Continuous saponification-acidification reaction method and system for cholic acid production

Abstract

The application discloses a continuous saponification-acidification reaction system and method for cholic acid production and relates to the field of biological chemical industry. The method first adjusts the viscosity of a raw material liquid, continuously injects the raw material liquid into an alkali solution according to a set equivalent ratio and carries out a hydrolysis reaction; then carries out online dilution and heat exchange cooling on the saponification liquid to obtain a to-be-acidified liquid; in the acidification stage, a multi-point acid injection strategy is adopted, high-shear mixing is cooperated to make the acid liquid millisecond dispersion, fluid shear thinning characteristics and a wall slip layer are utilized to prevent fouling; the acidification slurry then enters a low-shear flow field to carry out crystal aging and cultivation, and the crystal particle size is optimized by controlling the residence time distribution; finally, solid-liquid separation is carried out, and feedback regulation is carried out based on process parameters. The method effectively solves the fouling and blocking problem of a high-viscosity solid-liquid phase change system, and realizes continuous and stable production of high-purity cholic acid.

Description

Technical Field

[0001] This invention relates to the field of biochemical and pharmaceutical intermediate production technology, specifically to a continuous saponification-acidification reaction method and system for bile acid production. Background Technology

[0002] Bile acids are important precursors for tauroursodeoxycholic acid and ursodeoxycholic acid, the core components of synthetic bear bile powder. In the industrial production of bile acids, the core processes typically include two key chemical steps: alkaline saponification and acid precipitation. Saponification refers to the complete hydrolysis of bound bile acids, such as tauroursodeoxycholic acid or glycocholic acid, in the raw materials into free bile salts under alkaline high-temperature conditions. Acidification involves precisely adjusting the pH of the system by adding inorganic acids to break down the hydrophilicity of the bile salts, allowing the free bile acids to precipitate as solid crystals. Current industrial production mainly employs fully automated batch reactor systems equipped with PID temperature control, stirring speed regulation, and online pH monitoring. DCS control improves production efficiency and compliance to a certain extent.

[0003] However, in large-scale production scenarios, such as annual production of ten to fifty tons, the aforementioned automated intermittent process still suffers from fundamental technical defects. Firstly, there are batch-to-batch stability differences. Due to fluctuations in the viscosity and solid content of the raw bile, a fixed heating and stirring program cannot guarantee a completely consistent degree of saponification in each batch, leading to fluctuations in the purity of the subsequent synthetic substrate. Secondly, there are thermal effects and mass transfer bottlenecks in the acidification process. The acidification reaction is strongly exothermic and accompanied by a dramatic phase transition from a clear liquid to a solid-liquid slurry. In large-volume reactors, the local concentration near the acid addition point is extremely high, and the temperature rises sharply, easily triggering local side reactions that lead to product degradation or darkening of color. Simultaneously, pH adjustment lags behind in areas far from the agitator. This macroscopic mixing unevenness results in a wide particle size distribution and numerous fine crystals in the precipitated bile acid particles, severely affecting the efficiency of subsequent centrifugation and washing.

[0004] To address these issues, the industry has attempted to introduce conventional continuous flow technologies such as tubular reactors or static mixers. However, under the specific operating conditions of bile acid production, simple continuous operation faces significant challenges. One issue is the clogging and scaling problems caused by phase change. Saponification solutions are typically high-viscosity fluids, and acidification instantly generates a large number of solid particles with a solid content exceeding 30%. In conventional pipelines, a hard acid crust easily forms at the acid-liquid contact surface, rapidly clogging channels or covering sensor probes, forcing frequent system shutdowns for cleaning and preventing truly long-term continuous operation. Another issue is the uncontrollable residence time distribution. Simple continuous pipelines cannot guarantee a uniform saponification residence time for all materials, potentially leading to some raw materials entering the acidification section without complete saponification due to short-circuiting, introducing difficult-to-remove impurities and failing to meet the pharmaceutical-grade purity requirement of no less than 99.5%.

[0005] In summary, existing automated batch reactors cannot solve the problems of uneven mass transfer and batch variations, while conventional continuous flow equipment cannot adapt to the drastic phase transition process of high-viscosity liquids transforming into solid-liquid slurries. Therefore, there is an urgent need to develop a continuous saponification and acidification reaction system that can precisely control micro-mixing effects, effectively prevent acidification scaling and clogging, and precisely control crystal growth, in order to meet the production requirements of high purity, high yield, and compliance with pharmaceutical manufacturing quality management standards. Summary of the Invention

[0006] This invention aims to at least solve one of the technical problems existing in the prior art. To this end, this invention proposes a continuous saponification-acidification reaction method for bile acid production, comprising the following steps:

[0007] The viscosity of the raw material liquid containing bile acid precursor is adjusted to obtain a homogeneous raw material liquid. The homogeneous raw material liquid and the alkaline solution are continuously injected at a set equivalent ratio and hydrolyzed to obtain a saponification completed liquid.

[0008] The saponification solution is cooled and diluted to obtain an acidification solution with a temperature lower than the boiling point of the acidification reaction and exhibiting shear-thinning characteristics.

[0009] Acid is continuously injected into the solution to be acidified along the flow direction through multiple acid injection points to gradually reduce its pH value. The acid is then dispersed by high-shear mixing downstream of each acid injection point to obtain an acidified slurry flow that resists wall adhesion.

[0010] The acidified slurry stream is introduced into a low-shear flow field and its residence time is controlled for aging to obtain a mature crystal slurry.

[0011] The mature crystal slurry is subjected to solid-liquid separation to obtain wet cholic acid, and the flow rate of the acid solution is adjusted based on the detection signal obtained at the solid-liquid separation point.

[0012] This application also discloses a continuous saponification-acidification reaction system for bile acid production, comprising:

[0013] The saponification liquid processing module is used to adjust the viscosity of the raw material liquid containing bile acid precursor to obtain a homogeneous raw material liquid. The homogeneous raw material liquid and alkali solution are continuously injected at a set equivalent ratio and hydrolyzed to obtain the saponification completed liquid.

[0014] The acidified liquid treatment module is used to cool and dilute the saponified liquid to obtain an acidified liquid with a temperature lower than the boiling point of the acidification reaction and exhibiting shear-thinning characteristics.

[0015] The acidified slurry flow treatment module is used to continuously inject acid into the liquid to be acidified along the flow direction through multiple acid injection points to gradually reduce its pH value, and to perform high-shear mixing on the acid downstream of each acid injection point to disperse it, thereby obtaining an acidified slurry flow that resists wall adhesion.

[0016] A mature crystal slurry processing module is used to introduce the acidified slurry stream into a low-shear flow field and control its residence time for aging to obtain a mature crystal slurry.

[0017] The adjustment module is used to perform solid-liquid separation on the mature crystal slurry to obtain wet cholic acid, and to adjust the flow rate and residence time of the acid solution based on the detection signal obtained at the solid-liquid separation point.

[0018] Compared with the prior art, the beneficial effects of the present invention are:

[0019] This invention first solves the problem of pipe wall scaling and clogging that easily occurs in continuous production of high-viscosity solid-liquid phase change systems, and improves the inherent safety of the process. Through a synergistic mechanism of rheological control and high-shear self-cleaning, the acidifying liquid is modulated into a shear-thinned fluid using online dilution. Combined with a low-viscosity slip layer induced on the wall surface by a high-shear mixer, online self-cleaning of the reactor inner wall is achieved using fluid shear stress, thus enabling long-term continuous operation under conditions with a solid content of over 30%. Simultaneously, an enthalpy removal step is introduced before acidification, forcibly lowering the reaction liquid temperature below the acidification boiling point, reserving space for neutralization heat capacity. This physically reduces the safety hazards of acid boiling and splashing, and the precise thermal integration and series reactor design eliminate the energy waste from repeated heating and cooling.

