Preparation method of ammonia water for improving survival rate of medical biological fermentation flora

Abstract

The invention relates to the technical field of ammonia water preparation, in particular to a preparation method of ammonia water for improving the survival rate of medical and biological fermentation flora, which comprises the following steps: purging inert gas from an inert gas inlet to a pipeline of an exhaust port of an absorption tower and the inside of the absorption tower; when it is judged that the risk that purging does not reach the standard exists according to the purging stability characterization value, whether purging reaches the standard or not is judged for the second time according to the oxygen concentration decreasing rate; when it is judged that purging does not reach the standard according to the purging stability characterization value, an optimization strategy is determined according to the flow resistance abnormity characterization value of the inert gas; after it is judged that purging meets the preset standard, the pretreated ultrapure water and high-purity liquid ammonia are conveyed into an absorption tower to be subjected to an absorption reaction, and crude ammonia water is obtained; and adjusting the crude ammonia water to a preset concentration, filtering, sterilizing and storing to obtain the ammonia water for improving the survival rate of the medical biological fermentation flora. According to the invention, the preparation efficiency of the ammonia water for improving the survival rate of the medical biological zymophyte flora is improved.

Description

Technical Field

[0001] This invention relates to the field of ammonia preparation technology, and in particular to a method for preparing ammonia for improving the survival rate of fermentation microorganisms in pharmaceuticals and biotechnology. Background Technology

[0002] The industrial production process of ammonia water is relatively mature, and its core focus is usually on the mixing efficiency of ammonia and water, the removal of reaction heat, and the precise control of the final concentration. In these processes, inert gas purging is recognized and used as a routine operation, but its main purpose is limited to safe replacement before equipment startup or specific maintenance. The control methods for such purging operations are often extensive and experience-based, typically using fixed time and flow parameters or reaching a broad safe oxygen concentration threshold as the endpoint. This "one-time pass" purging approach has a serious disconnect between its quality control objectives and the biochemical properties of the final ammonia water product. It cannot quantitatively assess and guarantee that the oxygen content within the entire reaction system, especially in pipe dead zones and deep within containers, is uniformly and stably replaced to an extremely low level completely harmless to microbial life activities. Therefore, even if the chemical purity of ammonia water prepared by existing methods meets the standards, when it is applied to highly sensitive pharmaceutical bio-fermentation processes, the trace dissolved oxygen it may carry and the dynamic oxygen infiltration caused by environmental fluctuations can easily cause oxidative stress and toxic inhibition to anaerobic or microaerophilic fermentation communities, resulting in a decrease in the survival rate of the community and becoming a bottleneck in the production of high-end bioproducts.

[0003] Chinese Patent Application Publication No. CN105478023A discloses an ammonia water preparation system with high production efficiency, safety, and the ability to produce ammonia water of various concentrations. The system includes an ammonia water preparer; the ammonia water preparer includes a static mixer for mixing incoming ammonia and process water to form ammonia water; the process water inlet of the static mixer is connected to the process water supply source via a frequency converter pump; the ammonia source inlet of the ammonia water preparer is connected to the ammonia supply source via an emergency shut-off valve; a pressure monitor is also included for monitoring the pressure in the static mixer; and a controller is also included, with the pressure monitor, frequency converter pump, and emergency shut-off valve all connected to the controller. This system can be used with ammonia sources of various quality grades and water qualities when preparing industrial ammonia water. Furthermore, the device can produce electronic-grade ammonia water and industrial ammonia water of various concentrations below 35% according to user needs. The system also has advantages such as high heat exchange efficiency and anti-scaling properties.

[0004] It can be seen that the above technical solution does not take into account the purging before feeding, which affects the impurity and dissolved oxygen content of the ammonia water and damages the biocompatibility of the ammonia water, thus resulting in poor ammonia water preparation efficiency. Summary of the Invention

[0005] Therefore, the present invention provides a method for preparing ammonia water to improve the survival rate of fermentation microorganisms in pharmaceuticals and biotechnology, thereby overcoming the problem in the prior art that considering purging before feeding affects the impurity and dissolved oxygen content of the prepared ammonia water, impairs the biocompatibility of the ammonia water, and thus leads to poor ammonia water preparation efficiency.

