CN115448927A - Epinastine hydrobromide crystal form II and preparation method thereof - Google Patents

Epinastine hydrobromide crystal form II and preparation method thereof Download PDF

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CN115448927A
CN115448927A CN202211297846.7A CN202211297846A CN115448927A CN 115448927 A CN115448927 A CN 115448927A CN 202211297846 A CN202211297846 A CN 202211297846A CN 115448927 A CN115448927 A CN 115448927A
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epinastine
hydrobromide
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theta
crystallization
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陈琳
吴晖
杨瀚
黄超民
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Chongqing Ruipolai Pharmaceutical Technology Co ltd
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Abstract

The invention discloses an epinastine hydrobromide crystal form II, wherein the X-ray powder diffraction of the crystal form II is 7.7 +/-0.2 at a 2 theta value 0 、9.6±0.2 0 、14.3±0.2 0 、21.2±0.2 0 、25.5±0.2 0 Has characteristic peaks. The epinastine hydrobromide crystal form II has good stability, and even if the crystal is placed for 30 days under the accelerated experiment conditions of the temperature T =40 ℃ and the relative humidity RH =75%, the impurity content is basically unchanged, so that the crystal is more beneficial to medicine storage and transportation, and the safety of clinical medication is ensured. The preparation method of the epinastine hydrobromide crystal form II is simple and is suitable for industrial production.