[0020] Secondly, this invention overcomes the limitations of micro-mixing in traditional acid precipitation processes, effectively suppressing side reactions and improving product purity. Addressing the issues of bile acid degradation, color darkening, and impurity co-precipitation caused by localized over-acidity during acidification, a strategy combining a gradient pH path and micro-mixing is employed. By injecting the total acid in stages and controlling the acid dispersion scale at the molecular level (millisecond level), the micro-mixing time is reduced to less than the nucleation induction time, fundamentally eliminating hotspots with extremely high localized supersaturation. This mechanism ensures that the reaction system remains in a mild chemical environment, effectively preventing impurity formation caused by localized over-acidity, thus improving the purity of the bile acid product and maintaining it at a stable high level.

[0021] Finally, this invention achieves precise engineering control of crystal particle size and full-process adaptive closed-loop control, significantly reducing downstream separation load and ensuring batch consistency. By establishing a crystal cultivation mechanism that decouples nucleation and growth and switches between strong and weak flow fields, the initial nucleation density is limited, providing sufficient mass transfer driving force for subsequent Ostwald ripening. This induces the dissolution and recrystallization of fine crystal nuclei onto the surface of large particles, thereby obtaining a mature crystal slurry with an extremely narrow particle size distribution. This solves the separation difficulties and mother liquor entrainment losses caused by small crystals in traditional processes. Simultaneously, a control architecture combining feedforward and feedback is constructed to address raw material viscosity fluctuations and component drift. Front-end viscosity-temperature decoupling eliminates transport errors, while back-end product indicators are used to correct front-end control parameters, ensuring that the system can automatically lock the reaction endpoint even under complex raw material changes. Attached Figure Description

[0022] Figure 1 This is a flowchart of the overall process of a continuous saponification-acidification reaction system.

[0023] Figure 2 This is a schematic diagram of the gradient pH control and micro-mixing mechanism in the acidification reaction unit;

[0024] Figure 3 This is a flowchart illustrating the connection and control process of the reaction system equipment.

[0025] Figure 4 This is a logic diagram of the graded reaction stage and the high-shear anti-scaling mechanism;

[0026] Figure 5 A schematic diagram of the modular structure of a continuous saponification-acidification reaction system for bile acid production;

[0027] Figure 6 A flowchart illustrating the steps of a continuous saponification-acidification reaction method for the production of bile acids. Detailed Implementation

[0028] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0029] Example 1:

[0030] like Figure 6 As shown, this invention proposes a continuous saponification-acidification reaction method for the production of bile acids, comprising the following steps:

[0031] The viscosity of the raw material liquid containing cholic acid precursor is adjusted to obtain a homogeneous raw material liquid. The homogeneous raw material liquid and alkali solution are continuously injected at a set equivalent ratio and hydrolyzed to obtain a saponified liquid.

[0032] The saponification solution is cooled and diluted to obtain an acidification solution with a temperature lower than the boiling point of the acidification reaction and exhibiting shear-thinning characteristics.

[0033] The acid solution to be acidified is continuously injected into multiple acid injection points along the flow direction to gradually reduce its pH value. The acid solution is then dispersed by high-shear mixing downstream of each acid injection point to obtain an acidified slurry flow that resists wall adhesion.

[0034] The acidified slurry flow is introduced into a low-shear flow field and its residence time is controlled for aging to obtain mature crystal slurry.

[0035] The mature crystal slurry is subjected to solid-liquid separation to obtain wet cholic acid, and the flow rate of the acid solution or the residence time of the aging is adjusted based on the detection signal obtained at the solid-liquid separation point.

[0036] More specifically, S1, the raw material liquid containing cholic acid precursor is sent to the pretreatment unit for heating or viscosity adjustment to obtain a homogeneous raw material liquid with stable flowability; the homogeneous raw material liquid and the alkali solution are continuously injected into the reaction system through a metering circuit equipped with a flow meter and a regulating valve, and the ratio is controlled according to the set saponification equivalent ratio to maintain the flow ratio of the alkali solution and the homogeneous raw material liquid within a preset range.

[0037] S2. The homogenized raw material solution and the alkali solution are introduced into the saponification reaction unit and subjected to continuous hydrolysis reaction under a set temperature and pressure. The nominal residence time of the saponification section is determined by the ratio of the effective volume of the saponification reaction unit to the total flow rate. A first process parameter is detected online at the outlet of the saponification reaction unit. The first process parameter includes at least one or more of pH, conductivity, viscosity, and near-infrared spectral data. When the first process parameter meets the preset fluctuation threshold within a continuous sampling period, the saponification completed solution is output.

[0038] S3. The completed saponification liquid is sent to the intermediate control unit, and the completed saponification liquid is diluted or heat exchanged online based on the first process parameters to adjust the solid content and temperature and obtain the acidification liquid.

[0039] S4. The acid solution to be acidified is continuously introduced into the acidification reaction unit, and the acid solution is injected into the coupling area of ​​the acidification reaction unit at multiple points; a high-shear mixer is set downstream of each acid injection point for micro-mixing, so that the acid solution is dispersed in the acid solution to be acidified within milliseconds and forms an acidification slurry flow that resists wall adhesion.

[0040] S5. The acidified slurry flow is introduced into the crystal growth unit and continuously aged under a low shear flow field. By controlling the residence time distribution of the acidified slurry flow in the crystal growth unit, a mature crystal slurry is obtained.

[0041] S6. The mature crystal slurry is continuously fed into the separation unit for solid-liquid separation to obtain wet cholic acid; the second process parameters are acquired online at the inlet of the acidification reaction unit and the separation unit; when the second process parameters deviate from the preset target range, the acid flow rate, the segmented acid addition ratio, or the residence time of the crystal cultivation unit are compensated and adjusted.

[0042] The step of feeding the feed solution containing cholic acid precursor into the pretreatment unit for heating or viscosity adjustment to obtain a homogeneous feed solution with stable flowability includes the following sub-steps:

[0043] S11: Install a flow stabilizing buffer tank or pulsation damper before the metering circuit to reduce pumping pulsation and filter out solid particles.

[0044] As shown in the figure As shown in the preprocessing unit on the left, this step is illustrated in the figure. The multi-level synergistic control architecture shown overcomes engineering challenges such as large viscosity fluctuations in animal bile paste raw materials (e.g., 2000–8000 centipoise (cP), numerous impurities, easy entrainment of air bubbles, and pulsation interference), ensuring the stability and stoichiometric accuracy of the continuous production process.

[0045] As shown in the figure The raw material tank shown is the core equipment for the steady-flow pretreatment. Steady-flow on the suction side is achieved by configuring a low-speed anchor-type agitator inside the raw material tank. The rotational speed of this agitator is set to... This design not only prevents the cholecystokinin from settling and stratifying, but also utilizes the tank volume to buffer transient flow fluctuations caused by upstream unloading, maintaining... The liquid level range, to ensure the diagram The feed pump connected downstream of the raw material tank has a stable suction head to prevent pump cavitation or unstable suction. The physical filtration stage uses a standard... The purpose of the dual basket filter is to intercept particles larger than [a certain size]. The hard particles prevent downstream heat exchangers and metering equipment from getting stuck, blocked, or deposited, and when the pressure difference reaches a preset threshold, such as... The system automatically switches to a backup filter cartridge for cleaning. A pneumatic pulsation damper is vertically installed on the high-pressure side of the feed pump outlet to eliminate pulsation on the discharge side. The pre-charge nitrogen pressure is set to the average working pressure at the pump outlet. of By utilizing the compression and rebound effect of the airbag to smooth out peaks and valleys, the pressure fluctuations of the fluid in the pipeline are controlled within a certain range. Within the fluctuation range.

