Propensity of salicylamide and ethenzamide cocrystallization with aromatic carboxylic acids Maciej Przybyłek, Dorota Zi´ołkowska, Karina Mroczy´nska, Piotr Cysewski PII: DOI: Reference:

S0928-0987(16)30040-9 doi: 10.1016/j.ejps.2016.02.010 PHASCI 3487

To appear in: Received date: Revised date: Accepted date:

7 January 2016 13 February 2016 15 February 2016

Please cite this article as: Przybylek, Maciej, Zi´ olkowska, Dorota, Mroczy´ nska, Karina, Cysewski, Piotr, Propensity of salicylamide and ethenzamide cocrystallization with aromatic carboxylic acids, (2016), doi: 10.1016/j.ejps.2016.02.010

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ACCEPTED MANUSCRIPT Propensity of salicylamide and ethenzamide cocrystallization with aromatic carboxylic acids Maciej Przybyłek1, Dorota Ziółkowska2, Karina Mroczyńska3, Piotr Cysewski1* 1

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Chair and Department of Physical Chemistry, Pharmacy Faculty, Collegium Medicum of Bydgoszcz, Nicolaus Copernicus University in Toruń, Kurpińskiego 5, 85-950 Bydgoszcz, Poland, [email protected] 2 University of Technology and Life Sciences in Bydgoszcz, Faculty of Chemical Technology and Engineering, Seminaryjna 3, 85-326 Bydgoszcz, Poland; 3 Research Laboratory, Faculty of Chemical Technology and Engineering, Seminaryjna 3, 85-326 Bydgoszcz * corresponding author

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Abstract The cocrystallization of salicylamide (2-hydroxybenzamide, SMD) and ethenzamide (2ethoxybenzamide, EMD) with aromatic carboxylic acids was examined both experimentally and theoretically. The supramolecular synthesis taking advantage of the droplet evaporative crystallization (DEC) technique was combined with powder diffraction and vibrational spectroscopy as the analytical tools. This led to identification of eleven new cocrystals including pharmaceutically relevant coformers such as mono- and dihydroxybenzoic acids. The cocrystallization abilities of SMD and EMD with aromatic carboxylic acids were found to be unexpectedly divers despite high formal similarities of these two benzamides and ability of the R2,2(8) heterosynthon formation. The source of diversities of the cocrystallization landscapes is the difference in the stabilization of possible conformers by adopting alternative intramolecular hydrogen boding patterns. The stronger intramolecular hydrogen bonding the weaker affinity toward intermolecular complexation potential. The substituent effects on R2,2(8) heterosynthon properties are also discussed.

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Keywords salicylamide, ethenzamide, pharmaceutical cocrystals, miscibility, aromatic carboxylic acids

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Chemical compounds studied in this article Salicylamide (PubChem CID: 5147); Ethenzamide (PubChem CID: 3282); Benzoic acid (PubChem CID: 243); Salicylic acid (PubChem CID: 338); Acetylsalicylic acid (PubChem CID: 2244); 4Acetamidobenzoic acid (PubChem CID: 19266); 2,6-Dihydroxybenzoic acid (PubChem CID: 9338); 3,4Dihydroxybenzoic acid (PubChem CID: 72); 2,4-Dihydroxybenzoic acid (PubChem CID: 1491); 4Hydroxybenzoic acid (PubChem CID: 135) 1. Introduction Many pharmaceutical applications of multicomponent solids such as cocrystals, salts, solvates and clathrates have been explored recently (Fernandes et al., 2003; Grifasi et al., 2015; Jug and Bećirević-Laćan, 2004; Salameh and Taylor, 2006; Shan and Zaworotko, 2008; Steed, 2013; Vishweshwar et al., 2006; Xu et al., 2014). Particularly, the cocrystallization is an useful approach of solubility enhancement Childs et al , 2013; ood and odr guez-Hornedo, 2009; Grifasi et al., 2015; McNamara et al., 2006) and other properties improvements (Hiendrawan et al., 2015a; Karki et al., 2009; Sanphui et al., 2015; Sun and Hou, 2008). However, not all multicomponent solids are classified as cocrystals (Thakuria et al., 2013) and according to the most often accepted definition (Aakeröy and Salmon, 2005; Aitipamula et al., 2012a; Bhogala and Nangia, 2008; Jones et al., 2011; Thakuria et al., 2013) two conditions must be met. First of all, coformers should be solid under ambient settings. Besides, after cocrystallization the formed homogeneous phase should comprise stoichiometric proportions of the components. Especial attention has been paid to pharmaceutical cocrystals comprising active pharmaceutical ingredient (API) cocrystalized with molecular complex of some excipients. These pharmaceutically accepted coformers are to be non-toxic and naturally occurring 1

