Lobeline hydrochloride compounds and methods of making same

Abstract

This invention provides a lobeline hydrochloride compound and its preparation method. The method includes: sequentially adding lobeline hydrochloride, methanol, and chloroform to a reaction vessel and stirring to dissolve them; slowly adding purified water while stirring, and continuing stirring after the addition is complete to obtain the material; then transferring it to a crystallization vessel, cooling it to 1-2°C, filtering it to obtain a filter cake, drying it, and pulverizing the filter cake to obtain lobeline hydrochloride dihydrate. During extensive long-term research on lobeline hydrochloride, the inventors unexpectedly obtained a new lobeline hydrochloride compound and its preparation method. The lobeline hydrochloride compound prepared by this method exhibits extremely high quality stability, improved solubility, and reduced hygroscopicity.

Description

Technical Field

[0001] This invention relates to the field of compounds, and particularly to lobeline hydrochloride and its preparation method. Background Technology

[0002] Lobeline hydrochloride, chemical formula C 22 H 27 NO2·HCl, chemical name: 2-[1-methyl-6-(β-hydroxyphenylethyl)-2-piperidinyl]acetophenone hydrochloride, is a respiratory stimulant that stimulates the carotid sinus and aortic body chemoreceptors. It has no direct excitatory effect on the respiratory center, but initially excites and then blocks the autonomic ganglia. It can be used for patients with respiratory failure, but should be used as directed by a physician. Larger doses can cause tachycardia, conduction block, respiratory depression, and even convulsions, nausea, vomiting, diarrhea, headache, dizziness, and tremors. It can also cause sweating, hypotension, hypothermia, tonic-clonic seizures, and coma. Its commonly used clinical dosage form is injection. Lobeline hydrochloride injection is mainly used for central respiratory depression caused by various reasons. Clinically, it is often used for neonatal asphyxia, carbon monoxide poisoning, and opioid poisoning. Further improving the quality of lobeline hydrochloride is of positive significance for its clinical use.

[0003] During a long period of extensive research on lobeline hydrochloride, the inventors unexpectedly obtained a new lobeline hydrochloride compound and its preparation method. The lobeline hydrochloride compound prepared by this method has extremely high quality stability, significantly improved solubility, and reduced hygroscopicity, which is significantly superior to the prior art. Summary of the Invention

[0004] The purpose of this invention is to provide a lobeline hydrochloride compound and its preparation method. The compound is lobeline hydrochloride dihydrate, which has good stability and solubility, low hygroscopicity, facilitates the preparation of pharmaceutical formulations, and improves the safety of medication.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] In a first aspect of the invention, a lobeline hydrochloride compound is provided.

[0007] The lobeline hydrochloride compound of this invention is lobeline hydrochloride dihydrate, and its molecular formula is: C 22 H 27 NO2·HCl·2H2O.

[0008] In a second aspect of the invention, a method for preparing lobeline dihydrate hydrochloride is provided, the method comprising:

[0009] S1. Lobeline hydrochloride, methanol, and chloroform are added sequentially to the reaction vessel at a stirring speed of 60-80 rpm and stirred until completely dissolved; the weight ratio of lobeline hydrochloride, methanol, and chloroform is: lobeline hydrochloride: methanol: chloroform = 1:3:2.

[0010] S2. Keep the temperature at 20°C, and slowly add purified water at a weight of 8 times that of methanol in S1 while stirring. Continue stirring for 15 minutes after the addition is complete.

[0011] S3. Transfer the material from step S2 to the crystallization vessel, cool it to 1-2℃, filter it to obtain a filter cake, and wash the filter cake twice with twice the weight of purified water.

[0012] S4. Place the filter cake obtained in S3 in a drying oven, dry it, and then crush the filter cake to obtain lobeline hydrochloride compound;

[0013] Furthermore, in step S2, the stirring speed is maintained at 100-110 rpm.

[0014] Furthermore, in S3, the cooling rate is 2.2-4.4℃ / min.

[0015] Furthermore, in step S4, the drying conditions are: drying at 70-75°C for 5-7 hours.

[0016] One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages:

[0017] 1. The present invention provides a lobeline hydrochloride dihydrate and its preparation method. During the long-term research on lobeline hydrochloride, the inventors unexpectedly obtained a new lobeline hydrochloride dihydrate and its preparation method. The lobeline hydrochloride dihydrate prepared by this method has extremely high quality stability, improved solubility, and reduced hygroscopicity, which is significantly better than the prior art.

