Sodium cromoglycate and preparation method thereof

Abstract

The invention relates to sodium cromoglycate and a preparation method thereof, the sodium cromoglycate is sodium cromoglycate trihydrate, and the molecular formula of the sodium cromoglycate is C23H14Na2O11. 3H2O. The sodium cromoglycate prepared by the invention is good in solubility, low in hygroscopicity, good in stability and simple in preparation process, and has obvious advantages compared with the prior art.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines and relates to sodium cromolyn and a preparation method thereof. Background Art

[0002] Sodium cromoglycate is an organic compound with the chemical formula C 23 H 14 Na2O 11 It is mainly used as an antiallergic drug, and has a good preventive and therapeutic effect on rapid allergic reactions. Its mechanism of action is to stabilize the cell membrane of mast cells, prevent mast cell degranulation, thereby inhibiting the release of allergic reaction mediators such as histamine, 5-hydroxytryptamine, and slow-reacting substances, and then inhibiting the adverse effects of allergic reaction mediators on tissues. Its effect of inhibiting the release of allergic reaction mediators may be through inhibiting intracellular cyclophosphoside phosphodiesterase, resulting in an increase in the concentration of intracellular cyclophosphoside (cAMP), preventing calcium ions from being transported into mast cells, thereby stabilizing the mast cell membrane and preventing the release of allergic reaction mediators. It is used to prevent the onset of allergic asthma, improve subjective symptoms, and increase the patient's tolerance to exercise. For patients who rely on corticosteroids, taking this product can reduce the dosage or completely stop it. Most children with chronic refractory asthma who use this product have partial or complete relief. When used in combination with isoproterenol, the effectiveness is significantly higher than when used alone. However, this product takes effect slowly and must be used for several days before it can be effective. If the disease has already occurred, the medication is mostly ineffective. Clinical studies have found that sodium cromoglycate is not only effective for allergic asthma in which allergic factors play a major role, but also for chronic asthma in which allergic effects are not obvious. It can be used for allergic rhinitis and seasonal hay fever to quickly control symptoms. The ointment is also effective for chronic allergic eczema and certain skin itching. 2% to 4% eye drops are suitable for hay fever, conjunctivitis and vernal keratoconjunctivitis. Sodium cromoglycate eye drops are widely used clinically. Sodium cromoglycate has poor photostability, is easy to change color when exposed to light, and has poor quality stability.

[0003] The inventors unexpectedly obtained a new sodium cromoglycate compound and a preparation method thereof during a long-term and extensive study on sodium cromoglycate. The sodium cromoglycate compound prepared by the method has extremely high quality stability, reduced hygroscopicity, improved solubility, and is significantly superior to the prior art. Summary of the invention

[0004] The object of the present invention is to provide sodium cromoglycate and a preparation method thereof. The compound has good stability and solubility, low hygroscopicity, is convenient for the preparation of pharmaceutical preparations, and improves the safety of medication.

[0005] The technical scheme provided by the invention is as follows: the sodium cromoglycate compound is sodium cromoglycate trihydrate, and its molecular formula is C23H14Na2O11·3H2O.

[0006] The sodium cromoglycate compound is a crystal, and the characteristic peaks in its spectrum are shown in the attached figure. Figure 1 shown.

[0007] The preparation method of the sodium cromoglycate compound comprises the following steps:

[0008] (1) Add purified water, methanol and sodium cromoglycate into a reaction pot in sequence, start stirring, heat to 40-46°C, and maintain for 25-30 minutes; the weight ratio of sodium cromoglycate, purified water and methanol is: sodium cromoglycate: water: methanol = 1:20:5;

[0009] (2) cooling to 22-26° C., maintaining a stirring speed of 100-120 rpm, and slowly adding a mixed solution of ethanol and chloroform in an amount of 7 times the weight of the purified water in step (1) while stirring; the weight ratio of the mixed solution of ethanol and chloroform is: ethanol:chloroform = 6:1;

