**1. Introduction**

Diclofenac (DIC), a phenylacetic derivative non-steroidal anti-inflammatory drug (NSAID), is widely used in human and veterinary practice for the treatment of acute and chronic pain as well as in inflammatory and degenerative rheumatic diseases [1,2]. Diclofenac exerts its action through the inhibition of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes, which inhibit the synthesis of prostaglandins [3]. According to the Biopharmaceutics Classification System (BCS), DIC is a class II drug with low solubility and high permeability [4]. Due to its low solubility (0.9 ± 0.1 μg/mL) [5], achieving its minimum effective concentration requires a higher dosage in the formulation. However, the side effects of DIC have shown dosage-dependency; these include gastrointestinal damage and bleeding, nausea, hepatotoxicity, or renal failure. Moreover, when DIC is administrated orally, its low solubility increases the residence time in the stomach and the contact with the gastric mucosa, increasing the risk of gastric damage [6]. However, poor solubility is a major drawback not only for DIC but also for other Active Pharmaceutical Ingredients (APIs). For that reason, significant efforts have been made by both the industry and academia to develop new methodologies to enhance the physicochemical properties of APIs. Pharmaceutical multicomponent solid forms have gained much interest in the last decade due to their great potential to overcome drug performance limitations [7]. These solid forms are crystalline materials composed of two or more components. At least one must be an API, and the other, called cocrystal former or coformer, must be pharmaceutically acceptable, which means to be recognized as a safe molecule. Both components are

**Citation:** Acebedo-Martínez, F.J.; Alarcón-Payer, C.; Barrales-Ruiz, H.M.; Niclós-Gutiérrez, J.; Domínguez-Martín, A.; Choquesillo-Lazarte, D. Towards the Development of Novel Diclofenac Multicomponent Pharmaceutical Solids. *Crystals* **2022**, *12*, 1038. https://doi.org/10.3390/ cryst12081038

Academic Editor: Brahim Benyahia

Received: 13 July 2022 Accepted: 23 July 2022 Published: 26 July 2022

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in a stoichiometric ratio and interact through non-covalent interactions, mainly hydrogen bonds. These non-covalent interactions guide the organization of the molecules in the crystalline structure and allow the modulation of the physicochemical properties without covalent alterations of the API, whose activity and efficacy remain intact [8]. The literature reports pharmaceutical salts and cocrystals of DIC with amide (isonicotinamide [9]), amine (metformin [10], L-proline [11]), and xanthine (theophylline [12]), as well as pyridine-based coformers [13].

Nucleobases, the main component of nucleic acids, have attracted interest from the crystal engineering point of view because they can establish different hydrogen bond patterns [14]. This ability has been explored previously to form cocrystals and salts through NH···O=C hydrogen bond motifs [15]. Amine-carbonyl synthon has a remarkable key role in the transfer of genetic information and nucleic acid-protein recognition [16]. Moreover, nucleobase-derived drugs exhibit different biological roles, including anti-viral, antibacterial, and antitumoral activities [17,18].

This work reports the synthesis and physicochemical characterization of new multicomponent forms with diclofenac and a nucleobase: adenine, cytosine, and isocytosine (Scheme 1). The single crystal structure of all solid forms is thoroughly described, providing valuable insights into the structural differences that drive their physicochemical properties, mainly stability and solubility.

**Scheme 1.** Chemical formula of diclofenac (DIC), adenine (ADE), cytosine (CYT), and isocytosine (ICT).