[0006] To achieve the above objectives, the present invention provides a method for preparing ammonia water for improving the survival rate of fermentation microorganisms in pharmaceutical and biological products, comprising: Inert gas is used to purge the pipeline from the inert gas inlet to the exhaust port of the absorption tower and the inside of the absorption tower at a preset purging flow rate and preset gas supply pressure. After the first preset purging time, the oxygen content concentration at the top exhaust port of the absorption tower, the highest point of the pipeline, and the farthest end of the pipeline is collected to obtain the purging stability characterization value. When it is determined that there is a risk of purging not meeting the preset standard based on the purging stability characterization value, the purging is further determined based on the oxygen concentration decrease rate at the farthest end of the pipeline within the second preset time period to determine whether the purging meets the preset standard. When the purging does not meet the preset standard based on the purging stability characterization value, the optimization strategy for the purging not meeting the preset standard is determined based on the abnormal flow resistance characterization value of the inert gas. The optimization strategy is to issue a blockage alarm, issue a leakage alarm, or increase the preset gas supply pressure. After determining that the purging meets the preset standards, the pretreated ultrapure water and high-purity liquid ammonia are respectively sent to the absorption tower for absorption reaction to obtain crude ammonia water. The crude ammonia water is adjusted to a preset concentration, filtered, sterilized, and then stored to obtain ammonia water for improving the survival rate of fermentation bacteria in pharmaceutical and biological products.

[0007] Furthermore, the pretreatment process of the ultrapure water involves passing the ultrapure water through a filter with a pore size smaller than a preset pore size for sterilization filtration. The pretreatment process of the high-purity liquid ammonia involves passing the high-purity liquid ammonia through a purifier containing an adsorbent to remove trace amounts of moisture and metallic impurities.

[0008] Furthermore, the process of determining whether purging meets the preset standards based on the purging stability characterization values ​​includes: The purge stability characterization value is compared with the first preset purge stability characterization value and the second preset purge stability characterization value, respectively; If the purge stability characterization value is less than the first preset purge stability characterization value, then the purge is determined to meet the preset standard; If the purge stability characterization value is greater than or equal to the first preset purge stability characterization value and less than the second preset purge stability characterization value, it is determined that there is a risk that the purge does not meet the preset standard, and the purge is further determined based on the oxygen concentration decrease rate at the farthest end of the pipeline within the second preset time period to determine whether the purge meets the preset standard. If the purge stability characterization value is greater than or equal to the second preset purge stability characterization value, it is determined that the purge does not meet the preset standard, and an optimization strategy is determined based on the abnormal flow resistance characterization value of the inert gas when the purge does not meet the preset standard.

[0009] Furthermore, the process of obtaining the purge stability characterization value includes: The pipeline from the inert gas inlet to the exhaust port of the absorption tower and the interior of the absorption tower are purged with inert gas. After purging for a first preset time, the oxygen concentration at the top exhaust port of the absorption tower is collected and recorded as the first oxygen concentration; the oxygen concentration at the highest point of the pipeline is collected and recorded as the second oxygen concentration; the oxygen concentration at the farthest end of the pipeline is collected and recorded as the third oxygen concentration. Calculate the standard deviations of the first oxygen concentration, the second oxygen concentration, and the third oxygen concentration; Calculate the arithmetic mean of the first oxygen concentration, the second oxygen concentration, and the third oxygen concentration; The ratio of the standard deviation to the arithmetic mean is denoted as the purge stability characterization value.

[0010] Furthermore, when it is determined for the second time that the purging does not meet the preset standard based on the comparison result that the oxygen concentration decrease rate at the farthest end of the pipeline within the second preset time period is less than the preset oxygen concentration decrease rate, the preset purging flow rate is increased based on the difference between the oxygen concentration decrease rate and the preset oxygen concentration decrease rate. The oxygen concentration decrease rate is the rate of change of the oxygen concentration at the farthest end of the pipeline over time within a second preset time period.

[0011] Furthermore, several adjustment methods are provided for increasing the preset purge flow rate, and each adjustment method increases the preset purge flow rate by a different amount.

[0012] Furthermore, the process of determining the optimization strategy when purging does not meet the preset standard based on the abnormal flow resistance characterization value of the inert gas includes: The abnormal flow resistance characterization value is compared with the preset abnormal flow resistance characterization value; If the abnormal flow resistance value is less than the preset abnormal flow resistance value, then the first optimization strategy is adopted; If the abnormal flow resistance value is greater than or equal to the preset abnormal flow resistance value, then a second optimization strategy is adopted, wherein the second optimization strategy is to issue a blockage alarm.

[0013] Furthermore, the process of obtaining the anomaly characterization value of the flow resistance includes: The real-time intake pressure and real-time intake flow rate of the inert gas at the inert gas inlet are obtained respectively. The ratio of the real-time intake pressure to the real-time intake flow rate is recorded as the flow resistance anomaly characterization value.

[0014] Furthermore, the first optimization strategy includes: Obtain the real-time inlet pressure of the inert gas at the inert gas inlet; The real-time intake pressure is compared with the preset intake pressure; If the real-time intake pressure is less than the preset intake pressure, the preset intake pressure is increased according to the difference between the preset intake pressure and the real-time intake pressure. If the real-time intake pressure is greater than or equal to the preset intake pressure, a leak alarm will be activated.

[0015] Furthermore, the increase in the preset air supply pressure is positively correlated with the intake pressure deviation value, wherein the intake pressure deviation value is the difference between the preset intake pressure and the real-time intake pressure.