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substances (Aitipamula et al., 2012a; Musumeci et al., 2011; Thakuria et al., 2013; Zhang et al., 2014). Substantial effort has been made in the exploration of supramolecular systems leading to rapid development of cocrystals screening both experimentally and theoretically. There are many methods of multicomponent crystals preparation classified into two broad categories depending on the cocrystal growth rate (Manin et al., 2014a), namely fast kinetic methods and slow thermodynamic approaches. Both can be implemented on variety manners including solvent evaporation (Hattori et al., 2015; Hiendrawan et al., 2015a; Lin et al., 2013; Przybyłek et al , 2016; ahman et al , 2011), spray drying (Alhalaweh and Velaga, 2010; Alhalaweh et al., 2013; Patil et al., 2014), neat and liquid assistant grinding (Hiendrawan et al., 2015a; Karki et al., 2007; Sanphui et al., 2015; Sun and Hou, 2008), slurry cocrystallization Bučar et al , 2010; Kojima et al , 2010; Takata et al , 2008), melting methods (Rahman et al., 2011; Repka et al., 2013; Yan et al., 2015) and supercritical fluids techniques (Cuadra et al., 2016; Hiendrawan et al., 2015b; Padrela et al., 2010, 2009). It is worth mentioning that many pharmaceutical cocrystals containing amides acting either as as API or excipients have been studied recently (Aitipamula et al., 2015, 2012b, 2009; Cuadra et al., 2016; Furuta et al., 2015; Gryl et al., 2008; Manin et al., 2014a, 2014b; Wang et al., 2013). The compounds containing amino-carbonyl group including aromatic amides, play many important roles in the medical applications. For examples nicotinamide (vitamin B3), pyrazinamide (antitubercular agent), vindesine (phytogenic and antineoplastic agent, tubulin modulator), L-glutamine (nutritional supplement), cerulenin (antifungal antibiotic), carbamazepine (anticonvulsant), nepafenac and the title compounds (non-steroidal antiinflammatory drugs) can be found within DrugBank and WHO Collaborating Centre for Drug Statistics Methodology (WHOCC) databases. On the other hand many drugs acting as cyclooxygenase-2 (COX2) inhibitors belong to the class of carboxylic acids. For example salicylic acid, aspirin and ibuprophen exhibit such activity. However, it was observed (Kalgutkar et al., 2000; Qandil, 2012) that amide and ester derivatives of anti-inflammatory agents have less gastric side effects. Another application of carboxylic acids are pharmaceutical excipients (Rowe, 2009). Noteworthy, benzoic acid and its derivatives have been often used as pharmaceutical cocrystal formers (Berry et al., 2008; Caira et al., 1995; Lin et al., 2015; Manin et al., 2014a, 2014b; Schultheiss and Newman, 2009; Varughese et al., 2010). From pharmaceutical viewpoint particularly important is the class of phenolic acids obtained after hydroxyl substituents attachment to aromatic ring of benzoic acid. According to many reports, these compounds reveal antioxidant activity (Piazzon et al., 2012; Rice-Evans et al., 1996; Sroka and Cisowski, 2003) and possess antimicrobial properties (Baskaran et al., 2013). Furthermore, the phenolic acids are added to food, cosmetics and pharmaceutical formulations to improve their stability (Ash and Ash, 2004; Jones et al., 2006; Vangala et al., 2011). The aim of this study is to examine the cocrystallization landscape of two active pharmaceutical ingredients (API) namely salicylamide and ethenzamide with aromatic carboxylic acids, including pharmaceutically relevant compounds such as acetylsalicylic acid, 4acetamidobenzoic acid (acedoben) as well as mono- and dihydroxybenzoic acids. For this purpose a droplet evaporative crystallization (DEC) technique has been applied. This fast and efficient method has been previously developed Cysewski et al , 2014; Przybyłek et al., 2015) and successfully applied for cocrystal screening Przybyłek et al , 2016). The experimental data characterizing salicylamide and ethenzamide cocrystallization propensities are also enriched by theoretical screening and detailed 2 analysis of R2 (8) heterosynthon properties. 2. Materials and methods 2.1. Materials All chemicals were applied without purification, as received from commercial suppliers. APIs considered in this study namely, salicylamide (2-hydroxybenzamide, SMD) and ethenzamide (2ethoxybenzamide, EMD) were obtained from Avantor Performance Materials Poland S.A. (Gliwice, Poland). Also the following compounds were taken from this provider, namely methanol, benzoic acid (BA), 2-fluorobenzoic acid (2FBA), 2-chlorobenzoic acid (2CBA), salicylic acid (SA), acetylsalicylic 2

