Polymorphic form of crocetin as well as preparation method and application thereof

Abstract

The invention discloses a crocetin polymorph as well as a preparation method and application thereof, and belongs to the technical field of medicines. The polymorph comprises a crystal form I, a crystal form II, a crystal form III, a crystal form IV, a crystal form V, a crystal form VI, a crystal form VII and a crystal form VIII. The crystal form I is prepared by reaction; the crystal form II is formed by desolventizing crystal forms V-VIII; the crystal form III is obtained through normal-temperature crystallization in N-methyl pyrrolidone; the crystal form IV is obtained by crystallizing N-methyl pyrrolidone at the temperature below 10 DEG C; the crystal form V is obtained through crystallization in pyridine; the crystal form VI is obtained by crystallizing in dimethyl sulfoxide; the crystal form VII is obtained by crystallizing in N, N-dimethylformamide; and the crystal form VIII is obtained by crystallizing in N, N-dimethylacetamide. The polymorph provided by the invention provides technical guarantee for subsequent research and development of drugs and maintenance of consistency of pharmacokinetic and pharmacokinetic properties of the drugs, and meanwhile, can also provide technical support for subsequent industrial production of drugs with specific crystal forms.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a polymorph of crocin, its preparation method, and its application. Background Technology

[0002] Saffron acid is a carotenoid dicarboxylic acid compound that has been found primarily in the stigmas of saffron flowers. Crocus sativus L. ) and gardenia fruit ( Gardenia jasminoides Ellis In the patents CN111135158A and CN109180469A, crocin is disclosed as having antidepressant and gut microbiota regulation applications. CN101811956A discloses a method for separating cis-trans isomers of crocin, and CN101811956A discloses a method for preparing trans-crocin, but neither patent addresses its crystal form. To date, there are no reports on the crystal forms of crocin. Different crystal forms of the same drug may exhibit significant differences in stability and bioavailability, thus affecting drug efficacy. Therefore, researching new crystal forms of crocin is of great significance in providing more information for drug research. Summary of the Invention

[0003] The purpose of this invention is to address the shortcomings of existing technologies by providing a polymorph of crocin, its preparation method, and its applications, thereby providing technical support for subsequent drug development and industrial production.

[0004] The objective of this invention is achieved through the following technical solution: the polymorph of crocin described in this invention is the polymorph of compound (I), and the structural formula of compound (I) is as follows: The polymorphs of the compounds of formula (I) include polymorph I, polymorph II, polymorph III, polymorph IV, polymorph V, polymorph VI, polymorph VII and polymorph VIII.

[0005] The X-ray powder diffraction pattern of crystal form I, expressed as a diffraction angle of 2θ±0.2°, shows characteristic peaks at 8.262, 16.016, and 26.103.

[0006] The X-ray powder diffraction pattern of crystal form I, expressed as a diffraction angle of 2θ±0.2°, has characteristic peaks at 8.199, 13.750, 16.480, 16.960, 20.875, and 26.090.

[0007] More intuitively, the X-ray powder diffraction pattern of crystal form I, expressed as a diffraction angle of 2θ±0.2°, shows a distinct characteristic peak at 26.100.

[0008] Preferably, crystal form I has one or more of the following characteristics: (1) The DSC curve of crystal form I has a melting endothermic peak at 275.95±3℃, and the melting process is accompanied by decomposition.

[0009] (2) The DSC curve of crystal form I has a decomposition exothermic peak at 283.91±3℃.

[0010] The X-ray powder diffraction pattern of crystal form II, expressed as a diffraction angle of 2θ±0.2°, has characteristic peaks at 13.770, 14.400, 16.419, 16.919, and 26.310.

[0011] The X-ray powder diffraction pattern of crystal form II, expressed as a diffraction angle of 2θ±0.2°, has characteristic peaks at 10.180, 13.730, 17.580, 21.780, and 26.500.

[0012] The X-ray powder diffraction pattern of crystal form II, expressed as a diffraction angle of 2θ±0.2°, has characteristic peaks at 8.380, 13.950, 16.331, 16.799, and 26.490.

[0013] More intuitively, the X-ray powder diffraction pattern of crystal form II, expressed as a diffraction angle of 2θ±0.2°, shows a distinct characteristic peak at 26.500.

[0014] Preferably, crystal form II has one or more of the following characteristics: (1) The DSC curve of crystal form II has a melting endothermic peak at 291.88±3℃, and the melting process is accompanied by decomposition.

