Rapid multigram scale end-to-end continuous flow synthesis of sulfonylurea anti-diabetes drugs: Gliclazide, chlorpropamide and tolbutamide

Herein we report multigram scale robust, efficient, and safe end-to-end continuous flow processes for the diabetes sulfonylurea drugs gliclazide, chlorpropamide and tolbutamide. The drugs were prepared via the treatment of an amine with a haloformate affording carbamate which was subsequently treated with a sulfonamide to afford sulfonylurea. Gliclazide was afforded in 87 % yield within 2.5 min total residence time with 26 g/h throughput; 0.2 Kg of the drug was produced in 8 h of running the system continuously. Chlorpropamide and tolbutamide were both afforded in 94 % yield within 1 min residence time with 184-188 g/h throughput; 1.4-1.5 Kg of the drugs was produced in 8 h of running the system continuously. N-substituted carbamates were used as safe alternatives to the hazardous isocyanates in constructing the sulfonyl urea moiety.

Bench-Scale Study of Aqueous MTBE Degradation by Combined Advanced Oxidation and Biological Processes

The oxidation of methyl tert-butyl ether (MTBE) by advanced oxidation processes in conjunction with biological treatment in investigated. Firsst, the degradation of MTBE by UV/H2O2 and UV/TiO2 is studied. It is found that the optimum molar ratio or H2O2/MTBE is about 14 while the optimum concentration of TiO2 is 1.5 g/L. In addition, it is observed that a combined process of UV/H2O2 and UV/TiO2 does not have any advantage over each of these processes alone. In the second phase, biodegradability of MTBE by aerobic microorganisms is evaluated in three different approaches including BODu assessment, removal of MTBE by non-acclimated, and acclimated microorganisms. It is shown that the acclimatization of microorganisms enhances the rate of biodegradation of MTBE. Finally, it is observed that the rate of bioreaction is not improved after a photochemical pre-treatment. It is also found that using the integration of photochemical and biological treatment reduced the total residence time.

Bench-Scale Study of Aqueous MTBE Degradation by Combined Advanced Oxidation and Biological Processes

The oxidation of methyl tert-butyl ether (MTBE) by advanced oxidation processes in conjunction with biological treatment in investigated. Firsst, the degradation of MTBE by UV/H2O2 and UV/TiO2 is studied. It is found that the optimum molar ratio or H2O2/MTBE is about 14 while the optimum concentration of TiO2 is 1.5 g/L. In addition, it is observed that a combined process of UV/H2O2 and UV/TiO2 does not have any advantage over each of these processes alone. In the second phase, biodegradability of MTBE by aerobic microorganisms is evaluated in three different approaches including BODu assessment, removal of MTBE by non-acclimated, and acclimated microorganisms. It is shown that the acclimatization of microorganisms enhances the rate of biodegradation of MTBE. Finally, it is observed that the rate of bioreaction is not improved after a photochemical pre-treatment. It is also found that using the integration of photochemical and biological treatment reduced the total residence time.

Pilot Plant Study of Aqueous Linear Alkylbenzene Sulfonate Degradation by Combined Advance Oxidation and Biological Processes

Photochemical degradation of linear alkybenzene sulfonate (LAS) using a pilot plant photoreactor is studied. LAS at 100 mg/L is degraded by UV-254 and UV/H2O2. Degradation of LAS is effectively enhanced by 720 mg/L H2O2. Moreover, the effectiveness of phototreatment on the biodegradability of LAS is examined. Both pretreated and untreated LAS are used in biological experiments. Combination of UV-254 with optimum concentration of H2O2 effectively enhanced the biodegradability of LAS. However, LAS at 100 mg/L can inhibit the growth of microorganisms. It is observed that the adaptation of activated sludge increases the biodegradation of LAS. However, due to the presence of intermediates in the effluent of the photoreactor, the biodegradability of this effluent is less than the biodegradability of the same as the concentration of untreated LAS. It is also observed that using the integration of UV/H2O2 and biological processes instead of single step of UV/H2O2, reduces the total residence time in chemical reactor while obtains the desired total efficiency.

Pilot Plant Study of Aqueous Linear Alkylbenzene Sulfonate Degradation by Combined Advance Oxidation and Biological Processes

Photochemical degradation of linear alkybenzene sulfonate (LAS) using a pilot plant photoreactor is studied. LAS at 100 mg/L is degraded by UV-254 and UV/H2O2. Degradation of LAS is effectively enhanced by 720 mg/L H2O2. Moreover, the effectiveness of phototreatment on the biodegradability of LAS is examined. Both pretreated and untreated LAS are used in biological experiments. Combination of UV-254 with optimum concentration of H2O2 effectively enhanced the biodegradability of LAS. However, LAS at 100 mg/L can inhibit the growth of microorganisms. It is observed that the adaptation of activated sludge increases the biodegradation of LAS. However, due to the presence of intermediates in the effluent of the photoreactor, the biodegradability of this effluent is less than the biodegradability of the same as the concentration of untreated LAS. It is also observed that using the integration of UV/H2O2 and biological processes instead of single step of UV/H2O2, reduces the total residence time in chemical reactor while obtains the desired total efficiency.

