**1. Introduction**

Risperidone (RSP), 3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one (Figure 1), is a benzoxazole derivative

**Citation:** Sbârcea, L.; T˘anase, I.-M.; Ledet,i, A.; Cîrcioban, D.; Vlase, G.; Barvinschi, P.; Micl˘au, M.; V˘aru¸t, R.-M.; Suciu, O.; Ledet,i, I. Risperidone/Randomly Methylated β-Cyclodextrin Inclusion Complex—Compatibility Study with Pharmaceutical Excipients. *Molecules* **2021**, *26*, 1690. https://doi.org/ 10.3390/molecules26061690

Academic Editors: Marina Isidori, Margherita Lavorgna and Rosa Iacovino

Received: 15 February 2021 Accepted: 15 March 2021 Published: 17 March 2021

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used in treating schizophrenia, behavioral, and psychological symptoms of dementia and irritability associated with autism [1,2]. This atypical antipsychotic drug blocks the serotonin-2 (5TH2) and dopamine-2 (D2) receptors in the brain. RSP is a member of the class of pyridopyrimdines that is practically insoluble in water and presents high lipophilicity (log *P* of 3.49), which makes it a class II candidate of the Biopharmaceutics Classification System (BCS) [1,3,4]. It exhibits the tendency of forming polymorphs [1], which could present different solubility, dissolution rates, and stability, leading to variations in the biopharmaceutical profile of its drug substance [5].

**Figure 1.** Chemical structure of risperidone.

Solubility is an essential feature of drugs, being one of the most critical and important characteristics that influence their bioavailability. Among the various approaches used to enhance the solubility of BCS II class drugs, encapsulation of the active pharmaceutical substances in cyclodextrins is a valuable strategy [5].

Cyclodextrins (CDs) are cyclic glucose oligomers consisting of six, seven, or eight glucose units (α, β, and γ-cyclodextrin), linked by 1,4-α-glycosidic bonds. CDs possess a hydrophobic internal cavity that provides a microenvironment for appropriate sized molecules and a hydrophilic outer surface responsible for their water-solubility. This particular structure of CDs confers them multiple applications in the pharmaceutical field, food, cosmetics, textile, and chemistry industry based on their property of forming guest–host inclusion complexes [6–10]. The inclusion complexation leads to an increase in the solubility of insoluble drug substances, including the antiviral drug remdesivir [11] to improve the chemical stability, the biological activity, and the bioavailability of guest molecules, to prevent drug–excipient or drug–drug interactions, to reduce/eliminate the unpleasant taste or odors and also ocular and gastrointestinal irritation [10,12–22]. Therefore, the encapsulation of the drug in the CD cavity results in a remarkable improvement of physicochemical, biopharmaceutical properties, and therapeutic potential of the guest [23–25]. Despite its low aqueous solubility, β-cyclodextrin (β-CD) has achieved pharmaceutical relevance due to its availability, lack of toxicity, appropriate internal cavity size for a wide variety of drug substances, and economic advantages [6,21,26]. The random substitution of any β-CD hydroxyl group creates a disruption of stable hydrogen bond system around the CD rim generating an intensive enhancement of its aqueous solubility. Thus, several CD derivatives of pharmaceutical interest have been developed, among them methylated β-CD [27,28].

Several papers have reported the interaction between RSP and CDs such as β-CD, hydroxypropyl-β-CD (HP-β-CD), and methyl-β-CD, in solid state and in solution [4,29,30]. In addition, the solubility of RSP in aqueous solution of α-, β-, γ- and HP-β-CDs has been evaluated [31]. In our recent paper, we have investigated in both solution and solid state the encapsulation of RSP in two methylated CDs, heptakis(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD) and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TM-β-CD) [22].

The efficiency, safety, quality, and stability of pharmaceutical dosage forms, which are the result of the active pharmaceutical ingredients (API) combination with excipients, are of major importance in the drug development process. A proper formulation design involves the selection of suitable excipients; although these pharmacologically-inactive substances are considered inert molecules, during the formulation stage and/or under storage of final product, interactions may occur even in solid state, leading to a diminution

of concentration of API [32–34]. Potential interactions between an API and excipients have to be evaluated because the incompatibilities between the components of a dosage form can affect the bioavailability, stability, potency, and safety of drug products [35,36]. According to the International Conference on Harmonisation (ICH) Q8 recommendations, a drug substance/excipient compatibility study should be evaluated as a part of pharmaceutical development [37].

Within this framework, the aim of this study was to investigate the encapsulation of RSP in randomly methylated β-CD (RM-β-CD) and to evaluate the compatibility of supramolecular adduct with selected pharmaceutical excipients. According to our knowledge, there is no study focused on RSP inclusion complex compatibility with excipients. In the present paper, the RSP/RM-β-CD inclusion complex has been characterized using solubility studies, thermal methods, spectroscopic techniques, and molecular modeling studies. Later, the interaction between the binary system and excipients, namely starch (STR), microcrystalline cellulose (CEL), magnesium stearate (MgSTE), and anhydrous lactose (LCT) has been studied by means of thermoanalytical tools (TG—thermogravimetry/DTG—derivative thermogravimetry/HF—heat flow), powder X-ray diffractometry (PXRD), and universal attenuated total reflectance Fourier transform IR spectroscopy (UATR-FTIR).
