Thermodynamic Assessment of the Pyrazinamide Dissolution Process in Some Organic Solvents

Abstract

Pyrazinamide is a first line drug used for the treatment of tuberculosis, a pathology that caused the death of more than 1.3 million people in the world during 2022, according to WHO, being a drug of current interest due to its relevance in pharmaceutical and medical sciences. In this context, solubility is one of the most important physicochemical parameters in the development and/or optimization of new pharmaceutical forms, so the present work aims to present a thermodynamic study of the solubility of pyrazinamide in nine organic solvents of pharmaceutical interest. Using the shake-flask method and UV/Vis spectrophotometry, the solubility of this drug was determined at 9 temperatures; the maximum solubility was obtained in dimethyl sulfoxide at 318.15 K (x2=0.0816±0.004) and the minimum in cyclohexane at 283.15 K (1.73±0.05×10-5). From the apparent solubility data, the thermodynamic functions of solution and mixing were calculated, indicating an endothermic process. In addition, the solubility parameter of pyrazinamide was calculated using the Hoftyzer-van Krevelen (32.90 MPa^1/2) and Bustamante (28.14 MPa^1/2) methods. The maximum solubility was reached in dimethyl sulfoxide and the minimum in cyclohexane. As for the thermodynamic functions, the entropy drives the solution process in all cases. In relation to the solubility parameter, it can be analyzed that the mathematical models offer approximations; however, the experimental data are still primordial at the time of inferring any process.

Keywords: Fedor; Hoftyzer-van Krevelen; pyrazinamide; shake-flask method; solubility; solubility parameters; thermodynamic properties; tuberculosis.

Figure 6

Diagram of the hypothetical solution process [55].

Figure 1

Molecular structure of the pyrazinamide [5].

Figure 2

Correlation between the solubility of pyrazinamide at 298.15 K and the solubility parameter of organic solvents.

Figure 3

Experimental solubility reported in this work and by other authors in various pure solvents. ∘: In this work; •: Zhang et al. [37]; ⧫: Blokhina et al. [36]; ▲: Maharana and Sarkar [33]; ∆: Hermanto et al. [34].

Figure 4

van’t Hoff–Krug plot for the solubility of pyrazinamide (3) in different organic solvents (⋆: cyclohexane; ⋄: DMF; ▲: 1,4-dioxane; ∆: DMSO; ■: chloroform; □: 1-propanol; ◯: NMP; •: 1-butanol, and ⧫: 1-octanol.

Figure 5

Relation between enthalpy (${\Delta }_{\mathrm{soln}}{H}^{\mathrm{o}}$) and entropy ($T_{\mathrm{hm}}{\Delta }_{\mathrm{soln}}{S}^{\mathrm{o}}$) in terms of the process of pyrazinamide (3) in nine organic solvents at $T_{\mathrm{hm}}$. The isoenergetic curves for ${\Delta }_{\mathrm{soln}}{G}^{\mathrm{o}}$ are represented by dotted lines.

Figure 7

Relation between enthalpy (${\Delta }_{\mathrm{mix}}{H}^{\mathrm{o}}$) and entropy ($T_{\mathrm{hm}}{\Delta }_{\mathrm{mix}}{S}^{\mathrm{o}}$) of the process mixing ofpyrazinamide (3) in nine organic solvents at $T_{\mathrm{hm}}$. The isoenergetic curves for ${\Delta }_{\mathrm{mix}}{G}^{\mathrm{o}}$ are represented by dotted lines.