New crystal form of diphenhydramine hydrochloride and preparation method thereof

Abstract

The invention discloses a new crystal form of diphenhydramine hydrochloride and a preparation method thereof. The X-ray powder diffraction pattern 2 theta of the crystal form has characteristic peaks at the positions of 9.367 + / -0.1 degrees, 10.393 + / -0.1 degrees, 12.366 + / -0.1 degrees, 16.436 + / -0.1 degrees, 18.611 + / -0.1 degrees, 20.421 + / -0.1 degrees, 22.051 + / -0.1 degrees, 24.860 + / -0.1 degrees, 26.914 + / -0.1 degrees and 31.497 + / -0.1 degrees; the invention also discloses a preparation method of the crystal form of diphenhydramine hydrochloride.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical pharmacy, and relates to the technical field of diphenhydramine hydrochloride preparation, and specifically provides a new crystal form of diphenhydramine hydrochloride and a preparation method thereof. Background Art

[0002] Diphenhydramine Hydrochloride, Chinese name is N, N-dimethyl-2-(diphenylmethoxy)ethylamine hydrochloride, CAS: 147-24-0, molecular formula is C 17 H 21 NO·HCl is a white crystalline powder with a molecular weight of 291.82. Its structural formula is as follows:

[0003]

[0004] Diphenhydramine hydrochloride is a very effective anti-allergic drug. It was discovered by Dr. George Rieveschl, a professor at the University of Cincinnati, in 1943 while studying the synthesis of scopolamine. In 1946, it was first marketed by McNeil-PPC Pharmaceuticals. It is the first antihistamine approved in the United States. Diphenhydramine hydrochloride can now be made into various dosage forms to facilitate clinical use, give full play to the therapeutic effects of the drug, and reduce or avoid adverse reactions. Diphenhydramine hydrochloride is suitable for allergic diseases of the skin and mucous membranes, such as hay fever, urticaria, allergic rhinitis, etc. It can also be used to prevent motion sickness such as seasickness, airsickness, and motion sickness.

[0005] As we all know, different crystal forms of the same drug often lead to differences in drug solubility, which can cause differences in drug dissolution and bioavailability, thereby affecting the absorption and utilization of the drug in the body, and then causing differences in drug efficacy. Therefore, the solubility of different crystal forms is one of the primary issues to pay attention to when selecting dosage forms in drug development, and it is also one of the keys to whether the drug can be effectively absorbed. Many drugs are often difficult to dissolve in water, so it is of great significance to improve solubility by screening different crystal forms, thereby improving their bioavailability and efficacy.

[0006] At present, many patents and articles have reported the preparation method and process of diphenhydramine hydrochloride, but none of them involve the crystal form of diphenhydramine hydrochloride. Therefore, it is very necessary to find a new crystal form of diphenhydramine hydrochloride with better stability, fluidity and solubility, so as to provide advantages for the industrial production of large-scale preparation of pharmaceutical preparations. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide a type of diphenhydramine hydrochloride crystals and a preparation method thereof that are different from the prior art. The purpose of the present invention is to provide a diphenhydramine hydrochloride crystal form represented by formula (I), and to provide a preparation method, a pharmaceutical composition and use thereof. The diphenhydramine hydrochloride crystal form is defined herein as "diphenhydramine hydrochloride crystal form A".

[0008]

[0009] The technical solutions for achieving the above purpose are as follows:

[0010] The invention provides a diphenhydramine hydrochloride crystal form A with a structural formula as shown in formula (I). The X-ray powder diffraction pattern of the crystal form A has diffraction peaks at diffraction angles 2θ of 9.367±0.1°, 10.393±0.1°, 12.366±0.1°, 16.436±0.1°, 18.611±0.1°, 20.421±0.1°, 22.051±0.1°, 24.860±0.1°, 26.914±0.1° and 31.497±0.1°.

[0011] The present invention also protects a method for preparing the new crystal form of diphenhydramine hydrochloride, which comprises the following steps:

[0012] (1) Mixing crude diphenhydramine hydrochloride with isopropanol, heating to 75-85° C., reflux and dissolving, stirring for 1 h, and then cooling to 60-65° C.;

[0013] (2) adding isopropyl ether to the solution obtained in step (1), cooling to 0-5°C, and crystallizing for 2 hours to precipitate a large amount of white solid; wherein the cooling rate during the cooling to 0-5°C is 20-40°C / h;

[0014] (3) collecting the white solid precipitated in step (2) by centrifugation, washing with an isopropyl ether solution, and heating and drying to obtain diphenhydramine hydrochloride crystal form A.

