Nalmefene base, and a preparation method and application thereof

Abstract

This application discloses nalmefene base, its preparation method, and its application, belonging to the field of pharmaceutical technology. The preparation method of nalmefene includes the following steps: mixing nalmefene hydrochloride with water to form an aqueous solution of nalmefene hydrochloride; reacting the aqueous solution of nalmefene hydrochloride with an aqueous solution of an alkaline component to form nalmefene base; the pH of the nalmefene hydrochloride is 4.0-6.5; the alkaline component includes at least one selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium acetate, ammonia, and sodium dihydrogen phosphate. This application uses nalmefene hydrochloride with a pH of 4.0-6.0 to undergo a desalting reaction with an aqueous solution of a strong base-weak acid salt or a weak base, crystallizing out nalmefene base. This effectively controls the particle size and shape of nalmefene base, obtaining small-particle-size, low-content, stable, and poorly soluble tablet-shaped nalmefene base without pulverization. It is less prone to burst release, meeting the requirements for sustained-release formulations, and the reaction is mild, green, and economical.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technology, and in particular to a nalmefenamic acid, its preparation method, and its application. Background Technology

[0002] Drug addiction, a chronic, relapsing brain disorder, refers to an individual's strong psychological dependence and physiological craving for a particular drug, leading to uncontrollable and continuous drug use and a series of negative consequences. Relapse refers to the act of an addict resuming drug use after a period of abstinence and is a crucial aspect of drug addiction treatment. Relapse prevention treatment typically needs to be continued for a period of time to ensure the addict's stable recovery and reduce the risk of relapse. Generally, drug treatment may take several weeks to months, while psychotherapy and psychosocial therapy require even longer to consolidate the therapeutic effect.

[0003] Nalmefene possesses a unique opioid receptor subtype binding spectrum. Compared to other opioid antagonists, nalmefene alone can optimize dopamine regulation not only during detoxification but also after detoxification, making it highly suitable for the treatment of opioid addiction. Currently marketed nalmefene products are mainly used to completely or partially reverse opioid-induced respiratory depression and reduce alcohol consumption in patients with alcohol dependence. The drug components are nalmefene hydrochloride monohydrate or nalmefene hydrochloride dihydrate, which have high bioavailability due to their good solubility.

[0004] However, nalmefene products are available in injection and oral tablet forms, neither of which offers long-term sustained-release therapy, resulting in poor compliance for long-term treatment of psychotropic drug addiction. Furthermore, patent literature describes long-acting sustained-release formulations of nalmefene, but sustained-release formulations prepared using nalmefene hydrochloride as a raw material (US20050031668A1) often exhibit a significant burst release after administration, easily causing patient agitation or discomfort. While poorly soluble nalmefene is less prone to burst release, poorly soluble drugs can also cause delayed release. Therefore, developing long-acting sustained-release formulations using small-particle-size nalmefene is key to solving the problem of burst or delayed release in formulations.

[0005] Implantable drugs offer the advantages of significantly reducing the frequency of medication administration and maintaining blood drug concentrations within the therapeutic window for extended periods, making them ideal long-acting sustained-release formulations. However, the production of implantable drugs places high demands on equipment, requiring both continuous production capacity and stable formulation properties. Therefore, hot-melt extrusion technology has emerged. However, hot-melt extrusion also places high demands on the properties of raw materials and excipients, especially when using biodegradable polyester as a carrier. Due to its low glass transition temperature, and the fact that the hot-melt temperature during extrusion molding should not be significantly higher than the carrier's glass transition temperature, the high-melting-point active pharmaceutical ingredient (API) is dispersed crystallinely within the carrier. Therefore, the particle size and crystal morphology of the API directly affect the properties of the extrudate. If the API particle size is large and insoluble in the system, the implant may exhibit a "fish-scale" surface, affecting not only the appearance of the formulation but also altering the release rate. Therefore, controlling the particle size and shape of the API is crucial for implantable drugs. Small-particle-size active pharmaceutical ingredients (APIs) are generally obtained through pulverization. However, pulverization not only consumes a significant amount of energy, resulting in resource waste, but also, due to the introduction of large amounts of mechanical and thermal energy during the pulverization process, can easily lead to an increase in related substances in the API. Furthermore, the effectiveness of pulverization is very limited; when the target particle size is small, it is difficult to achieve the desired result through pulverization.

[0006] Therefore, how to directly provide nalmefenamic acid with small particle size that meets the property requirements without crushing is a technical problem that urgently needs to be solved. Summary of the Invention

[0007] Based on this, the main objective of this application is to provide a method for synthesizing nalmefenine, which can effectively control the particle size and shape of nalmefenine, and obtain nalmefenine in the form of small particle size, low content of related substances, good stability, and poor water solubility without pulverization. It is not prone to burst release and can meet the performance requirements of sustained-release formulations. Furthermore, the synthesis process does not involve organic solvents, does not consume large amounts of energy, is green and economical, and is suitable for mass production.

[0008] The first aspect of this application provides a method for preparing nalmefene, comprising the following steps:

[0009] Nalmefene hydrochloride is mixed with water to form an aqueous solution of nalmefene hydrochloride.

[0010] The nalmefene hydrochloride aqueous solution is mixed with an aqueous solution of an alkaline component to form the nalmefene base;

[0011] The pH of the nalmefene hydrochloride is 4.0-6.5; the alkaline component includes at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium acetate, ammonia, and sodium dihydrogen phosphate.

[0012] In some embodiments, the molar ratio of nalmefene hydrochloride to the alkaline component is 1:1-1:4, optionally 1:2-1:4.

[0013] In some embodiments, the molar concentration of the nalmefene hydrochloride aqueous solution is 10 / 64 mol / L to 10 / 34 mol / L.

[0014] In some embodiments, the molar concentration of the aqueous solution of the alkaline component is 10 / 44 mol / L to 40 / 44 mol / L, and optionally 20 / 44 mol / L to 40 / 44 mol / L.

[0015] In some embodiments, the molar ratio of nalmefene hydrochloride to the alkaline component is 1:1-1:4, and optionally 1:2-1:4.

[0016] In some embodiments, the step of mixing the aqueous solution of nalmefene hydrochloride with the aqueous solution of an alkaline component includes: adding the aqueous solution of the alkaline component to the aqueous solution of nalmefene hydrochloride, or adding the aqueous solution of nalmefene hydrochloride to the aqueous solution of the alkaline component, and then reacting under stirring conditions.

[0017] In some embodiments, in the step of reacting under stirring conditions, the stirring speed is 50 rpm to 1000 rpm, optionally 100 rpm to 900 rpm; the stirring time is 20 min to 300 min, optionally 30 min to 240 min.

