Extreme Basicity of Biguanide Drugs in Aqueous Solutions: Ion Transfer Voltammetry and DFT Calculations

Abstract

Ion transfer voltammetry is used to estimate the acid dissociation constants Ka1 and Ka2 of the mono- and diprotonated forms of the biguanide drugs metformin (MF), phenformin (PF), and 1-phenylbiguanide (PB) in an aqueous solution. Measurements gave the pKa1 values for MFH(+), PFH(+), and PBH(+) characterizing the basicity of MF, PF, and PB, which are significantly higher than those reported in the literature. As a result, the monoprotonated forms of these biguanides should prevail in a considerably broader range of pH 1-15 (MFH(+), PFH(+)) and 2-13 (PBH(+)). DFT calculations with solvent correction were performed for possible tautomeric forms of neutral, monoprotonated, and diprotonated species. Extreme basicity of all drugs is confirmed by DFT calculations of pKa1 for the most stable tautomers of the neutral and protonated forms with explicit water molecules in the first solvation sphere included.

A review of phenformin, metformin, and imeglimin

“…Computational studies (molecular orbital, density functional calculations, etc.) confirm that the tautomerism and electron resonance stabilize biguanides and contributes to their mechanism of action (Langmaier et al, ; Saczewski & Balewski, ). Notably, X‐ray experiments indicate that 6A is the preferred tautomer while 6B is its minor form (Kathuria et al, ).…”

“…This unit is both biologically multiactive and synthetically versatile that could be readily derivatized via the circled N ‐atoms (Figure ; Katritzky, Tala, & Singh, ; Tahir, Badshah, & Hussain, ). The biguanide core, which is a merger of two guanidine units, is capable of eliciting a myriad of pharmacological effects via hydrogen bonding and ionic interactions with its receptors, at physiologic pH (Langmaier, Pizl, Samec, & Zalis, ; Saczewski & Balewski, ; Tahir et al, ). Although hydrogen bonding also contributes to the hydrophilic nature of biguanides, their characteristically high pKa (>12) leads to: mono‐ or di‐protonation at physiological pH and N ‐atom reactions with acids like HCl to make highly water soluble salts (Langmaier et al, ).…”

“…Structures 6A and 6B illustrate tautomeric versions of biguanides. A combination of electron distribution characteristics due to NC2N4C5N‐ conjugation and tautomeric forms (i.e., hydrogen or proton shifts shown in Figure , 6A and 6B ) contribute to the biguanide chemical/pharmacological profile (Bharatam, Patel, & Iqbal, ; Kathuria et al, ; Langmaier et al, ). Computational studies (molecular orbital, density functional calculations, etc.)…”

“…Figures 6A , 6AH + , and 6AH 2+ represent various protonation state ranges for biguanides (neutral, mono‐, and di‐protonated, respectively). It is hypothesized that greater protonation leads to greater biguanide stability (Langmaier et al, ). It appears that metformin's methyl groups prefers to be at the N3 or N7 position; whereas, phenformin's substitution is at the N6 position implying their antidiabetic profiles stem from structural differences (Bharatam et al, ).…”

Removal of Diquaternary Ammonium Cations From as-Synthesized SSZ-16 Zeolite

“…Thermal stability of SDA in alkaline solutions were analyzed after the heat treatment in an autoclave. SDA concentration was measured using cyclic voltammetry (CV) [17] with the home-made apparatus in J. Heyrovsky Institute of Physical Chemistry, CAS. SDA content in zeolite samples and SDA residua after their calcination were measured using elemental analysis performed on Elementar Vario EL III in CHNS operation mode, and further on with X-ray Photoelectron spectroscopy XPS using ESCA 3 Mk II spectrometer (VG) in fixed transmission mode.…”