A process control method based on traditional Chinese medicine lotion production

Abstract

This invention relates to the field of process control technology for the production of traditional Chinese medicine (TCM) lotions, and discloses a process control method for the production of TCM lotions, including: collecting near-infrared spectra of each batch of medicinal materials, extracting cell wall density characteristics to form a comprehensive quality fingerprint, controlling the endpoint of powder pulverization by calculating cell wall fragmentation, verifying the uniformity of the powder through multi-point spectroscopy after graded mixing; dynamically adjusting gradient heating parameters, and adjusting the concentration feed rate and vacuum degree in conjunction with real-time component data; monitoring the binding degree of solubilizer and active ingredients, grading and homogenizing after reaching the standard, collecting particle size distribution data to control the homogenization endpoint, and predicting transdermal efficiency after verifying uniformity; conducting a comprehensive quality assessment before sterilization, generating adaptive low-temperature pulse sterilization parameters by combining initial microbial load and active ingredient stability, monitoring the proportion of free active ingredients and changes in micelle particle size, automatically compensating for pH value and colloidal aggregation, and generating a comprehensive quality score to achieve integrated release.

Description

Technical Field

[0001] This invention relates to the field of process control technology for the production of traditional Chinese medicine lotions, and specifically to a process control method based on the production of traditional Chinese medicine lotions. Background Technology

[0002] The existing production process control methods for traditional Chinese medicine washes generally follow the control logic of oral preparations of traditional Chinese medicine manufactured by biopharmaceutical companies. They adopt a crude mode of independent control of single processes, operation with fixed parameters, and release after terminal testing. They fail to build a systematic control scheme that takes into account the unique characteristics of traditional Chinese medicine washes, such as external application, multiple compound ingredients, and liquid preparations. This results in poor batch consistency, large fluctuations in clinical efficacy, and prominent safety risks.

[0003] In existing technologies, the use of specified indicator component content as the standard for judging the quality of medicinal materials in the raw material pretreatment stage cannot comprehensively characterize the intrinsic quality differences of medicinal materials, such as cell wall structure, active ingredient morphology, and impurity composition. The use of fixed pulverization and mixing process parameters cannot adapt to the natural fluctuations of raw materials, resulting in common problems such as insufficient pulverization leading to incomplete extraction, excessive pulverization introducing a large number of impurities, and uneven mixing of medicinal materials of different densities, thus creating potential batch-to-batch variations from the outset. Extraction and concentration are operated as independent processes, requiring the extract to be allowed to stand and drain before transportation, resulting in long intermediate residence times that lead to degradation of active ingredients and microbial growth. The use of fixed temperature and time extraction processes cannot simultaneously account for the dissolution characteristics and stability differences of different components, and the uneven temperature and concentration fields within the tank further exacerbate localized overheating degradation and poor extraction efficiency. The following issues were identified: The concentration process uses a fixed feed rate and vacuum level, which easily leads to wall scorching and foam overflow, resulting in significant fluctuations in the quality of the concentrate; the preparation and homogenization processes use a fixed excipient feeding sequence and homogenization parameters, making it impossible to monitor the binding state of the solubilizer and active ingredient in real time, leading to a high risk of free drug precipitation; the fixed homogenization pressure and number of cycles cannot guarantee uniform micelle particle size distribution, and key attributes related to transdermal absorption are not included in process control, making it impossible to distinguish active forms in routine total content testing, resulting in issues of qualified indicators but insufficient efficacy; the sterilization process uses a high-temperature, high-pressure process with fixed temperature and time, which cannot adaptively adjust the sterilization intensity according to the initial microbial load and the stability of the active ingredient, and the final release only tests the total content and microbial limits, failing to reflect the actual transdermal efficiency and clinical efficacy of the product.

[0004] Therefore, there is a need to provide a process control method for the production of traditional Chinese medicine lotions. Summary of the Invention

[0005] The purpose of this invention is to provide a process control method for the production of traditional Chinese medicine lotions, constructing a closed-loop control system with transdermal-guided core quality attributes as the target, achieving adaptive process adjustment from source to end, and solving the long-standing problem of batch-to-batch differences in clinical efficacy of traditional Chinese medicine lotions despite qualified indicators. To solve the above-mentioned problems in the prior art, this invention is achieved through the following technical solution:

[0006] The first part, an embodiment of the present invention, provides a process control method for the production of traditional Chinese medicine lotions, which specifically includes the following steps:

[0007] Step 1: Collect near-infrared spectra of each batch of medicinal materials, extract cell wall density characteristics to form a comprehensive quality fingerprint, match historical database to generate exclusive pre-processing parameters, control the endpoint of medicinal material powder pulverization by calculating cell wall fragmentation, and verify the uniformity of medicinal material powder after graded mixing through multi-point spectroscopy.