[0018] In some embodiments, the preparation process of nalmefene hydrochloride includes: recrystallizing crude nalmefene hydrochloride with concentrated hydrochloric acid and drying it until the moisture content is less than 10 wt%.

[0019] In some embodiments, the mixing reaction is followed by a settling and drying step.

[0020] In some embodiments, the settling time is 60 min to 240 min.

[0021] In some embodiments, the drying conditions include: a drying temperature of 30°C-75°C, optionally 45°C-75°C; and a drying time of 36h-96h, optionally 42h-72h.

[0022] The second aspect of this application provides nalmefenidine prepared by the preparation method described in the first aspect.

[0023] A third aspect of this application provides a nalmefenine base with a D90 ≤ 30 μm and a crystalline morphology of plates.

[0024] The fourth aspect of this application provides the use of nalmefenamic acid as described in the second aspect or by a third party in the preparation of sustained-release formulations.

[0025] A fifth aspect of this application provides a sustained-release formulation comprising nalmefenidine as described in the second aspect or by a third party.

[0026] The beneficial effects of this application are:

[0027] 1. This application uses nalmefene hydrochloride with a pH of 4.0-6.5 to carry out a desalting reaction with an aqueous solution of a strong base weak acid salt or a weak base, crystallizing out nalmefene base. This method can effectively control the particle size and shape of nalmefene base, and obtain nalmefene base in the form of small particle size, low content of related substances, good stability, and poor water solubility without pulverization. The sustained-release formulation prepared using nalmefene base meets the performance requirements, is not prone to burst release or delayed release, and can achieve a near constant rate of stable release.

[0028] 2. The reaction in this application is mild, the synthesis process does not involve organic solvents and does not consume a lot of energy, making it green and economical and suitable for mass production. Attached Figure Description

[0029] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. The drawings are only for illustrating preferred embodiments and are not intended to limit this application. Throughout the drawings, the same reference numerals denote the same parts. In the drawings:

[0030] Figure 1 This is a scanning electron microscope image of Example 1.

[0031] Figure 2 This is a scanning electron microscope image of Comparative Example 1.

[0032] Figure 3 This is a scanning electron microscope image of Comparative Example 2.

[0033] Figure 4 This is a scanning electron microscope image of Comparative Example 3. Detailed Implementation

[0034] To facilitate understanding of this application, a more comprehensive description of the application will be provided below with reference to specific embodiments. Preferred embodiments of the application are given below. However, the application can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of this application.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0036] In this article, the technical features described in an open-ended manner include both closed technical solutions composed of the listed features and open technical solutions that include the listed features.

[0037] In this document, the terms “first” and “second” are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated.

[0038] In this description, "multiple" means two or more, such as two kinds, three kinds, etc., unless otherwise explicitly specified.

[0039] In this document, numerical ranges are referred to as continuous unless otherwise specified, and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when a range refers to an integer, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0040] Unless otherwise specified, the temperature parameters in this document can be either constant temperature processing or processing within a certain temperature range. The constant temperature processing allows for temperature fluctuations within the precision range controlled by the instrument.

[0041] In this document, "optional," "preferred," and "ideal" refer to embodiments of this application that provide certain beneficial effects under certain circumstances. However, other embodiments may also be preferred under the same or other circumstances. Furthermore, the description of one or more preferred embodiments does not imply that other embodiments are unavailable, nor is it intended to exclude other embodiments from the scope of this application.

[0042] Unless otherwise specified, all steps of this application may be performed sequentially or randomly, but sequentially is preferred.

[0043] The first aspect of this application provides a method for preparing nalmefene, comprising the following steps:

[0044] Nalmefene hydrochloride is mixed with water to form an aqueous solution of nalmefene hydrochloride.

[0045] The nalmefene hydrochloride aqueous solution is mixed with an aqueous solution of an alkaline component to form the nalmefene base;

[0046] The pH of the nalmefene hydrochloride is 4.0-6.5; the alkaline component includes at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium acetate, ammonia, and sodium dihydrogen phosphate.

[0047] Typically, nalmefene prepared by alkalization with nalmefene hydrochloride is in the form of needles or flakes, with a uniform particle size distribution exhibiting a standard normal distribution. If the solution is too alkaline during alkalization, the strong alkali will destroy the stability of nalmefene, leading to its dissolution; conversely, if the nalmefene hydrochloride is too acidic, the particle size of nalmefene will be too large, neither of which meets the performance requirements of sustained-release formulations.

[0048] This application uses nalmefene hydrochloride with a pH of 4.0-6.5 to carry out a desalting reaction with an aqueous solution of a strong base weak acid salt or a weak base, crystallizing out nalmefene base. This method can effectively control the particle size and shape of nalmefene base, and obtain flaky nalmefene base with small and uniform particle size, low content of related substances, good stability, and poor water solubility without the need for crushing. Moreover, the reaction is mild, green and economical.

[0049] During the experiment, the applicant discovered that the pH of nalmefene hydrochloride itself has a significant impact on its alkalization into nalmefene base. When the pH of nalmefene hydrochloride is 4.0-6.5, reaction with an aqueous solution of a weak base or a strong acid-weak base salt yields small-particle, water-insoluble flake-shaped nalmefene base. This flake-shaped nalmefene base exhibits good stability, and sustained-release formulations prepared using this nalmefene base meet the required properties, being neither prone to burst release nor delayed release, achieving a near-constant rate of stable release. Readily available nalmefene hydrochloride at different pH values ​​can be used, or nalmefene hydrochloride at different pH values ​​can be prepared in-house. For example, recrystallizing crude nalmefene hydrochloride with concentrated hydrochloric acid and drying it until the moisture content is less than 10 wt% can yield nalmefene hydrochloride at the desired pH. Most commercially available nalmefene hydrochloride is recrystallized using organic solvents, but this method carries the risk of solvent residue and has a low yield. Recrystallization with concentrated hydrochloric acid can improve the yield while avoiding organic solvent residue. However, if the moisture content is not controlled, nalmefene hydrochloride with pH < 4.0 will be obtained. Therefore, the moisture content needs to be controlled to < 10 wt%.

[0050] It should be noted that the pH of nalmefene hydrochloride was determined according to the 2020 edition of the Chinese Pharmacopoeia, Part II, General Chapter 0631, Acidity of Nalmefene Hydrochloride [Tests]. Take 0.10g of this product, add 10mL of water to dissolve it, and determine the pH according to the method (General Chapter 0631).