[0015] (2) The DSC curve of crystal form II has a decomposition exothermic peak at 296.24±3℃.

[0016] The X-ray powder diffraction pattern of crystal form III, expressed as a diffraction angle of 2θ±0.2°, shows characteristic peaks at 8.430, 9.910, 15.100, 15.550, 16.850, 18.860, 23.100, 25.460, 26.300, and 27.640.

[0017] Preferably, the X-ray powder diffraction pattern of crystal form III, expressed as a diffraction angle of 2θ±0.2°, has characteristic peaks at 8.430, 9.910, 15.100, 15.550, 16.850, 18.860, 19.940, 22.681, 23.100, 25.460, 26.300, 27.640, 32.361, and 37.100.

[0018] Preferably, the X-ray powder diffraction pattern of crystal form III, expressed as a diffraction angle of 2θ±0.2°, has characteristic peaks at 8.430, 9.910, 12.520, 13.731, 15.100, 15.550, 16.850, 18.860, 19.940, 20.800, 22.681, 23.100, 24.870, 25.460, 26.300, 27.640, 29.111, 29.620, 30.489, 31.850, 32.361, 34.551, 35.149, 36.300, 37.100, 37.790, 38.260, and 39.510.

[0019] Preferably, crystal form III is triclinic, space group P-1, with cell parameters a=5.0959(2)Å, α=76.064(1)°, b=10.6753(3)Å, β=110.654(6)°, c=12.0174(4)Å, γ=83.802(2)°, and cell volume=630.78(4)Å3.

[0020] Preferably, crystal form III has one or more of the following characteristics: (1) The TGA curve of crystal form III showed a weight loss of 22.7±1% at 160.0±3℃; (2) The DSC curve of crystal form III has an endothermic peak for solvent removal at 115.62±3℃; (3) The DSC curve of crystal form III has a melting endothermic peak at 287.24±3℃, and the melting process is accompanied by decomposition.

[0021] (4) The DSC curve of crystal form III has a decomposition exothermic peak at 292.30±3℃.

[0022] The X-ray powder diffraction pattern of crystal form IV, expressed as a diffraction angle of 2θ±0.2°, shows characteristic peaks at 9.801, 10.150, 13.630, 17.080, 17.500, 18.370, 21.700, 24.250, and 26.530.

[0023] Preferably, the X-ray powder diffraction pattern of crystal form IV, expressed as a diffraction angle of 2θ±0.2°, has characteristic peaks at 8.651, 9.801, 10.150, 12.669, 13.630, 15.371, 17.080, 17.500, 18.370, 19.680, 20.169, 20.480, 21.700, 24.250, 26.530, 29.661, and 30.040.

[0024] Preferably, the X-ray powder diffraction pattern of crystal form IV, expressed as a diffraction angle of 2θ±0.2°, has characteristic peaks at 8.651, 9.801, 10.150, 12.669, 13.630, 14.391, 15.371, 17.080, 17.500, 18.370, 18.889, 19.680, 20.169, 20.480, 21.700, 24.250, 26.530, 29.661, 30.040, 32.637, and 36.280.

[0025] Preferably, crystal form IV has one or more of the following characteristics: (1) The DSC curve of crystal form IV has a melting endothermic peak at 288.34±3℃, and the melting process is accompanied by decomposition.

[0026] (2) The DSC curve of crystal form IV has a decomposition exothermic peak at 293.03±3℃.

[0027] The X-ray powder diffraction pattern of crystal form V, expressed as a diffraction angle of 2θ±0.2°, has characteristic peaks at 9.620, 16.930, 19.590, 23.680, and 27.320.

[0028] Preferably, the X-ray powder diffraction pattern of crystal form V, expressed as a diffraction angle of 2θ±0.2°, has characteristic peaks at 9.620, 15.390, 16.930, 17.640, 19.590, 21.270, 21.630, 23.680, 25.880, 26.520, 27.320, and 27.960.

[0029] Preferably, the X-ray powder diffraction pattern of crystal form V, expressed as a diffraction angle of 2θ ± 0.2°, is within the ranges of 9.620, 10.380, 12.860, 13.310, 13.640, 14.871, 15.390, 16.930, 17.640, 19.590, 20.300, 21.270, 21.630, and 23.030. Characteristic peaks are observed at 23.680, 24.621, 25.090, 25.880, 26.520, 27.320, 27.960, 28.769, 29.460, 30.669, 31.170, 33.269, 33.899, 34.339, 34.659, 35.260, 36.290, and 37.001.

