Abstract
The thermodynamic properties of phenacetin in solid state and in saturated conditions in neat and binary solvents were characterized based on differential scanning calorimetry and spectroscopic solubility measurements. The temperature-related heat capacity values measured for both the solid and melt states were provided and used for precise determination of the values for ideal solubility, fusion thermodynamic functions, and activity coefficients in the studied solutions. Factors affecting the accuracy of these values were discussed in terms of various models of specific heat capacity difference for phenacetin in crystal and super-cooled liquid states. It was concluded that different properties have varying sensitivity in relation to the accuracy of heat capacity values. The values of temperature-related excess solubility in aqueous binary mixtures were interpreted using the Jouyban–Acree solubility equation for aqueous binary mixtures of methanol, DMSO, DMF, 1,4-dioxane, and acetonitrile. All binary solvent systems studied exhibited strong positive non-ideal deviations from an algebraic rule of mixing. Additionally, an interesting co-solvency phenomenon was observed with phenacetin solubility in aqueous mixtures with acetonitrile or 1,4-dioxane. The remaining three solvents acted as strong co-solvents.
Highlights
In order to confirm that no crystal phase or pseudopolymorphic transitions occurred during solubility measurements, the sediments collected after flask-shake experiments were analyzed using Differential Scanning Calorimetry (DSC) and FTIR-Attenuated Total Reflection (ATR) techniques
It was noted that all these solvents offer a significant solubility advantage, enhancing phenacetin solubility by more than two orders of magnitude compared to water
The thermodynamic properties relevant to solubility modelling were measured by providing experimental detail of parameters such as melting point, enthalpy of fusion, and heat capacity of solid and melt states
Summary
Phenacetin (CAS: 62-44-2, IUPAC name: N-(4-ethoxyphenyl)acetamide) is a white crystalline odorless substance. This organic compound is an acetanilide derivative and a close analog of paracetamol, with the hydroxyl group replaced with an ethanolic group. It was introduced as a drug in the late nineteenth century, and exhibits analgesic and antipyretic activities due to its cyclooxygenase-3 inhibiting properties [1,2]. Its use as a pain treatment has been limited due to its many side effects, including methemoglobinemia and hemolytic anemia [3,4,5], and its potential carcinogenic properties [6,7]
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