Deep eutectic solvent system based on amino acids derivatives

The focus of work presented here was to study and describe the following: (1) The effect of proline series molecules (L-Proline, N‐acetyl‐L‐proline, L‐prolinamide, N‐acetyl‐L‐prolinamide) on the stability of piperacillin and tazobactam considering experimental results and molecular modelling data. This is a very interesting family of molecules, since all of them are based on L- proline, yet significantly different when it comes to their overall charges and protonation states. L‐Proline is neutral, but zwitterionic, N‐acetyl‐ L‐proline is anionic, Lprolinamide is cationic, and N‐acetyl‐L‐prolinamide is neutral without any charged fragments. (2) Utilization of deep eutectic solvent systems (DES) for stabilization of piperacillin and tazobactam, where one of the components is N-acetyl-L-prolinamide. Furthermore, preparation and stability testing of formulations in the form of a deep eutectic solvent that comprise piperacillin and/or tazobactam and at least one N-acetyl amino acid amide was conducted. Some of the evaluated excipients were N-acetyl-D- alaninamide, and as mentioned above, N-acetyl-L- prolinamide. It was discovered that the stability of the formulation is more enhanced in the specific DES systems. More precisely, DES compositions provided improved stability over time (evaluated through specific impurities increase and purity drop) when stored refrigerated (2-8 °C), and at room temperature (25 °C) in comparison to liquid (aqueous) formulations that only contain piperacillin and/or tazobactam. Computational analysis utilized a combination of quantumchemical calculations and molecular dynamics simulations to characterize relevant interactions in solutions in relation with the studied degradation mechanisms, and to help in interpreting the observed experimental trends.