Preparation method and quality control method of levocarnitine oral solution

Abstract

The invention discloses a quality control method based on a levocarnitine oral solution preparation process, and relates to the technical field of quality detection. The quality control method based on the preparation process of the levocarnitine oral solution comprises the following steps: acquiring oral solution monitoring data; evaluating oral liquid quality; feeding back a result; and optimizing quality control parameters. According to the method, oral liquid quality evaluation is carried out through the obtained oral liquid monitoring data, the process quality feedback data is obtained, then the process parameter algorithm model is constructed according to the process quality feedback data, result feedback is carried out, and finally whether quality control parameter optimization is carried out or not is judged based on the process parameter algorithm model. The effect of improving the character stability of the prepared levocarnitine oral solution is achieved, and the problem that in the prior art, the quality of the prepared levocarnitine oral solution is difficult to control is solved.

Description

Technical Field

[0001] The present invention relates to the technical field of quality inspection, and particularly to a preparation method and a quality control method for levocarnitine oral solution Background Art

[0002] Levocarnitine is an essential natural substance in mammalian energy metabolism, and its main function is to promote lipid metabolism and generate ATP energy for the needs of human tissues. It is widely used clinically in the dialysis treatment of cardiovascular diseases, diabetes, liver diseases, kidney diseases, as well as the treatment of primary or secondary carnitine deficiency, etc. In the preparation process, first, the prescription composition of the oral solution needs to be determined. This usually refers to the prescription composition components of the original developed preparation and combines the current usage situation of domestic excipients, and optimizes the prescription composition and process through the single-factor investigation method. Multiple factors such as taste, pH value, sterilization effect, etc. will be considered during the optimization process to ensure the quality and stability of the final product

[0003] The existing methods mainly use high-performance liquid chromatography for content determination. This method has the advantages of strong specificity, high recovery rate, good linear relationship, and compliance with the requirements of reproducibility. At the same time, it is also necessary to conduct a comprehensive analysis and research on possible process impurities, degradation impurities, residual solvents, etc. to ensure the purity of the product

[0004] For example, a method for quality inspection of oral liquid and generation of fingerprint spectrum disclosed in the invention patent application with the publication number of: CN116124946A includes: Step 1, preparing several groups of oral liquid test samples; Step 2: Identifying the test samples in Step 1 by thin-layer identification; Step 3: Checking the density, pH value, and filling volume of the test samples in Step 1; Step 4: Generating a fingerprint spectrum by HPLC; Step 5: Conducting multi-index content determination on the fingerprint spectrum in Step 4, and detecting the quality of the test samples in Step 1 through the determination results

[0005] For example, the quality inspection method of Rong'e Yishen oral liquid disclosed in the invention patent application with the publication number of: CN117330678A includes: First, obtaining the characteristic HPLC fingerprint spectrum of the male silkworm moth negative test solution of the tested Rong'e Yishen oral liquid, then, extracting the relative peak areas of multiple characteristic fingerprint peaks from the characteristic HPLC fingerprint spectrum of the male silkworm moth negative test solution, then, arranging the relative peak areas of multiple characteristic fingerprint peaks in the sample dimension as the input vector of the relative peak areas of characteristic fingerprint peaks, then, conducting characteristic-guided correlation analysis on the characteristic HPLC fingerprint spectrum of the male silkworm moth negative test solution and the input vector of the relative peak areas of characteristic fingerprint peaks to obtain the characteristic fingerprint peak-guided fingerprint spectrum characteristics, and finally, based on the characteristic fingerprint peak-guided fingerprint spectrum characteristics, determining whether the tested Rong'e Yishen oral liquid meets the predetermined quality standards

[0006] However, in the process of implementing the inventive technical solution in the embodiments of the present application, it is found that the above technology has at least the following technical problems:

[0007] In the prior art, during the preparation of levocarnitine oral solution, the applicant found that due to process parameter problems, the components in the solution underwent chemical or physical changes, resulting in the color of the levocarnitine oral solution product changing from colorless and clear to darker (becoming light yellow) or turbid for no obvious reason, leading to low stability of the properties of the prepared levocarnitine oral solution, that is, quality control during the preparation process is relatively difficult. Since most of the patients using this product are patients with renal failure who need to strictly control their diet and medication, patients are extremely sensitive to changes in the product's properties. Therefore, changes in the product's properties, including turning yellow or becoming turbid, are likely to cause patients' resistance, affecting the sales and use of the product. Summary of the Invention

[0008] In view of the above problems, the embodiments of the present application provide a quality control method and system based on the preparation process of levocarnitine oral solution, which solves the problem of low stability of the properties of the prepared levocarnitine oral solution in the prior art and realizes the improvement of the stability of the properties of the prepared levocarnitine oral solution.

[0009] The embodiments of the present application provide a quality control method based on the preparation process of levocarnitine oral solution, including the following steps: S1, monitoring the preparation process of levocarnitine oral solution through a preset sensor to obtain oral liquid monitoring data, where the oral liquid monitoring data includes dissolution rate evaluation data, stirring speed influence evaluation data, and stirring frequency influence data; S2, performing oral liquid quality evaluation based on the oral liquid monitoring data to obtain process quality feedback data, where the oral liquid quality evaluation includes dissolution rate evaluation, stirring speed influence evaluation, and stirring frequency influence evaluation; S3, constructing a process parameter algorithm model based on the process quality feedback data and performing result feedback, where the process parameter algorithm model is used to feedback the color and turbidity degree of the levocarnitine oral solution; S4, judging whether to optimize the quality control parameters based on the process parameter algorithm model, where the parameter optimization is used to improve the quality stability of the levocarnitine oral solution.

[0010] Further, the dissolution rate evaluation data is obtained by processing the first parameter and the first preset value; the first parameter includes the number of water addition times, the maximum stirring speed, the maximum solute dispersion uniformity, and the maximum dissolution rate; the first preset value includes the maximum threshold of the preset number of water addition times, the maximum threshold of the preset stirring speed, the maximum threshold of the preset solute dispersion uniformity, the maximum threshold of the preset dissolution rate, and the preset dissolution weight value; the preset dissolution weight value includes the first dissolution weight, the second dissolution weight, and the third dissolution weight; the stirring speed influence evaluation data is obtained by processing the second parameter and the second preset value; the second parameter includes the stirring speed change amount, the oral liquid concentration change amount, the oral liquid conductivity change amount, and the oral liquid temperature change rate; the second preset value includes the maximum threshold of the preset stirring speed change amount, the maximum threshold of the preset concentration change amount, the maximum threshold of the preset oral liquid conductivity change amount, the maximum threshold of the preset oral liquid temperature change rate, and the preset stirring speed weight value; the preset stirring speed weight value includes the first stirring speed weight, the second stirring speed weight, the third stirring speed weight, and the fourth stirring speed weight; the stirring frequency influence data is obtained by processing the third parameter and the third preset value; the third parameter includes the stirring frequency, the dissolution rate change amount, and the final state bubble generation amount; the third preset value includes the maximum threshold of the preset stirring frequency, the maximum threshold of the preset dissolution rate change amount, the maximum threshold of the preset bubble generation amount, and the preset stirring frequency weight value; the preset stirring frequency weight value includes the first stirring frequency weight, the second stirring frequency weight, and the third stirring frequency weight.

[0011] Further, the specific acquisition process of the dissolution rate evaluation value is as follows: combining the obtained maximum dissolution rate and the maximum threshold of the preset dissolution rate to obtain the dissolution rate reflection value; combining the obtained dissolution rate reflection value with the maximum stirring speed, the maximum threshold of the preset stirring speed, and the first dissolution weight to obtain the first dissolution processing value; combining the obtained dissolution rate reflection value with the number of water addition times, the maximum threshold of the preset number of water addition times, and the second dissolution weight to obtain the second dissolution processing value; combining the obtained dissolution rate reflection value with the maximum solute dispersion uniformity, the maximum threshold of the preset solute dispersion uniformity, and the third dissolution weight to obtain the third dissolution processing value; combining the dissolution rate evaluation data and the preset dissolution rate evaluation weight to obtain the dissolution rate evaluation value; the dissolution rate evaluation data includes the first dissolution processing value, the second dissolution processing value, and the third dissolution processing value; the preset dissolution rate evaluation weight includes the preset first dissolution evaluation weight, the preset second dissolution evaluation weight, and the preset third dissolution evaluation weight.

[0012] Further, the limit expression of the dissolution rate evaluation value is as follows:

[0013]

[0014] In the formula, JBPGw denotes the dissolution rate evaluation value of levocarnitine oral solution in the w-th preset time period, where w = 1, 2,..., r, w represents the serial number of the preset time period, and r represents the total number of preset time periods, RJYSD w denotes the first dissolution treatment value of levocarnitine oral solution in the w-th preset time period, RJYSL w denotes the second dissolution treatment value of levocarnitine oral solution in the w-th preset time period, RJYJY w denotes the third dissolution treatment value of levocarnitine oral solution in the w-th preset time period, ε 1 denotes the preset first dissolution evaluation weight, ε 2 denotes the preset second dissolution evaluation weight, ε 3 denotes the preset third dissolution evaluation weight, and e represents the natural constant.

