<p>A significant number of resources are allocated to maintaining the resiliency of pharmaceutical supply chain as failure to do so thoroughly can result in drug shortages of essential medicines. Recently, the effects of COVID-19 exacerbated flaws in the current system causing the pharmaceutical industry and government organizations and to reassess relief strategies that could also strengthen the supply chain. Flow chemistry has become an attractive and prominent platform enabling continuous manufacturing (CM) technologies to synthesize active pharmaceutical ingredients (API) quickly according to demand. Compared to traditional batch chemistry, flow chemistry has demonstrated to be more robust in terms of throughput, scalability, and hazard reduction while maintaining a high degree of control and product quality. This work demonstrates these capabilities in reaction optimization and discovery with the overarching goal of domesticating CM to make essential medicines more affordable. A two-step process for the synthesis in diazepam was developed using a Chemtrix Labtrix S1 and Start microfluidic systems where purities as high as 98% were achieved. The system was successfully scaled up to a larger system that was able to produce 96% pure diazepam at a 91% yield. </p>

No description available.

No description available.

La pollution des eaux superficielles et souterraines par des composés organiques est bien connue comme une préoccupation majeure de l'environnement dans de nombreux pays. Si les polluants prioritaires sont actuellement surveillés par la directive cadre européenne sur l'eau, il est désormais urgent de prendre en considération les nouveaux polluants dérivés de principes actifs des produits pharmaceutiques et d'identifier leurs produits de transformation à risque. Ce travail de thèse propose une étude globale sur l'état et l'avenir des produis pharmaceutiques dans l'environnement, sur l'exemple de deux pharmaceutiques choisis, dans le cadre de cette importante problématique environnementale. Nous avons donc appliqué les procédés électrochimiques d'oxydation avancée, électro-Fenton (EF), oxydation anodique(OA) et photoélectro-Fenton solaire (PEFS), ainsi que le couplage électro-Fenton/traitement biologique pour une élimination effective des polluants médicamenteux furosémide et ranitidine. Les résultats obtenus confirment l'efficacité de ces technologies électrochimiques pour la minéralisation quasi-totale des produits pharmaceutiques étudiés. En outre, l'utilisation du pré-traitement par EF suivi d'un procédé biologique confirme la capacité de l'EF de transformer les polluants organiques en produits biodégradables qui peuvent être consommés par des microorganismes lors d'un traitement biologique, démontrant ainsi l'applicabilité potentiel de cette technique combinée, en termes d'une consommation énergétique réduite. L'identification des produits de transformation (PTs) des pharmaceutiques étudiés par voie électrochimique (électro-oxydation) et biologique (bioconversion) a été effectuée par différentes techniques d'analyse physico-chimiques. La biotransformation du FRSM a conduit à la formation de trois PT principales; saluamide, pyridinium et un dérivé céto-alcool. Les deux premiers ont aussi été détectés lors du traitement électrochimique, ce qui suggère la probabilité de les trouver dans l'environnement comme les produits de transformation les plus plausibles par des différentes conditions de dégradation. Les tests de toxicité basés sur l'inhibition de la bioluminescence des bactéries marines Vibrio fischeri ont montré que certains PT formés lors de traitement électrochimiques sont plus toxique que la molécule mère, car une augmentation de la toxicité globale de la solution a été observée au début des électrolyses. Néanmoins, la toxicité de la solution est complètement éliminée à la fin des traitements électrochimiques, ce qui indique l'efficacité de ces technologies aussi pour la détoxification des solutions des médicaments traités. Par conséquent, cette étude constitue une contribution importante à l'évaluation des risques environnementaux des produits pharmaceutiques / The present project contributes with valuable data for a better fundamental understanding on the fate of pharmaceutical residues in the environment, dealing with the main challenges concerning this increasingly worrying environmental issue. The used Electrochemical Advanced Oxidation Processes (EAOPs), electro-Fenton (EF) and anodic oxidation (AO), showed to be a very efficient alternative for the mineralization of acid solutions of the pharmaceuticals RNTD and FRSM, attaining almost complete mineralization of the drugs after 6h of electrolysis. A comparative study on the mineralization of RNTD solutions by EF and SPEF processes in a 2.5 L capacity pre-pilot flow plant demonstrates the higher oxidation capacity of SPEF, achieving very good mineralization rates, thus evidencing the potentiality of this technology at greater scale for the treatment of wastewaters containing pharmaceutical products. The application of an EF pre-treatment coupled with a biological process for the degradation of both drugs was conducted. EF pre-pretreatment was capable of enhancing the solution biodegradability envisaging a biological treatment, which efficiently removed the short-chain carboxylic acids that had been formerly generated during the pre-applied electrolysis. In this way, the combination of both processes was confirmed as a very promising technology for the treatment of pharmaceuticals-containing wastewater. Several transformation products (TPs) were detected and identified during the electrochemical oxidation of the studied drugs. Toxicity tests based on the bioluminescence of the marine bacteria V. fischeri. evidenced the toxicity some of these oxidation by-products, since the toxicity of the solution increased on the first stages of the electrolysis. However, the abatement of the toxicity in the final stages of the electrochemical treatments, demonstrated the effectiveness of these technologies for both the mineralization and detoxification of the RNTD and FRSM solutions. The use of the fungi Cunninghanella echinulate for the bioconversion of FRSM led to the formation of three main bio-transofrmation products: the previously identified saluamide and pyridinium, and the new detected keto-alcohol derivate. These TPs were generated by both, biological and electrochemical approches, evidencing their high probability to be found in environmental compartments as the most likely TPs of FRSM by different oxidation conditions. This study is thus presented as a very useful alternative for the assessment of the fate of pharmaceutical residues in the environment

