Many APIs and their metabolites once excreted from the patient or discharged into water courses are recalcitrant to further breakdown in sewage treatment plants (STPs) and natural water courses (rivers, lakes etc.). When entering the environment via the patient, APIs may be excreted unchanged, as mixtures of unchanged API alongside one or several major metabolite(s), or completely metabolised to single or mixtures of metabolite(s).
In the environment, there may be no, partial or full chemical breakdown of the excreted compounds. As with metabolites, breakdown products can be more problematic than the parent compound – potentially more toxic and more recalcitrant. Many APIs are not removed during typical sewage treatments, but can be adsorbed onto sewage sludge.
Therefore once released into the environment, an API or metabolite may:
Loss to air is almost never seen for most APIs, therefore the two main environments are water (major) and land (minor).
Persistence, Bioaccumulation & Toxicity (PBT) are used to determine whether a substance poses concern for the environment. These properties can combine and lead to substances that are, for example, very persistent and very bioaccumulative (vPvB). As a result of the threat PBT/vPvB substances can pose, substances need to be screened for possible PBT properties under REACH (find out more about REACH – here). 
In the environment, there are three main decomposition routes for API molecules or their metabolites:
1) Chemical: typically, simple hydrolysis occurring between pH 5 and 8 – the pH will depend on the exact aquatic environment. Owing to the stability designed into most pharmaceutical molecules, uncatalysed chemical reactions in the environment may be limited to the hydrolysis of esters and possibly oxidation of highly reactive groups like mercaptans. Chemical transformations will not lead directly to mineralisation, but to a chemical species closely related to the original API which could be resistant to further chemical-only transformations. Most API molecules are resistant to oxidation by air, but may be oxidised in the presence of catalysts.
2) Enzymatic (or biotic degradation): molecules can be absorbed by microorganisms or higher life forms and metabolised via enzyme catalysis. Xenobiotic materials are metabolised to make them more polar to aid excretion, or to begin a breakdown process to utilise the molecule as a carbon/nitrogen source. These enzymatic transformations tend to follow human metabolism pathways – oxidation, reduction, hydrolysis and other less common transformations. API molecules may encounter enzyme classes common to humans but with different selectivities (such as P450s, a superfamily of haemoproteins that catalyse the metabolism of a large number of clinically important drugs), and classes of oxidative enzymes not normally utilized in human metabolism. As with humans, there can also be secondary metabolism – formation of phosphates, sulphates, and glucuronides. It should be noted that occasionally transformations in the environment can reverse the beneficial metabolic transformations in patients; one of the most problematic API molecules, EE2, is partly excreted as the soluble glucuronide which does not have estrogenic and endocrine disruption properties. This is converted back in STPs to the parent API which exhibits these undesirable properties, Figure 1.
3) Photolytic decomposition/photochemical oxidation: direct photolytic decomposition (promotion to an excited state followed by a reaction) requires absorption of natural sunlight by the molecule (e.g. has an absorption maxima >290 nm). If a molecule has a UV/Vis maximum below 290 nm, it may still be decomposed by an indirect photochemical oxidation process, through reaction with high energy species like the ROO., OH. radicals and singlet oxygen, which are generated photochemically via dissolved sensitizers based on organic substances like humic acids. (More information on photodegradation and its impact on manufacturing, packaging, storage and testing of pharmaceutical products can be found in this article).
Most APIs are degraded in vivo via enzyme catalysis in microorganisms or in vitro by direct/indirect photochemical pathways.
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