Process for removing specific impurities of diphenhydramine citrate

Abstract

The invention discloses a process for removing specific impurities of diphenhydramine citrate. The identification is as follows: a graph is a related substance (HPLC) graph of a diphenhydramine citrate crude product, and the impurity is named as an impurity I when Rt is equal to 15.567 min; the impurity removal method comprises the following steps: dissolving a diphenhydramine citrate crude product in a solvent, heating and dissolving, cooling the system to 40-55 DEG C, growing crystals for more than 3 hours, cooling to 0-30 DEG C, crystallizing for 2-3 hours, and filtering to obtain a diphenhydramine citrate fine product; wherein the mass volume ratio of the crude product to the solvent is 1g: (8-12) ml, and the solvent is 95% ethanol. The impurity I is disclosed, identified and confirmed for the first time, and a basis is provided for setting an impurity limit. The diphenhydramine citrate is refined by adopting a crystal growing method, the refining effect is good, the removal rate of impurities I and other impurities is high, the operation is simple, and the method is particularly suitable for industrial production.

Description

Technical Field

[0001] The invention relates to a method for identifying and removing impurities in a process, and in particular to a method for identifying and removing impurities in diphenhydramine citrate, and belongs to the technical field of medicine. Background Art

[0002] Diphenhydramine citrate, also known as diphenhydramine citrate, benadryl citrate, benadryl citrate, benzylidene citrate, etc., has the chemical name N,N-dimethyl-2-(diphenylmethoxy)ethylamine citrate, CAS number: 88637-37-0, and the structural formula is as follows:

[0003] Diphenhydramine citrate is a histamine H1 receptor antagonist. At present, it is only included in the United States Pharmacopoeia (USP). Diphenhydramine hydrochloride is included in the Chinese Pharmacopoeia (Ch.P) and the European Pharmacopoeia (EP). In the classic medication regimen, it is quite effective in treating allergies, colds, insomnia and other symptoms. In recent years, diphenhydramine has also been gradually developed for the treatment of COVID 19, kidney damage, acute agitation, postoperative pain and other uses. There are no drugs with diphenhydramine citrate as the active ingredient on the market in China. Compared with diphenhydramine hydrochloride, citric acid has a lighter bitter taste and is more suitable for oral preparations.

[0004] There are many reported preparation methods for the active ingredient diphenhydramine citrate, and the synthetic route that can be used for commercial production is as follows: Synthetic route 1

[0005] CN104892435B et al. reported that diphenhydramine was synthesized from benzhydrol and N,N-dimethylethanol by high temperature, pressure or adding a catalyst.

[0006] Synthetic route 2

[0007] US2421714 et al. reported the preparation of diphenhydramine by high temperature synthesis of benzhydrol through halogenation or sulfonation and then reacting with N,N-dimethylethanol.

[0008] Synthetic route 3

[0009] US2577234 et al. reported the preparation of diphenhydramine by high temperature synthesis using N,N-dimethylethanol through halogenation or sulfonation and then reacting with benzhydrol.

[0010] All three synthetic routes have advantages and disadvantages. Route 1 has the lowest activity and requires the addition of a relatively expensive catalyst to complete the reaction, resulting in a high production cost. Route 2 has the highest activity, but the reaction solution is dark in color, and the precipitated solid requires multiple refining to obtain qualified medicinal properties, resulting in a low yield. Route 3 has moderate activity, good reaction effect, and extremely high yield, but the crude salt product has a large impurity I, and the refining and removal effect is poor. Therefore, if the third route is selected to increase the yield and reduce the total production cost, it is urgent to identify the structure of impurity I and simple impurity removal conditions. Summary of the invention

[0011] The purpose of the present invention is to overcome the deficiencies of the above-mentioned prior art, to provide for the first time a method for identifying and removing impurities I in diphenhydramine citrate, to fill the gap in the purification process of diphenhydramine citrate, to provide a basis for the formulation of the impurity I limit of route 3, and to ensure that the low-cost diphenhydramine citrate synthesis route becomes a commercial synthesis route. To achieve the above-mentioned purpose, the present invention adopts the following technical scheme: The impurity structure is as follows:

[0012] A method for removing impurities from diphenhydramine citrate, comprising the following steps: Dissolve the crude product of diphenhydramine citrate in a solvent, raise the temperature to dissolve it, cool the system to 40-55°C and grow crystals for more than 3 hours, cool to 0-30°C to crystallize for 2-3 hours, filter, and obtain the fine product of diphenhydramine citrate; wherein the mass volume ratio of the crude product to the solvent is 1g:8-12ml, and the solvent is 95% ethanol.

[0013] Preferably, the crystal growing time is 3 hours.

[0014] Preferably, the mass volume ratio of the crude product to the solvent is 1 g:9.5 ml.

[0015] Preferably, the solvent is 95% ethanol.

[0016] Preferably, the crude diphenhydramine citrate is mixed with a solvent and then heated to dissolve.

[0017] Preferably, the heating and dissolving temperature is 70-80°C.

[0018] Preferably, the crystallization temperature is controlled at 20-30° C., and the crystallization time is 2-3 hours.

[0019] Beneficial effects of the present invention: The present invention determines the structure of impurity I for the first time by mass spectrometry and hydrogen spectrum:

[0020] The invention adopts a crystal growing method to realize the crystallization and purification of diphenhydramine citrate, wherein diphenhydramine citrate is dissolved in 95% ethanol as a solvent, and then crystals are grown for a long time at a certain temperature, so that the purification effect is good.

[0021] The obtained diphenhydramine citrate finished product has a purity of more than 99.8%, all single impurities are less than 0.1%, the product yield is high, the operation is simple, and it is particularly suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the related substance (HPLC) spectrum of crude diphenhydramine citrate. The impurity with Rt=15.567min is named impurity I.

