The fate of APIs - learning.chem21.eulearning.chem21.eu/media/pdf/41/the-fate-of-apis-letter.pdf · Describe the fate of APIs in the environment in terms ... the API maybe excreted

The fate of APIsPharmaceuticals, their metabolites and products of incomplete degradation are presentin the environment and their fate and effects are not yet fully understood.[1] Buildingupon the previous lesson on Pharmaceuticals in the Environment, this module looks morein depth at the fate of APIs including routes into the environment, adsorption anddecomposition pathways including case studies on the breakdown products of severalspecific APIs.

Learning Objectives

By the end of this module you should:

Be aware of concerns surrounding pharmaceuticals in the environment;Understand the different routes by which pharmaceuticals enter the environment;Be aware of strategies to reduce environmental impact of pharmaceuticals in theenvironment;

and be able to:

Describe the fate of APIs in the environment in terms of their adsorption anddecomposition pathways;Describe sub-structures in molecules that can give rise to persistence in theenvironment.

1. K. Kümmerer, Presence, Fate and Risks of Pharmaceuticals in the Environment,in Green and Sustainable Medicinal Chemistry: Methods, Tools and Strategies forthe 21st Century Pharmaceutical Industry, L. Summerton, H. F. Sneddon, L. C.

This resource has been created as part of the IMI funded CHEM21 project (Chemical Manufacturing Methods for the 21st Century Pharmaceutical Industries). CHEM21 has receivedfunding from the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115360, resources of which are composed of financial contribution from the EuropeanUnion’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution.

The educational material is licensed (unless otherwise specified) under Creative Commons license CC BY-NC 4.0, which gives permission for it to be shared and adapted for non-commercial purposes as long as attribution is given. For full details please see our legal statements.

The views expressed in regards to education and training materials represent the aspiration of the CHEM21 consortium, although may not always be the view of eachindividual organisation. Referencing of external sources does not imply formal endorsement by the CHEM21 consortium.

http://dx.doi.org/10.1039/9781782625940-00063

https://creativecommons.org/licenses/by-nc/4.0/

Jones and J. H. Clark, Royal Society of Chemistry, Cambridge, UK, 2016, ch. 6, pp.63-72.





Routes into the environment

There are three main routes by which pharmaceutical molecules enter the environment,which are shown in Figure 1:

Normal patient use;Improper disposal of unwanted pharmaceuticals and related medical devices such aspatches, implants etc. into landfill or water courses;Point source pollution at sites of manufacture/formulation.

A fourth route which is starting to become more prevalent (or at least better detected) isthe illegal or off-label use of pharmaceuticals resulting in accumulation in unintendedspecies such as plants and animals.




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Figure 1: Main routes by which pharmaceutical molecules enter the environment

Normal patient use

After administration, the API maybe excreted unchanged in urine or faeces or metabolisedto new chemical entities. An API may give a single metabolite or multiple metabolites thatare excreted - these metabolites may or may not be pharmacologically active. Metabolismusually proceeds via oxidation, reduction or hydrolysis and can be followed by secondaryprocesses such as sulphate formation, glucuronidation etc. Almost all APIs and associatedmetabolites have such a low vapour pressure that loss via the lungs or partition into theatmosphere from contaminated water or soil is never observed as a major route into theenvironment. Thus drugs and metabolites are excreted and enter into the sewagetreatment system, or directly into the environment if no sewage system is in place.

Improper disposal

Improper disposal of unwanted or unused pharmaceuticals occurs via direct flushing ofproducts into the municipal sewage system or via municipal solid waste systems, whichare usually destined for landfill. Eventually APIs in landfill sites may leach out andcontaminate ground water, although if blister packed or in containers, these would haveto degrade first. Controlled landfill sites should collect leachate, therefore limiting thisroute to the environment - however, legislation governing this varies worldwide. Othersolids like syringes, implants and patches improperly disposed of in landfill could alsolead to API contamination of groundwater. Other improper disposal routes include theillegal landfilling or dumping into water courses of industrial waste containing APIresidues to avoid costs associated with proper disposal routes (land fill tax,incineration).[1] As an example, over 1,000 tonnes of unused or unwantedpharmaceuticals disposed of in Sweden in 2011. Whilst the majority (around 800 tonnes)were disposed of correctly through patient return or recycling stations, around 250tonnes were still disposed of through home disposal.[2]

