Colchicine eutectic crystal and preparation method and application thereof

Abstract

The invention belongs to the technical field of medicine crystals, and provides a colchicine eutectic crystal and a preparation method and application thereof, and the colchicine eutectic crystal comprises a eutectic substance of colchicine and tartaric acid. The colchicine eutectic crystal is good in fluidity, the solubility is effectively improved compared with a raw material medicine, and the photo-thermal stability is remarkably improved. The preparation method of the colchicine eutectic crystal is simple in process and suitable for industrialization.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical crystal technology, and in particular to a colchicine cocrystal, its preparation method, and its application. Background Technology

[0002] Colchicine is a highly effective anti-gout drug, originally used to treat familial Mediterranean fever. It is now commonly used to treat arthritis and rheumatic pain. This drug improves pain symptoms by lowering serum inflammatory factor levels. Colchicine can also improve acute and chronic coronary syndromes and has a good effect on the treatment of cardiovascular diseases.

[0003] Colchicine has a solubility of only 4.8 mg / mL in ethyl acetate, which is low and makes it difficult to meet the dosage required for industrial production. In addition, colchicine powder is loose and has poor flowability, which will cause problems in formulation such as tableting and mixing in subsequent production.

[0004] Colchicine is easily decomposed by light and undergoes an electrocyclic reaction upon exposure to light. Therefore, light-blocking agents are needed to mitigate its photodegradation during the preparation of colchicine formulations. However, commonly used light-blocking agents such as titanium dioxide pose a potential genotoxicity risk. Therefore, a new strategy is needed to improve the photostability of colchicine while avoiding the toxicity of additives. Summary of the Invention

[0005] The present invention aims to at least solve one of the aforementioned technical problems existing in the prior art. Therefore, the object of the present invention is to provide a colchicine eutectic, its preparation method, and its application.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: In a first aspect, the present invention provides a colchicine eutectic comprising a eutectic of colchicine and tartaric acid.

[0007] In some embodiments, the molar ratio of colchicine to tartaric acid is 1.0:(0.8-1.2); such as 1.0:0.9, 1.0:1.0, 1.0:1.1, etc.

[0008] In some embodiments, the tartaric acid is D-tartaric acid.

[0009] In some embodiments, the colchicine cocrystal uses colchicine as the active pharmaceutical ingredient and D-tartaric acid as the cocrystal ligand.

[0010] In some embodiments, the colchicine eutectic X-ray powder diffraction pattern measured by Cu Kα rays has diffraction angles 2θ of 7.15°±0.2°, 13.11°±0.2°, 18.37°±0.2°, 21.97°±0.2°, and 24.63°±0.2°.

[0011] In some embodiments, the colchicine eutectic X-ray powder diffraction pattern measured by Cu Kα rays has a first main strong peak at a diffraction angle 2θ of 7.15°±0.2°; a second main strong peak at 13.11°±0.2°; and characteristic peaks different from those of colchicine or tartaric acid at 7.15°±0.2°, 8.40°±0.2°, 11.06°±0.2°, and 11.92°±0.2°.

[0012] In some embodiments, the colchicine eutectic X-ray powder diffraction pattern measured by Cu Kα rays also has diffraction peaks at one or more locations with diffraction angles 2θ of 5.88°±0.2°, 8.4°±0.2°, 11.06°±0.2°, 11.92°±0.2°, 13.94°±0.2°, 14.42°±0.2°, 16.32°±0.2°, 16.73°±0.2°, 17.75°±0.2°, 19.88°±0.2°, 20.60°±0.2°, 23.59°±0.2°, 26.82°±0.2°, 27.45°±0.2°, and 28.99°±0.2°.

[0013] In some embodiments, the X-ray powder diffraction pattern of the colchicine eutectic measured by Cu Kα rays contains at least the following characteristic peaks, the diffraction angle 2θ and relative intensities of which are shown in Table 1: Table 1

[0014] In some embodiments, the colchicine eutectic is an orthorhombic crystal system, space group I41; the cell parameters are a=20.8297(2) Å, b=20.8297(2) Å, c=15.0348(3) Å, α=90°, β=90°, γ=90°.

[0015] In some embodiments, the cell volume of the colchicine eutectic is 6523.25(18) Å. 3 .

