八步连续流全合成维生素B_(1)工艺研究

Vitamin B_(1) is widely applied in the healthcare and food industry as an antineuritic and antioxidant to maintain the normal functioning of nerve conduction,the heart,and the gastrointestinal tract.This study reports on an integrated eight-step continuous-flow synthesis of vitamin B_(1) from commercially available 2-cyanoacetamide.The proposed continuous-flow process is based on advances in chemistry,engineering,and equipment design,and affords improved performance and safety compared with batch-mode manufacturing.Several challenges were precisely investigated and controlled,including mixing,unexpected clogging,solvent switches,an exothermic reaction,and the prevention of side reactions,using various micro-channel flow reactors,mixers,separators,and continuous filters.Vitamin B_(1) was produced with a separated yield of 47.7% and high purity,with a total residence time of about 3.5 h.This eight-step continuous-flow protocol enables technology involving up to six of the key principles of green chemistry.Hence,the application of flow technology is of paramount importance for improving security,reducing waste,and,in particular,improving the efficiency of batch operations that require several days for manufacturing.

Perspectives on the flexibility analysis for continuous pharmaceutical manufacturing processes

Pharmaceutical continuous manufacturing,especially under the context of COVID-19 pandemic,is regarded as an emerging technology that can guarantee the adequate quality assurance and mitigate process risk while guaranteeing the desirable economic performance.Flexibility analysis is one approach to quantitively assess the capability of chemical process to guarantee feasible operation in face of variations on uncertain parameters.The aim of this paper is to provide the perspectives on the flexibility analysis for continuous pharmaceutical manufacturing processes.State-of-the-art and progress in the flexibility analysis for chemical processes including concept evolution,mathematical model formulations,solution strategies,and applications are systematically overviewed.Recent achievements on the flexibility/feasibility analysis of the downstream dosage form manufacturing process are also touched upon.Further challenges and developments in the field of flexibility analysis for novel continuous manufacturing processes of active pharmaceutical ingredients along with the integrated continuous manufacturing processes are identified.

Flexibility analysis for continuous ibuprofen manufacturing processes

Continuous ibuprofen(a widespread used analgesic drug)manufacturing is full of superiorities and is a fertile field both in industry and academia since it can not only effectively treat rheumatic and other chronic and painful diseases,but also shows great potential in dental diseases.As one of central elements of operability analysis,flexibility analysis is in charge of the quantitative assessment of the capability to guarantee the feasible operation in face of variations on uncertain parameters.In this paper,we focus on the flexibility index calculation for the continuous ibuprofen manufacturing process.We update existing state-of-the-art formulations,which traditionally lead to the max-max-max optimization problem,to approach the calculation of the flexibility index with a favorable manner.Advantages regarding the size of the mathematical model and the computational CPU time of the modified method are examined by four cases.In addition to identifying the flexibility index without any consideration of control variables,we also investigate the effects of different combinations of control variables on the flexibility property to reveal the benefits from taking recourse actions into account.Results from systematic investigations are expected to provide a solid basis for the further control system design and optimal operation of continuous ibuprofen manufacturing.

Control strategy and methods for continuous direct compression processes

We presented a control strategy for tablet manufacturing processes based on continuous direct compression.The work was conducted by the experts of pharmaceutical companies,machine suppliers,academia,and regulatory authority in Japan.Among different items in the process,the component ratio and blended powder content were selected as the items requiring the control method specific to continuous manufacturing different from the conventional batch manufacturing.The control and management of the Loss in Weight(LIW)feeder were deemed the most important,and the Residence Time Distribution(RTD)model were regarded effective for setting the control range and for controlling of the LIW feeder.Based on these ideas,the concept of process control using RTD was summarized.