[0051] In this application, the molar ratio of nalmefene hydrochloride to the alkaline component mainly affects the degree of alkalization of nalmefene hydrochloride, and can be adjusted according to the reaction effect without particular limitation. Specifically, the molar ratio of nalmefene hydrochloride to the alkaline component is 1:1-1:4, and can be selected from 1:2-1:4, such as 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, etc.

[0052] In this application, the molar concentration of the nalmefene hydrochloride aqueous solution and the molar concentration of the alkaline component aqueous solution, as well as the ratio of the molar concentration of the nalmefene hydrochloride aqueous solution to the molar concentration of the alkaline component aqueous solution, have a certain impact on the reaction efficiency and can be adjusted according to actual needs.

[0053] Specifically, the molar concentration of the nalmefene hydrochloride aqueous solution is 10 / 64 mol / L to 10 / 34 mol / L, for example, 10 / 64 mol / L, 10 / 44 mol / L, 10 / 34 mol / L, etc.; the molar concentration of the alkaline component aqueous solution is 10 / 44 mol / L to 40 / 44 mol / L, optionally 20 / 44 mol / L to 40 / 44 mol / L, specifically 10 / 44 mol / L, 0.3 mol / L, etc. The concentrations are L, 0.4 mol / L, 20 / 44 mol / L, 0.5 mol / L, 0.6 mol / L, 30 / 44 mol / L, 0.7 mol / L, 0.8 mol / L, 0.9 mol / L, 40 / 44 mol / L, etc.; the molar ratio of nalmefene hydrochloride to the alkaline component is 1:1-1:4, optionally 1:2-1:4, such as 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, etc.

[0054] In this application, there are no particular limitations on the mixing order and addition flow rate of the nalmefene hydrochloride aqueous solution and the alkaline component aqueous solution. The alkaline component aqueous solution can be added to the nalmefene hydrochloride aqueous solution, or the nalmefene hydrochloride aqueous solution can be added to the alkaline component aqueous solution. The addition flow rate is not particularly limited and can be 0.5 mL / s to 400 mL / s.

[0055] Understandably, after the mixing reaction, a settling and drying step may also be included. The purpose of settling is to precipitate nalmefene base for separation; the settling time can be 60 min-240 min, for example 60 min, 90 min, 120 min, 150 min, 180 min, 210 min, 240 min, etc. The drying temperature should not be too high. Specifically, the drying conditions include: a drying temperature of 30℃-75℃, preferably 45℃-75℃, for example 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃; and a drying time of 36 h-96 h, preferably 42 h-72 h, for example 36 h, 42 h, 48 h, 54 h, 60 h, 66 h, 72 h, 78 h, 84 h, 90 h, 96 h, etc.

[0056] The second aspect of this application provides nalmefenidine prepared by the preparation method described in the first aspect.

[0057] The nalmefenamic acid of this application has small particle size, low content of related substances, and good stability, which can meet the performance requirements of sustained-release formulations.

[0058] A third aspect of this application provides a nalmefenine base with a D90 ≤ 30 μm and a crystalline morphology of plates.

[0059] The nalmefenamic acid of this application has a small particle size, D90≤30μm; the crystal morphology is plate-like and has good stability, which can meet the performance requirements of sustained-release formulations.

[0060] The fourth aspect of this application provides the use of nalmefenamic acid as described in the second aspect or by a third party in the preparation of sustained-release formulations.

[0061] The nalmefenamic acid of this application has small particle size, low content of related substances, and good stability, which can meet the performance requirements of sustained-release formulations.

[0062] A fifth aspect of this application provides a sustained-release formulation comprising nalmefenidine as described in the second aspect or by a third party.

[0063] It is worth noting that the raw materials used in the embodiments of this application are all ordinary commercially available products, and their sources are not specifically limited.

[0064] Crude nalmefene hydrochloride: prepared in-house and obtained by recrystallization in an organic solvent.

[0065] The following are specific examples.

[0066] Example 1

[0067] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 according to the pharmacopoeia method.

[0068] Take 3.93 g of the above-mentioned nalmefene hydrochloride and 44 mL of purified water (molar concentration 1 / 4.4 mol / L), stir to fully dissolve the nalmefene hydrochloride, and the pH of the solution is 5.0; take 2.52 g of sodium bicarbonate and 44 mL of purified water (molar concentration 3 / 4.4 mol / L), stir to fully dissolve the sodium bicarbonate, and the pH of the solution is measured to be 8.4; at room temperature, add the nalmefene hydrochloride solution to the sodium bicarbonate solution at a flow rate of 26.9 mL / s, stir at 350 rpm to precipitate crystals, stir for 60 min, let stand for 120 min, take the supernatant and measure the pH to be 8.0, then filter, wash with three times the volume of purified water of the suspension, collect the nalmefene filter residue, and dry in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base. Its scanning electron microscope image (magnification 500×) is shown in [reference needed]. Figure 1 It can be seen that it has a sheet-like structure.

[0069] Example 2

[0070] The pH of commercially available nalmefene hydrochloride (manufacturer: RUSAN PHARMA LTD; batch number: NMFXO22001) was determined to be 5.7 using the pharmacopoeia method.

[0071] Take 3.93g of the above-mentioned nalmefene hydrochloride and 44mL of purified water (molar concentration of 1 / 4.4mol / L), stir to fully dissolve the nalmefene hydrochloride, and the pH of the solution is 5.0; take 2.52g of sodium bicarbonate and 44mL of purified water (molar concentration of 3 / 4.4mol / L), stir to fully dissolve the sodium bicarbonate, and the pH of the solution is measured to be 8.4; at room temperature, add the nalmefene hydrochloride solution to the sodium bicarbonate solution at a flow rate of 26.9mL / s, stir at 350rpm to precipitate crystals, stir for 60min, let stand for 120min, take the supernatant and measure the pH of 8.0, then filter, wash with three times the volume of purified water of the suspension, collect the nalmefene filter residue, and dry in a 45℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0072] Example 3

[0073] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0074] Take 3.93g of the above-mentioned nalmefene hydrochloride and 44mL of purified water (molar concentration of 1 / 4.4mol / L), stir to fully dissolve the nalmefene hydrochloride, and the pH of the solution is 5.0; take 2.52g of sodium bicarbonate and 44mL of purified water (molar concentration of 3 / 4.4mol / L), stir to fully dissolve the sodium bicarbonate, and the pH of the solution is measured to be 8.4; at room temperature, add the nalmefene hydrochloride solution to the sodium bicarbonate solution at a flow rate of 26.9mL / s, stir at 350rpm to precipitate crystals, stir for 60min, let stand for 120min, take the supernatant and measure the pH of 8.0, then filter, wash with three times the volume of purified water of the suspension, collect the nalmefene filter residue, and dry in a 75℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0075] Example 4

