Crystal structure of pirfenidone (5-methyl-1-phenyl-1H-pyridin-2-one): an active pharmaceutical ingredient (API)

Barbero, M.; Mossotti, M.; Sironi, A.; Giovenzana, G.B.; Colombo, V.

doi:10.1107/S2056989019006418

research communications

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ISSN: 2056-9890

Volume 75| Part 7| July 2019| Pages 984-986

https://doi.org/10.1107/S2056989019006418

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Crystal structure of pirfenidone (5-methyl-1-phenyl-1H-pyridin-2-one): an active pharmaceutical ingredient (API)

Mauro Barbero,^a,^b Matteo Mossotti,^b Angelo Sironi,^c Giovanni Battista Giovenzana ^a and Valentina Colombo ^c ^*

^aDipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2/3, I-28100, Novara, Italy, ^bR&D Division, PROCOS S.p.A., Via G. Matteotti 249, 28062 Cameri (Novara), Italy, and ^cDipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, I-20133 Milano, Italy
^*Correspondence e-mail: valentina.colombo@unimi.it

Edited by B. Therrien, University of Neuchâtel, Switzerland (Received 4 April 2019; accepted 6 May 2019; online 11 June 2019)

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.

Keywords: crystal structure; pirfenidone; active pharmaceutical ingredient (API); idiopathic pulmonary fibrosis (IPF); hydrogen bonding.

CCDC reference: 1914224

1. 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.

2. 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.

3. 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 R₄³(20) ring motifs, and lying parallel to the ab plane (Figs. 2 and 3). The R₄³(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) x-1, y, z; (ii) $[-x+2, y-{\script{1\over 2}}, -z+2]$ .

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.

4. 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.

5. 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.

6. 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[F² > 2σ(F²)], wR(F²), 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
Δρ_max, Δρ_min (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)
Computer programs: APEX2 and SAINT (Bruker, 2010), SHELXT2017 (Sheldrick, 2015a ), SHELXL2017 (Sheldrick, 2015b ), ORTEP-3 for Windows (Farrugia, 2012 ), Mercury (Macrae et al., 2008 ), PLATON (Spek, 2009) and publCIF (Westrip, 2010 ).

Supporting information

CCDC reference: 1914224

Crystal structure: contains datablocks Pirfenidone, Global. DOI: https://doi.org/10.1107/S2056989019006418/tx2011sup1.cif

CSD search results. DOI: https://doi.org/10.1107/S2056989019006418/tx2011sup3.pdf

checkCIF report

Computing details top

Data collection: APEX2 (Bruker, 2010); cell refinement: SAINT (Bruker, 2010); data reduction: SAINT (Bruker, 2010); program(s) used to solve structure: SHELXT2017 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2017 (Sheldrick, 2015b); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXL2017 (Sheldrick, 2015b), PLATON (Spek, 2009) and publCIF (Westrip, 2010).

5-Methyl-1-phenylpyridin-2(1H)-one top

Crystal data top

C₁₂H₁₁NO	D_x = 1.269 Mg m⁻³
M_r = 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 top

Bruker SMART APEX CCD diffractometer	1879 reflections with I > 2σ(I)
ω scans	R_int = 0.019
Absorption correction: multi-scan (SADABS; Bruker, 2010)	θ_max = 27.2°, θ_min = 2.1°
T_min = 0.692, T_max = 0.746	h = −8→8
4547 measured reflections	k = −9→10
2128 independent reflections	l = −13→13

Refinement top

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(F_o²) + (0.0528P)² + 0.0476P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.095	(Δ/σ)_max < 0.001
S = 1.04	Δρ_max = 0.11 e Å⁻³
2128 reflections	Δρ_min = −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 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.

Refinement. none

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
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) top

	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) top

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) top

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.

Acknowledgements

VC gratefully acknowledges Professor H. Stoeckli-Evans for her helpful and valuable suggestions.

Funding information

Funding for this research was provided by: Università degli Studi di Milano (grant No. PSR2018_DIP_005_COLOMBO_VALENTINA to Valentina Colombo).

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research communications\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

Crystal structure of pirfenidone (5-methyl-1-phenyl-1H-pyridin-2-one): an active pharmaceutical ingredient (API)

1. Chemical context

2. Structural commentary

3. Supra­molecular features

4. Database Survey

5. Synthesis and crystallization

6. Refinement

Supporting information

Acknowledgements

Funding information

References

research communications

3. Supramolecular features