Unused medicines arise from a wide range of factors: patients not completing theprescribed course, failure to take due to undesirable side effects, out of date drugs,





damaged packaging, and many others. It is debatable as to the extent of the escape ofAPIs into the environment via this route compared to normal patient use and point sourcepollution.[3]

1. S. Castensson and A. Ekedahl, Pharmaceutical Waste: The Patient Role, Greenand Sustainable Pharmacy, 2010, 179-200.

2. Measures to reduce disposal of pharmaceuticals in distribution and health care(Last accessed: April, 2016).

3. C. G. Daughton and I. S. Ruhoy, Environmental footprint of pharmaceuticals: Thesignificance of factors beyond direct excretion to sewers, EnvironmentalToxicology and Chemistry, 2009, 28, 2495-2521.

Multiple choice question

1. What are the main potential means of APIs entering the environment?1. Excreted directly from the body2. Incineration3. Solvent/VOC loss4. Improper disposal5. Disposal in controlled landfill sites6. Point Source Pollution

Answers on last page




http://dx.doi.org/10.1007/978-3-642-05199-9_12

http://www.dbu.de/media/281112025041jsge.pdf

http://dx.doi.org/10.1897/08-382.1


Areas of concern

All xenobiotic materials released through human activities have the potential to causeissues in the environment, including but not limited to pharmaceuticals. It is the fact thatpharmaceuticals exhibit biological activities that has led to their consideration as an areaof concern – this is especially true of antibiotics, oncology drugs and drugs exhibitingendocrine disrupting activities. For example, a number of oestrogenic residues like ethinylestradiol (EE2) are known to be very potent and deleterious to health, but for most APIsthe risk to human health is considered negligible in a high quality drinking watersource.[1][2][3]The volumes of water needed to consume a single therapeutic dose of APIspresent as micro-contaminants are high.[4][5] Unfortunately, access to high quality, puredrinking water is not a universal human benefit, and serious issues can arise if drinkingwater sources become contaminated with high levels of APIs.[6] Even for EE2, the datasuggests that there will only be a risk at high point source concentrations of EE2.[7] [8]

Pharmaceuticals are a small sector of a wider chemical industry where current data onthe fate and biological activity in the environment is very limited. [9] Outside of thepharmaceutical industry, some widely used industrial chemicals have been shown to havepotent endocrine disruption potential (e.g. phthalates, alkylphenols) [10].

Apart from potential effects on humans, the presence of APIs in aquatic and otherenvironments can cause undesired effects in other species – for highly active compoundslike hormones and central nervous system (CNS) drugs these effects could be expected tooccur at low concentration levels. It is clear that the increasing estrogenicity of water hasled to issues with the feminisation of male fish, although the effects of other APIs from theCNS class are unclear.[11][12][13]

While in most cases, the scientific study and debate continues regarding the potential ofharm caused by PIE, there are a number of instances where pharmaceuticals in theenvironment have caused well documented problems – diclofenac and the Gyps vulturesbeing a notable example. At the turn of the century, a large and precipitous decline in thepopulation of Gyps vulture species was noted in the Indian sub-continent, and threespecies are now listed as critically endangered.[14][15] This was traced to the presence ofthe NSAID diclofenac in the corpses of cattle and other farm animals utilised by the





vultures as a food source. Gyps vultures are very sensitive to diclofenac (LD50 < 1000 μgkg-1), which causes acute and lethal kidney failure. India, Nepal and Pakistan banned theveterinary use of diclofenac, but recent data suggests ~5% of animal corpses still containhigh levels of diclofenac.[16]

1. M. Schriks, M. B. Heringa, M. M. E. van der Kooi, P. de Voogt and A. P. van Wezel,Toxicological relevance of emerging contaminants for drinking water quality,Water Research, 2010, 44, 461-476.

2. Vde Jesus Gaffney, C. M. M. Almeida, A. Rodrigues, E. Ferreira, M. João Benolieland V. Vale Cardoso, Occurrence of pharmaceuticals in a water supply systemand related human health risk assessment, Water Research, 2015, 72, 199-208.

3. N. C. Rowney, A. C. Johnson and R. J. Williams, Cytotoxic drugs in drinking water:A prediction and risk assessment exercise for the thames catchment in the UnitedKingdom, Environmental Toxicology and Chemistry, 2009, 28, 2733-2743.

