Dexhanol crystal form as well as preparation method and application thereof

Abstract

The invention provides a dexhanol crystal form as well as a preparation method and application thereof, and belongs to the technical field of medical crystallization. The invention provides a crystal form I of dextroborneol, and in an X-ray powder diffraction pattern of the crystal form, characteristic peaks exist at 2theta diffraction angles of 7.60 + / -0.2 degrees, 8.35 + / -0.2 degrees, 15.25 + / -0.2 degrees, 17.55 + / -0.2 degrees and 30.70 + / -0.2 degrees. The dextroborneol crystal form I provided by the invention has excellent reproducibility, stability and solubility, meets the requirements of preparations, and has good development and application prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical crystallization, and particularly relates to a dextroborneol crystal form, a preparation method and uses thereof. Background Art

[0002] Borneol, also known as d-borneol, has the following structural formula:

[0003]

[0004] Dextroborneol, also known as natural borneol, is a colorless, transparent or white flaky solid found in a wide range of natural plants, such as mugwort and camphor. It has numerous pharmacological effects, including anti-inflammatory, analgesic, and anti-cerebral ischemia, and therefore holds significant value in the pharmaceutical field. Dextroborneol is the main ingredient in the concentrated solution for injection of edaravone and dextroborneol (CN200980100527.9). It is also used as a flavoring and fragrance, and as an important chemical raw material, in a wide range of applications in industries such as food, tobacco, and daily chemicals.

[0005] In drug development, the crystal form of a compound significantly influences a drug's stability, solubility, bioavailability, and efficacy. Different crystal forms may exhibit varying physicochemical properties, thus impacting drug performance. For example, some crystal forms may exhibit improved solubility, potentially enhancing drug bioavailability, while others may possess greater stability, potentially extending a drug's shelf life. Therefore, developing new crystal forms is crucial for improving drug performance and efficacy.

[0006] To date, no crystalline forms of borneol have been reported. Therefore, developing a simple, efficient, environmentally friendly, and controllable method for preparing crystalline forms of borneol is of great practical significance for improving the quality and performance of drugs. Summary of the Invention

[0007] The object of the present invention is to provide a crystalline form of dextroborneol and a preparation method and use thereof.

[0008] The present invention provides a borneol crystal form. In an X-ray powder diffraction spectrum of the crystal form, characteristic absorption peaks are present at 2θ diffraction angles of 7.60±0.2°, 8.35±0.2°, 15.25±0.2°, 17.55±0.2° and 30.70±0.2°.

[0009] Furthermore, in the X-ray powder diffraction spectrum of the crystal form, the peak area percentage of the characteristic peak at 2θ diffraction angle is:

[0010] Diffraction angle 2θ Peak area percentage % 7.60±0.2° 6.5％ 8.35±0.2° 4.7％ 15.25±0.2° 100.0％ 17.55±0.2° 27.2％ 30.70±0.2° 2.0％ .

[0011] Furthermore, the X-ray powder diffraction spectrum of the crystal form is as follows Figure 1 shown.

[0012] The present invention also provides a method for preparing the above-mentioned borneol crystal form, which is selected from method 1, method 2 or method 3:

[0013] Method 1: dissolving borneol in a water-miscible organic solvent to form a borneol solution, then mixing with water, crystallizing, filtering, and drying to obtain the product;

[0014] Method 2: Mix dextroborneol with an alkane solvent, heat to dissolve, crystallize, filter, and dry to obtain the product;

[0015] Method 3: Mix dextroborneol with water to form a suspension, then introduce saturated steam, crystallize the evaporated oil-water mixture, filter, and dry to obtain the product.

[0016] The "oil-water mixture" in the present invention refers to a mixed system formed by mixing dextroborneol (oil phase) and water.

[0017] Furthermore, in method 1, the organic solvent is methanol, ethanol, n-propanol, isopropanol, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide or acetone; the usage ratio of dextroborneol to the organic solvent is 10 g: 1 to 10 mL; and the crystallization conditions are: crystallization at 10 to 40° C. for 1 to 5 hours.

[0018] Furthermore, in method 2, the alkane solvent is n-hexane; the usage ratio of borneol to the alkane solvent is 10 g: 1-10 mL; the temperature of the heated dissolution is 50-70° C.; and the crystallization conditions are: crystallization at -50-10° C. for 2-48 h.

[0019] Furthermore, in method 3, the ratio of borneol to water is 10 g: 1-10 mL; and the crystallization conditions are: crystallization at 0-30° C. for 2-48 h.