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acid (aspirin, ASA), 4-acetamidobenzoic acid (acedoben, 4ABA) 3-hydroxybenzoic acid (3HBA), 2,6dihydroxybenzoic acid (2,6DHBA), 2,5-dihydroxybenzoic acid (2,5DHBA) and 3,4-dihydroxybenzoic acid (3,4DHBA). From Sigma-Aldrich (USA) there were purchased the following chemicals 2,4dihydroxybenzoic acid (2,4DHBA), 3,5-dihydroxybenzoic acid (3,5DHBA), 4-hydroxybenzoic acid (4HBA), 2-bromobenzoic acid (2BBA) and 2-iodobenzoic acid (2IBA).

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2.2. Samples preparation procedure and measurements The cocrystals screening was performed taking advantage of the droplet evaporative crystallization (DEC) technique Cysewski et al , 2014; Przybyłek et al , 2016, 2015). This very simple, time and chemicals preserving approach, yet very efficient, was already validated and successfully applied for new cocrystals preparation Przybyłek et al , 2016). In this technique the crystallite deposited on the glass surface are analyzed based on the powder X-ray diffraction (PXRD) and Fourier transform infrared-total attenuated reflectance techniques. The DEC procedure consists of mixing methanolic solutions of SMD (0.7 M), EMD (0.1 M) and potential cocrystal formers in 1:1 proportions and allowing the fast drying of the 20µL-droplets of these mixtures after dropping on the glass surface. The cocrystals occurrence was confirmed by comparison of PXRD and FTIR-ATR spectra of bi-component crystallites with ones recorded for pure components under the same conditions. In the case of low solubility of API the crystallite layers were obtained after repeating of evaporation up to 5 times for obtaining the PXRD diffraction patterns of sufficient quality. The FTIR-ATR spectra reported in this study were recorded using Bruker Alpha-PFT-IR spectrometer with diamond attenuated total reflection (ATR) equipment. The PXRD patterns were performed using PW3050/60 goniometer with Empyrean XRD tube Cu LFF DK303072 (5o-40o 2 range, 0.02o step with). All diffraction patterns were preprocessed in Reflex module of Accelrys Material Studio 8.0 (Accelrys, San Diego, 2015) including Kα2 stripping, background subtraction, curve smoothing and normalization.

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2.3. Calculation details 2.3.1. Mixing enthalpy estimation The excess thermodynamic functions characterizing components affinities in liquid state under super cooled conditions are often used as a measure of cocrystallization propensities (Eckert and Klamt, 2014; Loschen and Klamt, 2015). This post-quantum mechanical thermodynamic analysis takes advantage of the Conductor like Screening Model for Real Solvents model (COSMO-RS) (Klamt and Schüürmann, 1993; Klamt, 2011) for sigma profiles generation at semiempirical AM1 (Dewar et al., 1985) level. Based on the statistical analysis offered by COSMOtherm software (Eckert and Klamt, 2014) (parametrization BP_SVP_AM1_C30_1501.ctd) it is possible to obtain the mixing enthalpy. The negative enough values of mixing enthalpy is supposed to indicate that the mixture is thermodynamically favored over the pure component liquids. The miscibility under super cooled liquid is often associated with miscibility in the solid state, hence documenting the ability of cocrystallization (Loschen and Klamt, 2015). The geometries of all amides and coformers were optimized using MOPAC2012 (Maia et al., 2012; Stewart, 2016) both in the gas phase and in the condensed phase modeled with and aid of the COSMO-RS approach. 2.3.2. Computations of the substituent effects on the heterosynthon properties The full gradient optimization was performed for 180 pairs of para-substituted benzoic acid analogues with salicylamide or enthenzamide using B97XD density functional with 311++G** basis set as implemented in GAUSSIAN package (Frisch, 2009). The contributions to the pair stabilization energy was performed based on the absolutely-localized orbitals method (ALMO) implemented in QChem package (Shao et al., 2014). In this approach it is possible to decompose the total intermolecular binding energy into several contributions including the charge-transfer (CT) portion of the binding energy (Krylov and Gill, 2013). Besides, the amount of bidirectional charge transfer from and to monomers interacting via hydrogen bonding can be quantified utilizing complementary occupied-virtual orbitals formalism (Khaliullin et al., 2008). In order to obtain more accurate results 3