4. P. E. Stackelberg, E. T. Furlong, M. T. Meyer, S. D. Zaugg, A. K. Henderson and D.B. Reissman, Response to comment on “Persistence of pharmaceuticalcompounds and other organic wastewater contaminants in a conventionaldrinking-water-treatment plant”, Science of the total environment , 2006, 354, 93-97.

5. C. A. Kinney, E. T. Furlong, S. L. Werner and J. D. Cahill, Presence and distributionof wastewater‐derived pharmaceuticals in soil irrigated with reclaimed water,Environmental Toxicology and Chemistry, 2006, 25, 317-326.

6. WHO Water Sanitation Health (Last accessed: ).7. J. P. Laurenson, R. A. Bloom, S. Page and N. Sadrieh, Ethinyl Estradiol and Other

Human Pharmaceutical Estrogens in the Aquatic Environment: A Review ofRecent Risk Assessment Data, AAPS J, 2014, 16, 299-310.

8. A. Wise, K. O’Brien and T. Woodruff, Are oral contraceptives a significantcontributor to the estrogenicity of drinking water?†, Environmental science &technology, 2010, 45, 51-60.

9. D. Taylor and T. Senac, Human pharmaceutical products in the environment –The “problem” in perspective, Chemosphere, 2014, 115, 95-99.




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http://www.who.int/water_sanitation_health/emerging/info_sheet_pharmaceuticals/en/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933577/pdf/12248_2014_Article_9561.pdf

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10. E. Rahman Kabir, M. Sharfin Rahman and I. Rahman, A review on endocrinedisruptors and their possible impacts on human health, Environmental Toxicologyand Pharmacology, 2015, 40, 241-258.

11. W. Sanchez, W. Sremski, B. Piccini, O. Palluel, E. Maillot-Maréchal, S. Betoulle, A.Jaffal, S. Aït-Aïssa, F. Brion, E. Thybaud, N. Hinfray and J. - M. Porcher, Adverseeffects in wild fish living downstream from pharmaceutical manufacturedischarges, Environment International, 2011, 37, 1342-1348.

12. N. Gilbert, Drug waste harms fish, Nature News, 2011, 476, 265-265.13. J. P. Sumpter, R. L. Donnachie and A. C. Johnson, The apparently very variable

potency of the anti-depressant fluoxetine, Aquatic Toxicology, 2014, 151, 57-60.14. M. A. Taggart, K. R. Senacha, R. E. Green, R. Cuthbert, Y. V. Jhala, A. A. Meharg, R.

Mateo and D. J. Pain, Analysis of nine NSAIDs in ungulate tissues available tocritically endangered vultures in India, Environmental science & technology, 2009,43, 4561-4566.

15. M. A. Taggart, K. R. Senacha, R. E. Green, Y. V. Jhala, B. Raghavan, A. R. Rahmani,R. Cuthbert, D. J. Pain and A. A. Meharg, Diclofenac residues in carcasses ofdomestic ungulates available to vultures in India, Environment International,2007, 33, 759-765.

16. M. Saini, M. A. Taggart, D. Knopp, S. Upreti, D. Swarup, A. Das, P. K. Gupta, R.Niessner, V. Prakash, R. Mateo and R. J. Cuthbert, Detecting diclofenac inlivestock carcasses in India with an ELISA: A tool to prevent widespread vulturepoisoning, Environmental Pollution, 2012, 160, 11-16.


1. Why has there been an increasing focus on Pharmaceuticals in theEnvironment (PIE) in recent years?1. APIs are stable, therefore will not break down in the environment.2. New analytical methods capable of detecting molecules at lower levels

have allowed us to detect previously undetected pharmaceutical residues3. Risk of overdosing from APIs in tap water4. The fate of many APIs in the environment is still largely unknown5. Whilst the effect of APIs on humans is known, effects on other organisms




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may not be






Absorption and decomposition pathways

Many APIs and their metabolites once excreted from the patient or discharged into watercourses are recalcitrant to further breakdown in sewage treatment plants (STPs) andnatural 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 severalmajor 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 excretedcompounds. As with metabolites, breakdown products can be more problematic than theparent compound – potentially more toxic and more recalcitrant.[1] [2] Many APIs are notremoved during typical sewage treatments, but can be adsorbed onto sewage sludge.

