Research On A Novel Continuous Manufacturing Process Of Sinomenine Hydrochloride Based On The Concept Of Green Chemistry

Green manufacturing and continuous manufacturing are the development trends both domestically and internationally.Sinomenine hydrochloride is the main effective ingredient of Zhengqing Fengtongning in Chinese Pharmacopoeia Vol.I.There are many problems of the existing industrial production processes,such as high solvent toxicity,multiple steps,excessive solid waste,and low atomic utilization efficiency,which do not conform to the concept of green manufacturing.The green degree scores are only between 54-64 points.In this study,a novel preparation process of sinomenine hydrochloride was proposed to solve the above problems,ensuring product quality by controlling material properties and process parameters.Subsequently,the self-made microstructure devices were optimized for continuous manufacturing.Finally,the continuous manufacturing equipment was constructed,which integrating the online testing devices and process control strategies.The green and continuous manufacturing of sinomenine hydrochloride was achieved.The main researches of this thesis are as follows.1.A novel purification process of sinomenine hydrochloride dealing with acid water extract.Through preliminary literature research,1-heptanol was selected as a new extractant.It has the lower solvent toxicity than chloroform and benzene.The original "calcium salt precipitation-extraction-acidic precipitation" process was replaced with an "extraction-washing-stripping" process.The maximum distribution coefficient of 1-heptanol for sinomenine was determined to be 27.4 by the liquid-liquid equilibrium method.The alkalization p H value,1-heptanol amount,stripping solution amount,and the stripping p H value were selected as the critical process parameters by analyzing the data collected from definitive screening designed experiments.The purity of sinomenine hydrochloride in extract was the critical material attribute.The mathematical models were established to identify the relationships between the above-mentioned parameters and the purity and yield of sinomenine hydrochloride.Finally,the feasibility of recycling 1-heptanol and crystallization mother liquor was proved.Due to the novel process solved the problems of high solvent toxicity and excessive solid waste residue,and appropriately shortened the process flow,the green degree increased to 85 points.The purity of sinomenine hydrochloride crystals exceeded 85%,and the yield increased by 20%.Compared with the acid extraction process in industry,the amount of solid waste for each kilogram of product was reduced by about 10 kilograms.2.A novel organic solvent extraction and purification process of sinomenine hydrochloride.In order to further shorten the process and improve atomic economy,anisole was selected as the new extractant.It can be directly used for extracting sinomenine from the medicinal material of Caulis Sinomenii.Anisole has high selectivity for sinomenine in solid-liquid extraction,and can be washed with water in the subsequent purification step.Its maximum distribution coefficient for sinomenine was determined to be as high as 43.9.A novel extraction and purification process was proposed that included only three process units after medicinal material alkalization,which were heating extraction,water washing,and acidification crystallization.It was found that the batches of medicinal materials had little impact on the two process evaluation indicators of crystal purity and sinomenine transfer rate.The alkalization time,extraction temperature,washing solution amount,and hydrochloric acid concentration were the critical process parameters.The mathematical models between critical process parameters and sinomenine purity and transfer rate were established.The model R2 values were both greater than 0.85.The design space was constructed and successfully validated.The recommended operating ranges of the critical process parameters were: 3.0-4.0 h of alkalization time,60.0-80.0 ℃ of extraction temperature,2.0-3.0(v/v)of washing solution amount,and 2.0-2.4 mol/L of hydrochloric acid concentration.Finally,the transfer rate of sinomenine was increased to about 70% by recycling crystallization mother liquor.Since the novel process solved the problems of long process flow and poor atomic economy,the green degree increased to 90 points.The production cost of this new process was expected to decrease by about 20% compared to the previous chapter’s process.In addition,this process is insensitive to quality difference among batches of medicinal materials,showing good robustness,and may be suitable for dealing with different batches of Caulis Sinomenii in industrial production.3.Optimization research on microstructure device and its operating parameters.A selfmade membrane phase separator was applied to the continuous phase separation process of anisole phase and water phase.The structure and operating parameters of the phase separator were optimized with the organic phase separation rate and the water phase entrainment rate as indicators.It was found that the phase separation effect of the phase separator increased with the increase of membrane pore size and back pressure,and decreased with the increase of channel height,total flow rate,and the volume ratio of organic phase to water phase.The optimized parameters values were: 0.4 mm of channel height,20 m L/min of organic phase flow rate,2.0:1.0(v/v)of organic phase to water phase volume ratio,and 0.50 bar of the back pressure.Linear equation fitting results showed that the organic phase flow rate through the membrane was proportional to the back pressure.The T-shaped single channel mixer was applied to the continuous extraction process.It was found that the relative extraction rate decreased with the increase of the mixer inner diameter and increased with the increase of the flow rate.The continuous phase Reynolds number was the critical parameter.The mathematical model between the continuous phase Reynolds number and the relative extraction rate was established.The model R2 value was greater than 0.97.A higher the continuous phase Reynolds number led to a higher relative extraction rate.When the continuous phase Reynolds number exceeded 360,the relative extraction rate was close to 100%.Finally,the model was applied to the continuous acidification process to verify its applicability.4.Research on the continuous manufacturing process of sinomenine hydrochloride.A continuous manufacturing equipment was constructed using the optimized phase separator,two T-shaped single channel mixers,and online spectrometer to achieve continuous water washing,phase separation,and acidification crystallization.Nearinfrared(NIR)spectroscopy was used to establish quantitative models for the contents of sinomenine and water in the extract after water washing,with R2 values of the models greater than 0.8.The residence time distribution of sinomenine in both partial and overall processes was measured by the pulse method.The average residence time（？） from the raw material to the two process monitoring points and the overall process were 110 s,133s,and 156 s,respectively.The dimensionless variances 2 were 0.07,0.03,and 0.05,respectively,all of which were close to 0.It could be concluded that the flow pattern was closed to the advection flow.Based on two online monitoring devices,UV detector and NIR spectrometer,a series of process control strategies including online monitoring,real time release testing,disturbance management and diversion strategy were developed to ensure the state of control.Expected results were achieved by two normal batches and two simulated abnormal batches.Finally,continuous and batch manufacturing products were compared,and the average relative deviation of crystal purity and yield were less than 8%.The sinomenine hydrochloride crystals by continuous manufacturing purity exceeded 88%.Adopting continuous manufacturing not only solved the low efficiency problem in batch manufacturing,but also enabled real-time analysis of production status to prevent accidents.Therefore,the green degree further increased to 104 points.The research conforms to the development trend of green and continuous manufacturing,providing a foundation for achieving continuous manufacturing of sinomenine hydrochloride.