3.3.3. Thermal Analysis

Next, the electrothermal measurement on NDH showed a water spot at 70–100 ◦C, decomposed from 239.5 ◦C (change to a yellow mass), and finally melted at 288 ◦C. LP melted at 227 ◦C, as well as NDH, was continued by decomposition. Meanwhile, the new crystals released globules of water from about 50 ◦C, became very wet at ~86 ◦C, melted at ~116 ◦C as a clear liquid, and decomposed after ~200 ◦C, indicated by the color change and gas release. Thus, it can be concluded that the new cocrystal had a lower melting point than the starting components. In addition, all samples decomposed after melting.

The DSC and DTA/TG measurement results are presented in Figure 4. Figure 4a depicts a DSC thermogram overlay of NDH, LP, and NDP crystals. Figure 4a shows that NDH had endothermic curves at 50 and 70 ◦C, which indicates water release, next it melted at ~280 and oxidized at 288 ◦C. This data met the reference of ND tetrahydrate, as well as the FTIR spectra [26]. Meanwhile, LP melted and decomposed at 227 ◦C. Next, all thermograms of NDP cocrystals from aqueous 90% of methanol, ethanol, and acetone in this figure reveal the similar first endothermic peaks at 86.4, 85.2, and 85.3 ◦C; and the second peaks at 114.5, 115.2, and 116.5 ◦C, respectively. The first curves are predicted as the first step of water release, and the second curves indicate the last part of the water molecule release, which concurrently occurs with the melting point. It can be seen here that the melting point of NDP at 114–116 ◦C was significantly lower than the starting components (288 and 227 ◦C). The samples decomposed after 200 ◦C, which was indicated by an endothermic curve of DSC/DTA thermogram and the sharp loss of mass, as shown by the TG thermogram. These data in line electrothermal analysis results. The decrease of melting point reflects hydrogen bond formation between the compounds with the water molecule, which contributed crucially. The new thermal profile can be expected to impact on other physicochemical properties such as solubility, dissolution rate, and stability [14,15,20,47–51].

The DSC thermogram was then elaborated with DTA/TG data in Figure 4b, which shows that the mass decrease of NDP cocrystal was ± 14.2% *w*/*w* or equal to four water molecules. Hereafter, this new phase was estimated as a tetrahydrate form, named diclofenac sodium proline tetrahydrate (NDPT). A small difference in the transition temperature was shown between DSC and DTA/TG. The water release and melting point temperature on DTA/TG thermograms are shown similar to electrothermal data, but the endothermic peak of DTA was depicted lower than DSC. This difference was caused by the open pan used in DTA/TG versus the closed pan used in the DSC measurement.

The open pan used in DTA/TG measurement facilitated the loss of water freely, as did the open capillary tube used in the electrothermal study. Therefore, the endothermic peak of the melting point on the DSC thermogram was at the end of the DTA endothermic peak and the transition point of TG thermograms, 116 ◦C. Following the specification and the standard operation of the procedure analysis, the closed pan was preferred to maintain the DSC's instrument durability. DSC is more sensitive than DTA and highly influenced by liquid or gas contaminants. Prior analysis using electrothermal, which was elaborated with DTA/TG, showed that ND, LP, and the NDP cocrystal broke down and released water and gas; therefore, the closed pan was the best choice for DSC analysis.

The relationship between hydrate release and cocrystal melting mechanism of NDP can be studied from the DTA (red) and TG (blue) thermogram. The TG thermogram in Figure 4b shows that 10.7% mass, equal to three water molecules, decreased sharply in the temperature range of 50 to 85 ◦C. This following by a flatter curve until 100 ◦C, which shows the weight decreased up to 12.3% *<sup>w</sup>*/*<sup>w</sup>*, or equal to 3.5 water molecules. Finally, the last step of loss water, which demonstrated on the thermogram as −2% of weight, equivalent to half moles of water, was evident at 100–116 ◦C. This final water release was related to the endothermic peak at 107 ◦C on the DTA thermogram, which concurrently indicated the melting point of the cocrystal. These thermal data led to the prediction that the water molecules interacted in the different strengths in NDPT, and the last part of the water release was responsible for the cocrystal breaking.

(**a**) 

**Figure 4.** (**a**) Differential scanning calorimetry (DSC) thermogram of diclofenac sodium hydrate (NDH); L-proline (LP); and NDP cocrystals from acetone, ethanol, and methanol, respectively. (**b**) DTA and TG thermogram of NDP, shown ~14.2% mass decrease or equal to 4 water molecules.
