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

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(pKa1) = 85.49 kJ·mol−1, ΔH0(pKa2) = 86.42 kJ·mol−1, and ΔH0(pKa3) = 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(pKa1) = 217.47 J·K−1·mol−1, ΔS0(pKa2) = 204.87 J·K−1·mol−1, and ΔS0(pKa3) = 92.63 J·K−1·mol−1 at 25 °C and proved irreversible dissociation reactions.