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3. Results and discussion Focusing attention on cocrystal landscape of salicylamide (SMD) and ethenzamide (EMD) is justified by their analgesic and antipyretic properties. Both SMD and EMD are non-prescription drugs belonging to non-steroidal anti-inflammatory agents with medicinal uses similar to those of aspirin. Typically they are administered in combination with other components as acetaminophen, aspirin or caffeine in the over-the-counter pain remedies. These drugs are poorly soluble in water and cocrystallization with more soluble formers might be one of the remedy to this limitation. The selected coformers belonging to the group of well soluble aromatic carboxylic acids seem to be a rational choice especially that many of them such as BA, SA, 3HBA, 4HBA, 2,4DHBA and 3,4DHBA are known to be non-toxic and approved food additives. Hence, they can be found on GRAS (Generally Recognized as Safe) or EAFUS (Everything Added to Food in the United States) lists. In this paper the cocrystallization landscapes of both SMD and EMD are studied experimentally for limited number of coformers and further extended via computational analysis. Finally, the R22 (8) heterosynthon responsible for the major energetic contributions to the solid stabilization is characterized in details based on quantum chemistry computations.

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3.1. Experimental evidences of cocrystals formation The solid state mixtures comprising salicylamide or ethenzamide and one of 15 aromatic carboxylic acids were prepared and analyzed according to previously described procedure Przybyłek et al., 2016). The complete documentation of experimental results for all analyzed systems is provided in the supporting materials in Fig. S1-S22. Here, in the main text only exemplary cases are discussed. The identification of the cocrystals formation can be confirmed by direct inspection of the corresponding PXRD patterns. The fortunate circumstance of reducing majority of signals obtained from oriented samples compared to bulk crystallization allows for almost immediate identification of the new peaks characterizing molecular complexes in the solid state. Additional confirmation comes from FTIR spectra offering further proof by documenting occurrence of band shifts related to alteration of intermolecular interactions mainly due to changes in the hydrogen bonding patterns. For example cocrystallization of both studied benzamides with 2,4-dihydroxybenzoic acid can be inferred from Fig.1. In this case the SMD-2,4HBA binary system is detectable by new small diffraction signals at 2θ=6 8o and 26.8o, which cannot be assigned to pure components and these signals most probably correspond to new cocrystal phase. In the case of EMD-2,4HBA mixture a new intense PXRD peak at 2θ=18 9o appears as a consequence of cocrystal formation. Since it is often observed overlapping of the reflexes coming from cocrystals with peaks that might come from pure components additional confirmation is desirable and for this purpose the FTIR-ATR method is often used. As it can be inferred from Fig.1b and Fig.1d there are significant changes in the absorption bands shifts when comparing to vibrational spectra recorded for mixtures with pure components. As it can be directly inferred from Fig.1b, formation of the SMD-2,4DHBA cocrystal leads to the relatively small blue shift (from 3394 to 3412 cm-1) of N-H stretching mode absorption band, (NH) and significant red shift (from 3370 to 3303 cm-1) of O-H stretching absorption band, (OH). Changes in the O-H stretching vibration mode regions of carboxylic acids induced by new hydrogen bonds formation can be observed on spectra recorded for other mixtures as well. However, in the majority of cases the observed (NH) shifts are much more noticeable. Noteworthy, particularly significant blue shifts appeared in the case of EMD cocrystals (Fig. 1d, supplementary Figs. S12, S13, S16, S20S22). As we reported in the previous work Przybyłek et al , 2016), similar (NH) analogical shifts were also observed for cocrystals of urea and carboxylic aromatic acids. This regularity can be explained by the formation of a new NH∙∙∙O hydrogen bonding involving amide and carboxylic acid.

