The crystal structure of pirfenidone, [5-methyl-1-phenylpyridin-2(1H)-one], an active pharmaceutical ingredient (API) approved in Europe and Japan for the treatment of idiopathic pulmonary fibrosis (IPF), is reported here for the first time. It was crystallized from toluene by the temperature gradient technique, and crystallizes in the chiral monoclinic space group P21.
Keywords: crystal structure, pirfenidone, active pharmaceutical ingredient (API), idiopathic pulmonary fibrosis (IPF), hydrogen bonding
Abstract
The crystal structure of pirfenidone, C12H11NO [alternative name: 5-methyl-1-phenylpyridin-2(1H)-one], an active pharmaceutical ingredient (API) approved in Europe and Japan for the treatment of Idiopathic pulmonary fibrosis (IPF), is reported here for the first time. It was crystallized from toluene by the temperature gradient technique, and crystallizes in the chiral monoclinic space group P21. The phenyl and pyridone rings are inclined to each other by 50.30 (11)°. In the crystal, molecules are linked by C–H⋯O hydrogen bonds involving the same acceptor atom, forming undulating layers lying parallel to the ab plane.
Chemical context
Idiopathic Pulmonary Fibrosis (IPF) is a lung disease characterized by cough, scars and dyspnea that leads to progressive and irreversible loss of lung function. Pirfenidone (systematic name: 5-methyl-1-phenyl-1H-pyridin-2-one) has been approved in Japan since 2008 (Pirespa®) and in Europe since 2011 (Esbriet®) for the treatment of IPF, even if its mechanism of action has not been completely elucidated (Richeldi et al., 2011 ▸). Different synthetic approaches have been reported, mainly relying on N-arylation reactions of 5-methyl-2-pyridone (Liu et al., 2009 ▸; Crifar et al., 2014 ▸; Jung et al., 2016 ▸; Falb et al., 2017 ▸). Pirfenidone has been known since 1974 (Gadekar, 1974 ▸) and its antifibrotic properties were described in 1990 (Margolin, 1990 ▸). Nevertheless, despite its formulation as oral tablets, no information on the solid-state structure of this compound has been reported to date. In the present study, we report and analyse the crystal structure of pirfenidone.
Structural commentary
The molecular structure of pirfenidone is shown in Fig. 1 ▸. This axially chiral molecule crystallizes in the monoclinic space group P21, with one molecule in a general position. The molecule is far from planar with the phenyl (C7–C12) and pyridinone (N1/C1–C5) rings subtending a dihedral angle of 50.30 (11)°.
Figure 1.
A view of the molecular structure of pirfenidone with the atom labelling. Displacement ellipsoids are drawn at the 50% probability level.
Supramolecular features
In the crystal, molecules are linked by C—H⋯O hydrogen bonds involving the same acceptor atom (Table 1 ▸), forming an undulating network, enclosing 
(20) ring motifs, and lying parallel to the ab plane (Figs. 2 ▸ and 3 ▸). The (20) ring motifs are clearly visible in Fig. 3 ▸. There are no other significant intermolecular contacts present according to the analysis of the crystal structure using PLATON (Spek, 2009 ▸).
Table 1. Hydrogen-bond geometry (Å, °).
| D—H⋯A | D—H | H⋯A | D⋯A | D—H⋯A |
|---|---|---|---|---|
| C8—H8⋯O1i | 0.93 | 2.33 | 3.203 (3) | 156 |
| C10—H10⋯O1ii | 0.93 | 2.46 | 3.310 (3) | 152 |
Symmetry codes: (i) 
; (ii) 
.
Figure 2.
A view along the a axis of the crystal packing of pirfenidone. The C—H⋯O hydrogen bonds (see Table 1 ▸) are shown as dashed lines.
Figure 3.
A view along the c axis of the crystal packing of pirfenidone. The C—H⋯O hydrogen bonds (see Table 1 ▸) are shown as dashed lines.
