Measurement and Correlation of the Solubility of 5-Fluorouracil in Pure and Binary Solvents

Abstract

The solubility of 5-fluorouracil (5-FU), a widely used chemotherapeutic agent to treat solid tumors, which include colorectal, head and neck, breast, and lung cancer, was determined at temperatures ranging from 278.15 to 333.15 K in 11 pure solvents and binary water + ethanol solvent mixtures using the polythermal method. It was demonstrated that the solubility of 5-FU increases with increasing temperature in the pure solvents and at constant solvent composition in the solvent mixtures. Moreover, the solubility of 5-FU in the solvent mixtures exceeds its solubility in pure water and ethanol. The experimental solubility data of 5-FU in the pure solvents and solvent mixtures were correlated using the modified Apelblat and λh model equations. The predicted solubility data obtained agree with the experimental data based on the calculated relative deviation (RD) and the average relative deviation (ARD%) values. The selected solvents are categorized as either Class 2 or 3 (less toxic and lower risk to human health) solvents, and hence the correlated and experimentally derived solubility data of 5-FU presented provide a pathway to develop and engineer enhanced pharmaceutical processes and products based on this compound.

Interaction of 5‐fluorouracil with β‐cyclodextrin: A density functional theory study with dispersion correction

“…However, from the experimental side, the formation of the 5FU‐βCD complex is supported by higher solubility of 5FU in water in the presence of βCD, as well as its better solubility in methanol. [ 6,9 ] In other words, an equilibrium between 5FU present in water and inside the host cage is concluded from these results (see also Equation ).…”

“…Thus, the interaction with methanol OH groups is stronger than with water, which is in agreement with experimentally observed solubility of 5FU in methanol that is two times higher than that in water. [ 6 ] Note that, even when starting from methanol molecules oriented with their methyl groups toward the 5FU solute, they rotated around upon optimization favoring the H‐bonding interactions with the OH groups of methanol. This indicates that 5FU prefers strong interactions with the hydrophilic OH groups over the hydrophobic inner part of the βCD cavity.…”

“…[ 3 ] 5FU is hardly soluble in water (12.5 mg/L) and better in methanol, acetone, and dimethylsulfoxide (DMSO) . [ 4–8 ] To improve the bioavailability of 5FU and to reduce its side effects, weak noncovalent (inclusion) complexes with hosts like α‐ or β‐cyclodextrins (αCD, βCD) [ 4,5,9–12 ] and with other drug carriers could be formed. [ 13 ] There have been several reports discussing the possible formation of inclusion complexes between 5FU and βCD in solution, as well as in the solid state.…”

“…[ 53 ] The importance of dispersion correction for the theoretical characterization of several types of inclusion complexes was shown by Grimme in his seminal paper “Supramolecular binding thermodynamics by dispersion‐corrected density functional theory.” [ 45 ] However, this aspect of βCD inclusion complex formation with 5FU has not yet been studied. It is known that, compared to water, 5FU has a higher solubility in methanol [ 4–8 ] that contains, in principle, a similar nonpolar CH 3 group as in βCD (methyl vs methylene). Therefore, we first wanted to understand the interactions of 5FU with water and with methanol, which serve as model structures for the smaller and larger rim OH···O network of βCD.…”

Measurement and Correlation of the Solubility of β-Cyclodextrin in Different Solutions at Different Temperatures and Thermodynamic Study of the Dissolution Process

“…Commonly used methods for solubility determination are the equilibrium method [18,19] and the dynamic method [20,21]. The solubility of β-Cyclodextrin in different solutions was investigated with the dynamic method under atmospheric pressure at temperatures ranging from 303.15 to 353.15 K. The determined procedure was carried out following the procedure reported in Reference [22].…”