Preparation method of ranitidine hydrochloride small rod-like crystal habit

Abstract

The invention discloses a ranitidine hydrochloride small rod-like crystal habit preparation method, which comprises: directly crystallizing ranitidine hydrochloride in 95% ethanol to obtain ranitidine hydrochloride small rod-like crystal habit powder. The preparation method disclosed by the invention is beneficial to controlling the growth of NDMA impurities in ranitidine hydrochloride, the growth speed of the NDMA impurities in the prepared ranitidine hydrochloride small rod-like crystal habit powder is 40 times slower than that in commercially available ranitidine hydrochloride agglomerated crystal habit powder, and the stability is remarkably improved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceuticals, and in particular relates to a method for preparing small rod-shaped crystals of ranitidine hydrochloride. Background Art

[0002] Ranitidine hydrochloride chemical name: N-[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N-methyl-2-nitro-1,1-ethylenediamine hydrochloride, the structural formula is as follows, it is a histamine H2 receptor blocker, can inhibit basal gastric acid secretion and gastric acid secretion after stimulation, and can also inhibit the secretion of pepsin. Due to its rapid oral absorption, small dosage, few times of taking, few side effects, low recurrence rate, and easy acceptance by patients, it is an essential drug for the treatment of digestive system diseases in various hospitals.

[0003]

[0004] However, since the ranitidine hydrochloride raw material is unstable during long-term storage, it produces low-concentration carcinogenic dimethylnitrosamine (NDMA) impurities, causing most of the domestic ranitidine hydrochloride production companies to stop production, and it is urgent to solve the problem of excessive growth of NDMA impurities in raw materials. The Chinese patent with publication number CN112028862A discloses a preparation method of ranitidine hydrochloride with low NDMA content, which strictly controls temperature, pH, volume ratio and other conditions to obtain by acid addition salt formation, the steps are cumbersome and difficult to repeat and stably control, and there is a risk of over-adjustment in the pH range, which is not easy to stably control the product crystal habit, and NDMA will still be produced during the long-term storage of the product. Summary of the invention

[0005] Purpose of the invention: The purpose of the present invention is to provide a method for preparing small rod-shaped crystals of ranitidine hydrochloride with high stability.

[0006] Technical solution: The preparation method of the ranitidine hydrochloride rod-shaped crystal habit of the present invention is to directly crystallize the ranitidine hydrochloride in 95% ethanol to obtain the ranitidine hydrochloride rod-shaped crystal habit powder.

[0007] Preferably, the crystallization method comprises the following steps:

[0008] (1) Add ranitidine hydrochloride to 95% ethanol, stir, and heat to dissolve;

[0009] (2) cooling to precipitate solids, and then stirring at the same temperature;

[0010] (3) Add 95% ethanol dropwise again;

[0011] (4) After cooling again, keep warm and stir;

[0012] (5) Filter, wash and dry.

[0013] Preferably, the mass ratio of ranitidine hydrochloride to 95% ethanol in step (1) is 1:1-3.

[0014] Preferably, the temperature after heating in step (1) is 50-60°C.

[0015] Preferably, the temperature after cooling in step (2) is 15-25°C.

[0016] Preferably, the temperature of the heat preservation and stirring in step (2) is 15 to 25° C., and the heat preservation and stirring time is 1 to 12 hours.

[0017] Preferably, in step (3), the mass ratio of ranitidine hydrochloride to 95% ethanol is 1:1-3.

[0018] Preferably, the temperature after cooling again in step (4) is -10 to 0°C.

[0019] Preferably, the temperature of the heat preservation and stirring in step (4) is -10 to 0°C, and the heat preservation and stirring time is 1 to 2 hours.

[0020] Preferably, the drying in step (5) is vacuum drying at a drying temperature of 50 to 60°C.

[0021] Principle of the invention: The ranitidine hydrochloride obtained by the present invention is a small rod-shaped crystal habit, while the commercially available sample without recrystallization is an agglomerated crystal habit. There is an obvious difference between the two crystal habits in the process of storage stability.