[0016] Compared with existing technologies, the beneficial effects of this invention are as follows: by purging the production environment before the synthesis reaction begins, and ensuring purging quality through multi-level intelligent judgment, this invention systematically and proactively eliminates the risk of introducing dissolved oxygen and impurities that may be toxic to pharmaceutical fermentation bacteria, which may be carried by traditional ammonia water. This lays a fundamental foundation for the subsequent steps to prepare ammonia water products with high biocompatibility. By setting preliminary judgments of purging stability characterization values, secondary judgments of oxygen concentration decrease rates, and optimized adjustments of flow resistance anomaly characterization values, the entire purging process is transformed from an open-loop operation that relies on experience and fixed time into a closed-loop quality control process with sensing, judgment, and adaptive capabilities, thereby improving the final ammonia water preparation efficiency.

[0017] Furthermore, this invention uses a three-level judgment based on the purging stability characterization value. By introducing two preset thresholds, the purging results are precisely classified into three states: compliant, critically risky, and non-compliant, achieving a refined assessment of purging quality. The introduction of a secondary judgment mechanism for the critically risky state reflects the prudence and fault tolerance of the method. For the non-compliant state, the method directly enters the optimization adjustment, reflecting the timeliness of the method, thereby improving the reliability of the judgment.

[0018] Furthermore, this invention defines the purging stability characterization value as being obtained based on oxygen concentration data at three key locations: the exhaust port at the top of the absorption tower, the highest point of the pipeline, and the farthest point. Selecting these three monitoring points can comprehensively reflect the purging status of different spatial locations within the ammonia preparation system, especially the most difficult-to-replace dead zone areas. The purging stability characterization value not only focuses on whether the oxygen content is low, but also on whether it fluctuates, thereby improving the accuracy of judging the intrinsic state of the purging quality.

[0019] Furthermore, this invention achieves dynamic optimization of the purging process by adjusting the preset purging flow rate when the secondary judgment fails to meet the standard. When the system is in a critical risk state and the trend is unfavorable, it indicates that the existing purging intensity is insufficient to improve the situation. At this time, the purging flow rate is automatically increased. This feedback adjustment based on real-time monitoring data enables the purging process to automatically respond to small changes in system resistance or insufficient initial parameter settings, thereby enhancing the adaptive capability of the method.

[0020] Furthermore, this invention uses the comparison results between the abnormal flow resistance characterization value and the preset value to trigger the first optimization strategy or the second optimization strategy respectively, thereby effectively distinguishing between the two completely different fault modes of blockage and leakage. This provides a key decision-making basis for taking completely different and correct countermeasures, thus improving fault handling from blind investigation to precise diagnosis. Attached Figure Description

[0021] Figure 1 This is a flowchart of a method for preparing ammonia water to improve the survival rate of fermentation microorganisms in pharmaceuticals and biological products, according to an embodiment of the present invention. Figure 2 This is a flowchart illustrating how the purging process determines whether it meets a preset standard based on the purging stability characterization value, according to an embodiment of the present invention. Figure 3 This is a flowchart of an embodiment of the present invention for determining whether the purging meets the preset standard based on the oxygen concentration decrease rate at the farthest end of the pipeline within a second preset time period; Figure 4 This is a flowchart illustrating the optimization strategy for determining when purging does not meet preset standards in an embodiment of the present invention. Detailed Implementation

[0022] To make the objectives and advantages of the present invention clearer, the present invention will be further described below with reference to embodiments; it should be understood that the specific embodiments described herein are merely for explaining the present invention and are not intended to limit the present invention.

[0023] Preferred embodiments of the present invention will now be described with reference to the accompanying drawings. Those skilled in the art should understand that these embodiments are merely illustrative of the technical principles of the present invention and are not intended to limit the scope of protection of the present invention.

[0024] It should be noted that the data in this embodiment are all derived from a comprehensive analysis and evaluation of historical test data and corresponding historical test results from the three months prior to this test. Those skilled in the art will understand that the method described in this invention can determine the above-mentioned parameters in the following ways: selecting the value with the highest proportion based on the data distribution as the preset standard parameter; using weighted summation to obtain the value as the preset standard parameter; substituting each historical data point into a specific formula and using the value obtained by that formula as the preset standard parameter; or other selection methods, as long as the method described in this invention can clearly define different specific situations in the single-item judgment process through the obtained values.

[0025] Please see Figure 1 , Figure 2 , Figure 3 as well as Figure 4 The flowcharts shown are as follows: a method for preparing ammonia water to improve the survival rate of fermentation microorganisms in pharmaceuticals according to an embodiment of the present invention; a flowchart for determining whether purging meets a preset standard based on the purging stability characterization value according to an embodiment of the present invention; a flowchart for determining whether purging meets a preset standard a second time based on the oxygen concentration decrease rate at the farthest end of the pipeline within a second preset time period according to an embodiment of the present invention; and a flowchart for determining the optimization strategy when purging does not meet the preset standard according to an embodiment of the present invention.

