Desenvolvimento de rota sintética da Rosiglitazona em processo batelada e microrreator capilar / Rosiglitazone synthetic route development in batch process and capillary microreactor

Para que os fármacos possam ser comercializados economicamente, a sua escala de produção deve ser aumentada para atender à demanda do mercado. Atualmente, a maior parte dos fármacos são sintetizados em processos batelada que possuem limitações quanto à eficiência de mistura, temperatura e pressão. O uso de microrreatores surge como alternativa na indústria químico-farmacêutica, aumentando a eficiência dos processos de maneira segura. Ferramentas utilizadas no segmento computacional multidisciplinar teórico, como o DFT (Density Functional Theory), podem prever e compreender o comportamento das reações químicas, podendo ter grande utilidade na síntese de novos fármacos economizando tempo, investimento e reduzindo a geração de resíduos. A diabetes mellitus é uma doença de caráter epidêmico, que a cada ano vem aumentando o número de casos. O emprego de fármacos derivados das glitazonas no tratamento de diabetes mellitus tipo 2 é recomendado devido ao excelente controle glicêmico que esta classe de fármacos oferece. Neste trabalho, foi sintetizada a Rosiglitazona, um fármaco derivado das glitazonas, que auxilia no tratamento da diabetes mellitus tipo 2, sendo estudadas duas rotas de síntese distintas, que foram otimizadas com o intuito de maximizar o rendimento de seus intermediários, obtendo a Rosiglitazona com pureza de cerca de 94%. Foi realizada, para os intermediários, aqui denominados, 1R, 2R2 e 3R2 a síntese one-pot e para os intermediários 1R, 2R1 e 3R2 foi realizada a transposição do processo usual em batelada para fluxo contínuo no microrreator, com rendimentos de até 93%. Com o auxílio da química quântica computacional, a reação de síntese do intermediário 1R, foi elucidada teoricamente e determinadas as grandezas termodinâmicas (ΔH‡, ΔG‡ e ΔS‡) no estado de transição, que foram comparadas com os valores experimentais, sendo constatada uma boa concordância, com desvio máximo de 14%

In order for drugs to be commercialized economically, their production scale must be increased to meet market demand. Currently, most drugs are synthesized in batch processes that have limitations in terms of mixing efficiency, temperature and pressure. The use of microreactors appears as an alternative in the chemical-pharmaceutical industry, increasing the efficiency of the synthesis processes in a safe way. Tools used in the theoretical multidisciplinary computational segment, such as DFT (Density Functional Theory), can predict and understand the behavior of chemical reactions, and can be very useful in the synthesis of new drugs, saving time, investment and reducing waste generation. Diabetes mellitus is an epidemic disease that has been increasing the number of cases every year. The use of drugs derived from glitazones in the treatment of type 2 diabetes mellitus is recommended due to the excellent glycemic control that this class of drugs offers. In this work, Rosiglitazone, a drug derived from glitazones, which helps in the treatment of type 2 diabetes mellitus, was synthesized. Two different synthetic routes were studied and optimized in order to maximize the yield of its intermediates, obtaining Rosiglitazone with purity of about 94%. One-pot synthesis was performed to 1R, 2R2 and 3R2 intermediates, and the transposition from the usual batch process to continuous flow in microreactor was performed to 1R, 2R1 and 3R2 intermediates, with yields of up to 93%. With the aid of computational quantum chemistry, the intermediate 1R synthesis reaction was theoretically elucidated and the thermodynamic properties were determined (ΔH‡, ΔG‡ and ΔS‡) in the transition state, which were compared with the experimental results, obtaining good agreement, with a maximum deviation of 14%

Desenvolvimento de rota sintética da Rosiglitazona em processo batelada e microrreator capilar / Rosiglitazone synthetic route development in batch process and capillary microreactor

