Design of greener drugs: aligning parameters in pharmaceutical R&D and drivers for environmental impact.

Active pharmaceutical ingredients (APIs) in the environment, primarily resulting from patient excretion, are of concern because of potential risks to wildlife. This has led to more restrictive regulatory policies. Here, we discuss the 'benign-by-design' approach, which encourages the development of environmentally friendly APIs that are also safe and efficacious for patients. We explore the challenges and opportunities associated with identifying chemical properties that influence the environmental impact of APIs. Although a straightforward application of greener properties could hinder the development of new drugs, more nuanced approaches could lead to drugs that benefit both patients and the environment. We advocate for an enhanced dialogue between research and development (R&D) and environmental scientists and development of a toolbox to incorporate environmental sustainability in drug development.

How data on transformation products can support the redesign of sulfonamides towards better biodegradability in the environment.

Sulfonamide antibiotics (SUAs) released into the environment can affect environmental und human health, e.g., by accelerating the development and selection of antimicrobial resistant bacteria. Benign by Design (BbD) of SUAs is an effective risk prevention approach. BbD principles aim for fast and complete mineralization or at least deactivation of the SUA after release into the aquatic environment. Main objective was to test if mixtures of transformation products (TPs) generated via photolysis of SUAs can be used as an efficient way to screen for similarly effective but better biodegradable SUA alternatives. Six SUAs were photolyzed (Hg ultraviolet (UV) light), and generated UV-mixtures analysed by high performance liquid chromatography coupled to an UV and tandem mass spectrometry detector. UV-mixtures were screened for antibiotic activity (luminescence bacteria test, LBT, on luminescence and growth inhibition of Aliivibrio Fischeri) and environmental biodegradability (manometric respirometry test, MRT, OECD 301F) using untreated parent SUAs in comparison. Additionally, ready environmental biodegradability of three commercially available hydroxylated sulfanilamide derivatives was investigated. SUA-TPs contributed to acute and chronic bacterial luminescence inhibition by UV-mixtures. LBT's third endpoint, growth inhibition, was not significant for UV-mixtures. However, it cannot be excluded for tested TPs as concentrations were lower than parents' concentrations and inhibition by most parental concentrations tested was also not significant. HPLC analysis of MRT samples revealed that one third of SUA-TPs was reduced during incubation. Three of these TPs, likely OH-SIX, OH-SMX and OH-STZ, were of interest for BbD because the sulfonamide moiety is still present. However, hydroxylated sulfanilamide derivatives, tested to investigate the effect of hydroxylation on biodegradability, were not readily biodegraded. Thus, improving mineralization through hydroxylation as a general rule couldn't be confirmed, and no BbD candidate could be identified. This study fills data gaps on bioactivity and environmental biodegradability of SUAs' TP-mixtures. Findings may support new redesign approaches.

Designing greener active pharmaceutical ingredients: Insights from pharmaceutical industry into drug discovery and development.

Active pharmaceutical ingredients (APIs), their metabolites and transformation products (TPs) are found as pollutants in the environment. They can impact human and environmental health. To address this issue, an efficient, long-term prevention strategy could be the design of APIs that have less impact on the natural environment, i.e. the design of greener APIs, by the implementation of environmental parameters into the drug discovery and development process (also abbreviated R&D for 'research and development'). Our study aimed to evaluate the feasibility of the design of greener APIs based on insights from drug design experts working in large, research-based pharmaceutical companies. The feasibility evaluation also identified needs and incentives for process modification. For this purpose, 30 R&D and environmental experts from seven globally active pharmaceutical companies were interviewed along a structured questionnaire. Main findings are that the interviewed experts saw manifold opportunities to include properties rendering APIs greener in different stages along the R&D process. This implementation would be favoured by the fact that the pharmaceutical R&D process is very flexible and relies on balancing multiple parameters. Furthermore, some API properties that reduce environmental risks were considered compatible with common desirable properties for application. Environmental properties should be considered early during R&D, i.e. when molecules are screened and optimized. It has been found that availability of suitable in silico models and in vitro assays is crucial for this environmental consideration. Their attributes, e.g. throughput and costs, determine at which process stage they can be successfully applied. An intensified exchange between R&D and environmental experts within and outside companies would push the industrial application of the benign by design approach for APIs forward. Collaboration across pharmaceutical companies, authorities, and academia is seen as highly promising in this respect. Financial, social, and regulatory incentives would support future design of greener APIs.

GREENER Pharmaceuticals for More Sustainable Healthcare.

Medicines are essential to human health but can also impact the aquatic and terrestrial environment after use by patients and release via excreta into wastewater. We highlight the need for a GREENER approach to identify and meet important environmental criteria, which will help reduce the impact of medicinal residues on the environment. These criteria include effect reduction by avoiding nontarget effects or undesirable moieties, exposure reduction via lower emissions or environmental (bio)degradability, no PBT (persistent, bioaccumulative, and toxic) substances, and risk mitigation. With all of these criteria, however, patient health is of primary importance as medicines are required to be safe and efficacious for treating diseases. We discuss the feasibility of including these criteria for green by design active pharmaceutical ingredients in the process of drug discovery and development and which tools or assays are needed to accomplish this. The integrated GREENER approach can be used to accelerate discussions about future innovations in drug discovery and development.

Transformation products of sulfonamides in aquatic systems: Lessons learned from available environmental fate and behaviour data.

Sulfonamides (SUAs) and their transformation products (TPs) contribute to environmental pollution. Importance of research on TPs' properties has been emphasised, e.g. allowing a comprehensive environmental risk assessment of their parent compounds. However, TPs' properties have been discussed in reviews on SUAs only marginally, if at all. For the first time, a scientific literature review aims to discuss the current state of knowledge on SUA-TPs including research gaps, and commonalities of SUA-TPs and TPs in general. Literature on SUA-TPs was consulted systematically to collect data on occurrence, physicochemical properties, degradability, and (eco)toxicity. TPs of 14 SUAs were reviewed, and aspects applicable for TPs in general were identified to guide future handling of TPs as a complex category of compounds. The data of sulfamethoxazole (SMX), the main representative, was analysed in more detail to discuss insights on a chemical level. Literature search resulted in 607 SUA-TPs reported in 222 publications. Only for 4%, 31%, and 35% of these TPs, data on occurrence in aquatic systems, on degradation, and (eco)toxicity, respectively, was found. Several mixtures of SUA-TPs were more ecotoxic than their parent compounds, e.g. 10 of 15 mixtures of SMX-TPs. Only few TPs were tested as single substance. Although several TPs could be eliminated experimentally, their mineralisation rate remained often unknown. Thus, further transformation to persistent TPs could not be ruled out. Standardised biodegradability tests of individual TPs would monitor their mineralisation rate, but are almost completely lacking. Reasons are likely poor availability of TPs, but also the focus on abiotic water treatment. Data assessment demonstrated that data of high significance according to standard methods, e.g. OECD methods for chronic (eco)toxicity and ready biodegradability, is needed to assess environmental risks of prioritised TPs, but also to redesign their parent pharmaceutical for complete environmental mineralisation in a long-term (Benign by Design).