Database Survey
A search of the Cambridge Structural Database (CSD, Version 5.40, February 2019; Groom et al., 2016 ▸) for 1-phenylpyridin-2(1H)-ones, excluding structures with ring atoms being included in further cyclic moieties, gave 40 hits (see supporting information file S1). Only six of these compounds involve an unsubstituted phenyl ring as in the title compound. When considering compounds with no substituent in position-6 of the pyridinone ring (on atom C5 in the title compound; Fig. 1 ▸) only three structures fit this extra criteria, viz. S-ethyl 2-oxo-1-phenyl-1,2-dihydro-3-pyridinecarbothioate (CSD refcode NOLBIA; Liu et al., 2008 ▸), monoclinic space group P21, 4-chloro-6-oxo-1-phenyl-1,6-dihydropyridine-3-carbaldehyde (QIWFIM; Xiang et al., 2008 ▸), monoclinic space group P21/c, and methyl 5-benzoyl-2-oxo-1-phenyl-1,2-dihydropyridine-4-carboxylate (TEMKIH; Shao et al., 2012 ▸), orthorhombic space group Pna21 with two independent molecules in the asymmetric unit. In these three compounds, the phenyl ring is inclined to the pyridone ring by ca 65.50, 64.66 and 55.83/57.12°, respectively. This dihedral angle in the title compound, pirfenidone, is 50.30 (11)°. In the other three compounds [AQIKIV (Gorobets et al., 2010 ▸), BAFPUV (Dyachenko et al., 2011 ▸) and WEDCEP (Allais et al., 2012 ▸) – see supporting information file S1] with a substituent in position-6 of the pyridinone ring the corresponding dihedral angle varies from ca 73.02 to 89.28° as a result of steric hindrance.
Synthesis and crystallization
Pirfenidone was obtained in > 99.5% purity according to the method published previously (Mossotti et al., 2018 ▸). Single crystals were grown in the following way: approximately 100 mg of pirfenidone in 2 mL of toluene was heated until complete dissolution. The flask with this solution was then closed and kept at 273–278 K. Well-formed colourless crystals of pirfenidone were obtained after 1 week. The melting point of this crystal form, determined by DSC analysis (heating rate 10 K min−1), is 383 K. This crystallization procedure must be performed in order to grow single crystals suitable for X-ray diffraction analysis and not with the aim of increasing the purity of the product. It is worth nothing that the industrial process is already optimized for the isolation of a pure API (> 99.5%) and a further crystallization step is not needed to improve its purity. We performed several other crystallization trials in order to search for other possible forms of pirfenidone; however, each crystallization attempt gave rise to the same crystal form.
Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2 ▸. The H atoms were included in calculated positions and treated as riding: C—H = 0.93–0.96 Å with U iso(H) = 1.5U eq(C-methyl) and 1.2U eq(C) for other H atoms.
Table 2. Experimental details.
| Crystal data | |
| Chemical formula | C12H11NO |
| M r | 185.22 |
| Crystal system, space group | Monoclinic, P21 |
| Temperature (K) | 293 |
| a, b, c (Å) | 6.2525 (8), 7.797 (1), 10.2810 (13) |
| β (°) | 104.744 (2) |
| V (Å3) | 484.70 (11) |
| Z | 2 |
| Radiation type | Mo Kα |
| μ (mm−1) | 0.08 |
| Crystal size (mm) | 0.50 × 0.45 × 0.05 |
| Data collection | |
| Diffractometer | Bruker SMART APEX CCD |
| Absorption correction | Multi-scan (SADABS; Bruker, 2010 ▸) |
| T min, T max | 0.692, 0.746 |
| No. of measured, independent and observed [I > 2σ(I)] reflections | 4547, 2128, 1879 |
| R int | 0.019 |
| (sin θ/λ)max (Å−1) | 0.643 |
| Refinement | |
| R[F 2 > 2σ(F 2)], wR(F 2), S | 0.037, 0.095, 1.04 |
| No. of reflections | 2128 |
| No. of parameters | 127 |
| No. of restraints | 1 |
| H-atom treatment | H-atom parameters constrained |
| Δρmax, Δρmin (e Å−3) | 0.11, −0.20 |
| Absolute structure | Flack x determined using 762 quotients [(I +)−(I −)]/[(I +)+(I −)] (Parsons et al., 2013 ▸) |
| Absolute structure parameter | 0.3 (4) |
Supplementary Material
Crystal structure: contains datablock(s) Pirfenidone, Global. DOI: 10.1107/S2056989019006418/tx2011sup1.cif
CSD search results. DOI: 10.1107/S2056989019006418/tx2011sup3.pdf
CCDC reference: 1914224
Additional supporting information: crystallographic information; 3D view; checkCIF report
Acknowledgments
VC gratefully acknowledges Professor H. Stoeckli-Evans for her helpful and valuable suggestions.
