Nalmefene hydrochloride impurity removal monitoring system and removal method

Abstract

The invention discloses a nalmefene hydrochloride impurity removal monitoring system and a nalmefene hydrochloride impurity removal monitoring method, and relates to the technical field of pharmaceutical chemistry, firstly, a crystallization solvent is prepared, a nalmefene mixture is added into the crystallization solvent for primary crystallization and secondary re-crystallization, so that methyl diphenyl phosphine oxide is better separated in the crystallization process, and the purity of the nalmefene hydrochloride impurity is improved; according to the method, the impurity removal capacity of methyl diphenyl phosphine oxide is remarkably improved, so that the purity of nalmefene hydrochloride is improved, meanwhile, the crystallization process is monitored in real time, the abnormal crystallization time period when the impurity removal reaction does not reach the set threshold value is recognized, and therefore early warning prompt for abnormal crystallization is achieved; according to the method, the condition that the impurity removal of the nalmefene hydrochloride is not ideal can be found in time, finally, the content of the impurity of the nalmefene hydrochloride after crystallization is monitored, the high efficiency of the crystallization process of the nalmefene hydrochloride is improved, and the removal effectiveness of the impurity of the nalmefene hydrochloride is ensured.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a nalmefene hydrochloride impurity removal monitoring system and a removal method. Background Art

[0002] Nalmefene hydrochloride is a specific morphine receptor blocker, a naltrexone analog with a 6-methylene structure, and has gradually become a substitute for naloxone. Nalmefene hydrochloride has a certain effect on various types of pain and inflammation, and has gradually become one of the common analgesics and anti-inflammatory drugs.

[0003] Prior art, such as the invention patent with publication number: CN117843650A, is a method for refining nalmefene hydrochloride. The method uses crude nalmefene hydrochloride, mixes isopropanol and water as a solvent, adds activated carbon to reflux and filter, and then cools and crystallizes, collects solids, washes and dries in sequence to obtain high-purity nalmefene hydrochloride. The mass ratio of nalmefene hydrochloride to water is 1:(0.5-2), and the mass ratio of nalmefene hydrochloride to isopropanol is 1:(1-10).

[0004] In combination with the above scheme, it is found that in the current removal of impurities in nalmefene hydrochloride, there is a problem of incomplete removal of methyl diphenyl phosphine oxide in nalmefene hydrochloride, which will affect the purity of nalmefene hydrochloride, and the lack of multiple crystallization preparations for nalmefene hydrochloride may make it impossible to efficiently remove the impurities in nalmefene hydrochloride, resulting in the impurity content in nalmefene hydrochloride exceeding the standard. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides a nalmefene hydrochloride impurity removal monitoring system and removal method, which can effectively solve the problems involved in the above-mentioned background technology.

[0006] To achieve the above objectives, the present invention is implemented by the following technical scheme: A method for removing impurities from nalmefene hydrochloride, comprising: step a: after the reaction of naltrexone and methyl triphenylphosphonium bromide is completed, quenching, extraction, washing and concentration are performed to obtain a nalmefene mixture; step b: the nalmefene mixture is added to a first dichloromethane solvent, stirred to dissolve, and hydrochloric acid is added to adjust the pH for the first time to perform a crystallization. Step c: after collecting the solid obtained by the first crystallization, the solid is dissolved in water, and ammonia water is added to adjust the pH for the second time; step d: adding a second dichloromethane solvent for extraction, and adding hydrochloric acid to the second dichloromethane solvent phase to adjust the pH for the third time, and performing a second re-crystallization to obtain nalmefene hydrochloride.

[0007] Furthermore, the ratio of the first dichloromethane dosage to the naltrexone dosage is 3-20kg:1kg.

[0008] Furthermore, the ratio of the first dichloromethane dosage to the naltrexone dosage is 3-20kg:1kg.

[0009] Furthermore, the pH range of the first adjustment by hydrochloric acid is 0.5-6.

[0010] Furthermore, the pH range of the second adjustment of the ammonia water is 7-10.

[0011] Furthermore, the pH range of the third adjustment with hydrochloric acid is 0.5-6.

[0012] The second aspect of the present invention also provides a removal monitoring system for the method for removing impurities from nalmefene hydrochloride, comprising: a crystallization process monitoring module, which is used to monitor the crystallization process of the nalmefene mixture, and obtain real-time data of the crystallization process of the nalmefene mixture in each monitoring time period, and analyze to obtain the physical dynamic compliance index of the impurity removal of the nalmefene mixture in each monitoring time period; a crystallization process early warning module, which is used to provide early warning prompts based on the physical dynamic compliance index of the impurity removal of the nalmefene mixture in each monitoring time period and locate the abnormal crystallization period; a nalmefene hydrochloride impurity content monitoring feedback module, which is used to monitor and obtain the content of nalmefene hydrochloride impurities after crystallization, and provide monitoring feedback prompts.

[0013] Furthermore, the physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period is analyzed. The specific analysis process is: deploy several monitoring time periods, obtain the pH value of the nalmefene mixed solution at the start time point of crystallization in each monitoring time period and the pH value of the nalmefene mixed solution at the end time point of crystallization in each monitoring time period, and obtain the pH change of the nalmefene mixed solution in each monitoring time period after processing to meet the measurement value.

[0014] The average temperature, average stirring speed and conductivity during the crystallization of nalmefene were monitored in each monitoring time period, and the reaction stability index of the nalmefene mixed solution in each monitoring time period was obtained through processing.

[0015] According to the pH change compliance value of the nalmefene mixed solution in each monitoring time period and the reaction stability index of the nalmefene mixed solution in each monitoring time period, a comprehensive analysis was conducted to obtain the physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period.

