Novel doxylamine succinate crystal form and preparation method thereof

Abstract

The invention discloses a doxylamine succinate crystal form J. In an X-ray diffraction pattern of the doxylamine succinate crystal form J, characteristic peaks exist at 2 theta angles of 9.19 + / -0.2 degrees, 11.19 + / -0.2 degrees, 13.10 + / -0.2 degrees, 13.81 + / -0.2 degrees, 16.67 + / -0.2 degrees, 17.28 + / -0.2 degrees, 18.48 + / -0.2 degrees, 20.47 + / -0.2 degrees, 23.18 + / -0.2 degrees and 27.90 + / -0.2 degrees. The invention also discloses a preparation method of the doxylamine succinate crystal form J. The solubility of the doxylamine succinate crystal form J is higher than that of a doxylamine succinate original crystal form, so that the dissolution speed of a preparation can be increased, and the preparation can take effect quickly; the hygroscopicity of the doxylamine succinate crystal form J is lower than that of a doxylamine succinate original crystal form, so that the doxylamine succinate crystal form J is beneficial to production of the doxylamine succinate crystal form J; the doxylamine succinate crystal form J has good chemical stability and crystal form purity, and is easy for large-scale preparation.

Description

Technical Field

[0001] The present invention belongs to the field of chemical synthesis, and relates to a new crystal form of doxylamine succinate and a preparation method thereof. Background Art

[0002] Doxylamine succinate is an ethanolamine antihistamine drug, which has anticholinergic, antihistamine and sedative-hypnotic effects, and is applicable to the short-term treatment of various allergic skin diseases, hay fever, allergic rhinitis, asthmatic bronchitis and insomnia. In October 1978, the FDA approved the marketing of the 25 mg tablet of doxylamine succinate of CHATTEM company to help relieve difficulty in falling asleep, and it became an OTC (over-the-counter drug) in 1979. On April 8, 2013, the FDA approved doxylamine succinate and pyridoxine hydrochloride (trade name Diclegis) as an oral sustained-release tablet for the treatment of pregnant women with nausea and vomiting who do not respond well to conservative treatment.

[0003] Polymorphism of drugs is a hot field in drug research. Different crystal forms of drugs have great differences in stability, bioavailability, etc. Therefore, a comprehensive study on drug polymorphism should be carried out as much as possible to ensure obtaining the best crystal form, so as to make the drug have higher stability, bioavailability, etc. The crystal forms of doxylamine succinate mainly include crystal form A (CN105218433A) and crystal form S (CN106674089A). The former is a crystal form of one molecule of succinate of doxylamine, and the latter is a crystal form of 3 / 2 molecules of succinate of doxylamine. Summary of the Invention

[0004] The purpose of the present invention is to provide a new crystal form J of doxylamine succinate which is easy to prepare, has good stability, high purity and good reproducibility, and a preparation method thereof.

[0005] The purpose of the present invention is achieved by the following technical solutions:

[0006] Doxylamine succinate crystal form J is a crystal of 3 / 2 molecular hydrate of doxylamine succinate with a structure as shown in formula 1:

[0007]

[0008] In the X-ray diffraction pattern of doxylamine succinate crystal form J, characteristic peaks are present at 2θ angles of 9.19±0.2°, 11.19±0.2°, 13.10±0.2°, 13.81±0.2°, 16.67±0.2°, 17.28±0.2°, 18.48±0.2°, 20.47±0.2°, 23.18±0.2°, 27.90±0.2°.

[0009] Preferably, in the X-ray diffraction pattern of doxylamine succinate polymorph J, characteristic peaks are present at 2θ angles of 9.19±0.2°, 11.19±0.2°, 11.45±0.2°, 12.42±0.2°, 13.10±0.2°, 13.81±0.2°, 14.75±0.2°, 16.67±0.2°, 17.28±0.2°, 18.48±0.2°, 19.46±0.2°, 19.80±0.2°, 20.07±0.2°, 20.47±0.2°, 21.65±0.2°, 22.59±0.2°, 23.18±0.2°, 25.54±0.2°, 27.90±0.2°, 31.60±0.2°, 32.65±0.2°.

[0010] More preferably, in the X-ray powder diffraction pattern of doxylamine succinate polymorph J, the relative intensity of the characteristic peak at 2θ angle of 18.48±0.2° is 100%.