supplementary crystallographic information
Crystal data
| C12H11NO | Dx = 1.269 Mg m−3 |
| Mr = 185.22 | Melting point: 375 K |
| Monoclinic, P21 | Mo Kα radiation, λ = 0.71073 Å |
| a = 6.2525 (8) Å | Cell parameters from 2547 reflections |
| b = 7.797 (1) Å | θ = 3.3–27.2° |
| c = 10.2810 (13) Å | µ = 0.08 mm−1 |
| β = 104.744 (2)° | T = 293 K |
| V = 484.70 (11) Å3 | Plate, colourless |
| Z = 2 | 0.50 × 0.45 × 0.05 mm |
| F(000) = 196 |
Data collection
| Bruker SMART APEX CCD diffractometer | 1879 reflections with I > 2σ(I) |
| ω scans | Rint = 0.019 |
| Absorption correction: multi-scan (SADABS; Bruker, 2010) | θmax = 27.2°, θmin = 2.1° |
| Tmin = 0.692, Tmax = 0.746 | h = −8→8 |
| 4547 measured reflections | k = −9→10 |
| 2128 independent reflections | l = −13→13 |
Refinement
| Refinement on F2 | Hydrogen site location: inferred from neighbouring sites |
| Least-squares matrix: full | H-atom parameters constrained |
| R[F2 > 2σ(F2)] = 0.037 | w = 1/[σ2(Fo2) + (0.0528P)2 + 0.0476P] where P = (Fo2 + 2Fc2)/3 |
| wR(F2) = 0.095 | (Δ/σ)max < 0.001 |
| S = 1.04 | Δρmax = 0.11 e Å−3 |
| 2128 reflections | Δρmin = −0.20 e Å−3 |
| 127 parameters | Absolute structure: Flack x determined using 762 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013) |
| 1 restraint | Absolute structure parameter: 0.3 (4) |
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. |
| Refinement. none |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)
| x | y | z | Uiso*/Ueq | ||
| N1 | 0.7599 (2) | 0.5275 (2) | 0.62509 (16) | 0.0382 (4) | |
| O1 | 1.0951 (2) | 0.6634 (3) | 0.69330 (17) | 0.0602 (5) | |
| C1 | 0.9386 (3) | 0.6188 (3) | 0.6002 (2) | 0.0437 (5) | |
| C5 | 0.5769 (3) | 0.4849 (3) | 0.5233 (2) | 0.0395 (5) | |
| H5 | 0.460421 | 0.428046 | 0.545647 | 0.047* | |
| C7 | 0.7635 (3) | 0.4782 (3) | 0.76141 (19) | 0.0401 (5) | |
| C4 | 0.5595 (3) | 0.5219 (3) | 0.3929 (2) | 0.0430 (5) | |
| C12 | 0.9445 (4) | 0.3913 (3) | 0.8390 (2) | 0.0497 (5) | |
| H12 | 1.066616 | 0.368712 | 0.805687 | 0.060* | |
| C8 | 0.5830 (3) | 0.5134 (3) | 0.8108 (2) | 0.0481 (5) | |
| H8 | 0.462114 | 0.572084 | 0.758231 | 0.058* | |