[0023] Figure 2 This is the mass spectrum of impurity I.

[0024] Figure 3 This is the hydrogen spectrum of impurity I. DETAILED DESCRIPTION

[0025] The present invention is further described below in conjunction with embodiments. It should be noted that the following description is only for explaining the present invention and does not limit its contents.

[0026] The crude diphenhydramine citrate synthesis route of the present invention is as follows: diphenhydramine is prepared by referring to the method in patent US2577234, and then salified with citric acid to obtain the crude diphenhydramine citrate ( Figure 1 HPLC: 98.701%, impurity I: 0.842%): Example 1

[0027] Add 10 g of crude diphenhydramine citrate and 95 ml of 95% ethanol into a three-necked flask, heat to 70-80 °C, the system becomes clear, slowly cool to 50 °C and stir for 3.0 hours, then cool to 20 °C and stir for 3.0 hours, filter, and dry to obtain 9.00 g of a white solid, HPLC: 99.941%, impurity I: 0.040%, yield 90.0%. Example 2

[0028] Add 10 g of crude diphenhydramine citrate and 80 ml of 95% ethanol into a three-necked flask, heat to 70-80 °C, the system becomes clear, slowly cool to 55 °C and stir for 6.0 hours, then cool to 30 °C and stir for 6.0 hours, filter, and dry to obtain 9.05 g of a white solid, HPLC: 99.899%, impurity I: 0.037%, yield 90.5%. Example 3

[0029] Add 10 g of crude diphenhydramine citrate and 120 ml of 95% ethanol into a three-necked flask, heat to 70-80 °C, the system becomes clear, slowly cool to 40 °C and stir for 12.0 hours, then cool to 0 °C and stir for 12.0 hours, filter, and dry to obtain 8.40 g of a white solid, HPLC: 99.903%, impurity I: 0.063%, yield 84.0%. Example 4

[0030] The crude citric acid mother liquor was separated and purified from impurity I peak for structural confirmation. Figure 2 is the mass spectrum, Figure 3 The structure of impurity I is determined by structural analysis.

[0031] Comparative Example 1 Add 10 g of crude diphenhydramine citrate and 120 ml of anhydrous ethanol to a three-necked flask, heat to 70-80 °C, stir for 0.5 h, reduce to 20 °C, stir for 3.0 h, filter, and dry to obtain 8.50 g of a white solid, HPLC: 98.859%, impurity I: 0.517%, yield 85.0%.

[0032] Comparative Example 2 Add 10 g of crude diphenhydramine citrate and 120 ml of 95% ethanol into a three-necked flask, heat to 70-80 °C, stir for 0.5 h, quickly reduce the temperature to 20 °C and stir for 3.0 h, filter and dry to obtain 8.40 g of white solid, HPLC: 99.323%, impurity I: 0.315%, yield 84.0%.

[0033] Comparative Example 3 Add 10 g of crude diphenhydramine citrate, 30 ml of purified water, and 90 ml of anhydrous ethanol into a three-necked flask, heat to 70-80 ° C, stir for 0.5 h, quickly reduce the temperature to 20 ° C and stir for 3.0 h, filter, and dry to obtain 6.00 g of white solid, HPLC: 99.093%, impurity I: 0.339%, yield 60.0%.

[0034] Comparative Example 4 Add 10 g of crude diphenhydramine citrate and 120 ml of ethyl acetate into a three-necked flask, heat to 60-70 °C, stir for 0.5 h, reduce to 20 °C, stir for 3.0 h, filter, and dry to obtain 8.60 g of a white solid, HPLC: 98.780%, impurity I: 0.562%, yield 95.0%.

[0035] Comparative Example 5 Add 10 g of crude diphenhydramine citrate, 30 ml of purified water, and 80 ml of acetone to a three-necked flask, heat to 45-55 °C, stir for 0.5 h, reduce to 20 °C, stir for 3.0 h, filter, and dry to obtain 6.50 g of a white solid, HPLC: 97.973%, impurity I: 0.786%, yield 65.0%.

[0036] Although the above describes the specific implementation methods of the present invention, it does not limit the scope of protection of the present invention. Based on the technical solution of the present invention, various modifications or variations that can be made by those skilled in the art without creative work are still within the scope of protection of the present invention.

[0037] Although the present invention has been illustrated and described with specific embodiments, it will be appreciated that many other changes and modifications may be made without departing from the spirit and scope of the present invention. Therefore, it is intended to include all such changes and modifications within the scope of the present invention in the appended claims.

Claims

1. A process for removing impurities from diphenhydramine citrate, characterized in that: The impurity structure is as follows: ， The cleaning process steps are as follows: Dissolve the crude product of diphenhydramine citrate in a solvent, raise the temperature to dissolve it, cool the system to 40-55°C and grow crystals for more than 3 hours, cool to 0-30°C to crystallize for 2-3 hours, filter, and obtain the fine product of diphenhydramine citrate; wherein the mass volume ratio of the crude product to the solvent is 1g:8-12ml, and the solvent is 95% ethanol.

2. The method for preparing diphenhydramine citrate according to claim 1, wherein The solvent used was 95% ethanol.

3. The impurity removal method of diphenhydramine citrate according to claim 1, characterized in that, The volume ratio of the crude diphenhydramine citrate to the 95% is 1:8-12.

4. The impurity removal method of diphenhydramine citrate according to claim 1, characterized in that: The crystal growing temperature is 40-55° C., and the crystal growing time is greater than 3 hours.

5. The impurity removal method of diphenhydramine citrate according to claim 1, characterized in that, The crystallization temperature is controlled at 0~30℃ and the crystallization time is 2~3h.

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