Mianserin hydrochloride monohydrate crystal form I and preparation method thereof

Abstract

The present invention relates to a new crystal form I of mianserin hydrochloride monohydrate and a preparation method thereof, and belongs to the field of pharmaceutical chemistry. In the X-ray powder diffraction pattern of the new crystal form I of mianserin hydrochloride monohydrate of the present invention, the 2θ diffraction angles have characteristic peaks at 8.39, 12.84, 13.84, 14.66, 16.21, 17.61, 19.49, 21.27, 22.36, 25.39, 25.93, and 27.73. In the preparation method of the new crystal form I of mianserin hydrochloride monohydrate of the present invention, no organic solvent is required, and the obtained crystal form is single, and its processing characteristics such as dissolution and efficacy are more stable than those of traditional mixed crystals or amorphous forms.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry and relates to a new crystal form I of mianserin hydrochloride and a preparation method thereof. Background Art

[0002] Mianserin Hydrochloride is a new generation of tetracyclic compounds, which mainly has sedative and antidepressant effects in clinical practice. It was developed by Organon of the Netherlands and launched in 1985. Its antidepressant effect is comparable to various antidepressants currently available, but its anticholinergic side effects are extremely low at therapeutic doses, and it has no significant effect on the cardiovascular system. Long-term use does not damage myocardial contractility and intramyocardial conduction, and it has a wide range of drug compatibility.

[0003] According to the database of the website of the State Food and Drug Administration, mianserin hydrochloride is only produced by Shandong Renhetang Pharmaceutical Co., Ltd., with the approval number of National Medicine Standard H20010440 and the implementation standard of WS1-(X-247)-2004Z-2021.

[0004] Mianserin hydrochloride is chemically known as 1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-α]azepine Hydrochloride, molecular formula is C18H20N2·HCl, CAS number is: 21535-47-7, structural formula is as follows.

[0005]

[0006] The synthetic preparation route of this product is as follows: benzaldehyde and ethanolamine are used as starting materials, and a crude product is obtained through multi-step reactions. The crude product is refined by hydrochloric acid-ethyl acetate to obtain the final product.

[0007]

[0008] The refining process is as follows:

[0009]

[0010] Under the existing refining process, some products are mixed crystals or amorphous, or their purification and crystallization process uses organic solvents, and the recovery and treatment of organic solvents consumes a lot of manpower and material resources and is very likely to cause environmental pollution and occupational injuries. In addition, in the mianserin hydrochloride products prepared according to the existing method, there will be impurities exceeding the provisions of the relevant guidelines, and most of the products are amorphous, which brings certain instability to the efficacy and processing. Summary of the invention

[0011] The main purpose of the present invention is to provide a new crystal form I of mianserin hydrochloride monohydrate, which has the characteristics of high stability, high purity and few impurities, and the preparation process is simple, without the need to use organic solvents, effectively saving manpower and material resources and avoiding environmental pollution.

[0012] The present invention adopts the following technical solutions to achieve the above purpose:

[0013] A new crystal form I of mianserin hydrochloride monohydrate, wherein in an X-ray powder diffraction pattern of the new crystal form I of the monohydrate, 2θ diffraction angles have characteristic absorption peaks at 8.39, 12.84, 13.84, 14.66, 16.21, 17.61, 19.49, 21.27, 22.36, 25.39, 25.93, and 27.73.

[0014] The above-mentioned new monohydrate crystal form I has the following Figure 1 The X-ray powder diffraction peak pattern is shown.

[0015] Furthermore, the above-mentioned new monohydrate form I has thermal absorption peaks at 134.77±3°C, 270.66±3°C, 289.60±3°C and 323.86±3°C according to differential scanning calorimetry analysis.

[0016] The present invention provides a method for preparing the above-mentioned new crystal form I of mianserin hydrochloride monohydrate, which mainly comprises the following steps:

[0017] Add purified water to mianserin hydrochloride, stir and heat to 90-95°C to dissolve it, put it into cold hydrazine and mechanically stir to cool to 0-10°C, stir for 30-50 minutes to precipitate crystals, filter, rinse the filter cake with ice water, and dry it naturally at room temperature 25°C for 12-18 hours to obtain new crystal form I.

[0018] The mass-volume ratio of mianserin hydrochloride to water is 1:(8-10), g / mL.

[0019] The present invention provides the use of the new monohydrate crystal form I, that is, it can be used to prepare antidepressant drugs.

[0020] The present invention also provides a pharmaceutical composition, which is prepared from the above-mentioned new monohydrate crystal form I and pharmaceutical excipients.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] 1. The new crystal form I of mianserin hydrochloride monohydrate prepared by the present invention has high purity, which can reach more than 99.5%, and low impurity content, with the maximum content of a single impurity not exceeding 0.1%.

[0023] 2. The new crystal form I of mianserin hydrochloride monohydrate prepared by the present invention has a single crystal form, and its processing characteristics such as dissolution and efficacy are more stable than those of traditional mixed crystals or amorphous forms.

