3.7.2. Dissolution Testing

Dissolution testing was performed to observe how salt cocrystal formation a ffected the ND release rate. Tests were carried out with samples equivalent to 200 mg ND in 900 mL gastric medium (pH 1.2) and intestinal medium (pH 6.8) [25,26,48,55–57]. Diclofenac solubility has been reported to be influenced by pH medium and has the optimum dissolution in pH neutral to base [25,48,57]. Based on dissolution profiles on pH 1.2 medium (Figure 17a), the maximum drug release from all samples (ND, NDPM, and NDPT) was achieved after 15 min dissolution, but in a very low concentration. This result was in line with the information from references [26,49,58]. Due to the acidity of ND (pKa: 4, at 25 ◦C), it showed that in the gastric medium, each sample was not completely separated because hydrogen ions inhibited diclofenac dissociation. However, NDPM was superior in increasing the percentage of drug release. Based on the Henderson–Hasselbach's equation at a pH below the pKa of

**Figure 17.** Dissolution profile of anhydrous diclofenac sodium (ND), salt cocrystal diclofenac–sodium– proline–monohydrate (NDPM), and salt cocrystal diclofenac–sodium–proline–tetrahydrate (NDPT) in (**a**) gastric pH (1.2) medium and (**b**) intestinal pH (6.8) medium.

ND dissolved in the pH 6.8 medium. However, it needed time, which was represented by the dissolution profile in Figure 17b. This figure shows that NDPM dissolution was fastest at intestinal pH, which reached a maximum concentration (100% released of 200 mg drug) after 5 min. NDPT needed

only 10 min. Meanwhile, the ND curve still increased after 45 min. This means that NDPM was superior in releasing diclofenac in pH 6.8 medium compared to the single ND and the NDPT. As shown in this figure, the existence of LP can push the dissolution, even in the physical mixture. However, the cocrystal formation made the interaction between ND and LP intensively by a stronger hydrogen bonding than the physical mixture. The very immediate entire release of NDPT occurs because the hydroxyl ion can accelerate the dissociation of diclofenac.

The increase in diclofenac solubility from NDPM and NDPT was due to the ability of LP to arrange the coordinate binding with Na<sup>+</sup> and interact as a zwitterion molecule with diclofenac acid. This extraordinary double action of LP facilitated contact between the diclofenac moiety and the dissolution medium, in addition to the dissociation of Na<sup>+</sup> with diclofenac molecule in the media. By increasing dissolution, NDP salt cocrystals can be expected to improve diclofenac bioavailability [6,59]. The dissolution profile of the salt cocrystals was better than the previous non-salt cocrystal of diclofenac–proline [20], as the sink dissolution conditions can lead to problems with the absorption step of the drug [47,60] did not exist. ND had a good dissolution profile in the buffered pH 6.8 medium, but the cocrystals were superior. The amphoteric ability of LP may adjust the pH to the optimum environment for diclofenac dissolution (the medium pH was measured as 6.8–7.0 after the final dissolution), along with hydrotropic property, which contributes to improve dissolution. NDPM showed a faster dissolution than NDPT for a similar reason to the solubility data. The monohydrate crystal lattice is smaller and has a looser and more spacious space compared to the tetrahydrate form, as presented in Figures 8 and 14, making it dissolve faster. This data was in accordance with anhydrous ND, which has a higher solubility than its hydrate forms [26,28,29].