[0020] The present invention also provides a pharmaceutical composition, which is a preparation prepared by taking the above-mentioned dextroborneol crystal form as an active ingredient and adding commonly used pharmaceutical excipients.

[0021] The present invention also provides use of the above-mentioned borneol crystal form in preparing anti-inflammatory, analgesic and anti-cerebral ischemic drugs.

[0022] The present invention has achieved the following beneficial effects:

[0023] The present invention provides a crystalline form I of dextroborneol. The X-ray powder diffraction pattern of this crystalline form shows characteristic peaks at 2θ diffraction angles of 7.60±0.2°, 8.35±0.2°, 15.25±0.2°, 17.55±0.2°, and 30.70±0.2°. The crystalline form I of dextroborneol provided by the present invention has excellent reproducibility, stability, and solubility, meets formulation requirements, and has good development and application prospects.

[0024] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0025] The following is a further detailed description of the present invention through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-mentioned content of the present invention fall within the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The X-ray powder diffraction pattern of the crystalline form of borneol obtained in Example 1 is shown.

[0027] Figure 2 This is the X-ray powder diffraction pattern of Example 2.

[0028] Figure 3 This is the X-ray powder diffraction pattern of Example 3.

[0029] Figure 4 This is the X-ray powder diffraction pattern of Example 4.

[0030] Figure 5 This is the X-ray powder diffraction pattern of Comparative Example 1.

[0031] Figure 6 This is the X-ray powder diffraction pattern of Comparative Example 2. DETAILED DESCRIPTION

[0032] The raw materials and equipment used in the present invention are all known products and are obtained by purchasing commercially available products.

[0033] “V / m” in the Examples or Comparative Examples of the present invention represents “mL / g”.

[0034] The testing methods of the X-ray powder diffraction test and melting point test of the borneol crystal form in the Examples of the present invention and the Comparative Examples are as follows:

[0035] (1) X-ray powder diffraction test

[0036] Testing instrument: X-ray diffractometer DX-2700

[0037] Test method: Scanning range: 3°~53°; Scanning step: 0.05°.

[0038] (2) Melting point test

[0039] Testing instrument: Melting point instrument MP30

[0040] Test method: ① Grind the dried sample in a mortar and put it into a capillary. With the help of a clean glass tube, place it vertically on a watch glass. Insert the capillary from the top and let it fall freely. Repeat several times to make the powder gather tightly at the sealed end of the capillary. The filling height is about 3mm. ③ Adjust the instrument temperature to 195℃ and the heating rate to 3℃ / min. After the initial temperature of the instrument is constant, insert the capillary containing the sample into the measuring hole of the instrument for measurement. After the instrument displays the initial melting temperature and the final melting temperature, record the readings. Perform three parallel measurements and take the average value.

[0041] Example 1. Preparation of borneol crystal form

[0042] 10.0 g of borneol was added to 3 V / m of n-heptane, heated to 60°C, and stirred until completely dissolved. The mixture was then cooled to -20°C for crystallization for 2 hours. The mixture was filtered and dried under vacuum to obtain borneol. X-ray powder diffraction analysis confirmed the product to be borneol Form I. The product purity was 99.95%, and the process yield was 89.5%.

[0043] In the X-ray powder diffraction pattern of borneol crystal form I, the 2θ diffraction angles have characteristic peaks at 7.60±0.2°, 8.35±0.2°, 15.25±0.2°, 17.55±0.2° and 30.70±0.2°. Figure 1 The melting point is 207-208°C.

[0044] Example 2, Preparation of borneol crystal form

[0045] 10.0 g of borneol was added to 1.0 V / m ethanol and stirred to dissolve. The mixture was then added dropwise to 10 V / m purified water to precipitate a solid. The solid was stirred and crystallized for 2 hours, filtered, and vacuum dried to obtain borneol, which was confirmed by X-ray powder diffraction to be borneol Form I. The product purity was 99.80%, and the process yield was 90.6%.

[0046] In the X-ray powder diffraction pattern of borneol crystal form I, the 2θ diffraction angles have characteristic peaks at 7.60±0.2°, 8.35±0.2°, 15.25±0.2°, 17.55±0.2° and 30.70±0.2°. Figure 2 The melting point is 206-208°C.

