Microreactor Technology as a Tool for the Synthesis of a Glitazone Drug Intermediate

Abstract

One of the bottlenecks in the pharmaceutical industry is drug production scaleup, which can be performed by microreactor technology. Such an approach was applied to the synthesis of (Z)-5-(4-hydroxybenzylidene)thiazolidine-2,4-dione, a bioactive aromatic heterocyclic compound belonging to the class of glitazones. n-Propanol was the best solvent and piperidine the best catalyst for the batch reaction, which was completed in only 5.5 h. In the microreactor, the productivity was almost independent of solvent. The microreactor behaved as a plug-flow reactor and operated at a steady state for ten hours without efficiency loss. The results suggest that microreactors may replace batch reactors in scaling up drug production.

Residence Time Distribution of a Capillary Microreactor Used for Pharmaceutical Synthesis

“… noted that the effect of rectangular microchannel dimensions on fluid mechanic is associated with the aspect ratio between depth and width, in which there is a narrowing of the E curve for low aspect ratios. The formation of micromixing and secondary flow patterns (Dean vortices) in microscale devices with several bends are also pointed out in the literature as a cause for plug‐like flow at low Reynolds numbers , .…”

“…Recently, Pinheiro et al. and Silva et al. developed a continuous‐flow microsystem for the synthesis of TZD derivatives and observed several benefits over batch processes, such as feasibility to perform the synthesis of TZD derivatives and higher process efficiency.…”

“…One example is the continuous-flow synthesis of thiazolidine-2,4dione (TZD) derivatives, which are associated with antidiabetic, anti-inflammatory, antimicrobial, antiarthritics, and anticancer effects [16]. Recently, Pinheiro et al [17] and Silva et al [18] developed a continuous-flow microsystem for the synthesis of TZD derivatives and observed several benefits over batch processes, such as feasibility to perform the synthesis of TZD derivatives and higher process efficiency. An accurate characterization of the fluid flow in this microsystem can provide useful information for process modeling and optimization, enhancing the effectiveness of this process [1].…”

Evaluation of Reaction Between 2,4-Thiazolidinedione and P-Methoxybenzaldehyde in Microreactors for Production of Drugs for Treatment of Diabetes Mellitus Type 2

“…The optimized operating conditions were obtained for the batch reactor (processing time) and microreactor (residence time), the promoter base selection and optimal concentration was also performed, in order to maximize reactants conversion and reaction yield. The reactor performance was compared using the parameter of equivalent number of microreactor, nºMR [15], defined as the number of microreactors required to provide the same mass amount of a standard batch output. Furthermore, reaction rate constant, activation energy and thermodynamic parameters of transition state (enthalpy ∆H*, entropy ∆S* and Gibbs free energy ∆G*) were also obtained.…”

Microrreatores Capilares Como Alternativa Aos Tradicionais Reatores Batelada Na Síntese Do Intermediário Farmacêutico (Z)-5-(4-Clorobenzilideno)tiazolidina-2,4-Diona

“…Os microrreatores capilares são por definição reatores tubulares (PFRs) em tamanho miniatura, com diâmetro médio dos capilares variando entre 10 e 100 μm e volume total de 1 mL. Por conta de suas dimensões diminutas o fluxo contínuo ocorre em regime laminar, pois o número de Reynolds (Re) é usualmente baixo, da ordem de 1 a 10 (Watts e Wiles, 2012; Pinheiro et al, 2018). A Figura 2 mostra o microrreator utilizado para a reação química entre TZD e 4clorobenzaldeído.…”