[0016] Furthermore, the physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period is used to quantitatively evaluate the compliance of the impurity removal reaction of the nalmefene mixture in each monitoring time period by analyzing the real-time data of the crystallization process of the nalmefene mixture.

[0017] Furthermore, according to the physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period and the abnormal crystallization period is located, an early warning prompt is given, and the specific process is as follows:

[0018] According to the physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period, it is compared with the set physical dynamic compliance index threshold of impurity removal of the nalmefene mixture. If the physical dynamic compliance index of impurity removal of the nalmefene mixture in a certain monitoring time period is lower than the physical dynamic compliance index threshold of impurity removal of the nalmefene mixture, then the monitoring time period is marked as an abnormal crystallization period, thereby obtaining each abnormal crystallization period, and issuing an early warning prompt for each abnormal crystallization period.

[0019] Furthermore, the content of nalmefene hydrochloride impurities after crystallization is monitored and monitored and feedback is given. The specific process is: the content of nalmefene hydrochloride impurities after crystallization is monitored and monitored and feedback is given. The specific process is: according to the high performance liquid chromatography of the crystallization process of the nalmefene mixture, the content of nalmefene hydrochloride impurities and the yield of nalmefene hydrochloride after crystallization are analyzed and obtained, and the content of nalmefene hydrochloride impurities is compared with the set nalmefene hydrochloride impurity content threshold and the yield of nalmefene hydrochloride is compared with the set nalmefene hydrochloride yield threshold, and if the content of nalmefene hydrochloride impurities after crystallization is higher than or equal to the nalmefene hydrochloride impurity content threshold, or the yield of nalmefene hydrochloride is lower than the set nalmefene hydrochloride yield threshold, feedback is given.

[0020] The present invention has the following beneficial effects:

[0021] (1) The present invention provides a nalmefene hydrochloride impurity removal monitoring system. First, a crystallization solvent is prepared, and a nalmefene mixture is added to the crystallization solvent for primary crystallization and secondary re-crystallization, so that methyl diphenyl phosphine oxide can be better separated during the crystallization process, and the removal capacity of methyl diphenyl phosphine oxide impurities is significantly improved. At the same time, the crystallization process is monitored in real time to obtain the physical dynamic compliance index of impurity removal of the nalmefene mixture, and the crystallization process is monitored and warned. Finally, the content of nalmefene hydrochloride impurities after crystallization is monitored, and feedback prompts are provided, which is helpful to improve the purity of nalmefene hydrochloride, thereby effectively removing impurities in nalmefene hydrochloride.

[0022] (2) By monitoring and comparing the physical dynamic compliance index of impurity removal of the nalmefene mixture, the abnormal crystallization period in which the impurity removal reaction does not reach the set threshold in certain monitoring time periods can be identified, thereby realizing early warning of abnormal crystallization, which is beneficial for timely discovering the unsatisfactory impurity removal reaction of nalmefene hydrochloride, helping production personnel to quickly adjust production parameters, avoid or reduce impurity residues, ensure the stability and reliability of the quality of nalmefene hydrochloride, and thus improve production efficiency and the qualified rate of nalmefene hydrochloride.

[0023] (3) The present invention monitors the crystallization process of the nalmefene mixture and obtains real-time data, and analyzes and obtains the physical dynamic compliance index of impurity removal, which can effectively monitor and optimize the crystallization process, and monitor and warn the crystallization process, which is helpful to achieve the removal of nalmefene hydrochloride impurities, and can make more precise control of the removal of nalmefene hydrochloride impurities, thereby improving the purity of nalmefene hydrochloride.

[0024] (4) The present invention can effectively remove impurities in nalmefene hydrochloride by subjecting nalmefene hydrochloride to a primary crystallization and a secondary re-crystallization, thereby improving the purity of nalmefene hydrochloride and helping to ensure the effectiveness of removing impurities in nalmefene hydrochloride.

[0025] Of course, it is not necessary to achieve all the advantages mentioned above at the same time in implementing any nalmefene hydrochloride of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 It is a schematic diagram of system module connection of the present invention.

[0027] Figure 2 It is a schematic diagram of the method flow of the present invention.

[0028] Figure 3 This is the reaction formula of the reaction of naltrexone and methyltriphenylphosphonium bromide of the present invention. DETAILED DESCRIPTION

[0029] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0030] See also Figure 1 As shown, an embodiment of the present invention provides a nalmefene hydrochloride impurity removal monitoring system and removal method technical solution: a nalmefene hydrochloride impurity removal monitoring system, comprising a crystallization solvent preparation module, for adding a nalmefene mixture obtained by the reaction of naltrexone and methyltriphenylphosphonium bromide into a crystallization solvent for crystallization.

[0031] It should be noted that after the reaction of naltrexone and methyltriphenylphosphonium bromide is completed, the mixture is quenched, extracted, washed and concentrated to obtain the nalmefene mixture.

[0032] The crystallization process monitoring module is used to monitor the crystallization process of the nalmefene mixture, obtain the real-time data of the crystallization process of the nalmefene mixture in each monitoring time period, and analyze and obtain the physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period.

[0033] The crystallization process early warning module is used to provide early warning prompts based on the physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period and locate abnormal crystallization time periods.

[0034] The nalmefene hydrochloride impurity content monitoring and feedback module is used to monitor the content of nalmefene hydrochloride impurities after crystallization and provide monitoring feedback prompts.