[0015] Preferably, in step (1), the ratio of the crude diphenhydramine hydrochloride to isopropyl alcohol is 1 g: 2-4 ml.

[0016] Preferably, in step (2), the ratio of the added isopropyl ether to the isopropyl alcohol in step (1) is 1-2 ml:2 ml.

[0017] Preferably, in step (3), the drying treatment is performed by vacuum drying, the drying temperature is 60-65° C., and the vacuum degree is ≤—0.08 MPa.

[0018] The 2θ angle of the crystal form of the present invention is obtained by selecting the main peak with strong relative intensity in the X-ray diffraction spectrum, and the crystal structure is not necessarily limited to these values, that is, it may contain peaks other than these.

[0019] In addition, generally speaking, when measuring crystals by X-ray analysis, the peaks thereof may have some measurement errors due to the measuring instrument, measuring conditions, the presence of attached solvents, etc. For example, the 2θ angle may have a measurement error of about ±0.1°, so when identifying the crystal structure, some errors should be taken into account, and crystals characterized by substantially the same X-ray spectrum as above are within the scope of the present invention.

[0020] The diphenhydramine hydrochloride crystal form provided by the present invention has good stability under long-term conditions, and has higher solubility than the prior art, which is of great significance for improving drug efficacy and reducing drug loading, and the preparation method is simple to operate, has good repeatability, is conducive to cost control in industrial production, and has extremely high economic value. The time cycle of industrial mass production is greatly shortened, production efficiency is improved, production energy consumption is reduced, and the cost of industrial mass production is reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is the X-ray diffraction test report of diphenhydramine hydrochloride crystal form A;

[0022] Figure 2 The DSC spectrum (differential scanning calorimetry) of diphenhydramine hydrochloride crystal form A;

[0023] Figure 3 It is the TGA spectrum (thermogravimetric analysis) of diphenhydramine hydrochloride crystal form A;

[0024] Figure 4 IR spectrum (infrared absorption spectrum) of diphenhydramine hydrochloride crystal form A;

[0025] Figure 5 This is the HPLC chart of the newly prepared diphenhydramine hydrochloride crystal form A;

[0026] Figure 6 The HPLC chart of diphenhydramine hydrochloride crystal form A placed at room temperature and sealed conditions for 3 months;

[0027] Figure 7 This is the HPLC chart of diphenhydramine hydrochloride crystal form A placed at room temperature and sealed conditions for 6 months. DETAILED DESCRIPTION

[0028] The present invention is further described in detail below in conjunction with specific embodiments. The examples given are only for illustrating the present invention, but not for limiting the scope of the present invention. The embodiments of the present invention are given for the purpose of illustration and description, and are not intended to be exhaustive or to limit the present invention to the disclosed forms. The embodiments are selected and described in order to better illustrate the principles and practical applications of the present invention, and to enable those of ordinary skill in the art to understand the present invention and design various embodiments with various modifications suitable for specific purposes.

[0029] The X-ray powder diffraction pattern of the present invention was collected on a Bruker D8 Advance X-ray diffractometer. The method parameters of the X-ray powder diffraction of the present invention are as follows:

[0030] Test conditions: 40kv 40mA Slit: 1.0 / 1.0 / Ni / 0.2 Step size: 0.02° Target type: CuRange: 3.00-40.00Deg scan Rate: 10.00Deg / min.

[0031] The differential scanning calorimetry (DSC) diagram of the present invention is collected on a NETZSCH DSC 3500 differential thermal analyzer. The method parameters of the differential scanning calorimetry (DSC) of the present invention are as follows:

[0032] Temperature range: 25-245℃;

[0033] Heating rate: 10℃ / min.

[0034] The thermogravimetric analysis (TGA) graph of the present invention was collected on a PerkinElmer TGA4000 thermogravimetric analyzer. The method parameters of the thermogravimetric analysis (TGA) of the present invention are as follows:

[0035] Temperature range: 30-265℃;

[0036] Heating rate: 10℃ / min.

[0037] The infrared absorption spectrum (IR) of the present invention is collected on a Bruker TENSOR 27 infrared spectrometer. The method parameters of the infrared absorption spectrum (IR) of the present invention are as follows:

[0038] Instrument calibration: The instrument wave number is calibrated using the infrared spectrum absorption peak of polystyrene film;

[0039] Method: KBr tablet method.

[0040] Example 1: Diffraction peaks of diphenhydramine hydrochloride crystals.