[0030] Preferably, the crystal form V is a monoclinic crystal system with space group P21 / c, and the cell parameters are a=9.3728(5)Å, α=90°, b=10.3669(6)Å, β=107.825(2)°, c=14.8907(7)Å, γ=90°, and the cell volume is 1377.43(13)Å3.

[0031] Preferably, crystal form V is desolventized to obtain crystal form II.

[0032] Crystal form VI is a monoclinic crystal system with space group P21 / c. The cell parameters are a=8.8923(3)Å, α=90°, b=9.8872(4) Å, β=102.585(1)°, c=15.4927(5)Å, γ=90°, and cell volume=1329.39(8)Å3.

[0033] Preferably, crystal form VI is obtained by desolventizing crystal form II.

[0034] The X-ray powder diffraction pattern of crystal form VII, expressed as a diffraction angle of 2θ±0.2°, has characteristic peaks at 15.270, 17.590, 17.769, 25.860, and 26.550.

[0035] Preferably, the X-ray powder diffraction pattern of crystal form VII, expressed as a diffraction angle of 2θ±0.2°, has characteristic peaks at 5.860, 11.700, 15.270, 17.381, 17.590, 17.769, 25.020, 25.860, 26.550, 27.140, and 30.420.

[0036] Preferably, the X-ray powder diffraction pattern of crystal form VII, expressed as a diffraction angle of 2θ±0.2°, has characteristic peaks at 5.860, 11.700, 13.441, 13.710, 15.270, 15.630, 15.900, 17.381, 17.590, 17.769, 18.260, 20.980, 21.710, 25.020, 25.860, 26.550, 27.140, 29.950, 30.420, 31.590, 35.590, and 36.020.

[0037] Preferably, crystal form VII is a triclinic crystal system with space group P-1, cell parameters a=6.3204(4)Å, α=88.851(3)°, b=7.5677(4) Å, β=78.330(3)°, c=15.2230(9)Å, γ=68.541(2)°, and cell volume=662.48(7)Å3.

[0038] Preferably, crystal form VII is obtained by desolvation to obtain crystal form II.

[0039] Crystal type VIII is a monoclinic crystal system with space group P21 / n. The cell parameters are a=9.0256(3) Å, α=90°, b=11.2448(4) Å, β=104.973(2)°, c=14.8569(7) Å, γ=90°, and cell volume=1456.65(10) Å3.

[0040] Preferably, crystal form II is obtained after desolventizing crystal form VIII.

[0041] The method for preparing polymorphs of crocin according to the present invention uses one of the following methods to prepare polymorphs of crocin: Method 1: Add compound I to a good solvent and stir to dissolve. Add the resulting solution to an antisolvent and stir. Filter the solution, wash the resulting filter cake, and dry it to obtain the final product. Method 2: Add compound I to a good solvent, heat and stir to dissolve, allow the resulting saturated solution to stand and cool to crystallize, filter, and obtain the product; Method 3: Add compound I to a solvent and shake for 1-2 days, centrifuge, remove the supernatant, and vacuum dry to obtain the product; Method 4: Add compound I to a solvent, suspend and stir at 0-50℃ for 4-7 days, filter, and vacuum dry to obtain the product; Method 5: Add compound I to an alkaline solution with pH > 9 and stir for 1 hour. Adjust the pH of the solution to < 4 with acid, filter, and vacuum dry to obtain the product. Method 6: Dissolve compound I in a solvent, filter, place the filtrate in an antisolvent environment for gas-liquid diffusion, filter, and vacuum dry to obtain the product; Method 7: Place compound I in a solvent environment for gas-solid diffusion to obtain the product; Method 8: Add compound I to a solvent, suspend and stir at 0-50℃ for 4-7 days, filter, and vacuum dry to obtain the product; Method 9: Add compound I to a solvent, suspend and stir at 0-50℃ for 4-7 days, filter, vacuum dry, and heat treat under nitrogen protection to obtain the product; The solvent is one or more of water or organic solvents; the organic solvent is one or more of alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, benzene, sulfoxides, amides, or alkanolamines; the good solvent is one or more of methanol, ethanol, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, ethanolamine, isopropanolamine, and 3-aminopropanol; the antisolvent is one or more of isopropanol, acetone, ethyl acetate, isopropyl acetate, methyl acetate, acetonitrile, methyl tert-butyl ether, toluene, dichloromethane, water, or n-hexane. The alkaline solution contains one or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and ammonia water; the acid used includes one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, and other acids with pKa < 4.