[0035] It should be noted that a nalmefene hydrochloride impurity removal monitoring system also includes a database for storing the physical dynamic compliance index threshold of the impurity removal of the nalmefene mixture, the nalmefene hydrochloride impurity content threshold, the nalmefene hydrochloride yield threshold, the correction factor corresponding to the temperature value, the correction factor corresponding to the stirring speed, the correction factor corresponding to the conductivity, the reference temperature during the crystallization process of nalmefene in each monitoring time period, the reference stirring speed during the crystallization process of nalmefene in each monitoring time period, the reference conductivity during the crystallization process of nalmefene in each monitoring time period, the pH reference change value of the nalmefene mixed solution, the compensation factor corresponding to the pH value of the nalmefene mixed solution, the weight factor corresponding to the pH change compliance measurement value, the weight factor corresponding to the reaction stability index, and the adjustment compensation coefficient.

[0036] It should be noted that the nalmefene mixture is added to dichloromethane, stirred to dissolve, hydrochloric acid is added to adjust the pH, the solid obtained by crystallization is collected, and then the solid is dissolved in water, ammonia water is added to adjust the pH, extracted with dichloromethane, hydrochloric acid is added to the dichloromethane phase to adjust the pH, and nalmefene hydrochloride is obtained by crystallization.

[0037] It should be noted that the impurities produced by the conversion of methyl triphenylphosphine bromide are triphenylphosphine oxide and methyl diphenylphosphine oxide. Triphenylphosphine oxide is easy to remove during the crystallization process of nalmefene hydrochloride, while methyl diphenylphosphine oxide is easily precipitated along with the product during the crystallization process, and its removal ability is relatively weak, which will affect the purity of nalmefene hydrochloride.

[0038] Specifically, the crystallization solvent is dichloromethane solution.

[0039] It should be noted that this embodiment uses dichloromethane as a solvent as a crystallization solvent for nalmefene hydrochloride, because dichloromethane can significantly increase the solubility of the impurity methyl diphenyl phosphine oxide in nalmefene hydrochloride, making it easier for methyl diphenyl phosphine oxide to dissolve together with nalmefene hydrochloride. When the solvent system is supersaturated, methyl diphenyl phosphine oxide and nalmefene hydrochloride are more likely to precipitate simultaneously, thereby achieving better separation of methyl diphenyl phosphine oxide during the crystallization process, and significantly improving the removal capacity of methyl diphenyl phosphine oxide impurities.

[0040] It should be noted that, after one crystallization using a dichloromethane solution, the remaining methyl diphenyl phosphine oxide was less than 1%, and after a second crystallization using a dichloromethane solution, methyl diphenyl phosphine oxide was not detected in nalmefene hydrochloride (below the detection limit of 0.01%).

[0041] Specifically, the nalmefene mixture obtained after the reaction of naltrexone and methyltriphenylphosphonium bromide is added to a crystallization solvent for crystallization, including primary crystallization and secondary crystallization, wherein the primary crystallization is to quench, extract, wash and concentrate the solution obtained after the reaction of naltrexone and methyltriphenylphosphonium bromide to obtain the nalmefene mixture, add dichloromethane solution, stir and dissolve to obtain a solid after crystallization.

[0042] The second re-crystallization is to dissolve the solid after the first crystallization in water, add ammonia water, and extract it in a dichloromethane solution to obtain the solid after the second re-crystallization.

[0043] It should be noted that the amount of dichloromethane used for the first crystallization is 3 to 20 kg / kg, preferably 5 to 10 kg / kg, based on the amount of naltrexone fed.

[0044] It should be noted that the amount of dichloromethane used in the secondary re-crystallization is 3 to 20 kg / kg, preferably 6 to 10 kg / kg, based on the amount of naltrexone fed.

[0045] It should be noted that the pH range of adding hydrochloric acid to adjust the pH in the primary crystallization is 0.5 to 6, preferably 2 to 4.

[0046] It should be noted that the pH range of adding ammonia water to adjust the pH in the secondary recrystallization is 7 to 10, preferably 8 to 9.

[0047] It should be understood that the process of obtaining the purity of the crystalline precipitate of the nalmefene mixture at the end of the crystallization process is as follows: after the nalmefene mixture crystals are completely precipitated, the crystalline precipitate is collected from the solution using an appropriate tool (such as a glass rod), and the crystalline precipitate is washed to remove impurities remaining on the surface of the crystal. The washing can be carried out using an appropriate solvent (such as cooled methanol) to ensure that the crystal purity is higher after washing. The washed crystalline precipitate is placed in a dryer to completely dry it, and the crystalline precipitate sample is subjected to high performance liquid chromatography to determine its purity.

[0048] It should be noted that the specific process of the first crystallization is as follows: 25 g of methyltriphenylphosphonium bromide is added to 56 g of 2-methyltetrahydrofuran, 9 g of potassium tert-butoxide is added in batches, stirred for 2 h, a 2-methyltetrahydrofuran solution of naltrexone (8 g of naltrexone is dissolved in 32 g of 2-methyltetrahydrofuran) is added, the reaction is carried out for 2 h, an ammonium chloride solution is added to quench, 30 g of water is added, the liquid is separated, the organic phase is washed twice with 16 g of water, the organic phase is concentrated under reduced pressure, 64 g of dichloromethane is added to dissolve, hydrochloric acid is added to adjust the pH of the system to 3, filtered, washed with 8 g of dichloromethane and dried to obtain 9.3 g of nalmefene hydrochloride (the purity of nalmefene hydrochloride in HPLC is 99.409%, and the methyldiphenylphosphine oxide is detected to be 0.378%).