[0011] Furthermore, the doxylamine succinate polymorph J of the present invention has an X-ray powder diffraction pattern as Figure 4 shown.

[0012] The thermogravimetric analysis pattern of the doxylamine succinate polymorph J of the present invention shows a weight loss of 6.705%. Combining with the NMR data, it indicates that it contains about 3 / 2 molecules of crystal water; the differential scanning calorimetry analysis pattern shows endothermic peaks at about 43°C to 59.99°C and 100.49°C to 104.09°C, indicating that it melts at around 59.99°C and 104.09°C with endothermic peaks.

[0013] In the infrared absorption spectrum of the doxylamine succinate polymorph J of the present invention, absorption peaks are present at 3427.9, 3053.1, 2976.8, 2938.7, 2874.4, 2768.0, 2461.2, 1720.8, 1616.6, 1586.5, 1470.5, 1429.4, 1314.3, 1181.6, 993.4, 926.9, 701.5, 627.9 cm -1 -1.

[0014] Another object of the present invention is to provide a preparation method of the doxylamine succinate polymorph J as described above, and the synthetic route is as follows:

[0015]

[0016] Including: at room temperature, dissolve doxylamine (Compound 2, chemical name: N,N-dimethyl-2-[1-phenyl-1-(2-pyridyl)ethoxy]ethylamine) in an organic solvent to obtain a doxylamine solution, and cool it to 0 ± 5 °C; dissolve succinic acid in water or a water-containing solvent to obtain a succinic acid solution; at a temperature of 0 ± 5 °C, slowly add the succinic acid solution dropwise to the doxylamine solution. After the addition is complete, stir and react. After the reaction is complete, filter and dry to obtain doxylamine succinate polymorph J (Compound 1, chemical name: N,N-dimethyl-2-[1-phenyl-1-(2-pyridyl)ethoxy]ethylamine succinate 3 / 2 hydrate).

[0017] The molar ratio of the doxylamine to succinic acid is 1:0.9 to 1:1.0.

[0018] The organic solvent is selected from one or more of ethanol, dichloromethane, tetrahydrofuran, isopropanol, acetone, and ethyl acetate.

[0019] Preferably, the organic solvent is selected from acetone or a mixed solvent of acetone and a solvent selected from tetrahydrofuran, isopropanol, and ethyl acetate with a volume ratio of 1:0.5 to 1:2.

[0020] The mass-volume ratio of the doxylamine to the organic solvent is 1:1 to 1:20 g / mL, preferably 1:2 to 1:8 g / mL, and more preferably 1:3 to 1:6 g / mL.

[0021] The water-containing solvent is a mixed solution prepared by mixing water and a solvent selected from methanol, ethanol, or isopropanol in a volume ratio of 0.5:1 to 2:1.

[0022] Preferably, the water-containing solvent is a mixed solution prepared by mixing water and a solvent selected from methanol, ethanol, or isopropanol in a volume ratio of 1:1. The mass-volume ratio of the succinic acid to the water or water-containing solvent used to dissolve it is 1:0.5 to 1:10 g / mL, preferably 1:0.5 to 1:6 g / mL, and more preferably 1:0.9 to 1:1.1 / mL.

[0023] The reaction temperature is -10 to 30 °C, preferably 0 ± 5 °C; the reaction time is 1 to 12 h, preferably 6 to 8 h.

[0024] Another object of the present invention is to provide the use of the doxylamine succinate polymorph J in the preparation of antihistamine drugs or drugs for preventing, alleviating, and treating allergic skin diseases, hay fever, allergic rhinitis, asthmatic bronchitis, insomnia, and nausea and vomiting symptoms in the early, middle, and late stages of pregnancy in pregnant women, etc.

[0025] Another object of the present invention is to provide a pharmaceutical composition, which uses doxylamine succinate polymorph J as the active ingredient and mixes doxylamine succinate polymorph J with pharmaceutically acceptable adjuvants, diluents or carriers.

[0026] The dosage forms of the pharmaceutical composition are oral solid preparations such as orally disintegrating tablets, capsules, film-coated tablets, etc.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0028] 1) The solubility of doxylamine succinate polymorph J is higher than that of the original doxylamine succinate crystal form, which can improve the dissolution rate of the preparation, is beneficial to the rapid onset of the preparation, improves the bioavailability, and can be made into oral solid preparations such as orally disintegrating tablets (rapid onset), capsules, film-coated tablets, etc.

