Method for preparing bismuth ranitidine citrate

Abstract

The invention discloses a method for preparing bismuth ranitidine citrate, which comprises the following steps: ① reacting ranitidine base with bismuth citrate at a temperature of 90 to 100° C. to obtain a solution containing bismuth ranitidine citrate; ② cooling the solution containing bismuth ranitidine citrate obtained in step ① to 50 to 60° C., adding activated carbon, and heat preservation for decolorization; ③ filtering, dropping the filtrate into pre-treated anhydrous ethanol, stirring for crystallization; ④ centrifugal filtering, washing the filter cake with anhydrous ethanol, vacuum drying, and crushing to obtain bismuth ranitidine citrate powder. The method of the invention is processed by pre-introducing ammonia and other reducing gases into anhydrous ethanol, so that the content of the maximum single impurity I can be significantly reduced, thereby greatly reducing the content of the total impurity, and no substances such as sodium sulfite will remain, and 767-type injection activated carbon is used for decolorization to obtain an off-white product, and a loose and non-agglomerated product can also be obtained by controlling the crystallization temperature.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical compound preparation, and particularly relates to a method for preparing ranitidine bismuth citrate. Background Art

[0002] Ranitidine bismuth citrate is a salt obtained by the reaction of ranitidine and bismuth citrate.

[0003] Chinese patent document CN103896888A discloses a method for preparing ranitidine bismuth citrate. The technical concept of the method is to reduce the trace impurities contained in anhydrous ethanol by treating the anhydrous ethanol, thereby reducing the content of the largest single impurity I. The technical means adopted is to add sodium salt to commercially available industrial-grade anhydrous ethanol.

[0004] The structural formula of the largest single hetero compound I is as follows:

[0005] .

[0006] Since adding sodium salt to anhydrous ethanol will produce sodium bisulfite, sodium sulfite will remain in the final product, affecting the quality of the drug.

[0007] In addition, ranitidine bismuth citrate has strong hygroscopicity and is very easy to agglomerate during the drying process to form shachima-like blocky solids. Summary of the invention

[0008] The object of the present invention is to solve the above problems and provide a method for preparing ranitidine bismuth citrate which can effectively control the maximum single impurity I and the total impurity content and does not cause residual sodium sulfite.

[0009] The technical scheme for achieving the above-mentioned object of the present invention is: a method for preparing bismuth ranitidine citrate, comprising the following steps: 1. reacting ranitidine base with bismuth citrate at a temperature of 90-100 DEG C to obtain a solution containing bismuth ranitidine citrate; 2. cooling the solution containing bismuth ranitidine citrate obtained in step 1 to 50-60 DEG C, adding activated carbon, and heat-insulating to decolorize; 3. filtering, dropping the filtrate into pre-treated anhydrous ethanol, stirring and crystallizing; 4. centrifugally filtering, washing the filter cake with anhydrous ethanol, vacuum drying, and pulverizing to obtain bismuth ranitidine citrate powder.

[0010] The pretreatment refers to the introduction of reducing gas into the anhydrous ethanol. This is because the applicant surprisingly found through a large number of experiments that the introduction of reducing gases such as ammonia, sulfur dioxide, and hydrogen sulfide into the anhydrous ethanol can significantly reduce the content of the largest single impurity I, thereby greatly reducing the total impurity content, and the introduction of ammonia has the best effect.

[0011] The type of activated carbon used for decolorization in the above step ② has a great influence on the decolorization effect. After a large number of experiments, the applicant found that the decolorization effect of type 767 injection activated carbon is the best. The decolorized solution is clear and bright yellow, and a white powder can be obtained in the end. The powder obtained by using the common type 302 medicinal activated carbon and type 772 activated carbon is light yellow.

[0012] The crystallization temperature of step ③ is crucial to the morphology of the product. After a large number of experiments, the applicant finally found that loose and non-agglomerated ranitidine citrate powder can be obtained at a crystallization temperature of 35±5°C.

[0013] The present invention has the positive effects:

[0014] (1) The method of the present invention is to introduce a reducing gas such as ammonia into anhydrous ethanol in advance for treatment, which can significantly reduce the content of the largest single impurity I, thereby greatly reducing the content of total impurities, and no substances such as sodium sulfite will remain.

[0015] (2) The method of the present invention preferably uses 767 type injection activated carbon as a decolorizing agent, which can achieve a better decolorizing effect, thereby obtaining a lighter color, off-white bismuth citrate ranitidine powder, further improving the quality of the drug.

[0016] (3) The method of the present invention can obtain loose and non-agglomerated bismuth citrate ranitidine powder by controlling the crystallization temperature. DETAILED DESCRIPTION

[0017] (Example 1)

[0018] ① Add 54 g of ranitidine base and 39 g of bismuth citrate to 90 g of water, heat to 95° C. with stirring and keep warm for 20 min to obtain a solution containing bismuth citrate ranitidine.