[0049] It should be noted that the specific process of the secondary recrystallization is as follows: 25.7 kg of methyl triphenylphosphonium bromide is added to 56.2 kg of 2-methyltetrahydrofuran, 8.8 kg of potassium tert-butoxide is added in batches, stirred for 2 hours, and a 2-methyltetrahydrofuran solution of naltrexone (8.0 kg of naltrexone dissolved in 32.05 kg of 2-methyltetrahydrofuran), react for 2h, add ammonium chloride solution to quench, add 30.3kg water, separate the liquids, wash the organic phase twice with 16.5kg water, concentrate the organic phase under reduced pressure, add 64.3kg dichloromethane to dissolve, add hydrochloric acid to adjust the pH of the system to 3, filter, wash with 8.0kg dichloromethane, collect the filter cake, add 80.3kg water, add ammonia water to adjust the pH to 8-9, add 64.3kg dichloromethane, add hydrochloric acid to adjust the pH of the system to 3, filter, and dry the filter cake to obtain 9.0kg nalmefene hydrochloride (the purity of nalmefene hydrochloride in HPLC is 99.886%, and methyl diphenylphosphine oxide is not detected (below the detection limit of 0.01%)).

[0050] Specifically, the physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period is analyzed, and the specific analysis process is: deploy several monitoring time periods, obtain the pH value of the nalmefene mixed solution at the start time point of crystallization in each monitoring time period and the pH value of the nalmefene mixed solution at the end time point of crystallization in each monitoring time period, and obtain the pH change compliance measurement value of the nalmefene mixed solution in each monitoring time period after processing.

[0051] It should be understood that the several monitoring time periods deployed should include the first crystallization and the second re-crystallization of nalmefene hydrochloride.

[0052] The average temperature, average stirring speed and conductivity during the crystallization of nalmefene were monitored in each monitoring time period, and the reaction stability index of the nalmefene mixed solution in each monitoring time period was obtained through processing.

[0053] It should be noted that the reaction stability index of the nalmefene mixed solution in each monitoring time period is obtained by analyzing the temperature and stirring speed during the crystallization of nalmefene in each monitoring time period, and the change in ion concentration can be reflected by the change in the conductivity of the solution, and the change in ion concentration may affect the reaction stability of the nalmefene mixed solution. Therefore, by monitoring the change in the conductivity of the solution, the stability of the solution can be evaluated, and the reaction stability index of the nalmefene mixed solution in each monitoring time period can be calculated. In this embodiment, it is obtained by the following calculation method, and the specific calculation method is as follows:

[0054]

[0055] In the formula, δ i represents the reaction stability index of the nalmefene mixed solution in the i-th monitoring period, T i represents the average temperature during the crystallization of nalmefene in the i-th monitoring period, V i represents the average stirring speed during the crystallization of nalmefene in the i-th monitoring period, d i represents the conductivity during the crystallization of nalmefene in the i-th monitoring period, ΔT i represents the reference temperature during the crystallization of nalmefene in the set i-th monitoring time period, ΔV i represents the reference stirring speed during the crystallization of nalmefene in the set i-th monitoring time period, Δd represents the reference conductivity during the crystallization of nalmefene in the set i-th monitoring time period, ε1 represents the correction factor corresponding to the set temperature, ε2 represents the correction factor corresponding to the set stirring speed, i represents the number of each monitoring time period, ε3 represents the correction factor corresponding to the set conductivity, i=1,2,3,...,n, and n represents the total number of monitoring time periods.

[0056] It should be noted that the average temperature during the crystallization process of nalmefene can be obtained through temperature sensors, thermometers or other temperature monitoring equipment in the experiment. During the crystallization process, the temperature may change over time. Therefore, recording and calculating the average value of these temperature data can provide an overall temperature indicator, reflecting the overall temperature change trend during the crystallization process. Monitoring and analysis of the average temperature can also help understand the temperature control of the nalmefene crystallization process, and can provide a reference for optimizing the production process.

[0057] It should be noted that the average stirring speed during the crystallization of nalmefene refers to the average value of all stirring speed data recorded during the crystallization process, which can be obtained by the stirrer or stirring equipment in the experiment.

[0058] It should be noted that monitoring the stirring speed and temperature during the crystallization of nalmefene is crucial for the stability of the solution and the stability of the reaction. A higher stirring speed can increase the convection rate and mass transfer rate of the solute in the solution, which is beneficial to the mixing and distribution of the solute. The increase in temperature will also increase the molecular thermal motion, promote the diffusion and mass transfer of the solute molecules, and accelerate the mixing and reaction rate. Therefore, high stirring speed and high temperature may promote each other and increase the solubility and reaction rate of the solute.

[0059] It should be noted that the reference temperature during the crystallization of nalmefene is determined based on previous experiments or process experience to ensure that the crystallization process of nalmefene is carried out under appropriate temperature conditions. For example, it is assumed that the reference temperature during the crystallization of nalmefene is 50 degrees Celsius based on previous experiments and process experience. This means that during the entire crystallization process, the temperature of the solution is monitored and controlled to ensure that it is always maintained at around 50 degrees Celsius. This reference temperature can be used as a benchmark to evaluate the actual temperature changes and whether it is necessary to adjust the stirring speed or other operating parameters to maintain the temperature within a suitable range.

[0060] It should be noted that the reference stirring speed during the crystallization of nalmefene is determined based on previous experiments or process experience to ensure that the crystallization process of nalmefene is carried out under appropriate mixing conditions. Exemplarily, it is assumed that the reference stirring speed during the crystallization of nalmefene is determined to be 150 rpm (rotations per minute) based on previous experiments and process experience to ensure that nalmefene and other components in the solution are fully mixed and to promote the dissolution and precipitation of the solute.

