## 1 Introduction  
The water environment (freshwater, seawater, groundwater) is the ultimate repository from several classes or organic micro-pollutants emitted from different pollution sources [1, 2] from the direct discharge of untreated sewage or due to the limited efficiency of conventional wastewater treatment plants (WWTPs) [3, 4, 5, 6]. Among these compounds, pharmaceuticals have become an issue of great concern for the scientific community politicians and the public [7, 8], as these compounds have been found to negatively affect freshwater fish and invertebrates as well as contribute to the development of antibiotic-resistant bacteria [9, 10, 11, 12, 13]. In the present paper, we chose to work on three classes of therapeutics, among the most sold and consumed in Lebanon and in France (therapeutics, anti-depressants and \(\beta\)-blockers), known for their eco-toxicities (based on their Predicted No-Effect Concentration (PNEC)), endocrine-disruption activities and their abilities to promote antimicrobial resistance [14, 15, 16, 17, 18, 19]. To complete the selection of the molecules, and in line with the approach taken by several authors [20,21], we look at their incomplete metabolization (excretion factor), low removal in wastewater treatment plant and the frequency of their detection in aquatic environments [22, 23, 24]. This prioritization led us to select azythromycin and erythromycincin (antibiotics), fluoxetine ([\(n\)-methyl-3-phenyl-3-[4-(trifluoromethylomethyl)phenoxy]propan-1-amine], also known by the trade names Prozac(r), Sarafem(r) or Fontex(r), anti-depressant) and sotalol (\(\beta\)-blocker), also known by its trade names Betapace(r), Sorine(r) or Stolyze(r), whose physical-chemical properties, ecotoxicities, excretions factors, and removal rates in wastewater plants are given Table 1.  
As can be seen from the physical-chemical properties of these four molecules, their simultaneous determination may be challenging since these compounds present a wide range of properties such as polarity, solubility, acid dissociation constants, partition coefficients, and stabilities under acidic and basic conditions [25]. Even if ultra-high pressure liquid chromatography (UHPLC) and tandem mass spectroscopy (MS\({}^{n}\)) using updated source designs and acquisition methods is known to allow detection of pharmaceuticals at very low concentrations, especially by use of smaller particle size chromatographic columns (below 2.0 \(\upmu\)m) [25, 26, 27], simultaneous determination of such compounds within the same chromatographic method has not been yet reported, even in papers dealing with multi-residue analysis of pharmaceuticals. Indeed, sotalol (hydrophilic and polar) is often better detected by use of an hydrophilic column [28], whereas fluoxetine and azithromycin (lipophilic and moderately polar) and erythromycincin (lipophilic and non-polar) are separated by reversed-phase C18 [26, 27, 29, 30]. In the present study, we developed a UHPLC-MS method using a novel column stationary phase capable of providing a selectivity within a wide elution window and increased retention for both polar and non-polar analytes. Moreover, the analysis of the four targeted molecules has been conducted by direct injection without using sample preparation techniques such as Solid-Phase Extraction (SPE) to avoid matrix interferences that may affect electrospray ionization (signal suppression or enhancement), as already mentioned by several authors [17, 31]. The need for an analysis that is cost-effective and easy to implement is important for laboratories conducting occurrence studies on pharmaceuticals in real waters. The UHPLC-MS method allows for the first time the simultaneous determination of erythromycincin, azithromycin, fluoxetine and sotalol in the same run and in a short, time-saving method. The method was validated by measuring these compounds in real Lebanese and French freshwater and seawaters.