MS05-P06 Stability of API. Lactamization of γ-amino acids in crystal state Marek Glowka (Faculty of Chemistry, Lodz, Poland) Waldemar Maniukiewicz (Faculty of Chemistry, Lodz, Poland)email: marek.glowka@p.lodz.plγ-Aminobutyric acid (GABA) plays numerous physiological functions and its derivatives are potential active pharmaceutical ingredients (API).  
At the moment two of them (Baclofen and Gabapentin – see below) are widely used.  Baclofen (Kemstro, Lioresal) is an agonist of GABA receptors.  
It shows significant muscle relaxant activity and is used as antispastic drug while Gabapentin (Prebalin, Lyrica) shows anticonvulsant activity and is
used mainly as antileptic drug, in neurophatic pain and in generalized anxiety disorder.
 
GABA and its neutral derivatives exist in a dipolar (zwitterionic) form both in solid states and in solutions (see below), which theoretically should
prevent possible nucleophilic attack of the electron lone pair at N atom (engaged in N-H bond in protonated forms) on the carboxylic carbon
(only in neutral carboxylic group) with formation either cyclic ɤ-lactam or linear peptide.  
The reaction is observed quite often in solutions, where a tiny concentration of the neutral form of the amino acids being in equilibrium
with the ionic forms allows such reaction to go.
The reaction (shown below) was also observed in the solid state by Borka [1] in the case of Baclofen at elevated temperatures.  
Surprisingly, one of several solid Baclofen forms under study in our laboratory revealed the lactamization reaction in moderate temperatures.
 
The analysis of crystal structures of γ-amino acids found in Cambridge Structural Database and in our archives (unpublished ones)
allowed us to point out several factors, which have to be taken into account when considering perspective stability of such API.

The most important features are:
 
  • conformation of the main amino acid chain,
  • shortest intra- and intermolecular distances between amino and carboxyl groups,
  • geometry and strength hydrogen bonds formed by the two reacting groups,
  • relative spatial orientation of the two groups,
  • possibility of rotation of the carboxyl group.
The common values of the analyzed factors and their inluence on lactamization of ɤ-amino acid will be presented.
 
References:

[1] L. Borka. (1979). Acta Pharm Suec, 16, 345-348.
Keywords: GABA derivatives, Lactamization in crystals, API stability