[0029] 2) When preparing oral solid dosage forms such as tablets and capsules, it is necessary to control the humidity of the production environment to improve the powder fluidity and mixing uniformity. The hygroscopicity of doxylamine succinate polymorph J of the present invention is lower than that of the original doxylamine succinate crystal form. The low hygroscopicity is beneficial to the production and storage of the preparation of this product, and can avoid the problems of special control of the environmental humidity due to the high hygroscopicity of the original crystal form, resulting in increased costs and operation difficulties, and the easy hygroscopicity and deterioration of the drug during storage.

[0030] 3) Doxylamine succinate polymorph J has very good stability under conditions such as high temperature, high humidity, and light, has good chemical stability and crystal form purity, is easy to prepare on a large scale, can be better applied to the preparation of pharmaceutical preparations and large-scale production, and has broad application prospects.

[0031] 4) The preparation method of doxylamine succinate polymorph J is simple in operation, good in reproducibility, and simple in post-treatment, and can meet large-scale industrial production.

[0032] 5) The yield of doxylamine succinate polymorph J reaches more than 80%, and the purity reaches more than 99.7%, which has important application prospects. Description of the Drawings

[0033] Figure 1 1H NMR spectrum of doxylamine succinate polymorph J prepared in Example 1.

[0034] Figure 2 13C NMR spectrum of doxylamine succinate polymorph J prepared in Example 1.

[0035] Figure 3 Mass spectrum of doxylamine succinate polymorph J prepared in Example 1.

[0036] Figure 4 X-ray powder diffraction pattern of doxylamine succinate polymorph J prepared in Example 1.

[0037] Figure 5 TG analysis spectrum of doxylamine succinate polymorph J prepared in Example 1.

[0038] Figure 6 DSC analysis spectrum of doxylamine succinate polymorph J prepared in Example 1.

[0039] Figure 7 IR absorption spectrum of doxylamine succinate polymorph J prepared in Example 1.

[0040] Figure 8 Powder diffraction pattern of the factor test of doxylamine succinate polymorph J prepared in Example 1; wherein, Figure 8 in it, GZ5d and GZ10d are the X-ray powder diffraction patterns of doxylamine succinate polymorph J after 5 days and 10 days of light exposure respectively, GW5d and GW10d respectively represent the X-ray powder diffraction patterns of doxylamine succinate polymorph J after 5 days and 10 days of high temperature, and GS5d and GS10d respectively represent the X-ray powder diffraction patterns of doxylamine succinate polymorph J after 5 days and 10 days of high humidity.

[0041] Figure 9 Powder diffraction pattern of the factor test of the existing polymorph of doxylamine succinate; wherein, Figure 9 in it, GZ5d and GZ10d are the X-ray powder diffraction patterns of doxylamine succinate polymorph J after 5 days and 10 days of light exposure respectively, GW5d and GW10d respectively represent the X-ray powder diffraction patterns of doxylamine succinate polymorph J after 5 days and 10 days of high temperature, and GS5d and GS10d respectively represent the X-ray powder diffraction patterns of doxylamine succinate polymorph J after 5 days and 10 days of high humidity. Detailed implementation mode

[0042] The technical solution of the present invention is further illustrated by the following examples. The examples are only used to illustrate the preferred implementation modes of the present invention more specifically and are not used to limit the technical solution of the present invention. Any method and material similar or equivalent to the content described can be used in the present invention. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art.

[0043] The experimental methods without specific conditions noted in the following examples are usually prepared according to conventional conditions.

[0044] Example 1

[0045] Under nitrogen protection, doxylamine (Compound 2, N,N-dimethyl-2-[1-phenyl-1-(2-pyridyl)ethoxy]ethylamine, 100.0 g, 369.86 mmol) and acetone (300 mL) were stirred evenly at room temperature to obtain a doxylamine solution. The solution was cooled to 0 ± 5 °C and maintained at this temperature. An aqueous solution of 40 mL of succinic acid (43.67 g, 369.80 mmol) was slowly added dropwise to the doxylamine solution. After the addition was complete, the mixture was stirred at 0 ± 5 °C for 8 h for crystallization. It was then filtered and dried to obtain doxylamine succinate polymorph J (Compound 1, 116.41 g, yield 81.03%, HPLC purity 99.8%).