Description

Epinastine hydrobromide crystal form II and preparation method thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, relates to epinastine hydrobromide, and particularly relates to an epinastine hydrobromide crystal form II and a preparation method thereof.
Background
Epinastine is se:Sup>A histamine H1 receptor antagonist, has an inhibitory effect on histamine, leukotriene C4, PAF, 5-hydroxytryptamine, and can inhibit the release of se:Sup>A slow-reacting substance A (SRS-A) chemical mediator, and is suitable for preventing and treating adult diseases such as allergic rhinitis, urticarise:Sup>A, eczemse:Sup>A, dermatitis, skin pruritus, prurigo, psoriasis vulgaris accompanied with pruritus, allergic bronchial asthmse:Sup>A, etc.
Epinastine, developed by Boehringer Ingelheim and Sankyo, was marketed in japan under the trade name ales in 1994, and by virtue of its extremely low central sedative and cardiotoxic effects, rapidly became the best-marketed drug in the antiallergic market. The raw material medicine on the market at present is epinastine hydrochloride, and the structure of the epinastine hydrochloride is as follows:
Figure BDA0003900928660000011
there are three main methods for synthesizing epinastine hydrochloride in the prior art.
Firstly, according to the chemical synthesis method of epinastine hydrochloride described in the Japanese patent of invention JP43469885, 6-chloromethyl-6,11-dihydro-dibenzo [ b, e ] azepine is subjected to substitution reaction to generate 6- [ N-phthalimido-methyl ] -11-dihydro-dibenzo [ b, e ] azepine, and then the epinastine hydrobromide is synthesized through three steps of palladium-carbon hydrogenation reduction, hydrazine hydrate hydrazinolysis and cyanogen bromide cyclization, and then epinastine hydrochloride is further synthesized. The process route is as follows:
Figure BDA0003900928660000012
second, the method for synthesizing epinastine hydrochloride as disclosed in US patent No. 4313931: the process route for preparing epinastine hydrochloride from 6-chloro-11-H-dibenzo [ b, e ] azepine is as follows:
Figure BDA0003900928660000021
the third method, as reported in chinese patent CN101130544a, is to use 6-chloromethyl-6,11-dihydro-dibenzo [ b, e ] azepine as a starting material, directly react with ammonia gas to prepare 6-aminomethyl-11-hydro-dibenzo [ b, e ] azepine, then reduce with sodium borohydride, cyclize with cyanogen bromide to prepare epinastine hydrobromide, and further synthesize epinastine hydrochloride. The process route is as follows:
Figure BDA0003900928660000022
disclosure of Invention
During the preparation process of the epinastine hydrochloride medicament, a plurality of impurities including the impurity 1 are easily out of limits. After a great deal of research, it is found that the impurity 1 in epinastine hydrochloride is an oxidation impurity which is easy to generate in preparation and storage, and precisely, the impurity 1 has an important relation with epinastine hydrobromide which is an important intermediate of epinastine hydrochloride, while epinastine hydrobromide crystals prepared in the prior art such as JP200230885, US4313931, CN101130544a and CN103509025a are the same, and the crystal is poor in stability, and will decompose after a long storage time, resulting in an increase in the content of the impurity 1.
Figure BDA0003900928660000023
In order to solve the problems in the prior art, the invention aims to provide a novel crystal form of epinastine hydrobromide, which has good stability and can well meet the requirements of producing high-quality epinastine hydrochloride bulk drugs.
The structure of epinastine hydrobromide is as follows:
Figure BDA0003900928660000031
for convenience, in the invention, epinastine hydrobromide crystals prepared in JP200230885, US4313931, CN101130544a and CN103509025a in the prior art are referred to as epinastine hydrobromide crystal form I, and the new crystal form provided by the invention is referred to as epinastine hydrobromide crystal form II.
In order to realize the purpose of the invention, the following technical scheme is provided:
the epinastine hydrobromide crystal form II is characterized in that the X-ray powder diffraction thereof has characteristic peaks at 2 theta angles of 7.7 +/-0.2 degrees, 9.6 +/-0.2 degrees, 14.3 +/-0.2 degrees, 21.2 +/-0.2 degrees and 25.5 +/-0.2 degrees.
The relative peak intensity of the epinastine hydrobromide crystal form II of the invention at the diffraction angle 2 theta of 9.6 +/-0.2 degrees is 100 percent; the relative peak intensity of 7.7 plus or minus 0.2 degrees at the diffraction angle 2 theta is more than 70 percent and less than 100 percent; the relative peak intensity of 21.2 +/-0.2 degrees at the diffraction angle 2 theta is more than 60 percent and less than 80 percent; the relative peak intensity at 25.5 +/-0.2 DEG of diffraction angle 2 theta is more than 50% and less than 70%.
Preferably, the epinastine hydrobromide crystal form II of the present invention has characteristic peaks at 2 θ angles of 7.7 ± 0.2 °, 9.6 ± 0.2 °, 12.9 ± 0.2 °, 13.9 ± 0.2 °, 14.3 ± 0.2 °, 15.5 ± 0.2 °, 21.2 ± 0.2 °, 22.5 ± 0.2 °, 25.5 ± 0.2 °, 25.8 ± 0.2 °, and 26.9 ± 0.2 ° in X-ray powder diffraction.
More preferably, the epinastine hydrobromide crystal form II of the present invention has characteristic peaks at 2 θ angles of 6.8 ± 0.2 °, 7.7 ± 0.2 °, 9.6 ± 0.2 °, 11.9 ± 0.2 °, 12.9 ± 0.2 °, 13.9 ± 0.2 °, 14.3 ± 0.2 °, 15.5 ± 0.2 °, 18.2 ± 0.2 °, 21.2 ± 0.2 °, 22.5 ± 0.2 °, 23.0 ± 0.2 °, 25.3 ± 0.2 °, 25.5 ± 0.2 °, 25.8 ± 0.2 °, 26.9 ± 0.2 °, and 27.8 ± 0.2 ° in X-ray powder diffraction.
Most preferably, the crystal form II of the epinastine hydrobromide has a pattern shown in figure 2 by X-ray powder diffraction.
In a second aspect, the invention aims to provide a method for preparing the epinastine hydrobromide crystal form II, which is simple to operate, does not need special equipment, and is suitable for industrial production.
The invention discloses a preparation method of epinastine hydrobromide crystal form II, which is characterized by comprising the following steps: comprises dissolving epinastine hydrobromide in water under heating, and cooling for crystallization.
Preferably, in the preparation method, the dissolving temperature is 50-100 ℃; more preferably from 80 ℃ to 100 ℃.
Preferably, in the preparation method, the crystallization temperature of the cooling crystallization is 0-40 ℃; more preferably 10 to 20 ℃.
Preferably, in the preparation method, the crystallization time is 1 to 5 hours; more preferably 2 to 3 hours.
