Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Jul 3;26(13):4078.
doi: 10.3390/molecules26134078.

Thermodynamic Characteristics of Phenacetin in Solid State and Saturated Solutions in Several Neat and Binary Solvents

Maciej Przybyłek  1 , Anna Kowalska  1 , Natalia Tymorek  1 , Tomasz Dziaman  2 , Piotr Cysewski  1
Affiliations

Thermodynamic Characteristics of Phenacetin in Solid State and Saturated Solutions in Several Neat and Binary Solvents

Maciej Przybyłek et al. Molecules. .

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.

Keywords: co-solvency; excess solubility; fusion thermodynamics; heat capacity; ideal solubility; phenacetin; synergistic effect.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
FTIR-ATR spectra recorded for phenacetin sample before and after DSC measurements.
Figure 2
Figure 2
Distributions of measured values of heat capacities of phenacetin in solid and melt states (a), along with derived heat capacity change upon melting (b).
Figure 3
Figure 3
Thermodynamic properties of phenacetin according to the different assumptions for heat capacity change upon melting defined in Table 2.
Figure 4
Figure 4
The temperature trends of enthalpy and entropy contributions to fusion Gibbs free energy expressed as weighted percentages %H = |∆Xfus|/(|∆Hfus| + |∆TSfus|), where X = H or TS.
Figure 5
Figure 5
Distribution of phenacetin ideal solubility computed using different models of ∆Cp(T), overlaid over (a) bean plots of ideal solubility of 60 selected solids computed using different models of ∆Cp(T) for ambient conditions, and (b) as a function of temperature using model 1.
Figure 6
Figure 6
Distribution of ideal solubility computed at room temperature using different models of ∆Cp for exemplary solids. The literature experimental data used for calculations were obtained from ref. [61] (myo-inositol, mannitol), ref. [62] (risperidone), ref. [50] (meglumine), and ref. [48] (4-hydroxybenzoic acid, 3-hydroxybenzoic acid).
Figure 7
Figure 7
Comparison of selected phenacetin solubility measurements in neat solvents: [a] this study, [b] ref. [36], [c] ref. [63], and [d] ref. [35]. Values of water mole fractions were multiplied by a factor of 102.
Figure 8
Figure 8
Comparison of solubility in binary solvents measured in [a] this study (T = 25 °C), with the literature data [b] ref. [37] (T = 25 °C), and [c] ref. [63] (T = 24.8 °C).
Figure 9
Figure 9
The trends of phenacetin excess solubility as a function of increasing value of organic solvent molar fraction in studied binary aqueous mixtures at room temperature.
Figure 10
Figure 10
Comparison of accuracy of additive model (Equation (13)) and Jouyban–Acree approach defined in Equation (14).
See this image and copyright information in PMC

References

    1. Clissold S.P. Paracetamol and Phenacetin. Drugs. 1986;32:46–59. doi: 10.2165/00003495-198600324-00005. - DOI - PubMed
    1. Chandrasekharan N.V., Dai H., Roos K.L.T., Evanson N.K., Tomsik J., Elton T.S., Simmons D.L. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression. Proc. Natl. Acad. Sci. USA. 2002;99:13926–13931. doi: 10.1073/pnas.162468699. - DOI - PMC - PubMed
    1. Jensen C.B., Jollow D.J. The role of N-hydroxyphenetidine in phenacetin-induced hemolytic anemia. Toxicol. Appl. Pharmacol. 1991;111:1–12. doi: 10.1016/0041-008X(91)90128-2. - DOI - PubMed
    1. Peters G., Baechtold-Fowler N., Bonjour J.P., Chométy-Diézi F., Filloux B., Guidoux R., Guignard J.P., Peters-Haefeli L., Roch-Ramel F., Schelling J.L., et al. General and renal toxicity of phenacetin, paracetamol and some anti-mitotic agents in the rat. Arch. Toxicol. 1972;28:225–269. doi: 10.1007/BF00330059. - DOI - PubMed
    1. Easley J.L., Condon B.F. Phenacetin-induced Methemoglobinemia and Renal Failure. Anesthesiology. 1974;41:99–100. doi: 10.1097/00000542-197407000-00028. - DOI - PubMed

LinkOut - more resources