[0015] Furthermore, the stirring speed influence evaluation value is obtained by combining the stirring speed influence evaluation data and the preset stirring speed influence weight; the stirring speed influence evaluation data includes the first stirring speed weighted value, the second stirring speed weighted value, the third stirring speed weighted value, and the fourth stirring speed weighted value; the first stirring speed weighted value is obtained by combining the stirring speed change influence value, the oral liquid concentration change amount, the preset maximum concentration change amount threshold, and the first stirring speed weight; the second stirring speed weighted value is obtained by combining the stirring speed change influence value, the oral liquid conductivity change amount, the preset maximum oral liquid conductivity change amount threshold, and the second stirring speed weight; the third stirring speed weighted value is obtained by combining the stirring speed change influence value, the oral liquid temperature change rate, the preset maximum oral liquid temperature change rate threshold, and the third stirring speed weight; the fourth stirring speed weighted value is obtained by combining the stirring speed change influence value, the dissolution rate evaluation value, and the fourth stirring speed weight; the stirring speed change influence value is obtained by combining the stirring speed change amount and the preset maximum stirring speed change amount threshold; the preset stirring speed influence weight includes the preset first stirring speed influence weight, the preset second stirring speed influence weight, the preset third stirring speed influence weight, and the preset fourth stirring speed influence weight.

[0016] Further, the specific process of obtaining the evaluation value of the stirring frequency is as follows: Obtain the stirring frequency influence value by processing the stirring frequency and the maximum threshold of the preset stirring frequency; Obtain the first stirring frequency weighted value by processing the stirring frequency influence value, the change amount of the dissolution rate, the maximum threshold of the preset dissolution rate change amount, and the first stirring frequency weight; Obtain the second stirring frequency weighted value by processing the stirring frequency influence value, the final state bubble generation amount, the maximum threshold of the preset bubble generation amount, and the second stirring frequency weight; Obtain the third stirring frequency weighted value by processing the stirring frequency influence value, the dissolution rate evaluation value, and the third stirring frequency weight; Obtain the evaluation value of the stirring frequency influence by processing the stirring frequency influence data and the preset stirring frequency influence weight; The stirring frequency influence data includes the first stirring frequency weighted value, the second stirring frequency weighted value, and the third stirring frequency weighted value; The preset stirring frequency influence weight includes the preset first stirring frequency influence weight, the preset second stirring frequency influence weight, and the preset third stirring frequency influence weight.

[0017] Further, the specific process of constructing a process parameter algorithm model based on the process quality feedback data and performing result feedback is as follows: Input the process quality feedback data of the obtained historical time period and the corresponding preset feedback result into the preset initial process training model for training to obtain the process parameter algorithm model; Input the obtained real-time process quality feedback data into the process parameter algorithm model to output the real-time feedback result; The preset feedback result includes the preset oral liquid color and the preset oral liquid turbidity set by the preset personnel; The feedback result includes the oral liquid color and the oral liquid turbidity.

[0018] Further, the specific process of determining whether to optimize the quality control parameters based on the process parameter algorithm model is as follows: If the pH value of the prepared oral liquid is within the preset pH value range, optimize the quality control parameters, otherwise optimize the parameters; The pH value of the prepared oral liquid represents the pH value of the levocarnitine oral solution corresponding to the process quality feedback data; The parameter optimization includes stirring speed adjustment and stirring frequency adjustment; The quality control parameter optimization includes color control optimization and turbidity control optimization; The process of color control optimization is as follows: Compare the oral liquid color output by the process parameter algorithm model with the standard color result; If the obtained oral liquid color does not meet the standard color result, optimize the parameters, otherwise obtain the corresponding process quality feedback data and the oral liquid color output by the process parameter algorithm model.

[0019] Further, the specific process of the turbidity control optimization is as follows: compare the turbidity of the oral liquid output by the process parameter algorithm model with the turbidity result of the standard oral liquid; if the obtained turbidity of the oral liquid is greater than the turbidity result of the standard oral liquid, perform parameter optimization, otherwise obtain the corresponding process quality feedback data and the turbidity of the oral liquid output by the process parameter algorithm model; determine whether the pH value of the prepared oral liquid at this time is within the preset pH value range, if it is not within the preset pH value range, re-optimize the quality control parameters, otherwise obtain the qualified monitoring data, and the qualified monitoring data represents the process quality feedback data, the turbidity of the oral liquid output by the process parameter algorithm model, and the color of the oral liquid corresponding to the pH value of the prepared oral liquid within the preset pH value range.

[0020] The embodiment of the present application provides a quality control system based on the preparation process of levocarnitine oral solution, including an oral liquid monitoring data acquisition module, an oral liquid quality evaluation module, a result feedback module, and a quality control parameter optimization module: wherein, the oral liquid monitoring data acquisition module is used to monitor the preparation process of levocarnitine oral solution through a preset sensor to obtain oral liquid monitoring data, and the oral liquid monitoring data includes dissolution rate evaluation data, stirring speed influence evaluation data, and stirring frequency influence data; the oral liquid quality evaluation module is used to evaluate the quality of the oral liquid according to the oral liquid monitoring data to obtain process quality feedback data, and the oral liquid quality evaluation includes dissolution rate evaluation, stirring speed influence evaluation, and stirring frequency influence evaluation; the result feedback module is used to construct a process parameter algorithm model according to the process quality feedback data and perform result feedback, and the process parameter algorithm model is used to feedback the color and turbidity of levocarnitine oral solution; the quality control parameter optimization module is used to determine whether to optimize the quality control parameters based on the process parameter algorithm model, and the parameter optimization is used to improve the quality stability of levocarnitine oral solution.

[0021] Unless otherwise specified, the "levocarnitine oral solution" referred to in the present invention all refers to the "levocarnitine oral solution" with the following formula: purified water, DL-malic acid, methylparaben, propylparaben, levocarnitine, saccharin sodium, with a specification of 118 ml: 11.8 g and a levocarnitine content of 11.8 g / 118 ml. Among them, methylparaben and propylparaben are preservatives, and saccharin sodium is a sweetening agent; DL-malic acid is a flavoring agent and a buffering agent.

[0022] One or more technical solutions provided in the embodiments of the present application have at least the following technical effects or advantages:

[0023] 1. By obtaining the monitoring data of the oral liquid, the quality of the oral liquid is evaluated to obtain process quality feedback data. Then, based on the process quality feedback data, a process parameter algorithm model is constructed and the results are fed back. Finally, based on the process parameter algorithm model, it is determined whether to optimize the quality control parameters, thereby improving the accuracy of the quality control parameter optimization, and further improving the physical stability of the prepared levocarnitine oral solution, effectively solving the problem of difficult quality control in the preparation of levocarnitine oral solution in the prior art.

[0024] 2. By combining the dissolution rate evaluation data and the preset dissolution rate evaluation weight, the dissolution rate evaluation value is obtained. Then, by combining the stirring speed influence evaluation data and the preset stirring speed influence weight, the stirring speed influence evaluation value is obtained. Finally, by processing the stirring frequency influence data and the preset stirring frequency influence weight, the stirring frequency influence evaluation value is obtained, thereby achieving the precise quantification of improving the physical stability of levocarnitine oral solution, and further improving the accuracy of evaluating the physical properties of levocarnitine oral solution.

[0025] 3. By inputting the process quality feedback data of the obtained historical time period and the corresponding preset feedback results into the preset initial process training model for training to obtain the process parameter algorithm model, and then inputting the obtained real-time process quality feedback data into the process parameter algorithm model to output the real-time feedback results, thereby improving the reliability of the real-time feedback results output by the process parameter algorithm model, and further improving the accuracy of the real-time feedback results output by the process parameter algorithm model. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 It is a flowchart of the quality control method based on the preparation process of levocarnitine oral solution provided by the embodiment of the present application;

[0027] Figure 2 It is a statistical chart of the change of the maximum dissolution rate - dissolution rate reflection value provided by the embodiment of the present application;

[0028] Figure 3 It is a schematic structural diagram of the quality control system based on the preparation process of levocarnitine oral solution provided by the embodiment of the present application. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0029] Embodiments of the present application provide a quality control method and system for the preparation process of levocarnitine oral solution, which solve the problems of low physical stability and difficult quality control in the prior art for preparing levocarnitine oral solution. By presetting sensors to monitor the preparation process of levocarnitine oral solution to obtain oral solution monitoring data, then evaluating the quality of the oral solution based on the oral solution monitoring data to obtain process quality feedback data, then constructing a process parameter algorithm model based on the process quality feedback data and performing result feedback, and finally judging whether to optimize the quality control parameters based on the process parameter algorithm model, the improvement of the physical stability of the prepared levocarnitine oral solution is achieved.