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Fig. 1. PXRD and FTIR-ATR characteristics of salicylamide-2,4-dihydroxybenzoic acid (SMD-2,4HBA) (a, b) and ethenzamide-2,4-dihydroxybenzoic acid (EMD-2,4HBA) (c, d) crystallites deposited on the glass surface. Our experimental PXRD data (black lines) were enriched with simulated diffraction patterns of coformers (grey lines). The polymorph I and II of 2,4-dihydroxybenzoic acid are denoted by refcodes ZZZEEU08 and ZZZEEU04, respectively. Similar analysis scrutinized using data provided in the supporting materials allows for documenting the cocrystallization landscapes of both studied here drugs. The conclusions drawn from performed experiments were summarized in the Table 1 proving identification of eleven new cocrystals that have not been previously reported. The content of the Table 1 was enriched by cocrystals identified by other authors including records deposited in the Cambridge Structural Database. There are positive and negative observations of drugs miscibility in the solid state. Although in the former case the conclusion is definitive in the case of lack of identification of cocrystal the inference is not the absolute. The full confirmation of solids immiscibility can be obtained only from full phase diagram and classification as simple eutectic system (Berry et al., 2008; Cherukuvada and Guru Row, 2014; Prasad et al., 2014; Yamashita et al., 2014, 2013) since successful cocrystallization can depend on conditions of synthesis Friščić et al , 2009; agnière et al , 2009; Leyssens et al., 2012; Manin et al., 2014a, 2014b; Schartman, 2009). However, DEC technique applied in this study was found to be quite reliable tool for urea/aromatic carboxylic acids miscibility screening Przybyłek et al , 2016). Noteworthy, formation of the SMD-BA and the EMD-4HBA molecular complexes in the solid state was confirmed also in the earlier studies (Aitipamula et al., 5

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2012b; Manin et al., 2014a). According to our observations, the SMD-BA cocrystal formation can be evidenced by the appearance of an intense peak at 2θ=14 7o on the diffraction pattern and additionally by a characteristic (NH) blue shift from 3395 to 3406 cm-1 on the FTIR-ATR spectra (supplementary Fig.S1). In the case of the EMD-4HBA system, multicomponent crystal phase can be confirmed by overlapping of the majority of PXRD peaks with diffraction pattern of EMD-4HBA monocrystal reported by Aitipamula et al. (2012b) (Fig. S20). The above examples demonstrate once again the reliability of DEC cocryslallization procedure.

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Table 1 Salicylamide (SMD) and 2-ethoxybenzamide (EMD) cocrystals screening results enriched with the examples taken from the literature and CSD. The experimental evidences of new molecular complexes reported in this study are given in supplementary materials as indicated by figure numbers. Cocrystal identification cocrystal former SMD source EMD Source (Manin et al., benzoic acid (BA) yes yes Fig.S12* 2014a), Fig.S1* 2-fluorobenzoic acid (2FBA) yes Fig.S2* yes Fig.S13* 2-chlorobenzoic acid (2CBA) no Fig.S3* no Fig.S14* 2-bromobenzoic acid (2BBA) no Fig.S4* no Fig.S15* 2-iodobenzoic acid (2IBA) no Fig.S5 yes Fig.S16* (Manin et al., 4-acetamidobenzoic acid (4ABA) yes no Fig.S17* 2014a, 2014b) (Manin et al., acetylsalicylic acid (ASA) no no Fig.S18* 2014a) (Manin et al., salicylic acid (SA) yes yes REHSAA** 2014a) 3-hydroxybenzoic acid (3HBA) no Fig.S6* no Fig.S19* (Aitipamula et al., 4-hydroxybenzoic acid (4HBA) yes Fig.S7* yes 2012b), Fig.S20* 2,4-dihydroxybenzoic acid yes Fig. 1 yes Fig. 1 (2,4DHBA) 2,5-dihydroxybenzoic acid yes Fig.S8* yes QULLUF** (2,5DHBA) 2,6-dihydroxybenzoic acid yes Fig.S9* yes GEQXEH** (2,6DHBA) 3,4-dihydroxybenzoic acid no Fig.S10* yes Fig.S21* (3,4DHBA) 3,5-dihydroxybenzoic acid no Fig.S11* yes Fig.S22* (3,5DHBA) * this study experiment documented in supporting materials; **CSD refcode 3.2. Extending of SMD and EMD cocrystallization landscapes The data provided in the Table 1 led to the conclusion that cocrystallization is quite common for both studied benzamides. These abilities of ethenzamide seem to be slightly broader compared to salicylamide. Although the list of carboxylic acid used as coformers is quite extended it would be interesting to analyze the cocrystallization potential of SMD and EMD from much broader perspective. For this purpose the CSD was searched against all carboxylic acids that were used as coformers involved in any binary cocrystals. This led to the set of great variety of aromatic carboxylic acids distinguishable by the type, number and positions of the substituents attached to the aromatic ring. The resulting set of 161 acids was then used as probe for cocrystallization landscape of SMD and 6