| C6 | 0.3599 (4) | 0.4732 (3) | 0.2835 (2) | 0.0579 (6) | |
| H6A | 0.400128 | 0.387266 | 0.227127 | 0.087* | |
| H6B | 0.304346 | 0.572565 | 0.230447 | 0.087* | |
| H6C | 0.247695 | 0.428652 | 0.322817 | 0.087* | |
| C11 | 0.9409 (5) | 0.3383 (3) | 0.9672 (2) | 0.0616 (7) | |
| H11 | 1.061057 | 0.278817 | 1.019737 | 0.074* | |
| C3 | 0.7416 (4) | 0.6079 (3) | 0.3637 (2) | 0.0527 (6) | |
| H3 | 0.737708 | 0.633055 | 0.274701 | 0.063* | |
| C2 | 0.9189 (4) | 0.6537 (3) | 0.4608 (2) | 0.0540 (6) | |
| H2 | 1.033979 | 0.710617 | 0.436893 | 0.065* | |
| C9 | 0.5836 (4) | 0.4604 (4) | 0.9395 (2) | 0.0623 (7) | |
| H9 | 0.462501 | 0.484254 | 0.973553 | 0.075* | |
| C10 | 0.7616 (5) | 0.3728 (4) | 1.0174 (2) | 0.0649 (7) | |
| H10 | 0.760634 | 0.337171 | 1.103577 | 0.078* |
Atomic displacement parameters (Å2)
| U11 | U22 | U33 | U12 | U13 | U23 | |
| N1 | 0.0355 (8) | 0.0426 (9) | 0.0362 (8) | 0.0009 (8) | 0.0084 (7) | 0.0007 (7) |
| O1 | 0.0399 (8) | 0.0725 (11) | 0.0631 (11) | −0.0111 (8) | 0.0038 (7) | −0.0046 (9) |
| C1 | 0.0368 (10) | 0.0430 (12) | 0.0524 (12) | 0.0007 (9) | 0.0134 (9) | −0.0023 (10) |
| C5 | 0.0380 (9) | 0.0395 (11) | 0.0398 (10) | −0.0026 (9) | 0.0078 (8) | 0.0011 (9) |
| C7 | 0.0411 (10) | 0.0397 (11) | 0.0362 (10) | −0.0013 (8) | 0.0034 (8) | 0.0002 (8) |
| C4 | 0.0524 (11) | 0.0376 (11) | 0.0376 (10) | −0.0009 (10) | 0.0087 (9) | −0.0001 (9) |
| C12 | 0.0496 (12) | 0.0478 (12) | 0.0459 (12) | 0.0081 (10) | 0.0017 (10) | −0.0051 (10) |
| C8 | 0.0395 (10) | 0.0602 (13) | 0.0435 (11) | −0.0003 (10) | 0.0082 (8) | 0.0070 (11) |
| C6 | 0.0705 (15) | 0.0570 (15) | 0.0399 (11) | −0.0077 (13) | 0.0026 (11) | −0.0004 (11) |
| C11 | 0.0708 (16) | 0.0522 (14) | 0.0469 (13) | 0.0053 (12) | −0.0126 (12) | 0.0046 (11) |
| C3 | 0.0694 (15) | 0.0522 (14) | 0.0410 (11) | −0.0091 (11) | 0.0224 (11) | 0.0002 (10) |
| C2 | 0.0559 (13) | 0.0556 (14) | 0.0576 (14) | −0.0113 (12) | 0.0276 (11) | −0.0015 (11) |
| C9 | 0.0595 (14) | 0.0851 (19) | 0.0450 (13) | −0.0110 (13) | 0.0183 (11) | 0.0036 (13) |
| C10 | 0.0826 (19) | 0.0688 (17) | 0.0378 (12) | −0.0134 (16) | 0.0054 (12) | 0.0103 (12) |
Geometric parameters (Å, º)
| N1—C5 | 1.381 (2) | C8—C9 | 1.386 (3) |