[0046] S12: The raw material liquid containing bile acid precursor is continuously transported to the pretreatment unit, and a closed-loop control system is formed by an online viscosity detection device and a heat exchanger; when the detected viscosity is higher than a preset threshold, the temperature is increased, and when the detected viscosity is lower than the preset threshold, the temperature is decreased, so as to obtain the homogeneous raw material liquid with constant flow.

[0047] The viscosity threshold range is determined as follows: Shear rate-viscosity curves are measured for different batches of raw materials within a predetermined temperature range. The overlapping range that simultaneously meets the allowable inlet viscosity of the metering pump, the allowable pressure drop of the heat exchanger, and the subsequent acid dispersion requirements is determined as the target delivery and mixing viscosity range. In this embodiment, this range can be set to 50–100 centipoise (cP) at 40–50 °C. (See figure) As shown in the pretreatment unit, this conditioning process is achieved through a heat exchanger and a downstream online viscometer, as illustrated in the figure. The middle label is The dynamic closed-loop feedback loop is achieved through the equipment. The online rotational viscometer is installed at the outlet straight pipe section of the heat exchanger, and the length of this straight pipe section is... Double the pipe diameter, and with The system communicates in real time. When the detected viscosity exceeds the upper limit, such as during a cold start in winter or under high solids content conditions, Enlarged image The heat medium in the heat exchanger is The valve opening for saturated steam raises the material from room temperature to [temperature value missing]. To reduce viscosity to a set range; when viscosity is below the lower limit, such as in high-temperature summer conditions, Reduce the opening of the heat transfer fluid valve or switch to a normal temperature cooling water circuit to prevent excessively low viscosity from causing internal leakage of the metering pump or runaway reaction. Simultaneously, set... An over-temperature alarm prevents raw material deterioration. This adjustment eliminates environmental and batch variations, outputting a homogeneous raw material solution with constant rheological properties.

[0048] S13: The mass flow rate signals of the homogenized raw material liquid and the alkali solution are collected by a mass flow meter. The control system adjusts the opening of the regulating valve based on the deviation between the measured mass flow rate and the set saponification equivalent ratio through a PID algorithm to realize the closed-loop control of the chemical metering ratio of the homogenized raw material liquid and the alkali solution.

[0049] like Figure 1As shown, mass flow meters are installed on both the raw material liquid pipeline and the alkali liquid pipeline, and the mass flow rate is measured using the Coriolis force principle. The DCS sets the real-time mass flow rate of the raw material liquid as the main variable and calculates the alkali liquid flow rate setpoint based on the preset saponification equivalent ratio. The saponification equivalent ratio is determined by the offline titration results of the bile acid precursor content in the raw material liquid and the stoichiometric relationship of the saponification reaction, for example, the molar ratio of sodium hydroxide (NaOH) to bile acid precursor is 1.2:1. The mass flow meter on the alkali liquid pipeline measures the actual alkali liquid flow rate, and the controller uses a PID algorithm to adjust the speed of the alkali liquid feed pump or the opening of the regulating valve. The proportional coefficient and integral time of the PID are tuned after obtaining the process gain and time constant through small-amplitude step tests near the design flow rate, and the tuning endpoint is defined as the absence of continuous oscillation of the ratio deviation and convergence within the allowable time.

[0050] The step of online detection of the first process parameters at the outlet of the saponification reaction unit includes the following sub-steps:

[0051] S21: The saponification reaction unit is a multi-stage series continuous stirred tank or a plug flow tubular reactor, so that the variance of the actual residence time distribution of the fluid micro-elements in the saponification reaction unit is less than a preset value.

[0052] The core of this step lies in constructing a reaction environment that approximates an ideal plug flow reactor (PFR) by connecting multiple reactors in series, in order to solve the problem of residence time distribution broadening in a single-stage continuous stirred-tank reactor (CSTR). (See figure) As shown in the saponification reaction unit, the hardware selected is... Series The group, namely "1# reactor", "2# reactor", and "3# reactor" marked in the diagram, has a single reactor effective volume set to [missing information]. The total effective volume of the system is Given that the system exhibits certain characteristics during saponification... High viscosity and significant non-Newtonian properties, configuration diagram of each stage of the reaction vessel. The heating jacket and double-layer combined agitator shown have a wall-mounted anchor impeller at the bottom to reduce wall stagnation, and an inclined blade turbine impeller at the top to enhance radial circulation. The agitator motor is driven by a frequency converter and its speed is controlled at [specific speed range]. To ensure that the stirring power density is maintained at To achieve uniform mixing throughout the reactor. The reactor spacing is as shown in the diagram. The overflow pipe shown is connected by gravity overflow, and the closed-loop control formed by the differential pressure level gauge and the pneumatic regulating valve keeps the liquid level stable and accurate within a certain range. This reduces shear degradation while utilizing liquid level differences to achieve unidirectional flow, thus mitigating the risks of interstage backflow and mixing. During process operation, Cascade control is used to precisely maintain the reaction temperature at And fluctuations are controlled within Within this range, the system pressure remains at Slight positive pressure. Set the total system flow rate to... Nominal stay time Locked to The number of reactor stages, total effective volume, and nominal residence time are determined based on the time required for complete saponification obtained from the feedstock hydrolysis kinetics test and the results of the tracer residence time distribution (RTD) test; the selection of parameters is based on the premise that the saponification rate at the final stage outlet reaches the preset quality standard and the proportion of short-circuit material does not exceed the allowable value.

[0053] S22: Collect time series data of the first process parameters and calculate the standard deviation based on the sliding time window algorithm; when the standard deviation is continuously lower than the set noise threshold and the duration is not less than the nominal residence time of the saponification stage, determine that the system has entered a steady state and trigger the output of the saponification completed liquid.

[0054] This step utilizes an online conductivity meter as a key indicator of the reaction extent, and combines statistical processing to eliminate noise and false steady-state misjudgments. In the final stage reactor... Figure 1 An online conductivity meter with temperature compensation is installed at the outlet of the "3# reactor" and is periodically calibrated using a 0.01 mol / L potassium chloride standard solution. The DCS collects data at a frequency of 1 Hz (once per second) to maintain a first-in-first-out (FIFO) data buffer. The algorithm first calculates the median and median absolute deviation (MAD) of the window data, removes outliers that deviate from the median by more than a preset multiple of MAD, and then calculates the arithmetic mean and standard deviation of the remaining data. The noise threshold is determined by collecting multiple baseline windows when the system is in a stable saponification state, taking the larger value between the upper limit of the baseline standard deviation and the instrument repeatability error; the mean change rate threshold is determined by conversion based on the allowable change in outlet saponification rate and the offline calibration relationship between conductivity and saponification rate. When the window standard deviation and mean change rate continuously meet the corresponding thresholds for a duration not less than the nominal residence time of the saponification section, the system is considered to have entered a steady state and the output is switched; if the criteria fail after switching, the material is switched back to reflux mode and an alarm is triggered.