[0076] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0077] Take 3.93g of the above-mentioned nalmefene hydrochloride and 44mL of purified water (molar concentration of 1 / 4.4mol / L), stir to fully dissolve the nalmefene hydrochloride, and the pH of the solution is 5.0; take 0.84g of sodium bicarbonate and 44mL of purified water (molar concentration of 1 / 4.4mol / L), stir to fully dissolve the sodium bicarbonate, and the pH of the solution is measured to be 8.3; at room temperature, add the nalmefene hydrochloride solution to the sodium bicarbonate solution at a flow rate of 26.9mL / s, stir at 350rpm to precipitate crystals, stir for 60min, let stand for 120min, take the supernatant and measure the pH of 6.9, then filter, wash with three times the volume of purified water of the suspension, collect the nalmefene filter residue, and dry in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0078] Example 5

[0079] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0080] Dissolve 3.93g of the above-mentioned nalmefene hydrochloride in 44mL of purified water (molar concentration of 1 / 4.4mol / L), and stir until the nalmefene hydrochloride is fully dissolved. The pH of the solution is 5.0. Dissolve 1.68g of sodium bicarbonate in 44mL of purified water (molar concentration of 2 / 4.4mol / L), and stir until the sodium bicarbonate is fully dissolved. The pH of the solution is measured to be 8.4. At room temperature, the nalmefene hydrochloride solution is added to the sodium bicarbonate solution at a flow rate of 26.9mL / s, and stirred at 350rpm to precipitate crystals. The stirring time is 60min, and the solution is allowed to stand for 120min. The pH of the supernatant is measured to be 7.8. The solution is then filtered, washed with three times the volume of purified water, and the nalmefene residue is collected. The residue is dried in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0081] Example 6

[0082] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0083] Dissolve 3.93 g of the above-mentioned nalmefene hydrochloride in 44 mL of purified water (molar concentration of 1 / 4.4 mol / L), and stir until the nalmefene hydrochloride is fully dissolved. The pH of the solution is 5.0. Dissolve 2.10 g of sodium bicarbonate in 44 mL of purified water (molar concentration of 2.5 / 4.4 mol / L), and stir until the sodium bicarbonate is fully dissolved. The pH of the solution is measured to be 8.5. At room temperature, add the nalmefene hydrochloride solution to the sodium bicarbonate solution at a flow rate of 26.9 mL / s, stir at 350 rpm to precipitate crystals, stir for 60 min, let stand for 120 min, take the supernatant and measure the pH to be 8.0. Then filter, wash with three times the volume of purified water of the suspension, collect the nalmefene filter residue, and dry in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0084] Example 7

[0085] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0086] Dissolve 3.93 g of the above-mentioned nalmefene hydrochloride in 44 mL of purified water (molar concentration of 1 / 4.4 mol / L), and stir until the nalmefene hydrochloride is fully dissolved. The pH of the solution is 5.0. Dissolve 3.70 g of sodium bicarbonate in 44 mL of purified water (molar concentration of 4 / 4.4 mol / L), and stir until the sodium bicarbonate is fully dissolved. The pH of the solution is measured to be 8.5. At room temperature, add the nalmefene hydrochloride solution to the sodium bicarbonate solution at a flow rate of 26.9 mL / s, stir at 350 rpm to precipitate crystals, stir for 60 min, let stand for 120 min, take the supernatant and measure the pH to be 8.2. Then filter, wash with three times the volume of purified water of the suspension, collect the nalmefene filter residue, and dry in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0087] Example 8

[0088] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0089] Dissolve 3.93g of the above-mentioned nalmefene hydrochloride in 44mL of purified water (molar concentration of 1 / 4.4mol / L), and stir until the nalmefene hydrochloride is fully dissolved. The pH of the solution is 5.0. Dissolve 2.52g of sodium bicarbonate in 44mL of purified water (molar concentration of 3 / 4.4mol / L), and stir until the sodium bicarbonate is fully dissolved. The pH of the solution is measured to be 8.4. At room temperature, the nalmefene hydrochloride solution is added to the sodium bicarbonate solution at a flow rate of 1.0mL / s, and stirred at 350rpm to precipitate crystals. The stirring time is 60min, and the solution is allowed to stand for 120min. The pH of the supernatant is measured to be 7.9. The solution is then filtered, washed with three times the volume of purified water, and the nalmefene residue is collected. The residue is dried in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0090] Example 9

[0091] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0092] Dissolve 3.93g of the above-mentioned nalmefene hydrochloride in 44mL of purified water (molar concentration of 1 / 4.4mol / L), and stir until the nalmefene hydrochloride is fully dissolved. The pH of the solution is 5.0. Dissolve 2.52g of sodium bicarbonate in 44mL of purified water (molar concentration of 3 / 4.4mol / L), and stir until the sodium bicarbonate is fully dissolved. The pH of the solution is measured to be 8.4. At room temperature, add the nalmefene hydrochloride solution to the sodium bicarbonate solution at a flow rate of 4.4mL / s, stir at 350rpm to precipitate crystals, stir for 60min, let stand for 120min, take the supernatant and measure the pH of 8.2. Then filter, wash with three times the volume of purified water of the suspension, collect the nalmefene filter residue, and dry in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0093] Example 10

[0094] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0095] Dissolve 3.93g of the above-mentioned nalmefene hydrochloride in 44mL of purified water (molar concentration of 1 / 4.4mol / L), and stir until the nalmefene hydrochloride is fully dissolved. The pH of the solution is 5.0. Dissolve 2.52g of sodium bicarbonate in 44mL of purified water (molar concentration of 3 / 4.4mol / L), and stir until the sodium bicarbonate is fully dissolved. The pH of the solution is measured to be 8.4. At room temperature, add the nalmefene hydrochloride solution to the sodium bicarbonate solution at a flow rate of 26.9mL / s, stir at 100rpm to precipitate crystals, stir for 60min, let stand for 120min, take the supernatant and measure the pH to be 7.5. Then filter, wash with three times the volume of purified water of the suspension, collect the nalmefene filter residue, and dry in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0096] Example 11

[0097] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0098] Dissolve 3.93g of the above-mentioned nalmefene hydrochloride in 44mL of purified water (molar concentration of 1 / 4.4mol / L), and stir until the nalmefene hydrochloride is fully dissolved. The pH of the solution is 5.0. Dissolve 2.52g of sodium bicarbonate in 44mL of purified water (molar concentration of 3 / 4.4mol / L), and stir until the sodium bicarbonate is fully dissolved. The pH of the solution is measured to be 8.4. At room temperature, the nalmefene hydrochloride solution is added to the sodium bicarbonate solution at a flow rate of 26.9mL / s, and stirred at 900rpm to precipitate crystals. The stirring time is 60min, and the solution is allowed to stand for 120min. The pH of the supernatant is measured to be 7.5. The solution is then filtered, washed with three times the volume of purified water, and the nalmefene residue is collected. The residue is dried in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0099] Example 12