[0047] Example 3, Preparation of borneol crystal form

[0048] 10.0 g of borneol was added to 1.0 V / m of tetrahydrofuran and stirred to dissolve. Purified water (10 V / m) was slowly added dropwise to the system to precipitate a solid. The solid was stirred and crystallized for 2 hours, filtered, and vacuum-dried to obtain borneol, which was confirmed by X-ray powder diffraction to be borneol Form I. The product purity was 99.75%, and the process yield was 92.1%.

[0049] In the X-ray powder diffraction pattern of borneol crystal form I, the 2θ diffraction angles have characteristic peaks at 7.60±0.2°, 8.35±0.2°, 15.25±0.2°, 17.55±0.2° and 30.70±0.2°. Figure 3 The melting point is 207-209°C.

[0050] Example 4, Preparation of borneol crystal form

[0051] 10.0 g of borneol was added to 10 V / m of purified water and stirred to form a suspension. Saturated steam was continuously introduced into the system. The resulting oil-water mixture was cooled by 15°C and allowed to stand for 24 hours to precipitate a solid. The solid was then filtered and vacuum-dried to obtain borneol, which was confirmed by X-ray powder diffraction to be borneol Form I. The product had a purity of 99.78% and a process yield of 91.3%.

[0052] In the X-ray powder diffraction pattern of borneol crystal form I, the 2θ diffraction angles have characteristic peaks at 7.60±0.2°, 8.35±0.2°, 15.25±0.2°, 17.55±0.2° and 30.70±0.2°. Figure 4 The melting point is 205-208°C.

[0053] The results of Examples 1 to 4 show that the purity and yield of the borneol crystal form I obtained under the conditions of Example 1 are the highest, with a purity of 99.95% and a yield of 89.5%.

[0054] The following comparative samples are prepared by comparative examples.

[0055] Comparative Example 1: Preparation of borneol crystal form

[0056] 10.0 g of borneol was added to 3 V / m petroleum ether (60-90° C.), crystallized at 10° C. for 15 h, filtered, and vacuum-dried to obtain borneol; the product purity was 98.21%, and the process yield was 77.06%.

[0057] In the X-ray powder diffraction pattern of the crystalline form of dexamethasone, the 2θ diffraction angles have characteristic peaks at 7.60±0.2°, 8.30±0.2°, 9.70±0.2°, 10.90±0.2°, 14.36±0.2°, 15.25±0.2°, 16.24±0.2°, 17.55±0.2°, 20.95±0.2° and 30.80±0.2°. Figure 5 The melting point is 203-205°C.

[0058] Comparative Example 2: Preparation of borneol crystal form

[0059] Referring to the method of Example 1 in patent application document CN119039104A, borneol crystals were obtained by recrystallization using n-heptane as the solvent. The product purity was 98.83% and the process yield was 92.6%.

[0060] In the X-ray powder diffraction pattern of the crystalline form of dexamethasone, the 2θ diffraction angles have characteristic peaks at 7.60±0.2°, 8.40±0.2°, 14.40±0.2°, 15.25±0.2°, 16.24±0.2°, 17.70±0.2°, 21.10±0.2° and 30.70±0.2°. Figure 6 The melting point is 205-206°C.

[0061] Comparative Example 3: Preparation of borneol crystal form

[0062] Referring to the method of Example 3 in patent application document CN119039107A, a crystalline form of borneol was obtained by recrystallization using n-heptane as the solvent. This recrystallization method used the same solvent as that used in Comparative Example 2, and the resulting crystalline form of borneol exhibited an X-ray powder diffraction pattern identical to that of Comparative Example 2.

[0063] The beneficial effects of the present invention are demonstrated by experimental examples below.

[0064] Experimental Example 1: Testing the stability of borneol crystal form I

[0065] 1. Experimental methods

[0066] (1) X-ray powder diffraction test

[0067] Testing instrument: X-ray diffractometer DX-2700

[0068] Test method: Scanning range: 3°~53°; Scanning step: 0.05°.

[0069] (2) Melting point test

[0070] Testing instrument: Melting point instrument MP30

[0071] Test method: ① Grind the dried sample in a mortar and put it into a capillary. With the help of a clean glass tube, place it vertically on a watch glass. Insert the capillary from the top and let it fall freely. Repeat several times to make the powder gather tightly at the sealed end of the capillary. The filling height is about 3mm. ③ Adjust the instrument temperature to 195℃ and the heating rate to 3℃ / min. After the initial temperature of the instrument is constant, insert the capillary containing the sample into the measuring hole of the instrument for measurement. After the instrument displays the initial melting temperature and the final melting temperature, record the readings. Perform three parallel measurements and take the average value.