Du fait de sa consommation en plein essor et d’une élimination partielle par les procédés conventionnels de traitement des eaux, l'ibuprofène, un médicament anti-inflammatoire non stéroïdien, a été détecté dans les ressources en eau, suscitant de plus en plus d'inquiétude quant à son impact possible sur l'environnement et la santé. Par ailleurs, les procédés d'oxydation avancée (POA), parmi lesquels la réaction Fenton, ont montré d’excellents résultats pour l'élimination de divers composés organiques. Traditionnellement basé sur l'utilisation du peroxyde d'hydrogène et des ions ferreux en solution, l'application à grande échelle de ce POA est encore limitée par une fenêtre de pH étroite (2 à 4) et une récupération difficile du catalyseur à base de fer. Ce travail a étudié l'oxydation Fenton de l'ibuprofène et l'activation de la réaction par irradiation ultrasonore (US) et rayonnement ultraviolet/visible (UV/Vis) et de manière à abaisser la concentration de fer dissous ou à améliorer l'activité de catalyseurs hétérogènes. A cet effet, on a d'abord évalué l'efficacité des POA individuels homogènes (sonolyse, photolyse, sono- et photo-oxydation avec H2O2, oxydation Fenton), en fonction de paramètres opératoires tels que la longueur d'onde lumineuse et la fréquence ultrasonore. Ensuite, on a examiné leurs combinaisons deux-par-deux et globale (sonophotolyse, oxydation sono-, photo- et sono-photo- Fenton) en mettant l'accent sur l'identification d'effets synergiques. En particulier, les oxydations US/Fenton et Vis/Fenton se sont révélées plus efficaces que la somme des procédés individuels grâce à la sono- et photo-régénération des ions ferreux. Ces résultats ont également servi de référence pour l'évaluation des systèmes hétérogènes. Parmi les solides testés, on a montré qu’une zéolite dopée au fer (de type Fe/ZSM5) était un catalyseur prometteur pour l'oxydation de l'ibuprofène par le peroxyde, en raison d'une efficacité élevée à pH naturel et d’une faible lixiviation du fer. Cependant, dans ce cas, on n’a observé au mieux qu'une addition d’effets des ultrasons ou de la lumière et de l'oxydation Fenton hétérogène. Outre la conversion du polluant et du carbone organique total (COT), la formation des principaux produits de dégradation a été suivie pour différents procédés et des voies possibles de dégradation ont été proposées. L’effet matrice a également été examiné en utilisant un effluent de station, qui a eu pour conséquence de réduire la performance de tous les procédés d'oxydation, en raison d'un pH tampon alcalin ou de l’atténuation de la lumière. / Due to booming consumption and only partial removal by conventional water treatment processes, ibuprofen, a non-steroidal anti-inflammatory drug, has been detected in water resources, raising increasing concerns for possible environmental and health impact. On the other hand, advanced oxidation processes (AOPs), among which Fenton reaction, have shown successful results forremoval of various organic compounds. Traditionally based on the use of hydrogen peroxide and ferrous ions in solution, large-scale application of this AOP is still limited by narrow pH window (2 to 4) and uneasy recovery of iron catalyst. This work investigated Fenton-based oxidation of ibuprofen, and reaction activation by ultrasound (US) irradiation and ultraviolet/visible light (UV/Vis) so as to lower the required concentration of dissolved iron catalyst or improve the activity of heterogeneous counterparts. To that purpose, the efficacy of individual homogeneous AOPs (sonolysis, photolysis, ultrasound/H2O2, light/H2O2, Fenton oxidation) was evaluated first, varying operating parameters such as light wavelength and ultrasound frequency. Then, their two-by-two and overall combinations (sonophotolysis, sono-Fenton, photo-Fenton and sono-photo-Fenton oxidation) were examined with emphasis on the identification of synergistic effects. In particular, combined US/Fenton and Vis/Fenton oxidation were found more effective than the sum of individualprocesses due to sono- and photo-regeneration of ferrous ions. These results also served as a reference for the assessment of heterogeneous systems. Among tested solids, iron-containing zeolite (Fe-ZSM5 type) was shown to be a promising catalyst for peroxide oxidation of ibuprofen due to high efficiency at natural pH and low iron leaching. However, in this case, no more than additive effects was observed between ultrasound/light irradiation and heterogeneous Fenton oxidation. Beside pollutant and Total Organic Carbon conversion, main degradation products were monitored for different processes and some plausible degradation pathways were proposed. Water matrix impact was also addressed using wastewater plant effluent, which resulted into hindered performance of all oxidation processes either due to alkaline buffer or light attenuation effect.

