**1. Introduction**

Diclofenac is a well-established non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic, and antipyretic activities [1], and is the most widely consumed NSAID in some countries. In Indonesia, diclofenac is one of the three most widely used NSAID drugs and represents 14.4% of all NSAIDs consumed in the country [2]. Based on the Biopharmaceutics Classification System (BCS), diclofenac is a class II compound with high permeability but low solubility, which results in limited bioavailability. Therefore, it is necessary to increase the solubility of the compound.

Techniques that can improve the solubility and bioavailability of drugs include cosolvation, surfactant usage, pH adjustment, solid dispersion, salt formation, and cocrystallization [3–7]. Pharmaceutical cocrystals are multicomponent systems in which two or more components, in a drug–drug or drug–coformer combination, are present in a stoichiometric ratio and bonded together with hydrogen interactions in a crystal lattice [7]. The rationale behind screening for suitable coformers for pharmaceutical development of a hydrophobic drug should consider the rule of five by Lapinski, i.e., hydrogen bonding, halogen bonding (and non-covalent bonding in general), length of the carbon chain, molecular recognition points, and aqueous solubility [8,9].

Cocrystals can be classified into three groups: anhydrous/non-solvated cocrystal, hydrate/solvate cocrystal, and salt cocrystal [9–11]. We are focusing on salt cocrystallization, which is a special kind of cocrystal having a salt structure (anion and cation) with a neutral coformer. It is expected to have a combined benefit of the salt and cocrystal properties, such as improved stability, solubility, dissolution, as well as enhanced the bioavailability [12–16]. As previously reported, salt cocrystal niclosamide and salt cocrystal pefloxacin can enhance solubility and dissolution [17,18]. Moreover, our previous research has shown that a salt cocrystal can be made from saccharine sodium salt with theophylline, as well as acidic saccharine with a similar excipient [19].

Diclofenac acid is a poorly soluble drug. Recently, we have attempted and reported on a cocrystal of neutral diclofenac acid with a zwitterionic coformer, L-proline (LP), which increased the drug solubility by more than 7.6-fold [20]. However, the solubility level was not improved over the salt form, diclofenac sodium, which has been developed and more commonly used in dosage forms at the present time [21–29]. Some reports have described that this sodium salt can be found in anhydrous and several hydrated forms, i.e., the tetrahydrate [24–26], pentahydrate [27], trihydrate [28], and 4.75-hydrate [29], respectively. These phenomena that cause commercial of anhydrous diclofenac sodium (ND) are often found in the mixture with the hydrate phases (NDH) during distribution and storage [28]. Fortunately, NDH could change back to ND by heating and drying [25,26,28,29].

This study aimed to discover salt cocrystals of NDH with LP (abbreviated NDP) to obtain the drug's superior properties, namely, stability, solubility, and dissolution [3–7,14–20]. Considering that ND was unstable, we initially arranged a cocrystal from NDH to develop a suitable and practical method, which can be performed readily even under the ambient conditions. As LP is a zwitterion, it was not expected to form a salt with diclofenac acid moiety. The cationic and anionic groups in this amino acid were predicted to arrange strong hydrogen bonds or charge interactions with other molecules [20]. The most important of LP physicochemical aspects are its high wettability, hydrotropic property, and its flexibility to dissolve in a wide pH range [20,30–32]. Besides, LP was selected again in this work due to its safety, economy, and availability.

The experiment began with screening the physical interaction between the compounds using a phase diagram, and then the cocrystal was isolated utilizing a specific molar ratio of components. The cocrystal was characterized by binocular microscope, infrared spectroscopy, thermal analysis, and powder X-ray di ffractometry, then it was assessed by single crystal X-ray di ffractometry until the final 3D structure was determined. Due to the pseudopolymorphism phenomenon of this new multicomponent cocrystal, the parameters that need to be discussed are the hydrate stability, which was tested by drying and humidifying at specific temperature and humidity levels. The next steps were solubility and dissolution tests. The results of this study are expected to demonstrate that this new phase derived from ND and LP increases the solubility and dissolution of ND and is stable.