[0046] 1 H NMR (600 MHz, DMSO-d6) δ: 8.48 (dd, 1H, Ar-H, J1 = 0.72, J2 = 4.68), 7.77 (m, 1H, Ar-H), 7.63 (m, 1H, Ar-H), 7.37 (m, 2H, Ar-H), 7.29 (m, 2H, Ar-H), 7.23 (m, 2H, Ar-H), 7.18 (m, 2H, Ar-H), 5.82 (s, br, 3H, COOH, H2O), 3.39 (m, 2H, -CH2), 2.68 (m, 2H, -CH2), 2.37 (s, 4H, -CH2), 2.29 (d, 6H, -CH3, J = 4.2), 1.91 (s, 3H, -CH3). 13 C NMR (600 MHz, DMSO-d6) δ: 174.40, 164.28, 148.23, 145.45, 136.64, 127.91, 126.67, 126.04, 121.94, 120.21, 81.65, 59.91, 58.28, 44.85, 30.21, 23.54. TOF MS ES(+) (m / z): 271.18 [M+H] + )

[0047] In the X-ray powder diffraction pattern ( Figure 4 ) detected using Cu-Kα radiation, doxylamine succinate polymorph J has the following characteristic peaks, and the 2θ angles and d values are shown in Table 1.

[0048] Table 1. 2θ angle values and relative intensities of characteristic peaks of doxylamine succinate polymorph J

[0049] 2θ (±0.2°) d value (Å) 2θ (±0.2°) d value (Å) 9.19 9.6280 19.80 4.4848 11.19 7.9076 20.07 4.4239 11.45 7.7253 20.47 4.3397 12.42 7.1256 21.65 4.1047 13.10 6.7598 22.59 3.9365 13.81 6.4107 23.18 3.8372 14.75 6.0061 25.54 3.4874 16.67 5.3185 27.90 3.1985 17.28 5.1315 31.60 2.8310 18.48 4.8005 32.65 2.7424 19.46 4.5607

[0050] The thermogravimetric analysis pattern of doxylamine succinate polymorph J is as shown in Figure 5As shown, it shows a weight loss of 6.705%, indicating that it contains about 3 / 2 crystal waters; the differential scanning calorimetry analysis pattern of doxylamine succinate polymorph J is as Figure 6 shown, showing endothermic peaks at about 43°C to 59.99°C and 100.49°C to 104.09°C, indicating that it melts at around 59.99°C and 104.09°C and there are endothermic peaks.

[0051] In the infrared absorption spectrum of doxylamine succinate polymorph J ( Figure 7 ), absorption peaks are present at 3427.9, 3053.1, 2976.8, 2938.7, 2874.4, 2768.0, 2461.2, 1720.8, 1616.6, 1586.5, 1470.5, 1429.4, 1314.3, 1181.6, 993.4, 926.9, 701.5, 627.9 cm -1 .

[0052] Example 2

[0053] Prepare a solution of succinic acid (43.67 g, 369.86 mmol) using 20 mL of water and 20 mL of isopropanol.

[0054] Under nitrogen protection, doxylamine (100.0 g, 369.86 mmol), acetone (150 mL), and ethyl acetate (150 mL) were stirred evenly at room temperature, cooled to 0 ± 5°C, and the temperature was maintained at 0 ± 5°C. A solution of succinic acid (43.67 g, 369.86 mmol) was slowly added dropwise to the doxylamine solution. After the addition was complete, it was kept stirring and crystallizing at 0 ± 5°C for 7 h, filtered, and dried to obtain doxylamine succinate polymorph J (115.49 g, yield 80.39%, HPLC purity 99.7%).

[0055] Example 3

[0056] Under nitrogen protection, N,N-dimethyl-2-[1-phenyl-1-(2-pyridyl)ethoxy]ethylamine (100.0 g, 369.86 mmol), acetone (200 mL), and acetonitrile (100 mL) were stirred evenly at room temperature to obtain a doxylamine solution. It was cooled to 0 ± 5°C, and the temperature was maintained at 0 ± 5°C. A 40 mL aqueous solution of succinic acid (41.49 g, 351.34 mmol) was slowly added dropwise thereto. After the addition was complete, it was kept stirring and crystallizing at 0 ± 5°C for 6 h, filtered, and dried to obtain doxylamine succinate polymorph J (111.37 g, yield 81.60%, HPLC purity 99.9%).

