A method for preparing ranitidine hydrochloride in a rod-like crystal habit

Abstract

The application discloses a preparation method of ranitidine hydrochloride small rod-like crystal habit, and the preparation method comprises the following steps: directly crystallizing ranitidine hydrochloride in 95% ethanol to obtain ranitidine hydrochloride small rod-like crystal habit powder. The preparation method is beneficial to controlling the growth of NDMA impurities in ranitidine hydrochloride, and 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 the ranitidine hydrochloride agglomerated crystal habit powder on the market, and the stability is obviously improved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmacy, and particularly relates to a preparation method of small rod-shaped crystal habit of ranitidine hydrochloride. BACKGROUND

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

[0003]

[0004] However, due to the instability of ranitidine hydrochloride raw material during long-term storage, low-concentration carcinogenic substance dimethyl nitrosamine (NDMA) impurities are generated, resulting in the shutdown of most domestic ranitidine hydrochloride production enterprises, and the problem of excessive growth of NDMA impurities in raw materials needs to be solved. A preparation method of ranitidine hydrochloride with low NDMA content is disclosed in Chinese Patent No. CN112028862A. The method strictly controls the temperature, pH, volume ratio and other conditions to obtain the product by acid salt formation. The steps are complicated and difficult to repeat and stably control. At the same time, there is a risk of pH adjustment, and it is not easy to stably control the crystal habit of the product. NDMA may still be generated during long-term storage of the product. SUMMARY

[0005] The purpose of the present application is to provide a preparation method of small rod-shaped crystal habit of ranitidine hydrochloride with high stability.

[0006] The preparation method of small rod-shaped crystal habit of ranitidine hydrochloride according to the present application is to directly crystallize ranitidine hydrochloride in 95% ethanol to obtain small rod-shaped crystal habit powder of ranitidine hydrochloride.

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

[0008] (1) Ranitidine hydrochloride is added to 95% ethanol and stirred, and the temperature is raised to dissolve the solution;

[0009] (2) After cooling, the solid is precipitated and the temperature is kept constant while stirring;

[0010] (3) 95% ethanol is added again;

[0011] (4) After cooling again, keep the temperature constant while stirring;

[0012] (5) filtration, washing and drying.

[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℃.

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

[0016] Preferably, the temperature for incubation and stirring in step (2) is 15-25℃, and the incubation and stirring time is 1-12h.

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

[0018] Preferably, the temperature after re-cooling in step (4) is -10-0℃.

[0019] Preferably, the temperature for incubation and stirring in step (4) is -10-0℃, and the incubation and stirring time is 1-2h.

[0020] Preferably, the drying in step (5) is vacuum drying, and the drying temperature is 50-60℃.

[0021] Principle of the invention: the obtained ranitidine hydrochloride is small rod-like crystal habit, while the commercially available sample without recrystallization is agglomerated crystal habit, and there is obvious difference between the two crystal habits in stability.

[0022] Advantages: compared with the prior art, the present application has the following obvious advantages: the preparation method is beneficial to control the increase of NDMA impurity of ranitidine hydrochloride, the obtained small rod-like crystal habit powder of ranitidine hydrochloride has 40 times slower increase speed of NDMA impurity than the agglomerated crystal habit powder of commercially available ranitidine hydrochloride, the stability is obviously improved, and the preparation steps are simple and stable. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 PLM diagram of small rod-like crystal habit of Example 1;

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

[0025] The technical solutions of the present application will be further described below in combination with the drawings.

[0026] Example 1

[0027] 20 g ranitidine hydrochloride was added to 20 g 95% ethanol, warmed to 60 °C to dissolve, filtered, cooled to 20 °C to precipitate solids, stirred for 1 h, added 20 g 95% ethanol dropwise, cooled to -5 °C, stirred for 2 h, suction filtered, and dried at 50 °C under vacuum for 5 h to obtain ranitidine hydrochloride small rod-like crystal habit powder 18.5 g, yield: 92.5%. PLM photograph is shown in Figure Figure 1 .

[0028] Example 2

[0029] 100 g ranitidine hydrochloride was added to 120 g 95% ethanol, warmed to 50 °C to dissolve, filtered, cooled to 18 °C to precipitate solids, stirred for 1 h, added 100 g 95% ethanol dropwise, cooled to -5 °C, stirred for 2 h, suction filtered, and dried at 50 °C under vacuum for 5 h to obtain ranitidine hydrochloride small rod-like crystal habit powder 19.0 g, yield: 95.0%.

[0030] Example 3

[0031] 50 g ranitidine hydrochloride was added to 50 g 95% ethanol, warmed to 60 °C to dissolve, filtered, cooled to 23 °C to precipitate solids, stirred for 1 h, added 100 g 95% ethanol dropwise, cooled to -5 °C, stirred for 2 h, suction filtered, and dried at 50 °C under vacuum for 5 h to obtain ranitidine hydrochloride small rod-like crystal habit powder 19.2 g, yield: 96.0%.