[0061] In a specific embodiment, the correction factor corresponding to the temperature is determined by previous experimental research or based on theoretical calculations. This correction factor takes into account the effect of temperature on the measurement result and is usually used to correct the experimental data to obtain more accurate results. For example, it is assumed that it is found through experimental measurement that the result measured at 25 degrees Celsius is 10% higher than the actual value. Then at 25 degrees Celsius, the correction factor can be set to 0.1 to correct the deviation and obtain more accurate data.

[0062] In a specific embodiment, the correction factor corresponding to the stirring speed is usually determined based on experimental data and experience to ensure that the desired crystal quality and yield are obtained. For example, if the experiment finds that the crystal growth rate increases by 5% for every 10 rpm increase in stirring speed, then the correction factor may be 0.5 (i.e., 5% divided by 10 rpm).

[0063] In a specific embodiment, the correction factor corresponding to the temperature value ranges from 0 to 1. The correction factor corresponding to the temperature value is extracted from a database. A comprehensive evaluation index system can be constructed through temperature monitoring data and expert evaluation during the historical crystallization process of nalmefene. The correction factor corresponding to the temperature value can be evaluated by determining the influence of temperature on the crystallization process of nalmefene through the hierarchical analysis method.

[0064] In a specific embodiment, the correction factor corresponding to the stirring speed ranges from 0 to 1. The correction factor corresponding to the stirring speed is extracted from a database. A comprehensive evaluation index system can be constructed through monitoring data of the stirring speed during the crystallization process of nalmefene in history and expert evaluation. The correction factor corresponding to the stirring speed is evaluated by determining the influence of the stirring speed on the crystallization process of nalmefene through the hierarchical analysis method.

[0065] In a specific embodiment, the correction factor corresponding to conductivity ranges from 0 to 1. The correction factor corresponding to conductivity is extracted from a database. A comprehensive evaluation index system can be constructed through monitoring data of conductivity changes during the crystallization process of nalmefene in history and expert evaluation. The correction factor corresponding to the conductivity change is evaluated by determining the influence of conductivity changes on the crystallization process of nalmefene through the hierarchical analysis method.

[0066] According to the pH change compliance value of the nalmefene mixed solution in each monitoring time period and the reaction stability index of the nalmefene mixed solution in each monitoring time period, a comprehensive analysis was conducted to obtain the physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period.

[0067] Specifically, the physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period is used to quantitatively evaluate the compliance of the impurity removal reaction of the nalmefene mixture in each monitoring time period by analyzing the real-time data of the crystallization process of the nalmefene mixture.

[0068] Specifically, according to the physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period, the abnormal crystallization time period is located and an early warning prompt is given. The specific process is: according to the physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period, it is compared with the set physical dynamic compliance index threshold of impurity removal of the nalmefene mixture. If the physical dynamic compliance index of impurity removal of the nalmefene mixture in a certain monitoring time period is lower than the physical dynamic compliance index threshold of impurity removal of the nalmefene mixture, the monitoring time period is marked as an abnormal crystallization time period, thereby obtaining each abnormal crystallization time period, and giving an early warning prompt for each abnormal crystallization time period.

[0069] It should be noted that locating the abnormal crystallization period for early warning also includes obtaining the compensation value of the abnormal crystallization period in each monitoring time period. The specific analysis conditions are:

[0070]

[0071] In the formula, C i represents the compensation value of the abnormal crystallization period in the i-th monitoring time period, represents the physical dynamic compliance index of impurity removal of nalmefene mixture in the i-th monitoring period, represents the set physical dynamic compliance index threshold value of impurity removal of the nalmefene mixture, and k represents the set adjustment compensation coefficient.

[0072] According to the compensation value of the abnormal crystallization period, the control parameters corresponding to the set compensation value interval of the abnormal crystallization period are matched to obtain the control parameters of the abnormal crystallization period, and the abnormal crystallization period is controlled according to the control parameters of the abnormal crystallization period.

[0073] It should be noted that the control parameters of the abnormal crystallization period automatically adjust the operating parameters to keep the crystallization process in a stable working state. In this embodiment, the control parameters of the abnormal crystallization period include the amount and temperature of methyl diphenyl phosphine oxide used in the preparation reaction.

[0074] It should be noted that the specific process of regulating the abnormal crystallization period according to the control parameters of the abnormal crystallization period is: extracting the temperature and concentration of the solution during the abnormal crystallization period, as well as the amount of methyl diphenyl phosphine oxide used in the preparation reaction, and comparing the temperature and concentration during the abnormal crystallization period with the historical data under normal operating conditions. Check whether there are significant differences, such as sudden changes in temperature or concentration. If the abnormal crystallization is related to the temperature, the heating or cooling system can be adjusted to stabilize the solution temperature. If the abnormal crystallization is related to the amount of reagents, the amount of methyl diphenyl phosphine oxide added for the preparation reaction can be adjusted to adjust the chemical composition and reaction kinetics of the mixture.

[0075] It should be noted that the threshold value of the physical dynamic compliance index of impurity removal of the nalmefene mixture is analyzed and determined based on the theoretical and experimental results of the impurity removal reaction. For example, it is assumed that the average value of the physical dynamic compliance index of impurity removal of the nalmefene mixture is set to 0.95 based on a series of experiments and data analysis. Then, according to the experimental results and quality control requirements, a threshold is formulated, which is usually a reasonable range of the average value. For example, setting the threshold to 0.90 means that when the physical dynamic compliance index of impurity removal is lower than 0.90, the reaction effect is considered to be unsatisfactory and further optimization or adjustment of conditions is required.

