<p>Osnovni cilj istraživanja u okviru doktorske disertacije je definisanje<br />kriterijuma na osnovu optimizacije usvojenog stepena sorbiranja i<br />degradacije za modele transporta farmaceutika u aluvijalnim podzemnim<br />vodama, koji služe kao polazna osnova za postavke budućih izvori&scaron;ta<br />podzemne vode. Dobijeni su novi podaci i informacije koje će se koristiti za<br />procenu pona&scaron;anja farmaceutika, kao i za projektovanje i optimizaciju novih<br />sistema za efikasnu za&scaron;titu i upravljanje podzemnim vodama. Potpuno novi<br />rezultati se odnose na određivanje stepena eliminacije farmaceutika tokom<br />primene metode rečne obalske filtracije, kao i teorijsko i eksperimentalno<br />poređenje realnih podataka o stepenu sorbiranja i razgradnje farmaceutika.</p> / <p>The main goal of dissertation is to define new criteria based on the<br />optimization of applied sorption and degradation degree for groundwater<br />pharmaceuticals transport model, which serve as a basis for development<br />and design of the future drinking water facilities. New data and information&rsquo;s<br />are obtained and can be used for assessment of pharmaceutical behavior in<br />alluvial groundwater and for design of new and innovative systems for more<br />efficient protection and groundwater management. Novel results are referred<br />on the determination of the pharmaceuticals elimination during river bank<br />filtration and on the theoretical and experimental comparison of real data for<br />the sorption and degradation capacity of selected pharmaceuticals.</p>

The selection of a representative sample is a delicate problem when drug seizures comprised of large number of units arrive at the Swedish National Forensic Centre (NFC). If deviating objects in the selected sample size are found, additional analyzes are required to investigate how representative the results are for the entire population. This generates further pressure on operational analysis flow. With the goal to provide a tool which forensic scientists at NFC can base their assessment of the representative nature of the selected sampling of large drug seizures on, this project investigated the possibilities of evaluating the level of homogeneity in drug seizures using near-infrared (NIR) hyperspectral imaging along with principal component analysis (PCA). A total of 27 sample groups (homogeneous, heterogeneous and seized sample groups) were analyzed and different predictive models were developed. The models were either based on quantifying the variation in NIR spectra or in PCA scores plots. It was shown that in the spectral range of 1300-2000 nm, using a pre-processing combination of area normalization, quadratic (second polynomial) detrending and mean centering, promising predictive abilities of the models in their evaluation of the level of homogeneity in drug seizures were achieved. A model where the approximated signal-dependent variation was related to the quotient of significant and noise explained variance given by PCA indicated most promising predictive abilities when quantifying the variation in NIR spectra. Similarly, a model where a rectangular area, defined by the maximum distances along PC1 and PC2, was related to the cumulative explained variance of the two PCs showed most promising predictive abilities when quantifying the variation in PCA scores plots. Different zones for which within sample groups are expected to appear based upon their degree of homogeneity could be established for both models. The two models differed in sensitivity. However, more comprehensive studies are required to evaluate the models applicability from an operational point-of-view.

This literature study provides a comprehensive overview of the current knowledge of mRNA-based pharmaceuticals, technologies and applications.  mRNA-based pharmaceuticals have newly been bought into focus as a potential brand-new drug class and many believe that it has the potential to transform areas of medicine. The corona pandemic showed that mRNA vaccines could be created fast and safely which highlighted the unique potential of mRNA therapy. This resulted in a major investment in mRNA therapeutics and attracted attention to synthetic mRNA as a new drug modality. The sequence of nucleotides in synthetically produced (IVT) mRNA can easily be altered to produce different proteins in vivo. This leads to a broad range of therapeutical applications such as protein replacement therapy, immunotherapy, genome editing, cellular programming, and vaccines.  The disadvantages of the mRNA technique will be discussed; primarily the low stabilization in vivo and low target delivery, which have partly been solved today. By nucleobase modifications the stabilization can be improved and by delivery systems an increased target delivery can be achieved.  The clinical promise of mRNA therapeutics and vaccines is crystal clear, however, their novelty brings new manufacturing challenges. Technologies and strategies to address these challenges will be concluded in this paper.

