*3.5. Diclofenac Sodium-Proline Monohydrate Salt Cocrystal Isolation, Characterization, and Structure Determination*

We attempted to discover the other hydrate form of NDP by arranging the different circumstances of cocrystal production, called condition II. This condition was performed by storing all starting materials in a desiccator with silica gel for 24 h (0% RH/25 ± 2 ◦C) to minimize water existence. FTIR, TG, and PXRD were used to evaluate the solid state of ND and LP. As a result, we observed that even NDH back to ND, in line with the works in [25,26]. Based on the previous data of NDPT, the water molecule was shown to be prominent in the intermolecular interaction. From a screening, the starting materials of ND and LP were still found when the pure solvent (≥98%) was used. Thus, next cocrystal was collected using the purer solvents than that was used to produce NDPT, but it should still provide a small amount of water, i.e., the aqueous 90–95% *v*/*v* organic solvents. From this condition, a new crystal habit differed to NDPT was obtained successfully. The photographs present the newest crystalline morphology in Figure 9 (left) compared to the previous structure, NDPT, in Figure 9 (right).

**Figure 8.** The Na chain structure in NDPT (diclofenac–sodium–proline–tetrahydrate), Na<sup>+</sup> is in violet.

**Figure 9.** Crystal of the new diclofenac–sodium–proline–monohydrate (**a**) compared to NDPT (**b**) under a binocular microscope observation (100×).

The DTA/TG results of the newest cocrystal are revealed in Figure 10 below. Red and blue curves represent DTA and TG thermograms, respectively, which show the water release from room temperature to 200 ◦C. Approximately 2% of water released gradually at 30–100 ◦C, followed by a rapid loss of the left of ~ 2% water molecule (equal to 0.5 moles of water) at 100–116 ◦C, which occurred together with the melting point shown by a peak on DTA thermogram at 106 ◦C. It means that NDPM's melting point was not significantly different from NDPT. The total water release was ~4% *<sup>w</sup>*/*<sup>w</sup>*, or equal to a monohydrate. Therefore, it was named diclofenac sodium–proline–monohydrate (NDPM). Based on TG data, as well as shown in the NDPT thermogram, half moles of water molecule interacted strongly with the other components in NDP, which released lastly by breaking down the cocrystal completely.

**Figure 10.** DTA and TG thermograms of NDPM.

PXRD analysis collected the diffractogram pattern of NDPM, which is depicted in Figure 11, showing the distinguished peaks at 2θ = 4.0◦, 8.2◦, 12.4◦, and 13.3◦; compared to NDPT peaks at 2θ = 4.3◦, 7.2◦, 10.4◦, and 13.0◦. This data confirmed that the new crystal obtained from the condition II was a different phase than NDPT, which then was determined further by SCXRD.

**Figure 11.** The measured diffraction pattern of NDPM (red) shows the different profile compared to NDPT (blue).

The structure determination using SCXRD at −180 ◦C confirmed that the new phase was a monohydrate, which consisted of diclofenac–sodium–proline–water (1:1:1:1). The ORTEP draw of NDPM structure is depicted in Figure 12a. In addition, Figure 12b reveals the similarity of the empirical and calculated diffractogram. Thus, the data show that NDPM structure has been determined entirely.

**Figure 12.** (**a**) ORTEP cell view and molecular structure graph of NDPM; Na<sup>+</sup> is in violet. (**b**) The measured and calculated diffractograms of NDPM.

The detailed element configuration of NDPM is shown in Figure 13. This figure presents that diclofenac is coordinated around the Na<sup>+</sup> network to form a layer structure. Meanwhile, LP allowed Na<sup>+</sup> to build a coordination network. However, the data of NDPM were not as perfect as the NDPT data, due to the instability and very thin crystal habit of this phase. Crystal NDPM was shown to be unstable and immediately transformed into NDPT, indicated by the habit change of the cocrystal under ambient conditions. This property was confirmed by TG/DTA and PXRD, which will be discussed further in Section 3.6 (Stability Testing).

**Figure 13.** The order of diclofenac–sodium–proline (NDP) system. L-proline (LP) allows Na<sup>+</sup> to form a coordination work with diclofenac site. Na<sup>+</sup> is in violet.

The crystal data of NDPM is listed in Table 2 below.


In conclusion, the multicomponent of ND with LP was found in two forms, which were tetrahydrate (NDPT) and monohydrate (NDPM) salt cocrystals. The crystal data of NDPT and NDPM have been submitted to Cambridge Crystallographic Data Center (CCDC) with the deposit number 1938590 and 1983478, respectively. At the present time, the anhydrous phase is under investigation and not ye<sup>t</sup> developed because it is difficult to compose, even in its powder form. This fact underlies the prediction that the presence of water is crucial in the formation of hydrogen bonds in this new salt cocrystal multicomponent system.
