Acid Dissociation Constants, Enthalpy, Entropy and Gibbs Energy of Bedaquiline by UV-Metric Spectral and pH-Metric Analysis

Abstract

Bedaquiline (trade name Sirturo) is an antibiotic used to treat pulmonary tuberculosis that is resistant to other antibiotics. The pH-spectrophotometric and pH-potentiometric titrations allowed the measurement of two near successive and one distant dissociation constants. The neutral bedaquiline LH molecule was able to protonate and dissociate in pure water to form soluble species L⁻, LH, ${\text{LH}}_{2}^{ + }$, ${\text{LH}}_{3}^{2 + }$ and ${\text{LH}}_{4}^{3 + }$. In the pH range 2–7, three dissociation constants can be reliably estimated. REACTLAB (UV-metric spectral analysis) values are: ${\text{p}}K_{{{\text{a}}1}}^{T}$ = 3.91(09), ${\text{p}}K_{{{\text{a}}2}}^{T}$ = 4.58(12) and ${\text{p}}K_{{{\text{a3}}}}^{T}$ = 5.26(07) at 25 °C and ${\text{p}}K_{{{\text{a}}1}}^{T}$ = 3.61(30), ${\text{p}}K_{{{\text{a2}}}}^{T}$ = 4.44(15) and ${\text{p}}K_{{{\text{a3}}}}^{T}$ = 5.54(33) at 37 °C. ESAB (pH-metric analysis) values are: ${\text{p}}K_{{{\text{a}}1}}^{T}$ = 3.21(39), ${\text{p}}K_{{{\text{a2}}}}^{T}$ = 3.68(31) and ${\text{p}}K_{{{\text{a3}}}}^{T}$ = 5.21(42) at 25 °C and ${\text{p}}K_{{{\text{a}}1}}^{T}$ = 3.31(12), ${\text{p}}K_{{{\text{a2}}}}^{T}$ = 3.67(15) and ${\text{p}}K_{{{\text{a3}}}}^{T}$ = 5.73(08) at 37 °C. Molar enthalpy ΔH⁰, molar entropy ΔS⁰ and Gibbs energy ΔG⁰ were calculated from the spectra using the dependence of ln K on 1/T. The potentiometric data showed positive enthalpy ΔH⁰(pK_a1) = 85.49 kJ·mol⁻¹, ΔH⁰(pK_a2) = 86.42 kJ·mol⁻¹, and ΔH⁰(pK_a3) = 65.84 kJ·mol⁻¹ values and the dissociation reactions were endothermic. The entropy ΔS⁰ at 25 °C was positive for the three dissociation constants ΔS⁰(pK_a1) = 217.47 J·K⁻¹·mol⁻¹, ΔS⁰(pK_a2) = 204.87 J·K⁻¹·mol⁻¹, and ΔS⁰(pK_a3) = 92.63 J·K⁻¹·mol⁻¹ at 25 °C and proved irreversible dissociation reactions.

Graphic Abstract