[0100] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0101] Dissolve 3.93g of the above-mentioned nalmefene hydrochloride in 44mL of purified water (molar concentration of 1 / 4.4mol / L), and stir until the nalmefene hydrochloride is fully dissolved. The pH of the solution is 5.0. Dissolve 2.52g of sodium bicarbonate in 44mL of purified water (molar concentration of 3 / 4.4mol / L), and stir until the sodium bicarbonate is fully dissolved. The pH of the solution is measured to be 8.4. At room temperature, the nalmefene hydrochloride solution is added to the sodium bicarbonate solution at a flow rate of 26.9mL / s, and stirred at 350rpm to precipitate crystals. The stirring time is 30min, and the solution is allowed to stand for 120min. The pH of the supernatant is measured to be 8.2. The solution is then filtered, washed with three times the volume of purified water, and the nalmefene residue is collected. The residue is dried in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0102] Example 13

[0103] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0104] Dissolve 3.93g of the above-mentioned nalmefene hydrochloride in 44mL of purified water (molar concentration of 1 / 4.4mol / L), and stir until the nalmefene hydrochloride is fully dissolved. The pH of the solution is 5.0. Dissolve 2.52g of sodium bicarbonate in 44mL of purified water (molar concentration of 3 / 4.4mol / L), and stir until the sodium bicarbonate is fully dissolved. The pH of the solution is measured to be 8.4. At room temperature, the nalmefene hydrochloride solution is added to the sodium bicarbonate solution at a flow rate of 26.9mL / s, and stirred at 350rpm to precipitate crystals. The stirring time is 240min, and the solution is allowed to stand for 120min. The pH of the supernatant is measured to be 8.3. The solution is then filtered, washed with three times the volume of purified water, and the nalmefene residue is collected. The residue is dried in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0105] Example 14

[0106] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0107] Dissolve 3.93g of the above-mentioned nalmefene hydrochloride in 34mL of purified water (molar concentration of 1 / 3.4mol / L), and stir until the nalmefene hydrochloride is fully dissolved; the pH of the solution is measured to be 5.0. Dissolve 2.52g of sodium bicarbonate in 44mL of purified water (molar concentration of 3 / 4.4mol / L), and stir until the sodium bicarbonate is fully dissolved; the pH of the solution is measured to be 8.4. At room temperature, add the nalmefene hydrochloride solution to the sodium bicarbonate solution at a flow rate of 26.9mL / s, stir at 350rpm to precipitate crystals, stir for 60min, let stand for 120min, take the supernatant and measure the pH to be 8.0, then filter, wash with three times the volume of purified water of the suspension, collect the nalmefene filter residue, and dry in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0108] Example 15

[0109] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0110] Dissolve 3.93g of the above-mentioned nalmefene hydrochloride in 64mL of purified water (molar concentration of 1 / 6.4mol / L), and stir until the nalmefene hydrochloride is fully dissolved; the pH of the solution is measured to be 5.0. Dissolve 2.52g of sodium bicarbonate in 44mL of purified water (molar concentration of 3 / 4.4mol / L), and stir until the sodium bicarbonate is fully dissolved; the pH of the solution is measured to be 8.4. At room temperature, add the nalmefene hydrochloride solution to the sodium bicarbonate solution at a flow rate of 26.9mL / s, stir at 350rpm to precipitate crystals, stir for 60min, let stand for 120min, take the supernatant and measure the pH to be 7.3, then filter, wash with three times the volume of purified water of the suspension, collect the nalmefene filter residue, and dry in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0111] Example 16

[0112] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0113] Dissolve 3.93g of the above-mentioned nalmefene hydrochloride in 44mL of purified water (molar concentration of 1 / 4.4mol / L), and stir until the nalmefene hydrochloride is fully dissolved; the pH of the solution is measured to be 5.0. Dissolve 2.52g of sodium bicarbonate in 34mL of purified water (molar concentration of 3 / 3.4mol / L), and stir until the sodium bicarbonate is fully dissolved; the pH of the solution is measured to be 8.4. At room temperature, add the nalmefene hydrochloride solution to the sodium bicarbonate solution at a flow rate of 26.9mL / s, stir at 350rpm to precipitate crystals, stir for 60min, let stand for 120min, take the supernatant and measure the pH to be 8.0, then filter, wash with three times the volume of purified water of the suspension, collect the nalmefene filter residue, and dry in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0114] Example 17

[0115] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0116] Dissolve 3.93g of the above-mentioned nalmefene hydrochloride in 44mL of purified water (molar concentration of 1 / 4.4mol / L), and stir until the nalmefene hydrochloride is fully dissolved; the pH of the solution is measured to be 5.0. Dissolve 2.52g of sodium bicarbonate in 64mL of purified water (molar concentration of 3 / 6.4mol / L), and stir until the sodium bicarbonate is fully dissolved; the pH of the solution is measured to be 8.4. At room temperature, add the nalmefene hydrochloride solution to the sodium bicarbonate solution at a flow rate of 26.9mL / s, stir at 350rpm to precipitate crystals, stir for 60min, let stand for 120min, take the supernatant and measure the pH to be 8.0, then filter, wash with three times the volume of purified water of the suspension, collect the nalmefene filter residue, and dry in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0117] Example 18

[0118] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 10.0%, and test the pH to 4.0 using the pharmacopoeia method.

[0119] Dissolve 3.93g of the above-mentioned nalmefene hydrochloride in 44mL of purified water (molar concentration of 1 / 4.4mol / L), and stir until the nalmefene hydrochloride is fully dissolved; the pH of the solution is measured to be 3.0. Dissolve 2.52g of sodium bicarbonate in 44mL of purified water (molar concentration of 3 / 4.4mol / L), and stir until the sodium bicarbonate is fully dissolved; the pH of the solution is measured to be 8.4. At room temperature, add the nalmefene hydrochloride solution to the sodium bicarbonate solution at a flow rate of 26.9mL / s, stir at 350rpm to precipitate crystals, stir for 60min, let stand for 120min, take the supernatant and measure the pH to be 7.5, then filter, wash with three times the volume of purified water of the suspension, collect the nalmefene filter residue, and dry in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0120] Example 19

[0121] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.0%, and test the pH to 6.5 using the pharmacopoeia method.