[0076] Specifically, the content of nalmefene hydrochloride impurities after crystallization is monitored and monitoring feedback prompts are performed. The specific process is: according to the high performance liquid chromatography of the crystallization process of the nalmefene mixture, the content of nalmefene hydrochloride impurities and the yield of nalmefene hydrochloride after crystallization are analyzed and obtained, and the content of nalmefene hydrochloride impurities is compared with the set nalmefene hydrochloride impurity content threshold value and the yield of nalmefene hydrochloride is compared with the set nalmefene hydrochloride yield threshold value respectively. If the content of nalmefene hydrochloride impurities after crystallization is higher than or equal to the nalmefene hydrochloride impurity content threshold value, or the yield of nalmefene hydrochloride is lower than the set nalmefene hydrochloride yield threshold value, feedback prompts are performed.

[0077] In a specific embodiment, the threshold value of the impurity content of nalmefene hydrochloride is usually set according to the standard regulations of the drug or according to the requirements of the production process, in order to ensure the quality and safety of the drug.

[0078] For example, assuming that according to the drug registration regulations or the company's internal standards, the total impurity content threshold of nalmefene hydrochloride is 0.05%, which means that the total content of various impurities in nalmefene hydrochloride cannot exceed 0.05%. If the actual total impurity content detected exceeds this threshold, corresponding measures need to be taken.

[0079] In a specific embodiment, the content of nalmefene hydrochloride impurities in the crystallization process is obtained by high performance liquid chromatography (HPLC). HPLC is widely used in the fields of drug analysis, environmental analysis, food testing, chemical biology, etc., and is a very important analytical method. In an embodiment, the content of nalmefene hydrochloride impurities in the first crystallization and the second re-crystallization process can be obtained by high performance liquid chromatography (HPLC).

[0080] It should be noted that the specific process of using high performance liquid chromatography (HPLC) to analyze the content of nalmefene hydrochloride impurities in the crystallization process is: injecting the nalmefene mixture into the HPLC system for separation and analysis. The HPLC system includes a high-pressure pump, an injector, a chromatographic column and a detector. The nalmefene mixture is transported to the chromatographic column by a high-pressure pump and separated between the stationary phase and the mobile phase filled in the column. Different impurities have different retention times in the chromatographic column and can be separated. When the nalmefene mixture passes through the detector, the signals of different impurities are recorded to form a chromatogram. By comparing the chromatogram of the sample nalmefene mixture with the chromatogram of the standard, the presence and content of each impurity in the sample can be determined. During the analysis, it is also necessary to use an appropriate mobile phase and gradient elution program to ensure the best separation effect. The test results are usually processed by Agilent ChemStation software to generate peak area and concentration data of each impurity. In the entire detection process, finally, by analyzing samples at multiple time points, the change curve of nalmefene hydrochloride impurities in the crystallization process can be drawn.

[0081] In a specific embodiment, as shown in Table 1, Table 1 is an example data of the HPLC test results of nalmefene hydrochloride obtained by a single crystallization of dichloromethane, which lists the test results of the nalmefene hydrochloride content and impurities obtained by a single crystallization of dichloromethane.

[0082] Table 1 HPLC test results of nalmefene hydrochloride obtained by single crystallization of dichloromethane

[0083]

[0084] In a specific embodiment, as shown in Table 2, Table 2 is an example of the HPLC test results of nalmefene hydrochloride obtained by secondary recrystallization of dichloromethane, which lists the test results of the nalmefene hydrochloride content and impurities obtained by secondary recrystallization of dichloromethane.

[0085] Table 2 HPLC test results of nalmefene hydrochloride obtained by secondary recrystallization of dichloromethane

[0086]

[0087] Specifically, the pH change of the nalmefene mixed solution in each monitoring time period conforms to the measured value, which is obtained by the following calculation method in the embodiment, and the specific calculation method is as follows:

[0088]

[0089] In the formula, ω i It means that the pH change of the nalmefene mixed solution meets the measured value, pH 2irepresents the pH value of the nalmefene mixed solution at the end time of crystallization in the i-th monitoring period, PH 1i represents the pH value of the nalmefene mixed solution at the starting time point of crystallization in the i-th monitoring time period, ΔPH represents the set pH reference change value of the nalmefene mixed solution, α represents the compensation factor corresponding to the set pH value of the nalmefene mixed solution, i represents the number of each monitoring time period, i=1,2,3,...,m, and m represents the total number of monitoring time periods.

[0090] It should be understood that pH refers to the negative logarithm of the concentration of hydrogen ions in a solution, which is usually used to indicate the acidity and alkalinity of a solution. The pH value of a nalmefene mixed solution may change over time. In different monitoring time periods, in this embodiment, the pH value is usually measured using a pH meter or a pH electrode. A pH meter is an instrument specifically used to measure the pH value of a solution. The pH value of the solution is determined by immersing a pH electrode in the solution and by changing the potential of the electrode. The change in pH may vary. For example, when an acidic or alkaline substance is added to the solution, a change in pH may occur. In addition, if a reaction related to acid-base neutralization occurs in the nalmefene mixed solution, a change in pH may also occur. Therefore, obtaining the pH value in each monitoring time period helps to observe the change in pH value during crystallization. For example, it is assumed that in a nalmefene mixed solution, after a period of reaction, the pH value obtained is 7.2. This means that during this time period, the acidity and alkalinity of the solution are in a neutral state, that is, the concentrations of hydrogen ions and hydroxide ions in the solution are equal, and a pH value of 7 indicates neutrality.

