Home About Learning Products Chemistry Consultancy Services ISO 17025 Consultancy Services Resources Contact Site Map

Copywrite © David Trew Consulting Ltd and Dr. David Trew  2013-2021

Terms of Use

Privacy Policy

Version 1.6.1

David Trew

Consulting Ltd

The Chemistry of Multi-Protonic Compounds.

Part 1: Fundamentals of Multi Protonic Equilibrium

It is well known that the acid-base chemistry of a drug substance plays a key role in the development of a new drug. The acid-base chemistry of a compound will determine predominant ionic species present at any given pH. This in turn will affect its:

Solubility and rate of dissolution in the gastrointestinal tract

Permeability across biological membranes

Bioavailability

Stability and degradation under different conditions

Access to the site of action

Pharmacodynamics and pharmacokinetics


Equilibrium constants, which can be expressed either as dissociation constants pKa or protonation constants log K, are normally used to characterize, in numerical terms, the acid base chemistry of compounds that have either a single protonatable site, such as acetic acid 1




                                      




pKa = [CH3COO-][H+]              

            [CH3COOH]



Or a compound with well-separated equilibrium constants such as glycine 2,



 

            





pKa1 = [H3N+CH2COO-][H+]                                                                                         


                                            

  

log K1= [H3N+CH2COOH]

 [H3N+CH2COO-][H+] log K1= [H3N+CH2COO-]

 [H2NCH2COO-][H+]


where protonation occurs in a sequential step wise fashion. These equilibrium constants are often called the macroscopic constants. In addition, it is possible to assign a particular equilibrium with protonation of a specific site on the molecule.


However, in a compound with overlapping constants (where ΔpKa < 3), such as urocanic acid (pKa = 3.5, 5.8 and 13) 3, which consists of an imidazole ring and a propenoic acid side chain. The constants K1 and K2, respectively, represented by equation (iii) characterise the acid-base equilibria as a whole and are called the macroscopic equilibrium constants and the species Ur-, UrH and UrH2+ are called the macro-species. These macroscopic equilibrium constants, however, do not provide information on the specific site being protonated.





  …..(iii)





K1  =         [UrH]                           K2  =    [UrH2+]

      


Instead of the sequential stepwise protonation seen with glycine; between pH 1 and 9 urocanic acid establishes the multi-protonic pH dependent equilibrium shown in Scheme 1 below



  





















Scheme 1


 k1 = [5]   k2 = [3]   k3 = [6]    k4 = [6]




Above pH 9 (but below pH 10) urocanic acid predominantly exists in the urocanate anion represented by structure 4. As the pH of the solution is lowered protonation can occur either at the imidazole nitrogen site to yield the zwitterion represented by structure 5 followed by protonation at the carboxylate site to give the urocanoium cation 6. Alternatively protonation can initially occur at the carboxylate site to yield the neutral urocanic acid molecule, structure 3; this is then followed by protonation at the imidazole nitrogen to give the urocanoium cation 6.


The structures 3 to 6 are called micro-species and the equilibria k1 to k4 that exist between them are called the microscopic equilibrium constants. The protonation pathways 4--> 5  -->6 and 4-->3-->6 occur simultaneously and thus, the macroscopic species represented by UrH in equation (iii) consists of two microscopic species, 3 and 5.   For this reason, the macroscopic equilibrium constants (pKas or log Ks) in a compound with over lapping constants (ΔpKa < 3) cannot be assigned to specific sites, but instead are properties belonging to the molecule as a whole.


This should be considered when discussing the acid-base chemistry of a candidate drug molecule in the Chemistry, Manufacturing and Controls section of a new drug application. In addition, the acid base profile of a multi-protonic compound should be taken into account when seeking to predict its degradation chemistry,



2

pKa2 = [H2NCH2COO-][H+]


[H3N+CH2COO-]

[H3N+CH2COOH]

[Ur-][H+]                                  [UrH][H+]


 [4][H+]    [4][H+]   [5][H+]     [3][H+]

PDF Document

Please Click Here to Find Out How David Trew Consulting Ltd Can Help You with Your Drug Degradation Studies
Please Click Here to Find Out How David Trew Consulting Ltd Can Help You with Your Drug Degradation Studies