[0022] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: the preparation method of the present invention is conducive to controlling the growth of NDMA impurities in ranitidine hydrochloride, and the prepared ranitidine hydrochloride small rod-shaped crystal powder has a growth rate 40 times slower than that of NDMA impurities in the commercially available ranitidine hydrochloride agglomerated crystal powder, and the stability is significantly improved, and the preparation steps are simple, stable and controllable. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the PLM image of the small rod-shaped crystal habit in Example 1;

[0024] Figure 2 This is the PLM diagram of the agglomerated crystal habit of Comparative Example 1. DETAILED DESCRIPTION

[0025] The technical solution of the present invention is further described below in conjunction with the accompanying drawings.

[0026] Example 1

[0027] 20g of ranitidine hydrochloride was added to 20g of 95% ethanol, heated to 60℃ to dissolve, filtered, cooled to 20℃ to precipitate solid, stirred for 1h, 20g of 95% ethanol was added dropwise, cooled to -5℃, stirred for 2h, filtered, vacuum dried at 50℃ for 5h, and 18.5g of small rod-shaped crystal powder of ranitidine hydrochloride was obtained, with a yield of 92.5%. PLM photo as shown Figure 1 shown.

[0028] Example 2

[0029] 100 g of ranitidine hydrochloride was added to 120 g of 95% ethanol, the temperature was raised to 50 ° C to dissolve, filtered, cooled to 18 ° C to precipitate solid, stirred for 1 h, 100 g of 95% ethanol was added dropwise, cooled to -5 ° C, stirred for 2 h, filtered, and vacuum dried at 50 ° C for 5 h to obtain 19.0 g of ranitidine hydrochloride small rod-shaped crystal powder, yield: 95.0%.

[0030] Example 3

[0031] 50 g of ranitidine hydrochloride was added to 50 g of 95% ethanol, the temperature was raised to 60 ° C to dissolve, filtered, cooled to 23 ° C to precipitate solid, stirred for 1 h, 100 g of 95% ethanol was added dropwise, the temperature was lowered to -5 ° C, stirred for 2 h, filtered, and vacuum dried at 50 ° C for 5 h to obtain 19.2 g of ranitidine hydrochloride small rod-shaped crystal powder, with a yield of 96.0%.

[0032] Example 4

[0033] 20 kg of ranitidine hydrochloride was added to 20 kg of 95% ethanol, the temperature was raised to 60 ° C to dissolve, filtered, cooled to 15 ° C to precipitate solid, stirred for 1 hour, 40 kg of 95% ethanol was added dropwise, the temperature was lowered to -5 ° C, stirred for 2 hours, filtered, and vacuum dried at 50 ° C for 5 hours to obtain 19.03 kg of ranitidine hydrochloride small rod-shaped crystal powder, with a yield of 95.2%.

[0034] Example 5

[0035] Add 20g of ranitidine hydrochloride to 60g of 95% ethanol, heat to 60℃ to dissolve, filter, cool to 25℃ to precipitate solid, stir for 12h, add 60g of 95% ethanol dropwise, cool to -10℃, stir for 1h, filter, and vacuum dry at 60℃ for 5h to obtain 18.5g of ranitidine hydrochloride rod-shaped crystalline powder, yield: 92.5%.

[0036] Example 6

[0037] Add 20g of ranitidine hydrochloride to 60g of 95% ethanol, heat to 60℃ to dissolve, filter, cool to 25℃ to precipitate solid, stir for 5h, add 60g of 95% ethanol dropwise, cool to 0℃, stir for 2h, filter, and vacuum dry at 60℃ for 5h to obtain 18.2g of ranitidine hydrochloride rod-shaped crystalline powder, yield: 91.0%.

[0038] Comparative Example 1

[0039] The conventional preparation method includes adding 5g of ranitidine base to a hydrochloric acid ethanol solution, adjusting the pH to 6, precipitating ranitidine hydrochloride solid, filtering, washing with ethanol twice, and drying to obtain 4g of ranitidine hydrochloride solid. PLM photo as Figure 2 shown.

