0.997 |
C2—C3 | 1.412 (8) | C15—H152 | 0.982 |
C3—C4 | 1.388 (8) | C16—C17 | 1.528 (7) |
C3—H31 | 0.987 | C17—H171 | 0.964 |
C4—C5 | 1.393 (8) | C17—H172 | 0.959 |
C4—H41 | 0.915 | C17—H173 | 0.972 |
C14—O2—C25 | 108.9 (4) | C9—C10—H101 | 113.0 |
C2—N1—C7 | 125.6 (5) | N1—C10—H101 | 111.1 |
C2—N1—C10 | 119.1 (5) | C9—C10—H102 | 112.2 |
C7—N1—C10 | 115.0 (4) | N1—C10—H102 | 110.6 |
N3—N2—C8 | 102.8 (5) | H101—C10—H102 | 108.3 |
N2—N3—C11 | 113.1 (5) | C9—C11—N3 | 106.3 (6) |
N2—N3—C12 | 120.7 (5) | C9—C11—H111 | 127.7 |
C11—N3—C12 | 126.1 (5) | N3—C11—H111 | 126.0 |
C5—N4—C13 | 121.4 (5) | N3—C12—H121 | 109.3 |
C5—N4—C25 | 126.8 (5) | N3—C12—H122 | 109.1 |
C13—N4—C25 | 110.8 (5) | H121—C12—H122 | 110.4 |
C15—N5—C16 | 124.7 (5) | N3—C12—H123 | 109.2 |
C15—N5—H51 | 116.4 | H121—C12—H123 | 107.0 |
C16—N5—H51 | 118.6 | H122—C12—H123 | 111.8 |
F1—C1—C2 | 119.4 (6) | N4—C13—C14 | 102.8 (5) |
F1—C1—C6 | 114.9 (6) | N4—C13—H131 | 110.2 |
C2—C1—C6 | 125.8 (6) | C14—C13—H131 | 112.0 |
C1—C2—N1 | 125.4 (6) | N4—C13—H132 | 110.9 |
C1—C2—C3 | 113.4 (5) | C14—C13—H132 | 112.7 |
N1—C2—C3 | 121.2 (5) | H131—C13—H132 | 108.1 |
C2—C3—C4 | 123.1 (5) | C13—C14—O2 | 103.4 (5) |
C2—C3—H31 | 119.1 | C13—C14—C15 | 113.5 (5) |
C4—C3—H31 | 117.8 | O2—C14—C15 | 109.3 (4) |
C3—C4—C5 | 120.2 (5) | C13—C14—H141 | 111.0 |
C3—C4—H41 | 121.4 | O2—C14—H141 | 110.2 |
C5—C4—H41 | 118.4 | C15—C14—H141 | 109.4 |
N4—C5—C4 | 118.9 (6) | C14—C15—N5 | 112.6 (5) |
N4—C5—C6 | 122.5 (5) | C14—C15—H151 | 109.3 |
C4—C5—C6 | 118.6 (5) | N5—C15—H151 | 107.6 |
C5—C6—C1 | 118.9 (6) | C14—C15—H152 | 109.0 |
C5—C6—H61 | 120.7 | N5—C15—H152 | 108.1 |
C1—C6—H61 | 120.4 | H151—C15—H152 | 110.1 |
N1—C7—C8 | 100.5 (5) | N5—C16—O3 | 123.2 (5) |
N1—C7—H71 | 111.8 | N5—C16—C17 | 114.3 (6) |
C8—C7—H71 | 111.7 | O3—C16—C17 | 122.4 (6) |
N1—C7—H72 | 109.7 | C16—C17—H171 | 110.9 |
C8—C7—H72 | 113.0 | C16—C17—H172 | 109.7 |
H71—C7—H72 | 109.9 | H171—C17—H172 | 108.3 |
C7—C8—N2 | 134.7 (6) | C16—C17—H173 | 108.9 |
C7—C8—C9 | 112.4 (5) | H171—C17—H173 | 108.4 |
N2—C8—C9 | 112.9 (6) | H172—C17—H173 | 110.6 |
C8—C9—C10 | 110.5 (5) | O2—C25—N4 | 110.2 (6) |
C8—C9—C11 | 104.9 (5) | O2—C25—O1 | 121.1 (5) |
C10—C9—C11 | 144.6 (6) | N4—C25—O1 | 128.6 (6) |
C9—C10—N1 | 101.6 (5) |
Experimental details
Crystal data | |
Chemical formula | C18H20FN5O3 |
Mr | 373.39 |
Crystal system, space group | Monoclinic, P21 |
Temperature (K) | 150 |
a, b, c (Å) | 4.8358 (17), 10.293 (4), 17.403 (6) |
β (°) | 97.524 (10) |
V (Å3) | 858.7 (5) |
Z | 2 |
Radiation type | Mo Kα |
µ (mm−1) | 0.11 |
Crystal size (mm) | 0.31 × 0.04 × 0.01 |
Data collection | |
Diffractometer | Area diffractometer |
Absorption correction | Multi-scan (APEX2; Bruker, 2006) |
Tmin, Tmax | 1.00, 1.00 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 5186, 1725, 1180 |
Rint | 0.041 |
(sin θ/λ)max (Å−1) | 0.617 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.049, 0.087, 0.96 |
No. of reflections | 1725 |
No. of parameters | 245 |
No. of restraints | 1 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.52, −0.49 |
Computer programs: APEX2 (Bruker, 2006), SHELXS86 (Sheldrick, 2008), CRYSTALS (Betteridge et al., 2003), DIAMOND (Crystal Impact, 2009), publCIF (Westrip, 2010).
