Contents lists available at ScienceDirect European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps Improving the solubility of an antifungal thiazolyl hydrazone derivative by cyclodextrin complexation Iara R. Silva a , Thales Kronenberger b , Elionai C.L. Gomes c , Isabela C. César a , Renata B. Oliveira a , Vinícius G. Maltarollo a, ⁎ a Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais – Av. Presidente Antônio Carlos, 6627, Campus Pampulha – CEP: 31270-901Belo Horizonte, Minas Gerais – Brasil b Department of Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Strasse 14, Tübingen DE 72076, Germany c Departamento de Química, Instituto de Ciências Exatas – Universidade Federal de Minas Gerais – Av. Presidente Antônio Carlos, 6627, Campus Pampulha – CEP: 31270- 901Belo Horizonte, Minas Gerais – Brasil ARTICLE INFO Keywords: Cyclodextrins complexation Cyclodextrin binding mode Thiazolyl hydrazone ABSTRACT RN104, named 2-[2-(cyclohexylmethylene)hydrazinyl)]-4-phenylthiazole, is a thiazolyl hydrazone derivative with promising antifungal activity. A HPLC-DAD method was carried out using C18 end-capped column (250 × 4.6 mm, 5 µm) and a mobile phase composed of water and acetonitrile (15:85 v/v) at a fow rate of 1.2 mL/min, injection volume 25 μL and DAD detection at 240 nm. The method showed to be selective, linear in the range of 20 to 240 µg/mL, precise, accurate and robust.Due to the low solubility of RN104 in water, the de- velopment of inclusion complexes using diferent cyclodextrins (β-CD, γ-CD and 2-HP-β-CD) was investigated, as well as the interaction mode between RN104 and cyclodextrins using molecular docking followed by semi- empirical calculations. Among tested cyclodextrins, the best results were obtained with 2-HP-β-CD, which promoted an 18-fold increase in RN104’s aqueous solubility. 1. Introduction The modern drug design and development process aims, in the early stages, to obtain a potent and non-toxic compound that interact with relevant biological targets for treatment of diseases, which could later be introduced in the clinics upon optimization. However, it is important to optimize not only potency and toxicity, but also the physicochemical properties to avoid late clinical trial failures, due to unsuitable phar- macokinetic profle (Oprea and Matter, 2004). Controversially, several drugs currently available on therapeutics have poor pharmacokinetic profle and, usually, relies on formulation strategies aiming to improve their applicability. In this sense, a commonly employed strategy for improving aqueous solubility and bioavailability is to complex the drug with cyclodextrins (CD) (Sharma and Baldi, 2016). Other observed improvements of the CD complexations are the increase of gastrointestinal stability, dis- solution rates and duration of therapeutic activity (Zhang and Ma, 2013). Cyclodextrins are cyclic oligosaccharides which contains multiple glucopyranose units linked by a α-(1,4) bonds and have been used as pharmaceutical adjuvants for over 20 years (Jambhekar and Breen, 2016; Sharma and Baldi, 2016; Szente et al., 2016). An inclusion complex (IC) between CDs and drugs is formed by dynamic forces as electrostatic, Van der Waals and hydrogen bond interactions (Szente et al., 2016). CDs usually are recognized as non-toxic and pharmacologically in- active excipients that can be employed in pharmaceutical products and foods (Jansook et al., 2018; Kurkov and Loftsson, 2013). There are several examples of commercial antifungal drugs in complex with CDs as clotrimazole, itraconazole, ketoconazole, grizeofulvin, among many others (Macaev et al., 2013; Tiwari et al., 2010). We herein report a similar solubility issue for the 2-[2-(cyclohex- ylmethylene)hydrazinyl)]-4-phenylthiazole (namely RN104, Fig. 1), which is a new thiazolyl hydrazone derivative previously synthetized by our group. RN104 has promising antifungal activity against the genera Cryptococcus spp. and Candida spp. (Sá et al., 2017, 2015) in a high nanomolar range. RN104 also showed activity against clinical isolates and in vivo models (Sá et al., 2018), with no toxicity in rat peritoneal macrophages, VERO cell model (Sá et al., 2015) and no haemolytic activity in human erythrocytes (Sá et al., 2017). Further- more, the low toxicity of RN104 was confrmed in four mammalian cell https://doi.org/10.1016/j.ejps.2020.105575 Received 9 February 2020; Received in revised form 7 September 2020; Accepted 22 September 2020 ⁎ Corresponding author at: Laboratório de Química Farmacêutica,Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais – Av. Presidente Antônio Carlos, 6627, Campus Pampulha – CEP: 31270-901Belo Horizonte, Minas Gerais – Brasil. E-mail address: maltarollo@ufmg.br (V.G. Maltarollo). European Journal of Pharmaceutical Sciences 156 (2021) 105575 Available online 25 September 2020 0928-0987/ © 2020 Published by Elsevier B.V. T