[0091] It should be understood that the pH reference change value of the nalmefene mixed solution is determined by previous experimental studies or process experience. This value can be determined based on the chemical properties of the nalmefene mixed solution and the environmental conditions in which it is located to ensure that the solution is within an appropriate pH range, which is conducive to the stability and reaction process of nalmefene. For example, it is assumed that according to previous experiments and process experience, the pH reference change value of the nalmefene mixed solution is determined to be maintained within the range of pH 6.0 ± 0.5 during the crystallization process. This means that the pH value of the solution is monitored and controlled throughout the crystallization process to ensure that it is always maintained within this range.

[0092] It should be understood that the compensation factor corresponding to the pH value of the nalmefene mixed solution is determined by previous experimental studies or process experience to correct the reading of the pH electrode to obtain an accurate pH value of the solution. For example, assuming that it is found in the experiment that in the nalmefene mixed solution, the reading of the pH electrode has a fixed deviation from the actual pH value, which needs to be corrected by the compensation factor. For example, assuming that it is found that the electrode reading is 0.2 units lower in the experiment, the compensation factor can be set to 0.2 to correct the electrode reading obtained in the actual measurement to obtain the accurate pH value of the solution.

[0093] Specifically, the physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period can be identified and quantitatively analyzed by mass spectrometry analysis technology, such as liquid chromatography-mass spectrometry (LC-MS) or gas chromatography-mass spectrometry (GC-MS), to evaluate the physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period. In the embodiment, it is obtained by the following calculation method, and the specific calculation method is as follows:

[0094]

[0095] In the formula, represents the physical dynamic compliance index of impurity removal of nalmefene mixture in the i-th monitoring period, ω i Indicates that the pH change of the nalmefene mixed solution in the i-th monitoring period meets the measurement value, δ i represents the reaction stability index of the nalmefene mixed solution in the i-th monitoring time period, γ1 represents the weight factor corresponding to the set pH change in accordance with the measured value, γ2 represents the weight factor corresponding to the set reaction stability index, and e represents a natural constant.

[0096] In a specific embodiment, as shown in Table 3, Table 3 is an example data of each weight factor in the physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period, which lists the weight factor corresponding to the pH change compliance measurement value and the weight factor corresponding to the reaction stability index.

[0097] Table 3 Example data of each weight factor in the physical dynamic compliance index of impurity removal of nalmefene mixture

[0098] PH changes correspond to the weighting factors corresponding to the measured values 0.44 Weight factor corresponding to the reaction stability index 0.46

[0099] It should be noted that the weight factor corresponding to the PH change conforming to the measured value is determined based on experiments or professional knowledge, and is used to measure the degree of influence of different parameters on the final result. For example, in an experiment, when the weight factor corresponding to the PH change conforming to the measured value is 0.44, and the pH value change conforming to the measured value is 7, according to the weight factor corresponding to the PH change conforming to the measured value of 0.44, then the contribution of this experiment to the physical dynamic conformity index of impurity removal of the final nalmefene mixture is 7*0.44=3.08.

[0100] It should be noted that the weight factor corresponding to the reaction stability index is usually determined based on experimental data, expert opinions or system analysis, and is used to measure the influence of different parameters on the final result. For example, in an experiment, it was found that the reaction stability index had a slightly higher influence on the quality of the final product than the pH change compliance value on the quality of the final product. Therefore, a weight of 0.46 was given. When the weight factor corresponding to the reaction stability index is 0.46, and the reaction stability index is 9, then the contribution of this experiment to the physical dynamic compliance index of impurity removal of the final nalmefene mixture is 9*0.46=4.14.

[0101] It should be noted that the weight factors corresponding to the pH changes in accordance with the measured values ​​and the weight factors corresponding to the reaction stability index are both obtained from the database, and the weight factors corresponding to the pH changes in accordance with the measured values ​​and the weight factors corresponding to the reaction stability index range from 0 to 1.

[0102] like Figure 2 As shown, the second aspect of the present invention also provides a method for removing impurities from nalmefene hydrochloride, comprising: after the reaction of naltrexone and methyltriphenylphosphonium bromide is completed, quenching, extracting, washing and concentrating to obtain a nalmefene mixture, adding it to a dichloromethane solvent, stirring to dissolve it, and adding hydrochloric acid to adjust the pH to perform a crystallization, monitoring the crystallization process to obtain the pH value in the solvent after the crystallization, and analyzing the purity of nalmefene hydrochloride and the content of impurities by high performance liquid chromatography.

[0103] After collecting the solid obtained by crystallization, the solid is dissolved in water, ammonia water is added to adjust the pH, dichloromethane is added for extraction, and hydrochloric acid is added to the dichloromethane phase to adjust the pH, and secondary recrystallization is performed to obtain nalmefene hydrochloride. The secondary recrystallization process is monitored, and the purity and impurity content of nalmefene hydrochloride after the secondary recrystallization are obtained by combining high performance liquid chromatography analysis, and then the impurity removal physical dynamic compliance index of the nalmefene mixture in each monitoring time period is analyzed to obtain each abnormal crystallization period, and an early warning prompt is given for each abnormal crystallization period.

[0104] like Figure 3As shown, it is the reaction formula of naltrexone and methyl triphenylphosphonium bromide, wherein the conversion of methyl triphenylphosphonium bromide will produce impurities triphenylphosphine oxide and methyl diphenylphosphine oxide. Triphenylphosphine oxide is easy to remove during the crystallization process of nalmefene hydrochloride, while methyl diphenylphosphine oxide is easy to precipitate together with the product during the crystallization process, and its removal ability is weak, which will affect the purity of nalmefene hydrochloride.