[0055] The step of performing online dilution or heat exchange treatment on the saponification solution based on the first process parameters to adjust the solid content and temperature and obtain the solution to be acidified includes the following sub-steps:

[0056] S31: The saponification completed liquid is introduced into a flash cooler or heat exchanger to reduce the temperature of the saponification completed liquid to the set acidification initiation temperature; the acidification initiation temperature is 5-15°C lower than the boiling point of the acidification reaction.

[0057] As shown in the figure As shown in the intermediate control unit in the middle section, this step mainly utilizes the flash cooler or heat exchanger marked in the diagram to reduce the temperature of the material before acidification, reserving a temperature rise margin for the exothermic process of the subsequent acidification reaction. The subsequent acidification process is accompanied by significant exothermic reactions; when acid is added to the local mixing zone, it can easily cause localized temperature rises and flash evaporation, thereby increasing the risk of sudden boiling and gas-liquid entrainment splashing. Therefore, a heat exchange device is installed between the saponification unit and the acidification unit. A spiral plate heat exchanger suitable for medium and low pressure conditions or a wide-channel plate-shell heat exchanger suitable for high pressure and high solids content conditions is preferred. Its wide-channel design adapts to high-viscosity solids-containing systems while inhibiting material deposition and blockage. A bypass pipeline and online pressure drop monitoring instruments are also installed. When the pressure drop of the heat exchanger exceeds a set threshold, such as... It automatically switches to bypass mode to ensure continuous system operation. The system uses the heat exchanger outlet temperature as the primary controlled variable, simultaneously monitoring the inlet and outlet temperatures, and adjusting the refrigerant side via cascade regulation. The system implements closed-loop cooling control of the warm water flow rate; it also features temperature interlock protection, triggering an emergency refrigerant replenishment or system shutdown warning when the outlet temperature exceeds the safe range. The system sets the acidification initiation temperature to be lower than the boiling initiation temperature at the operating pressure. And combined with verified safety upper limit calibration, for example, set to This allows for sufficient temperature rise margin to accommodate the heat of reaction released after the acid is added, ensuring that the system temperature remains below the boiling point during acidification, reducing the risk of sudden boiling and improving the intrinsic safety level of the system.

[0058] S32: Based on the first process parameters or solid content detection value, inject dilution water or circulating acidification mother liquor in proportion to make the solid content lower than the critical delivery threshold, so as to obtain the acidified liquid with shear thinning characteristics.

[0059] After ensuring thermal safety through the enthalpy removal process, further rheological control is needed to address the challenges of conveying and mixing high-viscosity materials. While cooling resolves the thermal safety risks, the saponification liquid still maintains a high viscosity, exhibiting characteristics of a high-viscosity, paste-like pseudoplastic fluid, with a solid content reaching [missing information]. Direct transport will lead to increased pipeline pressure drop, a surge in pumping energy consumption, and exacerbate the risk of material retention and salt deposition on the pipeline walls. Therefore, as shown in the figure... As shown, the system is equipped with an online dilution module consisting of a water injection pump, an electromagnetic flow meter, a check valve, and a static mixer on the heat exchanger outlet pipeline.

[0060] The DCS system uses an online solids content analyzer as the main signal to calculate the basic dilution ratio, supplemented by an online viscometer signal as a correction signal for dynamic adjustment. The dilution medium is injected proportionally via a water pump: process soft water preheated to the upper limit of the acidification initiation temperature, such as 80°C, suitable for scenarios with high material purity requirements, or other treated materials... High-precision filtration and acidity control at It is also suitable for circulating acidification mother liquor in energy-saving and emission-reduction scenarios. (Materials are shown in the diagram.) The splitting and recombining structure of the static mixer generates a shearing effect, achieving rapid and uniform dilution within the pipeline and controlling the solid content of the system within the target delivery window, for example... This operation can significantly reduce the apparent viscosity and yield stress of the system, thereby enhancing its pseudoplastic characteristics, i.e., its rheological index. This not only reduces pipeline pressure drop and improves flow stability, but also provides a suitable rheological basis for the formation of a low-viscosity lubricating layer on the inner wall of the high-shear mixer in subsequent processes, ensuring the subsequent mixing effect.

[0061] The step of injecting acid into the coupling region of the acidification reaction unit at multiple points, and setting up a high-shear mixer downstream of each injection point for micro-mixing, includes the following sub-steps:

[0062] S41: Distribute the total acid amount to at least two acid injection points arranged along the flow direction, so that the pH value of the fluid in each mixing chamber decreases in a stepwise manner.

[0063] As shown in the figure The acidification reaction unit in the middle and its diagram As shown in the upper part of the macroscopic path, this step differs from the traditional single-point, one-time acid injection method. Instead, it employs a three-point distributed injection strategy to construct a smooth flow path. A downward path is used to avoid product degradation caused by localized over-acidity. Hardware-wise, three acid injection points are arranged along the flow direction of tubular reactors suitable for continuous mass production or multi-stage series reactors suitable for small-batch, high-precision control, as shown in Figure [Figure Number Missing]. "Acid injection point" "Acid injection point" "Acid injection point" "and diagram" Nodes in ,node and nodes A mixing section of appropriate length is set downstream of each acid injection point. The length of this section is determined based on the fluid velocity and viscosity, and is typically [length missing]. Double the pipe diameter to ensure sufficient acid dispersion and avoid local concentration accumulation. The system employs total acid quantity feedforward calculation and segmentation. A closed-loop control strategy based on the sum of feedback corrections: First, based on the feed flow rate and... The initial alkalinity is used to calculate the total acid volume. The initial distribution ratio at each acid injection point is determined by offline acid-base titration to determine the total acid consumption. The ratio is then selected based on the pH response, crystal size, and impurity entrainment results under different acid injection ratios. In this embodiment, 40% for the first stage, 35% for the second stage, and 25% for the third stage can be used as initial values, corrected by online pH feedback. Simultaneously, the downstream online pH of each section is monitored in real time. Value, when Deviation exceeds At that time, the acid volume at the corresponding acid injection point is finely adjusted to ensure... Gradient stability. The specific piecewise control logic is shown in the figure. As shown: The first-level acid injection point is the node. The pre-neutralization zone will contain the fluid. From the initial Control to This section is dominated by neutralization reactions, with a low risk of crystallization, and can accommodate higher acid injection rates; the second-stage acid injection point is the node. Nucleation control area will Further control to ,like Figure 2 As shown in the dashed box, this section is located within the metastable zone width (MSZW), which is a sensitive area for bile acid crystallization. By precisely controlling the acid injection rate and mixing intensity, the local instantaneous supersaturation peak is reduced, thus minimizing impurity entrainment caused by explosive nucleation. The third-level acid injection point is the node. The finish line adjustment area will Fine-tuning to the target endpoint, for example As shown in the figure The product enters the complete sedimentation zone as shown, to improve sedimentation completion and stabilize product purity. The above-mentioned stepwise... The descent strategy can significantly reduce the probability of localized over-acid regions, mitigate the risk of product degradation and discoloration under strong acid conditions, and optimize fluid shear thinning characteristics, providing a suitable rheological basis for subsequent micro-mixing and online self-cleaning steps.

[0064] S42: The high-shear mixer is set downstream of each acid injection point, so that the acid solution is dispersed to the molecular scale in milliseconds, making the micro-mixing time less than the nucleation induction time; and the shearing action generated by the high-speed fluid on the inner wall of the high-shear mixer cavity is used to peel off the attached crystal nuclei, thereby realizing the online self-cleaning of the high-shear mixer.