[0010] (3) Filter the material from step (2) into a crystallization kettle, cool it to 2-4°C at a rate of 2-2.4°C / min, filter it to obtain a filter cake, and rinse the filter cake twice with 3 times the weight of ethanol;

[0011] (4) The filter cake obtained in step (3) is placed in a drying oven at 60-66° C., dried for 7 hours, then crushed, passed through a 40-60 mesh sieve, and flattened to a thickness not exceeding 4 mm. The filter cake is placed in a constant temperature and humidity chamber at 30-38° C. and 70-75% humidity for 30-35 hours, taken out, and dried under vacuum conditions. The drying starting temperature is 25° C., and the temperature is increased by 5° C. every hour to 65° C., and dried at 65° C. to constant weight to obtain a sodium cromoglycate compound.

[0012] It should be noted that the ratio of sodium cromoglycate, methanol, ethanol, chloroform and water, the reaction temperature, the cooling rate, the mesh size of the sieve, the flattened thickness, the constant temperature and humidity, the time, and the heating rate are crucial to obtaining the sodium cromoglycate compound of the present invention. According to a large number of experiments conducted by the applicant, the sodium cromoglycate compound of the present invention cannot be obtained by changing the relevant parameters of the present application.

[0013] The sodium cromoglycate used can be synthesized according to known techniques or purchased commercially. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 This is the X-ray powder diffraction pattern of the sodium cromoglycate compound prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0015] Study on the properties of sodium cromoglycate trihydrate

[0016] 1. Elemental analysis

[0017] The sodium cromoglycate trihydrate prepared by the method of the present invention was subjected to elemental analysis, and the results showed that the contents of C were 48.80%, H was 3.51%, and Na was 8.11% (accurate to two decimal places), which was consistent with the theoretical values ​​of sodium cromoglycate trihydrate. The theoretical values ​​of sodium cromoglycate trihydrate were: C: 48.76%, H: 3.53%, and Na: 8.13% (accurate to two decimal places).

[0018] 2. Differential thermal analysis

[0019] The sodium cromoglycate trihydrate prepared by the method of the present invention was subjected to differential thermal analysis and compared with the sodium cromoglycate trihydrate raw material. The results showed that the sodium cromoglycate trihydrate had an absorption peak between 125 and 130°C, indicating that there was crystal water or crystallization solvent in the sample, while the reference substance had no absorption peak, indicating that there was no crystal water or crystallization solvent in the sample.

[0020] 3. Moisture analysis

[0021] The water content of the sodium cromoglycate trihydrate of the present invention was measured by Karl Fischer water determination method, and the result was between 9.52% and 9.58%, which was consistent with the theoretical water content of sodium cromoglycate trihydrate of 9.54%, and the two results were consistent, indicating that the sample contained only water and no other solvents.

[0022] Comprehensive elemental analysis, differential thermal analysis, and moisture analysis results can prove that the sodium cromoglycate of the present invention contains 3 molecules of crystal water.

[0023] 4. Experimental comparative analysis

[0024] Sample 1: the sodium cromoglycate compound prepared in Example 1 of the present invention;

[0025] Sample 2: Sodium cromoglycate raw material marketed product;

[0026] 4.1 Characteristic Study:

[0027] Samples 1-2 were subjected to characteristic research according to the test method of this application. The results are shown in Table 1

[0028] Table 1 Results of study on the properties of sodium cromoglycate

[0029]

[0030] 4.2 Stability and high humidity test:

[0031] Samples 1-2 were placed under high temperature (60°C), high humidity (RH92.5%±5%), and light (4500lx) conditions for 10 days. Samples were taken on the 10th day to examine the content and moisture content. The results were compared with those on day 0, see Table 2.

[0032] Table 2 Test results of factors affecting sodium cromoglycate trihydrate

[0033]

[0034] The test results in Table 2 show that sodium cromoglycate trihydrate has good stability and low hygroscopicity. The same test was also carried out in other embodiments of the present invention, and similar results were obtained.