Systematic Model-Based Steady State and Dynamic Optimization of Combined Cooling and Antisolvent Multistage Continuous Crystallization Processes

Currently, one of the key challenges in the pharmaceutical industry is the transformation of traditional batch production methods into robust continuous processes with the intention of reducing manufacturing costs and time and improving product quality. Crystallization is by far the most important purification technology in Pharma, as more than 80% of the active pharmaceutical ingredients (API) require at least one crystallization step. A successful crystallization process requires tight control over crystal size, shape and polymorphic purity. A rigorous and systematic methodology is presented to design and optimize multistage combined cooling and antisolvent continuous (mixed-suspension, mixed-product removal- MSMPR) crystallizers. The crystallization of acetylsalicylic acid (API) in ethanol (solvent) and water (anti-solvent) is used as a case study. A predictable and validated mathematical model of the system, which consists of a one-dimensional population balance model, was used to develop several optimizations strategies. Firstly, the attainable region of the mean particle size was determined for both minimum and maximum attainable crystal size. The method helped identify the most suitable number of stages and total residence time or volume for a cascade of continuous crystallizers. This was followed by a steady state optimization which helped determine the optimal operating temperatures and antisolvent flowrates. To minimize the startup time, a series of dynamic optimization strategies were implemented, assuming starting from empty vessels. The optimal dynamic profiles of the temperature and antisolvent flow rate, at different crystallization steps, were identified using a systematic and rigorous approach allowing a reduction in the startup time by 31%.

Continuous-Flow Synthesis of (–)-Oseltamivir Phosphate (Tamiflu)

Herein the anti-influenza drug (–)-oseltamivir phosphate is prepared in continuous flow from ethyl shikimate with 54% overall yield over nine steps and total residence time of 3.5 min from the individual steps. Although the procedure involved intermediate isolation, the dangerous azide chemistry and intermediates involved were elegantly handled in situ. It is the first continuous-flow process for (–)-oseltamivir phosphate involving azide chemistry and (–)-shikimic acid as precursor.

Experimental measurement and numerical modelling of dye washout for investigation of blood residence time in ventricular assist devices

Ventricular assist devices have become the standard therapy for end-stage heart failure. However, their use is still associated with severe adverse events related to the damage done to the blood by fluid dynamic stresses. This damage relates to both the stress magnitude and the length of time the blood is exposed to that stress. We created a dye washout technique which combines experimental and numerical approaches to measure the washout times of ventricular assist devices. The technique was used to investigate washout characteristics of three commercially available and clinically used ventricular assist devices: the CentriMag, HVAD and HeartMate II. The time taken to reach 5% dye concentration at the outlet (T05) was used as an indicator of the total residence time. At a typical level of cardiac support, 5 L/min and 100 mmHg, T05 was 0.93, 0.28 and 0.16 s for CentriMag, HVAD and HeartMate II, respectively, and increased to 5.06, 1.64 and 0.96 s for reduced cardiac support of 1 L/min. Regional variations in washout characteristics are described in this article. While the volume of the flow domain plays a large role in the differences in T05 between the ventricular assist devices, after standardising for ventricular assist device volume, the secondary flow path was found to increase T05 by 35%. The results explain quantitatively, for the first time, why the CentriMag, which exerts low shear stress magnitude, has still been found to cause acquired von Willebrand Syndrome in patients.

Scalable synthesis of sequence-defined, unimolecular macromolecules by Flow-IEG

We report a semiautomated synthesis of sequence and architecturally defined, unimolecular macromolecules through a marriage of multistep flow synthesis and iterative exponential growth (Flow-IEG). The Flow-IEG system performs three reactions and an in-line purification in a total residence time of under 10 min, effectively doubling the molecular weight of an oligomeric species in an uninterrupted reaction sequence. Further iterations using the Flow-IEG system enable an exponential increase in molecular weight. Incorporating a variety of monomer structures and branching units provides control over polymer sequence and architecture. The synthesis of a uniform macromolecule with a molecular weight of 4,023 g/mol is demonstrated. The user-friendly nature, scalability, and modularity of Flow-IEG provide a general strategy for the automated synthesis of sequence-defined, unimolecular macromolecules. Flow-IEG is thus an enabling tool for theory validation, structure–property studies, and advanced applications in biotechnology and materials science.

Modeling the Total Residence Time in a Rotary Dryer

A mathematical model for the rotary dryer that determines the total residence time is developed. Experiments were performed in a laboratory-scale direct contact rotary dryer with the gas flowing concurrently with the solids. The model predictions depicted that the total residence time decreases with increasing the inclination of the rotary drum, the speed of rotation and the radius of rotary drum. The validation of the model was carried out experimentally for maize while varying the inclination of the rotary drum and the speed of rotation. The experimental results were observed to be in good agreement with the model predictions.