[0008] Step 2: The graded and mixed medicinal powder is put into the integrated closed unit for extraction and concentration. Multi-stage independent heating and online circulation are used to ensure uniform temperature and concentration fields inside the tank. The gradient heating parameters are dynamically adjusted by collecting the spectral data of the extract. The concentration feed rate and vacuum degree are adjusted in conjunction with the real-time component data.

[0009] Step 3: The concentrated drug solution is sent to the mixing tank. The order, speed and stirring parameters of the excipients are adjusted according to the real-time composition. The binding degree of the solubilizer and the active ingredient is monitored. After the standard is met, the drug solution is graded and homogenized. Particle size distribution data is collected to control the homogenization endpoint. After verifying the uniformity, the transdermal efficiency is predicted.

[0010] Step 4: Conduct a comprehensive quality assessment of the drug solution with qualified transdermal efficiency before sterilization. Combine the initial microbial load and the stability of active ingredients to generate adaptive low-temperature pulse sterilization parameters, monitor the proportion of free active ingredients and changes in micelle size, automatically compensate for pH value and colloidal aggregation, and generate a comprehensive quality score to achieve integrated release.

[0011] Specifically, the method for forming a comprehensive quality fingerprint is as follows:

[0012] Characteristic peak intensity data related to cell wall compactness, proportion of free active ingredients, content of sedimentary impurities, and content of volatile components were extracted from the preprocessed spectral data.

[0013] The characteristic peak intensity data is integrated with four physical indicators, namely moisture, bulk density, hardness, and water absorption rate, to form a comprehensive quality fingerprint feature vector for the corresponding batch of medicinal materials.

[0014] Specifically, the method for generating the dedicated preprocessing parameters is as follows:

[0015] The comprehensive quality fingerprint feature vector is compared with the pre-established historical production database. The 10 most similar batches of historical data are found through similarity analysis, and the corresponding optimal grinding temperature, grinding speed, grinding time and mixing time are extracted.

[0016] Based on the quality differences between the current batch and historical batches, the extracted parameters are fine-tuned to generate exclusive pretreatment process parameters;

[0017] Specifically, the method for calculating cell wall fragmentation is as follows:

[0018] During the pulverization process, an online laser particle size analyzer is used to collect the particle size distribution data of the powder once per second; the cell wall fragmentation degree is calculated in real time by the difference between the cumulative proportion of powder with a particle size of less than 10 μm and the cumulative proportion of powder with a particle size of greater than 100 μm.

[0019] The pulverization process automatically stops when the cell wall fragmentation reaches the range corresponding to the historical best value.

[0020] Specifically, the method for verifying uniformity is as follows:

[0021] After pulverization, airflow classification technology is used to separate the powder into three grades: coarse powder, medium powder, and fine powder. The coarse powder is returned to the pulverizer for further pulverization, while the medium and fine powders are sent to different mixing chambers. The mixing time is dynamically adjusted according to the differences in particle size and density between the different grades of powder.

[0022] After mixing, spectral data were collected at 10 different locations within the mixing chamber, and similarity was calculated to evaluate uniformity.

[0023] Specifically, the method for obtaining the integrated closed unit for extraction and concentration is as follows:

[0024] The multi-functional extraction tank and the low-temperature falling film concentrator are directly connected through a closed pipeline. The extract does not need to be allowed to stand and drain, and is continuously transported directly from the bottom of the extraction tank to the concentrator.

[0025] An online buffer tank is installed in the middle to adjust the flow rate of the extract and the feed speed of the concentrator, so as to realize continuous production of extraction and concentration.

[0026] Specifically, the multi-segment independent heating method is as follows:

[0027] The extraction tank adopts a multi-segment independent heating structure, with independent temperature sensors and heating controllers for the tank wall, tank bottom, and central heating pipe; real-time collection of temperature data at different locations and dynamic adjustment of heating power for each segment ensure that the temperature difference at different locations inside the tank is controlled within a preset threshold range; an online extraction liquid circulation system is used to transport the extraction liquid from the bottom of the tank to the top of the tank for spraying.

[0028] Specifically, the method for adjusting the concentration feed rate and vacuum level in conjunction is as follows:

[0029] The feed rate of the concentrator is dynamically adjusted based on real-time composition and flow rate data of the extract. When the proportion of free active ingredients in the extract is high, the feed rate is increased.

