*3.1. ND and NDH Preparation*

The hydrate forms of ND have been extensively reported [24–29]. In this experiment, NDH was used as the initial material due to its stability compared to anhydrous ND, as previously stated, to absorbed water from the environment quickly. The instability of anhydrous ND raw material in pharmaceutical manufacturing caused it to mix with the hydrate forms. However, the dehydrated material can be obtained by heating or drying of NDH under specific conditions [25,26,28,29]. Therefore, we considered using NDH as the first starting material for the cocrystal screening instead of ND. First, NDH was prepared by storing the commercial ND (claimed as anhydrous) under ambient conditions (72 ± 2% RH/25 ± 2 ◦C) for 24 h.

As has been cited in Introduction section, there are some reported hydrate forms. However, FTIR, PXRD, and TG data confirmed that the NDH obtained from this technique was a tetrahydrate, which consisted of 20% water [26,28]. We also checked that even NDH changed to ND by restoring it in the desiccator with silica gel for 24 h (referred to anhydrous ND analysis standard, 99.9%, from Sigma Aldrich, Jakarta, Indonesia), also met the reports [25,26,28]. The NDH has been rechecked to be stable during the experiment, following the works in [25,26,29]. In addition, we also observed that NDH could be dehydrated and back to ND entirely by storing it in a desiccator with silica gel during 24 h. Powder X-ray di ffractogram and TG thermogram data of NDH and ND comparing to anhydrous ND analysis standard are attached in Supplementary S1–S3.

### *3.2. Determination of Molar Ratio in NDP for Cocrystallization*

The fixed molar ratio of ND and LP for arranging the cocrystal was determined using thermal profile analysis. Modification of covalent bonds in a chemical structure can change its melting behavior. Within the survey, 50 cocrystal samples were analyzed, and 51% of the cocrystals analyzed had melting points between those of the active pharmaceutical ingredient (API) and coformer, while 39% were lower than either the API or coformer. Only 6% had melting points higher than the starting materials, and 4% had melting points equal to either the API or coformer [15]. Thermal analysis through the construction of melting temperature versus the composition on a phase diagram is known to establish whether a combination forms a cocrystal or eutectic [15,33–36]. A typical binary phase diagram of a eutectic mixture will depict a V shape with one eutectic point. A cocrystal forms a "W" shape, with two eutectic points, and one higher melting point between them.

The melting temperature data (*y*-axis) of NDH–LP mixtures were plotted against the NDH molar fraction (*x*-axis) to produce a phase diagram (Figure 1). The phase diagram showing a "W" cocrystal typical pattern, with two eutectic points found at the molar fractions of ND 0.3 (at 88 ◦C) and 0.6 (at 98 ◦C), respectively. The graphic reveals that the 0.5 molar fraction of ND is the peak, has a higher melting temperature (at 116 ◦C) than the eutectic points. Therefore, NDH–LP (abbreviated NDP system) could be predicted to form a cocrystal with the 1:1 molar ratio as the fixed stoichiometric proportion.

**Figure 1.** Phase diagram of diclofenac sodium hydrate (NDH) and L-proline (LP) composed from a series of molar ratios, represented by the molar fraction of NDH in the mixture towards the melting point.