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EMD. For this purpose the values of mixing enthalpies (Hmix) were estimated using approach offered by COMSOtherm program (Eckert and Klamt, 2014). It is worth mentioning that the post-quantum mechanical thermodynamic analysis based on the Conductor like Screening Model for Real Solvents (COSMO-RS) have been widely applied for pharmaceutics miscibility with different additives and solubility evaluations (Abramov et al., 2012; Connelly et al., 2015; Klamt, 2012, 2011; Klamt et al., 2002; Loschen and Klamt, 2015; Pozarska et al., 2013). The dissemination of Hmix charactering all of considered here pairs is presented in Fig.2 in the form of smoothed histograms. These curves confirm mentioned discrepancy in the cocrystallization abilities between both of analyzed drugs. Indeed, the majority of aromatic carboxylic acids seem to be freely miscible with ethenzamide. The red line in Fig. 2 defines the critical value of Hmix showing high probability of miscibility. In the case of EMD almost 99% of mixtures with acids fall into this region. On the contrary the histogram of salicylamide interactions with carboxylic acids is more shifted toward higher values of Hmix, what results in reduction of miscible pars down to about 76% cases. It is well known that urea is very good cocrystal former Przybyłek et al , 2016) being able to cocrystalize with variety of compounds (Alhalaweh et al., 2013, 2010; Chang and Lin, 2011; Deutsch and Bernstein, 2008; Martí-Rujas et al., 2011; Powell et al., 2015; Tothadi, 2014; Videnova-Adrabińska, 1996). This is also confirmed by corresponding plot in Fig.2 documenting that about 99% of aromatic carboxylic acids exhibit miscibility under super cooled conditions what is regarded (Klamt, 2012) as sufficient condition for cocrystallization. Thus, ethenzamide is more similar to urea than benzamide, which is able to form the homogeneous mixtures with 94% of acids. 30%

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Fig.2. The distributions of Hmix characterizing pairs of amides with either of 161 aromatic carboxylic acids involved in binary systems deposited in CSD. Apart from data of SMD and EMD also ones for benzamide (BMD) and urea (U) were provided. The percentages in the legend denote population of pairs with high affinities of components defined by Hmix≤-0.57kcal/mol (Eckert and Klamt, 2014; Loschen and Klamt, 2015) and this threshold was marked with the red line. 3.3. The R22 (8) heterosynthon properties It is typical for cocrystals formed by benzamides with carboxylic acids to adopt the hydrogen 2 bonding motive classified by graph descriptor as R2 (8) heterosynthon (Etter et al., 1990; Grell et al., 2000) in which the carboxylic and amide groups are able to form 8-center ring stabilized by two very strong hydrogen bonds. Both interacting components are able to play the role of donor and acceptor, what forms two alternative channels allowing for electron density flow in both directions. There is 7

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another interesting aspect related to conformations of studied here benzamides, namely both molecules can benefit its stability from intra-molecular hydrogen bonds formed between amide group and oxygen atom of hydroxy- or ethoxy-substituent. As it is documented in Scheme 1 there are two alternative types of such intramolecular stabilization in the case and SMD only one for EMD. The intramolecular interactions of salicylamide in the form A are much stronger if compared to B conformer. As a consequence the estimated Boltzmann probability of A isomer is five orders higher suggesting that this structure is predominant. In the case of EMD there is only one possibility of intramolecular hydrogen bonding by adoption of form B and this configuration is supposed to 2 dominate over other isomers. Interestingly, formation of the R2 (8) heterosynthon does not significantly alter this observations. Although, small substituent effect can be observed as it is documented in Fig.3, for both benzamides the energy difference between conformers A and B is promoted by presence of electron withdrawing groups and slightly reduced by the effect of electron donating groups. Thus, the relative stability of conformers is not affected by intermolecular 2 interactions and formation of R2 (8) heterosynthon with aromatic carboxylic acids.