[0030] When the content of heat-sensitive components in the extract is high, the feed rate is reduced while the vacuum degree of the concentrator is increased; during the concentration process, the viscosity, solid content and free active ingredient ratio of the concentrate are monitored in real time.

[0031] Specifically, the method for monitoring the binding degree between the solubilizer and the active ingredient is as follows:

[0032] Raman spectral data of the drug solution were acquired in real time using an online Raman spectrometer; the binding degree was calculated in real time by comparing the characteristic peak intensity changes of free solubilizer, free active ingredient, and solubilizer-active ingredient complex.

[0033] The degree of binding is calculated by the ratio of the characteristic peak intensity of the complex to the sum of the characteristic peak intensities of the free solubilizer and the free active ingredient; when the degree of binding reaches a preset threshold, the homogenization process begins.

[0034] Specifically, the method for generating the comprehensive quality score is as follows:

[0035] By integrating real-time quality data from the sterilization process with quality data from pre-sterilization and preceding processes, a full lifecycle quality archive for this batch of products is formed.

[0036] Based on a pre-established product quality evaluation model, a comprehensive quality score for the batch of products is automatically generated. When the comprehensive quality score meets the preset release standard, the product is deemed qualified and released, and all quality data is uploaded to the drug traceability system.

[0037] The second part, an embodiment of the present invention, provides a process control system for the production of traditional Chinese medicine lotions, which specifically includes the following modules:

[0038] Adaptation module: Collects near-infrared spectra of each batch of medicinal materials, extracts cell wall density characteristics to form a comprehensive quality fingerprint, matches historical database to generate exclusive preprocessing parameters, controls the endpoint of medicinal material powder pulverization by calculating cell wall fragmentation, and verifies the uniformity of medicinal material powder after graded mixing through multi-point spectroscopy.

[0039] Protection module: The graded and mixed medicinal powder is put into the integrated closed unit for extraction and concentration. Multi-stage independent heating and online circulation are used to ensure uniform temperature and concentration fields inside the tank. The gradient heating parameters are dynamically adjusted by collecting the spectral data of the extract. The concentration feed rate and vacuum degree are adjusted in conjunction with the real-time component data.

[0040] Control module: The concentrated drug solution is sent into the mixing tank. The order, speed and stirring parameters of excipient feeding are adjusted according to the real-time composition. The binding degree of solubilizer and active ingredient is monitored. After reaching the standard, the drug is graded and homogenized. Particle size distribution data is collected to control the homogenization endpoint. After verifying the uniformity, the transdermal efficiency is predicted.

[0041] Balance module: Performs a comprehensive quality assessment on drug solutions with qualified transdermal efficiency prediction before sterilization. Combines initial microbial load and active ingredient stability to generate adaptive low-temperature pulse sterilization parameters, monitors the proportion of free active ingredients and changes in micelle size, automatically compensates for pH value and colloidal aggregation, and generates a comprehensive quality score to achieve integrated release.

[0042] The beneficial effects of this invention are:

[0043] 1. By using a pretreatment adaptive control driven by the full-dimensional quality fingerprint of medicinal materials, the shortcomings of judging the quality of medicinal materials by pharmacopoeia indicators and components cannot characterize the differences in cell wall structure and active forms are solved. The system matches historical databases to generate exclusive process parameters and replaces fixed pulverization time with real-time calculated cell wall fragmentation, thus resolving the contradiction between insufficient and excessive pulverization and eliminating batch differences caused by raw material fluctuations from the source. The system constructs an integrated closed unit for extraction and concentration, which solves the defects of long intermediate residence time of extract, degradation of active ingredients and microbial growth caused by independent operation of two processes. Through multi-stage independent heating and online circulation control of temperature and concentration differences in the tank, the system collects spectral data of the extract to dynamically adjust gradient heating parameters. The concentration feed rate and vacuum degree are linked with the real-time quality of the extract, solving the problems of local overheating degradation, insufficient extraction and concentration wall clogging.

[0044] 2. Establish a transdermal efficiency-oriented closed-loop control system for solution preparation and homogenization to address the shortcomings of fixed excipients and homogenization parameters in ensuring the binding degree of solubilizers and active ingredients. Real-time monitoring of binding degree via online Raman spectroscopy and dynamic adjustment of excipient dosing rhythm are used, with real-time particle size distribution data controlling the homogenization endpoint. Simultaneously, multi-dimensional data is combined to predict transdermal efficiency and trigger secondary optimization, resolving issues of transdermal efficiency differences caused by free drug precipitation and uneven micelle size. Achieve integrated intelligent control for sterilization and release, addressing the problem of incomplete sterilization or excessive degradation due to fixed high-temperature sterilization parameters. Adaptive low-temperature pulse parameters are generated based on initial microbial load and activity stability. Real-time monitoring of changes in free active ingredients and micelle structure occurs during sterilization. Automatic compensation for pH and colloidal aggregation occurs after sterilization. Finally, integrated release is achieved by merging quality data from the entire process. Attached Figure Description

