Thermodynamic elucidation and prediction of chemical synergism in complex chemical processes

Summary of the activity and results obtained in 2024

The goal of this project is to investigate synergism in complex chemical processes through a rigorous thermodynamic approach, with applications in chemistry, biochemistry, and the pharmaceutical, medical, and chemical industries. The research focuses on elucidating synergistic interactions, identifying conditions that favor or inhibit this phenomenon, and promoting synergistic mixtures as sustainable alternatives to costly individual reactants. By deepening the understanding of synergism and antagonism phenomena, the project aims to develop efficient chemical processes with a reduced environmental impact.

A comprehensive methodology has been developed, based on standard thermodynamic data, mass balance equations, and experimental observations, to evaluate the conditions under which synergism and antagonism manifest during extraction processes. Theoretical and experimental studies targeted well-documented systems, such as Zn²⁺-thenoyltrifluoroacetone-TBP, providing detailed insights into the distribution of chemical species between the aqueous and organic (benzene) phases as a function of pH, temperature, and chemical composition. The analysis of these systems allowed for the definition of a synergism index (SI) to quantify the phenomenon and identify the conditions triggering the transition from synergism to antagonism.

Advanced thermodynamic calculations and theoretical simulations provided an in-depth understanding of the behavior of selected systems, validating the proposed methodology through the correlation of results with experimental data from the literature. The findings offer a robust foundation for predicting synergism and antagonism phenomena under various experimental conditions, such as the chemical composition and pH of heterogeneous liquid-liquid systems.

The applicability of the results spans multiple fields:

1. Optimization of industrial processes – The use of synergistic mixtures can significantly reduce production costs and increase the efficiency of chemical processes.
2. Development of new reagents and products – Chemical synergism offers a viable alternative to expensive reactants, fostering innovation in the pharmaceutical and chemical industries.
3. Sustainability – Reducing resource consumption and environmental impact through the use of synergistic mixtures instead of less efficient conventional processes.

The project also included dissemination of the results at three international conferences: MARBLUE 2024 (Constanța, Romania), IasiCHEM 2024 (Iași, Romania), and SIMI 2024 (Constanța, Romania) and one national conference with international participation (Tiraspol 2024). Participation in these events facilitated the exchange of ideas and collaborations with experts in the field, advancing research in chemical synergism.

By applying this methodology, the project findings provide an innovative framework for the design and implementation of sustainable chemical processes with significant implications in analytical chemistry, pharmaceuticals, biochemistry, and synthetic organic chemistry. These contributions support the development of a sustainable model for resource utilization and environmental impact reduction, addressing current challenges in chemical and industrial research.

Summary of the activity and results obtained in 2025

Over recent years, chemical synergism in heterogeneous systems has emerged as a key concept in understanding how multiple ligands or interacting components can collectively modify the stability of solid phases and enhance solubility. Despite its importance across environmental chemistry, pharmaceuticals, materials science, and catalysis, the lack of a unified thermodynamic framework has limited the ability to characterize synergism quantitatively. This study addresses this gap by introducing a general theoretical methodology that enables predictive modelling of synergistic and antagonistic effects in systems containing both dissolved species and excess solid phase.

The core innovation lies in defining the Synergistic Coefficient (SC), a quantitative descriptor that measures the extent to which an auxiliary ligand enhances or diminishes the effect of a primary ligand in a mixed system. Unlike previous qualitative interpretations, SC provides a direct, rigorous means to evaluate how variations in pH, chemical composition, complex stability, and solid–solution equilibria influence the overall behavior of heterogeneous mixtures. A positive SC indicates a favorable synergistic response, while negative values reflect antagonism, allowing for systematic comparison and optimization of chemical mixtures.

The methodology was applied to two major fields of relevance. The first involves iron-containing mineral systems, where dissolution processes are governed by intricate equilibria between Fe(III), siderophores, and auxiliary ligands. The modelling reveals that even low concentrations of siderophores, when combined with suitable co-ligands such as oxalate or phenanthrolines, can significantly enhance mineral dissolution through the formation of stable binary and ternary complexes. These findings have important implications for nutrient acquisition in soils, microbial iron uptake, contaminant mobility, and environmental remediation strategies.

The second application concerns pharmaceutical solubilization, specifically drug–cyclodextrin–organic acid systems. Many poorly soluble drugs benefit from ternary complex formation, which stabilizes dissolved species and leads to substantial increases in apparent solubility. Repaglinide, selected as a model compound, exhibits pronounced synergistic effects when combined with hydroxypropyl-β-cyclodextrin and L-arginine. The thermodynamic model successfully describes the conditions under which synergistic solubilization occurs, providing a rational basis for formulation design and excipient selection.

Overall, this unified thermodynamic approach offers a powerful tool for understanding and predicting multicomponent interactions in heterogeneous environments. By bridging systems as diverse as soil minerals and pharmaceutical formulations, the methodology demonstrates both conceptual depth and broad practical applicability. The introduction of the Synergistic Coefficient represents a significant advancement in the quantitative treatment of synergism and provides a foundation for future investigations aiming to optimize chemical processes in environmental science, medicine, and material development.