**1. Introduction**

Recent past literature related to crystal engineering revealed that there is an intensification of interest in the preparation, crystallization, solid-state characterization and the studying of the X-ray single-crystal structure of active pharmaceutical ingredients (APIs) and their novel solid forms that includes polymorph [1–5], multi-component crystal such as cocrystals [6–8], salt [9], and solvate [10–14] due to their potential applications in the improvement of physicochemical properties of APIs such as solubility [15–17], stability [18–20], hygroscopicity [21], bioavailability [22–24] and so on. Further, advancement in this research area directed towards the understanding crystal–structure, studying supramolecular synthons, hydrogen/halogen bonding interaction and other various non-covalent interactions within them [25–27] as well as correlating structure with the physicochemical properties [28–32]. These structure-property relation studies are helpful and encourage many researchers towards designing and synthesis of new functional molecular solids, and multi-component complexes of APIs, and other molecular entities with desirable and specific chemical or physical properties [33–38].

**Citation:** Tamboli, M.I.; Okamoto, Y.; Utsumi, Y.; Furuishi, T.; Wang, S.; Umeda, D.; Putra, O.D.; Fukuzawa, K.; Uekusa, H.; Yonemochi, E. Crystal Structures of Antiarrhythmic Drug Disopyramide and Its Salt with Phthalic Acid. *Crystals* **2021**, *11*, 379. https://doi.org/10.3390/ cryst11040379

Academic Editor: Duane Choquesillo-Lazarte

Received: 27 February 2021 Accepted: 30 March 2021 Published: 6 April 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Disopyramide (2-diisopropylaminoethyl)-phenyl-2-pyridineacetamide (DPA) was developed [39] as a class IA antiarrhythmic drug with a pharmacological profile of action similar to that of quinidine and procainamide in that targets sodium channels to inhibit conduction [40,41]. Currently, DPA and [C21H30N3O]**<sup>+</sup>** [H2PO4] − disopyramide dihydrogen phosphate are intravenously and orally administrated for clinical use. DPA displaying polymorphism behavior and two solid forms were reported in the literature and named as a low-melting type crystal (85–87 ◦C) and a high-melting type crystal (95–98 ◦C) [42]. Of the two crystal forms, the high melting point type crystal is thermodynamically stable, and the low melting point type crystal is easily converted to the high melting point type crystal [42]. However, single-crystal X-ray data of either of crystal form were not present in the Cambridge Structural Database *(*CSD*)*, whereas the crystal structure of [C21H30N3O]**<sup>+</sup>** [H2PO4] − disopyramide dihydrogen phosphate has been reported by Kawamura and Hirayama in 2011 [43]. Furthermore, X-single crystal structure of (+)-disopyramide (2R,3R)-bitartrate salt was reported in 1980 for determining the absolute configuration of disopyramide by Burke and Nelson [44], and the structure was not present in the CSD. Moreover, to the best knowledge of the authors, not much research has been carried out with respect to creating the novel salt form of DPA. mura and Hirayama in 2011 [43]. Furthermore, X-single crystal structure of (+)-disopyramide (2R,3R)-bitartrate salt was reported in 1980 for determining the absolute configuration of disopyramide by Burke and Nelson [44], and the structure was not present in the CSD. Moreover, to the best knowledge of the authors, not much research has been carried out with respect to creating the novel salt form of DPA. DPA has asymmetric carbon marked by a star that is connected to four different groups shown in Figure 1a. It has a flexible molecular framework as well as the presence of a hydrogen bond donor and acceptor site, and hence there will be a high possibility to form multicomponent crystals. Thus, it could be the potential candidate in exploring its different conformational modification by obtaining X-ray single crystal structures of different solid forms of DPA. We are going to focus on the crystallization and crystal engineering research on active pharmaceutical ingredients (APIs), particularly on improving the physicochemical properties of drug molecules by undertaking polymorphic study [45], making multi-com-

*Crystals* **2021**, *11*, x FOR PEER REVIEW 2 of 20

able and specific chemical or physical properties [33–38].

solids, and multi-component complexes of APIs, and other molecular entities with desir-

developed [39] as a class IA antiarrhythmic drug with a pharmacological profile of action similar to that of quinidine and procainamide in that targets sodium channels to inhibit conduction [40,41]. Currently, DPA and [C21H30N3O]**+**[H2PO4]**−** disopyramide dihydrogen phosphate are intravenously and orally administrated for clinical use. DPA displaying polymorphism behavior and two solid forms were reported in the literature and named as a low-melting type crystal (85–87 °C) and a high-melting type crystal (95–98 °C) [42]. Of the two crystal forms, the high melting point type crystal is thermodynamically stable, and the low melting point type crystal is easily converted to the high melting point type crystal [42]. However, single-crystal X-ray data of either of crystal form were not present in the Cambridge Structural Database *(*CSD*)*, whereas the crystal structure of [C21H30N3O]**+**[H2PO4]**−** disopyramide dihydrogen phosphate has been reported by Kawa-

Disopyramide (2-diisopropylaminoethyl)-phenyl-2-pyridineacetamide (DPA) was

DPA has asymmetric carbon marked by a star that is connected to four different groups shown in Figure 1a. It has a flexible molecular framework as well as the presence of a hydrogen bond donor and acceptor site, and hence there will be a high possibility to form multicomponent crystals. Thus, it could be the potential candidate in exploring its different conformational modification by obtaining X-ray single crystal structures of different solid forms of DPA. ponent crystals [46], such as its solvates [47], cocrystals [48], and salts [49]. In this report, we discuss the X-ray single-crystal structure of the lower melting temperature form of DPA and novel DPA\_PA salt [Phthalic acid (PA), Figure 1b], detailed crystal structure analysis and its characterization.

**Figure 1.** Structures of (**a**) racemic disopyramide (DPA) and (**b**) phthalic acid (PA). **Figure 1.** Structures of (**a**) racemic disopyramide (DPA) and (**b**) phthalic acid (PA).

**2. Materials and Methods**  *2.1. Materials*  DPA and PA were purchased from Tokyo Chemical Industry Co. Ltd. (Tokyo, Japan). All other analytical-grade solvents and reagents were commercially obtained and used without further purification. We are going to focus on the crystallization and crystal engineering research on active pharmaceutical ingredients (APIs), particularly on improving the physicochemical properties of drug molecules by undertaking polymorphic study [45], making multicomponent crystals [46], such as its solvates [47], cocrystals [48], and salts [49]. In this report, we discuss the X-ray single-crystal structure of the lower melting temperature form of DPA and novel DPA\_PA salt [Phthalic acid (PA), Figure 1b], detailed crystal structure analysis and its characterization.