[0045] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0046] Figure 1 This is a flowchart of the process control method for the production of traditional Chinese medicine lotion provided in Embodiment 1 of the present invention;

[0047] Figure 2 This is a schematic diagram of the process control system for the production of traditional Chinese medicine lotion provided in Embodiment 2 of the present invention. Detailed Implementation

[0048] To enable those skilled in the art to better understand the present invention, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. 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 should fall within the scope of protection of the present invention.

[0049] Example 1: As Figure 1 As shown in the figure, the process control method for the production of traditional Chinese medicine lotion provided by the embodiment of the present invention specifically includes the following steps:

[0050] Step 1: Collect near-infrared spectra of each batch of medicinal materials, extract cell wall density characteristics to form a comprehensive quality fingerprint, match historical database to generate exclusive pre-processing parameters, control the endpoint of medicinal material powder pulverization by calculating cell wall fragmentation, and verify the uniformity of medicinal material powder after graded mixing through multi-point spectroscopy.

[0051] In a specific embodiment, a near-infrared spectrometer was used to collect spectral data of each batch of medicinal materials in the full wavelength range of [1000nm, 2500nm]. At the same time, data on four physical indicators of the medicinal materials, namely moisture content, bulk density, hardness and water absorption rate, were also collected. All data were collected in triplicate, and the average value was taken as the original data of the quality fingerprint of the corresponding batch of medicinal materials.

[0052] The acquired near-infrared spectral data were preprocessed, including smoothing, baseline correction, and normalization to eliminate noise and background interference.

[0053] Characteristic peak intensity data related to cell wall compactness, proportion of free active ingredients, content of sedimentary impurities, and content of volatile components are extracted from the preprocessed spectral data; the characteristic peak intensity data are fused with physical index data to form a comprehensive quality fingerprint feature vector for the corresponding batch of medicinal materials;

[0054] The comprehensive quality fingerprint feature vector of the corresponding batch of medicinal materials is compared with the pre-established historical production database, which contains production data of thousands of batches of medicinal materials of different qualities and corresponding final product quality data.

[0055] By similarity analysis, 10 batches of historical data that are closest to the quality of the corresponding batch of medicinal materials are found. The optimal pulverizing temperature, pulverizing speed, pulverizing time and mixing time are extracted from these historical data. Based on the quality differences between the corresponding batch of medicinal materials and the historical batches, the extracted parameters are fine-tuned to generate exclusive pretreatment process parameters for the corresponding batch of medicinal materials.

[0056] During the pulverization process, an online laser particle size analyzer collects the particle size distribution data of the powder once per second. The particle size distribution data includes: cumulative distribution characteristic particle size, distribution width parameter, distribution morphology parameter and derived calculation parameters. The cell wall fragmentation degree is calculated in real time using the particle size distribution data. The cell wall fragmentation degree is obtained by the difference between the cumulative proportion of powder with a particle size of less than 10 μm and the cumulative proportion of powder with a particle size of greater than 100 μm.

[0057] When the cell wall fragmentation reaches the range corresponding to the historical best value, the grinding will automatically stop instead of a fixed grinding time. An online near-infrared spectrometer is used to detect the change in the proportion of free active ingredients in real time during the grinding process. When the decrease in the proportion of free active ingredients is close to the historical maximum allowable value, the grinding speed and temperature will be automatically reduced to prevent further conversion of active ingredients.

[0058] After pulverization, air classifier technology is used to separate the powder into three grades: coarse powder, medium powder, and fine powder. The coarse powder is returned to the pulverizer for further pulverization, while the medium and fine powders are sent to different mixing chambers. The mixing process uses a three-dimensional motion mixer, and the mixing time is dynamically adjusted according to the differences in particle size and density of the different grades of powder.

[0059] After mixing, near-infrared spectrometers are used to collect spectral data at 10 points at different locations within the mixing chamber. The similarity of the spectral data at different locations is calculated to evaluate the mixing uniformity. When the similarity of the spectral data at all locations reaches or exceeds the preset value, the mixing is deemed qualified.

[0060] Step 2: The graded and mixed medicinal powder is put into the integrated closed unit for extraction and concentration. Multi-stage independent heating and online circulation are used to ensure uniform temperature and concentration fields inside the tank. The gradient heating parameters are dynamically adjusted by collecting the spectral data of the extract. The concentration feed rate and vacuum degree are adjusted in conjunction with the real-time component data.

