Research Article A Novel Eutectic-Based Transdermal Delivery System for Risperidone Faisal Al-Akayleh, 1 Samer Adwan, 2 Mai Khanfer, 3 Nasir Idkaidek, 1 and Mayyas Al-Remawi 1,4 Received 13 July 2020; accepted 7 October 2020 Abstract. This paper reports for the first time the possible formation of a novel room temperature therapeutic deep eutectic solvent (THEDES) of risperidone (RIS) with some fatty acids, namely capric acid (C10; CA), lauric acid (C12; LA), and myristic acid (C14; MA). All mixtures of RIS and MA yielded a solid or pasty-like solid and were readily discarded. Some of the prepared THEDESs from RIS and CA or LA have spontaneously transformed into a transparent liquid, without any precipitate at room temperature by simple physical mixing of the components. From the DSC thermograms, phase diagrams of the eutectic systems were constructed and the lowest obtained melting point for a RIS:CA mixture was 17°C at 40:60% w/w ratio. While 22°C was recorded as the lowest melting point for RIS:LA at a ratio of 30:70% w/w, solubility improvement of RIS was up to 70,000-fold compared with water. Freeze-drying microscopy provided valuable information regarding the phase change and transitions the drug undergoes as a function of temperature and it clarifies the interpretation of the DSC results and provides valuable evidence of drug crystals co- melting within the fatty acid base. The presence of natural fatty acid as one component of THEDES and the depression in the melting point significantly (P < 0.05) enhanced RIS skin permeation. Rheological studies showed a viscosity temperature dependency of the DES and well fitted to the Arrhenius equation. Application of the obtained THEDES on the shaved skin of rats revealed the absence of any irritation or edema effects. KEY WORDS: risperidone; fatty acids; eutectic mixtures; low melting point; room temperature eutectic mixtures. INTRODUCTION Risperidone (RIS), a benzisoxazole derivative, is an antipsychotic drug that is commercially available as a conventional tablet, disintegrating tablet, oral liquid solution, and long-acting intramuscular injection (1). This antipsychotic medicine is the first-line drug in the treatment of schizophre- nia, mixed and manic states associated with bipolar disorder and irritability in children and adolescents with autism (2,3). RIS has a molecular weight of 410.49 g/mol and it shows low aqueous solubility and is sparingly soluble in ethanol. The drug has low bioavailability, because of its hepatic first-pass metabolism and its high drug-protein binding (4). Among the reported strategies to overcome the problem of first-pass metabolism of drugs, transdermal drug delivery systems (TDDS) are of crucial importance (5,6). However, drug diffusion through the stratum corneum is a major challenge facing TDDS (7,8). Various physical and chemical approaches have been extensively reported in the literature aimed to enhance drug permeation and overcoming the barrier func- tion of the skin (some examples are refs. 9–15). The poor water solubility and dissolution rate of over than 40% of the approved active pharmaceutical ingredients (APIs) and nearly 90% of drugs under development is one of the biggest challenges which limit their formulation develop- ment, clinical application, and marketability (16). Overcom- ing skin barrier (for transdermal delivery) and dissolution problems (for oral drug delivery) were successfully achieved by deep eutectic solvents (DESs). In the last two decades, DESs have emerged as an advantageous new class of ionic liquids (ILs) analogs. Although DESs and ILs share some characteristics, the terms are not interchangeable. DESs offer many advantages that turn them superior alternatives to the ILs and organic solvents. Contrary to the ILs, most of the DESs are environmentally benign solvent systems, less toxic, often biodegradable, and cheaper to produce, and no waste or by- products are generated upon their preparation (17–20). DESs consist of two or more components, one acts as a hydrogen 1 Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy and Medical Sciences, Petra University, Amman, Jordan. 2 Department of Pharmaceutical Sciences, Faculty of Pharmacy, Zarqa University, Zarqa, Jordan. 3 Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, University of Science and Technology, Irbid, Jordan. 4 To whom correspondence should be addressed. (e–mail: malremawi@uop.edu.jo) AAPS PharmSciTech (2021) 22:4 DOI: 10.1208/s12249-020-01844-4 1530-9932/20/0000-0001/0 # 2020 American Association of Pharmaceutical Scientists