[0105] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device.

[0106] The preferred embodiments of the present invention disclosed above are only used to help illustrate the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to the specific implementation methods described. Obviously, many modifications and changes can be made according to the content of this specification. This specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can understand and use the present invention well. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. A method for removing impurities from nalmefene hydrochloride, characterized in that: include: Step a: after the reaction of naltrexone and methyltriphenylphosphonium bromide is completed, quenching, extraction, washing and concentration are performed to obtain a nalmefene mixture; Step b: adding the nalmefene mixture to the first dichloromethane solvent, stirring to dissolve, and adding hydrochloric acid to adjust the pH for the first time to perform a crystallization; Step c: After collecting the solid obtained by the first crystallization, dissolving the solid in water, and adding ammonia water to adjust the pH for the second time; Step d: adding a second dichloromethane solvent for extraction, adding hydrochloric acid to the second dichloromethane solvent phase to adjust the pH for the third time, and performing a second re-crystallization to obtain nalmefene hydrochloride.

2. A method for removing impurities from nalmefene hydrochloride, characterized in that: include: The ratio of the first dichloromethane dosage to the naltrexone dosage is 3-20kg:1kg.

3. A method for removing impurities from nalmefene hydrochloride, characterized in that: include: The ratio of the first dichloromethane dosage to the naltrexone dosage is 3-20kg:1kg.

4. A method for removing impurities from nalmefene hydrochloride, characterized in that: include: The pH range of the first adjustment with hydrochloric acid is 0.5~6.

5. A method for removing impurities from nalmefene hydrochloride, characterized in that: include: The pH range for the second adjustment with ammonia water is 7~10.

6. A method for removing impurities from nalmefene hydrochloride, characterized in that: include: The pH range of the third adjustment with hydrochloric acid is 0.5~6.

7. A removal monitoring system applied to the method for removing impurities from nalmefene hydrochloride as claimed in any one of claims 1 to 6, characterized in that: include: A crystallization process monitoring module is used to monitor the crystallization process of the nalmefene mixture, obtain real-time data of the crystallization process of the nalmefene mixture in each monitoring time period, and analyze and obtain the physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period; The crystallization process early warning module is used to locate the abnormal crystallization period and issue early warning prompts according to the physical dynamic compliance index of the impurity removal of the nalmefene mixture in each monitoring time period; The nalmefene hydrochloride impurity content monitoring and feedback module is used to monitor the content of nalmefene hydrochloride impurities after crystallization and provide monitoring feedback prompts.

8. A nalmefene hydrochloride impurity removal monitoring system according to claim 7, characterized in that: The analysis obtained the physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period, and the specific analysis process was as follows: Deploy several monitoring time periods, respectively obtain the pH value of the nalmefene mixed solution at the start time point of crystallization in each monitoring time period and the pH value of the nalmefene mixed solution at the end time point of crystallization in each monitoring time period, and obtain the pH change of the nalmefene mixed solution in each monitoring time period after processing to meet the measurement value; The average temperature, average stirring speed and conductivity during the crystallization of nalmefene are monitored in each monitoring time period, and the reaction stability index of the nalmefene mixed solution in each monitoring time period is obtained through processing; According to the pH change compliance value of the nalmefene mixed solution in each monitoring time period and the reaction stability index of the nalmefene mixed solution in each monitoring time period, a comprehensive analysis was conducted to obtain the physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period.

9. A nalmefene hydrochloride impurity removal monitoring system according to claim 7, characterized in that: The physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period represents the compliance degree of the impurity removal reaction of the nalmefene mixture in each monitoring time period, which is used to quantitatively evaluate the compliance degree of the impurity removal reaction of the nalmefene mixture in each monitoring time period by analyzing the real-time data of the crystallization process of the nalmefene mixture.

10. A nalmefene hydrochloride impurity removal monitoring system according to claim 7, characterized in that: The physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period and the location of abnormal crystallization period are used for early warning prompts. The specific process is as follows: According to the physical dynamic compliance index of impurity removal of the nalmefene mixture in each monitoring time period, it is compared with the set physical dynamic compliance index threshold of impurity removal of the nalmefene mixture. If the physical dynamic compliance index of impurity removal of the nalmefene mixture in a certain monitoring time period is lower than the physical dynamic compliance index threshold of impurity removal of the nalmefene mixture, then the monitoring time period is marked as an abnormal crystallization period, thereby obtaining each abnormal crystallization period, and issuing an early warning prompt for each abnormal crystallization period.

11. A nalmefene hydrochloride impurity removal monitoring system according to claim 7, characterized in that: The monitoring obtains the content of nalmefene hydrochloride impurities after crystallization, and performs monitoring feedback prompts, and the specific process is: The content of nalmefene hydrochloride impurities after crystallization is monitored and monitored and feedback is given. The specific process is: according to the high performance liquid chromatography of the crystallization process of the nalmefene mixture, the content of nalmefene hydrochloride impurities and the yield of nalmefene hydrochloride after crystallization are analyzed and obtained, and the content of nalmefene hydrochloride impurities is compared with the set nalmefene hydrochloride impurity content threshold and the yield of nalmefene hydrochloride is compared with the set nalmefene hydrochloride yield threshold, and feedback is given if the content of nalmefene hydrochloride impurities after crystallization is higher than or equal to the nalmefene hydrochloride impurity content threshold, or the yield of nalmefene hydrochloride is lower than the set nalmefene hydrochloride yield threshold.

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