[0057] Example 4

[0058] Prepare a solution of succinic acid (39.31 g, 332.88 mmol) using 20 mL of water and 20 mL of isopropanol.

[0059] Under nitrogen protection, doxylamine (100.0 g, 369.86 mmol), acetone (100 mL), and tetrahydrofuran (200 mL) were stirred evenly at room temperature to obtain a doxylamine solution. The solution was cooled to 0 ± 5 °C and maintained at this temperature. A solution of succinic acid (39.31 g, 332.88 mmol) was slowly added dropwise to the doxylamine solution. After the addition was complete, the mixture was stirred at 0 ± 5 °C for 7 h to crystallize. It was then filtered and dried to obtain doxylamine succinate polymorph J (108.13 g, yield 83.62%, HPLC purity 99.8%).

[0060] Example 5

[0061] A comparative study on the solubility of doxylamine succinate polymorph J (Example 1) and the original polymorph of doxylamine succinate (polymorph A, hereinafter the same) was carried out with reference to the method under Item 15 (2) of the General Notices - Items and Requirements - Part II of the Chinese Pharmacopoeia (2020 Edition).

[0062] Test method: Weigh the powdered test substance or measure the liquid test substance, and place it in a certain volume of solvent at 25 °C ± 2 °C. Vigorously shake it for 30 seconds every 5 minutes; observe the dissolution situation within 30 minutes. If there are no visible solute particles or droplets, it is considered completely dissolved.

[0063] Investigate the solubility of this product in deionized water and absolute ethanol respectively. The specific operation is as follows: Weigh the powdered doxylamine succinate polymorph J or the original polymorph of doxylamine succinate, add it to a certain volume of solvent, and vigorously shake it for 30 seconds every 5 minutes at 25 °C ± 2 °C; observe the dissolution situation of doxylamine succinate polymorph J and the original polymorph of doxylamine succinate within 30 minutes.

[0064] Record the total amount of deionized water, ethanol used and the time respectively. The results are shown in Table 2.

[0065] Table 2. Results of the comparative study on the solubility of doxylamine succinate polymorph J and the original polymorph of doxylamine succinate

[0066]

[0067] Note: mL / g represents the amount of deionized water or ethanol used per g of doxylamine succinate polymorph J or the original polymorph.

[0068] As can be seen from Table 2, doxylamine succinate polymorph J and the original polymorph of doxylamine succinate are both extremely soluble in deionized water and soluble in ethanol; moreover, the solubility of doxylamine succinate polymorph J is significantly higher than that of the original polymorph. Preparing oral solid preparations such as orally disintegrating tablets (rapid onset of action), capsules, and film-coated tablets with doxylamine succinate polymorph J can improve the dissolution rate of the preparation, facilitate the rapid onset of action of the preparation, and improve bioavailability.

[0069] Example 6

[0070] Investigation on the stability of doxylamine succinate polymorph J and the original polymorph of doxylamine succinate of the present invention

[0071] Stability

[0072] The stability of doxylamine succinate polymorph J was detected in accordance with the "Guidelines for Stability Testing of Raw Materials and Preparations" in Part IV of the Chinese Pharmacopoeia 2020 Edition.

[0073] High temperature test: Spread doxylamine succinate polymorph J and the original polymorph of doxylamine succinate flat in petri dishes, place them in an oven, and place them at 60 °C for 10 days. Sampling was carried out on the 5th and 10th days for X-ray powder diffraction and related substance detection to investigate the stability of the polymorph.

[0074] High humidity test: Spread doxylamine succinate polymorph J and the original polymorph of doxylamine succinate flat in petri dishes, place them in a thermostatic and humidity-controlled incubator, and place them at 25 °C under conditions of relative humidity of 90% and 75% for 10 days. Sampling was carried out on the 5th and 10th days for X-ray powder diffraction and related substance detection to investigate the stability of the polymorph.

[0075] Strong light irradiation test: Spread doxylamine succinate polymorph J and the original polymorph of doxylamine succinate flat in petri dishes, place them in a strong light irradiation test chamber, and place them under the condition of illuminance of 4500 lx ± 500 lx for 10 days. Sampling was carried out on the 5th and 10th days for X-ray powder diffraction and related substance detection to investigate the stability of the polymorph. The results of the stability investigation are shown in Table 3.

