**1. Introduction**

In the past few decades, a number of drugs have shown poor physicochemical properties, especially aqueous solubility and stability, often affecting their absorption in the gastrointestinal tract [1]. Multicomponent crystal formation is an effective strategy to improve pharmacokinetic profiles without altering the main chemical structures and inherent biological activity [2,3]. Co-crystals and salts are two common forms of multicomponent crystals which might have higher solubility and faster dissolution behavior compared to untreated drugs [4,5]. Compared to cocrystals, salt formation is the simplest and most cost-effective strategy and has significant advantages in addressing poor aqueous solubility because of ionizable drugs [6].

Aripiprazole (ARI), a third-generation antipsychotic, is a dopamine D2 receptor partial agonist and D1 receptor agonist which can ameliorate hyperprolactinemia induced by other antipsychotic drugs and cause fewer side effects, such as weight gain, diabetes, and dyslipidemia [7,8]. However, ARI belongs to the Biopharmaceutics Classification System (BCS) class II and its clinical use is limited by its poor aqueous solubility [9,10]. As a weakly basic drug, salt formation is one of the most popular and effective approaches to improve physicochemical properties, especially solubility [6,11,12]. Many salts of ARI have been reported. Freire et al. reported successively eight crystal structures of ARI salts with nitrate, perchlorate, oxalate, phthalate, homophthalate, thiosalicilate, and two

**Citation:** Zhou, Q.; Tan, Z.; Yang, D.; Tu, J.; Wang, Y.; Zhang, Y.; Liu, Y.; Gan, G. Improving the Solubility of Aripiprazole by Multicomponent Crystallization. *Crystals* **2021**, *11*, 343. https://doi.org/10.3390/ cryst11040343

Academic Editor: Emilio Parisini

Received: 27 February 2021 Accepted: 25 March 2021 Published: 28 March 2021

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different dihidrogenphosphates [13–16]. Nanubolu et al. reported five ARI salts with benzoic acid, 2,4-dihydroxy benzoic acid, 2,5-dihydroxy benzoic acid, salicylic acid, and hydrochloric acid [17]. However, these studies mainly focus on the structure illustration, and key pharmaceutical properties were not given. While Zhao et al. synthesized six ARI salts with gallic acid, 4-aminosalicylic acid, acetylsalicylic acid, maleic acid, fumaric acid, and malic acid and evaluated their solubility and dissolution profile [18], new ARI salts with ideal pharmaceutical properties are still in demand.

Continuing to explore the excellent salts of ARI, we successfully obtained a new ARI salt with adipic acid (ADI) and its acetone hemisolvate, along with a known ARI salt with salicylic acid (SAL). The molecular structures of the ARI and cocrystal formers (CCF) are displayed in Scheme 1. Their comprehensive characterizations were conducted using powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The crystal structures of the ARI-ADI salt acetone hemisolvate and ARI-SAL salt were elucidated by single-crystal X-ray diffraction (SXRD) for the first time. Furthermore, computational studies, including molecular electrostatic potential surface (MEPS) and Hirshfeld surface analysis (HSA), were applied to explore molecular interactions between the active pharmaceutical ingredient (API) and CCF. Above all, their pharmaceutical properties, such as powder hygroscopicity, stability, solubility, and the intrinsic dissolution rate (IDR), were evaluated. The results showed that the solubility and IDR of the ARI-ADI salt and its acetone hemisolvate significantly improved. This study provides a potential strategy to increase the solubility of poorly water-soluble drugs and gain a comprehensive understanding of the structure–property relationship.

**Scheme 1.** Molecular structures of aripiprazole and cocrystal formers.