Therefore once released into the environment, an API or metabolite may:

Decompose to innocuous fragments and eventually be mineralised – converted tocarbon dioxide, nitrates, sulphates etc.Decompose to more recalcitrant fragments that are persistent.Be recalcitrant – i.e. does not decompose, and may or may not show undesirablebiological activity.Bind to organic solids such as soils, river/lake sediments and sludge in STPs where itcould accumulate or slowly decompose. This binding rapidly reduces theconcentration of the API in solution, but may not necessarily remove it from theenvironment. The extent (efficiency) of binding is dependent on the nature of thesolid and thus will be location dependant.

Loss to air is almost never seen for most APIs, therefore the two main environments arewater (major) and land (minor).

1. M. Bergheim, R. Gminski, B. Spangenberg, M. Dębiak, A. Bürkle, V. Mersch-





Sundermann, K. Kümmerer and R. Gieré, Recalcitrant pharmaceuticals in theaquatic environment: a comparative screening study of their occurrence,formation of phototransformation products and their in vitro toxicity,Environmental Chemistry, 2014, 11, 431-444.

2. X. - H. Wang and A. Yu- Chen Lin, Is the phototransformation of pharmaceuticals anatural purification process that decreases ecological and human health risks?,Environmental Pollution, 2014, 186, 203-215.

Persistence, Bioaccumulation & Toxicity (PBT)

Assessment of a chemical substance related to releases to water are based on three mainproperties – Persistence, Bioaccumulation & Toxicity (PBT). Any one of these propertiesmay cause a problem, and they are often interactive: two of them together may causesignificant problems. If a chemical substance is known to exhibit all three properties, thenit is likely to be affected by chemical regulation. However, although compounds used inpharmaceutical production are covered under REACH, the Active PharmaceuticalIngredient itself is exempt.[1]

Persistence (P) – the compound is recalcitrant and not biodegraded hence will persistin the environment. Bioaccumulation (B) – concentration of materials from water into organisms, usuallyin lipids/fats. This property is very difficult and expensive to measure in vivo andusually the octanol/water partition coefficient (Kow) is used as a surrogate indicatorof bioaccumulation.Toxicity (T) – kills or is deleterious to microorganisms/animals. It is worth noting,however, that Endocrine Disruptor (ED) issues are more complicated: toxicity candepend on organism life stage, e.g. infancy vs adulthood. Additionally, toxicity may beindirect, making an organism more prone to infection or disease by e.g. triggeringchanges in DNA leading to mutation, or promoting the development of enzymes thatinactivate antibiotics.[2]

1. EFPIA Management of PIE (Last accessed: ).2. E. Rahman Kabir, M. Sharfin Rahman and I. Rahman, A review on endocrine




http://dx.doi.org/10.1071/EN13218

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disruptors and their possible impacts on human health, Environmental Toxicologyand Pharmacology, 2015, 40, 241-258.

Decomposition routes

In the environment, there are three main decomposition routes for API molecules or theirmetabolites:

1) Chemical: typically, simple hydrolysis occurring between pH 5 and 8 – the pH willdepend on the exact aquatic environment. Owing to the stability designed into mostpharmaceutical molecules, uncatalysed chemical reactions in the environment may belimited to the hydrolysis of esters and possibly oxidation of highly reactive groups likemercaptans. Chemical transformations will not lead directly to mineralisation, but to achemical species closely related to the original API which could be resistant to furtherchemical-only transformations. Most API molecules are resistant to oxidation by air, butmay be oxidised in the presence of catalysts.

2) Enzymatic (or biotic degradation): molecules can be absorbed by microorganisms orhigher life forms and metabolised via enzyme catalysis. Xenobiotic materials aremetabolised to make them more polar to aid excretion, or to begin a breakdown processto utilise the molecule as a carbon/nitrogen source. These enzymatic transformationstend to follow human metabolism pathways – oxidation, reduction, hydrolysis and otherless common transformations. API molecules may encounter enzyme classes common tohumans but with different selectivities (such as P450s, a superfamily of haemoproteinsthat catalyse the metabolism of a large number of clinically important drugs), and classesof oxidative enzymes not normally utilized in human metabolism. As with humans, therecan also be secondary metabolism – formation of phosphates, sulphates, andglucuronides. It should be noted that occasionally transformations in the environmentcan reverse the beneficial metabolic transformations in patients; one of the mostproblematic API molecules, EE2, is partly excreted as the soluble glucuronide which doesnot have estrogenic and endocrine disruption properties. This is converted back in STPsto the parent API which exhibits these undesirable properties, Figure 1.