[0026] This invention provides a method for preparing ammonia water to improve the survival rate of fermentation microorganisms in pharmaceuticals and biotechnology, comprising: Step S1: High-purity nitrogen (purity ≥99.999%) is used as an inert gas to purge the pipeline from the inert gas inlet to the exhaust port of the absorption tower and the inside of the absorption tower at a preset purging flow rate of 25 L / min and a preset supply pressure of 0.4 MPa. After the first preset purging time of 5 min, the oxygen content concentration at the top exhaust port of the absorption tower, the highest point of the pipeline, and the farthest end of the pipeline is collected to obtain the purging stability characterization value. Step S2: When it is determined that there is a risk that the purging does not meet the preset standard based on the purging stability characterization value, the purging is further determined based on the oxygen concentration decrease rate at the farthest end of the pipeline within the second preset time period of 30 seconds. Step S3: When the purging does not meet the preset standard according to the purging stability characterization value, the optimization strategy for the purging does not meet the preset standard is determined according to the abnormal flow resistance characterization value of the inert gas. The optimization strategy is to issue a blockage alarm, issue a leakage alarm, or increase the preset gas supply pressure. Step S4: After determining that the purging meets the preset standard, the pretreated ultrapure water is sprayed into the top of the absorption tower (spray flow rate 50L / h), and the pretreated high-purity liquid ammonia is introduced into the bottom air inlet of the absorption tower (air inlet flow rate 10L / h). The gas and liquid react in countercurrent contact within the packing layer. The temperature inside the absorption tower is controlled at 25℃ and the pressure is controlled at 0.15MPa. The crude ammonia water generated by the reaction is discharged from the bottom outlet of the absorption tower to obtain crude ammonia water. Step S5: Add pretreated ultrapure water to the crude ammonia water to adjust to a preset concentration of 8wt%. After the concentration adjustment is completed, the ammonia water is sequentially filtered through a precision filter (0.22μm, filtration pressure 0.15MPa) to remove minute impurities, and then sterilized by an ultraviolet sterilizer (power 30W, flow rate 5L / min, sterilization time 30s). The sterilized ammonia water is then transported to a stainless steel storage tank and sealed with high-purity nitrogen (the nitrogen pressure in the storage tank is maintained at 0.05MPa) to obtain ammonia water for improving the survival rate of fermentation bacteria in pharmaceutical and biological products.

[0027] It should be noted that the data in this embodiment are all results obtained through preliminary experiments before this test using the method described in this invention. Each preset value can be adjusted according to the specific application, as long as the method described in this invention can clearly define different specific situations in the single-item judgment process through the acquired values. The preset values ​​set in this embodiment are all obtained from preliminary experiments, including the correction coefficients, which were also selected through experimental verification.

[0028] In this embodiment, the packed absorption tower has a diameter of 500 mm and a height of 5000 mm. The tower is filled with polypropylene stepped ring packing, and the packing layer height is 3000 mm.

[0029] Specifically, the farthest point of the pipeline is the location where the airflow along the purging airflow direction is most difficult to reach and where the displacement resistance is greatest. In a typical linear pipeline layout, this point is the point physically furthest from the inert gas inlet; for pipelines with branches or complex structures, this point is the end of the branch with the greatest flow resistance or a dead angle where air pockets are easily formed.

[0030] Specifically, the pretreatment process of the ultrapure water involves passing the ultrapure water through a polyethersulfone filter cartridge with a pore size smaller than the preset pore size of 0.22 micrometers for sterilization filtration. The filtration pressure is controlled at 0.2 MPa and the filtration flow rate is 50 L / h, ensuring that the number of bacteria in the ultrapure water after filtration is less than or equal to 1 CFU / mL. The pretreatment process of the high-purity liquid ammonia involves passing the high-purity liquid ammonia through a purifier containing molecular sieves and activated alumina adsorbent to remove trace amounts of moisture and metallic impurities.

[0031] Specifically, the process of determining whether purging meets the preset standards based on the purging stability characterization value includes: The purge stability characterization value is compared with the first preset purge stability characterization value of 0.10 and the second preset purge stability characterization value of 0.30, respectively. If the purge stability characterization value is less than the first preset purge stability characterization value, then the purge is determined to meet the preset standard; If the purge stability characterization value is greater than or equal to the first preset purge stability characterization value and less than the second preset purge stability characterization value, it is determined that there is a risk that the purge does not meet the preset standard, and the purge is further determined based on the oxygen concentration decrease rate at the farthest end of the pipeline within the second preset time period to determine whether the purge meets the preset standard. If the purge stability characterization value is greater than or equal to the second preset purge stability characterization value, it is determined that the purge does not meet the preset standard, and an optimization strategy is determined based on the abnormal flow resistance characterization value of the inert gas when the purge does not meet the preset standard.