[0076] Table 3. Results of the stability investigation of doxylamine succinate polymorph J and the original polymorph of doxylamine succinate

[0077]

[0078] Note: *: The ignore limit is 0.01%.

[0079] As can be seen from Table 3, the original crystal form of doxylamine succinate has good stability under light, but poor stability under high temperature and high humidity. Under high temperature and high humidity conditions, the impurities in the product increase significantly. After the original crystal form of doxylamine succinate is treated at high temperature for 5 days, it is relatively stable, but after 10 days of high temperature treatment, the maximum single impurity increases to 0.42%, and the purity decreases by 2.18%; it is relatively stable after 5 days of high humidity treatment, and after 10 days of high humidity treatment, the maximum single impurity increases to 5.65%, and the purity decreases by 5.96%. The powder diffraction (XRD) test shows that there is no change in both crystal forms (see Figure 8 and Figure 9 ), but when all samples are tested for related substances, the results show that: compared with doxylamine succinate, the crystal form J of doxylamine succinate has better stability. Under the accelerated stability test, the impurities basically do not increase significantly, and the purity does not decrease significantly, indicating that the crystal form J of doxylamine succinate significantly improves the stability of doxylamine succinate.

[0080] The experimental results show that high temperature, high humidity, and strong light have no effect on the stability of the crystal form J of doxylamine succinate.

[0081] Hygroscopicity

[0082] Refer to the "Guideline for the Hygroscopicity Test of Drugs" in General Principles of Part IV of the Chinese Pharmacopoeia 2020 Edition to determine the hygroscopicity of the crystal form J of doxylamine succinate. The specific test method is as follows: Take a dry stoppered glass weighing bottle (outer diameter 50 mm, height 15 mm), place it in a suitable constant temperature dryer (with ammonium chloride or ammonium sulfate saturated solution placed at the bottom) at 25°C ± 1°C or an artificial climate chamber (set temperature 25°C ± 1°C, relative humidity 80% ± 2%) one day before the test, and accurately weigh the weight (m1). Take about 1 g of this product and spread it evenly in the above-mentioned weighing bottle. The thickness of the test sample is generally about 1 mm, and accurately weigh the weight (m2). Open the weighing bottle and place it together with the bottle cap under the above-mentioned constant temperature and humidity conditions for 24 hours. Cover the weighing bottle cap and accurately weigh the weight (m3).

[0083] Calculate the weight gain percentage according to the following formula.

[0084]

[0085] According to the description of hygroscopicity characteristics and the definition of hygroscopic weight gain, the hygroscopicity results of doxylamine succinate and crystal form J are obtained. The results are shown in Table 4. The weight gain percentage of the crystal form J of doxylamine succinate is 1.8%, but it is significantly lower than that of the original crystal form of doxylamine succinate.

[0086] Table 4. Results of the hygroscopicity investigation of the crystal form J of doxylamine succinate and the original crystal form of doxylamine succinate

[0087] Name Weight gain percentage Hygroscopicity Doxylamine succinate original crystal form 14.6％ Hygroscopic Doxylamine succinate crystal form J 1.8％ Slightly hygroscopic

[0088] In summary, the doxylamine succinate polymorph J of the present invention can improve the solubility, stability of doxylamine succinate, and improve its hygroscopicity, which is more conducive to the formulation and use of the product, and improves the safety of the product.

[0089] The above embodiments only have an exemplary effect on the present invention and do not have any restrictive effect. Any non-substantive modifications made by those skilled in the art based on the present invention shall fall within the protection scope of the present invention.

Claims

1. Doxylamine succinate polymorph J, characterized in that: Doxylamine succinate polymorph J is a crystal of doxylamine succinate 3 / 2 molecular hydrate. In the X-ray diffraction pattern of doxylamine succinate polymorph J, characteristic peaks are present at 2θ angles of 9.19±0.2°, 11.19±0.2°, 13.10±0.2°, 13.81±0.2°, 16.67±0.2°, 17.28±0.2°, 18.48±0.2°, 20.47±0.2°, 23.18±0.2°, and 27.90±0.2°.