[0061] In a specific embodiment, the multi-functional extraction tank and the low-temperature falling film concentrator are directly connected through a closed pipeline. The extract does not need to be allowed to stand and drain, and is continuously transported directly from the bottom of the extraction tank to the concentrator, realizing continuous production of extraction and concentration. An online buffer tank is set in the middle to adjust the matching of the extract flow rate and the feed speed of the concentrator.

[0062] The extraction process employs a multi-stage gradient heating process, with the temperature and holding time of each stage dynamically adjusted based on real-time composition data of the extract.

[0063] The spectral data of the extract were collected every 5 minutes using an online near-infrared spectrometer, and the concentration, free state ratio, and content of process-induced sensitizing impurities of each core active ingredient were calculated in real time.

[0064] When the concentration increase rate of any component is lower than the preset value, the system automatically enters the next heating stage; when the content of process-induced sensitizing impurities is close to the historical maximum allowable value, the heating rate is automatically reduced and the holding time is shortened.

[0065] The extraction tank adopts a multi-segment independent heating structure, with independent temperature sensors and heating controllers for the tank wall, tank bottom and central heating tube;

[0066] By collecting temperature data from different locations in real time, the heating power of each section is dynamically adjusted to ensure that the temperature difference between different locations inside the tank is controlled within the preset temperature difference threshold range.

[0067] An online extraction liquid circulation system is adopted, in which the extraction liquid at the bottom of the tank is pumped to the top of the tank for spraying, thereby achieving forced circulation of the extraction liquid in the tank and ensuring that the concentration difference of components at different locations in the tank is controlled within the preset component concentration difference threshold range.

[0068] The feed rate of the concentrator is dynamically adjusted based on the real-time composition and flow data of the extract. When the proportion of free active ingredients in the extract is high, the feed rate is appropriately increased to shorten the concentration time.

[0069] When the content of heat-sensitive components in the extract is high, the feed rate should be appropriately reduced, while the vacuum degree of the concentrator should be increased and the evaporation temperature reduced.

[0070] During the concentration process, an online viscometer and an online near-infrared spectrometer are used to monitor the viscosity, solid content, and percentage of free active ingredients of the concentrate in real time.

[0071] When the solid content of the concentrate reaches the range corresponding to the historical best value, and the decrease in the proportion of free active ingredients is less than or equal to the historical maximum allowable value, the concentration will automatically stop.

[0072] During the concentration process, online image recognition technology is used to detect the foam height at the top of the concentrator and the wall formation on the inner wall of the heating tube in real time.

[0073] When the foam height approaches the preset value, the mechanical defoaming device is automatically activated, while the feeding speed is appropriately reduced and the vacuum degree is increased to suppress further foam generation.

[0074] When a tendency for wall formation is detected on the inner wall of the heating tube, the heating power is automatically reduced and the feeding speed is increased. The increased flow rate of the medicine flushes the inner wall of the heating tube, preventing wall formation.

[0075] Step 3: The concentrated drug solution is sent to the mixing tank. The order, speed and stirring parameters of the excipients are adjusted according to the real-time composition. The binding degree of the solubilizer and the active ingredient is monitored. After the standard is met, the drug solution is graded and homogenized. Particle size distribution data is collected to control the homogenization endpoint. After verifying the uniformity, the transdermal efficiency is predicted.

[0076] In a specific embodiment, the dynamic sequence and speed of excipient feeding are controlled during the liquid preparation process. The concentrate is sent into the liquid preparation tank, and the feeding sequence, feeding speed and stirring parameters of the excipients are dynamically adjusted according to the real-time composition data and physical property data of the concentrate.

[0077] Specifically, a pH adjuster is added to adjust the pH value of the drug solution to the range where the active ingredient is most stable, and a solubilizer is added. The addition rate of the solubilizer is dynamically adjusted according to the solid content and viscosity of the concentrate. After the solubilizer is added, preservatives and other excipients are added.

[0078] After each excipient is added, the binding between the excipient and the active ingredient is detected in real time using an online Raman spectrometer. Once the binding degree reaches the preset requirement, the next excipient is added.

[0079] Raman spectroscopy data of the drug solution were acquired in real time using an online Raman spectrometer. By comparing the changes in characteristic peak intensity of free solubilizer, free active ingredient, and solubilizer-active ingredient complex, the binding degree of solubilizer and active ingredient was calculated in real time.