[0016] In some embodiments, the X-ray powder diffraction pattern of the colchicine eutectic, measured by Cu Kα rays, is as follows: Figure 2 The curve of narcissin D-tartaric acid is shown.

[0017] In some embodiments, the differential scanning calorimetry curve of the colchicine eutectic has characteristic peaks at 180℃-188℃, such as at 181℃-187℃, 182℃-186℃, 183℃-185℃, and 184±0.5℃.

[0018] In some embodiments, the differential scanning calorimetry (DSC) curve of the colchicine eutectic is as follows: Figure 3 The curve of narcissin D-tartaric acid is shown.

[0019] In some embodiments, the angle of repose of the colchicine eutectic is 41-44°; such as 41.0-43.8°.

[0020] In some embodiments, the colchicine eutectic has a solubility of 6.0-7.0 mg / mL in ethyl acetate at 18-25°C (e.g., 19°C, 20°C, 21°C, 22°C, 23°C, 24°C), such as 6.3-6.7 mg / mL.

[0021] A second aspect of the present invention provides a method for preparing the colchicine eutectic, comprising the following steps: The colchicine eutectic was prepared by dissolving colchicine and tartaric acid in ethyl acetate and suspending them.

[0022] In some embodiments, the mass ratio of colchicine to tartaric acid is 3:(0.5-4.0); such as 3:(0.6-3.7), 3:(1.0-2.0), 3:(1.0-1.5), etc.

[0023] In some embodiments, the mass ratio of colchicine to ethyl acetate is (25-35):1, such as (28-32):1.

[0024] In some embodiments, the suspension is carried out at 10-40°C; for example, 20-30°C.

[0025] In some embodiments, the suspension includes agitated suspension; the agitation rate is 200 rpm to 300 rpm; and the agitation time is 8 to 24 hours, such as 12 to 20 hours.

[0026] In some embodiments, the preparation method of the colchicine cocrystal further includes purification of the product, the specific purification operations including filtration and drying; the drying is carried out under a vacuum of 0.05-0.15 bar; the drying temperature is 25-35°C, such as 28-32°C; the drying time is 8-24 h, such as 12-20 h.

[0027] A third aspect of the present invention provides a pharmaceutical composition comprising the colchicine cocrystal.

[0028] In some embodiments, the pharmaceutical composition further includes pharmaceutically acceptable excipients.

[0029] In some embodiments, the pharmaceutical composition is a solid oral dosage form.

[0030] In some embodiments, the pharmaceutically acceptable excipients include (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; (c) binders, such as carboxymethyl cellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (d) humectants, such as glycerin; (e) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain complex silicates, and sodium carbonate; (f) solution retarders, such as paraffin wax; (g) absorption enhancers, such as quaternary ammonium compounds; (h) wetting agents, such as cetyl alcohol and glyceryl monostearate; (i) adsorbents, such as kaolin and bentonite; (j) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and combinations comprising one or more of the aforementioned additives.

[0031] A fourth aspect of the present invention provides the use of the colchicine cocrystal or the pharmaceutical composition thereof in the preparation of a treatment for a disease.

[0032] In some embodiments, the diseases include acute gouty arthritis, chronic gout, cystic diseases (such as polycystic kidney disease or cystic fibrosis), slow viral infections, central or peripheral demyelinating diseases, multiple sclerosis, cancer, inflammatory diseases (such as rheumatoid arthritis), glaucoma, Dupuytren's contracture, idiopathic pulmonary fibrosis, primary amyloidosis, acute or chronic coronary syndrome, recurrent pericarditis, acute pericarditis, asthma, post-pericardiotomy syndrome, proliferative vitreoretinopathy, Behcet's disease, familial Mediterranean fever, idiopathic thrombocytopenic purpura, primary biliary cirrhosis, and pyoderma gangrenosa.

[0033] The beneficial effects of this invention are: The colchicine eutectic of this invention exhibits excellent fluidity, significantly improved solubility compared to the active pharmaceutical ingredient, and markedly enhanced photothermal stability.

[0034] The colchicine eutectic preparation method of the present invention is simple and suitable for industrialization. Attached Figure Description

[0035] Figure 1 This is an ellipsoidal diagram of colchicine:D-tartaric acid in Example 1 of the present invention.

[0036] Figure 2 The above is a comparison PXRD spectrum of colchicine:D-tartaric acid eutectic and monomeric components in Example 1 of this invention.