[0065] To reduce the restricted mass transfer and scaling tendency during the acidification process of high-viscosity slurries, as shown in the figure... The inline high-shear mixer shown in the figure The enlarged microscopic mechanism diagram in the lower half shows that in this step, the downstream distance of each acid injection point does not exceed [a certain value]. At a pipe diameter multiple, the stator-rotor gap is set to be... Intensive mixing is achieved using an inline high-shear mixer; combined with the preceding process... Step-modulated shear-thinning fluid characteristics, selecting appropriate rotational speed This makes the characteristic shear rate reach The scale ensures the mixing effect and fluid compatibility. Regarding the micro-mixing mechanism, such as... Figure 2 As shown in the flow field inside the mixer, the high-shear mixer rapidly disperses the injected red acid solution and significantly reduces the concentration gradient through a strong shear and stretching flow field, reducing the mixing scale to near the Kolmogorov scale, thereby shortening the micro-mixing time. ;when Controlled to be less than the nucleation induction time of the system At that time, this time is usually Furthermore, it can be determined through offline micro-titration experiments, which allows for an ideal precipitation path of mixing followed by nucleation, avoiding nucleus disorder caused by sudden changes in local supersaturation, thereby improving the uniformity of crystal size distribution. Regarding the online self-cleaning mechanism, as shown in the figure... The enlarged diagram on the right shows the anti-scaling mechanism of the wall, relying on the preceding gradient. The optimized shear-thinning fluid characteristics result in strong near-wall flow during high-shear mixer operation. According to the shear-thinning effect curve in the lower left corner, the apparent viscosity of the fluid decreases sharply with increasing shear rate, forming a low-viscosity liquid film slip layer at the equipment wall. This slip layer generates significant fluid wall shear stress. Its value Furthermore, it can be verified through fluid dynamics simulation and pulsating pressure; when When the effective adhesion strength of the crystal nuclei to the wall surface exceeds that determined by offline wall deposition experiments, as shown in the figure... As shown, the primary crystal nuclei on the wall are forcibly stripped and entrained into the main fluid along with the autogenous liquid. This mechanism can significantly reduce the wall deposition rate, enabling the device to operate at higher solid content levels. To maintain a low scaling tendency under normal operating conditions and reduce the frequency of downtime for cleaning. In addition, the system synchronously monitors the mixer operating current and pressure drop across upstream and downstream pipe sections. When the mixer is clean and the acidifying solution is being delivered at the rated flow rate, the system records the motor current reference value I0 and the pressure drop reference value ΔP0. The allowable current increment ΔIlim is determined based on the drive motor's allowable current, and the allowable pressure drop increment ΔPlim is determined based on the smaller of the remaining head of the delivery pump and the allowable working pressure difference of the mixer. I0+ΔIlim and ΔP0+ΔPlim are set as the current threshold and pressure drop threshold, respectively. When either measured value exceeds the corresponding threshold, a scaling tendency is identified, and a short-term online flush is automatically triggered. This flush uses process soft water preheated to the acidification initiation temperature, and the flushing pressure is [not specified]. Duration is If the parameters still do not meet the standards after rinsing, switch to bypass operation to ensure long-term stable and continuous operation of the system.

[0066] The step of introducing the acidified slurry stream into the crystal growing unit and continuously aging it under a low shear flow field includes the following sub-steps:

[0067] S51: The acidified slurry flow at the peak of nucleation is introduced into the crystal growing unit with low-speed stirring, so that the flow field is switched from high shear turbulence to laminar or weak turbulence.

[0068] As shown in the figure As shown in the crystal growth unit on the right, this step aims to reduce the shear and collision intensity of the crystal slurry after the nucleation stage, creating a stable environment for subsequent crystal maturation, which is beneficial for continuous crystal growth and reduces the risk of breakage and secondary nucleation. The hardware uses the diagram... The vertical crystal culture vessel shown is equipped with a large-diameter axial-flow low-shear agitator, preferably a three-bladed backward-curved hydrofoil, with the agitator diameter to vessel diameter ratio set as follows: And it is compatible with solid content, for example High solids content crystalline slurry; as shown in the figure As indicated in the label, a flow guide is installed inside the reactor to avoid strong radial shearing and form a stable axial circulating flow field, maximizing the reduction of shear intensity while ensuring crystal suspension and preventing sedimentation. The acidified crystal slurry from the nucleation section outlet is fed using a method selected based on its viscosity characteristics: low-viscosity crystal slurry, for example, with a viscosity less than... Bottom tangential feeding is used, while high-viscosity crystal slurry is fed axially from the bottom, with the feed rate controlled at [specific value missing]. To avoid disrupting the low-shear flow field inside the vessel, the stirring speed is adjusted by a frequency converter. In the low-speed range, combined with impeller parameters, the stirring power density is reduced to a minimum. Estimated average energy dissipation rate Composed of high-shear mixing segment The magnitude dropped to 1 On the order of magnitude. This flow field switching can significantly reduce the velocity gradient between the near-wall region and crystal particles, reducing the probability of crystal collision and breakage; at the same time, it suppresses local... To mitigate concentration fluctuations and prevent unexpected secondary nucleation caused by localized oversaturation peaks, this method provides a morphologically complete and quantitatively stable crystal substrate for subsequent Ostwald ripening.

[0069] S52: By controlling the residence time distribution of the acidified slurry flow in the crystal growth unit through structural design or remixing ratio, fine crystals are induced to dissolve and recrystallize on the surface of large crystals, so as to obtain the mature crystal slurry with narrow particle size distribution and easy filtration.

[0070] This step promotes the crystal aging process, including Ostwald ripening and grain rearrangement mechanisms, by precisely controlling residence time, circulation ratio, and a stable temperature and solubility environment. This optimizes crystal particle size distribution and morphology, and improves subsequent filtration performance. The crystal cultivation unit is selected based on production capacity requirements: for small-batch production, an Oslo-type crystallizer with an internal flow guide tube is used, which is conducive to the growth of large particles; for large-scale continuous production, a 3-4 stage series overflow stirred tank is used. Through flow guide tube separation and interstage overflow structure, a narrow residence time distribution approximating the ideal plug flow PFR is constructed. The dimensionless residence time distribution variance σθ² is controlled within 0.1, and the overall average residence time is set to 2-6 hours to meet the crystal aging and growth requirements. The DCS system constructs a multi-parameter closed-loop control loop: It uses feedback data from online turbidity meters and slurry density meters, combined with mother liquor solubility monitored by an online refractometer, and temperature sensor data, to estimate the crystallization load based on a preset multiple linear regression calibration model. This model takes online turbidity, slurry density, mother liquor refractive index, and temperature as inputs, and the mass of crystals per unit volume obtained by filtering, drying, and weighing synchronously sampled slurry as output. It employs a single-layer linear weighted architecture of y=b0+b1x1+b2x2+b3x3+b4x4. Calibration samples covering a predetermined operating range are used to fit coefficients b0 to b4 using the least squares method, and reserved samples are used to verify the estimation error. Recalibration is performed when the error exceeds a preset allowable value. By adjusting the speed of the propeller or internal circulation pump in the guide tube, the internal circulation ratio is controlled within the range of 3-8, and the supersaturation concentration difference, characterized by the difference between the actual and equilibrium solubility of bile acid per unit mass of mother liquor, is controlled within 0.05-0.15. The system maintains a stable thermodynamic environment (temperature fluctuation within ±0.5°C and solubility deviation less than 2%), using kg of cholic acid per kg of mother liquor. In this controlled system, based on the Gibbs-Thomson effect, thermodynamically unstable fine crystals (e.g., less than 5 μm in diameter) preferentially dissolve as solute due to their larger specific surface area and higher solubility. The solute migrates to and recrystallizes onto the surface of thermodynamically stable larger crystals (e.g., greater than 20 μm in diameter), achieving a process of grain selection. This aging process narrows the crystal size distribution span (d90-d10) / d50 from over 2.5 to below 1.8, reducing the proportion of fine crystals to less than 5%. Ultimately, the average particle size of the product is controlled to 50-100 μm, significantly improving crystal morphology regularity and reducing the filter cake specific impedance by more than 30%. This adapts the system to subsequent plate and frame filtration or centrifugal filtration processes, improving filtration rate and filter cake moisture content. The step of acquiring second process parameters online at the inlet of the acidification reaction unit or the separation unit; and adjusting the acid flow rate, the segmented acid addition ratio, or the residence time of the crystal cultivation unit when the second process parameters deviate from the preset target range includes the following sub-steps:

[0071] S61: The mature crystal slurry is continuously fed into a centrifuge or filter for solid-liquid separation to obtain the wet cholic acid; and an online detection point is set at the outlet of the acidification reaction unit or the inlet of the separation unit to obtain the second process parameters.

[0072] As shown in the figure As shown in the rightmost separation and feedback unit, this step is the core detection link for building closed-loop control, aiming to acquire terminal quality parameters and process feedback signals through the sensor array shown in the figure. First, the mature crystal slurry obtained from the crystal ripening process is continuously transported to the solid-liquid separation unit via a variable frequency screw pump. For continuous production conditions, the method shown in the figure is preferred. The adaptable solids content shown A horizontal spiral sedimentation centrifuge is used for crystal slurry production, while a plate and frame filter press with automatic plate pulling and pressing functions is used for intermittent production to ensure separation efficiency and operational continuity. To achieve accurate feedback, the system sets detection points at both the separation inlet and the mother liquor outlet to avoid single-point distortion. Specifically, before the separation inlet... A crystal slurry pretreatment device for removing large particulate impurities is installed at the pipe diameter section, and is equipped with the corresponding installation diagram. Wear-resistant and anti-adhesion online sensor array The electrode is equipped with an automatic flushing device that activates every hour and a daily calibration mechanism, serving as the core criterion for closed-loop control of the acidification endpoint. Simultaneously, a focused beam reflection measurement (FBRM) instrument or an online laser particle size analyzer is installed in the separation inlet pipeline to monitor the chord-length distribution (CLD) and fine grains (i.e., particles smaller than a certain size). The counting ratio is adjusted to ensure that the target fine crystal ratio is less than [a certain percentage]. and Particle size maintained at The range. Furthermore, a Coriolis mass flow meter or differential pressure density meter adapted to high-viscosity crystalline slurry is used to obtain the target... The changes in slurry density and solid content are used to compensate for fluctuations in raw material concentration. Finally, a measurement range is set at the outlet of the separated mother liquor. Online conductivity meter or refractive index range An online refractometer, combined with an offline calibrated linear regression model, was used to estimate the concentrations of soluble salts and residual bile salts in the mother liquor, and the target residual concentration was determined to be less than [a certain value]. The degree of precipitation completion and the risk of solute loss.

[0073] S62: When the second process parameter deviates from the set target range, a cascade control strategy is adopted and at least two of the following are dynamically adjusted according to priority: total acid flow rate, segmented acid addition ratio, and residence time of the crystal culture unit.

[0074] like Figure 1 The control loop connection shown by the dashed line at the bottom. This step employs a multivariable coordinated closed-loop control strategy, preferably model predictive control (MPC) or hierarchical cascade control, to address the regulation challenges caused by multi-parameter coupling and process lag. (Figure) In The controller will transmit the data acquired by the sensor array in real time to, including, and grain fineness ratio and mother liquor conductivity and solid content The parameters are compared with the preset target range. Once the parameters deviate from the target and exceed the range, the error will be recorded. and grain fineness ratio The control dead zone is defined, meaning dynamic compensation is performed according to a preset priority. Simultaneously, adjustment limits and rate-of-change constraints are set, and a first-order hysteresis filter is used in conjunction with process hysteresis characteristics to avoid oscillations. The control logic first executes the first priority, i.e., stoichiometric correction. A value deviating from the target range, such as being too high, indicates insufficient acid content. gradient The total acid flow rate in the control process is used as the main manipulated variable. A second-level execution response is achieved by adjusting the metering pump speed, and the response is based on the system residence time. Set points time With filter parameters Stepwise regression. Next, the second priority step, crystal morphology correction, is performed. Normal, but the proportion of fine grains is increased or Particle size is lower than the target value. Adjusting the gradient The proportion of acid added in stages during the control process is within the specified range. Within the range, the peak value of local supersaturation is reduced, while the high-shear mixer speed of the micro-mixing process is adjusted accordingly, i.e., the speed is reduced when the proportion of fine grains increases. When the particle size is too large, the adjustment is increased. Finally, the third priority step, deep maturation correction, is performed. If the particle size index still does not meet the standard, the total feed rate is adjusted. Adjust the effective liquid level of the incubator within the specified range or via a level control valve to change the residence time from the baseline. extend And simultaneously link the outlet temperature of the heat exchange process The acid injection rate is adjusted to maintain thermal safety.

[0075] S63: When the second process parameter exceeds the safety limit or shows a drift trend, the bypass buffer or reflux recovery mode is triggered, and the main line is switched back to continuous production after the steady state is restored.

[0076] This step establishes a system safety barrier and self-healing mechanism to address abnormal operating conditions that conventional compensation cannot eliminate and to ensure continuous production stability. When a key parameter is detected to exceed the alarm limit... or And the proportion of fine grains is greater than And the conductivity of the mother liquor is greater than And continue The above, or trend analysis showing a deviation rate exceeding or When the fine grain ratio is / min, The emergency response mode is automatically triggered. The system immediately switches the three-way valve at the inlet of the separation unit to introduce the substandard crystal slurry into the capacity-adapted system. A bypass buffer tank with a maximum throughput of twice that of the mains, and at a rate not exceeding the feed rate from the upstream section. The preset proportion of reflux is returned to the buffer section before the inlet of the acidification unit, and the upper limit of the reflux flow rate is set. With the rate of change constraint Simultaneously, the acidification unit's dilution module replenishes process soft water according to the reflux solids content and dilutes it to the required solids content. The following measures are taken to avoid impacting upstream operating conditions. During bypass operation, the system automatically initiates online cleaning. Program, using and pressure The process soft water is used to treat the separation unit and detection electrodes for a certain period of time. The rinsing process is carried out simultaneously, while the bypass buffer tank utilizes a low-shear agitator and temperature control device to... The preset formula automatically adjusts for acid or water replenishment. It maintains this adjustment once key parameters return to the target range. back, Execute three-way valve position gradual change rate And retain after switching A stable and smooth switchback to restore the mainline to continuous production mode, if the switchback occurs... If the internal parameters deviate from the alarm limit again, the system will automatically switch back to bypass and trigger an audible and visual alarm, awaiting manual intervention.

[0077] The rheological properties of the acidified liquid are controlled to match the micro-mixing and self-cleaning of the high-shear mixer: the dilution ratio is adjusted to make the acidified liquid exhibit shear-thinning characteristics; and the shear rate of the high-shear mixer is set to reduce the apparent viscosity of the acidified liquid, so that a low-viscosity liquid film slip layer is formed on the inner wall of the mixer.