2. The doxylamine succinate polymorph J according to claim 1, wherein: In the X-ray diffraction pattern of doxylamine succinate polymorph J, characteristic peaks are present at 2θ angles of 9.19±0.2°, 11.19±0.2°, 11.45±0.2°, 12.42±0.2°, 13.10±0.2°, 13.81±0.2°, 14.75±0.2°, 16.67±0.2°, 17.28±0.2°, 18.48±0.2°, 19.46±0.2°, 19.80±0.2°, 20.07±0.2°, 20.47±0.2°, 21.65±0.2°, 22.59±0.2°, 23.18±0.2°, 25.54±0.2°, 27.90±0.2°, 31.60±0.2°, and 32.65±0.2°.

3. The doxylamine succinate polymorph J according to claim 1, characterized in that: The described doxylamine succinate polymorph J has an X-ray powder diffraction pattern as shown in Figure 4.

4. The doxylamine succinate polymorph J according to claim 1, characterized in that: The differential scanning calorimetry analysis pattern of doxylamine succinate polymorph J shows endothermic peaks at approximately 43°C to 59.99°C and 100.49°C to 104.09°C.

5. The doxylamine succinate polymorph J according to claim 1, characterized in that: In the infrared absorption spectrum of doxylamine succinate polymorph J, absorption peaks are observed at 3427.9, 3053.1, 2976.8, 2938.7, 2874.4, 2768.0, 2461.2, 1720.8, 1616.6, 1586.5, 1470.5, 1429.4, 1314.3, 1181.6, 993.4, 926.9, 701.5, 627.9 cm -1 .

6. A method for preparing the doxylamine succinate polymorph J according to claim 1, characterized in that: Including: At room temperature, dissolve doxylamine in an organic solvent to obtain a doxylamine solution, and cool it to 0±5°C. Dissolve succinic acid in water or a water-containing solvent to obtain a succinic acid solution; at a temperature of 0±5°C, slowly add the succinic acid solution dropwise to the doxylamine solution. After the addition is complete, stir the reaction. After the reaction is complete, filter and dry to obtain doxylamine succinate polymorph J. Among them, the organic solvent is selected from one or more of ethanol, dichloromethane, tetrahydrofuran, isopropanol, acetone, and ethyl acetate; the mass-volume ratio of doxylamine to the organic solvent is 1:1 to 1:20 g / mL. The water-containing solvent is a mixed solution prepared by mixing water with a solvent selected from methanol, ethanol, or isopropanol in a volume ratio of 0.5:1 to 2:1; the mass-volume ratio of succinic acid to the water or water-containing solvent used to dissolve it is 1:0.5 to 1:10 g / mL.

7. The preparation method of doxylamine succinate polymorph J according to claim 6, characterized in that: The molar ratio of doxylamine to succinic acid is 1:0.9 to 1:1.

0. The organic solvent is selected from acetone or a mixed solvent of acetone and a solvent selected from tetrahydrofuran, isopropanol, and ethyl acetate in a volume ratio of 1:0.5 to 1:

2. The mass-volume ratio of doxylamine to the organic solvent is 1:2 to 1:8 g / mL, preferably 1:3 to 1:6 g / mL. The water-containing solvent is a mixed solution prepared by mixing water with a solvent selected from methanol, ethanol, or isopropanol in a volume ratio of 1:

1. The mass-volume ratio of the succinic acid to the water or aqueous solvent used for dissolving it is 1:0.5 to 1:6 g / mL, preferably 1:0.9 to 1:1.1 / mL. The reaction temperature is -10 to 30 °C, preferably 0 ± 5 °C; the reaction time is 1 to 12 h, preferably 6 to 8 h.

8. Use of the doxylamine succinate polymorph J according to any one of claims 1-5 in the preparation of an antihistamine drug or a drug for preventing, alleviating or treating allergic skin diseases, hay fever, allergic rhinitis, asthmatic bronchitis, insomnia, and nausea and vomiting symptoms in the early, middle and late stages of pregnancy.

9. A pharmaceutical composition, characterized in that: The pharmaceutical composition uses the doxylamine succinate polymorph J according to any one of claims 1-5 as an active ingredient, and mixes the doxylamine succinate polymorph J with a pharmaceutically acceptable adjuvant, diluent or carrier.

10. The pharmaceutical composition according to claim 9, characterized in that: The dosage form of the pharmaceutical composition is an orally disintegrating tablet, a capsule or a film-coated tablet.

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