[0018] 2. In the preparation method of lobeline hydrochloride dihydrate provided by the present invention, the ratio of lobeline hydrochloride, methanol, chloroform, and purified water, as well as the reaction temperature, cooling rate, and time, are crucial to obtaining the lobeline hydrochloride compound of the present invention. According to the applicant's extensive experiments, changing the relevant parameters of this application will not yield the lobeline hydrochloride compound described in the present invention. Detailed Implementation

[0019] The present invention will be described in detail below with reference to specific embodiments and examples, thereby making the advantages and various effects of the present invention more clearly apparent. Those skilled in the art should understand that these specific embodiments and examples are for illustrative purposes only and are not intended to limit the present invention.

[0020] Throughout this specification, unless otherwise specified, the terminology used herein should be understood as having the meaning commonly used in the art. Therefore, 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 invention pertains. In the event of any conflict, this specification shall prevail.

[0021] Unless otherwise specified, all raw materials, reagents, instruments and equipment used in this invention can be obtained by purchasing them from the market or by existing methods.

[0022] Lobeline hydrochloride used can be synthesized using known techniques or purchased commercially.

[0023] The present application will now be described in detail with reference to embodiments and experimental data.

[0024] Example 1: Preparation of lobeline hydrochloride compound

[0025] (1) Add 5 kg of lobeline hydrochloride, 15 kg of methanol and 10 kg of chloroform to the reaction vessel in sequence at a stirring speed of 60 rpm and stir until completely dissolved;

[0026] (2) Keep the temperature at 20°C and slowly add 120 kg of purified water while stirring at a stirring speed of 100 rpm. Continue stirring for 15 minutes after adding the water.

[0027] (3) Transfer the material from step (2) to the crystallization vessel, cool it to 1°C at a rate of 2.2°C / min, filter it to obtain a filter cake, and rinse the filter cake twice with twice the weight of purified water.

[0028] (4) Place the filter cake obtained in step (3) in a drying oven and dry it at 70°C for 7 hours. After drying, crush the filter cake to obtain lobeline hydrochloride compound.

[0029] Example 2 Preparation of lobeline hydrochloride compound

[0030] (1) Add 5 kg of lobeline hydrochloride, 15 kg of methanol and 10 kg of chloroform to the reaction vessel in sequence at a stirring speed of 60 rpm and stir until completely dissolved;

[0031] (2) Keep the temperature at 20°C and slowly add 120 kg of purified water while stirring at a stirring speed of 110 rpm. Continue stirring for 15 minutes after adding the water.

[0032] (3) Transfer the material from step (2) to the crystallization vessel, cool it to 2°C at a rate of 4.4°C / min, filter it to obtain a filter cake, and rinse the filter cake twice with twice the weight of purified water.

[0033] (4) Place the filter cake obtained in step (3) in a drying oven and dry it at 75°C for 5 hours. After drying, crush the filter cake to obtain lobeline hydrochloride compound.

[0034] Example 3 Preparation of lobeline hydrochloride compound

[0035] (1) Add 5 kg of lobeline hydrochloride, 15 kg of methanol and 10 kg of chloroform to the reaction vessel in sequence at a stirring speed of 60 rpm and stir until completely dissolved;

[0036] (2) Keep the temperature at 20°C and slowly add 120 kg of purified water while stirring at a speed of 105 rpm. Continue stirring for 15 minutes after adding the water.

[0037] (3) Transfer the material from step (2) to the crystallization vessel, cool it down to 1.5°C at a rate of 3.3°C / min, filter it to obtain a filter cake, and rinse the filter cake twice with twice the weight of purified water.

[0038] (4) Place the filter cake obtained in step (3) in a drying oven and dry it at 72°C for 6 hours. After drying, crush the filter cake to obtain lobeline hydrochloride compound.

[0039] Comparative Example 1

[0040] (1) Add 5 kg of lobeline hydrochloride, 15 kg of methanol and 9.5 kg of chloroform to the reaction vessel in sequence at a stirring speed of 60 rpm and stir until completely dissolved;

[0041] (2) Keep the temperature at 20°C and slowly add 120 kg of purified water while stirring at a stirring speed of 100 rpm. Continue stirring for 15 minutes after adding the water.

