Nalfurafine hydrochloride crystal form and preparation method thereof

Abstract

The invention relates to a nalfurafine hydrochloride crystal form and a preparation method thereof.The X-ray powder diffraction pattern of the nalfurafine hydrochloride crystal form has characteristic peaks at the 2 theta angles of 6.9 degrees, 10.5 degrees, 15.3 degrees, 16.7 degrees and 20.2 degrees, the preparation method comprises the following steps that nalfurafine free alkali is dissolved in absolute ethyl alcohol, hydrochloric acid is dropwise added while stirring is conducted at the room temperature, after the hydrochloric acid is dropwise added, stirring is conducted at the room temperature, and then the nalfurafine hydrochloride crystal form is obtained; continuously stirring to separate out crystals, and filtering, washing and drying to obtain a nalfurafine hydrochloride crystal form; the nalfurafine hydrochloride crystal form provided by the invention has a unique X-ray powder diffraction pattern different from the existing known crystal form, has good physical and chemical stability, is beneficial to long-term storage of drugs, and has the advantages of simple process, convenience in operation, room-temperature reaction, mild conditions, no need of special equipment, low production cost and environmental friendliness; and the product has high crystal form purity and chemical purity and good reproducibility, and is suitable for industrial large-scale production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry crystallization, in particular to a nalfurafine hydrochloride crystal form and a preparation method thereof. BACKGROUND

[0002] Nalfurafine hydrochloride is a highly selective kappa-opioid receptor agonist, mainly used for treating pruritus in hemodialysis patients. US7803942 reports that nalfurafine hydrochloride has three crystal forms A, B and C, and discloses the preparation method of the related crystal forms; US8816084 reports a nalfurafine hydrochloride X crystal form and a preparation method thereof. The preparation processes of the crystal forms in the above patents are complicated and lengthy, and need to use a mixed system of multiple organic solvents or use anhydrous hydrochloric acid organic solution as a salting reagent, which is not suitable for mass production and is not conducive to environmental protection. There are crystal forms or amorphous forms of nalfurafine hydrochloride in the prior art, which have poor physical and chemical properties, and many have problems such as poor stability, easy to convert crystals or unsatisfactory solubility.

[0003] Therefore, the present application proposes a nalfurafine hydrochloride crystal form and a preparation method thereof to solve the above problems. SUMMARY

[0004] The technical problem to be solved by the present application is to provide a nalfurafine hydrochloride crystal form with good stability, suitable for development and production of pharmaceutical preparations, and a preparation method thereof.

[0005] To solve the above technical problems, the technical scheme of the present application is as follows: a nalfurafine hydrochloride crystal form and a preparation method thereof, the innovation point of which is that the X-ray powder diffraction pattern of the nalfurafine hydrochloride crystal form has characteristic peaks at 2θ angles of 6.9°, 10.5°, 15.3°, 16.7° and 20.2°.

[0006] Further, the X-ray powder diffraction pattern of the nalfurafine hydrochloride crystal form is as shown in Figure 1 .

[0007] The preparation method of the above nalfurafine hydrochloride crystal form comprises the following steps: dissolving nalfurafine free base in anhydrous ethanol, adding hydrochloric acid dropwise under stirring at room temperature, continuing to stir after the addition of hydrochloric acid is completed to precipitate crystals, and then filtering, washing and drying to obtain the nalfurafine hydrochloride crystal form.

[0008] Further, the use amount ratio of the nalfurafine free base to anhydrous ethanol is 1g:5-20ml.

[0009] Further, the use amount ratio of the nalfurafine free base to anhydrous ethanol is 1g:10ml.

[0010] Further, the stirring speed is 100-500 rpm.

[0011] Further, the stirring speed is 300 rpm.

[0012] Further, the time for continuing stirring is greater than 12 hours.

[0013] Further, the time for continuing stirring is 18-24 hours.

[0014] Further, the ratio of the amount of nafurelin free base to hydrochloric acid is 1 g:0.2 ml.