Para que os fármacos possam ser comercializados economicamente, a sua escala de produção deve ser aumentada para atender à demanda do mercado. Atualmente, a maior parte dos fármacos são sintetizados em processos batelada que possuem limitações quanto à eficiência de mistura, temperatura e pressão. O uso de microrreatores surge como alternativa na indústria químico-farmacêutica, aumentando a eficiência dos processos de maneira segura. Ferramentas utilizadas no segmento computacional multidisciplinar teórico, como o DFT (Density Functional Theory), podem prever e compreender o comportamento das reações químicas, podendo ter grande utilidade na síntese de novos fármacos economizando tempo, investimento e reduzindo a geração de resíduos. A diabetes mellitus é uma doença de caráter epidêmico, que a cada ano vem aumentando o número de casos. O emprego de fármacos derivados das glitazonas no tratamento de diabetes mellitus tipo 2 é recomendado devido ao excelente controle glicêmico que esta classe de fármacos oferece. Neste trabalho, foi sintetizada a Rosiglitazona, um fármaco derivado das glitazonas, que auxilia no tratamento da diabetes mellitus tipo 2, sendo estudadas duas rotas de síntese distintas, que foram otimizadas com o intuito de maximizar o rendimento de seus intermediários, obtendo a Rosiglitazona com pureza de cerca de 94%. Foi realizada, para os intermediários, aqui denominados, 1R, 2R2 e 3R2 a síntese one-pot e para os intermediários 1R, 2R1 e 3R2 foi realizada a transposição do processo usual em batelada para fluxo contínuo no microrreator, com rendimentos de até 93%. Com o auxílio da química quântica computacional, a reação de síntese do intermediário 1R, foi elucidada teoricamente e determinadas as grandezas termodinâmicas (ΔH‡, ΔG‡ e ΔS‡) no estado de transição, que foram comparadas com os valores experimentais, sendo constatada uma boa concordância, com desvio máximo de 14%

In order for drugs to be commercialized economically, their production scale must be increased to meet market demand. Currently, most drugs are synthesized in batch processes that have limitations in terms of mixing efficiency, temperature and pressure. The use of microreactors appears as an alternative in the chemical-pharmaceutical industry, increasing the efficiency of the synthesis processes in a safe way. Tools used in the theoretical multidisciplinary computational segment, such as DFT (Density Functional Theory), can predict and understand the behavior of chemical reactions, and can be very useful in the synthesis of new drugs, saving time, investment and reducing waste generation. Diabetes mellitus is an epidemic disease that has been increasing the number of cases every year. The use of drugs derived from glitazones in the treatment of type 2 diabetes mellitus is recommended due to the excellent glycemic control that this class of drugs offers. In this work, Rosiglitazone, a drug derived from glitazones, which helps in the treatment of type 2 diabetes mellitus, was synthesized. Two different synthetic routes were studied and optimized in order to maximize the yield of its intermediates, obtaining Rosiglitazone with purity of about 94%. One-pot synthesis was performed to 1R, 2R2 and 3R2 intermediates, and the transposition from the usual batch process to continuous flow in microreactor was performed to 1R, 2R1 and 3R2 intermediates, with yields of up to 93%. With the aid of computational quantum chemistry, the intermediate 1R synthesis reaction was theoretically elucidated and the thermodynamic properties were determined (ΔH‡, ΔG‡ and ΔS‡) in the transition state, which were compared with the experimental results, obtaining good agreement, with a maximum deviation of 14%.

Desirability Function in analytical method development for determination of glitazones and metabolites employing HF-LPME

Abstract Thiazolidinedione, often shortened to TZD or glitazone, helps lower insulin resistance, which is the underlying problem for many people with type 2 diabetes. The two most known glitazones are pioglitazone (PGZ), with the brand name medicine Actos®, and rosiglitazone (RSG), which is Avandia®. This study presented a multivariate optimization in the microextraction procedure employing Fractional Factorial Design (FFD) combined with Desirability Function (DF) to determine TZD and metabolites in biological samples. Microextraction requires several parameters to be optimized; however, most of them still use univariate optimization. Finding optimum conditions by simple response is relatively simple, but the problems, in case of microextractions, are often more complex when it has more responses. For example, changing one factor that promotes one response may suppress the effect of the others. Thus, this multivariate optimization was applied for two bioanalytical methods for determination of TZD and metabolites, one by HPLC and other by CE, both using Hollow Fiber Liquid-Phase Microextraction (HF-LPME). The results establish the optimal values and elucidate how the factors that affect HF-LPME procedure perform in extraction efficiency for TZDs. Additionally, this study demonstrates that DF can be an important tool to optimize microextraction procedures.