The epinastine hydrobromide as the crystallization raw material can be prepared by any synthesis method for preparing epinastine hydrobromide in the prior art.
In a third aspect, the invention aims to provide pharmaceutical application of epinastine hydrobromide crystal form II. The crystal form II of epinastine hydrobromide can also be used as an active ingredient to prepare epinastine hydrobromide preparations for clinical use.
The invention relates to application of epinastine hydrobromide crystal form II in preparing an antiallergic medicament. Furthermore, the epinastine hydrobromide crystal form II is used for preparing medicines for treating diseases related to histamine H1 receptor antagonism, wherein any one or combination of diseases such as allergic rhinitis, urticaria, dermatitis, eczema, cutaneous pruritus, migraine, bin-Hoton syndrome, tension headache, bronchial asthma, muscle pain, inflammatory pain, neuralgia, psoriasis, allergic conjunctivitis and the like is preferred.
In a preferred technical scheme of the invention, the daily dose of the epinastine hydrobromide crystal form II is 5mg-40mg, and the epinastine hydrobromide crystal form II can be administered in a single dose or multiple doses.
In a fourth aspect, the invention also provides an antiallergic pharmaceutical composition, which is a pharmaceutical preparation prepared by taking the crystal form II of epinastine hydrobromide as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
The anti-allergic pharmaceutical composition is prepared by adopting conventional preparation technical means or pharmaceutical methods in the field, and the epinastine hydrobromide crystal form II is prepared into a proper medicament form, and comprises the following components: tablets, capsules, injections, pills, tinctures, suppositories, ointments (ointments, creams), ophthalmic preparations, implants, syrups, mists (aerosols, powders, sprays), films, granules, powders, otic preparations, nasal preparations, oral solutions (oral suspensions, oral emulsions), lotions (rinses, enemas), liniments (paints, films), gels, patches and the like; preferably tablets, capsules, ophthalmic preparations.
Compared with the crystal form I, the crystal form II of epinastine hydrobromide has obviously improved stability, and even if the crystal form II is placed for 30 days under the accelerated experiment conditions of the temperature T =40 ℃ and the relative humidity RH =75%, the impurity content is basically unchanged, so that the crystal form II of epinastine hydrobromide is more favorable for medicine storage and transportation, and the safety of clinical medication is ensured. The preparation process of the epinastine hydrobromide crystal form II is simple, convenient to operate, high in yield and beneficial to large-scale production.
Drawings
Figure 1 is an XRPD pattern of epinastine hydrobromide form I;
figure 2 is an XRPD pattern of epinastine hydrobromide form II.
Detailed Description
The above examples are merely representative for further understanding of the nature of the present invention, and are not intended to limit the scope of the present invention in any way. Unless otherwise indicated, when the present invention relates to percentages between liquids, said percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentages between solid and liquid, said percentages being weight/volume percentages; the balance being weight/weight percent.
The detection parameters for detecting XRPD were as follows:
parameter name Set value
Material Material Cu
Voltage (KV) 30KV
Current (mA) 10mA
Scan Range (deg) 3.0000-40.0000
Scan mode Default
Scanning speed Scan speed 0.15s/Step
Scanning step length Scan step length (deg) 0.0200
Example 1 preparation of epinastine hydrobromide form I
6-aminomethyl-6,11-dihydro-5H-dibenzo [ b, e ] azepine was prepared by the method reported in CN 101130544A.
Adding 200mL of ethanol into 33g of 6-aminomethyl-6,11-dihydro-5H-dibenzo [ b, e ] aza Zhuo Zhong, dropwise adding a mixed solution of 35g of cyanogen bromide and 100ml of tetrahydrofuran at the temperature of below 50 ℃, reacting at the temperature of 40-50 ℃ for 24 hours, cooling to 10-20 ℃, stirring for crystallization for 2-3 hours, filtering, drying a filter cake at the temperature of 40-50 ℃ under reduced pressure to constant weight to obtain epinastine hydrobromide crystal form I with the weight of 35g.
The obtained crystal form is detected by an XRPD detector, XRPD data of the crystal form are obtained, and the result is shown in table 1 and figure 1.
TABLE 1 PXRD values for form I
Pos.[°2Th.] Rel.Int.[％]
5.725 12.5
8.529 41.4
17.154 21.1
19.390 100.0
19.950 11.3
22.386 32.1
22.708 16.9
23.042 23.7
25.060 9.4
25.837 9.4
26.979 13.7
29.305 14.4
30.907 5.4
33.156 8.0
37.117 3.6
Example 2 preparation of Epinastine hydrobromide form II
A500 ml three-necked flask was charged with 300ml of water at a time, and 20g of epinastine hydrobromide prepared in example 1 was added with stirring. Heating to reflux, stirring to dissolve, slowly cooling to 10-20 ℃, filtering, drying a filter cake at 40-50 ℃ under reduced pressure to constant weight to obtain the epinastine hydrobromide crystal form II with the weight of 15g.
The obtained crystal form II is detected by an XRPD detector to obtain XRPD data, and the result is shown in a table 2 and a figure 2.
Table 2 XRPD values of form II
Figure BDA0003900928660000071
Figure BDA0003900928660000081
Example 3 epinastine hydrobromide form I and form II stability studies.
Form I and form II were examined for stability after 30 days at a temperature T =40 ℃ and relative humidity RH =75%, and the results are given in table 3 below:
table 3 epinastine hydrobromide crystal form I and crystal form II stability results
Figure BDA0003900928660000082
According to the results in table 3 above, it is shown that in the accelerated experiment of temperature T =40 ℃ and relative humidity RH =75%, the crystal form II is relatively stable and has more application value. The epinastine hydrobromide crystal form II can be used as a pharmaceutical active ingredient and has good drug forming property, and can be used as an intermediate for preparing epinastine hydrochloride to reduce impurities of the epinastine hydrochloride and improve purity and quality controllability.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, without departing from the principle of the present invention, it is possible to make various improvements and modifications to the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.