[0122] Dissolve 3.93g of the above-mentioned nalmefene hydrochloride in 44mL of purified water (molar concentration of 1 / 4.4mol / L), and stir until the nalmefene hydrochloride is fully dissolved; the pH of the solution is measured to be 5.9. Dissolve 2.52g of sodium bicarbonate in 44mL of purified water (molar concentration of 3 / 4.4mol / L), and stir until the sodium bicarbonate is fully dissolved; the pH of the solution is measured to be 8.4. At room temperature, add the nalmefene hydrochloride solution to the sodium bicarbonate solution at a flow rate of 26.9mL / s, stir at 350rpm to precipitate crystals, stir for 60min, let stand for 120min, take the supernatant and measure the pH to be 7.4, then filter, wash with three times the volume of purified water of the suspension, collect the nalmefene filter residue, and dry in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0123] Example 20

[0124] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0125] Dissolve 3.93 g of the above-mentioned nalmefene hydrochloride in 44 mL of purified water (molar concentration of 1 / 4.4 mol / L), and stir until the nalmefene hydrochloride is fully dissolved. The pH of the solution is 5.0. Dissolve 3.00 g of potassium bicarbonate in 44 mL of purified water (molar concentration of 3 / 4.4 mol / L), and stir until the potassium bicarbonate is fully dissolved. The pH of the solution is measured to be 8.7. At room temperature, add the nalmefene hydrochloride solution to the potassium bicarbonate solution at a flow rate of 26.9 mL / s, stir at 350 rpm to precipitate crystals, stir for 60 min, let stand for 120 min, take the supernatant and measure the pH of 7.7. Then filter, wash with three times the volume of purified water of the suspension, collect the nalmefene filter residue, and dry in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0126] Example 21

[0127] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0128] Dissolve 3.93g of the above-mentioned nalmefene hydrochloride in 44mL of purified water (molar concentration of 1 / 4.4mol / L), and stir until the nalmefene hydrochloride is fully dissolved. The pH of the solution is 5.0. Dissolve 2.13g of disodium hydrogen phosphate in 44mL of purified water (molar concentration of 3 / 4.4mol / L), and stir until the disodium hydrogen phosphate is fully dissolved. The pH of the solution is measured to be 9.2. At room temperature, the nalmefene hydrochloride solution is added to the disodium hydrogen phosphate solution at a flow rate of 26.9mL / s, and stirred at 350rpm to precipitate crystals. The stirring time is 60min, and the solution is allowed to stand for 120min. The pH of the supernatant is measured to be 6.7. The solution is then filtered, washed with three times the volume of purified water, and the nalmefene residue is collected. The residue is dried in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0129] Example 22

[0130] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0131] Dissolve 3.93g of the above-mentioned nalmefene hydrochloride in 44mL of purified water (molar concentration of 1 / 4.4mol / L), and stir until the nalmefene hydrochloride is fully dissolved. The pH of the solution is 5.0. Dissolve 1.05g of ammonia in 44mL of purified water (molar concentration of 3 / 4.4mol / L), and stir until the ammonia is fully dissolved. The pH of the solution is measured to be 11.5. At room temperature, add the nalmefene hydrochloride solution to the ammonia solution at a flow rate of 26.9mL / s, stir at 350rpm to precipitate crystals, stir for 60min, let stand for 120min, take the supernatant and measure the pH to be 9.7. Then filter, wash with three times the volume of purified water of the suspension, collect the nalmefene filter residue, and dry in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0132] Example 23

[0133] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0134] Dissolve 3.93g of the above-mentioned nalmefene hydrochloride in 44mL of purified water (molar concentration of 1 / 4.4mol / L), and stir until the nalmefene hydrochloride is fully dissolved. The pH of the solution is 5.0. Dissolve 1.59g of sodium carbonate in 44mL of purified water (molar concentration of 3 / 4.4mol / L), and stir until the sodium carbonate is fully dissolved. The pH of the solution is measured to be 10.6. At room temperature, add the nalmefene hydrochloride solution to the sodium carbonate solution at a flow rate of 26.9mL / s, stir at 350rpm to precipitate crystals, stir for 60min, let stand for 120min, take the supernatant and measure the pH to be 9.8. Then filter, wash with three times the volume of purified water of the suspension, collect the nalmefene filter residue, and dry in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0135] Example 24

[0136] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0137] Dissolve 3.93g of the above-mentioned nalmefene hydrochloride in 44mL of purified water (molar concentration of 1 / 4.4mol / L), and stir until the nalmefene hydrochloride is fully dissolved. The pH of the solution is 5.0. Dissolve 2.52g of sodium bicarbonate in 44mL of purified water (molar concentration of 3 / 4.4mol / L), and stir until the sodium bicarbonate is fully dissolved. The pH of the solution is measured to be 8.4. At room temperature, add the sodium bicarbonate solution to the nalmefene hydrochloride solution at a flow rate of 26.9mL / s, stir at 350rpm to precipitate crystals, stir for 60min, let stand for 120min, take the supernatant and measure the pH to be 8.0. Then filter, wash with three times the volume of purified water of the suspension, collect the nalmefene filter residue, and dry in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0138] Comparative Example 1

[0139] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 15%, and test the pH to 2.8 using the pharmacopoeia method.

[0140] Dissolve 3.93 g of nalmefene hydrochloride in 44 mL of purified water (molar concentration 1 / 4.4 mol / L), and stir until the nalmefene hydrochloride is fully dissolved. The pH of the solution is 2.0. Dissolve 2.52 g of sodium bicarbonate in 44 mL of purified water (molar concentration 3 / 4.4 mol / L), and stir until the sodium bicarbonate is fully dissolved. The pH of the solution is 8.4. At room temperature, add the nalmefene hydrochloride solution to the sodium bicarbonate solution at a flow rate of 26.9 mL / s, stir at 350 rpm to precipitate crystals, stir for 60 min, let stand for 120 min, take the supernatant and measure the pH of 8.0. Then filter, wash with three times the volume of purified water, collect the nalmefene filter residue, and dry in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0141] Comparative Example 2

[0142] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 18%, and test the pH to 1.9 using the pharmacopoeia method.

[0143] Dissolve 3.93 g of nalmefene hydrochloride in 44 mL of purified water (molar concentration 1 / 4.4 mol / L), and stir until the nalmefene hydrochloride is fully dissolved. The pH of the solution is less than 1.0. Dissolve 2.52 g of sodium bicarbonate in 44 mL of purified water (molar concentration 3 / 4.4 mol / L), and stir until the sodium bicarbonate is fully dissolved. The pH of the solution is measured to be 8.4. At room temperature, add the nalmefene hydrochloride solution to the sodium bicarbonate solution at a flow rate of 26.9 mL / s, stir at 350 rpm to precipitate crystals, stir for 60 min, let stand for 120 min, and take the supernatant. The pH of the supernatant is measured to be 7.7. Then filter, wash with three times the volume of purified water, collect the nalmefene filter residue, and dry in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0144] Comparative Example 3

[0145] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 12%, and test the pH to 3.7 using the pharmacopoeia method.