[0030] The technical solution in the embodiments of the present application for solving the problems of low physical stability and difficult quality control in the preparation of levocarnitine oral solution is generally as follows:

[0031] By evaluating the quality of the oral solution based on the obtained oral solution monitoring data to obtain process quality feedback data, then constructing a process parameter algorithm model based on the process quality feedback data and performing result feedback, and finally judging whether to optimize the quality control parameters based on the process parameter algorithm model, the effect of improving the physical stability of the prepared levocarnitine oral solution is achieved.

[0032] To better understand the above technical solution, the above technical solution will be described in detail below in conjunction with the accompanying drawings of the specification and specific embodiments.

[0033] Such as Figure 1As shown in the figure, it is a flowchart of a quality control method based on the preparation process of levocarnitine oral solution provided by an embodiment of the present application. The method includes the following steps: S1, obtaining oral liquid monitoring data: monitoring the preparation process of levocarnitine oral solution through preset sensors to obtain oral liquid monitoring data. The preset sensors include: a speed sensor, a stirring speed sensor, and a temperature sensor. The oral liquid monitoring data includes dissolution rate evaluation data, stirring speed influence evaluation data, and stirring frequency influence data. Levocarnitine oral solution refers to a specific formulation of 118 mL levocarnitine oral solution; S2, oral liquid quality evaluation: performing oral liquid quality evaluation based on the oral liquid monitoring data to obtain process quality feedback data. The oral liquid quality evaluation includes dissolution rate evaluation, stirring speed influence evaluation, and stirring frequency influence evaluation. The process quality feedback data includes dissolution rate evaluation value, stirring speed influence evaluation value, and stirring frequency influence evaluation value; S3, result feedback: constructing a process parameter algorithm model based on the process quality feedback data and performing result feedback. The process parameter algorithm model is used to feedback the color and turbidity of levocarnitine oral solution; S4, quality control parameter optimization: judging whether to optimize the quality control parameters based on the process parameter algorithm model. The parameter optimization is used to improve the quality stability of levocarnitine oral solution; The dissolution rate evaluation data is used to reflect the influence degree of the first parameter on the dissolution situation during the preparation monitoring process of levocarnitine oral solution; The stirring speed influence evaluation data is used to reflect the influence situation of the second parameter on the pH value; The stirring frequency influence data is used to reflect the influence situation of the third parameter on the pH value rate change.

[0034] It should be added that the dissolution rate evaluation data is obtained by processing the first parameter and the first preset value; The first parameter includes the number of water addition times, the maximum stirring speed, the maximum solute dispersion uniformity, and the maximum dissolution rate; The maximum stirring speed represents the maximum stirring speed monitored within a preset time period; The maximum solute dispersion uniformity represents the maximum solute dispersion uniformity monitored within a preset time period; The maximum dissolution rate represents the maximum dissolution rate monitored within a preset time period; The first preset value includes the maximum threshold of the preset number of water addition times, the maximum threshold of the preset stirring speed, the maximum threshold of the preset solute dispersion uniformity, the maximum threshold of the preset dissolution rate, and the preset dissolution weight value; The preset dissolution weight value includes the first dissolution weight, the second dissolution weight, and the third dissolution weight.

[0035] Among them, the number of water addition times within a preset time period is obtained through a counter; The maximum stirring speed within a preset time period is obtained and counted by the stirring speed sensor to obtain the maximum stirring speed; The maximum solute dispersion uniformity within a preset time period is obtained and counted by an image analyzer and a light scattering instrument to obtain the maximum solute dispersion uniformity; The maximum dissolution rate within a preset time period is obtained by analyzing the change of solute concentration with an external-visible spectrophotometer and counting to obtain the maximum dissolution rate.

[0036] Specifically, the evaluation data of the stirring speed is obtained by processing the second parameter and the second preset value; the second parameter includes the stirring speed change amount, the oral liquid concentration change amount, the oral liquid conductivity change amount, and the oral liquid temperature change rate; the second preset value includes the maximum threshold value of the preset stirring speed change amount, the maximum threshold value of the preset concentration change amount, the maximum threshold value of the preset oral liquid conductivity change amount, the maximum threshold value of the preset oral liquid temperature change rate, and the preset stirring speed weight value; the preset stirring speed weight value includes the first stirring speed weight, the second stirring speed weight, the third stirring speed weight, and the fourth stirring speed weight.

[0037] Among them, the absolute value of the difference in the stirring speed between the initial state and the final state within a preset time period is obtained through a speed sensor and counted to obtain the stirring speed change amount; the absolute value of the difference in the concentration of the levocarnitine oral solution between the initial state and the final state within a preset time period is analyzed and counted through a densitometer and a UV-visible spectrophotometer to obtain the oral liquid concentration change amount; the absolute value of the difference in the conductivity of the levocarnitine oral solution between the initial state and the final state within a preset time period is obtained through a conductivity meter and counted to obtain the oral liquid conductivity change amount; the rate of change in the temperature of the levocarnitine oral solution within a preset time period is obtained through a temperature sensor and a timer and counted to obtain the oral liquid temperature change rate.

[0038] Specifically, the data affected by the stirring frequency is obtained by processing the third parameter and the third preset value; the third parameter includes the stirring frequency, the change amount of the dissolution rate, and the amount of bubbles generated at the final state; the third preset value includes the maximum threshold value of the preset stirring frequency, the maximum threshold value of the preset change amount of the dissolution rate, the maximum threshold value of the preset amount of bubbles generated, and the preset stirring frequency weight value; the preset stirring frequency weight value includes the first stirring frequency weight, the second stirring frequency weight, and the third stirring frequency weight.

[0039] Among them, the stirring frequency within a preset time period is obtained through a frequency meter (the frequency meter built in the stirrer), and the stirring frequency within the preset time period in this embodiment is a fixed value; the absolute value of the difference in the dissolution rate between the initial state and the final state within a preset time period is monitored through an optical dissolution rate measuring instrument to obtain the change amount of the dissolution rate; the number of bubbles in the levocarnitine oral solution at the final state within a preset time period is obtained through a bubble counter to obtain the amount of bubbles generated at the final state.

[0040] In this embodiment, the levocarnitine oral solution in this embodiment is all levocarnitine oral solution with a specification of 118 mL. Obtaining the monitoring data of the oral solution is the basis for evaluating the quality of the oral solution. Based on the monitoring data of the oral solution, process quality feedback data is obtained. The obtained dissolution rate evaluation value, stirring speed influence evaluation value, and stirring frequency influence evaluation value have an interactive effect; the higher the dissolution rate evaluation value, the more conducive it is to increasing the contact area and mixing uniformity between the solute and the solvent, thereby improving the influence of the stirring speed and stirring frequency on the pH value and the pH value change rate, helping to reduce the stirring speed influence evaluation value and the stirring frequency influence evaluation value, so as to improve the quality of the preparation of levocarnitine oral solution, and further achieving the effect of improving the character stability of the prepared levocarnitine oral solution.

[0041] In this embodiment, the preparation process of 118 mL of levocarnitine oral solution with a specific formulation is as follows: Add purified water accounting for about 80% of the total preparation volume to the concentrated preparation tank, start stirring with a stirring frequency of 30 - 50 Hz, start heating, and heat the purified water in the concentrated preparation tank to 80°C ± 5°C for standby; Start the external circulation system, and after the circulation returns, add methylparaben and propylparaben in sequence, and rinse the container and spray the tank wall with purified water, continue stirring for ≥30 min until the solution is clear, turn off the heating and external circulation system, start the cooling device, and cool the solution temperature to room temperature (10°C - 30°C); Add DL-malic acid, rinse the container and spray the tank wall with purified water, and continue stirring for 10 min until the solution is clear; Add levocarnitine, rinse the container and spray the tank wall with purified water, and continue stirring for 15 min until the solution is clear after levocarnitine is completely dissolved; Add saccharin sodium, rinse the container and spray the tank wall with purified water, and continue stirring for 10 min until the solution is clear; After the stirring ends, take a sample of the concentrated preparation solution for inspection; Make up the purified water to the total preparation volume according to the relative density of the concentrated preparation solution, circulate and stir for 30 min, and take the intermediate product to detect its properties, pH value, relative density, and content; The medicinal liquid is circulated and filtered through a 5-μm titanium rod filter for 30 min, monitor that the clarity of the solution is qualified, and after the intermediate product is qualified, then transport the medicinal liquid to the filling and sealing production line, adjust the filling volume to be qualified, and start filling and sealing; Packaging and warehousing: Label and package the selected qualified products and put them into storage. This preparation process is the best process obtained after optimizing by this method and system. The stress testing, accelerated stability testing, and long-term stability testing carried out in accordance with the currently effective "Basic Technical Guidelines for the Research of Chemical Pharmaceutical Preparations" of the national drug regulatory department show that including tests such as being placed upright / inverted at 40°C, being placed upright / inverted at 60°C, being exposed to light without packaging (upright / inverted), being exposed to light with packaging upright (upright / inverted), being placed at low temperature (upright / inverted), freeze-thaw (upright / inverted) testing, etc., the levocarnitine oral solution prepared by this process did not show discoloration or turbidity in each batch during the stress testing, accelerated stability testing, and long-term stability testing, and the total impurity content calculated by the peak area of the external standard method using liquid chromatography was less than 1.0%. The chromatographic conditions for the related substances detection are the same as the quality standard of levocarnitine in the Chinese Pharmacopoeia. When parameters such as temperature or rotation speed exceed the scope of this process, the oral liquid will show discoloration or turbidity under different test conditions.

