Mauri Sergio Alves Palma.

The aim of this work is to investigate different manufacturing methods for microreactors either by ultra-precision machining process and further replication process, two photon lithography processes testing different polymeric resins, or laser process in glass. Ultra-precision process has the advantage of manufacturing master structures in metallic materials with precision. Afterwards, by means of micro-injection or hot embossing, the microreactors can be replicated with relative low costs. However, this process is geometric limited to the tool size of the milling process employed. Two photon lithography presents itself as a promising technology in order to manufacture such micro-structures within precision and is not limited towards the geometry of the microreactors. Laser process has the advantage of manufacturing the micro-features directly in a close workpiece. Therefore, reducing the assembly efforts. Furthermore, the goal is to test the microreactors and millirreators to synthesise drugs using chlorohydrin as reagents, which are: 1) epichlorohydrin, 2) 3-chloro-1,2-propanediol, 3) 1,3-dichloro-2-propanol and 4) glycidol. Chlorohydrin can be synthesized from glycerol, a by-product of biodiesel synthesis, which is widely available in the Brazilian and world markets, besides being non-toxic and already having wide use in pharmaceutical and food formulations. With this project, it is planned to synthesize the Active Pharmaceutical Ingredients (API), Atenolol, Metoprolol and Ranolazine, for the first time in flow, and to determine the kinetics of the intermediate reactions and the best operating conditions for each synthesis, in batch process and in flow in micro-millirreators.

Neste projeto atuaremos na prevenção da geração de poluentes através da aplicação dos princípios da Intensificação de Processos. A prevenção da geração de poluentes será alcançada neste trabalho através do aumento do rendimento das reações químicas, o que está sendo abordado em nosso grupo de pesquisa desde 1/9/2014 no projeto Microrreatores na Síntese de Fármacos financiado com o auxílio FAPESP processo no. 2014/07757-2, concluído em 28/02/2017. Esta linha de pesquisa teve continuidade através do projeto de pesquisa Síntese da Pioglitazona, Rosiglitazona e Lobeglitazona em fluxo contínuo em microrreatores capilares, financiado com auxílio FAPESP no. 2017/12830-9 concluído em 31/07/2020. O projeto estendido está disponível aos assessores.Durante a vigência do projeto de pesquisa, ora proposto, pretendemos formar 3 doutores, 2 mestres, orientar alunos de Iniciação Científica, supervisionar projetos de Pós-Doutoramento, enviar trabalhos completos e resumos para congressos nacionais e internacionais, publicar artigos em revistas indexadas internacionais e participar de eventos nacionais e internacionais para divulgação dos resultados da pesquisa sobre a Intensificação de Processos com microrreatores e milirreatores.

The objective of this work is to use capillary microreactors and milireactors to synthesize in flow APIs that use chlorohydrins as reagents, being: 1) epichlorohydrin, 2) 3-Chloro-1,2-propanediol, 3) 1,3-dichloro-2-propanol and 4) glycidol. Chlorohydrins can be synthesized sustainably from glycerol, a byproduct of biodiesel synthesis, which is widely available in the Brazilian and world market, besides being nontoxic and already having wide use in pharmaceutical and food formulations. The Active Pharmaceutical Ingredients (API), Atenolol, Metoprolol and Ranolazine will be synthesized for the first time in flow, and the kinetics of intermediate reactions and the best operating conditions for each synthesis, in batch and flow process will be determined. This project will be developed in collaboration with Prof. Agostino Cilibrizzi, King's College, London, UK, and Prof. Lucas Ducati (IQ/USP. Prof. Agostino Cilibrizzi will provide intellectual support in the development of new drug synthesis routes. Prof. Lucas will give intellectual support in the molecular mathematical modeling of the chemical reactions involved in the synthesis of these drugs.

Chamada CNPq n. 07/2022 - Apoio à Pesquisa Científica, Tecnológica e de Inovação: Bolsas de Mestrado e Dputorado - Ciclo 2022

The M.Sc. student Marcio José de Aguiar participated in the installation and testing of a DN 100 Mixer-Setter system in the "Department of Separation and Science Technology" of the Technical University of Kaiserslautern, Germany, from March 12th. to April 24th, 2018. under the supervision of Prof. Hans-Jorg Bart. This project was carried out within the research project funded by FAPESP number 2017/12830-9 entitled "Synthesis of Pioglitazone, Rosiglitazone and Lobeglitazone in Continuous Flow in Capillary Microreactors

The Ph.D. student Paulo Victor Cuesta Calvo conducted organic synthesis in NETmix reactor in the Department of Chemical Engineering of the Faculdade de Engenharia, Universidade do Porto, Portugal, from November 26th. to December 07th, 2018, under the supervision of Prof. Vítor Jorge Pais Vilar. This project was carried out within the research project funded by FAPESP number 2017/12830-9 entitled "Synthesis of Pioglitazone, Rosiglitazone and Lobeglitazone in Continuous Flow in Capillary Microreactors" and aims at a future research cooperation between the laboratories LSRE-LCM and MRT-Lab.

