Periodic Reporting for period 2 - SusPharma (MERGING SUSTAINABLE AND DIGITAL CHEMICAL TECHNOLOGIESFOR THE DEVELOPMENT OF GREENER-BY-DESIGN PHARMACEUTICALS)
Período documentado: 2024-03-01 hasta 2025-08-31
The SusPharma project was conceived as a transformative initiative aligned with the EU Chemical Strategy for Sustainability. Its vision is to ensure that pharmaceutical production evolves into a model of green innovation, digital intelligence, and economic resilience. The pharmaceutical sector, while indispensable for global health and prosperity, remains one of the most environmentally demanding branches of the chemical industry, with E-factors ranging from 25 to 100, far higher than other sectors such as oil and gas. To address this challenge, SusPharma proposes a paradigm shift from conventional batch manufacturing to continuous, automated, and sustainable processes that fully integrate renewable feedstocks, circular economy principles, and artificial intelligence. The project’s core scientific concept rests on six synergistic innovation pillars: the use of heterogeneous catalysis to replace toxic homogeneous systems; the valorization of bio-based feedstocks into high-value intermediates; the development of continuous-flow reactors that are cleaner, safer, and more efficient; the creation of digital purification and solvent recovery methods to promote circularity; the application of AI and robotics to enable autonomous synthesis; and finally, the development of fully aqueous encapsulation strategies for sustainable drug delivery. Through this vision, SusPharma redefines how medicines are discovered, synthesized, purified, and formulated, offering a blueprint for a competitive and environmentally responsible European pharmaceutical industry.
During months 19 to 36, SusPharma achieved substantial scientific progress across its nine work packages, translating conceptual innovation into practical demonstration. The research on heterogeneous for C-X bond formation led to the development of novel single-atom and oxide-based materials synthesized by homogeneous precipitation methods. Among the most significant results, the copper single-atom catalyst demonstrated outstanding recyclability and no measurable metal leaching, providing direct applications in the synthesis of intermediates for antidepressant and antipsychotic drugs. Further progress was achieved in the design of green catalytic methodologies, where photocatalytic and electrocatalytic transformations were coupled with renewable carbon sources to generate building blocks from bio-based substrates. This bridge between biomass valorization and fine chemistry represents a major step toward the integration of green feedstocks in drug synthesis. Continuous-flow synthesis was also at the core of SusPharma’s success. A unified automated flow platform delivered several first-in-class achievements, including Ir-free carbon-carbon coupling using carbon nitrides and metal-free aziridination reactions with drastically reduced carbon footprints. Reactor design was supported by computational fluid dynamics to optimize light penetration and mixing, achieving 80% emission reductions compared to traditional reactors. In parallel, the project pioneered an artificial intelligence-driven crystallization ecosystem capable of linking machine-learning-based solvent selection with digital twins for process optimization. This approach was further enhanced by the creation of a multi-objective Bayesian framework that ensured impurity control and scalability. A major milestone was the development of the hybrid Jouyban-Acree neural network, the first predictive model for green solvent design trained on over 30,000 solubility data points. Automation was advanced through a fully autonomous laboratory platform integrating robotics, AI, and real-time analytics. Digital twins were used to perform Bayesian discrimination and automated design of experiments, allowing self-optimization in reactions such as the Claisen-Schmidt condensation. The project also introduced robotic chromatography capable of error-free purification and traceable analytics. In the area of drug repurposing, SusPharma developed solvent-free mechanochemical routes for the co-crystallization of NSAIDs, such as ketoprofen-lysine-gabapentin. Machine learning models accurately predicted co-crystal formation probabilities, while Raman and solid-state NMR provided in situ monitoring. Finally, research on advanced encapsulation resulted in low-permeability alginate and poly-L-lysine capsules post-treated with tannic acid to achieve pH-responsive, linear diffusion. Altogether, these achievements illustrate SusPharma’s shift from an ambitious concept into a tangible, integrated technological reality that merges catalysis, process intensification, and digitalization.
The results obtained by SusPharma transcend the current state of the art in sustainable pharmaceutical chemistry. The project has introduced an unprecedented level of automation, merging artificial intelligence, robotics, and real-time analytics to create autonomous reaction design systems that minimize waste and maximize product quality. Self-optimizing digital twins now enable real-time model discrimination and predictive control, capabilities that were previously unavailable in pharmaceutical manufacturing. Equally transformative is the development of scalable, waste-free catalysts which provide environmentally benign alternatives to precious-metal systems, consistent with European strategies on circular economy and critical raw materials. In crystallization science, the introduction of hybrid AI frameworks has turned solvent and impurity selection into a predictive and data-driven process, reducing uncertainty by 40% and experimental workload by 60%. Mechanochemical co-crystallization, supported by AI-based screening, has achieved reproducibility and efficiency that redefine formulation development, while new aqueous encapsulation technologies enable precise control of drug release without reliance on organic solvents. These advances together demonstrate the feasibility of a pharmaceutical manufacturing paradigm that is both intelligent and sustainable. For industrial uptake, SusPharma identifies the need for further pilot-scale validation, integration with digital regulatory frameworks such as Quality by Design and Process Analytical Technology, and access to finance for green scale-up initiatives. The establishment of standardized digital twin protocols across Europe will also be essential. The project thus lays a strong foundation for a future pharmaceutical ecosystem defined by sustainability, automation, and circularity.