[0042] Further, the specific process for obtaining the dissolution rate evaluation value is as follows: Combine the obtained maximum dissolution rate and the preset maximum dissolution rate threshold to obtain the dissolution rate reflection value, that is, RJ w ; Combine the obtained dissolution rate reflection value with the maximum stirring speed, the preset maximum stirring speed threshold, and the first dissolution weight to obtain the first dissolution processing value, that is, RJYSD w ; Combine the obtained dissolution rate reflection value with the number of water addition times, the preset maximum number of water addition times, and the second dissolution weight to obtain the second dissolution processing value, that is, RJYSLw ; Combine the obtained dissolution rate reflection value with the maximum value of solute dispersion uniformity, the preset maximum threshold of solute dispersion uniformity, and the third dissolution weight to obtain the third dissolution treatment value, i.e., RJYJY w ; Combine the dissolution rate evaluation data and the preset dissolution rate evaluation weight to obtain the dissolution rate evaluation value; the dissolution rate evaluation data includes the first dissolution treatment value, the second dissolution treatment value, and the third dissolution treatment value; the preset dissolution rate evaluation weight includes the preset first dissolution evaluation weight, the preset second dissolution evaluation weight, and the preset third dissolution evaluation weight; the preset first dissolution evaluation weight is used to reflect the influence degree of the first dissolution treatment value on the dissolution rate evaluation value; the preset second dissolution evaluation weight is used to reflect the influence degree of the second dissolution treatment value on the dissolution rate evaluation value; the preset third dissolution evaluation weight is used to reflect the influence degree of the third dissolution treatment value on the dissolution rate evaluation value; the first dissolution weight is used to reflect the influence degree of the stirring speed on the first dissolution treatment value; the second dissolution weight is used to reflect the influence degree of the water addition times on the second dissolution treatment value; the third dissolution weight is used to reflect the influence degree of the solute dispersion uniformity on the third dissolution treatment value; the dissolution rate evaluation value is used to evaluate the dissolution situation during the preparation monitoring of levocarnitine oral solution.

[0043] Among them, the limit expression of the dissolution rate evaluation value is as follows:

[0044]

[0045] In the formula, JBPG w represents the dissolution rate evaluation value of levocarnitine oral solution in the w-th preset time period, w = 1, 2,..., r, w represents the number of the preset time period, r represents the total number of the preset time periods, RJYSD w represents the first dissolution treatment value of levocarnitine oral solution in the w-th preset time period, RJYSL w represents the second dissolution treatment value of levocarnitine oral solution in the w-th preset time period, RJYJY w represents the third dissolution treatment value of levocarnitine oral solution in the w-th preset time period, ε 1 represents the preset first dissolution evaluation weight, ε 2 represents the preset second dissolution evaluation weight, ε 3 represents the preset third dissolution evaluation weight, and e represents the natural constant.

[0046] RJ w represents the dissolution rate reflection value of levocarnitine oral solution in the w-th preset time period, RJSL w represents the maximum dissolution rate of levocarnitine oral solution in the w-th preset time period, JBSD wIt represents the maximum stirring speed of levocarnitine oral solution in the w-th preset time period, JSL w It represents the number of water addition times of levocarnitine oral solution in the w-th preset time period, JYD w It represents the maximum value of the solute dispersion uniformity of levocarnitine oral solution in the w-th preset time period, a 1 It represents the first dissolution weight, a 2 It represents the second dissolution weight, a 3 It represents the third dissolution weight, JBSD 0 It represents the maximum threshold of the preset stirring speed, JSL 0 It represents the maximum threshold of the preset number of water addition times, JYD 0 It represents the maximum threshold of the preset solute dispersion uniformity, RJSL 0 It represents the maximum threshold of the preset dissolution rate.

[0047] In this embodiment, the aforementioned database is a database for storing various setting data in the quality control method for the preparation process of levocarnitine oral solution provided in this application embodiment. The database includes but is not limited to the maximum threshold of the preset number of water addition times, the maximum threshold of the preset stirring speed, the maximum threshold of the preset solute dispersion uniformity, etc. The various numerical values therein are directly set by technicians. For example, the maximum threshold of the preset number of water addition times is represented by the maximum value of the number of water addition times in the historical time period, the maximum threshold of the preset stirring speed is represented by the maximum value of the stirring speed in the historical time period, the maximum threshold of the preset solute dispersion uniformity is represented by the maximum value of the solute dispersion uniformity in the historical time period, and the maximum threshold of the preset dissolution rate is represented by the maximum value of the dissolution rate in the historical time period.

[0048] It should be added that the database in this embodiment provides a mapping set for reflecting the mapping relationship between the stirring speed, the number of water addition times, and the solute dispersion uniformity and the corresponding weights. The real-time stirring speed, the number of water addition times, and the solute dispersion uniformity are input into the preset mapping set to obtain the corresponding preset dissolution weight value. The mapping relationship in this mapping set can be a one-to-one or many-to-one relationship. For example, in this embodiment, the value ranges of the first dissolution weight, the second dissolution weight, and the third dissolution weight are 0 - 1.

[0049] The database in this embodiment provides a mapping set for reflecting the mapping relationship between the first dissolution processing value, the second dissolution processing value, and the third dissolution processing value and the corresponding weights. The real-time first dissolution processing value, the second dissolution processing value, and the third dissolution processing value are input into the preset mapping set to obtain the corresponding preset dissolution rate evaluation weight. The mapping relationship in this mapping set can be a one-to-one or many-to-one relationship. For example, in this embodiment, the value ranges of the preset first dissolution evaluation weight, the preset second dissolution evaluation weight, and the preset third dissolution evaluation weight are 0 - 1.

[0050] Specifically, assume that the maximum dissolution rate RJSL w ranges from 50 to 100 (mg / min), and the preset maximum dissolution rate threshold RJSL 0 is fixed at 100 (mg / min). As Figure 2 shown, it is a statistical chart of the change of the maximum dissolution rate - dissolution rate reflection value provided by the embodiment of the present application. It can be seen from Figure 2 this that as the maximum dissolution rate gradually increases, the dissolution rate reflection value also gradually increases, indicating that the dissolution situation during the preparation monitoring of levocarnitine oral solution is gradually improved.

[0051] The algorithm of this embodiment combines the dissolution rate evaluation data to obtain the dissolution rate evaluation value. The larger the maximum dissolution rate, the better the dissolution situation, resulting in an increase in the dissolution rate evaluation value; the larger the maximum stirring speed, the maximum solute dispersion uniformity, and the number of water additions, the more conducive to the dissolution of the solute in the levocarnitine oral solution, resulting in an increase in the dissolution rate evaluation value.

[0052] In the algorithm of this embodiment, the dissolution rate evaluation data does not exist independently, and there is a mutual correlation between the independent variables, which requires comprehensive analysis. The more times of water addition is conducive to the full dissolution of the solute, but it may affect the concentration of the levocarnitine oral solution, thereby affecting the dissolution rate; the more times of water addition may lead to the redistribution of the solute in the levocarnitine oral solution, thereby affecting the solute dispersion uniformity; the higher the solute dispersion uniformity, the larger the contact area between the solute and the solvent, and the faster the dissolution rate; the solute dispersion uniformity is jointly affected by the stirring speed and the number of water additions. The increase in the stirring speed and the number of water additions helps to improve the solute dispersion uniformity. By analyzing the comprehensive influence between the parameters, the accurate evaluation of the dissolution situation during the preparation monitoring of levocarnitine oral solution is realized, and further the improvement of the physical stability of the prepared levocarnitine oral solution is realized.