Figure 1: Biotic transformations of EE2

3) Photolytic decomposition/photochemical oxidation: direct photolyticdecomposition (promotion to an excited state followed by a reaction) requires absorptionof natural sunlight by the molecule (e.g. has an absorption maxima >290 nm). If amolecule has a UV/Vis maximum below 290 nm, it may still be decomposed by an indirectphotochemical oxidation process, through reaction with high energy species like theROO., OH. radicals and singlet oxygen, which are generated photochemically via dissolvedsensitizers based on organic substances like humic acids. (More information onphotodegradation and its impact on manufacturing, packaging, storage and testing ofpharmaceutical products can be found in this article).

Most APIs are degraded in vivo via enzyme catalysis in microorganisms or in vitro bydirect/indirect photochemical pathways.


1. What are the main potential means of API degradation in the environment?1. Catalytic2. Enzymatic3. Thermal4. Photo-degradation5. Hydrolysis6. Oxidation by air




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Analysis of API fate

Listed below are 10 typical pharmaceutical molecules and their breakdown productsunder conditions likely to be encountered in the environment. A number of treatmentscollectively called advanced oxidation technologies/processes (AOT/AOP) can be used totreat waste water containing chemicals known to be recalcitrant and/or toxic in biologicaltreatment/sewage treatment plants before discharge into the environment.Decomposition products from AOT/AOP processing have not been included since thesetechnologies operate under harsh oxidative conditions that are never encountered in theenvironment. APIs may come into contact with milder technologies used to disinfectdrinking water, which would lead to partial oxidation.

Whatever the mode of reaction, unless a molecule is mineralised, it should not beassumed that one or two transformations will render a toxic/recalcitrant molecule less so.Transformation may result in products with greater environmental issues than theoriginal molecule.[1][2] Likewise, quantitifying the eco-toxicity of breakdown productscomputationally can present issues, e.g. with quantitative structure–activity relationship(QSAR) modelling since:

It is often inaccurate for the parent pharmaceutical molecules;The assigned structures for the transformation products could be incorrect;An unambiguous answer can only be reached from physical testing.

The ten molecules have been selected to give examples of APIs across differenttherapeutic areas and to show examples of biotic, direct and indirect photolyticdecomposition. Mainly, primary breakdown products are shown. These could be subjectto further degradation processes.

1) Diclofenac





Figure 1: Biotic and photo-degradation routes of diclofenac[3] [4] [5] [6]

2) Fluoxetine

Figure 2: Direct and indirect photo-degrdation of Fluoxetine [7]

3) Paroxetine




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Figure 3: Photo-degradation of paroxetine[8]

4) Atorvastin

Figure 4: Hydrolysis of Atorvastatin[9]




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5) Fluphenazine

Figure 5: Photo-degradation of Fluphenazine[10]

6) Tamoxifen




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Figure 6: Photodegradation of Tamoxifen[11]

7) Trimethoprim

Figure 7: Biotic and photo-degradation of Trimethoprim[12] [13] [14] [15]

8) Penicillin G




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Figure 8: Biotic and chemical breakdown of Penicillin G[16]

9) Ciproflaxacin

Figure 9: Photo-degradation of Ciprofloxacin[17] [18]

10) Valsartan

Figure 10: Biotic breakdown of Valsartan[19] [20]

1. M. Bergheim, R. Gminski, B. Spangenberg, M. Dębiak, A. Bürkle, V. Mersch-




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Sundermann, K. Kümmerer and R. Gieré, Recalcitrant pharmaceuticals in theaquatic environment: a comparative screening study of their occurrence,formation of phototransformation products and their in vitro toxicity,Environmental Chemistry, 2014, 11, 431-444.

2. X. - H. Wang and A. Yu- Chen Lin, Is the phototransformation of pharmaceuticals anatural purification process that decreases ecological and human health risks?,Environmental Pollution, 2014, 186, 203-215.