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Polypeptides are becoming an important component of the antibiotic therapeutics. The production demand of therapeutic polypeptides is increasing and there is a significant interest in developing more efficient production processes. In pharmaceutical industries, polypeptides are produced as a crude mixture. Reverse phase high performance liquid chromatography (RP HPLC) is used as a typical separation technique to purify the target polypeptide from other impurities. Currently organic modifier gradients are used to elute product peptides separately from impurities. In this work, we add a second, simultaneous counter-ion gradient, in the hope of increasing separation performance and call it double gradient reverse phase chromatography. A general procedure of the model-based optimization of a polypeptide crude mixture purification process was followed to evaluate the effects of the double gradients on industrial chromatographic process. The target polypeptide elution profile was modeled with a bi-Langmuir adsorption equilibrium isotherm. The isotherm parameters of the target polypeptide were estimated by the inverse method. The model parameters of the impurities were regressed from experimental data. The variations of the isotherm parameters with the modifier concentration and counter-ion concentration were taken into account of the adsorption model. After model calibration and validation by comparison with suitable experimental data, Pareto optimization of the process were carried out to analyze the differences between single gradient chromatography and double gradient chromatography. It was observed that the additional linear gradient of counter-ion concentration did not improve the separation process. Conclusively we were able to demonstrate the concept of double gradient reverse phase chromatography within limited time and possible least experimental efforts.

The presence of pharmaceuticals in the environment has raised an emerging interest due to the fact that they pose negative environmental impact and health hazards related to long-term toxicity effects. As conventional treatments are not able to totally remove these substances it is necessary to seek for alternative advanced technologies such as oxidation with chlorine dioxide (ClO2). The objective of this master thesis is thus to find the most optimal dose – reaction time of ClO2 for the oxidation and maximum removal of selected environmentally relevant pharmaceuticals. Factorial design and subsequent optimization with MODDE was selected as the best approach to find the optimal dose – time. Batch oxidation tests were conducted on 100mL aliquots treated with ClO2 using wastewater effluent from Henriksdal WWTP. Thereafter solid phase extraction and final determination of pharmaceuticals was carried out on a high performance liquid chromatography- triple quadrupole mass spectrometry (HPLC-MS/MS). Results showed that applying a dose of 5 mg ClO2/L and a reaction time of 10 minutes, it is possible to remove more than a half of the 17 analyzed substances. Besides most of the pharmaceuticals with high and moderate environmental risk, would pose a low risk for the environment after treatment with the optimal ClO2 dose – reaction time. Despite the fact that ClO2 could successfully degrade most environmentally relevant pharmaceuticals, deeper research concerning the formation of toxic by-products after oxidative treatment needs to be done before upscaling this technology to pilot or full scale as a suitable end of pipe technology for pharmaceuticals removal.