[0053] Further, the influence of the stirring speed on the evaluation value is obtained by combining the influence evaluation data of the stirring speed and the preset influence weight of the stirring speed; the influence evaluation data of the stirring speed includes the first stirring speed weighting value, the second stirring speed weighting value, the third stirring speed weighting value, and the fourth stirring speed weighting value; the first stirring speed weighting value is obtained by combining the influence value of the stirring speed change, the change amount of the oral liquid concentration, the preset maximum threshold of the concentration change amount, and the first stirring speed weight, that is, JBND w ; the second stirring speed weighting value is obtained by combining the influence value of the stirring speed change, the change amount of the oral liquid conductivity, the preset maximum threshold of the oral liquid conductivity change amount, and the second stirring speed weight, that is, JBDD w; The third stirring speed weighting value is obtained by combining the influence value of the stirring speed change, the change rate of the oral liquid temperature, the maximum threshold value of the preset oral liquid temperature change rate, and the third stirring speed weight, i.e., JBWS w ; The fourth stirring speed weighting value is obtained by combining the influence value of the stirring speed change, the dissolution rate evaluation value, and the fourth stirring speed weight, i.e., JBYSD w ; The influence value of the stirring speed change is obtained by combining the change amount of the stirring speed and the maximum threshold value of the preset stirring speed change amount, i.e., JBSDBH w ; The first stirring speed weight is used to reflect the influence degree of the change amount of the oral liquid concentration on the first stirring speed weighting value; the second stirring speed weight is used to reflect the influence degree of the change amount of the oral liquid conductivity on the second stirring speed weighting value; the third stirring speed weight is used to reflect the influence degree of the change rate of the oral liquid temperature on the third stirring speed weighting value; the fourth stirring speed weight is used to reflect the influence degree of the dissolution rate evaluation value on the fourth stirring speed weighting value; the preset stirring speed influence weight includes the preset first stirring speed influence weight, the preset second stirring speed influence weight, the preset third stirring speed influence weight, and the preset fourth stirring speed influence weight; the preset first stirring speed influence weight is used to reflect the influence degree of the first stirring speed weighting value on the stirring speed influence evaluation value; the preset second stirring speed influence weight is used to reflect the influence degree of the second stirring speed weighting value on the stirring speed influence evaluation value; the preset third stirring speed influence weight is used to reflect the influence degree of the third stirring speed weighting value on the stirring speed influence evaluation value; the preset fourth stirring speed influence weight is used to reflect the influence degree of the fourth stirring speed weighting value on the stirring speed influence evaluation value; the stirring speed influence evaluation value is used to evaluate the influence of the stirring speed on the pH value during the preparation monitoring of the levocarnitine oral solution.

[0054] Among them, the stirring speed influence evaluation value is obtained by the following method:

[0055]

[0056] JBYSD w = csch -1 (b 4 *JBPG w *JBSDBH w );

[0057] In the formula, JBSD w represents the stirring speed influence evaluation value of the levocarnitine oral solution in the w-th preset time period, w = 1, 2,..., r, w represents the number of the preset time period, r represents the total number of the preset time periods, JBND w represents the first stirring speed weighting value of the levocarnitine oral solution in the w-th preset time period, JBDD wRepresents the second stirring speed weighting value of levocarnitine oral solution in the w-th preset time period, JBWS w Represents the third stirring speed weighting value of levocarnitine oral solution in the w-th preset time period, JBYSD w Represents the fourth stirring speed weighting value of levocarnitine oral solution in the w-th preset time period, μ 1 Represents the preset influence weight of the first stirring speed, μ 2 Represents the preset influence weight of the second stirring speed, μ 3 Represents the preset influence weight of the third stirring speed, μ 4 Represents the preset influence weight of the fourth stirring speed, e represents the natural constant.

[0058] JBSDBH w Represents the influence value of the stirring speed change of levocarnitine oral solution in the w-th preset time period, SDBH w Represents the change amount of the stirring speed of levocarnitine oral solution in the w-th preset time period, NDBH w Represents the change amount of the oral liquid concentration of levocarnitine oral solution in the w-th preset time period, DDL w Represents the change amount of the oral liquid conductivity of levocarnitine oral solution in the w-th preset time period, WDSL w Represents the change rate of the oral liquid temperature of levocarnitine oral solution in the w-th preset time period, JBPG w Represents the dissolution rate evaluation value of levocarnitine oral solution in the w-th preset time period, b 1 Represents the weight of the first stirring speed, b 2 Represents the weight of the second stirring speed, b 3 Represents the weight of the third stirring speed, b 4 Represents the weight of the fourth stirring speed, SDBH 0 Represents the maximum threshold value of the preset stirring speed change amount, NDBH 0 Represents the maximum threshold value of the preset concentration change amount, DDL 0 Represents the maximum threshold value of the preset oral liquid conductivity change amount, WDSL 0 Represents the maximum threshold value of the preset oral liquid temperature change rate.

[0059] In this embodiment, the maximum threshold value of the preset stirring speed change amount is represented by the maximum value of the stirring speed change amount in the historical time period, the maximum threshold value of the preset concentration change amount is represented by the maximum value of the concentration change amount in the historical time period, the maximum threshold value of the preset oral liquid conductivity change amount is represented by the maximum value of the oral liquid conductivity change amount in the historical time period, and the maximum threshold value of the preset oral liquid temperature change rate is represented by the maximum value of the oral liquid temperature change rate in the historical time period.

[0060] It should be added that in the database of this embodiment, a mapping set is provided for reflecting the mapping relationship between the change amount of the oral liquid concentration, the change amount of the oral liquid conductivity, the change rate of the oral liquid temperature, and the evaluation value of the dissolution rate and the corresponding weights. The real-time change amount of the oral liquid concentration, the change amount of the oral liquid conductivity, the change rate of the oral liquid temperature, and the evaluation value of the dissolution rate are input into the preset mapping set to obtain the corresponding preset stirring speed weight value. The mapping relationship in this mapping set can be a one-to-one or many-to-one relationship. For example, in this embodiment, the value ranges of the first stirring speed weight, the second stirring speed weight, the third stirring speed weight, and the fourth stirring speed weight are 0-1.

[0061] In the database of this embodiment, a mapping set is provided for reflecting the mapping relationship between the first stirring speed empowerment value, the second stirring speed empowerment value, the third stirring speed empowerment value, and the fourth stirring speed empowerment value and the corresponding weights. The real-time first stirring speed empowerment value, the second stirring speed empowerment value, the third stirring speed empowerment value, and the fourth stirring speed empowerment value are input into the preset mapping set to obtain the corresponding preset stirring speed influence weight. The mapping relationship in this mapping set can be a one-to-one or many-to-one relationship. For example, in this embodiment, the value ranges of the preset first stirring speed influence weight, the preset second stirring speed influence weight, the preset third stirring speed influence weight, and the preset fourth stirring speed influence weight are 0-1.

[0062] The algorithm of this embodiment combines the analysis of the stirring speed influence evaluation data to obtain the stirring speed influence evaluation value. The greater the change amount of the stirring speed, the greater the impact on the pH of the levocarnitine oral solution, resulting in an increase in the stirring speed influence evaluation value. The greater the change amount of the oral liquid concentration, the change amount of the oral liquid conductivity, and the change rate of the oral liquid temperature, the greater the impact on the change amount of the stirring speed, resulting in an increase in the stirring speed influence evaluation value.

[0063] In the algorithm of this embodiment, the evaluation data of the influence of the stirring speed do not exist independently, and there is a mutual correlation between the independent variables, which requires comprehensive analysis. The larger the evaluation value of the dissolution rate, the greater the stirring speed may be required for the preparation of levocarnitine oral solution, which in turn leads to an increase in the evaluation value of the influence of the stirring speed; the greater the change in the stirring speed, it may directly affect the mixing uniformity and solute dispersion degree in the levocarnitine oral solution, and then affect the stability of the pH value; the greater the change in the stirring speed, it may affect the movement and distribution of ions in the levocarnitine oral solution, and then affect the change in the conductivity of the oral solution; when the stirring speed changes, the distribution state of the solute in the levocarnitine oral solution will also change, and then affect the change in the concentration of the oral solution; the change in the stirring speed may affect the heat exchange rate between the levocarnitine oral solution and the environment, and then affect the change rate of the temperature of the oral solution. By analyzing the comprehensive influence between the parameters, the accurate evaluation of the influence of the stirring speed on the pH value during the preparation monitoring of the levocarnitine oral solution is realized, and then the effect of improving the property stability of the prepared levocarnitine oral solution is achieved.