[0042] The beneficial effects of this invention are as follows: This invention provides polymorphs of crocin, which provides technical support for the subsequent drug development and to maintain the consistency of the drug's pharmacokinetic and pharmacodynamic properties. It can also provide technical support for the subsequent industrial production of drugs with specific polymorphs. Attached Figure Description

[0043] Figure 1 The PXRD pattern for crystal form I; Figure 2 The TGA-DSC spectrum of crystal form I; Figure 3 The PXRD pattern for crystal form II; Figure 4 The TGA-DSC spectrum of crystal form II; Figure 5 The PXRD pattern for crystal form III; Figure 6 The TGA-DSC spectrum is for crystal form III; Figure 7 This is a three-dimensional projection diagram of crystal form III; Figure 8 The PXRD pattern for crystal form IV; Figure 9 The TGA-DSC spectrum of crystal form IV; Figure 10 The PXRD pattern for crystal form V; Figure 11 The TGA-DSC spectrum of crystal form V; Figure 12 This is a three-dimensional projection diagram of crystal form V; Figure 13 The PXRD pattern for crystal form VI; Figure 14 The TGA-DSC spectrum of crystal form VI; Figure 15 This is a three-dimensional structural projection of crystal form VI; Figure 16 The PXRD pattern for crystal form VII; Figure 17 The TGA-DSC spectrum of crystal form VII; Figure 18 This is a three-dimensional projection of crystal form VII; Figure 19 The PXRD pattern for crystal form VIII; Figure 20 The TGA-DSC spectrum of crystal form VIII; Figure 21 This is a three-dimensional projection of crystal form VIII. Detailed Implementation

[0044] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0045] Example 1 Preparation of Saffron Acid Crystal Form I Add 0.5 mmol of crocin to a reaction tube, along with 0.5 mL of 2M sodium hydroxide solution and 5 mL of water. Heat and stir at 40°C for 1 hour. Add 0.6 mL of 2M hydrochloric acid solution, filter, retain the precipitate, and vacuum dry at 60°C. Take a sample for testing and label it as crystal form I. The test results are shown in [Figure 1]. Figure 1 and Figure 2 . Figure 2 The DSC results showed that the sample had an endothermic melting peak at 275.95℃ and an exothermic decomposition peak at 283.91℃. Combined with the TGA curve, it can be seen that the melting process of the sample is accompanied by decomposition.

[0046] Example 2 Preparation of Saffron Acid Crystal Form II Add 0.302 g of crocin to a round-bottom flask, add 25 mL of dimethyl sulfoxide, heat at 60 °C until clear, stop heating, allow to stand at room temperature to crystallize, filter, retain the precipitate, dry under vacuum at 60 °C, take a sample for testing, and label it as crystal form II. The test results are shown in [see attached table]. Figure 3 and Figure 4 . Figure 4 The DSC results showed that the sample had an endothermic melting peak at 291.88℃ and an exothermic decomposition peak at 296.24℃. Combined with the TGA curve, it can be seen that the melting process of the sample is accompanied by decomposition.

[0047] Example 3 Preparation of Saffron Acid Crystal Form III Add 1.378 g of crocin to a round-bottom flask, add 25 mL of N-methylpyrrolidone, heat at 60 °C until clear, stop heating, and allow to crystallize at room temperature to obtain crystal form III. Take a sample for testing; the test results are shown below. Figure 5 and Figure 6 . Figure 6 The TGA results showed that the sample lost 22.7% of its weight when heated from room temperature to 160.0℃. Figure 6 DSC results showed an endothermic peak for solvent removal at 115.62℃, an endothermic peak for melting at 287.24℃, and an exothermic peak for decomposition at 292.30℃. Combined with the TGA curve, it can be seen that the melting process of the sample is accompanied by decomposition. The stereoscopic projection diagram of this crystal form is shown below. Figure 7 Its crystal structure data are shown in Table 1.

[0048] Table 1. Crystal structure data of saffron acid crystal form III Example 4 Preparation of Saffron Acid Type IV Add 2.765 g of crocin to a round-bottom flask, add 50 mL of N-methylpyrrolidone, heat at 60 °C until clear, stop heating, allow to stand at 4 °C to crystallize, filter, retain the precipitate, dry under vacuum at 60 °C, take a sample for testing, and label it as crystal form IV. The test results are shown in [see attached table]. Figure 8 and Figure 9 . Figure 9 The DSC results showed that the sample had an endothermic melting peak at 288.34℃ and an exothermic decomposition peak at 293.03℃. Combined with the TGA curve, it can be seen that the melting process of the sample is accompanied by decomposition.