[0015] The present application has the following advantages: (1) The crystal form of nafurelin hydrochloride of the present application has a unique X-ray powder diffraction pattern different from the known crystal forms, and the crystal form shows good physical and chemical stability, which is beneficial to long-term storage of the drug.

[0016] (2) The preparation method of the crystal form of nafurelin hydrochloride of the present application uses anhydrous ethanol as a solvent, and has the advantages of simple process, convenient operation, room temperature reaction, mild conditions, no special equipment, low production cost, environmental friendliness, high purity of the crystal form and chemical purity of the product, good reproducibility, and suitability for industrialized production.

[0017] (3) The crystal form of nafurelin hydrochloride prepared by the preparation method of the present application is a white solid with good properties and good flowability, which is convenient for subsequent preparation processing. BRIEF DESCRIPTION OF DRAWINGS

[0018] The present application will be further described in detail below in combination with the drawings and specific embodiments.

[0019] Figure 1 The X-ray powder diffraction pattern of the crystal form of nafurelin hydrochloride of the present application.

[0020] Figure 2 The high performance liquid chromatogram of the crystal form of nafurelin hydrochloride prepared in Example 2 of the present application. DETAILED DESCRIPTION

[0021] In order to further illustrate the technical means and effects adopted by the present application to achieve the predetermined object, the specific embodiments, structures, features and effects according to the present application will be described in detail below in combination with the drawings and preferred embodiments.

[0022] Example 1 This embodiment provides a crystal form of nafurelin hydrochloride, and the X-ray powder diffraction pattern of the crystal form of nafurelin hydrochloride is as shown in Figure 1As shown in the X-ray powder diffraction pattern, there are characteristic peaks at 2θ angles of 6.9°, 10.5°, 15.3°, 16.7°, and 20.2°.

[0023] The nafuraftine hydrochloride crystal form exhibits good physical and chemical stability, which is beneficial for long-term storage of the drug.

[0024] Example 2 This example provides a preparation method of the nafuraftine hydrochloride crystal form of Example 1, which comprises the following steps: 10.00 g of nafuraftine free base is added to a 250 ml reaction bottle, 100 ml of anhydrous ethanol is added, mechanical stirring is started, the stirring speed is 300 rpm, after dissolution, 2 ml of hydrochloric acid is added dropwise under stirring at room temperature, after the completion of the addition of hydrochloric acid, the reaction mixture first forms a colloidal mixture, and the colloidal mixture is converted into white solid precipitation after continuous stirring for 20 hours, suction filtration is performed, the filter cake is washed with 10 ml of anhydrous ethanol, suction filtration is performed until no drops are hung, and the filter cake is dried under reduced pressure to obtain 10.12 g of white crystalline powder, i.e., the nafuraftine hydrochloride crystal form, with a yield of 94.0%.

[0025] The high-performance liquid chromatogram of the nafuraftine hydrochloride crystal form prepared in this example is shown in Figure 2 .

[0026] Example 3 This example provides a preparation method of the nafuraftine hydrochloride crystal form of Example 1, which comprises the following steps: 10.00 g of nafuraftine free base is added to a 250 ml reaction bottle, 150 ml of anhydrous ethanol is added, mechanical stirring is started, the stirring speed is 250 rpm, after dissolution, 2 ml of hydrochloric acid is added dropwise under stirring at room temperature, after the completion of the addition of hydrochloric acid, the reaction mixture first forms a colloidal mixture, and the colloidal mixture is converted into white solid precipitation after continuous stirring for 17 hours, suction filtration is performed, the filter cake is washed with 10 ml of anhydrous ethanol, suction filtration is performed until no drops are hung, and the filter cake is dried under reduced pressure to obtain 9.68 g of white crystalline powder, i.e., the nafuraftine hydrochloride crystal form, with a yield of 89.9%.

