Multicomponent solids of diclofenac with pyridine based coformers Pramod Kumar Goswami a, b, ** , Vineet Kumar a , Arunachalam Ramanan a, * a Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi,110016, India b University College of Engineering and Technology, Vinoba Bhave University, Hazaribagh, 825301, India article info Article history: Received 4 August 2019 Received in revised form 10 March 2020 Accepted 11 March 2020 Available online 12 March 2020 Keywords: Supramolecular synthon Multicomponent solids Conformational analysis Cocrystals abstract The present study reports nine crystalline forms of diclofenac acid which include cocrystals, salts, salt- cocrystals and salt hydrates with pyridines and amines based coformers utilizing acid … pyridine syn- thon. All the solids were successfully prepared and structurally characterized through PXRD, ATR, DSC and single crystal XRD. The crystal structures were analyzed and discussed in terms of acid … pyridine heterosynthon. The conformation of diclofenac acid in the multicomponent solids reported in this paper is compared with its polymorphs. The structural chemistry of diclofenac acid (DIC) is discussed based on carboxylic acid … pyridine synthon in terms of DIC-coformer dimer or DIC-coformer-DIC trimers. The influence of pKa in dictating the final solid is also discussed. © 2020 Elsevier B.V. All rights reserved. 1. Introduction Diclofenac acid, [2-(2,6-dichlorophenylamino)phenyl] acetic acid (DIC) is a class of phenyl acetic acid and a potent, non-steroidal anti-inflammatory analgesic (NSAIAs) [1‒6]. It is a weak acid with pKa of about 4 [7‒8]. DIC is a BCS class II drug [9] with extremely poor aqueous solubility (0.9 mg/ml) and high permeability like most NSAIDs [10‒11]. It is dosed orally as a soluble salt form of sodium or potassium for the relief of pain and inflammation; [12, 13] sodium salts are known in different forms of hydrates [14‒18]. Diclofenac diethylamine (DEA) has been used as a topical gel extensively in Europe since 1985 [19]. Several gelators of multiple drugs including DIC with primary amine utilizing N þ ‒H/O  supramolecular syn- thon to form 1-D H-bonded network have been exploited recently [20,21]. Eye drops of Na-DIC are used to treat the inflammation after eye surgery or seasonal allergic conjunctivitis [22‒24]. The major challenge with Na-DIC is that it undergoes intramolecular cyclization under the acidic condition leading to an inactive prod- uct [25]. DIC is further a by-product of aceclofenac which degrades in the presence of strong acidic or basic condition [26]. DIC shows conformational polymorphism and crystallizes in two monoclinic forms (polymorphs I and II) [27] and an orthorhombic form (polymorph III) [28]. Both monoclinic forms are closely related where the molecules interact with each other through the carboxyl dimer. The N‒H group intramolecularly hydrogen bonded to the carboxylic group through N‒H/O; there is no other major nonbonding interaction observed between the dimers. However, a significant difference is present in their torsion angle of phenyl- acetic acid group (96  and 109.4  in I and II respectively) [27]. Aakeroy et al. has screened and cocrystallized solids of DIC with a wide range of aromatic nitrogen containing compounds [29]. Coc- rystals and salts of DIC with piperazine [30], theophylline [31], isonicotinamide [32], amines [33‒35] and L-proline [36] are also reported. Though Aakeroy et al. has reported the formation of diclofenac salts with 2-aminopyridine, 3-aminopyridine and 4,4 0 - bipyridine, however there are no detailed crystal structures to examine the various interactions. This prompted us to further explore the structural landscape of DIC‒pyridine derivative system. Therefore, we investigated the formation of multicomponents forms of DIC with 4,4 0 -bipyridine (bpy); 1,2-bis(4-pyridyl)ethane (bpe); 1,2-bis(4-pyridyl)propane (bpp); 2-aminopyridine (2-apy), 3-aminopyridine (3-apy), 4-aminopyridine (4-apy) and ethyl- enediamine (en). Apart from this, a wide range of pharmaceutically acceptable GRAS coformers has also been screened with DIC. The complete lists of coformers used to screen the solids of DIC with unsuccessful results are tabulated in Table S1 . In this paper, we describe the detailed structural characterization of nine new solids: 2:1 * Corresponding author. ** Corresponding author. Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi,110016, India. E-mail addresses: pramodchem25@gmail.com (P.K. Goswami), aramanan@ chemistry.iitd.ac.in (A. Ramanan). Contents lists available at ScienceDirect Journal of Molecular Structure journal homepage: http://www.elsevier.com/locate/molstruc https://doi.org/10.1016/j.molstruc.2020.128066 0022-2860/© 2020 Elsevier B.V. All rights reserved. Journal of Molecular Structure 1210 (2020) 128066