The occurrence and source distribution of organic micropollutants (OMPs) have been investigated in Swedish surface waters, in 23 rivers connected to the lakes Vänern, Vättern and Mälaren, 3 Wastewater treatment plants (WWTPs) and 3 Drinking water plants (DWTPs) located in the middle of Sweden was sampled. Compounds such as pharmaceuticals, industrial chemicals, pesticides, personal care products, hormones, Per- and polyflouroalkyl substances (PFASs), isoflavones, stimulants and parabens were selected. The analysis was done by using solid phase extraction (SPE) and Ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Of the 121 studied compounds 91 was detected in concentration levels varying between a few ng/L up to 160 µg/L in wastewater effluent. The detected concentrations of 80 compounds in surface water from rivers varied from low ng L-1up to 3.3 µg/L, 43 OMPs within the range from low ng/L up to 370 ng/ L could be detected in the lakes and 35 OMPs could be found in levels from low ng/L up to 2.9 µg/L in the drinking water. The number of detected compounds and concentration levels clearly decreases from wastewater influent to effluent, rivers, lakes and lastly to drinking water. The concentration levels of OMPs in the surface water samples varied between sampling sites and the three lakes making it clear that Lake Mälaren is the most contaminated one out of these three. OMPs such as antibiotics, antidepressants and personal care products were most frequently detected in all samples. The highest total OMP concentration levels were found in Enköping river (79 µg/L), Lövsta river (33 µg/L), Ösan (16 µg/L) and Lillån (13 µg/L). A risk assessment for drinking water with regard to human health was conducted for two compounds by calculating the Benchmark Quotient (BQ) using drinking water equivalent levels (DWELs). Two compounds, carbamazepine and bezafibrate, was selected based on detection frequency and available toxicity data. While bezafibrate didn’t show any indications of risk to human health, carbamazepine had a BQ of 1.47 which indicates a risk to human health when humans are exposed to these concentration levels over a period of a lifetime. / Genom att använda en målanalys har förekomsten och fördelningen av organiska mikroföroreningar i svenska ytvatten studerats. Vattenprover från 23 vattendrag som antingen mynnar ut i eller börjar i någon av sjöarna Vänern, Vättern eller Mälaren, tre avloppsreningsverk och tre dricksvattenverk i mellersta Sverige har samlats in. Ämnen så som läkemedel, industriella kemikalier, pesticider, hudvårdsprodukter, hormoner, högflorerade ämnen (PFAS), isoflavoner, stimulanter och parabener valdes ut och analyserades med hjälp av fastfasextraktion och vätskekromatografi kopplad till masspektrometer (UPLC-MS/MS).Av de 121 utvalda ämnena kunde 91 av dessa detekteras i koncentrationer som varierade mellan några få ng L-1upp till 160 µg/L i utgående avloppsvatten. I vattendragen kunde 80 av de organiska mikroföroreningarna detekteras i koncentrationer mellan låga ng/L upp till 3.3 µg/L medan endast 43 kunde detekteras i sjöarna inom koncentrationsintervallet låga ng/L till 370 ng/L. Slutligen detekterades 29 mikroföroreningar i dricksvattnet där koncentrationerna varierade mellan några få ng/L upp till 2.9 µg/L. Resultatet visar att antalet detekterade organiska mikroföroreningar och deras respektive koncentrationer tydligt minskar vid jämförelse av de olika matriserna från ingående avloppsvatten till utgående, vattendrag, sjöar och slutligen i dricksvattnet. I ytvattenproverna varierade koncentrationsnivåerna av organiska mikroföroreningar mellan de olika vattendragen och det var tydligt att Mälaren är mer kontaminerad än Vänern och Vättern. Det gick också att se tydliga trender i vilka ämnen som vanligen detekterades i de olika proverna, särskilt bland läkemedlen då ämnen som är antibiotika-klassade eller hör till gruppen antidepressiva var vanligast förekommande. De högsta totala koncentrationerna av organiska mikroföroreningar kunde hittas i Enköpingsån (79 µg/L), Lövstaån (33 µg/L), Ösan (16 µg/L) samt Lillån (13 µg/L). Dessa fyra vattendrag är därmed de mest förorenade i denna studie och kan därför ses som särskilt förorenade. En riskanalys med hänsyn till människors hälsa gjordes på dricksvattnet genom att beräkna en referenskvot (BQ) med hjälp av ekvivalenta dricksvatten-nivåer (DWELs). De två ämnena karbamazepin och bezafibrat valdes på grund av deras detektionsfrekvens (FD) och tillgänglighet av toxicitetsdata. Bezafibrat visade ingen potentiell risk medan karbamazepin hade ett BQ-värde på 1,47 vilket indikerar en potentiell risk till människors hälsa om man utsätts för de funna koncentrationerna under hela sin livstid.

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The conventional treatment processes used in Swedish sewage treatment plants (STPs) are not designed to remove micropollutants such as pharmaceuticals and biocides. This leads to STPs being a major source of pharmaceuticals in the environment including surface waters, coastal waters, and groundwaters all over the world. The occurrence of these compounds combined with their adverse ecological effects makes them problematic. This study aims to investigate the removal of pharmaceuticals and biocides from six conventional STPs from small municipalities in Northern Sweden. It also aims to evaluate the suitability and potential of an advanced treatment process called electro-peroxone (E-peroxone) as an additional tertiary treatment step complementing the current STPs configurations, through batch experiments. The removal of pharmaceuticals and biocides in the studied STPs showed great variability. The occurrence of pharmaceuticals was mainly in line with previous research apart from caffeine and paracetamol concentrations. Several pharmaceuticals were detected above their respective critical environmental concentration (CEC) in effluent wastewaters. The removal of pharmaceuticals was heavily influenced by paracetamol. When excluding paracetamol, the total removal of pharmaceuticals ranged from -23% to 80% in the conventional processes. After E-peroxone treatment, removals, excluding paracetamol, ranged from 61% to 93%, and no average effluent concentrations exceeded their respective CEC. In this study, E-peroxone was conducted in not optimized batch-experiments due to time constraints, but still with promising results. In a full-scale application, water matrix specific optimizing should be performed. Therefore, the removal efficiencies of pharmaceutical residues by the E-peroxone process in a plant-specific configuration would most likely be significantly increased.