[0078] This step, based on the principles of non-Newtonian fluid mechanics, establishes a matching relationship between the rheological properties of the liquid to be acidified and key parameters of a high-shear mixer, including rotational speed, clearance, and flow rate. The aim is to reduce the tendency of traditional acidification reactors to foul due to wall adhesion. The implementation process includes three key steps: rheological parameter control, shear condition setting, and the formation of a near-wall lubricating flow layer.

[0079] First, the target rheological window of the acidified liquid needs to be established. During the online dilution and cooling process, the DCS control adjusts the injection ratio of dilution water based on real-time feedback of estimated online density or solid content and online viscosity signals. This ensures that the obtained acidified liquid exhibits significant pseudoplastic fluid characteristics, i.e., its rheological index... Preferred control at The following and more preferred Within this rheological range, the apparent viscosity of the fluid is no longer constant, but decreases significantly with increasing shear rate according to a power law. This property provides the material basis for achieving high-intensity mixing with low energy consumption, ensuring that the fluid maintains appropriate viscosity to preserve suspension stability under low-shear conditions during pipeline transport, while its apparent viscosity rapidly decreases upon entering the high-shear mixing region, thereby improving mixing and mass transfer efficiency.

[0080] To trigger the shear-thinning effect of the fluid, the system sets the rotational speed of the inline high-shear mixer. Clearance between stator and rotor This causes the characteristic shear rate to be generated. Press Estimate and in, for example The target range. Under the condition that the power-law model can describe it, as... Increased apparent viscosity is caused by the deconstruction and orientation of the internal structure of the material. A decrease occurred.

[0081] The system control target is set to a high shear rate in the core operating region of the mixer. This reduces the apparent viscosity of the fluid. Reduce to its initial state at the completion of saponification or its low-shear state during pipeline transport. Lower viscosity of to When the initial viscosity of the saponification solution is At that time, the effective viscosity within the mixing chamber is reduced to [a certain value] through high shear action. This in-situ low-viscosity effect allows acid-base reactions to proceed in a low-viscosity environment close to that of an aqueous fluid, significantly reducing mass transfer resistance and improving micro-mixing uniformity, thus facilitating the stable progress of the acidification reaction.

[0082] Based on the above rheological matching, this invention utilizes the rheological response of the fluid at the wall to construct an anti-fouling mechanism. In the high-shear mixer, near the inner wall of the cavity and the stator surface, due to the high shear rate, a near-wall lubricating flow layer with low apparent viscosity is formed, the thickness of which is related to the rotational speed, solid content, temperature, and wall roughness.

[0083] This lubricating layer reduces the effective retention time of the crystal nucleus and the wall surface, thereby reducing the probability of stable deposition of the crystal nucleus on the wall surface. Simultaneously, the near-wall scouring effect generated by high shear produces enormous tangential shear stress. .when When the effective adhesion strength exceeds that of the primary deposit, the primary crystal nuclei on the wall can be forcibly detached and reintroduced into the main fluid to continue growing, thereby reducing the scale formation rate. Through this synergistic mechanism of "rheological regulation + high-shear near-wall flushing," the dependence on external scale inhibitors can be significantly reduced, and the frequency of downtime cleaning can be decreased, thus supporting the long-term stable and continuous operation of the acidification reaction unit. The specific logic of the staged reaction phase and high-shear scale prevention is as follows: Figure 4 As shown.

[0084] A combined regulation strategy of gradient pH path control and Ostwald ripening induction is adopted: the supersaturation is kept in the metastable region by controlling the pH drop at each acid injection point to limit the nucleation density; and the average residence time of the crystal growth unit is set based on the nucleation density to obtain a mature crystal slurry with a narrow particle size distribution.

[0085] This step describes a cross-unit crystal engineering control strategy to establish a synergistic control relationship between the acidification nucleation stage and the aging growth stage. The core idea of ​​this strategy is to restrict nucleation and enhance growth; that is, by reducing the nucleus number density characterization index at the front end to reduce nucleation intensity, a higher solute supply per unit crystal is provided for the subsequent crystal growth, thereby directionally controlling the final grain size distribution. The implementation process includes three key steps: nucleation intensity control based on supersaturation peak constraints, aging residence time matching based on nucleation intensity characterization indexes, and aging condition control to promote solute redeposition to large crystals.

[0086] Gradient in the acidification reaction unit The control path establishes control logic aimed at reducing nucleation intensity. The DCS control is based on the width of the metastable region of the bile acid system determined through offline crystallization experiments under conditions consistent with actual production. Data, precisely setting acid injection points at each level Decrease In practice, the acid injection points of the first and second stages are controlled. This allows the reaction system to be determined by temperature and The peak supersaturation value was estimated by combining signals such as the mother liquor's conductivity or refractive index with a solubility model. Try to stay within the metastable region. This control prevents nucleation from entering unstable nucleation regions. This control favors heterogeneous nucleation or lower-rate homogeneous nucleation, thereby reducing the characterization index of initial nucleus density, i.e., online nucleation. The monitored fine crystal count rate or short string segment count ratio is kept within a preset range. This operation avoids explosive nucleation that would lead to a significant increase in the proportion of fine crystals, providing an excellent precursor basis for subsequent few-nucleus growth.

[0087] Having established a low nucleation intensity, a matching growth cycle must be provided for these limited nuclei. This invention establishes the average residence time of the aging unit. A dynamic matching rule between the nucleation intensity characterization index and the solute supply. The matching logic is that when the nucleation intensity is low, the single crystal can obtain a higher solute supply. The system can set, for example... A longer average residence time is used to promote crystal growth from the nascent size to the target grain size. DCS control is based on online... The monitored fine grains, for example, have a chord length less than The count rate and its trend are used as indicators of nucleation intensity, and the liquid level or total feed flow rate of the nucleation unit are adjusted within allowable ranges accordingly to correct for nucleation. The adjustment range and rate of change are limited, and a control dead zone and holding time criterion are set, meaning that adjustment is only made when the fine crystal count rate continuously exceeds the threshold for a certain period of time, in order to avoid disturbance amplification and system oscillation. This matching mechanism prevents the particle size from being too small due to insufficient aging, and also avoids the tendency of re-nucleation induced by excessive aging under local supersaturation fluctuations.

[0088] Through the synergy of the two aforementioned stages, the system successfully constructed a thermodynamic environment conducive to crystal aging mechanisms, including Ostwald ripening and selective dissolution-recrystallization. Within the crystal growing unit, due to controlled nucleation intensity, the supply of supersaturated solute per unit crystal surface area is relatively increased. Under certain solubility conditions, according to the Gibbs-Thomson effect, small crystallites can undergo selective dissolution and redeposit onto the surface of larger crystals. When the nucleation intensity is low, the supersaturated solute flux generated by dissolution... It can more effectively diffuse and deposit onto the surface of a controlled number of dominant crystal nuclei, avoiding the limitation of average growth rate caused by an excessive number of crystal nuclei. This resource concentration effect causes the particle size distribution to tend to shift towards larger particle sizes and then narrow under set operating conditions, with its average particle size... Adjustable to a preset target range, for example This significantly improves the efficiency of subsequent solid-liquid separation.

[0089] Example 2:

[0090] See Figure 5 A continuous saponification-acidification reaction system for bile acid production, comprising:

[0091] The saponification liquid processing module is used to adjust the viscosity of the raw material liquid containing bile acid precursor to obtain a homogeneous raw material liquid. The homogeneous raw material liquid and alkali solution are continuously injected at a set equivalent ratio and hydrolyzed to obtain the saponification completed liquid.