[0032] Specifically, the first preset purging stability characterization value ranges from [0.05, 0.15], and the second preset purging stability characterization value ranges from [0.20, 0.40]. Preferably, the first preset purging stability characterization value is 0.10, and the second preset purging stability characterization value is 0.30.

[0033] Specifically, the purging stability characterization value quantifies the relative uniformity and stability of the oxygen concentration distribution within the system after purging. The smaller the purging stability characterization value, the more consistent and stable the cleanliness of the entire system is, from the most difficult-to-replace dead corner to the exhaust port. When the purging stability characterization value is less than the first threshold, it indicates that high homogeneity has been achieved, which can be judged as excellent and passed directly. When the purging stability characterization value is between the first and second thresholds, it indicates that there is a potential risk to uniformity. A secondary judgment is made by monitoring the oxygen concentration change rate at the farthest end of the pipeline, which realizes adaptive control and avoids misjudgment and waste. When the purging stability characterization value is greater than or equal to the second threshold, it indicates that there is serious non-uniformity, which may be accompanied by abnormalities such as blockage or leakage. The problem is accurately located and optimization strategies are triggered based on the abnormal flow resistance characterization value.

[0034] Specifically, the process of obtaining the purge stability characterization value includes: The pipeline from the inert gas inlet to the exhaust port of the absorption tower and the interior of the absorption tower are purged with inert gas. After purging for a first preset time of 5 minutes, the oxygen concentration at the top exhaust port of the absorption tower is collected using an oxygen analyzer and recorded as the first oxygen concentration; the oxygen concentration at the highest point of the pipeline is collected and recorded as the second oxygen concentration; the oxygen concentration at the farthest end of the pipeline is collected and recorded as the third oxygen concentration. Calculate the standard deviations of the first oxygen concentration, the second oxygen concentration, and the third oxygen concentration; Calculate the arithmetic mean of the first oxygen concentration, the second oxygen concentration, and the third oxygen concentration; The ratio of the standard deviation to the arithmetic mean is denoted as the purge stability characterization value.

[0035] Specifically, the purging process is further determined based on the rate of decrease in oxygen concentration at the farthest end of the pipeline within a second preset time period to determine whether the purging meets a preset standard. If the oxygen concentration decrease rate is less than the preset oxygen concentration decrease rate of 1.0 ppm / min, it is determined that the purging does not meet the preset standard, and the preset purging flow rate is increased according to the difference between the oxygen concentration decrease rate and the preset oxygen concentration decrease rate. If the oxygen concentration decrease rate is greater than or equal to the preset oxygen concentration decrease rate, the purging is deemed to meet the preset standard.

[0036] Specifically, the process of obtaining the oxygen concentration decrease rate includes: At the start time t1 of the second preset duration Δt, the oxygen concentration value C3(t1) is recorded, and at the end time t2, the oxygen concentration value C3(t2) is recorded. The absolute value of the rate of change within the second preset time period is calculated using the formula P=[|C3(t2)-C3(t1)|] / Δt. The result P is the rate of decrease in oxygen concentration. The higher the oxygen concentration decrease rate, the faster the oxygen concentration at the farthest point decreases, and the purging is still actively effective. If the oxygen concentration decrease rate P is extremely small or close to zero, the replacement at the farthest point of the pipeline has stopped. In this embodiment, the preset oxygen concentration decrease rate is 1.0 ppm / min.

[0037] Specifically, if the oxygen concentration decrease rate calculated within the second preset time period is greater than or equal to the preset value, it indicates that the concentration decrease rate at the farthest point is faster than the preset minimum requirement, the purging power is sufficient, and the system determines that it meets the preset standard; if the value is less than the preset value, it indicates that the concentration decrease rate is slower than or equal to the preset requirement, the purging may not meet the standard under the specified conditions, the system determines that it does not meet the preset standard, and the flow optimization program is started.

[0038] Specifically, several adjustment methods are provided for increasing the preset purge flow rate, among which, If the difference in oxygen concentration is less than the first preset difference in oxygen concentration of 0.2 ppm / min, then the preset purging flow rate is increased to the corresponding value using the first adjustment coefficient of 1.04. If the difference in oxygen concentration is greater than or equal to the first preset difference in oxygen concentration and less than the second preset difference in oxygen concentration of 0.6 ppm / min, then the preset purging flow rate is increased to the corresponding value using the second adjustment coefficient of 1.08. If the difference in oxygen concentration is greater than or equal to the second preset difference in oxygen concentration, then the preset purging flow rate is increased to the corresponding value using the third adjustment coefficient of 1.12. The difference in oxygen concentration is the difference between the rate of decrease in oxygen concentration and the preset rate of decrease in oxygen concentration.