Duckweed species L. turionifera and W. borealis grow on Wellsville Municipal Sewage Lagoons in northern Utah and, when harvested, contribute to the removal of phosphorus and pharmaceuticals from wastewater. Microcosm studies showed that duckweed contains an average of 1% phosphorus (dry weight) and removes 113 mg-P/m2day under 200 μmol/m2sec light. Duckweed in laboratory experiments reduced influent phosphorus ranging from 3.88 to 5.2 mg-TP/L to effluent concentrations of 0.88 mg-P/L in 3 days to 0.16 mg-P/L (0.32 mg-TP/L) with continual harvesting and a liquid retention time of 46 days. Duckweed removal of pharmaceuticals was comparable to removal by membrane bio-reactors. Duckweed removed 99% acetaminophen mainly by plant uptake; 98% progesterone primarily by absorption to plant tissue; 90% fluoxetine by adsorption with some biological removal attributed to plants; and sulfamethoxazole removal varied between 25 to 90% depending on polarity. Carbamazepine did not react with duckweed. Typical influent wastewater concentrations of the five pharmaceuticals in this study were not toxic to duckweed with an EC50 value of 614 μg/L per compound. HPLC/MS detection of pharmaceuticals in liquid samples using solid phase extraction at a neutral pH and silanized glassware produced 92-102% recoveries. Analysis of extracted solids produced lower recoveries. Solid extraction efficiencies ranged from 56-70% for samples stored for 24 hours and decreased with increasing storage time. Field growth studies showed higher than expected duckweed growth rates in the spring compared to three models due to turion germination after the ice melts. The growth rates decreased in the fall due to turion formation in preparation for winter. Harvesting duckweed from the Wellsville Municipal Sewage Lagoons should begin after full surface coverage around June 17th and end when temperatures fall below 15 °C around September 15th. Bi-weekly harvests with a starting plant density of 75 g-dry duckweed/m2 for the lagoons operating at 0.547 MGD and 5 mg-TP/L are required to physically remove enough phosphorus in order to meet the city’s 432 kg-P/yr discharge permit. A duckweed phosphorus harvesting system in Wellsville was estimated to produce enough biomass to meet the P-discharge limit until the flow increases above 0.656 MGD around the Year 2017.