[0042] (3) Transfer the material from step (2) to the crystallization vessel, cool it to 1°C at a rate of 2.2°C / min, filter it to obtain a filter cake, and rinse the filter cake twice with twice the weight of purified water.

[0043] (4) Place the filter cake obtained in step (3) in a drying oven and dry it at 70°C for 7 hours. After drying, crush the filter cake to obtain lobeline hydrochloride compound.

[0044] Comparative Example 2

[0045] (1) Add 5 kg of lobeline hydrochloride, 15 kg of methanol and 10 kg of chloroform to the reaction vessel in sequence at a stirring speed of 60 rpm and stir until completely dissolved;

[0046] (2) Keep the temperature at 20°C and slowly add 110 kg of purified water while stirring at a stirring speed of 110 rpm. Continue stirring for 15 minutes after adding the water.

[0047] (3) Transfer the material from step (2) to the crystallization vessel, cool it to 2°C at a rate of 4.4°C / min, filter it to obtain a filter cake, and rinse the filter cake twice with twice the weight of purified water.

[0048] (4) Place the filter cake obtained in step (3) in a drying oven and dry it at 75°C for 5 hours. After drying, crush the filter cake to obtain lobeline hydrochloride compound.

[0049] Comparative Example 3

[0050] (1) Add 5 kg of lobeline hydrochloride, 15 kg of methanol and 10 kg of chloroform to the reaction vessel in sequence at a stirring speed of 60 rpm and stir until completely dissolved;

[0051] (2) Keep the temperature at 20°C and slowly add 120 kg of purified water while stirring at a speed of 105 rpm. Continue stirring for 15 minutes after adding the water.

[0052] (3) Transfer the material from step (2) to the crystallization vessel, cool it down to 2.5°C at a rate of 3.3°C / min, filter it to obtain a filter cake, and wash the filter cake twice with twice the weight of purified water.

[0053] (4) Place the filter cake obtained in step (3) in a drying oven and dry it at 72°C for 6 hours. After drying, crush the filter cake to obtain lobeline hydrochloride compound.

[0054] Comparative Example 4

[0055] (1) Add 5 kg of lobeline hydrochloride, 15 kg of methanol and 10 kg of chloroform to the reaction vessel in sequence at a stirring speed of 60 rpm and stir until completely dissolved;

[0056] (2) Keep the temperature at 20°C and slowly add 120 kg of purified water while stirring at a stirring speed of 100 rpm. Continue stirring for 15 minutes after adding the water.

[0057] (3) Transfer the material from step (2) to the crystallization vessel, cool it down to 1.5°C at a rate of 5.0°C / min, filter it to obtain a filter cake, and wash the filter cake twice with twice the weight of purified water.

[0058] (4) Place the filter cake obtained in step (3) in a drying oven and dry it at 72°C for 5 hours. After drying, crush the filter cake to obtain lobeline hydrochloride compound.

[0059] Experimental Example 1: Characteristic Study of Lobeline Hydrochloride Dihydrate

[0060] 1. Elemental Analysis

[0061] Elemental analysis was performed on the lobeline hydrochloride dihydrate prepared by the method of this invention. The results were: C: 64.45%, H: 7.83%, N: 3.43% (accurate to two decimal places), which is consistent with the theoretical values ​​of lobeline hydrochloride dihydrate, which are: C: 64.47%, H: 7.81%, N: 3.42% (accurate to two decimal places).

[0062] 2. Differential Thermal Analysis

[0063] Differential thermal analysis was performed on the lobeline hydrochloride dihydrate prepared by the method of this invention, and it was compared with lobeline hydrochloride, the raw material for preparing lobeline hydrochloride dihydrate. The results showed that the lobeline hydrochloride dihydrate had an absorption peak between 155 and 160 °C, indicating that the sample contained water of crystallization or a crystallization solvent, while the reference standard did not have an absorption peak, indicating that the sample did not contain water of crystallization or a crystallization solvent.

[0064] 3. Moisture analysis

[0065] The water content of the lobeline hydrochloride dihydrate described in this invention was determined using the Karl Fischer water determination method, and the results were between 8.77% and 8.81%, consistent with the theoretical water content of 8.79% for lobeline hydrochloride dihydrate. This indicates that the sample contains only water and no other solvents.