[0080] The binding degree is calculated by the ratio of the characteristic peak intensity of the complex of solubilizer and active ingredient to the sum of the characteristic peak intensities of free solubilizer and free active ingredient; when the binding degree is greater than or equal to the preset binding degree threshold, the premix is ​​deemed to be qualified and proceeds to the homogenization process; otherwise, it is deemed unqualified.

[0081] The homogenization process employs a staged homogenization process. The first stage of homogenization is used for initial dispersion, and the second stage of homogenization is used to form a uniform micelle structure. The homogenization pressure and number of homogenization stages are dynamically adjusted based on the real-time viscosity of the premix, the degree of component binding, and the target micelle particle size.

[0082] During homogenization, an online laser particle size analyzer is used to collect the particle size distribution data of the drug solution once per second, and the average micelle size and particle size distribution coefficient are calculated in real time. When the average micelle size enters the preset optimal range for transdermal absorption and the particle size distribution coefficient is less than 0.2, homogenization is automatically stopped. A jacketed cooling system is used to control the temperature of the homogenization chamber in real time to avoid degradation of active ingredients and destruction of micelle structure caused by temperature rise.

[0083] After homogenization, an online Raman spectrometer was used to collect spectral data at 10 points at different locations within the mixing tank. The similarity of the spectral data at different locations was calculated to evaluate the compositional uniformity of the drug solution. An online laser particle size analyzer was used to collect particle size distribution data at different locations to evaluate the uniformity of micelle size. When both compositional uniformity and particle size uniformity met the preset requirements, the mixing and homogenization processes were deemed qualified.

[0084] Based on the proportion of free active ingredients, average micelle size, particle size distribution coefficient, pH value and conductivity of the drug solution after homogenization, combined with the pre-established transdermal efficiency prediction model, the skin stratum corneum penetration efficiency and skin dermal layer retention efficiency of the corresponding batch of drug solution are calculated in real time.

[0085] If the predicted transdermal efficiency value does not reach the preset transdermal efficiency threshold of the corresponding product, a secondary homogenization process will be automatically triggered. Based on the difference between the predicted value and the target value, the pressure and number of secondary homogenization processes will be dynamically adjusted until the predicted transdermal efficiency value reaches the preset transdermal efficiency threshold of the corresponding product.

[0086] Step 4: Conduct a comprehensive quality assessment of the drug solution with qualified transdermal efficiency before sterilization. Combine the initial microbial load and the stability of active ingredients to generate adaptive low-temperature pulse sterilization parameters, monitor the proportion of free active ingredients and changes in micelle size, automatically compensate for pH value and colloidal aggregation, and generate a comprehensive quality score to achieve integrated release.

[0087] In a specific embodiment, before sterilization, the initial microbial load of the drug solution is detected by an online rapid microbial detector, the proportion of free active ingredients in the drug solution is detected by an online near-infrared spectrometer, the micelle size distribution of the drug solution is detected by an online laser particle size analyzer, and the pH value of the drug solution is detected by an online pH meter. These data are compared with the historical benchmark data of this batch of drug solution to comprehensively evaluate the initial quality status of the drug solution.

[0088] Based on the initial microbial load, active ingredient stability, and micelle structure stability of the drug solution, the optimal sterilization parameter combination is automatically generated. The sterilization parameter combination includes: sterilization temperature, number of pulses, holding time for each pulse, and interval time.

[0089] During sterilization, an online near-infrared spectrometer is used to monitor the change in the proportion of free active ingredients in the drug solution in real time, and an online laser particle size analyzer is used to monitor the change in micelle size distribution in real time. When the decrease in the proportion of free active ingredients is close to the historical maximum allowable value, or when the micelle size increases beyond the preset value, the sterilization temperature is automatically reduced and the number of pulses is increased to protect the active ingredients and micelle structure while ensuring the sterility level.

[0090] The sterilizer adopts a multi-segment heating structure, with independent temperature sensors and heating controllers at different locations. By collecting temperature data from different locations in real time, the heating power of each segment is dynamically adjusted to ensure that the temperature difference between different locations within the sterilizer is controlled within ±0.5℃.

[0091] A sterile air stirring system is used to introduce sterile air into the drug solution during pulse intervals to ensure temperature uniformity within the drug solution.

[0092] After sterilization, the pH value of the solution is immediately detected by an online pH meter. If the pH value of the solution drifts by more than ±0.2, the pH compensation system is automatically activated, and a pre-prepared buffer solution is added by micro-titration to adjust the pH value to the initial range.

[0093] An online turbidimeter is used to detect changes in the turbidity of the drug solution. If the turbidity exceeds the preset value, the low-temperature homogenization system is automatically activated to perform a slight homogenization treatment on the drug solution, eliminating the tiny colloidal aggregates formed during the sterilization process.