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Scheme 1. The schematic representation of structures of ethenzamide (2-ethoxybenzamide, EMD) and salicylamide (2-hydroxybenzamide, BMD).

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either SMD or EMD. The selected groups cover wide range of Hammett constant values, p, (Hansch et al., 1991) offering precise and complete interpretation of the studied heterosynthon sensitivity to acids strength. The first interesting property of such pairs is the energy of intermolecular interactions. For all optimized pairs the binding energy was estimated including the corrections for basis superposition error and accounting also for the dispersion contributions. In Fig.4 the presented plots characterize the interactions of SMD and EMD with each of studied para substituted carboxylic acids. Additionally, for comparison purposes plots documenting similar effects on benzamide and urea were also provided. It is clearly noticeable that the stabilization energies of pairs formed by each of these four amides with benzoic acids analogues are fairly linear function of Hammett constant values. The attachment of electron donating substituent weakens the interactions with considered amides. On the contrary the more electron withdrawing nature of the substituent the more stable pairs of such aromatic carboxylic acids with all four amides. The distributions presented on both panels of Fig.4 clarify previously mentioned discrepancies in the cocrystallization propensities between salicylamide and ethenzamide. The stabilization contribution coming from the heterosynthon formation of the former amide is significantly lower if compared to EMD. This trend is not affected by acid strength and that is why distributions of mixing enthalpies are so divers for SMD and EMD. This observation is additionally confirmed by histograms provided in Fig.4b. It is worth mentioning that the origin of the observed discrepancies in intermolecular interactions between studied benzamide is different orientation of substituent adopted by both amides. This leads to the alternate patterns of intra-molecular hydrogen bonds. In the case of salicylamide it is observed the intramolecular bonding of O-H…O type, while for ethenzamide the O…H-N type of hydrogen bond is formed. This has consequences on the ability of intermolecular interactions and increase of 2 intramolecular stabilization of the R2 (8) heterosynthon. There are also other interesting consequences of intra-stabilization effect. It is quite expected that the presence of the electron withdrawing groups makes the synthon more polar what can be quantified by amount of charge transfer from benzamide to carboxylic acid (B->A) and vice versa (A->B). This property expressed in terms of portion of electron charge dislocation is presented in Fig.5.

-1.0

-0.5

-15.5

-16.0

-17.5 -18.0 -18.5

0.0

0.5

b) 1.0

1.5

30%

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25%

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y = -0.564x - 16.464 R² = 0.865

U 20% 15%

y = -1.058x - 17.770 R² = 0.887

10%

y = -1.246x - 18.086 R² = 0.917

-19.0

-19.5 -20.0 -20.5

population

EBSSE [kcal/mol]

-17.0

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p

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a)

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SMD EMD BMD U

0% y = -1.468x - 18.257 R² = 0.906

-21.0

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-19.0

-18.0

-17.0

-16.0

Hmix [kcal/mol]

Fig.4. The intermolecular interactions of pairs comprising salicylamide, ethenzamide, benzamide or urea with para-substituted benzoic acid analogues. On left panel (a) the absolute values of binding energy are provided, while on the right side (b) the corresponding smoothed histograms of EBSSE were collected. a)

b)

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0.0

p 0.5

1.0

1.5

-1.0

10.0

0.5

1.0

1.5

y = 1.33x + 6.84 R² = 0.91

7.0

SMD EMD BMD U

6.0 y = 1.03x + 5.10 R² = 0.90

2.5

2.0 1.5

y = -0.35x + 1.90 R² = 0.77

y = -0.46x + 2.64 R² = 0.76

y = -0.42x + 2.46 R² = 0.79

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5.0

y = -0.39x + 3.18 R² = 0.91

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y = 1.24x + 7.79 R² = 0.93

SMD EMD BMD U

3.5

y = 1.39x + 7.41 R² = 0.94

QA->B [me-]

QB->A [me-]

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Fig.5. The substituent effect on charge transfer between constituents of C22(8) heterosynthon, where B denotes amide and A stands for acid.