3. J. Gröning, C. Held, C. Garten, U. Claußnitzer, S. R. Kaschabek and M. Schlömann,Transformation of diclofenac by the indigenous microflora of river sediments andidentification of a major intermediate, Chemosphere, 2007, 69, 509-516.

4. D. E. Moore, S. Roberts-Thomson, D. Zhen and C. C. Duke, PHOTOCHEMICALSTUDIES ON THE ANTIINFLAMMATORY DRUG DICLOFENAC, Photochemistry andPhotobiology, 1990, 52, 685-690.

5. A. Agüera, L. A. Pérez Estrada, I. Ferrer, E. M. Thurman, S. Malato and A. R.Fernández-Alba, Application of time-of-flight mass spectrometry to the analysisof phototransformation products of diclofenac in water under natural sunlight,Journal of Mass Spectrometry, 2005, 40, 908-915.

6. T. Poiger, H. - R. Buser and M. D. Müller, Photodegradation of the pharmaceuticaldrug diclofenac in a lake: Pathway, field measurements, and mathematicalmodeling, Environmental Toxicology and Chemistry, 2001, 20, 256-263.

7. M. W. Lam, C. J. Young and S. A. Mabury, Aqueous Photochemical ReactionKinetics and Transformations of Fluoxetine, Environmental Science & Technology,2005, 39, 513-522.

8. J. - W. Kwon and K. L. Armbrust, Hydrolysis and photolysis of paroxetine, aselective serotonin reuptake inhibitor, in aqueous solutions, EnvironmentalToxicology and Chemistry, 2004, 23, 1394-1399.

9. M. W. Lam and S. A. Mabury, Photodegradation of the pharmaceuticalsatorvastatin, carbamazepine, levofloxacin, and sulfamethoxazole in naturalwaters, Aquat. Sci., 2005, 67, 177-188.

10. C. Trautwein and K. Kümmerer, Ready biodegradability of trifluoromethylatedphenothiazine drugs, structural elucidation of their aquatic transformationproducts, and identification of environmental risks studied by LC-MS n and QSAR,Environ Sci Pollut Res, 2012, 19, 3162-3177.

11. M. DellaGreca, M. Rosaria Iesce, M. Isidori, A. Nardelli, L. Previtera and M. Rubino,Phototransformation products of tamoxifen by sunlight in water. Toxicity of thedrug and its derivatives on aquatic organisms, Chemosphere, 2007, 67, 1933-




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http://dx.doi.org/10.1111/j.1751-1097.1990.tb08667.x

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http://pubs.acs.org/doi/pdfplus/10.1021/es0494757

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http://dx.doi.org/10.1007/s00027-004-0768-8

http://dx.doi.org/10.1007/s11356-012-1002-1

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1939.12. J. J. Bergh, J. C. Breytenbach and P. L. Wessels, Degradation of trimethoprim,

Journal of Pharmaceutical Sciences, 1989, 78, 348-350.13. P. Eichhorn, L. P. Ferguson, S. Pérez and D. S. Aga, Application of Ion Trap-MS

with H/D Exchange and QqTOF-MS in the Identification of Microbial Degradatesof Trimethoprim in Nitrifying Activated Sludge, Analytical Chemistry, 2005, 77,4176-4184.

14. C. Sirtori, A. Agüera, W. Gernjak and S. Malato, Effect of water-matrix compositionon Trimethoprim solar photodegradation kinetics and pathways, WaterResearch, 2010, 44, 2735-2744.

15. T. Yi, W. Barr and W. F. Harper, Electron density-based transformation oftrimethoprim during biological wastewater treatment, Water Science andTechnology, 2012, 65, 689-696.

16. M. Bergheim, T. Helland, R. Kallenborn and K. Kümmerer, Benzyl-penicillin(Penicillin G) transformation in aqueous solution at low temperature undercontrolled laboratory conditions, Chemosphere, 2010, 81, 1477-1485.

17. T. Haddad and K. Kümmerer, Characterization of photo-transformation productsof the antibiotic drug Ciprofloxacin with liquid chromatography–tandem massspectrometry in combination with accurate mass determination using an LTQ-Orbitrap, Chemosphere, 2014, 115, 40-46.