[0019] ② The solution containing bismuth ranitidine citrate obtained in step ① is cooled to 55° C., 2.7 g of 767 type injection activated carbon is added, and the mixture is kept warm for decolorization for 30 min.

[0020] ③ Filter, add the filtrate dropwise into 1200g of pre-treated anhydrous ethanol, heat to 35℃ and stir to crystallize.

[0021] The pretreatment refers to passing ammonia gas into anhydrous ethanol at a flow rate of 100 mL / min for 3 hours.

[0022] ④ Centrifugal filtration, the filter cake was washed with anhydrous ethanol, vacuum dried, and crushed to obtain 61.1 g of off-white, loose, non-agglomerated bismuth citrate ranitidine powder with a yield of 87.6%.

[0023] According to HPLC detection, the ranitidine content was 41.55%, the bismuth content was 29.32%, the maximum single impurity I content was 0.18%, and the total impurity content was 0.55%.

[0024] (Example 2 to Example 3)

[0025] The methods of each embodiment are basically the same as those of embodiment 1, except that the gases pre-treated in step ③ are sulfur dioxide and hydrogen sulfide, respectively. The results are shown in Table 1.

[0026] (Comparative Example 1 to Comparative Example 2)

[0027] The methods of each comparative example are basically the same as those of Example 1, except that the gases pre-treated and introduced in step ③ are carbon dioxide and air, respectively. The results are still shown in Table 1.

[0028] (Comparative Example 3)

[0029] The method of Comparative Example 3 is basically the same as that of Example 1, except that no gas is introduced for pre-treatment in step ③. The results are still shown in Table 1.

[0030] Table 1

[0031] Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 gas Ammonia Sulfur dioxide Hydrogen sulfide carbon dioxide Air - Product color Off-white Off-white Off-white Off-white Light yellow Light yellow Ranitidine bismuth citrate 61.1g 60.7g 60.2g 60.5g 59.2g 60.2g Yield 87.6% 87.0% 86.2% 86.7% 84.9% 86.2% Ranitidine content 41.55% 41.17% 40.72% 38.76% 38.18% 39.48% Bismuth content 29.32% 29.08% 28.88% 26.85% 26.12% 28.19% Maximum single impurity I content 0.18% 0.22% 0.27% 0.74% 1.38% 0.79% Total impurities content 0.55% 0.76% 0.88% 2.01% 2.61% 1.22%

[0032] (Example 4 to Example 5)

[0033] The methods of each embodiment are basically the same as those of embodiment 1, except for the type of activated carbon used in step ②. The results are shown in Table 2.

[0034] Table 2

[0035] Example 1 Example 4 Example 5 Types of activated carbon 767 type activated carbon injection 772 type activated carbon 302 type medicinal activated carbon Product color Off-white Light yellow Light yellow Ranitidine bismuth citrate 61.1g 61.2g 60.8g Yield 87.6% 87.7% 87.1% Ranitidine content 41.55% 41.27% 41.41% Bismuth content 29.32% 29.12% 29.27% Maximum single impurity I content 0.18% 0.21% 0.20% Total impurities content 0.55% 0.72% 0.66%

[0036] (Example 6 to Example 7)

[0037] The methods of each embodiment are basically the same as those of embodiment 1, except for the crystallization temperature in step ③. The results are shown in Table 3.

[0038] (Comparative Example 4 to Comparative Example 5)

[0039] The methods of each comparative example are basically the same as those of Example 1, except for the crystallization temperature in step ③. The results are still shown in Table 3.

[0040] Table 3

[0041] Example 1 Example 6 Example 7 Comparative Example 4 Comparative Example 5 Crystallization temperature 35℃ 30℃ 40℃ 25℃ 45℃ Product form Loose without lumps Loose without lumps Loose without lumps More lumps Slightly lumpy

Claims

1. A method for preparing bismuth citrate ranitidine, comprising the following steps: ① Ranitidine base and bismuth citrate are reacted at a temperature of 90 to 100° C. to obtain a solution containing ranitidine citrate bismuth; ② The solution containing bismuth ranitidine citrate obtained in step ① is cooled to 50-60° C., activated carbon is added, and the mixture is kept warm for decolorization; The activated carbon is 767 type injection activated carbon; ③ Filter, add the filtrate dropwise into pre-treated anhydrous ethanol, stir and crystallize; the pre-treatment refers to introducing reducing gas into the anhydrous ethanol; the reducing gas is ammonia, sulfur dioxide or hydrogen sulfide; the crystallization temperature is 35±5°C; ④ Centrifugal filtration, wash the filter cake with anhydrous ethanol, vacuum dry it, and crush it to obtain bismuth ranitidine citrate powder.

2. The method for preparing bismuth citrate ranitidine according to claim 1, wherein: The reducing gas described in the above step ③ is ammonia.