[0040] Comparative Example 2

[0041] 20g of ranitidine hydrochloride was added to 20g of 95% ethanol, heated to 60°C to dissolve, filtered, cooled to -5°C to precipitate solid, stirred for 1h, 20g of 95% ethanol was added dropwise, cooled to -5°C, stirred for 2h, filtered, vacuum dried at 50°C for 5h, and 18.8g of solid powder was obtained, with a yield of 94.0%. The obtained product was agglomerated particles.

[0042] The samples obtained in Example 1 and Comparative Example 1 were subjected to accelerated stability tests. The samples obtained in Example 1 and Comparative Example 1 were placed in a 60°C high temperature test box in commercially available packaging (double polyethylene bag and one aluminum foil bag) for 3 days, and then sampled for testing. The limit of NDMA in long-term tests is no more than 0.36ppm. There is no detection limit standard for the 60°C accelerated test, which is only to quickly determine the sample growth rate and confirm whether the sample is stable. It was found through experimental data that the rod-shaped crystal habit obtained by direct crystallization at 60°C for 3 days is 40 times slower than the agglomerated crystal habit obtained by acid salt formation.

[0043] condition Crystal Learning Day 0 3-Day NDMA Results 60℃ Small particle size rod Not detected 0.28ppm 60℃ Agglomeration Not detected 11.70ppm

[0044] The samples obtained in Example 1 and Comparative Example 1 were subjected to long-term testing (NDMA limit 0.36ppm). The samples obtained in Example 1 and Comparative Example 1 were placed in a stability test box at 25±2°C and 60%±10% humidity using commercially available packaging (double-layer polyethylene bag and one-layer aluminum foil bag) for long-term placement inspection. The results of sampling and testing of NDMA were inspected in 1 month, 3 months, 6 months, 12 months, 18 months, and 24 months. The long-term experimental results showed that the small rod-shaped crystal habit was stable for 24 months, while the agglomerated habit was unqualified in 3 months and grew very fast.

[0045] condition Small rod-shaped crystals NDMA results Agglomerated crystal habit NDMA results Day 0 Not detected Not detected January Not detected 0.30ppm March Not detected 3.30ppm June Not detected 6.41ppm December Not detected 13.22ppm 18 months Not detected 25.02ppm 24 months Not detected 52.13ppm

Claims

1. A method for preparing small rod-shaped crystals of ranitidine hydrochloride, characterized in that: Ranitidine hydrochloride is directly crystallized in 95% ethanol to obtain ranitidine hydrochloride small rod-shaped crystal powder.

2. The preparation method according to claim 1, characterized in that: The crystallization method comprises the following steps: (1) Add ranitidine hydrochloride to 95% ethanol, stir, and heat to dissolve; (2) cooling to precipitate solids, and then stirring at the same temperature; (3) Add 95% ethanol dropwise again; (4) After cooling down again, keep warm and stir; (5) Filter, wash and dry.

3. The preparation method according to claim 2, characterized in that: The mass ratio of ranitidine hydrochloride to 95% ethanol in the step (1) is 1:1-3.

4. The preparation method according to claim 2, characterized in that: The temperature after heating in the step (1) is 50-60°C.

5. The preparation method according to claim 2, characterized in that: The temperature after cooling in step (2) is 15-25°C.

6. The preparation method according to claim 2, characterized in that: The temperature of the heat preservation and stirring in the step (2) is 15 to 25° C., and the heat preservation and stirring time is 1 to 12 hours.

7. The preparation method according to claim 2, characterized in that: In the step (3), the mass ratio of ranitidine hydrochloride to 95% ethanol is 1:1-3.

8. The preparation method according to claim 2, characterized in that: The temperature after cooling again in step (4) is -10 to 0°C.

9. The preparation method according to claim 2, characterized in that: The temperature of the heat preservation and stirring in the step (4) is -10 to 0°C, and the heat preservation and stirring time is 1 to 2 hours.

10. The preparation method according to claim 2, characterized in that: The drying in step (5) is vacuum drying at a drying temperature of 50 to 60°C.

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