*3.1. Crystal Structure Analysis*

Cocrystallization of **DL-H2ma** and **pic** in 1:1 molar ratio from ethyl acetate produced plate-shaped colorless crystals that belonged to a 1:1 cocrystal, a new polymorph that differs from the one known with a 2:2 **pic**-**D-H2ma** ratio (HOGGOB, [31]). The crystal structure was solved in monoclinic space group *P*21/*n*. The crystallographic asymmetric unit consists of one molecule each of **D-H2ma** and **pic** (Figure 1a). The crystal structure features an acid–amide heterosynthon *R*<sup>2</sup> <sup>2</sup>(8) between **D-H2ma** and **pic** involving O–H··· O (2.547(1) Å, 168.3(2)◦) and N–H··· O (2.929(2) Å, 166.6(2)◦) hydrogen bonds (Table S1). The *anti*-N–H of the **pic** forms an N–H··· O (2.948(2) Å, 126.3(1)◦) hydrogen bond with the same carboxylic oxygen atom of a symmetrically related acid molecule, and the hydroxyl O–H of the **D-H2ma** forms an O–H··· N (3.071(2) Å, 139.9(2)◦) hydrogen bond with the adjacent pyridine N of the **pic,** forming a second heterosynthon of graph set *R*<sup>2</sup> <sup>2</sup>(10). Thus, it generates a four-component supramolecular plane unit that consists of each two molecules of **D-H2ma** and **pic**, giving rise to a new ring motif *R*<sup>2</sup> <sup>4</sup>(8) in the same way as in the other polymorph [33] (Figure 1b).

Although little is known about the crystallization mechanisms involving the stages of molecular aggregation to form cocrystals [38], in this case it is likely that the mechanism is likely to include a first stage of molecular recognition between an acid molecule and another of amides, the well-known amide–acid heterosynthon. In a second stage, two of these heterodimers, symmetrically related, are associated by establishing new hydrogen bonds, to form the above tetrameters (Figure 1b).

**Figure 1.** (**a**) A view of the molecular structure of **1** showing atomic labeling and displacement ellipsoids drawn at the 50% probability level, and (**b**) four-component supramolecular unit showing the intermolecular interactions and the supramolecular synthons. Hydrogen bonds are shown as orange dashed lines. See Table S1 for symmetry codes.

Another aspect to consider is the molecular conformation of each of the cocrystals and the difference between them and with mandelic acid and the conformers. Conformational flexibility of pyridinecarboxamides is related to the torsion angle of the amide group in relation to the pyridine ring (θ1), and in mandelic acid to the torsion angles involving the carbonyl group of the carboxylic acid (θ2) and the group hydroxyl of the alcohol group (θ3) (Scheme 1). Table 2 compares the molecular conformations of pyridinecarboxamides and mandelic acid in these cocrystals.


**Table 2.** Torsional angles of pyridinecarboxamides and mandelic acid crystals and corresponding cocrystals.

\* θ1, θ<sup>2</sup> and θ<sup>3</sup> are defined in Scheme 1; values of torsional angles were calculated from the crystal structures in CSD.

In **1**, the oxygen atom of the amide group is opposite the nitrogen atom of the pyridine ring outside the pyridine plane, in a similar way to that of polymorph I of pure pic. In the mandelic acid molecule, small conformational changes are also observed, more pronounced in θ3, which are consistent with those existing in the second symmetrically independent molecule of **D-H2ma**, and close to those of the second molecule of polymorph II of **DL-H2ma** (Table 2). When these values are compared with those of the HOGGOB polymorph, noticeable and more pronounced discrepancies are observed in the torsion angles of the second symmetrically independent acid molecule, not only in θ<sup>3</sup> but also in θ2, probably due to the different hydrogen bonds in which the donor alcoholic OH groups participate.

In crystal packing, the flat units are arranged one next to the other in the plane "bc", without any interaction (Figure 2a), so that in the direction of the diagonal of the angle between the axes "a" and "c" are arranged intercalated in opposite orientations to form a 3D network with an internal zigzag-like orientation (Figure 2b). The absence of strong interactions between tetramers may justify for some softer properties in the cocrystals, compared to those of picolinamide.

**Figure 2.** Packing diagram for **1,** viewed (**a**) in the "bc" plane and (**b**) parallel to "b" axis.

From the cocrystallization of **DL-H2ma** and **nam** are known several structures of different stoichiometries in ratios 1:1, 2:1, 2:2 and 1:4 [23]. In this laboratory, the same **(nam**)-(**D-H2ma**) (1:1) cocrystal was prepared by crystallization from ethyl acetate. Crystal structure analysis of **2** revealed that the cocrystal belongs to monoclinic, *P*21 space group with one molecule each of **D-H2ma** and **nam** in the crystallographic asymmetric unit (Figure 3a). The crystal structure features an heterosynthon between the α-hydroxyl carbonyl group of **D-H2ma** and the amide group of **nam** involving O–H··· O (2.708(1) Å, 143.3(2)◦) and N–H··· O (3.002(1) Å, 155.4(2)◦) with ring motif *<sup>R</sup>*<sup>2</sup> 2(9) (Table S1). These heterodimers are further joined by hydrogen bonds through O–H carboxyl acid and pyridine N atom (2.684(1) Å, 175.0(2)◦), which is accompanied by a stabilizing C−H···O hydrogen bond (H···O, 2.342 Å; C···O, 3.103 Å), resulting in a supramolecular synthon of graph set *R*<sup>2</sup> <sup>2</sup>(7). In addition, the amide *anti*-N–H and hydroxy O atom N–H··· O (2.921(1) Å, 144.9(1)◦) form heterosyntons of graph set *R*<sup>3</sup> <sup>4</sup>(11), to originate a new four-component supramolecular unit that is repeated along infinite ribbons (Figure 3b). In the 3D network, these heterodimers are further joined by hydrogen bonds to form independent layers along "b" axis (Figure 4a) [32], extending in the "ca" plane simulating a zigzag chain that, unlike **1** (Figure 2b), all molecules are oriented in the same way (Figure 4b).