[0032] Example 4

[0033] 20 kg ranitidine hydrochloride was added to 20 kg 95% ethanol, warmed to 60 °C to dissolve, filtered, cooled to 15 °C to precipitate solids, stirred for 1 h, added 40 kg 95% ethanol dropwise, cooled to -5 °C, stirred for 2 h, suction filtered, and dried at 50 °C under vacuum for 5 h to obtain ranitidine hydrochloride small rod-like crystal habit powder 19.03 kg, yield: 95.2%.

[0034] Example 5

[0035] 20 g ranitidine hydrochloride was added to 60 g 95% ethanol, warmed to 60 °C to dissolve, filtered, cooled to 25 °C to precipitate solids, stirred for 12 h, added 60 g 95% ethanol dropwise, cooled to -10 °C, stirred for 1 h, suction filtered, and dried at 60 °C under vacuum for 5 h to obtain ranitidine hydrochloride small rod-like crystal habit powder 18.5 g, yield: 92.5%.

[0036] Example 6

[0037] 20 g ranitidine hydrochloride was added into 60 g 95% ethanol, warmed to 60 °C to dissolve, filtered, cooled to 25 °C to precipitate solid, stirred for 5 h, added 60 g 95% ethanol dropwise, cooled to 0 °C, stirred for 2 h, filtered, dried at 60 °C under vacuum for 5 h, to obtain 18.2 g of ranitidine hydrochloride small rod-like crystal habit powder, yield: 91.0%.

[0038] Comparative Example 1

[0039] Conventional preparation method, including adding 5 g ranitidine base into hydrochloric acid ethanol solution, adjusting pH to 6, precipitating ranitidine hydrochloride solid, filtering, washing with ethanol twice, drying to obtain 4 g of ranitidine hydrochloride solid. The PLM photograph is shown in Figure 2 .

[0040] Comparative Example 2

[0041] 20 g ranitidine hydrochloride was added into 20 g 95% ethanol, warmed to 60 °C to dissolve, filtered, cooled to -5 °C to precipitate solid, stirred for 1 h, added 20 g 95% ethanol dropwise, cooled to -5 °C, stirred for 2 h, filtered, dried at 50 °C under vacuum for 5 h, to obtain 18.8 g of solid powder, yield: 94.0%. The obtained product is agglomerated granules.

[0042] The samples obtained from Example 1 and Comparative Example 1 were subjected to accelerated stability test. The samples obtained from Example 1 and Comparative Example 1 were placed in a 60 °C high-temperature test box using commercially available packaging (double-layer polyethylene bag and one layer of aluminum foil bag) for 3 days, and samples were taken for detection. The limit of long-term test NDMA is not more than 0.36 ppm, and there is no detection limit standard for 60 °C accelerated test, which is only for rapid judgment of sample growth rate and confirmation of sample stability. Through experimental data, it was found that the small rod-like crystal habit obtained by direct crystallization has a 40-fold slower NDMA growth rate than the agglomerated crystal habit obtained by adding acid to form salt.

[0043] Conditions Crystal habit 0 days 3 days NDMA results 60℃ Small rod-like Not detected 0.28 ppm 60℃ Agglomerated Not detected 11.70 ppm

[0044] The samples obtained from Example 1 and Comparative Example 1 were subjected to long-term test (NDMA limit 0.36 ppm). The samples obtained from 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 of aluminum foil bag) for long-term placement observation. Samples were taken for detection at 1 month, 3 months, 6 months, 12 months, 18 months, and 24 months to observe the results of NDMA. The long-term test results show that the small rod-like crystal habit is stable for 24 months, while the agglomerated crystal habit is unqualified after 3 months of long-term test, and the growth rate is very fast.

[0045] Conditions Small rod-like crystal habit NDMA results Agglomerated crystal habit NDMA results 0 days Not detected Not detected 1 month Not detected 0.30 ppm 3 months Not detected 3.30 ppm 6 months Not detected 6.41 ppm 12 months Not detected 13.22 ppm 18 months Not detected 25.02 ppm 24 months Not detected 52.13 ppm

Claims

1. A process for the preparation of ranitidine hydrochloride small rod-like crystal habit, characterized by, The small rod-shaped crystal habit powder of ranitidine hydrochloride is obtained by directly crystallizing ranitidine hydrochloride in 95% ethanol; The crystallization method comprises the following steps: (1) ranitidine hydrochloride is added into 95% ethanol and stirred, and then heated to dissolve; (2) after cooling, solid is precipitated, and then heat preservation and stirring are carried out; (3) 95% ethanol is added again; (4) after cooling again, heat preservation and stirring are carried out; (5) filtration, washing and drying are carried out; In the step (1), the mass ratio of ranitidine hydrochloride to 95% ethanol is 1:1-3; and the temperature after heating is 50-60℃; In the step (2), the temperature after cooling is 15-25℃; the temperature of heat preservation and stirring is 15-25℃, and the heat preservation and stirring time is 1-12 h; In the step (3), the mass ratio of ranitidine hydrochloride to 95% ethanol is 1:1-3; In the step (4), the temperature after cooling again is-10-0℃; the temperature of heat preservation and stirring is-10-0℃, and the heat preservation and stirring time is 1-2 h.

2. The production method according to claim 1, characterized by, In the step (5), the drying is vacuum drying, and the drying temperature is 50-60℃.

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