[0064] Further, the specific process of obtaining the evaluation value of the influence of the stirring frequency is as follows: The influence value of the stirring frequency is obtained by processing the stirring frequency and the maximum threshold of the preset stirring frequency, that is, JBPLYX w ; The first weighted value of the stirring frequency, that is, JBRJ, is obtained by processing the influence value of the stirring frequency, the change amount of the dissolution rate, the maximum threshold of the preset change amount of the dissolution rate, and the first stirring frequency weight w ; The second weighted value of the stirring frequency, that is, JBQP, is obtained by processing the influence value of the stirring frequency, the amount of bubbles generated at the end state, the maximum threshold of the preset amount of bubbles generated, and the second stirring frequency weight w ; The third weighted value of the stirring frequency, that is, JBYPL, is obtained by processing the influence value of the stirring frequency, the evaluation value of the dissolution rate, and the third stirring frequency weight w; The stirring frequency influence evaluation value is obtained by processing the stirring frequency influence data and the preset stirring frequency influence weights; the stirring frequency influence data includes the first stirring frequency weighted value, the second stirring frequency weighted value, and the third stirring frequency weighted value; the preset stirring frequency influence weights include the preset first stirring frequency influence weight, the preset second stirring frequency influence weight, and the preset third stirring frequency influence weight; the preset first stirring frequency influence weight is used to reflect the influence degree of the first stirring frequency weighted value on the stirring frequency influence evaluation value; the preset second stirring frequency influence weight is used to reflect the influence degree of the second stirring frequency weighted value on the stirring frequency influence evaluation value; the preset third stirring frequency influence weight is used to reflect the influence degree of the third stirring frequency weighted value on the stirring frequency influence evaluation value; the first stirring frequency weight is used to reflect the influence degree of the change amount of the dissolution rate on the first stirring frequency weighted value; the second stirring frequency weight is used to reflect the influence degree of the final state bubble generation amount on the second stirring frequency weighted value; the third stirring frequency weight is used to reflect the influence degree of the dissolution rate evaluation value on the third stirring frequency weighted value; the stirring frequency influence evaluation value is used to evaluate the influence of the stirring frequency on the pH value change rate during the preparation monitoring of levocarnitine oral solution.

[0065] Among them, the stirring frequency influence evaluation value is obtained by the following method:

[0066]

[0067] JBYPL w = tanh -1 (c 3 *JBPG w *JBPLYX w );

[0068] In the formula, JBPL w represents the stirring frequency influence evaluation value of levocarnitine oral solution in the w-th preset time period, w = 1, 2,..., r, w represents the number of the preset time period, r represents the total number of the preset time periods, JBRJ w represents the first stirring frequency weighted value of levocarnitine oral solution in the w-th preset time period, JBQP w represents the second stirring frequency weighted value of levocarnitine oral solution in the w-th preset time period, JBYPL w represents the third stirring frequency weighted value of levocarnitine oral solution in the w-th preset time period, σ 1 represents the preset first stirring frequency influence weight, σ 2 represents the preset second stirring frequency influence weight, σ 3 represents the preset third stirring frequency influence weight, and e represents the natural constant.

[0069] JBPLYXw Denotes the influence value of the stirring frequency of levocarnitine oral solution in the w-th preset time period, JBPL w Denotes the stirring frequency of levocarnitine oral solution in the w-th preset time period, RJSL w Denotes the change amount of the dissolution rate of levocarnitine oral solution in the w-th preset time period, QPL w Denotes the final state bubble generation amount of levocarnitine oral solution in the w-th preset time period, JBPG w Denotes the dissolution rate evaluation value of levocarnitine oral solution in the w-th preset time period, c 1 Denotes the first stirring frequency weight, c 2 Denotes the second stirring frequency weight, c 3 Denotes the third stirring frequency weight, JBPL 0 Denotes the maximum threshold of the preset stirring frequency, RJSL 0 Denotes the maximum threshold of the preset change amount of the dissolution rate, QPL 0 Denotes the maximum threshold of the preset bubble generation amount.

[0070] In this embodiment, the maximum threshold of the preset stirring frequency change amount is represented by the maximum value of the stirring frequency in the historical time period, the maximum threshold of the preset change amount of the dissolution rate is represented by the maximum value of the change amount of the dissolution rate in the historical time period, and the maximum threshold of the preset bubble generation amount is represented by the maximum value of the bubble generation amount in the historical time period.

[0071] It should be added that the database in this embodiment provides a mapping set for reflecting the mapping relationship between the change amount of the dissolution rate, the final state bubble generation amount, the dissolution rate evaluation value and the corresponding weights. Input the real-time change amount of the dissolution rate, the final state bubble generation amount and the dissolution rate evaluation value into the preset mapping set to obtain the corresponding preset stirring frequency weight value. The mapping relationship in this mapping set can be a one-to-one or many-to-one relationship; for example, in this embodiment, the value ranges of the first stirring frequency weight, the second stirring frequency weight and the third stirring frequency weight are 0-1.

[0072] The database in this embodiment provides a mapping set for reflecting the mapping relationship between the first stirring frequency weighting value, the second stirring frequency weighting value and the third stirring frequency weighting value and the corresponding weights. Input the real-time first stirring frequency weighting value, the second stirring frequency weighting value and the third stirring frequency weighting value into the preset mapping set to obtain the corresponding preset stirring frequency influence weight. The mapping relationship in this mapping set can be a one-to-one or many-to-one relationship; for example, in this embodiment, the value ranges of the preset first stirring frequency influence weight, the preset second stirring frequency influence weight and the preset third stirring frequency influence weight are 0-1.

[0073] Specifically, assume the first stirring frequency weighting value JBRJw ranges from 0.3 to 0.5, the second stirring frequency weighting value JBQP w ranges from 0.3 to 0.5, the third stirring frequency weighting value JBYPL w ranges from 0.3 to 0.5, the preset influence weight σ of the first stirring frequency 1 is fixed at 0.4, the preset influence weight σ of the second stirring frequency 2 is fixed at 0.4, the preset influence weight σ of the third stirring frequency 3 is fixed at 0.2. As shown in Table 1, it is the statistical table of the change of the stirring frequency influence evaluation value provided by the embodiment of the present application:

[0074] Table 1 Statistical table of the change of the stirring frequency influence evaluation value

[0075]

[0076] As can be seen from the above table, as the first stirring frequency weighting value, the first stirring frequency weighting value, and the first stirring frequency weighting value gradually increase, the stirring frequency influence evaluation value also gradually increases, indicating that the influence degree of the stirring frequency in the preparation monitoring process of levocarnitine oral solution on the pH value gradually increases.

[0077] The algorithm of this embodiment combines the analysis of the stirring frequency influence data to obtain the stirring frequency influence evaluation value. The greater the stirring frequency, the greater the influence on the pH value change rate of levocarnitine oral solution, resulting in an increase in the stirring frequency influence evaluation value; the greater the change amount of the dissolution rate and the amount of end-state bubbles generated, the greater the influence on the stirring frequency of the solute of levocarnitine oral solution, resulting in an increase in the stirring frequency influence evaluation value.

[0078] In the algorithm of this embodiment, the stirring frequency influence data do not exist independently, and there is a mutual correlation between the independent variables, which needs to be comprehensively analyzed. The greater the dissolution rate evaluation value, the greater the stirring frequency required for preparing levocarnitine oral solution; as the stirring frequency increases, the solute particles in levocarnitine oral solution will be subjected to stronger shear force and impact force, thus accelerating the dispersion and dissolution rate of solute particles in the solvent, and further affecting the change amount of the dissolution rate; as the stirring frequency increases, the gas molecules in levocarnitine oral solution will be subjected to stronger interference, thus making it easier to form bubbles, and further affecting the amount of end-state bubbles generated. By analyzing the comprehensive influence between parameters, the accurate evaluation of the influence of the stirring frequency on the pH value in the preparation monitoring process of levocarnitine oral solution is realized, and the effect of improving the physical stability of the prepared levocarnitine oral solution is achieved.

[0079] Furthermore, the specific process of constructing a process parameter algorithm model based on process quality feedback data and performing result feedback is as follows: Input the process quality feedback data of the historical time period and the corresponding preset feedback results obtained into a preset initial process training model for training to obtain a process parameter algorithm model; Input the obtained real-time process quality feedback data into the process parameter algorithm model to output real-time feedback results; The preset feedback results include the preset oral liquid color and the preset oral liquid turbidity set by the preset personnel; The feedback results include the oral liquid color and the oral liquid turbidity; The preset initial process training model represents the obtained machine learning model (such as a feedback neural network model), the input of the process parameter algorithm model is the process quality feedback data, and the output is the feedback result.

[0080] It should be added that the specific process of judging whether to optimize the quality control parameters based on the process parameter algorithm model is as follows: Judge whether the pH value of the prepared oral liquid is within the preset pH value range; If the pH value of the prepared oral liquid is within the preset pH value range, perform quality control parameter optimization, otherwise perform parameter optimization; The pH value of the prepared oral liquid represents the pH value of the levocarnitine oral solution corresponding to the process quality feedback data; Parameter optimization includes adjusting the stirring speed and the stirring frequency; Quality control parameter optimization includes color control optimization and turbidity control optimization; The process of color control optimization is as follows: Compare the oral liquid color output by the process parameter algorithm model with the standard color result; If the obtained oral liquid color does not meet the standard color result, perform parameter optimization, otherwise obtain the corresponding process quality feedback data and the oral liquid color output by the process parameter algorithm model; The standard color result represents the color number range corresponding to the yellow No. 2 standard colorimetric solution.

