PROJECT DESCRIPTION
BACKGROUND
Every stage of the pharmaceutical supply chain has environmental impacts, which are often not well calculated, in particular because Active Pharmaceutical Ingredients (APIs) are mostly produced in emerging and developing countries with weaker environmental legislation and limited accounting and monitoring of emissions.
The requirements set in the European Green Deal with its ambition of zero pollution have prompted pharmaceutical companies to integrate green chemistry and green engineering principles into their production processes, leading to an optimisation of resource use and emissions, and a partial reshoring of APIs, raw materials and intermediates production. Currently, however, most of the flow chemistry applications are still at the research and development stage; few of them are applied in the industrial chemicals production and very few in the APIs manufacturing sector.
Trazodone (an anti-depression treatment) is traditionally produced by the application of standard batch chemistry. The batch process, although having been optimised over the years, is still only moderately efficient, with a high waste production and limited safety. Thus, there is a need to switch to an improved innovative technology, such as continuous/inflow.
In 2019, Angelini Pharma filed a patent for an improved process for the preparation of trazodone, carried out in a continuous mode in a flow reactor. The process aims to be safer and more efficient, with reduced reaction times and similar or higher yields and quality compared to state of the art and traditional batch procedures. This approach also potentially results in a more cost effective and environmentally friendly process.
Currently, the Technology Readiness Level (TRL) of the methodology is 5. The results obtained within the patent application are at the laboratory scale, while industrialisation requires needs further engineering activities to integrate the reaction in the production line and to optimise process parameters for a large-scale application.
OBJECTIVES
The LIFE-GREENAPI project’s general objective is to develop and demonstrate a more efficient, greener and innovative fine chemicals production process. The project specifically proposes a technological shift in API production.
Angelini Pharma, in collaboration with the University of Leiden, will engineer, test, scale-up and demonstrate the environmental benefits of an innovative approach for the manufacturing of APIs, switching from batch to flow-chemistry, at an industrial level. The technological innovation will be first developed and tested on trazodone, a high-production volume API, and then replicated at laboratory scale on two additional small molecules, to demonstrate the broad spectrum of applicability.
The innovation is aimed at reducing the environmental footprint of the trazodone production process (currently representing 72% of the European volumes), increasing process productivity and decreasing waste generation. This is done by applying flow/continuous process technologies to all the production steps whilst:
Improving productivity, through in-flow technologies; and
Reducing the environmental impacts, consuming less, or using more sustainable solvents, producing less waste, consuming less materials and resources, thus reducing the overall GHG emissions associated to the process.
In addition, the project aims to ensure the replication of the innovative process within the project duration, through:
The preparation of the new trazodone process for the Good Manufacturing Practices validation; and
The replication on two additional chemical structures, common in APIs production, to stimulate catalytic effects.
RESULTS
Based on the results of previous activities conducted at laboratory level, the project’s expected results through the application of flow-chemistry as compared to the traditional batch mode are:
Increased reaction rate and process efficiency (+9.4%)
Lower volumes of solvent use (-31.8%; -2.37 kg of solvents / kg of trazodone produced)
Improved energy efficiency (-33.4%; -1.8 kWh/kg trazodone produced)
Waste reduction (-28.4%; -3.6 kg/ kg of trazodone produced)
Improved water management efficiency considering both the process and the artesian water (-38%; -0.32 m3 saved / kg of trazodone produced)
Increased safety for employees due to a reduction in the handling of potentially hazardous or toxic materials in the inflow-process.