| N1—C1 | 1.402 (2) | C8—H8 | 0.9300 |
| N1—C7 | 1.448 (3) | C6—H6A | 0.9600 |
| O1—C1 | 1.232 (3) | C6—H6B | 0.9600 |
| C1—C2 | 1.432 (3) | C6—H6C | 0.9600 |
| C5—C4 | 1.349 (3) | C11—C10 | 1.375 (4) |
| C5—H5 | 0.9300 | C11—H11 | 0.9300 |
| C7—C8 | 1.378 (3) | C3—C2 | 1.338 (3) |
| C7—C12 | 1.384 (3) | C3—H3 | 0.9300 |
| C4—C3 | 1.417 (3) | C2—H2 | 0.9300 |
| C4—C6 | 1.501 (3) | C9—C10 | 1.376 (4) |
| C12—C11 | 1.386 (4) | C9—H9 | 0.9300 |
| C12—H12 | 0.9300 | C10—H10 | 0.9300 |
| C5—N1—C1 | 121.93 (17) | C4—C6—H6A | 109.5 |
| C5—N1—C7 | 118.39 (16) | C4—C6—H6B | 109.5 |
| C1—N1—C7 | 119.67 (16) | H6A—C6—H6B | 109.5 |
| O1—C1—N1 | 120.88 (19) | C4—C6—H6C | 109.5 |
| O1—C1—C2 | 124.9 (2) | H6A—C6—H6C | 109.5 |
| N1—C1—C2 | 114.20 (18) | H6B—C6—H6C | 109.5 |
| C4—C5—N1 | 122.94 (19) | C10—C11—C12 | 120.7 (2) |
| C4—C5—H5 | 118.5 | C10—C11—H11 | 119.7 |
| N1—C5—H5 | 118.5 | C12—C11—H11 | 119.7 |
| C8—C7—C12 | 120.74 (19) | C2—C3—C4 | 121.7 (2) |
| C8—C7—N1 | 119.42 (17) | C2—C3—H3 | 119.1 |
| C12—C7—N1 | 119.81 (19) | C4—C3—H3 | 119.1 |
| C5—C4—C3 | 116.47 (19) | C3—C2—C1 | 122.6 (2) |
| C5—C4—C6 | 122.2 (2) | C3—C2—H2 | 118.7 |
| C3—C4—C6 | 121.4 (2) | C1—C2—H2 | 118.7 |
| C7—C12—C11 | 119.0 (2) | C10—C9—C8 | 120.6 (2) |
| C7—C12—H12 | 120.5 | C10—C9—H9 | 119.7 |
| C11—C12—H12 | 120.5 | C8—C9—H9 | 119.7 |
| C7—C8—C9 | 119.3 (2) | C11—C10—C9 | 119.7 (2) |
| C7—C8—H8 | 120.4 | C11—C10—H10 | 120.2 |
| C9—C8—H8 | 120.4 | C9—C10—H10 | 120.2 |
Hydrogen-bond geometry (Å, º)
| D—H···A | D—H | H···A | D···A | D—H···A |
| C8—H8···O1i | 0.93 | 2.33 | 3.203 (3) | 156 |
| C10—H10···O1ii | 0.93 | 2.46 | 3.310 (3) | 152 |
Symmetry codes: (i) x−1, y, z; (ii) −x+2, y−1/2, −z+2.
Funding Statement
This work was funded by Università degli Studi di Milano grant PSR2018_DIP_005_COLOMBO_VALENTINA to Valentina Colombo.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Crystal structure: contains datablock(s) Pirfenidone, Global. DOI: 10.1107/S2056989019006418/tx2011sup1.cif
CSD search results. DOI: 10.1107/S2056989019006418/tx2011sup3.pdf
CCDC reference: 1914224
Additional supporting information: crystallographic information; 3D view; checkCIF report