Crystal structure of a 1:1 co-crystal of the anticancer drug gefitinib with azelaic acid

Gefitinib, the anticancer drug, has been co-crystallized with azelaic acid to obtain a 1:1 co-crystal in the monoclinic P21/n space group containing one molecule each of gefitinib and azelaic acid in the asymmetric unit. Both molecules are associated with each other through N—H⋯O, O—H⋯N, C—H⋯O and C—H⋯F hydrogen bonds.

In the title co-crystal, C 22 H 24 ClFN 4 O 3 ÁC 9 H 16 O 4 , gefitinib (GTB; systematic name: quinazolin-4-amine) co-crystallizes with azelaic acid (AA; systematic name: nonanedioic acid). The co-crystal has the monoclinic P2 1 /n centrosymmetric space group, containing one molecule each of GTB and AA in the asymmetric unit. A structure overlay of the GTB molecule in the co-crystal with that of its most stable polymorph revealed a significant difference in the conformation of the morpholine moiety. The significant deviation in the conformation of one of the acidic groups of azelaic acid from its usual linear chain structure could be due to the encapsulation of one acidic group in the pocket formed between the two pincers of GTB namely, the morpholine and phenyl moieties. Both GTB and AA molecules form N-HÁ Á ÁO, O-HÁ Á ÁN, C-HÁ Á ÁO hydrogen bonds with C-HÁ Á ÁF close contacts along with off-stacked aromaticinteractions between the GTB molecules.

Chemical context
Gefitinib (GTB, Iressa) is an orally administered chemotherapy treatment drug that inhibits tyrosine kinase (an enzyme that transports phosphates from ATP to the tyrosine residue of a protein) (Kobayashi & Hagiwara, 2013) for nonsmall-cell lung cancer (NSCLC), pancreatic cancer, breast cancer and several other types of cancer. Two polymorphs of GTB have been reported from our group previously, both of which crystallized in the triclinic P1 space group (Thorat et al., 2014). The drug-drug co-crystal of GTB with furosemide has also been published (Thorat et al., 2015). Some of the major side effects of GTB include rash, acne and dry skin. To overcome these after effects, there is a need for combination drug therapy. In this regard, we chose azelaic acid (AA), which is used for treating mild to moderate acne, both comedonal acne and inflammatory acne (Fitton & Goa, 1991). Furthermore, GTB is also known to form co-crystals with aliphatic dicarboxylic acids through N-HÁ Á ÁO and O-HÁ Á ÁN hydrogen bonds (Gonnade, 2015). AA is an aliphatic dicarboxylic acid (heptane-dicarboxylic acid), having seven CH 2 groups in the alkyl chain. Two polymorphs of AA have been reported earlier, the form is monoclinic, P2 1 /c (Caspari, 1928;Housty & Hospital, 1967) and the form crystallizes in the monoclinic C2/c space group (Housty & Hospital, 1967). Both GTB and AA are non-volatile solids at room temperature and their respective melting points are in the ranges 192-195 K and 378-381 K.

Structural commentary
The title compound GTB-AA (1:1) crystallizes in the monoclinic P2 1 /n centrosymmetric space group containing one molecule of each in the asymmetric unit ( Fig. 1, Table 1) (CCDC reference No. 2002536). The halophenyl ring of GTB and the alkyl (-CH 2 -) chain of AA exhibit positional disorder over two conformations, due to the free rotation around the N-C and C-C single bonds, respectively ( Fig. 2a and 2b). A structure overlay of the GTB molecule based on a fit of the quinazoline groups in the co-crystal structure with that of its stable polymorph [the crystal structure of the stable polymorph of GTB was retrieved from the Cambridge Structural Database (Groom et al., 2016), refcode: FARRUM02; Thorat et al., 2014] revealed a considerable difference in the orientation of the morpholine moiety [torsion angles, C19-C20-C21-N22 = 54.0 (2) for GTB in the co-crystal while the corresponding torsion angle in the stable polymorph of GTB is 74.3 (2) ] because of the conformationally flexible -CH 2spacer (Fig. 3). Whereas the conformation of the phenyl group showed a slight difference with a dihedral angle of 14.1 (2) (the angular difference between the planes of halophenyl ring of both structures). The quinazoline, morpholine and phenyl moieties of GTB have acquired a roughly planar geometry in the co-crystal [torsion angle C12-C5-C19-N22 = 14.4 (2) , only the N atom of morpholine is considered and not the full fragment], whereas in the stable polymorph of GTB, the morpholine moiety deviates significantly from the plane [the corresponding torsion angle is À75.7 (2) ]. The approximate planarity of the phenyl, quinazoline and morpholine (only N atom considered) moieties of GTB in the co-crystal seems to be due to the engagement of these groups with one of the acid groups of AA via N-HÁ Á ÁO and O-HÁ Á ÁN hydrogen bonds. The conformation of this acid group of AA shows a consid-

