3.7.1. Solubility Testing

Solubility is of utmost importance in the pharmaceutical field because the drug must dissolve before being absorbed. Table 3 depicts the solubility data for ND, NDPM, and NDPT. The solubility of the physical mixture of anhydrous ND with LP was conducted to represent the dried system, which was not found as the monohydrate cocrystal. Based on the solubility test results, after the equilibrium state, diclofenac was dissolved more readily from NDPM and NDPT, i.e., 4.08 and 3.31-fold increase compared ND solubility, respectively. NDPM was revealed to have higher solubility than NDPT, comparable to anhydrous ND behavior, which was superior to ND hydrate due to the lower of crystal lattice energy with a wider space between molecules [24–29]. The increased solubility of the NDP systems was related to the decrease in lattice energy, which promoted the breaking down of solid intermolecular bonds immediately [20,46,48–51,54].

In addition, the characteristic crystal structure associated with solubility in the NDP salt cocrystals was in the presence of a region consisting only of Na<sup>+</sup> ions and water molecules (Na chain) that has a su fficiently higher a ffinity for water than diclofenac acid and LP. Because of this higher a ffinity, Na<sup>+</sup> ions and water molecules would be dissolved first through the chain region. As a result, the entire NDP crystal breaks up and dissolves (reduction in lattice energy stabilization). Therefore, the presence of the Na chain and the LP layer would be one of the reasons why the solubility was higher than that of ND. Several studies have reported that such a layer or channel structure consisting only of higher solubility molecules improves the solubility of API multicomponent crystals [50,51].


**Table 3.** Solubility curve (in CO2-free distilled water, pH 7.0) of ND, NDPM, and NDPT.