[0092] The acidified liquid treatment module is used to cool and dilute the saponified liquid to obtain an acidified liquid with a temperature lower than the boiling point of the acidification reaction and exhibiting shear-thinning characteristics.

[0093] The acidified slurry flow treatment module is used to continuously inject acid into the liquid to be acidified along the flow direction through multiple acid injection points to gradually reduce its pH value, and to perform high-shear mixing of the acid downstream of each acid injection point to disperse it, thereby obtaining an acidified slurry flow that resists wall adhesion.

[0094] The mature crystal slurry processing module is used to introduce the acidified slurry flow into a low-shear flow field and control its residence time for aging to obtain mature crystal slurry.

[0095] The adjustment module is used to perform solid-liquid separation on the mature crystal slurry to obtain wet cholic acid, and to adjust the flow rate of the acid solution or the residence time of the aging process based on the detection signal obtained at the solid-liquid separation point.

[0096] In addition, the parts of the technical solutions provided in the embodiments of this application that are consistent with the implementation principles of the corresponding technical solutions in the prior art have not been described in detail, so as to avoid excessive elaboration.

[0097] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above descriptions are merely specific embodiments of the present invention and are not intended to limit the invention. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

[0098] The preset parameters or preset thresholds mentioned above are all set by those skilled in the art based on actual conditions or obtained through large-scale data simulation.

[0099] The above embodiments are only used to illustrate the technical methods of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical methods of the present invention without departing from the spirit and scope of the technical methods of the present invention.

Claims

1. A continuous saponification-acidification reaction method for the production of bile acids, characterized in that, Includes the following steps: The viscosity of the raw material liquid containing bile acid precursor is adjusted to obtain a homogeneous raw material liquid. The homogeneous raw material liquid and the alkaline solution are continuously injected at a set equivalent ratio and hydrolyzed to obtain a saponification completed liquid. The saponification solution is cooled and diluted to obtain an acidification solution with a temperature lower than the boiling point of the acidification reaction and exhibiting shear-thinning characteristics. Acid is continuously injected into the solution to be acidified along the flow direction through multiple acid injection points to gradually reduce its pH value. The acid is then dispersed by high-shear mixing downstream of each acid injection point to obtain an acidified slurry flow that resists wall adhesion. The acidified slurry stream is introduced into a low-shear flow field and its residence time is controlled for aging to obtain a mature crystal slurry. The mature crystal slurry is subjected to solid-liquid separation to obtain wet cholic acid, and the flow rate of the acid solution is adjusted based on the detection signal obtained at the solid-liquid separation point.

2. The continuous saponification-acidification reaction method for bile acid production according to claim 1, characterized in that, The process of adjusting the viscosity of the raw material liquid containing bile acid precursor to obtain a homogeneous raw material liquid includes: continuously conveying the raw material liquid and controlling it in a closed loop through online viscosity detection and heat exchange; raising the temperature when the detected viscosity is higher than a set threshold and lowering the temperature when it is lower than the set threshold to obtain the homogeneous raw material liquid with constant flowability.

3. The continuous saponification-acidification reaction method for bile acid production according to claim 1, characterized in that, The homogenized raw material solution and the alkali solution are continuously injected at a set equivalent ratio, including: collecting the mass flow rates of the homogenized raw material solution and the alkali solution respectively, and adjusting the opening of the feed valve according to the deviation between the measured mass flow rate and the set equivalent ratio.

4. The continuous saponification-acidification reaction method for bile acid production according to claim 1, characterized in that, The process of obtaining a saponified liquid by hydrolysis includes: carrying out the hydrolysis reaction in a multi-stage reactor connected in series; detecting process parameters online at the outlet of the final reactor; determining that a steady state has been reached when the fluctuation of the process parameters in continuous sampling is continuously lower than a set threshold; and outputting the saponified liquid.

5. The continuous saponification-acidification reaction method for bile acid production according to claim 1, characterized in that, The process of cooling and diluting the completed saponification liquid to obtain the acidification liquid includes: cooling the completed saponification liquid to a set temperature below the boiling point of the acidification reaction through heat exchange, and injecting dilution water or circulating acidification mother liquor in proportion according to the solid content of the completed saponification liquid, so that the solid content is reduced to below the set delivery threshold to obtain the acidification liquid.

6. The continuous saponification-acidification reaction method for bile acid production according to claim 1, characterized in that, The acid solution to be acidified is continuously injected into multiple acid injection points, and the acid solution is mixed with high shear downstream of each acid injection point. This includes: distributing the total amount of acid to at least two acid injection points arranged along the flow direction, so that the pH value of the acid solution to be acidified decreases stepwise along the flow direction; mixing the acid solution with high shear downstream of each acid injection point, so that the acid solution is dispersed to the molecular scale within milliseconds and the micro-mixing time is less than the nucleation induction time, and the shearing action of the high shear fluid on the inner wall of the mixing chamber is used to peel off the attached crystal nuclei to achieve online self-cleaning.

7. The continuous saponification-acidification reaction method for bile acid production according to claim 1, characterized in that, The acidified slurry flow is introduced into a low-shear flow field and its residence time is controlled for aging, including: switching the acidified slurry flow from a high-shear flow field to a laminar or weakly turbulent flow field, and controlling the residence time distribution of the acidified slurry flow to induce the dissolution of fine crystals and recrystallization on the surface of large crystals, so as to obtain the mature crystal slurry with a narrower particle size distribution.

8. The continuous saponification-acidification reaction method for bile acid production according to claim 1, characterized in that, By controlling the pH decrease at each acid injection point, the supersaturation of the acidification system is kept in the metastable region to limit the nucleation density; and the aging residence time is set based on the nucleation density to obtain the mature crystal slurry with a narrower particle size distribution.

9. The continuous saponification-acidification reaction method for bile acid production according to claim 1, characterized in that, Feedback adjustment is performed on the detection signal obtained from the solid-liquid separation point, including: when the detection signal deviates from the set range, using cascade control to dynamically adjust at least two of the following according to priority: acid flow rate, segmented acid addition ratio, and aging residence time; when the detection signal exceeds the safety limit or drift occurs, bypass buffering or reflux recovery is triggered, and continuous production is switched back after the steady state is restored.

10. A continuous saponification-acidification reaction system for the production of bile acid, characterized in that, include The saponification liquid processing module is used to adjust the viscosity of the raw material liquid containing bile acid precursor to obtain a homogeneous raw material liquid. The homogeneous raw material liquid and alkali solution are continuously injected at a set equivalent ratio and hydrolyzed to obtain the saponification completed liquid. The acidified liquid treatment module is used to cool and dilute the saponified liquid to obtain an acidified liquid with a temperature lower than the boiling point of the acidification reaction and exhibiting shear-thinning characteristics. The acidified slurry flow treatment module is used to continuously inject acid into the liquid to be acidified along the flow direction through multiple acid injection points to gradually reduce its pH value, and to perform high-shear mixing on the acid downstream of each acid injection point to disperse it, thereby obtaining an acidified slurry flow that resists wall adhesion. A mature crystal slurry processing module is used to introduce the acidified slurry stream into a low-shear flow field and control its residence time for aging to obtain a mature crystal slurry. The adjustment module is used to perform solid-liquid separation on the mature crystal slurry to obtain wet cholic acid, and to adjust the flow rate and residence time of the acid solution based on the detection signal obtained at the solid-liquid separation point.

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