**1. Introduction**

Crystal engineering deals with the study of non-covalent interactions within crystals, the understanding of crystal structures, and the design and synthesis of new solids with desired and specific properties by utilizing the hydrogen bond, supramolecular synthon strategy [1–5]. Crystal engineering approaches have been used in the preparation of novel solid active forms of pharmaceutical ingredients (APIs), for improving the physicochemical properties of drug molecules by making multi-component crystals, such as solvates [6], cocrystals [7–9], and salts [10]. In the supramolecular synthon strategy in the pharmaceutical field, salt formation of APIs remains a potential method to improve the solubility and stability of native APIs.

Disopyramide (2-diisopropylaminoethyl)-phenyl-2-pyridineacetamide) (DPA) is a class IA antiarrhythmic drug [11] that shows polymorphism behavior [12]. Disopyramide and its phosphate salt are intravenously and orally administrated for clinical use [13,14]. There is very limited research on the crystal engineering of DPA available in the literature [15], and there are only limited DPA phosphate salt [16] crystal structures of solid forms of DPA to be found in the Cambridge Structural Database (CSD). DPA has a basic nature and is likely to form salts/cocrystal adduct with different cofomers that have acid functionality. Moreover, DPA has a flexible molecular framework, with a hydrogen bond donor and acceptor site, and can adopt different orientations or conformations in the novel solid form; hence, from a crystal engineering viewpoint, DPA could be a molecules that has the potential for the exploration of different solid forms by the use of crystal engineering principles.

With this in mind, our intention is to explore the novel solid form of DPA by using different acidic coformers and to see their effect on the conformation of DPA and molecular

**Citation:** Tamboli, M.I.; Utusmi, Y.; Furuishi, T.; Fukuzawa, K.; Yonemochi, E. Crystal Structure of Novel Terephthalate Salt of Antiarrhythmic Drug Disopyramide. *Crystals* **2021**, *11*, 368. https://doi.org/10.3390/cryst11040368

Academic Editor: Sławomir J. Grabowski

Received: 28 February 2021 Accepted: 28 March 2021 Published: 31 March 2021

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packing in crystal structures, because there is only one crystal structure of DPA phosphate salt reported by Kawamura and Hirayama [16] in the CSD. In the current study, we have selected Terephthalic acid (TA) as the salt former, which has a para disubstituted carboxyl group on the benzene ring (Figure 1). In this article, we discuss the preparation method of DPA:TA salt and carry out X-ray single-crystal structural analysis; the obtained new salt was further evaluated by solid-state characterization. phosphate salt reported by Kawamura and Hirayama [16] in the CSD. In the current study, we have selected Terephthalic acid (TA) as the salt former, which has a para disubstituted carboxyl group on the benzene ring (Figure 1). In this article, we discuss the preparation method of DPA:TA salt and carry out X-ray single-crystal structural analysis; the obtained new salt was further evaluated by solid-state characterization.

With this in mind, our intention is to explore the novel solid form of DPA by using different acidic coformers and to see their effect on the conformation of DPA and molecular packing in crystal structures, because there is only one crystal structure of DPA

**Figure 1.** Structures of (**a**) racemic Disopyramide (DPA) and (**b**) Terephthalic acid (TA). **Figure 1.** Structures of (**a**) racemic Disopyramide (DPA) and (**b**) Terephthalic acid (TA).