[0035] 4.3 Solubility analysis

[0036] The solubility of samples 1-2 in water (25℃±2℃) is compared. The results are shown in Table 3:

[0037] Table 3 Solubility comparison

[0038]

[0039] The test results in Table 3 show that the solubility of the sodium cromoglycate compound prepared by the present invention is significantly improved. The same test was also carried out in other embodiments of the present invention, and similar results were obtained.

[0040] It can be seen from Tables 1-3 that the sodium cromoglycate trihydrate prepared by the present invention has better solubility and lower hygroscopicity than the sodium cromoglycate anhydrous compound; generally, the solubility and dissolution rate of drugs in water are in the order of hydrate < anhydrous < organic solvate, and compounds with higher hygroscopicity have better solubility. The sodium cromoglycate compound prepared by the present invention has achieved unexpected technical effects.

[0041] For a better understanding of the present invention, the following examples are provided to further illustrate the present invention, but the present invention is not limited to the following examples.

[0042] Example 1 Preparation of sodium cromoglycate compound

[0043] (1) Add purified water, methanol and sodium cromoglycate into the reaction pot in sequence, start stirring, heat to 40°C and keep for 25 minutes; the amount of sodium cromoglycate, purified water and methanol is: sodium cromoglycate: 1 kg, water: 20 kg, methanol: 5 kg;

[0044] (2) Cooling to 22°C, maintaining a stirring speed of 100 rpm, and slowly adding 140 kg of a mixed solution of ethanol and chloroform while stirring; the weight ratio of the mixed solution of ethanol and chloroform is: ethanol: chloroform = 6:1;

[0045] (3) Filter the material from step (2) into a crystallization kettle, cool it to 2°C at a rate of 2°C / min, filter it to obtain a filter cake, and rinse the filter cake twice with 3 times the weight of ethanol;

[0046] (4) The filter cake obtained in step (3) is placed in a drying oven at 60°C. After drying for 7 hours, the filter cake is crushed, passed through a 40-60 mesh sieve, and flattened to a thickness not exceeding 4 mm. The filter cake is placed in a constant temperature and humidity chamber at 30°C and 70% humidity for 30 hours, taken out, and dried under vacuum conditions. The drying starting temperature is 25°C, and the temperature is increased by 5°C every hour to 65°C. The filter cake is dried at 65°C to constant weight to obtain a sodium cromoglycate compound.

[0047] X-ray powder diffraction pattern is attached Figure 1 , content: 99.99%.

[0048] Example 2 Preparation of sodium cromoglycate compound

[0049] (1) Add purified water, methanol and sodium cromoglycate into the reaction pot in sequence, start stirring, heat to 46°C and keep for 30 minutes; the amount of sodium cromoglycate, purified water and methanol is: sodium cromoglycate: 1 kg, water: 20 kg, methanol: 5 kg;

[0050] (2) Cooling to 26°C, maintaining a stirring speed of 120 rpm, and slowly adding 140 kg of a mixed solution of ethanol and chloroform while stirring; the weight ratio of the mixed solution of ethanol and chloroform is: ethanol: chloroform = 6:1;

[0051] (3) Filter the material from step (2) into a crystallization kettle, cool it to 4°C at a rate of 2.4°C / min, filter it to obtain a filter cake, and rinse the filter cake twice with 3 times the weight of ethanol;

[0052] (4) The filter cake obtained in step (3) is placed in a drying oven at 66° C., dried for 7 hours, then crushed, passed through a 40-60 mesh sieve, and flattened to a thickness not exceeding 4 mm. The filter cake is placed in a constant temperature and humidity chamber at 38° C. and 75% humidity for 35 hours, taken out, and dried under vacuum conditions. The drying starting temperature is 25° C., and the temperature is increased by 5° C. every hour to 65° C., and dried at 65° C. to constant weight to obtain a sodium cromoglycate compound.

[0053] The X-ray powder diffraction pattern is consistent with that of Example 1, and the content is 99.96%.