[0024] 3. The crystal transformation process of the present invention does not use any organic solvents, does not introduce impurities, is green and environmentally friendly, is more operator-friendly in mass production, avoids contact with large amounts of organic solvents, and has a higher safety factor.

[0025] 4. In the preparation method of the present invention, water is used as a solvent in the mianserin hydrochloride crystal conversion process, which overcomes the technical prejudice that water is not used in the traditional mianserin hydrochloride crystal conversion process.

[0026] 5. The recovery rate of the new crystal form I of mianserin hydrochloride monohydrate prepared by the present invention is significantly higher than that of the product obtained by the existing purification and crystallization process. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Attached Figure 1 : X-ray powder diffraction pattern of new crystal form I of mianserin hydrochloride monohydrate;

[0028] Attached Figure 2 : Differential scanning calorimetry spectrum of new crystalline form Ⅰ of mianserin hydrochloride monohydrate;

[0029] Attached Figure 3 : XRPD peak characterization data of new crystal form I of mianserin hydrochloride monohydrate-1;

[0030] Attached Figure 4 : XRPD peak characterization data of new crystalline form Ⅰ of mianserin hydrochloride monohydrate-2. DETAILED DESCRIPTION

[0031] The present invention is further explained below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. After reading the present invention, various equivalent modifications to the present invention by those skilled in the art all fall within the scope of protection of the claims of this application.

[0032] Example 1

[0033] In a 250mL flask, 10g of mianserin hydrochloride was weighed and 100mL of purified water was added. The mixture was stirred and heated to 95°C to dissolve the mixture. The mixture was placed in cold hydrazine and mechanically stirred to cool to 0°C. The mixture was stirred for 30 minutes to precipitate crystals. The crystals were filtered and rinsed with ice water. The filter cake was dried naturally at room temperature of 25°C for 12 hours to obtain 8.6g of the product.

[0034] Example 2

[0035] In a 250mL flask, 10g of mianserin hydrochloride was weighed and added. 80mL of purified water was added, stirred and heated to 90°C to dissolve it. The mixture was placed in cold hydrazine and mechanically stirred to cool to 10°C. The mixture was stirred for 50 minutes to precipitate crystals. The crystals were filtered and rinsed with ice water. The filter cake was dried naturally at room temperature of 25°C for 18 hours to obtain 8.3g of the product.

[0036] Comparative Example 1

[0037] In a 250mL flask, 10g of mianserin hydrochloride was weighed and added. 90mL of isopropanol was added, stirred and heated to reflux (83°C). If the solution was insoluble, 10g of isopropanol was added and continued heating was performed to dissolve the solution. The solution was placed in cold hydrazine and mechanically stirred to cool to below -10°C to precipitate crystals. The solution was kept warm and stirred for 2h, and filtered. The filter cake was rinsed with isopropanol and dried in a forced air drying oven at 60°C for 4h to obtain 8.4g of the product.

[0038] Comparative Example 2

[0039] In a 250mL flask, 10g of mianserin hydrochloride was weighed and added. 150mL of chloroform was added, stirred and heated to reflux (62°C). If the solution is insoluble, recover it while hot. The filtrate was recovered and placed in cold hydrazine with mechanical stirring to cool to below -20°C. Crystals were precipitated. The mixture was stirred for 2h at this temperature and filtered. The filter cake was rinsed with chloroform and dried in a forced air drying oven at 60°C for 4h to obtain 7.1g of the product.

[0040] Comparative Example 3

[0041] In a 250mL flask, 10g of mianserin hydrochloride was weighed and 90mL of THF was added, followed by stirring and heating to reflux (68°C). If the solution is insoluble, 10mL of water was added, and the solution was placed in cold hydrazine and mechanically stirred to cool to below -10°C. The solution was stirred for 2h to precipitate crystals, and the filter cake was rinsed with THF and dried in a forced air drying oven at 60°C for 4h to obtain 7.6g of the product.

[0042] 1. Analysis of the number of crystal water

[0043] According to the comparison of the drying loss and water content of different samples, it was determined that the amount of crystal water per molecule of mianserin in the crystal forms of Example 1 and Example 2 was 1.

[0044] Table 1 Comparison of drying weight loss and moisture content of different samples

[0045] project Loss on drying (%) Moisture (%) Example 1 0.08 5.75 Example 2 0.09 5.74

[0046] 2. Crystal form analysis

[0047] Take an appropriate amount of the crystals obtained in Example 1, and the analysis method is the X-ray diffraction method of Part IV 0451 of the 2020 edition of the Chinese Pharmacopoeia, and the crystal form analysis of the crystals obtained in Example 1 is performed using an X-ray powder diffractometer.

[0048] Self-attached Figure 1 It can be seen that the X-ray powder diffraction pattern of the crystal form obtained in Example 1 has the following main characteristic absorption peaks at 2θ: 8.39, 12.84, 13.84, 14.66, 16.21, 17.61, 19.49, 21.27, 22.36, 25.39, 25.93, and 27.73.