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It is interesting to note that the stronger electron withdrawing character of the substituent the higher the charge transfer toward aromatic acid from either of amides. However, SMD is less prone to this effect compared to EMD, what in the light of mentioned intra-stability is quite understandable. The channel formed by carbonyl oxygen center is more affected by intramolecular hydrogen bonding in this case. The lack of such intramolecular interaction in the case of benzamide and urea results in much higher readiness to electron density outflow. Thus, EMD is more similar in this aspect to benzamide than to salicylamide. The stronger resistance of SMD to substituent effect on B->A electron transfer can also be inferred from the slops of linear trends presented in Fig.5a. This value is about 30% lower for SMD compared to EMD. The transfer of electron charge from amide toward acid is also associated with opposite effect, what can be inferred from Fig.5b. This alternative 2 channel of R2 (8) heterosynthon involves carbonyl group on the acid side. However, the observed charge transfer is pronounced in much lesser extend suggesting much stronger electron withdrawing character of carboxylic group than amide fragment. The observed absolute values of partial electron transfer are 3-5 times smaller in the A->B way compared to opposite direction. Furthermore, the absolute values of slopes are also 2-3 times smaller suggesting much smaller substituent effect on this kind of synthon polarization. Thus, taking into account both channels it is possible to conclude 2 that formation of the R2 (8) heterosynthon results in enrichment of the electron density on the acidic site irrespectively of the nature of the substituent. This conclusion holds also for benzamide and urea. It is also interesting to mention that apart from energetic and electronic effects of substituent 2 nature there are also numerous geometric consequences on the R2 (8) heterosynthon structure. For example it is observed deformation of the synthon geometry with the increase of electron withdrawing character of the substituent leading to increase of skewness of the system. This parameter defined as the mean value of so-called Donohue angles (Donohue, 1968) can be used for description of the geometries of hydrogen bonds involved on synthon formation (Katrusiak, 1995, 1993). This is associated with systematic increase of O-H…O’ and decrease of O…H’-O’ hydrogen bonds lengths with the rise of the electron withdrawing strength of the substituent. Here, the prime sign is used for denoting centers located on carboxylic groups. This is consistent for both studied here drugs. 4. Conclusions The cocrystallization abilities of salicylamide and ethenzamide with aromatic carboxylic acids are unexpectedly divers. Despite high formal similarities of these two benzamides the propensities of cocrystal formation explored both experimentally and theoretically revealed origin of this fundamental difference. The formal analogy between SMD and EMD comes from ability of the 2 formation of the same intermolecular pattern denoted by graph descriptor as R2 (8) heterosynthon. 10

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However, difference in stabilization of possible conformers by adopting alternative intramolecular hydrogen boding patterns is the main source of the observed difference in the cocrystallization landscape. Since salicylamide (SMD) and ethenzamide (EMD) are efficient analgesic and antipyretic drugs administered as non-prescription non-steroidal anti-inflammatory agents in combination with other components their miscibility in the solid state is important aspect of pharmaceutical relevance. Both APIs are poorly soluble in water and cocrystallization with more soluble coformers seems to be one of the simplest way of modulating their bio-availability. Particularly concentration on non-toxic and much better soluble aromatic carboxylic acids as potential coformers is rational also from the 2 perspective of structural pattern recognition via R2 (8) heterosynthon. The experiment observation of solid state miscibility of considered herein APIs with a set of substituted benzoic acid derivatives was assessed by means of supramolecular synthesis, taking advantage of the efficient DEC technique combined with powder diffraction and vibrational spectroscopy as the analytical tools. As it was documented above the phenolic acids turned out to be a good class of ethenzamide cocrystals formers and since they can prevent drugs from degradation, addition of these compounds to pharmaceutical formulations can potentially improve also their shelf life. It is worth mentioning that cocrystallization is an approach which gives the best dispersion of pharmaceutical ingredients and hence the most effective interaction with APIs. Finally the identification of eleven new cocrystals by means of DEC experimental approach confirms its usefulness and extends it applicability range.

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Acknowledgements This work utilized the COSMOtherm software kindly provided by COSMOlogic. This research was supported in part by PL-Grid Infrastructure. The allocation of computational facilities of Academic Computer Centre "Cyfronet" AGH / Krakow / POLAND is also acknowledged.

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