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%

Short-term competition and long-term convergence between domestic and global rating agencies: Evidence from China.

This article adds to the existing literature on global rating agencies (GRAs, i.e., the S&P, Moody's, and Fitch) and domestic rating agencies (DRAs). In our research, we introduce the reputation, rating cost and rating accuracy of rating agencies to improve the Hotelling model. According to the theoretical analysis and empirical tests, the results show that the open policy of the Chinese rating industry contributes to higher rating quality in the domestic bond market. This open policy leads to rating convergence between DRAs and GRAs from in the long term.

The Relationship Between Hospital Value-Based Purchasing Program Scores and Hospital Bond Ratings.

Tax-exempt hospitals and health systems often borrow long-term debt to fund capital investments. Lenders use bond ratings as a standard metric to assess whether to lend funds to a hospital. Credit rating agencies have historically relied on financial performance measures and a hospital's ability to service debt obligations to determine bond ratings. With the growth in pay-for-performance-based reimbursement models, rating agencies are expanding their hospital bond rating criteria to include hospital utilization and value-based purchasing (VBP) measures. In this study, we evaluated the relationship between the Hospital VBP domains--Clinical Process of Care, Patient Experience of Care, Outcome, and Medicare Spending per Beneficiary (MSPB)--and hospital bond ratings. Given the historical focus on financial performance, we hypothesized that hospital bond ratings are not associated with any of the Hospital VBP domains. This was a retrospective, cross-sectional study of all hospitals that were rated by Moody's for fiscal year 2012 and participated in the Centers for Medicare & Medicaid Services' VBP program as of January 2014 (N = 285). Of the 285 hospitals in the study, 15% had been assigned a bond rating of Aa, and 46% had been assigned an A rating. Using a binary logistic regression model, we found an association between MSPB only and bond ratings, after controlling for other VBP and financial performance scores; however, MSPB did not improve the overall predictive accuracy of the model. Inclusion of VBP scores in the methodology used to determine hospital bond ratings is likely to affect hospital bond ratings in the near term.

The urge to merge.

For many stand-alone hospitals, a merger, partnership, or affiliation may be the only option to access scale and remain viable in the nation's emerging new healthcare delivery system. These organizations can consider many options for affiliation, including traditional options such as affiliation with regional academic medical centers, a merger or takeover to become the corporate member of a large system, and acquisition by a for-profit system. Emerging options include mergers for scale and access to capital, private-equity transactions, and arrangements involving insurance vertical integration.

Health systems strengthening: a common classification and framework for investment analysis.

Significant scale-up of donors' investments in health systems strengthening (HSS), and the increased application of harmonization mechanisms for jointly channelling donor resources in countries, necessitate the development of a common framework for tracking donors' HSS expenditures. Such a framework would make it possible to comparatively analyse donors' contributions to strengthening specific aspects of countries' health systems in multi-donor-supported HSS environments. Four pre-requisite factors are required for developing such a framework: (i) harmonization of conceptual and operational understanding of what constitutes HSS; (ii) development of a common set of criteria to define health expenditures as contributors to HSS; (iii) development of a common HSS classification system; and (iv) harmonization of HSS programmatic and financial data to allow for inter-agency comparative analyses. Building on the analysis of these aspects, the paper proposes a framework for tracking donors' investments in HSS, as a departure point for further discussions aimed at developing a commonly agreed approach. Comparative analysis of financial allocations by the Global Fund to Fight AIDS, Tuberculosis and Malaria and the GAVI Alliance for HSS, as an illustrative example of applying the proposed framework in practice, is also presented.

Clinical quality is independently associated with favorable bond ratings.

The relation between clinical quality and bond rating for nonprofit hospitals has been proposed but never fully studied. We analyzed the relation between bond rating, clinical quality measures (The Joint Commission/Centers for Medicare and Medicaid Services [CMS] core measures), and balance sheet and income statement financial measures of 236 hospitals across the United States that are rated by Moody's Investors Service and that reported clinical quality measures to CMS during the study period. We found a statistically significant relation between higher quality measures and more favorable bond ratings. This association remained significant after controlling for traditional financial parameters.

What's new with the FHA's Section 242?

FHA hospital mortgage insurance, also called the Section 242 program, acts as a credit enhancement that allows borrowers to issue bonds up to the equivalent of an "AAA" rating, with the benefits of lower interest rates. Although the program has operated in relative obscurity over its 40 years of existence, the FHA has undertaken a new marketing campaign to raise its profile. Federal backing may make the program an attractive option amid today's financial turmoil in the capital markets.