A 1:2 cocrystal of genistein with isonicotinamide: crystal structure and Hirshfeld surface analysis Michal Sowa, a Katarzyna S ´ lepokura b and Ewa Matczak- Jon a * a Department of Chemistry, Wroclaw University of Technology, Wybrzez . e Wyspian ´ skiego 27, Wroclaw 50-370, Poland, and b Faculty of Chemistry, University of Wroclaw, 14 F. Joliot-Curie Street, Wroclaw 50-383, Poland Correspondence e-mail: ewa.matczak-jon@pwr.wroc.pl Received 3 September 2013 Accepted 26 October 2013 Genistein, a naturally occurring polyphenolic compound, was combined with isonicotinamide, a pharmaceutically accep- table coformer, to yield a 1:2 cocrystal [systematic name: 5,7- dihydroxy-3-(4-hydroxyphenyl)chromen-4-one–pyridine-4- carboxamide (1/2)], C 15 H 10 O 5 2C 6 H 6 N 2 O. The molecules in the cocrystalline phase are present in their neutral forms, and assemble a molecular layer by means of hydrogen bonding. Keywords: crystal structure; flavonoids; cocrystals; active pharmaceutical ingredients; genistein; Hirshfeld surface analysis. 1. Introduction Genistein is an isoflavonoid commonly present in legumes and food of soya origin (Coward et al., 1993), sharing structural features with a potent mammalian oestrogen, i.e. 17-oestra- diol. It is considered an active pharmaceutical ingredient (API) and has been widely studied as a possible antioxidant, anti-inflammatory, antibacterial and antitumour agent (Polk- owski & Mazurek, 2000; Zhang et al., 2012). Most of the scientific interest in genistein is owed to its health-prolonging effects, which were shown both in vivo and in vitro, and result in its possible application in the prevention and treatment of the diseases of affluence, i.e. obesity, diabetes and cancer, and genetic diseases (Rahman et al., 2012; Gilbert & Liu, 2013). Isonicotinamide is a pharmaceutically acceptable coformer widely used in cocrystallization of various carboxyl- and hydroxy-derived molecules, including quercetin (Smith et al., 2011), fisetin and luteolin (Sowa et al., 2013), diclofenac and clofibric acid (Ba ´ thori et al., 2011), 3-nitrophenol (Ratajczak et al., 2013) and orcinol (Mukherjee et al. , 2011). A common undesired property of many APIs, including genistein (Zhou et al., 2008; Rusin et al., 2010), is their low solubility in aqueous media, which leads to low bioavailability. There are several strategies for improving the solubility of pharmaceutically important molecules, such as the formation of salts, solvates or other forms (Huang & Tong, 2007; Babu & Nangia, 2011; Serajuddin, 2007; Brewster & Loftsson, 2007). Some evidence of solubility enhancement of genistein by salt formation (Polkowski et al., 2000) and complexation with either -cyclodextrins (Daruha ´zi et al., 2008) or high-amylose corn starch (Cohen et al., 2011) have already been demon- strated. Cocrystal formation is a technique advantageous over other methods, being independent of the specific physicochemical nature of the studied molecules (Blagden et al., 2007, and references therein). Cocrystallization of flavonoids from a pharmaceutical aspect emerged with studies of quercetin (Smith et al., 2011) and yielded promising results. More recently, we reported the structure and properties of a genis- tein–nicotinamide 1:1 monohydrate (Sowa et al., 2013), the first example of a pharmaceutical cocrystal of genistein. Continuing our research effort on flavonoid cocrystallization (Sowa et al., 2012, 2013), we present here a 1:2 cocrystal of genistein and isonicotinamide, denoted GenInam, which consists of both molecules in their neutral forms, hydrogen bonded into a layered network. 2. Experimental 2.1. Synthesis and crystallization Genistein was obtained from Sino-Future Bio-Tech Co. Ltd, isonicotinamide was obtained from Acros Organics and both were used without further purification. Genistein (25 mg, 0.091 mmol) and excess isonicotinamide (100 mg, 0.819 mmol) were dissolved in propan-2-ol (8 ml). The resulting solution was filtered and left for slow evaporation under ambient conditions to yield crystals of GenInam suitable for X-ray analysis. FT–IR (ATR, , cm 1 ): 3431 (bm), 3307 (w), 3162 (w), 1689 (m), 1619 (m), 1570 (m), 1554 (m), 1514 (m), 1455 (bm), 1390 (m), 1370 (m), 1307 (m), 1290 (m), 1245 (m), 1190 (s), 1173 (m), 1144 (m), 1061 (m), 1040 (m), 1008 (m), 918 (m), 880 (m), 828 (s), 787 (s), 751 (s), 701 (m), 633 (m), 563 (m), 512 (s), 403 (s). Decomposition point: 482 K (onset, thermogravimetry–differential scanning calorimetry), with subsequent loss of isonicotinamide molecules (calculated 47.4%, found 47.5%). 2.2. Refinement Crystal data, data collection and structure refinement details are summarized in Table 1. All H atoms were found in difference Fourier maps. In the final refinement cycles, pharmaceuticals and natural products Acta Cryst. (2013). C69, 1267–1272 doi:10.1107/S0108270113029545 # 2013 International Union of Crystallography 1267 Acta Crystallographica Section C Crystal Structure Communications ISSN 0108-2701