Claims (10)

1. An epinastine hydrobromide crystal form II, characterized in that: the powder diffraction of the powder at 2 theta is 7.7 +/-0.2 0 、9.6±0.2 0 、14.3±0.2 0 、21.2±0.2 0 、25.5±0.2 0 Has characteristic peaks.
2. The crystalline form II of claim 1, characterized in that: the crystal form II of epinastine hydrobromide has a diffraction angle 2 theta of 9.6 +/-0.2 0 The relative peak intensity at (a) is 100%; diffraction angle 2 theta of 7.7 +/-0.2 0 Greater than 70% and less than 100%; 21.2. + -. 0.2% at the diffraction angle 2. Theta 0 Greater than 60% and less than 80% relative peak intensity; 25.5 + -0.2 at a diffraction angle 2 theta 0 Greater than 50% and less than 70%.
3. The crystalline form II of claim 1, characterized in that: the powder diffraction of the powder at 2 theta angle is 7.7 +/-0.2 0 、9.6±0.2 0 、12.9±0.2 0 、13.9±0.2 0 、14.3±0.2 0 、15.5±0.2 0 、21.2±0.2 0 、22.5±0.2 0 、25.5±0.2 0 、25.8±0.2 0 、26.9±0.2 0 Has a characteristic peak.
4. The crystalline form II of claim 1, characterized in that: the powder diffraction of the X-ray is 6.8 +/-0.2 at the 2 theta angle 0 、7.7±0.2 0 、9.6±0.2 0 、11.9±0.2 0 、12.9±0.2 0 、13.9±0.2 0 、14.3±0.2 0 、15.5±0.2 0 、18.2±0.2 0 、21.2±0.2 0 、22.5±0.2 0 、23.0±0.2 0 、25.3±0.2 0 、25.5±0.2 0 、25.8±0.2 0 、26.9±0.2 0 、27.8±0.2 0 Has characteristic peaks.
5. The crystalline form II of any one of claims 1-4, characterized in that: has an XRPD pattern as shown in figure 2.
6. A process for the preparation of epinastine hydrobromide form II according to any of claims 1 to 5, characterized in that: heating and dissolving epinastine hydrobromide in water, and cooling for crystallization; the temperature for heating and dissolving is 50-100 ℃; the temperature for cooling and crystallizing is 0-40 ℃; the crystallization time of the crystallization is 1 to 5 hours.
7. The method of claim 6, wherein: the dissolving temperature is 80-100 ℃; the crystallization temperature is 10-20 ℃.
8. The method of claim 6, wherein: the crystallization time is 2-3 hours.
9. Use of epinastine hydrobromide crystal form II according to any of claims 1 to 5 for the manufacture of a medicament against allergic diseases; the allergic disease is any one or the combination of allergic rhinitis, urticaria, dermatitis, eczema, cutaneous pruritus, migraine, bin-Hoton syndrome, tension headache, bronchial asthma, myalgia, inflammatory pain, neuralgia, psoriasis, allergic conjunctivitis and the like.
10. An anti-allergic pharmaceutical composition characterized by: the crystal form II of epinastine hydrobromide as claimed in any of claims 1-5 is used as active ingredient, and pharmaceutically acceptable auxiliary materials are added.
CN202211297846.7A 2022-10-20 2022-10-20 Epinastine hydrobromide crystal form II and preparation method thereof Pending CN115448927A (en)

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CN1202111A (en) * 1995-11-14 1998-12-16 贝林格尔·英格海姆公司 Use of epinastine in the treatment of pain
CN1390129A (en) * 1999-11-12 2003-01-08 贝林格尔·英格海姆国际有限公司 Solutions containing epinastine
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