[0066] Based on the results of elemental analysis, differential thermal analysis, and moisture analysis, it can be proven that the lobeline hydrochloride of this invention contains two molecules of water of crystallization.

[0067] 4. Experimental Comparison and Analysis

[0068] Sample 1: Lobeline hydrochloride compound prepared in Example 1 of this invention;

[0069] Sample 2: Lobeline hydrochloride raw material;

[0070] 4.1 Characteristic Study:

[0071] Samples 1-2 were subjected to characteristic studies according to the test methods of this application, and the results are shown in Table 1.

[0072] Table 1 Results of Lobeline Hydrochloride Characterization Study

[0073]

[0074] 4.2 Stability and hygroscopicity test under high humidity:

[0075] Samples 1-2 were subjected to an influencing factor test. They were placed under high temperature (60℃), high humidity (RH 92.5%±5%), and light (4500lx) conditions for 10 days. Samples were taken on the 10th day to investigate the content and moisture content. The results were compared with those on day 0. The results are shown in Table 2.

[0076] Table 2. Experimental results of factors affecting lobeline dihydrate hydrochloride.

[0077]

[0078] Table 2 shows that lobeline dihydrate has good stability and low hygroscopicity. Similar results were obtained in other embodiments of the present invention.

[0079] 4.3 Solubility Analysis

[0080] The solubility of samples 1 and 2 in water (25℃±2℃) was compared, and the results are shown in Table 3:

[0081] Table 3 Solubility Comparison

[0082]

[0083] As can be seen from Tables 1-3, the lobeline hydrochloride dihydrate prepared by this invention has lower hygroscopicity and better solubility than the anhydrous lobeline hydrochloride compound. Generally, the order of hygroscopicity is hydrate > anhydrous > organic solvate. Compounds with better hygroscopicity have better solubility. The lobeline hydrochloride compound prepared by this invention has achieved unexpected technical effects.

[0084] Experimental Example 2: Comparison of Groups

[0085] The lobeline hydrochloride compounds prepared in Examples 1-3 and Comparative Examples 1-4 of this invention were subjected to characterization, hygroscopicity and accelerated stability tests (40℃±2℃, RH 75%±5%, for 3 and 6 months). The results are shown in Tables 4-6.

[0086] Table 4 Characteristic Study

[0087]

[0088] Table 5. Hygroscopicity test (RH 92.5%±5% for 10 days)

[0089]

[0090] Table 6 Accelerated Test Results

[0091]

[0092] As can be seen from the results in Tables 4-6, the lobeline hydrochloride compound prepared by this invention has significant advantages in terms of low hygroscopicity and stability compared with existing technologies. The preparation process parameters of the lobeline hydrochloride compound of this invention are crucial; even slight changes will prevent the lobeline hydrochloride compound of this invention from being obtained.

[0093] Finally, it should be noted that the terms “comprising,” “including,” or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0094] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including both the preferred embodiments and all changes and modifications falling within the scope of the invention.

[0095] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A lobeline hydrochloride compound, characterized in that, The lobeline hydrochloride compound is lobeline hydrochloride dihydrate, with the molecular formula C0. 22 H 27 NO2·HCl·2H2O.

2. The method for preparing the lobeline hydrochloride compound according to claim 1, characterized in that, The method includes: S1. Lobeline hydrochloride, methanol, and chloroform are added sequentially to the reaction vessel at a stirring speed of 60-80 rpm and stirred until completely dissolved; the weight ratio of lobeline hydrochloride, methanol, and chloroform is: lobeline hydrochloride: methanol: chloroform = 1:3:

2. S2. Keep the temperature at 20°C, and slowly add purified water at a weight of 8 times that of methanol in S1 while stirring. Continue stirring for 15 minutes after the addition is complete. S3. Transfer the material from step S2 to the crystallization vessel, cool it to 1-2℃, filter it to obtain a filter cake, and wash the filter cake twice with twice the weight of purified water. S4. Place the filter cake obtained in S3 in a drying oven, dry it, and then crush the filter cake to obtain lobeline hydrochloride compound.

3. The preparation method according to claim 2, characterized in that, The stirring speed in S2 is maintained at 100-110 rpm.

4. The preparation method according to claim 2, characterized in that, The cooling rate in S3 is 2.2-4.4℃ / min.

5. The preparation method according to claim 2, characterized in that, The drying conditions in S4 are: drying at 70-75°C for 5-7 hours.

Images