[0049] Example 5 Preparation of Saffron Acid Crystal Form V Add 0.306 g of crocin to a round-bottom flask, add 25 mL of pyridine, heat at 60 °C until clear, stop heating, and allow to crystallize at room temperature to obtain crystal form V. Take a sample for testing; the results are shown below. Figure 10 and Figure 11 . Figure 11 DSC results showed that the sample exhibited an endothermic melting peak at 292.31℃ and an exothermic decomposition peak at 297.39℃. Combined with the TGA curve, it was determined that the melting process was accompanied by decomposition. No endothermic desolvation peak was observed before melting. The sample's melting point was close to that of crystal form II, indicating that the sample transformed into crystal form II after desolvation. The stereoscopic projection diagram of this crystal form is shown below. Figure 12 Its crystal structure data are shown in Table 2.

[0050] Table 2. Crystal structure data of saffron acid (V crystal form) Example 6 Preparation of Saffron Acid Crystal Form VI Add 0.695 g of crocin to a round-bottom flask, add 25 mL of dimethyl sulfoxide, heat at 60 °C until clear, stop heating, and allow to crystallize at room temperature to obtain crystal form VI. Take a sample for testing; the results are shown below. Figure 13 and Figure 14 . Figure 14 DSC results showed that the sample exhibited desolvation endothermic peaks at 40.26℃ and 105.15℃, temperatures close to those of the dimethyl sulfide (37.5℃) and dimethyl disulfide (109℃) products of dimethyl sulfoxide degradation. A melting endothermic peak was observed at 291.31℃, and a decomposition exothermic peak at 295.83℃. Combined with the TGA curve, it was determined that the sample decomposed during melting. The melting point of the sample was close to that of crystal form II. Based on the powder diffraction results, it can be concluded that the sample transformed into crystal form II after desolvation. The stereoscopic projection diagram of this crystal form is shown below. Figure 15 Its crystal structure data are shown in Table 3.

[0051] Table 3. Crystal structure data of saffron acid crystal form VI Example 7 Preparation of Saffron Acid Crystal Form VII Add 0.392 g of crocin to a round-bottomed flask, add 25 mL of N,N-dimethylformamide, heat at 60 °C until clear, stop heating, and allow to crystallize at room temperature to obtain crystal form VII. Take a sample for testing; the test results are shown below. Figure 16 and Figure 17 . Figure 17 DSC results showed an endothermic melting peak at 293.00℃ and an exothermic decomposition peak at 297.44℃. Combined with the TGA curve, it was determined that the melting process was accompanied by decomposition. The sample's melting point was close to that of crystal form II, indicating that the sample transformed into crystal form II after solvent removal. A projection diagram of the three-dimensional structure of this crystal form is shown below. Figure 18 Its crystal structure data are shown in Table 4.

[0052] Table 4. Crystal structure data of saffron acid crystal form VII Example 8 Preparation of Saffron Acid Crystal Form VIII Add 0.607 g of crocin to a round-bottom flask, add 25 mL of N,N-dimethylacetamide, heat at 60 °C until clear, stop heating, and allow to crystallize at room temperature to obtain crystal form VIII. Take a sample for testing; the test results are shown below. Figure 19 and Figure 20 . Figure 20DSC results showed an endothermic melting peak at 291.43℃ and an exothermic decomposition peak at 295.57℃. Combined with the TGA curve, it was determined that the melting process was accompanied by decomposition. The sample's melting point was close to that of crystal form II. Based on the powder diffraction results, it can be concluded that the sample transformed into crystal form II after solvent removal. The stereoscopic projection diagram of this crystal form is shown below. Figure 21 Its crystal structure data are shown in Table 5.

[0053] Table 5. Crystal structure data of saffron acid crystal form VIII The above embodiments are used to explain and illustrate the present invention, but not to limit the present invention. Any modifications and changes made to the present invention within the spirit and scope of the claims shall fall within the protection scope of the present invention.

Claims

1. A polymorph of saffron acid, characterized in that, Saffron acid has the following structural formula: The polymorphs of the compound of formula (I) include polymorph I, polymorph II, polymorph III, polymorph IV, polymorph V, polymorph VI, polymorph VII, and polymorph VIII; specifically, polymorph I is prepared by reaction; polymorph II is formed by desolvation of polymorphs V-VIII; polymorph III is obtained by crystallization in N-methylpyrrolidone at room temperature; and polymorph IV is obtained by crystallization in N-methylpyrrolidone below 10°C. Crystal form V is obtained by crystallization in pyridine; crystal form VI is obtained by crystallization in dimethyl sulfoxide; crystal form VII is obtained by crystallization in N,N-dimethylformamide; and crystal form VIII is obtained by crystallization in N,N-dimethylacetamide.