[0041] A new crystal form of diphenhydramine hydrochloride, temporarily referred to as diphenhydramine hydrochloride crystal form A, has an X-ray diffraction test report as shown below: Figure 1 As shown. Figure 1 It can be seen that the X-ray powder diffraction pattern of the Form A crystals has diffraction peaks at diffraction angles 2θ of 9.367±0.1°, 10.393±0.1°, 12.366±0.1°, 16.436±0.1°, 18.611±0.1°, 20.421±0.1°, 22.051±0.1°, 24.860±0.1°, 26.914±0.1°, and 31.497±0.1°.

[0042] The differential scanning calorimetry (DSC) spectrum of diphenhydramine hydrochloride crystal form A is as follows: Figure 2 As shown; Thermogravimetric analysis (TGA) spectrum is as shown Figure 3 As shown; infrared absorption spectrum (IR) spectrum as shown Figure 4 shown.

[0043] Example 2: Preparation method of diphenhydramine hydrochloride crystals.

[0044] At room temperature, add 30g of crude diphenhydramine hydrochloride and 60ml of isopropanol to the reaction bottle; heat to 75-85°C, dissolve into a clear and transparent liquid, and stir for 1 hour. Cool to 60-65°C. Add 30ml of isopropyl ether solution to the reaction bottle, start cooling to 0-5°C, and keep warm for 2 hours for crystallization. Centrifuge, wash with 15ml of isopropyl ether, transfer to a vacuum drying oven after centrifugation, dry at 60-65°C, vacuum ≤-0.08MPa, dry for 6 hours, and obtain 27.6g of white powder with a yield of 92%.

[0045] Example 3: Solubility studies.

[0046] The solubility of the diphenhydramine hydrochloride crystal A obtained by the present invention in water, ethanol and acetone was tested respectively. The test results are shown in the following table:

[0047] Diphenhydramine hydrochloride solubility test results

[0048] Sample weight (g) Solvents Solvent volume (ml) Phenomenon in conclusion 1.00 water 0.8 Dissolve Very soluble 1.00 Ethanol 7.9 Dissolve Soluble 1.00 acetone 81.0 Dissolve Slightly soluble .

[0049] Experimental Example 4: Experiment on long-term influencing factors.

[0050] This experimental example tests the influencing factors of the diphenhydramine hydrochloride crystals of the present invention ( Figure 5 , Figure 6 , Figure 7 ), see the following table for details:

[0051] Test results of influencing factors

[0052] time Day 0 3 months 6 months Characteristics White crystalline powder White crystalline powder White crystalline powder purity 99.950％ 99.944％ 99.902％ .

[0053] The diphenhydramine hydrochloride crystals prepared by the present invention have relatively stable appearance, properties and related substances under long-term stability test conditions.

[0054] The above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art may make various changes or modifications based on the present invention. As long as they do not depart from the spirit of the present invention, they should all fall within the scope of the claims attached to the present invention.

Claims

1. The diphenhydramine hydrochloride crystalline form shown in the following formula (I) is defined herein as "diphenhydramine hydrochloride crystalline form A": The invention provides a diphenhydramine hydrochloride crystal form A. The X-ray powder diffraction pattern of the crystal has diffraction peaks at diffraction angles 2θ of 9.367±0.1°, 10.393±0.1°, 12.366±0.1°, 16.436±0.1°, 18.611±0.1°, 20.421±0.1°, 22.051±0.1°, 24.860±0.1°, 26.914±0.1° and 31.497±0.1°.

2. The method for preparing the crystal form according to claim 1, characterized in that: The preparation method comprises the following steps: (1) Mixing crude diphenhydramine hydrochloride with isopropanol, heating to 75-85° C., reflux and dissolving, stirring for 1 h, and then cooling to 60-65° C.; (2) adding isopropyl ether to the solution obtained in step (1), cooling to 0-5°C, and crystallizing for 2 hours to precipitate a large amount of white solid; wherein the cooling rate during the cooling to 0-5°C is 20-40°C / h; (3) collecting the white solid precipitated in step (2) by centrifugation, washing with an isopropyl ether solution, and heating and drying to obtain diphenhydramine hydrochloride crystal form A.

3. The preparation method according to claim 2, characterized in that: In the step (1), the ratio of the crude diphenhydramine hydrochloride to isopropyl alcohol is 1 g: 2-4 ml.

4. The preparation method according to claim 2, characterized in that: In the step (2), the ratio of the added isopropyl ether to the isopropyl alcohol in the step (1) is 1-2 ml:2 ml.

5. The preparation method according to claim 2, characterized in that: In the step (3), the drying process is performed by vacuum drying, the drying temperature is 60-65° C., and the vacuum degree is ≤—0.08 MPa.

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