Microreactors offer excellent heat and mass transfer, high surface/volume ratio with laminar flow and without axial dispersion. Microreactors have been used in the continuous-flow synthesis of pharmaceuticals, creating chemical libraries of compounds with pharmacological potential, continuous synthesis in multiple steps, particularly for rapid reactions that involve much heat, chemical process intensification and with chemical reactions where dangerous, toxic or explosive chemicals are present. Some advantages of drug synthesis in microreactors are the drastic reduction of reaction times, due to the elimination of inefficient mixing effects, increased yield and selectivity of the reactions and reduction of waste generation. The Chemical-Pharmaceutical Industry is the largest beneficiary of this new technology, because the microreactors can generate a number of compounds with pharmacological potential, several orders of magnitude greater than in traditional batch process, can lessen in years the time for commercial production of a new drug and can be extremely small and compact industrial units. This work aims at using a system of microreactors to produce the APIs Pioglitazone (Actos®), Rosiglitazone (Avandia®) and Lobeglitazona (Duvie®) for the first time in continuous flow process, determining the kinetics of those reactions, and the best operating conditions for each synthesis. This project will be developed in collaboration with Profs. Till Opatz (Johannes Gutenberg-University Mainz, Germany) who idealized the synthetic routes of the APIs, and Prof. Hans-Joerg Bart (Technical University of Kaiserslautern, Germany) who developed the purification processes of the intermediate products by liquid-liquid extraction in micro devices. O aluno de graduação Paulo Victor Cuesta Calvo desenvolveu, no âmbito deste projeto, no período de 20/11
a 20/12/2017, a pesquisa em cooperação intitulada "Different Methods in Microbuble Production" no "Laboratory of Separation Science and Technology" na Universidade de Kaiserslautern, Alemanha.

The undergraduate student Guilherme Leão de Azevedo Soter has a Scientific Initiation period on the "Department of Separation Science and Technology" of the "Technical University of Kaiserslautern", Germany, from September 1st. to December 20th. under the supervision of Prof. Hans-Jorg Bart. This project is carried out within the research project funded by FAPESP number 2014/07757-2 entitled "Micro Reactors in the Synthesis of Pharmaceuticals". The sutdent was granted with a scholarship for Scientific Initiation from AUCANI-University of São Paulo.

The M.Sc. student Renan Rodrigues de Oliveira Silva performed tests under the guidance of Ph.D. student Stefan Willersinn on the "Department of Separation and Science Technology" of the Technical University of Kaiserslautern, Germany, from March 14th. to April 15th. under the supervision of Prof. Hans-Jorg Bart. This project was carried out within the research project funded by FAPESP number 2014/07757-2 entitled "Micro Reactors in the Synthesis of Pharmacueticals".

The M.Sc. student Renan Rodrigues de Oliveira Silva followed the tests carried out by Ph.D. students Elnaz Shahbazali and Marc Escribà Gelonch, respectively, in the "Laboratory of Micro Flow Chemistry and Process Technology" of the "Department of Chemical Engineering" of the Technical University of Eindhoven, Netherlands, from April 18th. 28th. under the supervision of Prof. Volker Hessel. This project was carried out within the research project funded by FAPESP number 2014/07757-2 entitled "Micro Reactors in the Synthesis of Pharmacueticals".

Os microreatores possibilitam excelente transferência de calor e de massa, altíssima relação superfície/volume com um escoamento laminar e pistonado. Vêm sendo utilizados na síntese de fármacos em fluxo contínuo, criação de bibliotecas de compostos químicos com potencial farmacológico, síntese contínua em múltiplas etapas, particularmente para reações rápidas que envolvam muito calor, processos químicos intensivos e reações com produtos químicos muito perigosos, tóxicos ou explosivos. Algumas vantagens da síntese de fármacos em microreatores são a redução drástica dos tempos de reação, devido à eliminação dos efeitos da mistura ineficiente, aumento do rendimento e seletividade das reações e redução da geração de resíduos. A Indústria Químico-Farmacêutica é a maior beneficiária desta nova tecnologia, pois os microreatores podem gerar uma quantidade de compostos, com potencial farmacológico, várias ordens de grandeza maior do que no processo batelada tradicional, podem diminuir em anos o tempo para produção comercial de um novo fármaco e podem ser unidades industriais extremamente pequenas e compactas. O objetivo deste trabalho é utilizar um microreator para produzir moléculas orgânicas com potencial farmacológico que já foram sintetizadas em processos batelada no Departamento de Farmácia da FCF/USP, determinar a cinética das reações, determinar as melhores condições operacionais para cada síntese e desenvolver o modelo matemático do processo.

São estudadas as influências da temperatura, concentração inicial de íon ferroso, concentração inicial de peróxido de hidrogênio, relação molar íon ferroso/peróxido de hidrogênio, pH, concentração de íon fosfato, concentração de íon cloreto, concentração de íon sulfato e concentração de íon nitrato na concentração residual de antibióticos (doxiciclina, oxitetraciclina, vancomicina e enrofloxacina), concentração residual de peróxido de hidrogênio, concentração residual de íon ferroso e TOC em reator de vaso agitado operando em batelada. Também são estudados a citotoxicidade dos resíduos gerados e se procura identificar os subprodutos de reação através de análises em HPLC-MS.