*3.6. Stability Testing*

Several stability studies are typically performed during the development of cocrystals, including drying and humidifying studies. The type of stability test depends on the structural characteristics of the sample [20,23,52–54]. Due to the four water molecules and the two LP molecules coordinated to Na<sup>+</sup> (sodium), it can be predicted that NDP can be transformed from one hydrate to the other phase easily, as well as ND [23–29]. The existence of a cationic element, mainly alkaline, has been well known to absorb water molecules quickly and release the water under dry conditions. Therefore, the hydrate stability test under drying and extreme humidity were essential to perform.

### 3.6.1. Thermal Profile Analysis on Dried Stability Test Samples

Dried samples were evaluated using DTA/TG/DSC and the data are shown in Figure 14. Figure 14a is DTA thermogram of the samples, show the decreasing of dehydrated curve at ~30–100 and 100–125 ◦C by the heating. Next, the TG thermograms in Figure 14b show the release of water of the hydrate at 2–6 h, leaving approximately one water molecule after 12 h or equal to a monohydrate salt cocrystal. It finally lost almost all water molecules after 24 h of drying in a controllable incubator, set at 30% RH/40 ◦C. DSC analysis was also conducted to confirm the thermal data of the new phases. The obtained thermograms are presented in Figure 14c, which are equal with the DTA/TG profile. These data were then elaborated with PXRD analysis, which will be discussed in Section 3.6.3.

(**a**) 

**Figure 14.** *Cont.*

(**b**) 

**Figure 14.** DTA (**a**), TG (**b**), and DSC (**c**) thermograms of NDPT sample that was stored in the incubator 30% RH/40 ◦C for 0, 2, 6, 12, and 24 h.

3.6.2. Thermal Profile Analysis on Humidified Stability Test Samples

Figure 15a shows the NDPT cocrystal thermograms from DSC after 24, 48, and 72 h of storage in a chamber of 94 ± 2% RH/25 ± 2 ◦C. The first endothermic peak at ~86 ◦C is a water release point and the second endothermic peak is shown at ± 116 ◦C. The slightly different profile of the 72 h and

15 days samples were shown in the first endothermic curve, separated into two small peaks. However, TG thermograms in Figure 15b reveal that the water portion did not increase significantly after 15 days, which was ~0.5% *w*/*w* or equal to 0.1 moles of water molecules only. This data indicated that the tetrahydrate was still stable. PXRD analysis confirmed NDPT stability under this humid condition, as explained in Section 3.6.3, concurrently with the drying stability test result.

(**a**) 

**Figure 15.** DSC (**a**) and TG (**b**) thermograms of NDPT after storage at high relative humidity of 94% RH/25 ± 2 ◦C for 24, 48, 72 h, and 15 days.

(**b**)

### 3.6.3. PXRD Analysis of Stability Test Samples after Drying and Humidifying

PXRD was then used to confirm the thermal analysis data from the stability test on NDPT samples, which were collected both by drying and storage in humid conditions, shown in Figure 16. ND, NDH, and LP diffractograms were depicted as the reference. Previously, it was predicted that the drying of NDPT would produce NDPM, as did by heating NDH to produce ND [25,26]; however, the diffractogram data revealed that the dried sample after 6 h of storage at 30 ± 0.5% RH/40 ± 0.5 ◦C showed a mixture peaks of NDPT and the starting materials, i.e., ND and LP, without any less hydrate of NDP. In this figure, the specific peaks of samples are assigned by the ticks in yellow (NDPT), blue (NDH), and green (LP). Moreover, NDPT changed to a similar diffraction pattern with a mixture of the components, anhydrous ND and LP, which are depicted in the figure as the comparison, after 12–24 h of drying. The ND peaks at 2θ = 6.7◦, 8.6◦, 15.2◦, and 17.2◦ (blue ticks) appeared in the dried NDPT samples, as well as LP peaks at 2θ = 15.2◦, 18.0◦, 19.5◦, and 24.8◦ (purple ticks). The final mixture did not contain NDH due to the dry condition desorbed all water molecules. These data describe that water loss broke cocrystal binding and did not result in another new phase, including NDPM. Thus, the water molecule was crucial in the NDPT system to mediate the interaction between components in this tetrahydrate salt cocrystal.

**Figure 16.** Diffractogram of NDPT fresh preparation after drying in 30% RH/40 ◦C for 6 h and 24 h, dried NDPT after 2 h restored in 72 ± 2% RH/25 ± 2 ◦C, and dried NDPT after restored in a 94% RH/25 ± 2 ◦C chamber for 15 days. Anhydrous ND, NDH (tetrahydrate), and LP diffractograms were depicted as the comparison. Assigned peaks represent ND (blue ticks), LP (purple ticks), and NDPT (yellow ticks).

Inversely, Figure 16 also shows that after 2 h restored under ambient conditions (72 ± 2% RH/25 ± 2 ◦C), the diffractogram of the sample was back to the NDPT profile, with the specific peaks at 2θ = 4.3◦, 7.2◦, 13.0◦ (yellow ticks), without producing NDPM. Moreover, NDPT was still stable under high humidity, i.e., 94 ± 2% RH/25 ± 2 ◦C, until 15 days, indicated by the steady diffractograms. In conclusion, NDPT was a stable phase, comparable to NDH pseudo polymorphs' stability, which has been reported to be more stable than ND [25,26,28,29]. Anhydrous ND changed rapidly under ambient conditions to its hydrate (NDH) [25,26], similar to NDPM, which quickly transformed into NDPT. However, it di ffers from NDH-ND transformation, which can occur easily by drying under the dry condition (30% RH/40 ◦C), NDPT could not transform to the less hydrate by this manner.