[0049] 3. Differential Scanning Calorimetry

[0050] The crystals obtained in Example 1 were analyzed by differential scanning calorimetry. The analysis method was differential scanning calorimetry under the item of thermal analysis in Part IV of the 2020 edition of the Chinese Pharmacopoeia 0661. The differential scanning calorimetry endothermic peaks were at 134.77±3°C, 270.66±3°C, 289.60±3°C and 323.86±3°C.

[0051] IV. Determination of the content, impurities and recovery rate of the new crystal form I of mianserin hydrochloride of the present invention

[0052] The crystals obtained in Example 1, Example 2, Comparative Example 1, Comparative Example 2 and Comparative Example 3 of the present invention were measured according to the EP9.0 mianserin hydrochloride related substance determination method. The results are shown in Table 2.

[0053] Table 2 Comparison of purity and impurity content of different samples

[0054]

[0055]

[0056] As can be seen from Table 1, the crystals obtained in Example 1 and Example 2 have a high purity, both above 99.5%; the impurity content is low, with the highest single impurity content being 0.09%, both less than the identification limit of 0.10%, and the recovery rate level is above 80%. The crystals obtained in Example 1 and Example 2 are overall superior to the crystals obtained in Comparative Examples 1-3.

[0057] 4. Stability test

[0058] 1. Accelerated testing

[0059] The crystals obtained by the preparation methods described in Example 1, Example 2 and Comparative Example 1 were placed at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 6 months. Samples were taken at the 0th month, the 3rd month and the 6th month to examine the related substances and their contents.

[0060] Take the crystals obtained by the preparation methods described in Example 1, Example 2, and Comparative Example, and prepare tablets according to the following preparation process: weigh 30g of mianserin hydrochloride, 48g of starch, 18g of microcrystalline cellulose, and 3g of sodium carboxymethyl starch, pass through an 80-mesh sieve, mix well, then add 28g of 10% povidone K30 ethanol solution, granulate with a 20-mesh sieve, dry at 60°C until the moisture content is 3.0%, granulate with a 20-mesh sieve, add 1.3g of magnesium stearate, compress into 1000 tablets, and film-coat to obtain tablets. The obtained tablets are placed at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 6 months, and samples are taken at the 0th month, the 3rd month, and the 6th month to investigate the dissolution of the tablets.

[0061] Table 3 Accelerated stability test results of the crystal form

[0062]

[0063] 2. Long-term trials

[0064] The crystals obtained by the preparation methods described in Example 1, Example 2 and Comparative Example 1 were placed at a temperature of 25°C ± 2°C and a relative humidity of 60% ± 5% for 12 months. Samples were taken at the 0th month, the 3rd month, the 6th month, the 9th month and the 12th month to examine the related substances and their contents.

[0065] Take the crystals obtained by the preparation methods described in Example 1, Example 2, and Comparative Example 1, and prepare tablets according to the following preparation process: weigh 30g of mianserin hydrochloride, 48g of starch, 18g of microcrystalline cellulose, and 3g of sodium carboxymethyl starch, pass through an 80-mesh sieve, mix well, then add 28g of 10% povidone K30 ethanol solution, granulate through a 20-mesh sieve, dry at 60°C until the moisture content is 3.0%, granulate through a 20-mesh sieve, add 1.3g of magnesium stearate, compress into 1000 tablets, and film-coat to obtain tablets. The obtained tablets are placed at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 6 months, and samples are taken at the 0th month, the 3rd month, the 6th month, the 9th month, and the 12th month, respectively, to investigate the dissolution of the tablets.

[0066] Table 4 Long-term stability test results of the crystal form

[0067]

Claims

1. Mianserin hydrochloride Hydrate crystal form I, characterized in that In the X-ray powder diffraction pattern of the crystal form I, the 2θ diffraction angles have characteristic absorption peaks at 8.39, 12.84, 13.84, 14.66, 16.21, 17.61, 19.49, 21.27, 22.36, 25.39, 25.93, and 27.73, and the accuracy of the 2θ value is ±0.2; the crystal form I is analyzed by differential scanning calorimetry and has thermal absorption peaks at 134.77±3°C, 270.66±3°C, 289.60±3°C, and 323.86±3°C; The preparation method of the mianserin hydrochloride monohydrate crystal form I comprises the following steps: Purified water was added to mianserin hydrochloride, the mixture was stirred and heated to 90-95°C to dissolve, the mixture was placed in cold hydrazine and mechanically stirred to cool to 0-10°C, the mixture was stirred for 30-50 minutes to precipitate crystals, the mixture was filtered, the filter cake was rinsed with ice water, and the mixture was naturally dried at room temperature of 25°C for 12-18 hours to obtain Form I; wherein the mass-volume ratio of mianserin hydrochloride to water was 1:(8-10), g / mL.

2. Use of the mianserin hydrochloride monohydrate crystal form I as claimed in claim 1 in the preparation of antidepressant drugs.

3. A pharmaceutical composition prepared from the mianserin hydrochloride crystal form I described in claim 1 and pharmaceutical excipients.

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