[0039] Specifically, the process of determining the optimization strategy when purging does not meet the preset standard based on the abnormal flow resistance characterization value of the inert gas includes: The abnormal flow resistance value is compared with the preset abnormal flow resistance value of 0.016 MPa·min / L; If the abnormal flow resistance value is less than the preset abnormal flow resistance value, then the first optimization strategy is adopted; If the abnormal flow resistance value is greater than or equal to the preset abnormal flow resistance value, then a second optimization strategy is adopted, wherein the second optimization strategy is to issue a blockage alarm.

[0040] Specifically, the abnormal flow resistance value indicates the magnitude of the flow resistance of the inert gas in the entire flow path. The larger the value of the abnormal flow resistance value, the more serious the problem of poor airflow caused by blockage or local narrowing inside the pipeline or absorption tower. The smaller the value of the abnormal flow resistance value, the smaller the flow resistance and the smoother the airflow.

[0041] Specifically, the preset abnormal flow resistance value can be flexibly adjusted by those skilled in the art based on the pipeline diameter, length, structural complexity (such as whether there are branches or dead angles), and inert gas supply process parameters. The higher the sensitivity requirement for blockage warning, the smaller the preset abnormal flow resistance value should be. Preferably, the preset abnormal flow resistance value can be in the range of [0.012, 0.020], with the unit being MPa·min / L. In this embodiment, the preferred value is 0.016 MPa·min / L.

[0042] Specifically, after determining that the purging is unqualified based on the purging stability characterization value, the cause of the fault is determined by comparing the abnormal flow resistance characterization value with the preset flow resistance characterization value. When the abnormal flow resistance characterization value is greater than or equal to the preset value, the blockage of the pipeline or absorption tower will cause the airflow velocity to decrease and the flow to be uneven. It will be inevitable that the oxygen content in dead corners such as the farthest end of the pipeline will not meet the standard. At this time, the blockage alarm can be issued to accurately target the root cause of the flow obstruction. When the abnormal flow resistance characterization value is less than the preset value, there is no obvious obstruction in the airflow path. The excessive oxygen content is more likely caused by insufficient airflow power or leakage. In this case, real-time air intake pressure is introduced for differentiation.

[0043] Specifically, the process of obtaining the anomaly characterization value of the flow resistance includes: A pressure transmitter and a flow meter are installed on the main pipeline of the inert gas inlet; The pressure transmitter measures and outputs the real-time inlet pressure of the inert gas at the inert gas inlet. The flow meter measures and outputs the real-time inlet flow rate of the inert gas at the inert gas inlet. The ratio of the real-time intake pressure to the real-time intake flow rate is recorded as the flow resistance anomaly characterization value.

[0044] Specifically, the first optimization strategy includes: The real-time inlet pressure of the inert gas at the inert gas inlet is obtained using a pressure transmitter. The real-time intake pressure is compared with the preset intake pressure of 0.4 MPa; If the real-time intake pressure is less than the preset intake pressure, the preset intake pressure is increased according to the difference between the preset intake pressure and the real-time intake pressure. If the real-time intake pressure is greater than or equal to the preset intake pressure, a leak alarm will be activated.

[0045] Specifically, the increase in the preset air supply pressure is positively correlated with the intake pressure deviation value, where the intake pressure deviation value is the difference between the preset intake pressure and the real-time intake pressure. The positive correlation can be linear or nonlinear. The linear slope of the linear positive correlation is not specifically limited. For example, if the increase in the preset air supply pressure is set to ΔV and the intake pressure deviation value is set to ΔΦ, then ΔV = α × ΔΦ, where α is the rate adjustment coefficient. If α = 1.06, it can be understood that the larger the intake pressure deviation value, the larger the increase in the preset air supply pressure.

[0046] Specifically, when purging is deemed unqualified based on stable purging characteristics, but normal flow resistance (unobstructed airflow path) is determined based on abnormal flow resistance characteristics, there are only two possible core causes: First, insufficient inert gas replacement power, i.e., the real-time inlet pressure is lower than the preset inlet pressure. In this case, the inert gas cannot form sufficient airflow intensity and coverage, and the air in the dead corners of the pipeline cannot be effectively replaced, resulting in the detection of high residual oxygen content. Second, inert gas leakage, i.e., the real-time inlet pressure is greater than or equal to the preset inlet pressure. In this case, the gas supply power is sufficient, but gas is lost, and the inert gas used for replacement cannot form effective retention and circulation during the purging process, which will also result in the oxygen content not being able to drop to the qualified level. This strategy accurately distinguishes between the causes of insufficient power and leakage by comparing the real-time inlet pressure with the preset inlet pressure.