Sinomenine Purification by Continuous Liquid-Liquid Extraction Process with Centrifugal Extractors

Continuous manufacturing is considered as one of the future trends of pharmaceutical engineering. In this work, continuous liquid-liquid extraction for sinomenine purification was realized with the usage of centrifugal extractors. Chloroform was used as the extractant because of the high distribution coefficient (>100). Higher extraction ratio can be obtained when using the centrifugal extractor of Model CWL50-N. The extraction ratio of the second-stage extraction was higher than that of the first-stage extraction. The extraction ratio of the second-stage countercurrent extraction was higher than that of second-stage cross-flow extraction. When chloroform phase was recycled for liquid-liquid extraction, the extraction ratio was also higher than 95%. This work can also be an example of continuous liquid-liquid extraction for the separation of other Chinese medicine components.

Process analytical technologies and self-optimization algorithms in automated pharmaceutical continuous manufacturing

The pharmaceutical industry is now paying increased attention to continuous manufacturing.While the revolution to continuous and automated manufacturing is deepening in most of the top pharma companies in the world,the advancement of automated pharmaceutical continuous manufacturing in China is relatively slow due to some key challenges including the lack of knowledge on the related technologies and shortage of qualified personnels.In this review,emphasis is given to two of the crucial technologies in automated pharmaceutical continuous manufacturing,i.e.,process analytical technology(PAT)and self-optimizing algorithm.Research work published in recent 5 years employing advanced PAT tools and self-optimization algorithms is introduced,which represents the great progress that has been made in automated pharmaceutical continuous manufacturing.

In silico product design of pharmaceuticals

The increasing demand for personalized medicine necessitates the production of easily customizable dosage forms. As the number of possible dosage forms may scale toward infinity, their uniqueness requires a versatile production platform and numerical simulation in order to be manufactured efficiently. A mathematical description of these systems is the only feasible approach to manage such diverse properties of different products. However,experimental verification is still essential for evaluation of processability and related concomitant phenomena, such as possible solid state changes that may occur during production and storage.

FOTON Continues to hold its Championship as Global Largest Commercial Vehicle Manufacturer

Latest data from the China Association of Automobile Manufacturers(CAAM) shows that through 2010.China’s automobile sales surpassed 18 million, breaking the world record of annual auto sales previously held by the United States.Now that China has become a major global auto production player, how is Foton faring? CAAM statistics said production and sales volume of

Impact of the spindle number on the material transport and mixing during planetary roller melt granulation Author links open overlay panel

In comparison to the established twin-screw machines,the application of a planetary roller granulator for continuous operation of melt granulation is a promising alternative based on the unique process concept.An initial study focused on the material transport during processing as a key driver for the overall performance.Hereby,the impact of direct process parameters on the residence time distribution was the main objective.These investigations are complemented in this study by considering the free processing volume,which is defined by the number of planetary spindles applied within a module.The impact on the processing conditions is evaluated with respect to the process setting in terms of feed rate and rotation speed.The results highlight the potential of altering the underlying transport function in planetary roller melt granulation(PRMG)via the investigated direct process and equipment parameters.The impact of the feed rate is lower in comparison,while a higher rotation speed as well as a higher free processing volume promote material mixing.Moreover,a normalization of the determined residence time distribution(RTD)model data was feasible with respect to the process settings and the number of applied planetary spindles in the processing zone.This demonstrates the key role of the free processing volume in the fundamental mechanisms of material transport and mixing during PRMG.

Optimization of residence time distribution in RCDG and an assessment of its applicability in continuous manufacturing

Knowledge of residence time is a critical aspect in developing control and material diversion strategies for continuous manufacturing processes in pharmaceutical manufacturing.Dry granulation is a promising continuous granulation technique as it is fast and economical.In this study,a step-change method to determine residence time in roll compaction/dry granulation is introduced.The factors roll speed and rotational speed of the impeller in the powder inlet unit of the compactor were evaluated using a central composite circumscribed statistical design of experiments in order to optimize the residence time.The fill volume in the compactor was varied exemplarily.It was found that high roll speed,low rotational speed of the impeller and low fill volume in the compactor are beneficial to generate fast transition through the compactor.The impact of roll speed increase was estimated.It can be concluded that despite fast residence time in the process,high roll speed and its subsequent high material throughput can generate a large amount of material that has to be discarded if material diversion is required.