[0037] Figure 3 This is a DSC comparison spectrum of colchicine:D-tartaric acid eutectic and monomeric components in Example 1 of the present invention.

[0038] Figure 4 This is the colchicine:D-tartaric acid eutectic binary phase diagram of Example 1 of the present invention.

[0039] Figure 5 The results of photostability tests of colchicine:D-tartaric acid cocrystal and active pharmaceutical ingredient in Example 2 of this invention are shown. Detailed Implementation

[0040] The present invention will be further described in detail below through specific embodiments. Unless otherwise specified, the raw materials, reagents, or apparatus used in the embodiments and comparative examples are all available from conventional commercial sources or can be obtained by existing technical methods. Unless otherwise specified, the test or experimental methods are conventional methods in the art.

[0041] In the following examples or comparative examples, the purity of colchicine, D-tartaric acid, and L-malic acid was 99%, and the purity of ethyl acetate used was analytical grade.

[0042] Example 1 This embodiment prepares a colchicine-tartaric acid eutectic, the specific process of which is as follows: 2 mL of ethyl acetate, 30 mg of colchicine, and 20 mg of D-tartaric acid were added to a jacketed reaction flask. The resulting mixture was stirred and suspended at 20 °C for 18 h to obtain a yellow suspension. After filtration and washing, the product was vacuum dried in a vacuum oven at 30 °C for 12 h to obtain a pure colchicine:D-tartaric acid eutectic.

[0043] Example 2 This embodiment prepares a colchicine-tartaric acid eutectic, the specific process of which is as follows: 50 mL of ethyl acetate, 200 mg of colchicine, and 100 mg of D-tartaric acid were added to a jacketed reaction flask. The resulting mixture was stirred and suspended at 20 °C for 12 h to obtain a yellow suspension. After filtration and washing, the product was vacuum dried in a vacuum oven at 30 °C for 12 h to obtain a pure colchicine:D-tartaric acid eutectic.

[0044] Experimental Example 1 This experimental example describes the structural characterization of the colchicine eutectic prepared in Example 1. The specific process is as follows: The PXRD testing conditions are as follows: Bruker D8 Advance powder X-ray diffractometer (Germany), Cu target, 2θ angle range of 5-60°, step size of 0.0204°.

[0045] The differential scanning calorimeter (DSC) test conditions are as follows: TA DSC25 differential scanning calorimeter (USA), test temperature range 25-200℃, heating rate 10℃ / min.

[0046] Its crystal structure was characterized using SCXRD under the following conditions: X-ray single crystal diffractometer (XtaLABP200 FR-X, Rigaku, Japan), and test temperature of 150K.

[0047] Figure 1 The colchicine:D-tartaric acid ellipsoid diagram shows that no proton transfer occurred between colchicine and D-tartaric acid, therefore the product is a eutectic rather than a salt.

[0048] Figure 2 The PXRD comparison spectra of colchicine:D-tartaric acid eutectic and monomeric binary components are shown in Table 1. The diffraction angle 2θ and relative intensity of the colchicine:D-tartaric acid eutectic are shown in Table 1.

[0049] Figure 3 The image shows a DSC comparison of the colchicine:D-tartaric acid eutectic and the monomeric binary components. It can be seen that the melting point of the colchicine:D-tartaric acid eutectic is 184.10℃. Compared with the melting point of the raw materials, the melting point of the eutectic is increased, indicating improved thermal stability.

[0050] Table 2 shows the single crystal data and test parameters of colchicine:D-tartaric acid eutectic.

[0051] Table 2

[0052] It can be seen that the ratio of colchicine to D-tartaric acid molecules in the unit cell is 1:1. The main unit cell parameters of colchicine:D-tartaric acid are as follows: the unit cell belongs to the orthorhombic crystal system, space group I41, a=20.8297Å, b=20.8297Å, c=15.0348Å, α=90°, β=90°, γ=90°, Z=8.

[0053] Experimental Example 2 This experimental example characterizes the properties of the colchicine eutectic prepared in Example 2. The specific process is as follows: Solubility was determined by high performance liquid chromatography (HPLC) under the following conditions: LC-20AT (Japan), detection wavelength 210 nm, mobile phase methanol-dilute phosphoric acid (0.1%), mobile phase flow rate 1.0 mL / min, injection volume 10 μL; gradient elution, elution mode: phosphoric acid solution: methanol = 8:2 (0-8 min, v / v), 6:4 (8-10 min, v / v), 4:6 (10-30 min, v / v).