[0081] The specific process of turbidity control optimization is as follows: Compare the oral liquid turbidity output by the process parameter algorithm model with the standard oral liquid turbidity result; If the obtained oral liquid turbidity is greater than the standard oral liquid turbidity result, perform parameter optimization, otherwise obtain the corresponding process quality feedback data and the oral liquid turbidity output by the process parameter algorithm model; The standard oral liquid turbidity result represents the turbidity corresponding to the No. 1 turbidity standard solution; Judge whether the pH value of the prepared oral liquid at this time is within the preset pH value range. If it is not within the preset pH value range, perform quality control parameter optimization again. Otherwise, obtain qualified monitoring data. The qualified monitoring data represents the process quality feedback data corresponding to the pH value of the prepared oral liquid within the preset pH value range, the oral liquid turbidity and the oral liquid color output by the process parameter algorithm model.

[0082] In this embodiment, the preset pH value range is set by the preset personnel. In this embodiment, the preset pH value range is 4.0 - 6.0. The relative density of the levocarnitine oral solution prepared in this embodiment should be 1.000 - 1.040. The yellow No. 2 standard colorimetric solution corresponds to Method 1 of General Principles 0901 in Part IV of the Chinese Pharmacopoeia 2020 Edition, and the turbidity standard solution No. 1 corresponds to Method 1 of General Principles 0902 in Part IV of the Chinese Pharmacopoeia 2020 Edition. By inputting the process quality feedback data and the corresponding feedback results obtained in the historical time period into the feedback neural network model for training, a trained process parameter algorithm model is obtained. Then, the process quality feedback data obtained by real-time monitoring is input into the process parameter algorithm model. The input is the process quality feedback data, and the output is the feedback result. If the color of the oral liquid output does not meet the standard color result or the turbidity of the oral liquid is greater than the standard oral liquid turbidity result, parameter optimization is performed. After receiving the parameter optimization prompt, the preset personnel adjust the stirring speed and stirring frequency step by step in a preset multiple, which helps to optimize the preparation quality of the levocarnitine oral solution, thereby improving the character stability of the prepared levocarnitine oral solution.

[0083] As Figure 3 shown, it is a schematic structural diagram of the quality control system based on the preparation process of the levocarnitine oral solution provided by the embodiment of the present application. The quality control system based on the preparation process of the levocarnitine oral solution provided by the embodiment of the present application includes an oral liquid monitoring data acquisition module, an oral liquid quality evaluation module, a result feedback module, and a quality control parameter optimization module. Among them, the oral liquid monitoring data acquisition module is used to monitor the preparation process of the levocarnitine oral solution through a preset sensor to obtain oral liquid monitoring data. The oral liquid monitoring data includes dissolution rate evaluation data, stirring speed influence evaluation data, and stirring frequency influence data. The levocarnitine oral solution refers to a specific formulation levocarnitine oral solution with a specification of 118 ml: 11.8 g. The oral liquid quality evaluation module is used to evaluate the oral liquid quality based on the oral liquid monitoring data to obtain process quality feedback data. The oral liquid quality evaluation includes dissolution rate evaluation, stirring speed influence evaluation, and stirring frequency influence evaluation. The process quality feedback data includes dissolution rate evaluation values, stirring speed influence evaluation values, and stirring frequency influence evaluation values. The result feedback module is used to construct a process parameter algorithm model based on the process quality feedback data and perform result feedback. The process parameter algorithm model is used to feedback the color and turbidity of the levocarnitine oral solution. The quality control parameter optimization module is used to determine whether to optimize the quality control parameters based on the process parameter algorithm model. The parameter optimization is used to improve the quality stability of the levocarnitine oral solution.

[0084] In this embodiment, the oral liquid monitoring data acquisition module, the oral liquid quality assessment module, the result feedback module, and the quality control parameter optimization module interact with each other to jointly achieve the monitoring, assessment, feedback, and optimization of the oral liquid preparation process. The oral liquid monitoring data acquisition module is the basis for the oral liquid quality assessment module and the result feedback module. When the feedback result output by the process parameter algorithm model meets the preset conditions, that is, the color of the oral liquid conforms to the standard color result and the turbidity of the oral liquid is not greater than the standard oral liquid turbidity result, no quality control parameter optimization is performed. The quality control parameter optimization module receives the monitoring data of the oral liquid quality assessment module and the result feedback module. The cooperation of each module helps to ensure the stability and consistency of the quality of levocarnitine oral solution, and further improves the morphological stability of the prepared levocarnitine oral solution.

[0085] In summary, by obtaining the oral liquid monitoring data to evaluate the oral liquid quality and obtain the process quality feedback data, then constructing a process parameter algorithm model based on the process quality feedback data and performing result feedback, and finally judging whether to optimize the quality control parameters based on the process parameter algorithm model, the accuracy of the quality control parameter optimization is improved, and further the morphological stability of the prepared levocarnitine oral solution is improved, effectively solving the problem of low morphological stability of the prepared levocarnitine oral solution in the prior art.

[0086] Those skilled in the art should understand that the embodiments of the present invention can be provided as methods, systems, or computer program products. Therefore, the present invention can take the form of a complete hardware embodiment, a complete software embodiment, or an embodiment combining software and hardware aspects. Moreover, the present invention can take the form of a computer program product implemented on one or more computer-usable storage media (including but not limited to disk storage, CD-ROM, optical storage, etc.) containing computer-usable program code.

[0087] The present invention is described with reference to the flowcharts and / or block diagrams of methods, apparatuses (systems), and computer program products according to the embodiments of the present invention. It should be understood that each flow and / or block in the flowchart and / or block diagram, and the combination of flows and / or blocks in the flowchart and / or block diagram, can be realized by computer program instructions. These computer program instructions can be provided to the processor of a general-purpose computer, a special-purpose computer, an embedded processor, or other programmable data processing devices to generate a machine, so that the instructions executed by the processor of the computer or other programmable data processing devices generate a device for realizing the functions specified in one Figure 1 one flow or multiple flows and / or blocks Figure 1 one block or multiple blocks.

[0088] These computer program instructions may also be stored in a computer-readable memory that can direct a computer or other programmable data processing apparatus to operate in a particular manner, such that the instructions stored in the computer-readable memory produce an article of manufacture including instruction means that implement the function specified in one or more of the blocks and / or steps of the flowchart(s). Figure 1 one or more of the blocks and / or steps Figure 1 specified in one or more of the blocks and / or steps of the flowchart(s).

[0089] These computer program instructions may also be loaded onto a computer or other programmable data processing apparatus to cause a series of operational steps to be performed on the computer or other programmable apparatus to produce a computer-implemented process, whereby the instructions executed on the computer or other programmable apparatus provide steps for implementing the function specified in one or more of the blocks and / or steps of the flowchart(s). Figure 1 one or more of the blocks and / or steps Figure 1 specified in one or more of the blocks and / or steps of the flowchart(s).

[0090] Although the preferred embodiments of the present invention have been described, additional changes and modifications can be made by those skilled in the art once they learn of the basic inventive concept. Therefore, the appended claims are intended to be construed to cover the preferred embodiments as well as all changes and modifications falling within the scope of the present invention.

[0091] It is apparent that those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention is also intended to include these modifications and variations.

Claims

1. A quality control method based on the preparation process of L-carnitine oral solution, characterized in that: The following steps are involved: S1, monitoring the preparation process of the L-carnitine oral solution through a preset sensor to obtain oral solution monitoring data, wherein the oral solution monitoring data includes dissolution rate evaluation data, stirring speed impact evaluation data, and stirring frequency impact data; S2, performing oral liquid quality assessment based on oral liquid monitoring data to obtain process quality feedback data, wherein the oral liquid quality assessment includes dissolution rate assessment, stirring speed impact assessment, and stirring frequency impact assessment; S3, constructing a process parameter algorithm model based on the process quality feedback data and providing result feedback, wherein the process parameter algorithm model is used to provide feedback on the color and turbidity of the L-carnitine oral solution; S4, judging whether to perform quality control parameter optimization based on the process parameter algorithm model, wherein the parameter optimization is used to improve the quality stability of the L-carnitine oral solution.

