Analysis, Fate, and Toxicity of Chiral Pharmaceuticals in the Environment

INTRODUCTION

Pharmaceuticals are compounds of environmental concern due to their ubiquity and design to biologically affect specific biochemical and metabolic pathways. They have been detected in different environmental matrices including river waters, sediments, and soils (Dogan et al„ 2020; Petrie et ah, 2015; Sanganyado et ah, 2017; Zhou et ah, 2018). The main release pathway of pharmaceuticals and their metabolites into aquatic ecosystems is via discharge of effluents from wastewater treatment plants (WWTPs) to water bodies, due to their incomplete removal during treatment (Fatta-Kassinos et ah, 2011; Luo et ah, 2014).

Most research to date has investigated pharmaceuticals in river waters wdth concentrations typically reported in the ng/L to pg/L range observed (Camacho-Munoz et ah, 2010; Lindim et ah, 2016; Munoz et ah, 2009; Pereira et ah, 2017). Such concentrations pose a threat to the ecology of the receiving environment (Liu et ah, 2018; Minguez et ah, 2016; Osorio et ah, 2016; Watanabe et ah, 2016). Sludge disposal, direct animal excretion, or manure application to agricultural soils are the main pathways to enter the terrestrial environment (Ghirardini and Verlicchi, 2019; He et ah, 2020; Martin et ah, 2012). Pharmaceutical concentrations reported in soils are typically ng/g (Kumirska et ah, 2019; Martin et ah, 2012; Pico et ah, 2020). Whilst there is considerable research on the fate and toxicological effects of pharmaceuticals in the environment, there is a lack of studies which consider pharmaceutical stereochemistry.

The four stereoisomers of ephedrine

FIGURE 4.1 The four stereoisomers of ephedrine.

Approximately 50% of pharmaceuticals on the market are chiral compounds whereby they have one or more stereogenic center (Mane, 2016). A molecule containing one stereogenic center has two enantiomers which share the same chemical structure but different spatial arrangement of atoms around the stereogenic center (e.g., see Figure 4.1). Enantiomeric fraction (EF) is commonly used to describe the enantiomeric composition of chiral compounds:

where (+) is the concentration of the (+)-enantiomer and (-) is the concentration of the corresponding (-)-enantiomer. The EF can vary between 0 and 1, and 0.5 denotes a racemic composition. An EF of 0 or 1 represents the presence of a single enantiomer only. Compounds with two stereogenic centers will have two pairs of enantiomers and so on. Diastereomers are those stereoisomers that are not mirror images (e.g., see Figure 4.1). Chiral pharmaceuticals are often produced as racemates (i.e., equal concentrations of enantiomers). Less often, pharmaceuticals are dispensed as the race- mate and the enantiomerically pure form (e.g., f?/5(+)-ofloxacin and S(-)-ofloxacin or levofloxacin), or just in enantiomerically pure form (5(+)-naproxen).

Chiral pharmaceuticals exhibit stereoselectivity in their metabolism within the body and degradation during wastewater treatment (Camacho-Munoz et al„ 2019; Duan et ah, 2018; Vanessa et ah, 2009), environmental fate (Camacho-Munoz et ah, 2019; Ma et ah, 2016), and toxicity (Andres- Costa et ah, 2017). Therefore, to better appreciate the environmental risk and impact of chiral pharmaceuticals it is essential to undertake investigations at the enantiomeric level. However, a limiting factor has been the lack of analytical methodologies capable of enantiomeric determinations in complex environmental matrices.

ANALYSIS OF CHIRAL PHARMACEUTICALS IN THE ENVIRONMENT

Sampling and Sample Storage

Sample collection is an essential step in any analytical protocol. Appropriate sampling protocols as well as proper sample handling are necessary to ensure representative data is obtained. However, it is often under-investigated and could lead to erroneous data and misleading interpretations.

Ort et al. (2010) demonstrated that different active sampling approaches (grab and composite sampling) can provide biased results for pharmaceuticals in wastewater unless sampling is undertaken in a flow'-proportional manner with adequate sub-sampling collection frequencies. However, similar studies in environmental matrices such as river water are lacking. It can be considered that temporal changes to pharmaceuticals in river water will be comparatively less than those observed in waste- waters. Indeed, the majority of studies undertaken on chiral pharmaceuticals in river waters adopt grab sampling (Table 4.1). An important consideration for such sampling is enantiomer stability in collected samples during transport and storage prior to sample preparation.

Ramage et al. (2019) investigated the stability of pharmaceutical enantiomers in collected stream water samples. S(+)-amphctamine, S(+)-fluoxetine and R(-)-fluoxetine degraded by >25% in samples stored at 18°C over 48 h (Ramage et al., 2019). Other than the loss of total pharmaceutical concentration (i.e., sum of both enantiomers), the degradation of S(+)-amphetamine resulted in a change in EF from 0.5 to 0.1. In samples stored at 4°C no significant enantiomer degradation was observed over 48 h (Ramage et al., 2019).

Alternatively, the addition of a biocide (e.g., sodium azide) or pH adjustment can be used to limit microbial activity. However, care is needed if such approaches are to be considered. For example, the addition of sodium azide can be detrimental to subsequent enantiomeric separations with loss of chiral recognition previously noted (e.g., salbutamol and chlorpheniramine in river water treated with sodium azide at 1 g/L) (Baranowska, 2018). Sodium azide is also reported to be unsuitable for the stabilization of some pharmaceuticals including fluoxetine (Vanderford et al., 2011). Alternatively, sample adjustment to acidic pH can influence the partitioning of pharmaceuticals between the liquid phase and solid phase (suspended matter) of environmental matrices (Petrovic, 2014). Thus filtration of samples prior to pH adjustment is needed which may not be possible in the field. Nevertheless, analyte stability within samples needs to be incorporated into analytical method validation to ensure collected data is representative of what was collected.

Passive sampling is proposed as an alternative method of sampling river water (Pinasseau et al., 2019; Wong and MacLeod, 2009). Passive sampling relies on the transport of a pharmaceutical from the sample matrix to a receiving phase or sorbent contained within a passive sampling device. Both the Chemcatcher® and polar organic integrative sampler have been applied to determine pharmaceuticals in river waters (Rimayi et al.. 2019; TouSova et al., 2019). They can be used to estimate time-weighted average concentrations for seven days or longer. However, there is a paucity of information on their ability to maintain the enantiomeric composition of chiral pharmaceuticals during deployment. Nevertheless, the Chemcatcher with a disk receiving phase containing Oasis HLB successfully maintained the EF of atenolol, tramadol, and venlafaxine in wastewater effluent (Petrie et al., 2016). Further studies are needed to fully assess the suitability of passive samplers to provide quantitative information on chiral pharmaceuticals at the enantiomeric level.

 
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