[0047] Control Experiment 1: Performance Verification of Ammonia Products on the Survival Rate of Fermentation Microorganisms in Pharmaceuticals The ammonia solution in the experimental group was prepared strictly according to the method described in the embodiments of this invention, ensuring that the purging process met the standards through intelligent judgment, and using the prescribed ultrapure water, high-purity liquid ammonia, and post-treatment process, with a final ammonia concentration of 8 wt%. Control group ammonia water: without the intelligent judgment purging described in this invention (only simple purging with fixed duration and flow rate or no targeted purging at all), ordinary deionized water and industrial-grade liquid ammonia from the same source but without the precise purification treatment described in this invention were reacted in the same absorption tower and adjusted to the same concentration (8wt%), and then subjected to conventional filtration and sterilization. Fermentation strain: Bifidobacterium adolescentis was selected. Before the experiment, the preserved strain was continuously activated for two generations to ensure that it was in the logarithmic growth phase and had consistent activity. Basic fermentation medium (g / L): peptone 10.0, beef extract 10.0, yeast extract 5.0, glucose 20.0, dipotassium hydrogen phosphate 2.0, sodium acetate 5.0, ammonia water 2.0, magnesium sulfate 0.1, manganese sulfate 0.05, Tween-80, 1.0 mL added per liter of medium.

[0048] An experimental group (using a culture medium containing ammonia water of the present invention) and a control group (using a culture medium containing conventional ammonia water) were set up. The activated Bifidobacterium adolescentis seed liquid was inoculated into a fermenter containing 2L of culture medium at an inoculation amount of 5% (v / v).

[0049] The temperature was 37±0.2℃; the pH was maintained at 6.2±0.1 by automatic addition of sterile acid / alkali solution; the stirring speed was 100 rpm; high-purity nitrogen was introduced to maintain a slight positive pressure at the top of the tank and to maintain an anaerobic environment throughout the process (the dissolved oxygen (DO) probe reading in the fermentation broth was always below 0.1% air saturation); the total cultivation time was 72 hours.

[0050] Table 1. Results of Fermentation Performance Comparison Experiment

[0051] The comparative experimental data above clearly show that during the later stages of fermentation, from 24h to 48h (as shown in the table), the viable cell count in the experimental group using the ammonia water of this invention was higher than that in the control group, especially during the stationary phase (48h), where the survival rate increased by 133%. This indicates that the ammonia water of this invention can effectively reduce oxidative stress and impurity toxicity, and greatly delay the death of the cells. The maximum cell concentration, specific growth rate, and yield of major metabolites (lactic acid and acetic acid) in the experimental group were all increased, indicating that the overall growth activity and metabolic intensity of the bacterial community in the experimental group were superior to those in the control group.

[0052] The technical solution of the present invention has been described above with reference to the preferred embodiments shown in the accompanying drawings. However, it will be readily understood by those skilled in the art that the scope of protection of the present invention is obviously not limited to these specific embodiments. Without departing from the principles of the present invention, those skilled in the art can make equivalent changes or substitutions to the relevant technical features, and the technical solutions after these changes or substitutions will all fall within the scope of protection of the present invention.

Claims

1. A method for preparing ammonia water for improving the survival rate of fermentation microorganisms in pharmaceuticals and biotechnology, characterized in that, include: Inert gas is used to purge the pipeline from the inert gas inlet to the exhaust port of the absorption tower and the inside of the absorption tower at a preset purging flow rate and preset gas supply pressure. After the first preset purging time, the oxygen content concentration at the top exhaust port of the absorption tower, the highest point of the pipeline, and the farthest end of the pipeline is collected to obtain the purging stability characterization value. When it is determined that there is a risk of purging not meeting the preset standard based on the purging stability characterization value, the purging is further determined based on the oxygen concentration decrease rate at the farthest end of the pipeline within the second preset time period to determine whether the purging meets the preset standard. When the purging does not meet the preset standard based on the purging stability characterization value, the optimization strategy for the purging not meeting the preset standard is determined based on the abnormal flow resistance characterization value of the inert gas. The optimization strategy is to issue a blockage alarm, issue a leakage alarm, or increase the preset gas supply pressure. After determining that the purging meets the preset standards, the pretreated ultrapure water and high-purity liquid ammonia are respectively sent to the absorption tower for absorption reaction to obtain crude ammonia water. The crude ammonia water is adjusted to a preset concentration, filtered, sterilized, and then stored to obtain ammonia water for improving the survival rate of fermentation bacteria in pharmaceutical and biological products.

2. The method for preparing ammonia water for improving the survival rate of fermentation microorganisms in pharmaceuticals and biotechnology according to claim 1, characterized in that, The pretreatment process of the ultrapure water involves passing the ultrapure water through a filter with a pore size smaller than a preset pore size for sterilization filtration. The pretreatment process of the high-purity liquid ammonia involves passing the high-purity liquid ammonia through a purifier containing an adsorbent to remove trace amounts of moisture and metallic impurities.