2. The quality control method based on the preparation process of L-carnitine oral solution as claimed in claim 1, characterized in that: The dissolution rate evaluation data is obtained by processing the first parameter and the first preset value; The first parameters include the number of water additions, the maximum stirring speed, the maximum solute dispersion uniformity, and the maximum dissolution rate; The first preset value includes a preset maximum threshold value of water addition times, a preset maximum threshold value of stirring speed, a preset maximum threshold value of solute dispersion uniformity, a preset maximum threshold value of dissolution rate and a preset dissolution weight value; The preset dissolution weight values ​​include a first dissolution weight, a second dissolution weight and a third dissolution weight; The stirring speed impact assessment data is obtained by processing the second parameter and the second preset value; The second parameter includes the change in stirring speed, the change in oral liquid concentration, the change in oral liquid conductivity, and the change rate of oral liquid temperature; The second preset value includes a preset maximum threshold value of stirring speed change, a preset maximum threshold value of concentration change, a preset maximum threshold value of oral liquid conductivity change, a preset maximum threshold value of oral liquid temperature change rate, and a preset stirring speed weight value; The preset stirring speed weight values ​​include a first stirring speed weight, a second stirring speed weight, a third stirring speed weight and a fourth stirring speed weight; The stirring frequency influence data is obtained by processing the third parameter and the third preset value; The third parameter includes stirring frequency, dissolution rate change and final bubble generation amount; The third preset value includes a preset maximum threshold value of stirring frequency, a preset maximum threshold value of dissolution rate change, a preset maximum threshold value of bubble generation, and a preset weight value of stirring frequency; The preset stirring frequency weight values ​​include a first stirring frequency weight, a second stirring frequency weight and a third stirring frequency weight.

3. The quality control method based on the preparation process of L-carnitine oral solution as claimed in claim 2, characterized in that: The process quality feedback data includes a dissolution rate evaluation value, a stirring speed impact evaluation value, and a stirring frequency impact evaluation value; The specific process of obtaining the dissolution rate evaluation value is as follows: The dissolution rate reflection value is obtained by combining the obtained maximum dissolution rate value and the preset maximum dissolution rate threshold value; combining the obtained dissolution rate reflection value with the maximum stirring speed, the preset maximum stirring speed threshold and the first dissolution weight to obtain a first dissolution processing value; The obtained dissolution rate reflection value is combined with the number of water additions, the preset maximum threshold of the number of water additions, and the second dissolution weight to obtain a second dissolution processing value; The obtained dissolution rate reflection value is combined with the maximum value of the solute dispersion uniformity, the preset maximum threshold value of the solute dispersion uniformity and the third dissolution weight to obtain a third dissolution processing value; Combining the dissolution rate assessment data with the preset dissolution rate assessment weights to obtain a dissolution rate assessment value; The dissolution rate evaluation data includes a first dissolution process value, a second dissolution process value, and a third dissolution process value; The preset dissolution rate assessment weights include a preset first dissolution assessment weight, a preset second dissolution assessment weight, and a preset third dissolution assessment weight.

4. The quality control method based on the preparation process of L-carnitine oral solution as claimed in claim 3, characterized in that: The limiting expression of the dissolution rate evaluation value is as follows: In the formula, JBPG w represents the estimated dissolution rate of L-carnitine oral solution in the wth preset time period, w = 1, 2, ..., r, w represents the number of the preset time period, r represents the total number of preset time periods, RJYSD w represents the first dissolution processing value of L-carnitine oral solution in the wth preset time period, RJYSL w represents the second dissolution processing value of the L-carnitine oral solution in the wth preset time period, RJYJY w represents the third dissolution processing value of the L-carnitine oral solution in the wth preset time period, ε 1 Represents the preset first dissolution assessment weight, ε 2 Represents the preset second dissolution evaluation weight, ε 3 represents the preset third dissolution evaluation weight, and e represents a natural constant.

5. The quality control method based on the preparation process of L-carnitine oral solution as claimed in claim 3, characterized in that: The stirring speed impact assessment value is obtained by combining the stirring speed impact assessment data and the preset stirring speed impact weight; The stirring speed impact assessment data includes a first stirring speed weighted value, a second stirring speed weighted value, a third stirring speed weighted value and a fourth stirring speed weighted value; The first stirring speed weighted value is obtained by combining the stirring speed change influence value, the oral liquid concentration change amount, the preset concentration change amount maximum threshold value and the first stirring speed weight; The second stirring speed weighted value is obtained by combining the stirring speed change influence value, the oral liquid conductivity change amount, the preset oral liquid conductivity change amount maximum threshold value and the second stirring speed weight; The third stirring speed weighted value is obtained by combining the stirring speed change influence value, the oral liquid temperature change rate, the preset oral liquid temperature change rate maximum threshold value and the third stirring speed weight; The fourth stirring speed weighted value is obtained by combining the stirring speed change influence value, the dissolution rate evaluation value and the fourth stirring speed weight; The stirring speed change impact value is obtained by combining the stirring speed change amount and a preset stirring speed change amount maximum threshold value; The preset stirring speed influence weights include a preset first stirring speed influence weight, a preset second stirring speed influence weight, a preset third stirring speed influence weight, and a preset fourth stirring speed influence weight.

6. The quality control method based on the preparation process of L-carnitine oral solution as claimed in claim 3, characterized in that: The specific process of obtaining the stirring frequency impact assessment value is as follows: The stirring frequency influence value is obtained by processing the stirring frequency and the preset stirring frequency maximum threshold; The first stirring frequency weighted value is obtained by processing the stirring frequency influence value, the dissolution rate change, the preset dissolution rate change maximum threshold and the first stirring frequency weight; The second stirring frequency weighted value is obtained by processing the stirring frequency influence value, the final state bubble generation amount, the preset bubble generation amount maximum threshold and the second stirring frequency weight; The third stirring frequency weighted value is obtained by processing the stirring frequency influence value, the dissolution rate evaluation value and the third stirring frequency weight; The stirring frequency impact assessment value is obtained by processing the stirring frequency impact data and the preset stirring frequency impact weight; The stirring frequency influence data includes a first stirring frequency weighted value, a second stirring frequency weighted value and a third stirring frequency weighted value; The preset stirring frequency influence weights include a preset first stirring frequency influence weight, a preset second stirring frequency influence weight, and a preset third stirring frequency influence weight.

7. The quality control method based on the preparation process of L-carnitine oral solution as claimed in claim 1, characterized in that: The specific process of constructing a process parameter algorithm model based on process quality feedback data and providing result feedback is as follows: Input the acquired process quality feedback data of the historical time period and the corresponding preset feedback results into the preset initial process training model for training to obtain the process parameter algorithm model; Input the acquired real-time process quality feedback data into the process parameter algorithm model to output real-time feedback results; The preset feedback result includes the preset oral liquid color and the preset oral liquid turbidity set by the preset personnel; The feedback results include the color of the oral solution and the turbidity of the oral solution.

8. The quality control method based on the preparation process of L-carnitine oral solution as claimed in claim 1, characterized in that: The specific process of determining whether to optimize quality control parameters based on the process parameter algorithm model is as follows: If the pH value of the prepared oral solution is within the preset pH value range, the quality control parameters are optimized, otherwise the parameters are optimized; The pH value of the prepared oral solution represents the pH value of the L-carnitine oral solution corresponding to the process quality feedback data; The parameter optimization includes stirring speed adjustment and stirring frequency adjustment; The quality control parameter optimization includes color control optimization and turbidity control optimization; The process of color control optimization is as follows: Compare the oral solution color output by the process parameter algorithm model with the standard color result; If the obtained oral liquid color does not meet the standard color result, parameter optimization is performed, otherwise the corresponding process quality feedback data and the oral liquid color output by the process parameter algorithm model are obtained.

9. The quality control method based on the preparation process of L-carnitine oral solution as claimed in claim 8, characterized in that: The specific process of turbidity control optimization is as follows: Compare the turbidity of the oral solution output by the process parameter algorithm model with the turbidity result of the standard oral solution; If the obtained oral liquid turbidity is greater than the standard oral liquid turbidity result, parameter optimization is performed, otherwise the corresponding process quality feedback data and the oral liquid turbidity output by the process parameter algorithm model are obtained; Determine whether the pH value of the prepared oral liquid at this time is within the preset pH value range. If it is not within the preset pH value range, re-optimize the quality control parameters. Otherwise, obtain qualified monitoring data. The qualified monitoring data represents the process quality feedback data corresponding to the pH value of the prepared oral liquid within the preset pH value range, and the turbidity and color of the oral liquid output by the process parameter algorithm model.

10. A quality control system based on the preparation process of L-carnitine oral solution, characterized in that: It includes oral liquid monitoring data acquisition module, oral liquid quality assessment module, result feedback module and quality control parameter optimization module: The oral liquid monitoring data acquisition module is used to monitor the preparation process of the L-carnitine oral solution through a preset sensor to acquire oral liquid monitoring data, wherein the oral liquid monitoring data includes dissolution rate evaluation data, stirring speed impact evaluation data and stirring frequency impact data; The oral liquid quality assessment module is used to perform oral liquid quality assessment based on oral liquid monitoring data to obtain process quality feedback data, wherein the oral liquid quality assessment includes dissolution rate assessment, stirring speed impact assessment and stirring frequency impact assessment; The result feedback module is used to construct a process parameter algorithm model according to the process quality feedback data and to provide result feedback, and the process parameter algorithm model is used to provide feedback on the color and turbidity of the L-carnitine oral solution; The quality control parameter optimization module is used to determine whether to perform quality control parameter optimization based on the process parameter algorithm model, and the parameter optimization is used to improve the quality stability of L-carnitine oral solution.

Images