*3.4. NDPT Crystal Structure Determination*

The crystal structure of NDPT was determined by single-crystal X-ray analysis entirely, resulting in crystallographic data, which are listed in Table 1. From the study, NDP multicomponent crystal was confirmed to contain equimolar amounts of ND and LP. Furthermore, this crystal was found to be a hydrate with four water molecules for one molecule of ND and LP. Thus, it met with the TG result and was fixed to be a tetrahydrate. The salt cocrystal structure is depicted in Figure 6a, with the diffractogram is shown in Figure 6b.



(**a**)

**Figure 6.** (**a**) ORTEP cell view and molecular structure graph of NDPT; Na<sup>+</sup> is in violet. (**b**) The measured and calculated diffractograms of NDPT.

The crystallographic data of NDPT are listed in Table 1, which revealed that this new phase is a monoclinic crystal with the space group *P*2*1*.

Considering the atomic distance in the NDPT crystal structure, as shown in Figure 7, the C–O distance indicated that the diclofenac molecule was ionized. Based on this analysis, it can be concluded that the new crystal phase was a salt cocrystal, arranged from an ionized drug (diclofenac sodium) with a neutral coformer (LP) and supported by the water molecules as the bridge between the components. This interaction was different from the previous cocrystal of neutral diclofenac acid with LP [20]. The alkaline and ionized diclofenac can be expected to increase solubility and dissolution more than the neutral cocrystal, which then was proven further.

**Figure 7.** C–O distances in diclofenac molecules in NDPT.

Figure 8 presents the unique conformation of each component in the tetrahydrate salt cocrystals, which involves sodium, diclofenac, proline, and water. In the asymmetric unit of this crystal, there are two ND and two LP molecules and eight water molecules. From these water molecules, six molecules coordinate to Na<sup>+</sup>, and two molecules form hydrogen bonds with other water molecules, LP molecules, and diclofenac molecules without coordination to Na<sup>+</sup>. In addition, two LP molecules were also coordinated to Na<sup>+</sup>, which was a 6-coordinated structure totally. These coordination bonds formed a one-dimensional (along a-axis) chain consisting of Na atom and water molecules, and both diclofenac molecules were connected to this Na chain by hydrogen bonds with water molecules. Furthermore, the carboxy oxygen of the diclofenac molecule formed a hydrogen bond with the nitrogen atom of LP. The formation of this hydrogen bond (C=O ··· HN) was also detected by an FTIR band at 1620 cm<sup>−</sup><sup>1</sup> and the change of 500–600 cm<sup>−</sup><sup>1</sup> band. The LP molecule was disordered at the 5-membered ring.