[0072] 2. Experimental results

[0073] Table 1 Stability of borneol crystal form

[0074]

[0075] The results in Table 1 show that compared with the crystalline form of Comparative Example 1, the crystalline form stability and melting point stability of Examples 1 to 4 are significantly better. Compared with Comparative Example 2, the crystalline form stability of the dextroborneol prepared by the methods of Examples 1 to 4 is significantly better, and the melting point stability is similar. In summary, the dextroborneol crystalline form I prepared by Examples 1 to 4 of the present invention has significantly better stability.

[0076] Experimental Example 2: Testing the Solubility of Borneol Crystal Form I

[0077] 1. Experimental methods

[0078] According to the provisions on the investigation of the solubility of raw materials in Part II of the 2020 edition of the Chinese Pharmacopoeia, the solubility of the samples in ethanol, chloroform, water and ether was investigated using three batches of validation samples combined with process and quality research requirements.

[0079] 2. Experimental results

[0080] Table 2 Solubility of borneol crystal form

[0081]

[0082]

[0083] The results in Table 2 show that the solubility of the borneol Form I prepared by the methods of Examples 1 to 4 in ethanol and diethyl ether is significantly better than that of the borneol Forms prepared by the methods of Comparative Examples 1 and 2. Therefore, the borneol Form I prepared by Examples 1 to 4 of the present invention has significantly better solubility in ethanol and diethyl ether.

[0084] The above results show that the borneol crystal form I prepared by Examples 1 to 4 of the present invention has better stability and solubility.

[0085] In summary, the present invention provides a crystalline form of dextroborneol, its preparation method, and use. The present invention provides a crystalline form I of dextroborneol, wherein the X-ray powder diffraction pattern of the crystalline form has characteristic peaks at 2θ diffraction angles of 7.60±0.2°, 8.35±0.2°, 15.25±0.2°, 17.55±0.2°, and 30.70±0.2°. The dextroborneol crystalline form I provided by the present invention has excellent reproducibility, stability, and solubility, meets formulation requirements, and has good development and application prospects.

Claims

1. A crystalline form of borneol, characterized in that: In the X-ray powder diffraction spectrum of the crystal form, the 2θ diffraction angles have characteristic absorption peaks at 7.60±0.2°, 8.35±0.2°, 15.25±0.2°, 17.55±0.2° and 30.70±0.2°.

2. The borneol crystal form according to claim 1, characterized in that In the X-ray powder diffraction spectrum of the crystal form, the peak area percentage of the characteristic peak at 2θ diffraction angle is: 。 3. The borneol crystal form according to claim 1, characterized in that The X-ray powder diffraction spectrum of the crystal form is shown in FIG1 .

4. A method for preparing the borneol crystal form according to any one of claims 1 to 3, characterized in that: The method is selected from method 1, method 2 or method 3: Method 1: dissolving borneol in a water-miscible organic solvent to form a borneol solution, then mixing with water, crystallizing, filtering, and drying to obtain the product; Method 2: Mix dextroborneol with an alkane solvent, heat to dissolve, crystallize, filter, and dry to obtain the product; Method 3: Mix dextroborneol with water to form a suspension, then introduce saturated steam, crystallize the evaporated oil-water mixture, filter, and dry to obtain the product.

5. The method according to claim 4, characterized in that In method 1, the organic solvent is methanol, ethanol, n-propanol, isopropanol, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide or acetone; the amount ratio of the dextroborneol to the organic solvent is 10g:1-10mL; the crystallization conditions are: crystallization at 10-40°C for 1-5h.

6. The method according to claim 4, characterized in that In method 2, the alkane solvent is n-hexane; the usage ratio of dextroborneol to the alkane solvent is 10 g: 1-10 mL; the temperature for heating and dissolving is 50-70° C.; and the crystallization conditions are: crystallization at -50-10° C. for 2-48 h.

7. The method according to claim 4, characterized in that In method 3, the usage ratio of dextroborneol to water is 10 g: 1-10 mL; and the crystallization conditions are: crystallization at 0-30° C. for 2-48 h.

8. A pharmaceutical composition, characterized in that The preparation is prepared by taking the dextroborneol crystal form described in any one of claims 1 to 3 as an active ingredient and adding commonly used pharmaceutical excipients.

9. Use of the crystalline form of dextroborneol according to any one of claims 1 to 3 in the preparation of anti-inflammatory, analgesic and anti-cerebral ischemic drugs.

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