3. The method for preparing ammonia water for improving the survival rate of pharmaceutical and biological fermentation microorganisms according to claim 1, characterized in that, The process of determining whether purging meets the preset standard based on the purging stability characterization value includes: The purge stability characterization value is compared with the first preset purge stability characterization value and the second preset purge stability characterization value, respectively; If the purge stability characterization value is less than the first preset purge stability characterization value, then the purge is determined to meet the preset standard; If the purge stability characterization value is greater than or equal to the first preset purge stability characterization value and less than the second preset purge stability characterization value, it is determined that there is a risk that the purge does not meet the preset standard, and the purge is further determined based on the oxygen concentration decrease rate at the farthest end of the pipeline within the second preset time period to determine whether the purge meets the preset standard. If the purge stability characterization value is greater than or equal to the second preset purge stability characterization value, it is determined that the purge does not meet the preset standard, and an optimization strategy is determined based on the abnormal flow resistance characterization value of the inert gas when the purge does not meet the preset standard.

4. The method for preparing ammonia water for improving the survival rate of pharmaceutical and biological fermentation microorganisms according to claim 3, characterized in that, The process of obtaining the purge stability characterization value includes: The pipeline from the inert gas inlet to the exhaust port of the absorption tower and the interior of the absorption tower are purged with inert gas. After purging for a first preset time, the oxygen concentration at the top exhaust port of the absorption tower is collected and recorded as the first oxygen concentration; the oxygen concentration at the highest point of the pipeline is collected and recorded as the second oxygen concentration; the oxygen concentration at the farthest end of the pipeline is collected and recorded as the third oxygen concentration. Calculate the standard deviations of the first oxygen concentration, the second oxygen concentration, and the third oxygen concentration; Calculate the arithmetic mean of the first oxygen concentration, the second oxygen concentration, and the third oxygen concentration; The ratio of the standard deviation to the arithmetic mean is denoted as the purge stability characterization value.

5. The method for preparing ammonia water for improving the survival rate of fermentation microorganisms in pharmaceuticals and biotechnology according to claim 4, characterized in that, If, based on the comparison result that the oxygen concentration decrease rate at the farthest end of the pipeline within the second preset time period is less than the preset oxygen concentration decrease rate, it is determined for the second time that the purging does not meet the preset standard, the preset purging flow rate is increased according to the difference between the oxygen concentration decrease rate and the preset oxygen concentration decrease rate. The oxygen concentration decrease rate is the rate of change of the oxygen concentration at the farthest end of the pipeline over time within a second preset time period.

6. The method for preparing ammonia water for improving the survival rate of fermentation microorganisms in pharmaceuticals and biotechnology according to claim 5, characterized in that, Several adjustment methods are provided for increasing the preset purge flow rate, and each adjustment method increases the preset purge flow rate by a different amount.

7. The method for preparing ammonia water for improving the survival rate of fermentation microorganisms in pharmaceuticals and biotechnology according to claim 6, characterized in that, The process of determining the optimization strategy when purging does not meet the preset standard based on the abnormal flow resistance characterization value of the inert gas includes: The abnormal flow resistance characterization value is compared with the preset abnormal flow resistance characterization value; If the abnormal flow resistance value is less than the preset abnormal flow resistance value, then the first optimization strategy is adopted; If the abnormal flow resistance value is greater than or equal to the preset abnormal flow resistance value, then a second optimization strategy is adopted, wherein the second optimization strategy is to issue a blockage alarm.

8. The method for preparing ammonia water for improving the survival rate of pharmaceutical and biological fermentation microorganisms according to claim 7, characterized in that, The process of obtaining the anomaly characterization value of the flow resistance includes: The real-time intake pressure and real-time intake flow rate of the inert gas at the inert gas inlet are obtained respectively. The ratio of the real-time intake pressure to the real-time intake flow rate is recorded as the flow resistance anomaly characterization value.

9. The method for preparing ammonia water for improving the survival rate of pharmaceutical and biological fermentation microorganisms according to claim 7, characterized in that, The first optimization strategy includes: Obtain the real-time inlet pressure of the inert gas at the inert gas inlet; The real-time intake pressure is compared with the preset intake pressure; If the real-time intake pressure is less than the preset intake pressure, the preset intake pressure is increased according to the difference between the preset intake pressure and the real-time intake pressure. If the real-time intake pressure is greater than or equal to the preset intake pressure, a leak alarm will be activated.

10. The method for preparing ammonia water for improving the survival rate of fermentation microorganisms in pharmaceuticals and biotechnology according to claim 7, characterized in that, The increase in the preset air supply pressure is positively correlated with the intake pressure deviation value, wherein the intake pressure deviation value is the difference between the preset intake pressure and the real-time intake pressure.

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