[0027] Example 4 This example provides a preparation method of the nafuraftine hydrochloride crystal form of Example 1, which comprises the following steps: 10.00 g of nafuraftine free base is added to a 250 ml reaction bottle, 100 ml of anhydrous ethanol is added, mechanical stirring is started, the stirring speed is 300 rpm, after dissolution, 2 ml of hydrochloric acid is added dropwise under stirring at room temperature, after the completion of the addition of hydrochloric acid, the reaction mixture first forms a colloidal mixture, and the colloidal mixture is converted into white solid precipitation after continuous stirring for 18 hours, suction filtration is performed, the filter cake is washed with 10 ml of anhydrous ethanol, suction filtration is performed until no drops are hung, and the filter cake is dried under reduced pressure to obtain 10.00 g of white crystalline powder, i.e., the nafuraftine hydrochloride crystal form, with a yield of 92.9%.

[0028] Example 5 The present example provides a preparation method of the nafurafline hydrochloride crystal form of Example 1, comprising the following steps: 10.00 g of nafurafline free base is added to a 250 ml reaction bottle, 50 ml of anhydrous ethanol is added, mechanical stirring is started, the stirring speed is 100 rpm, after the solution is clarified, 2 ml of hydrochloric acid is added dropwise under stirring at room temperature, after the addition of hydrochloric acid is completed, the reaction mixture first forms a colloidal mixture, stirring is continued for 13 hours, the colloidal mixture is converted into white solid precipitation, suction filtration is performed, the filter cake is washed with 10 ml of anhydrous ethanol, suction filtration is performed until no drops are hung, the filter cake is dried under reduced pressure, 9.23 g of white crystalline powder, i.e., nafurafline hydrochloride crystal form, is obtained, and the yield is 85.8%.

[0029] Example 6 The present example provides a preparation method of the nafurafline hydrochloride crystal form of Example 1, comprising the following steps: 10.00 g of nafurafline free base is added to a 250 ml reaction bottle, 100 ml of anhydrous ethanol is added, mechanical stirring is started, the stirring speed is 300 rpm, after the solution is clarified, 2 ml of hydrochloric acid is added dropwise under stirring at room temperature, after the addition of hydrochloric acid is completed, the reaction mixture first forms a colloidal mixture, stirring is continued for 24 hours, the colloidal mixture is converted into white solid precipitation, suction filtration is performed, the filter cake is washed with 10 ml of anhydrous ethanol, suction filtration is performed until no drops are hung, the filter cake is dried under reduced pressure, 10.26 g of white crystalline powder, i.e., nafurafline hydrochloride crystal form, is obtained, and the yield is 95.3%.

[0030] Example 7 The present example provides a preparation method of the nafurafline hydrochloride crystal form of Example 1, comprising the following steps: 10.00 g of nafurafline free base is added to a 250 ml reaction bottle, 100 ml of anhydrous ethanol is added, mechanical stirring is started, the stirring speed is 300 rpm, after the solution is clarified, 2 ml of hydrochloric acid is added dropwise under stirring at room temperature, after the addition of hydrochloric acid is completed, the reaction mixture first forms a colloidal mixture, stirring is continued for 25 hours, the colloidal mixture is converted into white solid precipitation, suction filtration is performed, the filter cake is washed with 10 ml of anhydrous ethanol, suction filtration is performed until no drops are hung, the filter cake is dried under reduced pressure, 10.27 g of white crystalline powder, i.e., nafurafline hydrochloride crystal form, is obtained, and the yield is 95.4%.

[0031] Example 8 The present example provides a preparation method of the nafurafline hydrochloride crystal form of Example 1, comprising the following steps: 10.00 g of nafurafline free base is added to a 250 ml reaction bottle, 200 ml of anhydrous ethanol is added, mechanical stirring is started, the stirring speed is 80 rpm, after the solution is clarified, 2 ml of hydrochloric acid is added dropwise under stirring at room temperature, after the addition of hydrochloric acid is completed, the reaction mixture first forms a colloidal mixture, stirring is continued for 15 hours, the colloidal mixture is converted into white solid precipitation, suction filtration is performed, the filter cake is washed with 10 ml of anhydrous ethanol, suction filtration is performed until no drops are hung, the filter cake is dried under reduced pressure, 9.21 g of white crystalline powder, i.e., nafurafline hydrochloride crystal form, is obtained, and the yield is 85.6%.