This study assessed the chemical substances that can be used to investigate fecal contamination of surface waters and how they can be used to indicate and trace fecal contamination in oligotrophic rivers of Northern Sweden. It was found that, from previous studies, several chemicals can be used to trace fecal contamination of surface water, and these include pharmaceuticals, personal care products, sterols, stanols and bile acids. Pharmaceuticals have been successfully used to indicate fecal contamination in many tropical countries and some countries in the cold regions and thus can also be applied to oligotrophic rivers. Sterols, stanols and bile acids make it possible to accurately indicate and trace the different sources of fecal contamination and can also be used to distinguish between the different organisms from which those sterols and bile acids emanate. For these groups of chemicals analytical methods such as chromatography and mass spectrometry are used to decipher the different chemicals in the test samples of water or sediment. Overall, these methods can be used concurrently but the sterols and bile acids have more specificity compared to the pharmaceuticals and personal care products / <p>2021-07-06</p>

No description available.

Asthma is a prevalent, costly, and potentially deadly disease. Despite advances in the pharmacological treatment of asthma, many asthma sufferers do not benefit from their medication the way they should because they fail to take it as prescribed. The noncompliance rate for asthma is about 30% to 40%. In this study, I describe the theoretical and practical rationale for, as well as the development of, a brief self-report measure (called the Multidimensional Asthma Questionnaire $\{$MAQ$\}$) for assessing medication compliance in asthma sufferers. Results of the study showed that the MAQ had adequate internal validity and a four factor structure that was designated belief, threat, use, and knowledge respectively. Although it was hypothesized that scores on the MAQ would correlate positively with an independent measure of compliance that was based on pharmacists' medication refill records, this hypothesis was not supported. Neither the MAQ, nor two other measures for assessing the attitudes and beliefs of asthma patients, had any relationship to medication compliance as estimated by pharmacists' refill records. In fact, when scores on the three questionnaires were entered into a multiple regression analysis, the results showed that minimal patient identifying information (gender, marital status, and SES) did a better job of predicting compliance. These results underscore the complexities of accurately assessing and measuring compliance in asthma sufferers. Suggestions for future research are described.

A concept of removing of pharmaceuticals from a wastewater is become more important topic. Currently we can see the increasing consumption of pharmaceuticals worldwide and an increasing effective doses of pharmaceuticals due to the resistance of microorganisms. Generally, a medicine means an active substance or their mixtures. The medicine is used for positive influencing of human’s and animal’s health. Nevertheless, a long term presence of pharmaceuticals in the environment leads to chronic toxic aquatic organisms, possibilities of multiplication of multi-resistant pathogenic bacterial strains, deterioration of reproduction of animals and their endocrine system. My dissertation is focused on a removing of pharmaceuticals from the wastewater via advanced oxidation processes. Results of research showed that the advanced oxidation processes are able to reduce concentration of pharmaceuticals. Mainly priority of this problem is other cleaning level of the wastewater which flows away from urban WWTP to river. Wastewaters consist of large volume of pharmaceuticals due to excrements, urination and flushing of outdated pharmaceuticals. An efficiency of advanced oxidation processes on the removal selected types of pharmaceuticals is a part of practical selection of the dissertation.