[0094] All real-time quality data during the sterilization process are integrated with the quality data before sterilization and the quality data of the preceding processes to form a full life cycle quality file for this batch of products.

[0095] By combining full lifecycle quality data with a pre-established product quality evaluation model, a comprehensive quality score for the batch of products is automatically generated. When the comprehensive quality score meets the preset release standard, the batch of products is automatically deemed qualified and released. All quality data is then uploaded to the drug traceability system to achieve full traceability of product quality.

[0096] Example 2: Figure 2 As shown in the figure, the process control system for the production of traditional Chinese medicine lotion provided in this embodiment of the invention specifically includes the following modules:

[0097] Adaptation module: Collects near-infrared spectra of each batch of medicinal materials, extracts cell wall density characteristics to form a comprehensive quality fingerprint, matches historical database to generate exclusive preprocessing parameters, controls the endpoint of medicinal material powder pulverization by calculating cell wall fragmentation, and verifies the uniformity of medicinal material powder after graded mixing through multi-point spectroscopy.

[0098] Protection module: The graded and mixed medicinal powder is put into the integrated closed unit for extraction and concentration. Multi-stage independent heating and online circulation are used to ensure uniform temperature and concentration fields inside the tank. The gradient heating parameters are dynamically adjusted by collecting the spectral data of the extract. The concentration feed rate and vacuum degree are adjusted in conjunction with the real-time component data.

[0099] Control module: The concentrated drug solution is sent into the mixing tank. The order, speed and stirring parameters of excipient feeding are adjusted according to the real-time composition. The binding degree of solubilizer and active ingredient is monitored. After reaching the standard, the drug is graded and homogenized. Particle size distribution data is collected to control the homogenization endpoint. After verifying the uniformity, the transdermal efficiency is predicted.

[0100] Balance module: Performs a comprehensive quality assessment on drug solutions with qualified transdermal efficiency prediction before sterilization. Combines initial microbial load and active ingredient stability to generate adaptive low-temperature pulse sterilization parameters, monitors the proportion of free active ingredients and changes in micelle size, automatically compensates for pH value and colloidal aggregation, and generates a comprehensive quality score to achieve integrated release.

[0101] The above provides a detailed description of one embodiment of the present invention, but the content described is only a preferred embodiment of the present invention and should not be considered as limiting the scope of the present invention. The above formulas are all dimensionless numerical calculations, and the formulas are derived from software simulations based on a large amount of collected data to obtain the most recent real-world situation. The preset parameters in the formulas are set by those skilled in the art based on actual conditions and historical experience, and can be adjusted according to actual conditions. The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. All equivalent changes and improvements made in accordance with the scope of the present invention should still fall within the patent coverage of the present invention.

Claims

1. A process control method for the production of traditional Chinese medicine lotion, characterized in that, Includes the following steps: Near-infrared spectra of each batch of medicinal materials are collected, cell wall density characteristics are extracted to form a comprehensive quality fingerprint, and exclusive pre-processing parameters are generated by matching historical databases. The endpoint of medicinal material powder pulverization is controlled by calculating cell wall fragmentation. After the medicinal material powder is graded and mixed, the uniformity is verified by multi-point spectroscopy. The graded and mixed medicinal powder is put into an integrated closed unit for extraction and concentration. Multi-stage independent heating and online circulation are used to ensure uniform temperature and concentration fields inside the tank. The gradient heating parameters are dynamically adjusted by collecting the spectral data of the extract. The concentration feed rate and vacuum degree are adjusted in conjunction with the real-time component data. The concentrated drug solution is sent to the mixing tank. The order, speed and stirring parameters of excipient feeding are adjusted according to the real-time composition. The binding degree of solubilizer and active ingredient is monitored. After reaching the standard, the drug is graded and homogenized. Particle size distribution data is collected to control the homogenization endpoint. After verifying the uniformity, the transdermal efficiency is predicted. A comprehensive quality assessment is performed on drug solutions with qualified transdermal efficiency before sterilization. Adaptive low-temperature pulse sterilization parameters are generated by combining initial microbial load and active ingredient stability. The proportion of free active ingredients and changes in micelle size are monitored, pH value and colloidal aggregation are automatically compensated, and a comprehensive quality score is generated to achieve integrated release.

2. The process control method for the production of traditional Chinese medicine lotion according to claim 1, characterized in that, The method for forming a comprehensive quality fingerprint is as follows: Characteristic peak intensity data related to cell wall compactness, proportion of free active ingredients, content of sedimentary impurities, and content of volatile components were extracted from the preprocessed spectral data. The characteristic peak intensity data is integrated with four physical indicators, namely moisture, bulk density, hardness, and water absorption rate, to form a comprehensive quality fingerprint feature vector for the corresponding batch of medicinal materials.