[0032] Comparative Example 1 The comparative example provides a preparation method comprising the following steps: adding 10.00 g of nalfurafine free base into a 250 ml reaction bottle, adding 150 ml of acetone, starting mechanical stirring at a speed of 300 rpm, after the solution is clear, adding 2 ml of hydrochloric acid dropwise under stirring at room temperature, continuing to stir for 24 hours after the hydrochloric acid is added, the reaction solution is an oil, and no solid is precipitated.

[0033] Comparative Example 2 The comparative example provides a preparation method comprising the following steps: adding 10.00 g of nalfurafine free base into a 250 ml reaction bottle, adding 80 ml of methanol, starting mechanical stirring at a speed of 300 rpm, after the solution is clear, adding 2 ml of hydrochloric acid dropwise under stirring at room temperature, continuing to stir for 16 hours after the hydrochloric acid is added, the reaction solution is clear, and no solid is precipitated.

[0034] Comparative Example 3 The comparative example provides a preparation method comprising the following steps: adding 10.00 g of nalfurafine free base into a 250 ml reaction bottle, adding 150 ml of isopropyl alcohol, starting mechanical stirring at a speed of 300 rpm, after the solution is clear, adding 2 ml of hydrochloric acid dropwise under stirring at room temperature, continuing to stir for 38 hours after the hydrochloric acid is added, the reaction solution is a colloid, and no solid is precipitated.

[0035] The above is only a preferred embodiment of the present application, and does not limit the present application in any form. Although the present application has been disclosed as above, it is not intended to limit the present application. Any person skilled in the art can make some changes or modifications to the above disclosed technical content to obtain equivalent embodiments with equivalent changes, without departing from the technical solution of the present application. Any modification, change, and modification of the above embodiments, which does not depart from the technical solution of the present application, are still within the scope of the present application.

Claims

1. A crystalline form of nafuraftine hydrochloride characterized by: The X-ray powder diffraction pattern of the nafurafline hydrochloride crystal form has characteristic peaks at 2θ angles of 6.9°, 10.5°, 15.3°, 16.7°, and 20.2°.

2. The nafuraftine hydrochloride crystalline form of claim 1, characterized in that: The X-ray powder diffraction pattern of the nafurafline hydrochloride crystal form is shown in Figure 1.

3. A process for preparing the nafurafline hydrochloride crystalline form of claim 1, characterized in that: The method comprises the following steps: The nafurafline free base is dissolved in anhydrous ethanol, hydrochloric acid is added dropwise under stirring at room temperature, and after the addition of the hydrochloric acid is completed, stirring is continued to precipitate crystals, and after filtration, washing, and drying, nafurafline hydrochloride crystal form is obtained.

4. A process for preparing the nafurafline hydrochloride crystalline form according to claim 3, characterized in that: The use amount ratio of the nafurafline free base to anhydrous ethanol is 1g:5-20ml.

5. A process for preparing the nafurafline hydrochloride crystalline form according to claim 4, characterized in that: The use amount ratio of the nafurafline free base to anhydrous ethanol is 1g:10ml.

6. A process for preparing the nafurafline hydrochloride crystalline form of claim 3, characterized in that: The stirring speed is 100-500rpm.

7. A process for preparing the nafurafline hydrochloride crystalline form according to claim 7, characterized in that: The stirring speed is 300rpm.

8. A process for preparing the nafurafline hydrochloride crystalline form of claim 3, characterized in that: The time for continuing stirring is greater than 12 hours.

9. A process for preparing the nafurafline hydrochloride crystalline form of claim 9, characterized in that: The time for continuing stirring is 18-24 hours.

10. A process for preparing the nafurafline hydrochloride crystalline form of claim 3, characterized in that: The use amount ratio of the nafurafline free base to hydrochloric acid is 1g:0.2ml.

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