[0146] Dissolve 3.93 g of nalmefene hydrochloride (pH 3.7 as determined by pharmacopoeia method) in 44 mL of purified water (molar concentration 1 / 4.4 mol / L), and stir until fully dissolved; the pH of the solution is 2.7. Dissolve 2.52 g of sodium bicarbonate in 44 mL of purified water (molar concentration 3 / 4.4 mol / L), and stir until fully dissolved; the pH of the solution is 8.4. At room temperature, add the nalmefene hydrochloride solution to the sodium bicarbonate solution at a flow rate of 26.9 mL / s, stir at 350 rpm to precipitate crystals, stir for 60 min, let stand for 120 min, take the supernatant and measure the pH of 8.0, then filter, wash with three times the volume of purified water, collect the nalmefene filter residue, and dry in a 50℃ forced-air drying oven for 48 hours to obtain nalmefene base.

[0147] Comparative Example 4

[0148] Take crude nalmefene hydrochloride, add concentrated hydrochloric acid for recrystallization, filter and collect the residue, dry at 50-100℃, take samples every 2 hours until the moisture content is 4.5%, and test the pH to 5.7 using the pharmacopoeia method.

[0149] Dissolve 3.93g of nalmefene hydrochloride (pH 5.7 as determined by pharmacopoeia method) in 44mL of purified water (molar concentration 1 / 4.4mol / L), and stir until the nalmefene hydrochloride is fully dissolved. The pH of the solution is 5.0. Dissolve 1.2g of sodium hydroxide in 44mL of purified water (molar concentration 3 / 4.4mol / L), and stir until the sodium hydroxide is fully dissolved. The pH of the solution is 13.3. At room temperature, add the nalmefene hydrochloride solution to the sodium hydroxide solution at a flow rate of 26.9mL / s, stir at 350rpm to precipitate crystals, stir for 60min, let stand for 120min, and no crystals precipitate. Take the supernatant and measure its pH to be 12.7.

[0150] The parameters for the examples and comparative examples are shown in Table 1.

[0151] Table 1. Parameters of the Examples and Comparative Examples

[0152]

[0153] Experimental Example 1: Microscopic Morphology Observation

[0154] The microstructure of nalmefenamine in Examples 1-24 and Comparative Examples 1-4 was observed using scanning electron microscopy. The nalmefenamine in Examples 1-24 all exhibited a plate-like structure, with Example 1 being representative. Its scanning electron micrograph is shown below. Figure 1 The nalmefenine in comparative examples 1-3 has a sheet-like or block-like structure.

[0155] Furthermore, the results of Comparative Example 4 indicate that nalmefene hydrochloride cannot precipitate crystals in a strong alkaline solution. After the reaction is complete, the solution is clear and transparent, which may be because the strong alkaline solution has a high hydroxide concentration, forming a reversible coexistence system, and nalmefene base undergoes redissolution.

[0156] It is evident that the microstructure of nalmefenine is not only related to the pH of nalmefen hydrochloride, but also to the composition of the aqueous solution of the alkaline component. Only by using a weak base or a salt of a strong acid and a weak base can nalmefenine with the desired properties be obtained.

[0157] Experimental Example 2: Particle Size Determination of Nalmefine

[0158] Using a Malvern 3000 particle size analyzer, 0.1 g of the sample was placed in a 900 mL beaker, 10 mL of 1% Tween 80 solution was added to moisten it, and then water was added to 800 mL. The particle size and particle size distribution were determined according to the method of determination of particle size and particle size distribution (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0982, Method III, Wet Method) at a refractive index of 1.5, a rotation speed of 1500 rpm / min, and ultrasonication for 480 seconds. No crystals were precipitated in Comparative Example 4, so it was not tested. The results are shown in Table 2.

[0159] Limit: Particle size D90 ≤ 30 μm.

[0160] Table 2. Particle size of nalmefenidine in the examples and comparative examples

[0161]

[0162] As can be seen from Table 2, all of Examples 1-24 yielded nalmefenine with D90≤30μm and had high yields (molar yield>50%).

[0163] Specifically, as can be seen from Examples 1, 4, 5, 6, and 7, when the molar ratio of nalmefene hydrochloride to sodium bicarbonate is between 1:4 and 1:1, the particle size of nalmefene base is comparable, with D90 between 19 μm and 27 μm. It can be seen that the above molar ratios of nalmefene hydrochloride and sodium bicarbonate can all yield nalmefene base with the target performance. In particular, increasing the amount of sodium bicarbonate can increase the yield of nalmefene base. Examples 1, 12, and 13 show that when the stirring speed is between 30 min and 240 min, the nalmefene particles have similar sizes and D90 ≤ 30 μm. Examples 1, 14, and 15 show that when the molar concentration (mol / L) of nalmefene hydrochloride to purified water is in the range of 1:6.4-1:3.4, the nalmefene particles have similar sizes and D90 ≤ 30 μm. Examples 1, 4, 7, 16, and 17 show that when the molar concentration (mol / L) of sodium bicarbonate to purified water is in the range of 1:4.4-4:4.4, the nalmefene particles have similar sizes and D90 ≤ 30 μm. Examples 1, 18, and 19 show... When the pH of nalmefene hydrochloride is in the range of 4.0-6.5, the nalmefene base particles have similar sizes and D90≤30μm. As can be seen from Examples 1, 20, 21, 22, and 23, nalmefene hydrochloride solution can be desalted and precipitated with weak base or strong base weak acid salt solutions such as ammonia, sodium bicarbonate, potassium bicarbonate, disodium hydrogen phosphate, or sodium carbonate. The nalmefene particles all have unchanged plate-like microstructure, similar particle sizes, and D90≤30μm. The yield in Example 21 is relatively low because the reaction produces phosphoric acid, which increases the solubility of nalmefene. As can be seen from Examples 1 and 24, the desalting and precipitation of nalmefene hydrochloride solution and sodium bicarbonate solution is not affected by the order of addition.

