**1. Introduction**

The preparation of alternative salts, and more recently cocrystals, of many active pharmaceutical ingredients (APIs) has gained great attention as an important strategy in crystal engineering for the last decades. The use of salts and cocrystals for improving the physico-chemical properties of APIs has been demonstrated, as these solids can modify the solubility or dissolution rate, or even improve the physical stability. Around a half of the marketed products are estimated to be sold as salt forms [1]. Oxalic acid is among the different salt-forming acids listed for this purpose. It belongs to the second class of salt formers according to the *Handbook of Pharmaceutical Salts: Properties, Selection and Use* [1], as they are not naturally occurring but during their application have shown low toxicity and good tolerability. Through a search in the FDA Orange Book Database, we found only two approved examples, which are the specialty dosage forms commercialized as Lexapro® and Movantik®. The first one, in the market since 2009, is used for the treatment of depression and anxiety. Interestingly, it is not a classical salt, but in fact it is a hydrated cocrystal of a salt, composed of protonated escitalopram cations, oxalate dianions, unprotonated oxalic acid molecules and water molecules [2]. The second dosage form contains naloxegol oxalate, indicated for the treatment of opioid-induced constipation in adults with chronic non-cancer pain. Curiously, it was found through a small-scale screening due to the difficulties in preparing naloxegol in solid form [3]. As a result, two polymorphic forms were described, and the crystal structure resolution of Form B showed that it contained hydrogen oxalate anions [4]. In spite of the low incidence of oxalic acid in the list of the most used anions in APIs [5], many other examples have also been described in the literature exhibiting the interest of the scientific community for this coformer [6–9].

Among pharmaceutical compounds, nucleobases are of great value thanks to their contribution as structural components of several pharmaceuticals as well as for their

**Citation:** Benito, M.; Barceló-Oliver, M.; Frontera, A.; Molins, E. Oxalic Acid, a Versatile Coformer for Multicomponent Forms with 9-Ethyladenine. *Crystals* **2022**, *12*, 89. https://doi.org/10.3390/ cryst12010089

Academic Editor: Josep Lluís Tamarit

Received: 10 December 2021 Accepted: 5 January 2022 Published: 10 January 2022

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biological function as part of DNA and RNA. Very recently, a new cytosine derivative has been announced for COVID-19 oral treatment, molnupiravir [10].

After a careful revision of cocrystals or salts between oxalic acid and nucleobases or related compounds only a few examples resulted. These include pure adenine [11], N6-benzyladenine [12], or the following xanthines: caffeine [13,14], theobromine [15] and theophylline [16,17]. The only example described as a cytosine derivative was for the antiretroviral compound, lamivudine [9].

9-Ethyladenine (9ETADE) is a modified nucleobase with the amino group at N(9) blocked by an ethyl chain (Scheme 1a). We have previously reported the ability of this modified nucleobase to form different salts and/or cocrystals with alkyl dicarboxylic acids (HOOC-Xn-COOH, with n from 1 to 4) as coformers depending on the ΔpKa [18]. Now, as a continuation of our work related to this modified purine, we describe herein the special situation with oxalic acid. This is the most acidic (pKa = 1.19) and shortest alkyl dicarboxylic acid we have studied but the most versatile and promiscuous in rendering several solid forms.

**Scheme 1.** (**a**) Molecular structure of 9-ethyladenine with numbering and (**b**) compounds of 9-ethyladenine with oxalic acid prepared in this work.

Herein, we present several multicomponent forms obtained by combination of the model compound 9-ethyladenine and oxalic acid, which have been prepared by solvent/slurry crystallization or mechanochemistry (liquid assisted grinding (LAG) or neat grinding (NG)) and their full characterization. The crystal structures of the two anhydrous salts have been solved. Moreover, density functional theory (DFT) calculations were used to understand/study their supramolecular interactions focusing on the energetics of the Hbonds, which were computed by carrying out a topological analysis of the electron density.