Vertebral fractures in adult women with type 2 diabetes mellitus / Fracturas vertebrales en mujeres adultas con diabetes mellitus tipo 2

Introduction. Diabetes is a chronic disease associated with important comorbidities. Type 2 diabetes (T2DM) is associated with a three times increased risk of hip fracture but reports describing potential associations with vertebral fractures (VF) are contradictory. Our objective was to evaluate the factors involved in the prevalent VF in women with and without T2DM. Materials and methods. A cross-sectional design was used and the relationship between morphometric VF and T2DM in adult women was evaluated. The cases were adult women with morphometric VF and the controls were adult women without VF. Thoracic and spinal radiographs in lateral and antero-posterior projections were obtained. Bone mineral density (BMD) values of the lumbar spine (L-BMD) were measured by DXA. Results. A greater number of women with T2DM were found in the VF group (61% vs 31.5%). Non-T2DM women with VF were significantly older and with lower L-BMD than non-T2DM without VF. We observed a negative correlation between age and L-BMD (r=-0.463) in non-T2DM women, but not in the T2DM with FV group. T2DM was a risk factor for prevalent VF with OR of 3.540 (IC95% 1.750-7.160). Conclusion. Our study showed a higher prevalence of T2DM in the VF group. T2DM women with VF were younger and had higher L-BMD than non-T2DM women, L-BMD did not correlate with age and VF were not distributed according to BMD-L and age. (AU)

Introducción. La diabetes es una enfermedad crónica asociada con comorbilidades importantes. La diabetes tipo 2 (DM2) se asocia con un riesgo tres veces mayor de fractura de cadera pero la asociación con fracturas vertebrales (FV) es contradictoria. Nuestro objetivo fue evaluar los factores involucrados en las FV prevalentes en mujeres adultas con y sin DM2. Materiales y métodos. Se realizó un diseño transversal y se evaluó la relación entre FV morfométrica y DM2 en mujeres adultas. Los casos fueron mujeres adultas con FV morfométricas y los controles fueron mujeres adultas sin FV. Se obtuvieron radiografías torácicas y espinales en proyecciones lateral y anteroposterior. Los valores de densidad mineral ósea (DMO) de la columna lumbar (DMO-L) se midieron por DXA. Resultados. Se observó un mayor número de mujeres con DM2 en el grupo de FV (61% frente a 31.5%). Las mujeres sin DM2 con FV eran significativamente mayores y con una DMO-L más baja que las mujeres sin DM2 sin FV. Observamos una correlación negativa entre la edad y la DMO-L (r= -0.463) en mujeres sin DM2 y FV, pero no en DM2 con FV. La DM2 fue un factor de riesgo para FV prevalente con un OR 3.540 (IC95% 1.750-7.160). Conclusión. Nuestro estudio demostró una mayor prevalencia de DM2 en el grupo de FV. Las mujeres con DM2 y FV eran más jóvenes y tenían mayor DMO-L que las mujeres sin DM2, la DMO-L no correlacionó con la edad y las FV no se distribuyeron de acuerdo a la DMO-L y edad. (AU)

Seguridad cardiovascular de los antidiabéticos orales / Cardiovascular safety of oral antidiabetics

Resumen La Diabetes Mellitus tipo 2 (DM-2) es un equivalente de riesgo cardiovascular. Existe una gran variedad de fármacos para el control de la glicemia en los pacientes con DM-2, los cuales tienen diferencias en su perfil cardiovascular, unos han demostrado un beneficio en la reducción de riesgo de eventos cardiovasculares, otros tienen un efecto neutro, y en el caso de otros fármacos como las sulfonilureas y las tiazolinedionas existe dudas sobre su seguridad cardiovascular. Sien do DM-2 un equivalente de riesgo coronario, es fundamental tomar en cuenta el perfil de riesgo cardiovascular de estos medicamentos a la hora de iniciar alguna de estas drogas y no solo su eficacia para controlar los niveles de glicemia. El objetivo de esta revisión es comentar sobre los estudios más recientes que evalúan el riesgo cardiovascular con el uso de los distintos antidiabéticos orales.

Abstract Cardiovascular Safety of Oral Antidiabetics Diabetes Mellitus type 2 (DM-2) is an equivalent of cardiovascular risk. There is a wide variety of drugs for the glycemic control in patients with DM-2, which have differences in their cardiovascular profile, some have shown a benefit in reducing the risk of cardiovascular events, others have a neutral effect, and in the case of other drugs such as sulfonylurea and thiazolidinedione, there are doubts about their cardiovascular safety. Being DM-2 an equivalent of coronary risk, it is essential to consider the cardiovascular risk profile of these medicines when starting any of these drugs and not only their effectiveness in controlling glycaemia levels. The objective of this review is to comment on the most recent studies evaluating cardiovascular risk with the use of different oral antidiabetics.