18. J. Burhenne, M. Ludwig and M. Spiteller, Photolytic degradation offluoroquinolone carboxylic acids in aqueous solution, Environ Sci Pollut Res, 1997,4, 61-67.

19. K. Nödler, O. Hillebrand, K. Idzik, M. Strathmann, F. Schiperski, J. Zirlewagen andT. Licha, Occurrence and fate of the angiotensin II receptor antagonisttransformation product valsartan acid in the water cycle – A comparative studywith selected β-blockers and the persistent anthropogenic wastewaterindicators carbamazepine and acesulfame, Water Research, 2013, 47, 6650-6659.

20. S. Kern, R. Baumgartner, D. E. Helbling, J. Hollender, H. Singer, M. J. Loos, R. P.Schwarzenbach and K. Fenner, A tiered procedure for assessing the formation ofbiotransformation products of pharmaceuticals and biocides during activatedsludge treatment, Journal of Environmental Monitoring, 2010, 12, 2100-2111.




http://onlinelibrary.wiley.com/doi/10.1002/jps.2600780418/abstract

http://pubs.acs.org/doi/pdfplus/10.1021/ac050141p

http://ac.els-cdn.com/S0043135410000953/1-s2.0-S0043135410000953-main.pdf?_tid=cc71c52c-b47a-11e5-b752-00000aacb361&acdnat=1452087701_44ea270ec7798f0d916b93994a4333da

http://wst.iwaponline.com/content/65/4/689

http://ac.els-cdn.com/S0045653510009744/1-s2.0-S0045653510009744-main.pdf?_tid=ffed2aa0-b47e-11e5-b9f1-00000aab0f02&acdnat=1452089505_e9eef424068bde3f491892a3fdb1d526

http://ac.els-cdn.com/S004565351400215X/1-s2.0-S004565351400215X-main.pdf?_tid=7768b5fe-b47f-11e5-a58d-00000aacb35e&acdnat=1452089706_795045a41e73e8ecf8e4d6805bb3b33f

http://dx.doi.org/10.1007/BF02986278

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http://pubs.rsc.org/en/content/articlepdf/2010/em/c0em00238k


Environmental Risk Assessment (ERA)

Both the European Medicines Agency (EMA) and the US Food and Drug Administration(FDA) require the submission of an environmental risk assessment (ERA) with anapplication for a marketing license for a new pharmaceutical product. This ERA is basedon a defined set of experiments designed to look at the potential effects of the API onthree trophic life forms and bacteria, along with other experimentallydetermined/calculated figures that will give some idea of the PBT risk of the API.[1]

For some years in Sweden, data from the ERA has been made available to payers andprescribers in their database (www.fass.se). At a high level, fass.se was designed topromote the prescription of drugs with the lowest environmental fate impact, whilstensuring that the clinical benefits are equal for the patient. Some stakeholders would likeconsideration of the ERA to become part of the marketing authorisation for newpharmaceutical products.[2]

The ERA for an API runs through a number of phases, involving successive levels designedto generate more data if concern around a particular substance increases. The ERA isprincipally based around two figures: the calculated Predicted EnvironmentalConcentration (PEC) of the API in the environment (water) and the measuredconcentration at which no adverse environmental issues would be expected (PredictedNo Effect Concentration - PNEC). Many ERAs and the data submitted to regulatoryagencies are in the public domain[3][4][5] and can also be found by searching theFDA/EMA websites.

Many pharmaceutical companies carry out and publish studies above and beyond thoseneeded from a regulatory requirement. The regulatory requirement focuses mainly on thefate of the API in the aqueous environment, which is where pharmaceutical residues aremost likely destined.

1. European Medicines Agency Pre-Authorisation Evaluation of Medicines forHuman Use (Doc. Ref. EMEA/CHMP/SWP/4447/00), Guideline on The




http://www.fass.se/

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/10/WC500003978.pdf


Environmental Risk Assessment of Medicinal Products for Human Use (Lastaccessed: April, 2016).