Supramolecular features
The closely associated molecules of GTB and AA (through an O30-H30Á Á ÁN1 hydrogen bond) constitute a 'zero-dimensional' supramolecular motif wherein a carboxyl OH of AA donates its H atom to the quinazoline N atom (Fig. 1). Adjacent n-glide symmetry-related 'zero-dimensional' motifs are linked firmly along the ac diagonal by strong N-HÁ Á ÁO, O-HÁ Á ÁN and C-HÁ Á ÁO hydrogen bonds to generate a onedimensional linear chain structure (Fig. 5, Table 1). The cavity created by GTB as a result of its 'molecular clip'-like geometry encapsulates the other carboxylic acid group of AA. In the cavity, the carboxyl oxygen (O42) accepts the H atoms from amine N11-H11 and C5-H5 to form N11-H11Á Á ÁO42 i and C5-H5Á Á ÁO42 i hydrogen bonds (symmetry operations are given in the footnote to Table 1). In turn, the carboxyl OH (O41-H41) of AA donates its H atom to the morpholine N22 to make a O41-H41Á Á ÁN22 ii hydrogen bond. The neighbouring antiparallel chains are stitched centrosymmetrically through C2-H2Á Á ÁF1 iii contacts and C29-H29BÁ Á ÁO18 iv hydrogen bonds to form a two-dimensional layered assembly in the ac plane (Fig. 6). A view of the molecular packing down the b axis reveals the stacking of the 2D layers by aromaticinteractions between centrosymmetrically related quinazoline rings [interplanar spacing, 3.396 (13) Å ] (Cg2Á Á ÁCg2 vii , Cg2Á Á ÁCg3 vii , Cg2Á Á ÁCg3 viii and Cg3Á Á ÁCg3 vii ; Cg2 is the centroid of the N1/C2/N3/C4/C10/C9 ring and Cg3 is the centroid of the C5-C10 ring, Table 1). Molecules between the two layers are also connected by C27-H27BÁ Á ÁF1 vi contacts and C23-H23BÁ Á ÁO25 v , C21-H21BÁ Á ÁO31 vii , C13-H13Á Á ÁO30 viii and C39-H39AÁ Á ÁO30 ix hydrogen bonds to generate the three-dimensional packing (Fig. 7 The 'molecular clip'-like geometry of GTB that accommodates a carboxyl group of AA. The molecules interact through N-HÁ Á ÁO, O-HÁ Á ÁN and C-HÁ Á ÁO hydrogen bonds.

Figure 5
A one-dimensional chain formed by GTB and AA molecules along the ac diagonal via O-HÁ Á ÁN, N-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds.

Figure 6
Two-dimensional layered assembly of GTB and AA along the ac diagonal. The neighbouring one-dimensional chains are stitched through C-HÁ Á ÁF and C-HÁ Á ÁO hydrogen bonds.

Figure 7
The view of the molecular packing along the b axis showing the association of GTB molecules through aromaticinteractions along with C-HÁ Á ÁF and C-HÁ Á ÁO interactions.

Database survey
A search for the title co-crystal in the Cambridge Structural Database (CSD, Version 5.41, the update of March 2020; Groom et al., 2016) found no hits. However, searches for GTB and AA gave 8 and 35 hits, respectively. A search for the GTB molecule showed that the amine N-H moiety is involved in N-HÁ Á ÁO hydrogen-bond formation either with the morpholine oxygen in both of its polymorphs (Thorat et al., 2014) or with the water oxygen (Gilday et al., 2005;Thorat et al., 2015). For the AA search, 17 hits were found only for its two polymorphs (refcodes: AZELAC01-AZELAC17) wherein the AA molecules are found to be associated by the conventional dimeric O-HÁ Á ÁO hydrogen bonds (Caspari, 1928;Housty & Hospital, 1967). The remaining hits were for either co-crystals with amides (Tothadi & Phadkule, 2019;Thompson et al., 2011;Karki et al., 2009), pyridines (Braga et al., 2010;Martins et al., 2016;Krueger et al., 2017) or complexes with Ni (Zhao et al., 2012), Fe (Braga et al., 2006) or Ba (Grzesiak et al., 2012).

Synthesis and crystallization
Co-crystallization was carried out using equimolar amounts of commercial samples of GTB and AA by grinding combined with a slow evaporation method. The grinding experiment was performed manually using a mortar and pestle. The 1:1 stoichiometric molar ratio of GTB (45 mg, 0.1 mmol) and AA (19 mg, 0.1 mmol) was ground for about 15 minutes using dry (neat) grinding. The ground sample was dissolved in n-butanol and heated for $10 minutes to ensure the complete dissolution of the sample. The solution was filtered into the crystallization flask to remove the impurity and undissolved compound, and the solution was allowed to evaporate at room temperature (298-300 K). Elongated needle-shaped colourless crystals were obtained after 1-2 h. The melting point of the obtained co-crystal was 398-399 K.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. All H atoms (except for hydroxy and amine H atoms) were placed in geometrically idealized positions, with C-H = 0.95 Å for phenyl H atoms, C-H = 0.99 Å for methylene H atoms and C-H = 0.98 Å for methyl H atoms. They were constrained to ride on their parent atoms, with U iso (H) = 1.2U eq (C) for phenyl and methylene, and 1.5U eq (C) for methyl groups. The O-(O30) and N-bound H atoms were located in difference-Fourier maps and refined isotropically. However, the O-bound H atom was placed in a geometrically idealized positions using HFIX 148 as the O-H distance was longer when refined with its located position in the difference-Fourier map. It was constrained to ride on its parent atom (O41), with U iso (H) = 1.5U eq (O). The long O-H distance could be due to its involvement in the strong O-HÁ Á ÁN hydrogen-bond formation with N22. The difference  Crystal structure of a 1:1 co-crystal of the anticancer drug gefitinib with azelaic acid Christy P. George, Ekta Sangtani and Rajesh G. Gonnade

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.