N1—C10 | 1.472 (7) | C7—C8 | 1.504 (8) |
N2—N3 | 1.356 (7) | C8—C9 | 1.378 (8) |
N2—C8 | 1.343 (7) | C9—C11 | 1.376 (8) |
N3—C11 | 1.348 (7) |
The title compound, RWJ-416457, (I) (Foleno et al., 2007), belongs to the oxazolidinone class of compounds, which are the first new class of antibiotics in the past 30 years (Dresser & Rybak, 1998). Compound (I) is a novel antibiotic drug candidate which inhibits the growth of Gram-positive clinical pathogens, including health-care-associated methicillin-resistant Staphylococcus aureus (MRSA). Although prone to oxidation in aqueous solution, (I) is stable to oxidation as a crystalline solid. Compound (I) degrades via an oxidative mechanism in solution to give ring-opened species of the pyrrolopyrazole. The degradation is enhanced at lower pH and in the presence of metals such as copper and iron. Particular care was taken during characterization of the drug substance to analyze for trace metals. Crystals of the title compound were grown from a mixture of dimethyl sulfoxide (DMSO) and water.
Compound (I) has two carbonyl O atoms that can serve as hydrogen-bond acceptors and one secondary amide N atom that can act as a hydrogen-bond donor. It is found in the crystal structure that each molecule of (I) donates one N—H hydrogen bond to a neighbouring molecule and accepts one hydrogen bond. Together, the intermolecular interactions form (O═C—R—N—H···O ═C—R—N—H···)n linkages along the b-axis direction. The urethane carbonyl group of the oxazolidinone ring accepts the N—H hydrogen bond; the secondary amide carbonyl group is not involved in hydrogen bonding. There is no evidence of F···F short contacts, or C–H···π or π–π interactions between the aromatic rings.
Compound (I) is optically pure from the chemical synthesis, being assembled from enantiopure chiral starting material of the oxazolidinone ring (S configuration at the lone chiral centre on the molecule). This oxazolidinone ring is known to be a key component of the antibacterial properties of the compound. Unique to compound (I) is its pyrrolopyrazole ring system. A search of the Cambridge Structural Database (CSD; Version 1.11 of September 2009; Allen, 2002) for the pyrrolopyrazole ring system indicated that this moiety has not been previously characterized structurally. The rarity of this ring system is a likely contributor to the effectiveness of the molecule in combating bacteria that show resistance to other treatments (Foleno et al., 2007). This bicyclic eight-membered ring is also highly reactive, as observed from its solution chemistry in which ring opening occurs when the N1—C7 or N1—C10 bonds break. The degradation products are reactive aldehydes, which are susceptible to nucleophilic addition. Within living cells, the presence of aldehydes is undesirable, and these degradation products may alter the antibacterial nature of the compound.
One key observation for compound (I) is its long-term chemical stability as a crystalline material compared with its short solution half-life. The layers of hydrogen-bonded molecules likely act as protective barriers against oxygen attack on the bicyclic ring. Large-scale molecular motions are also forbidden in the solid state, so the cleavage of the pyrrolopyrazole ring and rearrangement to the aldehydes is less favourable. The molecule is free of such contraints in solution, resulting in rapid degradation of the compound.
The crystalline form of this compound provides further stability because of its low solubility in water. At 5.8 ng ml-1, the equilibrium solubility does not allow for significant amounts of compound to be in solution at any given time. Dissolved drug substance is a requirement for the solution-mediated degradation pathway. The crystalline drug has a further advantage because crystallization also acts as a purification step in removing metals and acid, which can persist beyond the final synthetic step, causing degradation of the drug candidate during its shelf-life. In light of the solution deficiencies of this compound, the drug in its crystalline form is therefore essential for stable storage as a drug candidiate in the clinic.