Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Solubility determination of raloxifene hydrochloride in ten pure solvents at various temperatures: Thermodynamics-based analysis and solute–solvent interactions Abdul Ahad a, ⁎ , Faiyaz Shakeel a , Omar Ali Alfaifi a , Mohammad Raish a , Ajaz Ahmad b , Fahad I. Al-Jenoobi a , Abdullah M. Al-Mohizea a a Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia b Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia ARTICLE INFO Chemicals studied in this article: 1-Butanol (PubChem CID: 263) Acetonitrile (PubChem CID: 6342) Dimethyl sulfoxide (PubChem CID: 679) Ethanol (PubChem CID: 702) Ethyl acetate (PubChem CID: 8857) Ethylene glycol (PubChem CID: 174) Isopropyl alcohol (PubChem CID: 3776) Polyethylene glycol-400 (PubChem CID: 174) Propylene glycol (PubChem CID: 1030) Raloxifene hydrochloride (PubChem CID: 54900) Transcutol (PubChem CID: 8146) Keywords: Apelblat equation Dissolution Raloxifene hydrochloride Solubility Thermodynamics ABSTRACT The purpose of the present study was to determine the solubility of raloxifene hydrochloride (RHCl) in ten solvents: water, ethanol, isopropyl alcohol (IPA), ethylene glycol (EG), propylene glycol (PG), polyethylene glycol-400 (PEG-400), Transcutol, 1-butanol, dimethyl sulfoxide (DMSO), and ethyl acetate (EA) at temperatures of 298.2–323.2 K and a pressure of 0.1 MPa. The solubility data obtained was fitted upon “Apelblat and Van't Hoff” equations. The maximum mole fraction solubility of RHCl was obtained in DMSO (5.02 × 10 -2 at 323.2 K), followed by PEG-400 (5.92 × 10 -3 at 323.2 K), EA (3.11 × 10 -3 at 323.2 K), Transcutol (1.22 × 10 -3 at 323.2 K), PG (2.19 × 10 -4 at 323.2 K), 1-butanol (1.96 × 10 -4 at 323.2 K), IPA (1.47 × 10 -4 at 323.2 K), ethanol (7.90 × 10 -5 at 323.2 K), EG (6.65 × 10 -5 at 323.2 K), and water (3.60 × 10 -5 at 323.2 K). Similar fashions were noticed at each studied temperature. The higher solubility of RHCl in DMSO, PEG-400, EA, and Transcutol was possibly referable to their lower polarity in comparison with water. The molecular interactions between the solute and solvent molecules were estimated by calculating parameters like activity coefficients, and more prominent solute–solvent molecular interactions were noted for RHCl–DMSO, RHCl–EA, and RHCl–PEG- 400 in comparison with the other solute–solvent combinations. The outcomes of the “apparent thermodynamic analysis” showed that the dissolution of RHCl was “endothermic, spontaneous and entropy-driven” in all in- vestigated solvents. The obtained solubility data of RHCl in commonly used solvents could be useful in the purification, recrystallization, and dosage form design of the drug. 1. Introduction Raloxifene hydrochloride (RHCl; molecular formula: C 28 H 27 NO 4 S·HCl; molar mass: 510.045 g mol -1 ; CAS number: 82640- 04-8; Fig. 1) is an oral second-generation selective estrogen receptor modulator utilized in the prevention and management of post- menopausal osteoporosis in women (Ravi et al., 2014). RHCl is a highly lipophilic drug (Log P = 5.69 (Reimao et al., 2014). Almost 60% of the oral dose is absorbed, but its inadequate aqueous solubility and wide- ranging pre-systemic metabolism via glucuronide conjugation limits its oral bioavailability (< 2%) (Hochner-Celnikier, 1999; Ravi et al., 2014). RHCl is almost entirely insoluble in water, which is the primary hurdle for the formulation development of RHCl, particularly for liquid dosage forms. The solubility information of poorly soluble drugs such as RHCl in various commonly used organic solvents and in water has significance to several industrial procedures like “recrystallization, purification, drug discovery, and formulation development” (Almarri et al., 2017; Alshora et al., 2016). Only a few reports are available on the solubility of RHCl. The “mole fraction solubility” of RHCl in water at temperature (T) = 298.2 K was reported as 1.01 × 10 -5 and 2.21 × 10 -5 by Chauhan (2015) and Bikiaris et al. respectively (Bikiaris et al., 2009; Chauhan, 2015). Chauhan (2015) also reported the solubility (3.73 × 10 -5 ) of RHCl in isopropyl alcohol (IPA) at T = 298.2 K (Chauhan, 2015). Elsheikh et al. reported the solubility of RHCl in propylene glycol (PG) (8.99 × 10 -5 ) and Transcutol (6.83 × 10 -4 ) at T = 303.2 K and “atmospheric pressure” (Elsheikh et al., 2012). Nevertheless, the solubilities of RHCl in other pure solvents like https://doi.org/10.1016/j.ijpharm.2018.04.024 Received 14 February 2018; Received in revised form 12 April 2018; Accepted 13 April 2018 ⁎ Corresponding author. E-mail addresses: abdulahad20@yahoo.com, aahad@ksu.edu.sa (A. Ahad). International Journal of Pharmaceutics 544 (2018) 165–171 Available online 18 April 2018 0378-5173/ © 2018 Elsevier B.V. All rights reserved. T