Green Chemistry and Engineering

Benign by Design

The tenth Principle of Green Chemistry states "Chemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment". One solution being put forward to reduce the burden of pharmaceuticals in the environment is the development of drug molecules with properties optimised for rapid and complete biodegradation after excretion. This design concept is called Benign by Design. After the Active Pharmaceutical Ingredient (API), any excipients (the other chemicals in a formulated medicine in addition to the API) should also be benign.

Any chemical that inevitably enters the environment must achieve fast and complete mineralisation to avoid incomplete degradation and persistent transformation products which may have a negative impact on the environment. The complexity of medicinal products and their metabolites and transformation products contributes to a cocktail of environmental pollutants which makes the assessment of environmental risks more challenging.  

Benign by Design takes advantage of the fact that (bio)degradability is strongly dependent on the ambient conditions in addition to the inherent properties of the molecule. Since the ambient conditions are changing along the lifecycle of an API (from production to transport and storage to application in the patient then excretion and finally exposure to the environment), the (bio)degradation potential varies as well. Conditions are characterised by numerous factors relevant for abiotic or biotic degradation processes. Examples are temperature, pH value, availability of light, oxygen and nutrients, and the composition of microorganisms (Kümmerer, 2007). Another important principle of Benign by Design is that small changes to chemical structure have an impact on the biodegradation rate. For example, phenol is more readily biodegradable than benzene due to the added hydroxy chemical group. As a consequence, it is possible to keep the functional parts of molecules while increasing the rate of biodegradation through slight molecular changes. 

Glufosfamide

Glufosfamide is often given as an example of a biodegradable version of ifosfamide, a drug which is persistent in the environment.  

Ifosfamide has several detrimental issues as a drug, including pharmacokinetic variability, resistance and severe host toxicity. Therefore, the ultimate design driver for the alternative glufosfamide was to achieve increased selectivity and efficacy in the patient. The chemical structure of glufosfamide contains a monosaccharide (sugar). Glufosfamide (tested in clinical trials) makes use of the normal cell glucose transport mechanism for its own transport into the cell. Glucose transport can be overexpressed and upregulated in certain cancer cell lines. Whilst glufosfamide was not intentionally designed for environmental mineralisation, this has been demonstrated in laboratory tests. The better environmental profile was a bonus, as opposed to a design feature, but highlights that the inclusion of natural product-like fragments like sugars could result in a safer environmental fate. 

Cip-Hemi

Another well-known example is the redesign of the fluoroquinolone antibiotic ciprofloxacin to increase its environmental degradability, and thus avoid the development and selection of antibiotic resistance through prolonged exposures. The most promising alternative to ciprofloxacin is Cip-Hemi with increased environmental degradability through hydrolysis of its hemiaminal and only slightly decreased antibiotic activity compared to ciprofloxacin. At pH ≤ 6 the rate of degradation by hydrolysis is greatly accelerated compared to physiological pH 7.4. This results in sufficient lifetime in the patient, and only hydrolysis after excretion. Hydrolysis leads to a transformation products with highly reduced antibacterial activity (Leder et al., 2021). Further research is needed to develop antibiotics that achieve complete and rapid environmental mineralisation.  

Environmental persistence  

Rules of thumb can create Benign by Design principles to increase the chances that an API (including its eventual metabolites and its transformation products) will not be persistent. Several examples have been proposed, including: 

Predictive tools

In the early stages of drug development, in silico models to predict environmental biodegradability is a valuable tool, especially because large collections of compounds need to be screened making experimental testing unfeasible. Both freely available and commercial software exist for this purpose and are in use already. In general, biodegradation prediction models provide 80-90% classification accuracy for common chemicals. However, models with increased prediction accuracy are still needed for APIs. Current models are based on data for bulk chemicals and are thus not well applicable to APIs which are structurally different from common chemicals. New prediction models for the biodegradability of pharmaceuticals are under development, e.g. within the EU Horizon research projects PREMIER and TransPharm. 

To provide guidance in predicting broader environmental performance of compounds, a selection of tools is listed below. Some are collections or suites of publicly available tools. This is a representative and not a comprehensive list of what is available. A more comprehensive selection of existing freely available and other commercial software (e.g. BIOWIN, VEGA, OCHEM Consensus, OPERA, Leadscope, OASIS, Case Ultra, SciQSAR, TOPKAT) and their persistence or biodegradation models can be found elsewhere (Bramke et al., 2023, see annex III, p. 68). It is important to note that any molecule tested within these models should be within the applicability domain of the model used. 

Here are some guiding principles when applying screening tools to assist a Benign by Design approach to API development: 

• Use fate and ecotoxicity assessments earlier on in the development pipeline to highlight potential environmental issues (high throughput screens might be advantageous); 

• Use predictive tools, but understand their limitations, e.g. in terms of applicability; 

• Look for structural similarity with compounds known to have negative environmental impact; 

• Look for plausible degradation pathways that lead to known pollutants; 

• Make use of ‘read across’ (analogous) data but understand the associated risks and limitations. 

Further design approaches to reduce pharmaceuticals in the environment

Reducing the dose of the API is another design strategy to reduce the amount that enters the environment, and hence, its environmental concentration. Reducing the dose may be a remedy if the API cannot be designed towards full mineralisation in the environment. Lower doses could be achieved through better targeted drug delivery routes (e.g., expanding the utility of pulmonary and transdermal/mucosal delivery), mechanisms of release (e.g., rapid-dissolving formulations, controlled release), and mechanisms for delivery of drugs to the target (e.g., antibody-linked drugs; in situ implants). Next to improving the drug delivery method, increasing the bioavailability and the on‑target specificity of the API could also help to reduce the necessary dose (Baron, 2012; Daughton, 2003).  

Note that designing APIs with higher potency, and hence, a lower dose compared to a compound with same properties but lower potency, isn’t an appropriate design approach. Although the lower dose would result in a lower concentration, this is compensated by the higher activity. Highly active APIs also tend to have a greater effect on environmental organisms due to their mechanism of action and the conservation of targets across species remaining the same as less potent drugs, but now active in lower concentrations.