[0054] Example 3 Preparation of sodium cromoglycate compound

[0055] (1) Add purified water, methanol and sodium cromoglycate into the reaction pot in sequence, start stirring, heat to 43°C and keep for 27 minutes; the amount of sodium cromoglycate, purified water and methanol is: sodium cromoglycate: 1 kg, water: 20 kg, methanol: 5 kg;

[0056] (2) Cooling to 24°C, maintaining a stirring speed of 110 rpm, slowly adding 140 kg of a mixed solution of ethanol and chloroform while stirring; the weight ratio of the mixed solution of ethanol and chloroform is: ethanol: chloroform = 6:1;

[0057] (3) Filter the material from step (2) into a crystallization kettle, cool it to 3°C at a rate of 2.2°C / min, filter it to obtain a filter cake, and rinse the filter cake twice with 3 times the weight of ethanol;

[0058] (4) The filter cake obtained in step (3) is placed in a drying oven at 63°C. After drying for 7 hours, the filter cake is crushed, passed through a 40-60 mesh sieve, and flattened to a thickness not exceeding 4 mm. The filter cake is placed in a constant temperature and humidity chamber at 34°C and a humidity of 73% for 33 hours, taken out, and dried under vacuum conditions. The drying starting temperature is 25°C, and the temperature is increased by 5°C every hour to 65°C. The filter cake is dried at 65°C to constant weight to obtain a sodium cromoglycate compound.

[0059] The X-ray powder diffraction pattern is consistent with that of Example 1, and the content is 99.97%.

[0060] Test Example 1:

[0061] The Example 1 of the present invention and the marketed product were subjected to accelerated testing in the following manner: the samples were placed in a stability test box (40°C ± 2°C, RH 75% ± 5%), and samples were taken at 1, 2, 3, and 6 months, respectively, for inspection. The results are shown in Table 4.

[0062] Table 4 Sodium cromoglycate accelerated test results

[0063]

[0064] It can be seen from the results in Table 4 that the sodium cromoglycate compound prepared by the present invention has good stability and has obvious advantages over the prior art. The same test was also carried out in other embodiments of the present invention and similar results were obtained.

[0065] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

1. A sodium cromoglycate, characterized in that The sodium cromoglycate is: sodium cromoglycate trihydrate, whose molecular formula is C 23 H 14 Na2O 11 ·3H2O.

2. Sodium cromoglycate as claimed in claim 1, characterized in that The sodium cromoglycate is a crystal, and its characteristic peaks in the spectrum are shown in FIG1 , which is determined by X-ray powder diffraction.

3. The method for preparing sodium cromoglycate according to claim 1 or 2, comprising the steps of: (1) Add purified water, methanol and sodium cromoglycate into a reaction pot in sequence, start stirring, heat to 40-46°C, and maintain for 25-30 minutes; the weight ratio of sodium cromoglycate, purified water and methanol is: sodium cromoglycate: water: methanol = 1:20:5; (2) cooling to 22-26° C., maintaining a stirring speed of 100-120 rpm, and slowly adding a mixed solution of ethanol and chloroform in an amount of 7 times the weight of the purified water in step (1) while stirring; the weight ratio of the mixed solution of ethanol and chloroform is: ethanol:chloroform = 6:1; (3) Filter the material from step (2) into a crystallization kettle, cool it to 2-4°C at a rate of 2-2.4°C / min, filter it to obtain a filter cake, and rinse the filter cake twice with 3 times the weight of ethanol; (4) The filter cake obtained in step (3) is placed in a drying oven at 60-66° C., dried for 7 hours, then crushed, passed through a 40-60 mesh sieve, and flattened to a thickness not exceeding 4 mm. The filter cake is placed in a constant temperature and humidity chamber at 30-38° C. and 70-75% humidity for 30-35 hours, taken out, and dried under vacuum conditions. The drying starting temperature is 25° C., and the temperature is increased by 5° C. every hour to 65° C., and dried at 65° C. to constant weight to obtain a sodium cromoglycate compound.

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