[0054] Flowability test method: The fixed funnel method was used as described in the Guidelines for Powder Flowability in General Chapter 9604 of Part IV of the Chinese Pharmacopoeia (2025). The angle of repose of colchicine and its eutectic was determined. The test was performed three times and the average value was taken to reduce experimental error.

[0055] Photostability testing method: The photostability of colchicine and eutectic samples was tested in a comprehensive pharmaceutical stability test chamber (CSH-111GSD-1P, Chuangce Technology). The test temperature was 25℃, the illumination was 5000 lx, and the UV intensity was 100 uw / cm. 2 The testing period was 10 days. Samples were taken before and after the test, and the concentration of colchicine in the samples was determined by high performance liquid chromatography to obtain the change in sample purity.

[0056] Figure 4 The diagram shows the binary phase diagram of colchicine:D-tartaric acid eutectic. It can be seen that the solubility of colchicine in ethyl acetate at 20℃ is 4.88 mg / mL, which increases to 5.12 mg / mL after the formation of the eutectic.

[0057] The flowability test results of colchicine:D-tartaric acid cocrystal and the active pharmaceutical ingredient are shown in Table 3. Table 3

[0058] It is evident that before the formation of the eutectic, the angle of repose of colchicine was 47.65°, indicating poor fluidity. After the formation of the eutectic, the angle of repose of the sample was 41.85°, and the fluidity of the sample was improved.

[0059] Colchicine: The photostability test results of D-tartaric acid cocrystal and colchicine raw material are as follows: Figure 5 Table 4.

[0060] Table 4

[0061] It can be seen that after the formation of the eutectic, the degradation rate of colchicine in the sample decreased from 7.517% to 1.435%, and the colchicine:D-tartaric acid eutectic showed better photostability.

[0062] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A colchicine eutectic, characterized in that: Including eutectic compounds of colchicine and tartaric acid.

2. The colchicine eutectic according to claim 1, characterized in that: The molar ratio of colchicine to tartaric acid is 1.0:(0.8-1.2); and / or the tartaric acid is D-tartaric acid.

3. The colchicine eutectic according to claim 1, characterized in that: The X-ray powder diffraction patterns of the colchicine eutectic measured by Cu Kα rays were 7.15°±0.2°, 13.11°±0.2°, 18.37°±0.2°, 21.97°±0.2°, and 24.63°±0.2° at diffraction angles 2θ.

4. The colchicine eutectic according to claim 3, characterized in that: The colchicine eutectic X-ray powder diffraction pattern measured by Cu Kα rays also shows diffraction peaks at one or more locations with diffraction angles 2θ of 5.88°±0.2°, 8.4°±0.2°, 11.06°±0.2°, 11.92°±0.2°, 13.94°±0.2°, 14.42°±0.2°, 16.32°±0.2°, 16.73°±0.2°, 17.75°±0.2°, 19.88°±0.2°, 20.60°±0.2°, 23.59°±0.2°, 26.82°±0.2°, 27.45°±0.2°, and 28.99°±0.2°.

5. The colchicine eutectic according to claim 1, characterized in that: The colchicine eutectic is an orthorhombic crystal system, space group I41; the cell parameters are a=20.8297(2) Å, b=20.8297(2) Å, c=15.0348(3) Å, α=90°, β=90°, γ=90°.

6. The colchicine eutectic according to claim 1, characterized in that: The differential scanning calorimetry curve of the colchicine eutectic has a characteristic peak at 180℃-188℃.

7. The colchicine eutectic according to claim 1, characterized in that: The angle of repose of the colchicine eutectic is 41-44°; and / or, the solubility of the colchicine eutectic in ethyl acetate at 18-25°C is 6.0-7.0 mg / mL.

8. A method for preparing the colchicine eutectic according to any one of claims 1-7, characterized in that: Includes the following steps: The colchicine eutectic was prepared by dissolving colchicine and tartaric acid in ethyl acetate and suspending them.

9. A pharmaceutical composition, characterized in that: Includes the colchicine eutectic as described in any one of claims 1-7.

10. The use of a colchicine eutectic according to any one of claims 1-7 or the pharmaceutical composition according to claim 9 in the preparation of a treatment for a disease.

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