Research On The Control Strategy Of Traditional Chinese Medicine Ethanol Precipitation Process Based On A Membrane Dispersion Micromixer

Ethanol precipitation is a purification process widely used in the production of modern dosage forms of traditional Chinese medicines(TCMs).In this study,the membrane dispersion micromixer was used in ethanol precipitation of TCMs to reduce the encapsulation loss of active components.In order to solve the problems of long standing time and improve batch-to-batch consistency of supernatant quality of ethanol precipitation,the methods of improving equipment,controlling concentrate quality,and establishing design space were put forward.The main researches of this thesis are as follows.1.Quantitative evaluation index of ethanol precipitation mixing effect.The Well-mixing Ratio(WMR)was proposed as an index to evaluate the mixing effect of an ethanol solution and a concentrate.The concept and requirements of mixing indicator were put forward,and the calculation formula of WMR was derived.Lobetyolin was verified to be the mixing indicator of Codonopsis Radix ethanol precipitation.In the stirring ethanol precipitation process of Codonopsis Radix concentrates,the lobetyolin recovery and WMR decreased with the increase of dry matter contents of concentrates(DM_C),increased with the increase of stirring speed,and increased with the decrease of concentrate droplet diameter and ethanol droplet diameter.The mixing effect of adding an ethanol solution to a concentrate was better than that of adding a concentrate to an ethanol solution.The results showed that the WMR value could quantitatively characterize the mixing effect of an ethanol solution and a concentrate during the ethanol precipitation process.2.The effects of membrane dispersion micromixer structure and process parameters on ethanol precipitation.The membrane dispersion micromixer was designed and applied to the ethanol precipitation of Codonopsis Radix concentrates.It was found that as membrane pore size decreased,mixing chamber width and depth decreased,the mixing effect increased.The structure of the micromixer was optimized.Lower DM_C or higher flow rates of two phases could lead to better mixing effect.The quantitative models of two-phase Reynolds number,mass ratio of ethanol solution to concentrates and evaluation indices of ethanol precipitation process were established.The WMR value obtained using micromixing technology was at least 15%higher than that of stirring at the same mixing time when the DM_C was 55%.Membrane dispersion technology is promising to reduce the encapsulation loss of active compounds in TCM ethanol precipitation.3.Research on the quality control method of concentrates in membrane dispersion micromixer intensified ethanol precipitation.Multiple properties of Codonopsis Radix concentrates were determined.Concentrate density could reflect the DM_C of concentrates.Concentrate viscosity was more suitable to describe the difference of solid composition of different batch concentrates than concentrate density.The quantitative relationship between density,viscosity,temperature,and concentrate DM_C was obtained by fitting.The quantitative models for the concentrate DM_C,iscosity,and process quality attributes were established.The prediction error ropagation method was used to establish the quality standard of Codonopsis Radix oncentrates.The results showed that the models had good prediction performance nd the quality standard of concentrates was reliable.Only the concentrate density as controlled in most industrial ethanol precipitation.In contrast,the concentrate uality control method established in this research are more suitable to maintain the onsistency of process quality attributes when the batches of materials are changed.4.Research on the control strategy of membrane dispersion ethanol precipitation rocess with a set of rapid cooling equipment.The heat exchanger was added before he continuous addition of ethanol to the micromixer.The temperature of the mixture was controlled by a temperature-controlled jacketed beaker.The ethanol precipitation system can be quickly and accurately cooled using this device.The time of standing refrigeration was reduced.The device was applied to ethanol precipitation process of Astragali radix concentrates.Quadratic models between the critical material attributes,critical process parameters and process critical quality attributes(CQAs)were established.The design space considering the material attributes was calculated according to the probability of attaining process CQAs standards and verified successfully.The quality of Astragali radix concentrates was controlled by an inequality group.The verification experiments were performed to treat the high-quality concentrates.The results were in good agreement with the predicted results.The control strategy proposed in this study is promising to be applied to other processes and improve the batch-to-batch consistency of TCM preparations.