Solubility of Collinin and Isocollinin in Pressurized Carbon Dioxide: Synthesis, Solubility Parameters, and Equilibrium Measurements Camilo Pardo-Castañ o, Andre ́ s C. García, Paola Benavides, and Gustavo Bolañ os* School of Chemical Engineering, Universidad del Valle, CL 13 100-00 Building E27, Cali, Colombia * S Supporting Information ABSTRACT: Collinin is a derivative of coumarin that has shown remarkable potential against cancer, tuberculosis, periodontitis, and other prevalent diseases, and is usually extracted from plants of the Rutaceae family at a very low yield. In this work, collinin and a position-isomer herein called isocollinin were synthesized at different scales (from 1 to 50 g of precursor) by a route consisting of two parallel and two sequential chemical reactions. The isomers were characterized by 1 H NMR, 13 C NMR, nuclear Overhauser enhancement spectroscopy NMR, melting temperature, and melting enthalpy. For each isomer, the Hansen solubility parameters and the radius of its solubility sphere were experimentally determined by solubility tests in 15 common solvents and two solvent blends. The solubility of each isomer in pressurized CO 2 was determined at 30 and 50 °C from 72.2 to 112.9 bar, by an in situ high-pressure spectrometry technique, which was validated with the anthracene-CO 2 system. The solubility of both isomers in CO 2 increased with pressure in the range of temperatures and pressures considered, but that of collinin exhibited an asymptotic behavior around 80.8 and 104.8 bar, at 30 and 50 °C, respectively. 1. INTRODUCTION Collinin is a geranyloxycoumarin that was originally isolated from the bark of the Australian tree Flindersia collina Bail by Anet et al. 1 in 1949, and it is known to be present in plants of the Rutaceae family. This compound has shown important activity both in vitro and in vivo against diseases such as cancer, 2-6 tuberculosis, 7 and periodontitis, 8 among several others. 9-12 Such activity and the prevalence of these pathologies make this substance an interesting leading compound for the development of effective pharmaceutical products, and thus, a knowledge on its properties, such as solubility in conventional and nonconventional solvents, is of interest to the pharmaceutical industry. At present, collinin is extracted from the leaves of Zanthoxylum schinifolium, a plant commonly used in the medical traditions of China, Japan, Korea, and Taiwan. 9 Unfortunately, solvent extraction of collinin provides very low yields (around 0.011 wt%) 3,7 and purities not higher than 97%. As a result, several routes for chemical synthesis have been proposed. For example, Curini et al. 13 and Maes et al. 14 studied and reported routes of chemical synthesis with overall molar yields as high as 24.6 and 6.8%, respectively. However, in the high-yield synthesis procedure reported by Curini and co- workers, two isomers were obtained and not enough evidence about their respective identification was reported. In addition, their proposed synthesis route has only been tested on a milligram scale. Because it is well known that synthesis yield at a larger scale is usually much lower than that obtained at milligram scale, it is important to obtain information on the synthesis yield of collinin at a gram scale to favor the research of this product as a potential pharmaceutical component. In this work, collinin and an isomer, henceforth called isocollinin, were synthesized and purified at a gram scale, by using an improved synthesis procedure based on that reported by Curini et al. 13 Both isomers were characterized by 1 H NMR, 13 C NMR, nuclear Overhauser enhancement spectros- copy (NOESY) NMR, melting enthalpy, melting temperature, and purity as estimated from melting point depression. Solubility experiments for both isomers were performed at room temperature (ca. 28 °C) in 15 common organic solvents Received: March 15, 2019 Accepted: August 2, 2019 Published: August 22, 2019 Article pubs.acs.org/jced Cite This: J. Chem. Eng. Data 2019, 64, 3799-3810 © 2019 American Chemical Society 3799 DOI: 10.1021/acs.jced.9b00234 J. Chem. Eng. Data 2019, 64, 3799-3810 Downloaded via UNIV DEL VALLE on September 13, 2019 at 02:41:56 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.