3. The process control method for the production of traditional Chinese medicine lotion according to claim 1, characterized in that, The method for generating the specific preprocessing parameters is as follows: The comprehensive quality fingerprint feature vector is compared with the pre-established historical production database. The 10 most similar batches of historical data are found through similarity analysis, and the corresponding optimal grinding temperature, grinding speed, grinding time and mixing time are extracted. Based on the quality differences between the current batch and historical batches, the extracted parameters are fine-tuned to generate exclusive pretreatment process parameters.

4. The process control method for the production of traditional Chinese medicine lotion according to claim 1, characterized in that, The method for calculating cell wall fragmentation is as follows: During the pulverization process, an online laser particle size analyzer is used to collect the particle size distribution data of the powder once per second; the cell wall fragmentation degree is calculated in real time by the difference between the cumulative proportion of powder with a particle size of less than 10 μm and the cumulative proportion of powder with a particle size of greater than 100 μm. When the cell wall fragmentation reaches the range corresponding to the historical best value, the pulverization will automatically stop.

5. The process control method for the production of traditional Chinese medicine lotion according to claim 1, characterized in that, The method for verifying uniformity is as follows: After pulverization, air classifier technology is used to separate the powder into three grades: coarse powder, medium powder, and fine powder. The coarse powder is returned to the pulverizer for further pulverization, while the medium and fine powders are sent to different mixing chambers. The mixing time is dynamically adjusted according to the differences in particle size and density between the different grades of powder. After mixing, spectral data were collected at 10 points at different locations within the mixing chamber, and similarity was calculated to evaluate uniformity.

6. The process control method for the production of traditional Chinese medicine lotion according to claim 1, characterized in that, The method for obtaining the integrated closed unit for extraction and concentration is as follows: The multi-functional extraction tank and the low-temperature falling film concentrator are directly connected through a closed pipeline. The extract does not need to be allowed to stand and drain, and is continuously transported directly from the bottom of the extraction tank to the concentrator. An online buffer tank is installed in the middle to adjust the flow rate of the extract and the feed rate of the concentrator, so as to realize continuous production of extraction and concentration.

7. The process control method for the production of traditional Chinese medicine lotion according to claim 1, characterized in that, The method of multi-segment independent heating is as follows: The extraction tank adopts a multi-segment independent heating structure, with independent temperature sensors and heating controllers for the tank wall, tank bottom and central heating pipe; real-time collection of temperature data at different locations and dynamic adjustment of heating power of each segment ensure that the temperature difference at different locations inside the tank is controlled within a preset threshold range; an online extraction liquid circulation system is adopted to transport the extraction liquid at the bottom of the tank to the top of the tank for spraying.

8. The process control method for the production of traditional Chinese medicine lotion according to claim 1, characterized in that, The method for adjusting the concentration feed rate and vacuum level in a coordinated manner is as follows: The feed rate of the concentrator is dynamically adjusted based on the real-time composition and flow data of the extract; when the proportion of free active ingredients in the extract is high, the feed rate is increased. When the content of heat-sensitive components in the extract is high, the feed rate is reduced while the vacuum degree of the concentrator is increased; during the concentration process, the viscosity, solid content and proportion of free active ingredients of the concentrate are monitored in real time.

9. The process control method for the production of traditional Chinese medicine lotion according to claim 1, characterized in that, The method for monitoring the binding degree between the solubilizer and the active ingredient is as follows: Raman spectral data of the drug solution were acquired in real time using an online Raman spectrometer; the binding degree was calculated in real time by comparing the characteristic peak intensity changes of free solubilizer, free active ingredient, and solubilizer-active ingredient complex. The degree of binding is calculated by the ratio of the characteristic peak intensity of the complex to the sum of the characteristic peak intensities of the free solubilizer and the free active ingredient; when the degree of binding reaches a preset threshold, the homogenization process begins.

10. The process control method for the production of traditional Chinese medicine lotion according to claim 1, characterized in that, The method for generating the comprehensive quality score is as follows: By integrating real-time quality data from the sterilization process with quality data from pre-sterilization and preceding processes, a full lifecycle quality archive for this batch of products is formed. Based on a pre-established product quality evaluation model, a comprehensive quality score for the batch of products is automatically generated. When the comprehensive quality score meets the preset release standard, the product is deemed qualified and released, and all quality data is uploaded to the drug traceability system.

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