2. B. Annonsbyrå, National Pharmaceutical Strategy Action Plan 2014 , Ministry ofHealth and Social Affairs Sweden, 2014.

3. Astra Zeneca Responsible Research (Last accessed: ).4. GSK Material Safety Data Sheets & Environmental Risk Assessments (Last

accessed: ).5. FASS (Last accessed: ).




http://www.government.se/contentassets/57e68c08f2f04e0490fb5638aac230f1/national-pharmaceutical-strategy---action-plan-2014

https://www.astrazeneca.com/sustainability/responsible-research.html

http://www.msds-gsk.com/

http://www.fass.se/LIF/startpage



1. What are the criteria that are assessed to determine the environmental hazardsof a molecule?1. Persistence, Bioavailability, Decomposition Temperature2. Persistence, Bioaccumulation, Toxicity3. Vapour Pressure, Boiling Point, Toxicity4. Vapour Pressure, Bioaccumulation, Decomposition Temperature5. Persistence, Boiling Point, Toxicity6. Vapour Pressure, Bioaccumulation, Toxicity






Summary and further reading

Further information on the mechanisms and pathways of API breakdown in theenvironment are provided in a number of comprehensive reviews on the fate of APImolecules in the environment and are provided in the recommended reading below.

Recommended reading:

K. Kümmerer, Presence, Fate and Risks of Pharmaceuticals in the Environment, in Greenand Sustainable Medicinal Chemistry: Methods, Tools and Strategies for the 21st CenturyPharmaceutical Industry, L. Summerton, H. F. Sneddon, L. C. Jones and J. H. Clark, RoyalSociety of Chemistry, Cambridge, UK, 2016, ch. 6, pp. 63-72.

T. Haddad, E. Baginska and K. Kümmerer, Transformation products of antibiotic andcytostatic drugs in the aquatic cycle that result from effluent treatment and abiotic/bioticreactions in the environment: An increasing challenge calling for higher emphasis onmeasures at the beginning of the pi, Water Research, 2015, 72, 75-126.

A. Barra Caracciolo, E. Topp and P. Grenni, Pharmaceuticals in the environment:Biodegradation and effects on natural microbial communities. A review, Journal ofPharmaceutical and Biomedical Analysis, 2015, 106, 25-36.

J. K. Challis, M. L. Hanson, K. J. Friesen and C. S. Wong, A critical assessment of thephotodegradation of pharmaceuticals in aquatic environments: defining our currentunderstanding and identifying knowledge gaps, Environmental Science: Processes &Impacts, 2014, 16, 672-696.

I. K. Konstantinou, D. A. Lambropoulou and T. A. Albanis, Photochemical Transformationof Pharmaceuticals in the Aquatic Environment: Reaction Pathways and Intermediates, inXenobiotics in the Urban Water Cycle , D. Fatta-Kassinos, K. Bester and K. Kümmerer,Springer Netherlands, 2010, ch. 10, vol. 16, pp. 179-194.

M. D. Celiz, J. Tso and D. S. Aga, Pharmaceutical metabolites in the environment:analytical challenges and ecological risks, Environmental Toxicology and Chemistry, 2009,28, 2473-2484.




http://dx.doi.org/10.1039/9781782625940-00063

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http://pubs.rsc.org/en/content/articlepdf/2014/em/c3em00615h

http://dx.doi.org/10.1007/978-90-481-3509-7_10

http://onlinelibrary.wiley.com/store/10.1897/09-173.1/asset/5620281202_ftp.pdf?v=1&t=ij4g8a35&s=5beff27926dfab044f1948fe54898500aadf89e9


K. Kümmerer, Pharmaceuticals in the Environment, Annual Review of Environment andResources, 2010, 35, 57-75.




http://www.annualreviews.org/doi/abs/10.1146/annurev-environ-052809-161223


Quiz answers

Routes into the environment - Multiple choice question

1. What are the main potential means of APIs entering the environment?Correct answers:

(u'Excreted directly from the body',)(u'Improper disposal',)(u'Point Source Pollution',)

Areas of concern - Multiple choice question

1. Why has there been an increasing focus on Pharmaceuticals in theEnvironment (PIE) in recent years?Correct answers:

(u'New analytical methods capable of detecting molecules at lower levelshave allowed us to detect previously undetected pharmaceutical residues',)(u'The fate of many APIs in the environment is still largely unknown',)(u'Whilst the effect of APIs on humans is known, effects on other organismsmay not be',)





The fate of APIs - learning.chem21.eulearning.chem21.eu/media/pdf/41/the-fate-of-apis-letter.pdf · Describe the fate of APIs in the environment in terms ... the API maybe excreted

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