**Figure 3.** (**a**) A view of the molecular structure of **2** showing atomic labeling and displacement ellipsoids drawn at the 50% probability level, and (**b**) four-component supramolecular unit showing the hydrogen patterns, as orange dashed lines, observed in **2**. See Table S1 for symmetry codes.

**Figure 4.** Packing diagram for **2**, viewed (**a**) in the "bc" plane and (**b**) in the "ca" plane.

In the **2** system, taking as reference the data of the structure of the polymorph ε (NICOAM07, from the CSD), in the crystals of pure **nam** it is observed that the O atom of the amide group is on the same side of the atom nitrogen of the pyridine ring (θ1, 26.8◦), which is the same conformation adopted by the polymorphs JILZOU01 [32] (−28.7◦) and JILZOU [33] (35.3 and 12.0◦). It should be noted that this conformation is opposite to that described above for the cocrystals of **1**. Regarding the **D-H2ma** molecule in the cocrystal, differences in conformation are also observed, as can be seen in the values of θ<sup>2</sup> and θ<sup>3</sup> compared with those of the two symmetrically independent molecules of the acid, although they do not differ in excess of those found in HOGGOB molecule **1** [31] (Table 2).

The new cocrystals of **DL-H2ma** with **inam** in a 1:1 ratio, prepared by crystallization in ethyl acetate, have also been previously obtained in warm ethanol [6]. The crystal structure revealed that cocrystals **3** belong to the monoclinic space group, *P*21/*c* with one molecule of each coformer in the asymmetric crystal unit (Figure 5a). **L-H2ma** and **inam** interact with each other via an acid–pyridine heterosynthon involving O–H··· N (2.624 Å, 177.3◦) hydrogen bond (Table S1). As in 2, the Npy···H−O hydrogen bond is accompanied by a complementary C−H···O hydrogen bond (H···O, 2.640 Å; C···O, 3.131 Å, CHO 127.9◦). The amide group forms a amide–amide homosynthon dimers of typical ring motif *R*<sup>2</sup> <sup>2</sup>(8) between **inam** molecules involving N–H··· O (2.881(1) Å, 179.7(2)◦). At the same time, these dimers are attached to **L-H2ma** molecules in two ways. One is through a O–H··· O bond formed between the hydroxyl O–H and the amide O of a nearest neighboring acid molecule (2.775(1) Å, 162.9(2)◦) whereas the second one is via N–H··· O (2.949(1) Å, 141.7(1)◦) between the amine *anti*-N–H and the hydroxy oxygen of the **L-H2ma** (Figure 5b), which is reinforced by a hydrogen bond C−H···O in which carbonyl participates, originating a heterosynthon of graph set *R*<sup>2</sup> <sup>2</sup>(10) (Figure 5b).

**Figure 5.** (**a**) A view of the molecular structure of **3** showing atomic labeling and displacement ellipsoids drawn at the 50% probability level, and (**b**) primary hydrogen-bond interactions in **3**. Hydrogen bonds are shown as orange dashed lines. See Table S1 for symmetry codes.

In **3**, **inam** is practically planar (θ1, −0.5◦), which contrasts with the values of this torsion angle found in polymorphs I, III and V of the pyridinecarboamide (Table 2). Conformational differences are also observed in the **L-H2ma** molecule. Note especially that the four molecules of the two polymorphs of **L-H2ma** have substantially different conformations from those found in the cocrystal, particularly θ3.

Another way to describe the hydrogen bond interactions in the crystal packing is considering two self-complementary amide–amide pairwise homosynthon dimers between **inam** mutually parallel molecules linked through two molecules of mandelic acid each by hydrogen bonds of O−H···O type between OH of the alcohol group and the carbonyl O atom of each symmetrically related amide, giving rise to a supramolecular dimer of graph set *R*<sup>4</sup> <sup>4</sup>(12), in the direction of the "a" axis (Figure 6a), and also in the plane "bc" by means of a carboxylic acid–pyridine interaction forming supramolecular heterosynthons of graph set *R*4 <sup>6</sup>(28) (Figure 6b). The set of these interactions gives rise to a crystal network constituted by independent layers parallel to the "a" axis (Figure 6c).

In the formation of cocrystals of **3**, the probable mechanism must include a first stage of molecular recognition between two amide molecules to form the well-known amide–amide homosynthon. In a second stage, two of those homodimers, symmetrically related, are associated by hydrogen bonds, to form the aforementioned tetrameters (Figure 6a,b).

**Figure 6.** View of amide–amide homosynthon showing (**a**) O−H···O interactions, (**b**) O−H···Npy interactions and (**c**) packing diagram for **3,** viewed in the "bc" plane.