[0164] Comparing Example 1 and Comparative Examples 1-3, it can be seen that when the pH of nalmefene hydrochloride is 1.9-3.7, the particle size D90 of nalmefene base is >30 μm. The D90 particle size is correlated with the pH of nalmefene hydrochloride, that is, the higher the acidity, the larger the D90 may be within a certain range. Therefore, the pH of nalmefene hydrochloride has a significant impact on the particle size of nalmefene base. Comparative Example 4, however, failed to precipitate crystals.

[0165] In summary, the shape and particle size of nalmefene base are related not only to the pH of nalmefene hydrochloride but also to the composition of the alkaline aqueous solution. The desired shape and particle size of nalmefene base can only be achieved by using a weak base or a strong acid-weak base salt. Therefore, the main reason for particle size control is likely that when the pH of nalmefene hydrochloride is between 4.0 and 6.5, nalmefene can be moderately alkalized and precipitated rapidly in a weakly alkaline solution system, meaning the nucleation rate is greater than the growth rate, thus yielding flaky nalmefene base with a smaller particle size.

[0166] Experimental Example 3: Related Substances

[0167] 1) Experimental Method: Accurately weigh an appropriate amount of the test sample and place it in a 100 mL volumetric flask. Add an appropriate amount of acetonitrile to dissolve it, and dilute with 0.1 mol / L hydrochloric acid solution to prepare a solution containing approximately 1 mg of nalmefene per mL. This solution is used as the test sample solution. Separately, accurately weigh an appropriate amount of nalmefene hydrochloride reference standard and prepare a solution containing 5 µg of nalmefene per mL with 0.1 mol / L hydrochloric acid solution. Measure the solution at a wavelength of 210 nm using high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, 0512).

[0168] 2) Limits: If there are impurity peaks in the chromatogram of the test solution, the content of a single impurity shall not exceed 0.5% and the total amount of all impurities shall not exceed 2.0% according to the external standard method of principal component. The results are shown in Table 3.

[0169] Table 3 Results of relevant substances before and after desalination.

[0170]

[0171] As shown in Table 3, when nalmefene hydrochloride undergoes desalting in aqueous solutions of the corresponding weak base or strong base-weak acid salt, the relevant substances not only do not increase, but also tend to decrease.

[0172] For comparison, commercially available nalmefenamic acid (Gansu State Farms Pharmaceutical Alkali Plant Co., Ltd., batch number CP232308003) was used as raw material, and the content of related substances before and after pulverization (mechanical pulverizer, model: 800C, manufacturer: Yongkang Hongtaiyang Electromechanical Co., Ltd.) was studied. The results are shown in Table 4.

[0173] Table 4. Results of related substances before and after nalmefene pulverization

[0174]

[0175] As shown in Table 4, using commercially available chemically synthesized nalmefenidine as raw material requires sophisticated pulverization equipment, and it is difficult to achieve the required particle size (D90≤30μm) through pulverization. Furthermore, the introduction of mechanical and thermal energy during pulverization leads to a significant increase in related substances. Therefore, it is impossible to prepare nalmefenidine with small particle size and low content of related substances through pulverization.

[0176] Accelerated stability tests were conducted on the nalmefenidine base of Example 1 at 40℃±2℃ and 75%±5% relative humidity. The results of the relevant substances are shown in Table 5.

[0177] Table 5 Accelerated stability of nalmefenidine in Example 1

[0178]

[0179] As can be seen from Table 5, the nalmefenidine of Example 1 can be stably stored for at least 6 months under accelerated conditions of 40℃±2℃ and 75%±5% relative humidity.

[0180] Test Example 4: Release Rate

[0181] Nalmefene implants were prepared using a hot melt extrusion process, and their average cumulative release rate in vitro was tested. The results are shown in Table 6.

[0182] Table 6. Average cumulative release rate of nalmefene implant in vitro

[0183]

[0184]

[0185]

[0186] As can be seen from Table 6, compared with Comparative Example 1, the particle size of nalmefenine significantly affects the in vitro cumulative release of nalmefenine implants; the larger the particle size, the slower the release.

[0187] In summary, the removal of hydrochloric acid ions from nalmefene hydrochloride in sodium bicarbonate solution at pH 4.0-6.5 satisfies the particle size requirements of the formulation without increasing impurities. It is environmentally friendly and stable during storage, without the involvement of organic solvents.

[0188] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0189] The embodiments described above merely illustrate various implementation methods of this application, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Therefore, the protection scope of this patent application should be determined by the appended claims.

Claims

1. A process for the preparation of nalmefene, characterized by, Includes the following steps: Nalmefene hydrochloride is mixed with water to form an aqueous solution of nalmefene hydrochloride. The nalmefene hydrochloride aqueous solution is mixed with an aqueous solution of an alkaline component to form the nalmefene base; The pH of the nalmefene hydrochloride is 4.0-6.5; the alkaline component includes at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium acetate, ammonia, and sodium dihydrogen phosphate.

2. The production method according to claim 1, wherein The molar ratio of nalmefene hydrochloride to the alkaline component is 1:1-1:4, and can be 1:2-1:

4. And / or, the molar concentration of the nalmefene hydrochloride aqueous solution is 10 / 64 mol / L to 10 / 34 mol / L; And / or, the molar concentration of the aqueous solution of the alkaline component is 10 / 44 mol / L to 40 / 44 mol / L, optionally 20 / 44 mol / L to 40 / 44 mol / L.

3. The preparation method according to claim 1, characterized in that, The step of mixing the aqueous solution of nalmefene hydrochloride with the aqueous solution of the alkaline component includes: adding the aqueous solution of the alkaline component to the aqueous solution of nalmefene hydrochloride, or adding the aqueous solution of nalmefene hydrochloride to the aqueous solution of the alkaline component, and then reacting under stirring conditions.

4. The preparation method according to claim 1, characterized in that, The preparation process of nalmefene hydrochloride includes: recrystallizing crude nalmefene hydrochloride with concentrated hydrochloric acid and drying it until the moisture content is less than 10 wt%.

5. The preparation method according to claim 1, characterized in that, The preparation process of the nalmefene hydrochloride includes the following steps: after the mixing reaction, it also includes the steps of standing and drying.

6. The preparation method according to claim 5, characterized in that, The settling time is 60 min - 240 min; And / or, the drying conditions include: a drying temperature of 30℃-75℃, optionally 45℃-75℃; and a drying time of 36h-96h, optionally 42h-72h.

7. Nalmefine prepared by the preparation method according to any one of claims 1-6.

8. A nalmefenidine base, characterized in that, The nalmefenine has a D90 ≤ 30 μm; the nalmefenine crystals are in the form of plates.

9. The use of nalmefene as described in claim 7 or 8 in the preparation of sustained-release formulations.

10. A sustained-release formulation, characterized in that, Includes nalmefenine as described in claim 7 or 8.

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