2. The polymorph of saffron acid according to claim 1, characterized in that: The characteristic peaks of the X-ray powder diffraction patterns for each crystal form, expressed as diffraction angles of 2θ ± 0.2°, are as follows: The X-ray powder diffraction pattern of crystal form I, expressed as a diffraction angle of 2θ±0.2°, shows characteristic peaks at 8.262, 16.016, and 26.

103. The X-ray powder diffraction pattern of crystal form II, expressed as a diffraction angle of 2θ±0.2°, shows characteristic peaks at 10.180, 13.730, 17.580, 21.780, and 26.

500. The X-ray powder diffraction pattern of crystal form III, expressed as a diffraction angle of 2θ±0.2°, shows characteristic peaks at 8.430, 9.910, 15.100, 15.550, 16.850, 18.860, 23.100, 25.460, 26.300, and 27.

640. The X-ray powder diffraction pattern of crystal form IV, expressed as a diffraction angle of 2θ±0.2°, shows characteristic peaks at 9.801, 10.150, 13.630, 17.080, 17.500, 18.370, 21.700, 24.250, and 26.

530. The X-ray powder diffraction pattern of crystal form V, expressed as a diffraction angle of 2θ±0.2°, shows characteristic peaks at 9.620, 16.930, 19.590, 23.680, and 27.

320. The X-ray powder diffraction pattern of crystal form VII, expressed as a diffraction angle of 2θ±0.2°, has characteristic peaks at 15.270, 17.590, 17.769, 25.860, and 26.

550.

3. The polymorph of saffron acid according to claim 1, characterized in that: Crystal form I and crystal form II each have a distinct characteristic peak, specifically: The X-ray powder diffraction pattern of crystal form I, expressed as a diffraction angle of 2θ±0.2°, shows a distinct characteristic peak at 26.100°. The X-ray powder diffraction pattern of crystal form II, expressed as a diffraction angle of 2θ±0.2°, shows a distinct characteristic peak at 26.500°.

4. The polymorph of saffron acid according to claim 1, characterized in that: The characteristic peaks of crystal form III, crystal form IV, crystal form V and crystal form VII are as follows: The X-ray powder diffraction pattern of crystal form III, expressed as a diffraction angle of 2θ±0.2°, shows characteristic peaks at 8.430, 9.910, 15.100, 15.550, 16.850, 18.860, 19.940, 22.681, 23.100, 25.460, 26.300, 27.640, 32.361, and 37.

100. The X-ray powder diffraction pattern of crystal form IV, expressed as a diffraction angle of 2θ ± 0.2°, shows characteristic peaks at 8.651, 9.801, 10.150, 12.669, 13.630, 15.371, 17.080, 17.500, 18.370, 19.680, 20.169, 20.480, 21.700, 24.250, 26.530, 29.661, and 30.

040. The X-ray powder diffraction pattern of crystal form V, expressed as a diffraction angle of 2θ±0.2°, shows characteristic peaks at 9.620, 15.390, 16.930, 17.640, 19.590, 21.270, 21.630, 23.680, 25.880, 26.520, 27.320, and 27.

960. The X-ray powder diffraction pattern of crystal form VII, expressed as a diffraction angle of 2θ±0.2°, shows characteristic peaks at 5.860, 11.700, 15.270, 17.381, 17.590, 17.769, 25.020, 25.860, 26.550, 27.140, and 30.

420.

5. The polymorph of saffron acid according to claim 1, characterized in that: The characteristic peaks of crystal form III, crystal form IV, crystal form V and crystal form VII are shown in more detail below: The X-ray powder diffraction pattern of crystal form III, expressed as a diffraction angle of 2θ ± 0.2°, shows characteristic peaks at 8.430, 9.910, 12.520, 13.731, 15.100, 15.550, 16.850, 18.860, 19.940, 20.800, 22.681, 23.100, 24.870, 25.460, 26.300, 27.640, 29.111, 29.620, 30.489, 31.850, 32.361, 34.551, 35.149, 36.300, 37.100, 37.790, 38.260, and 39.

510. The X-ray powder diffraction pattern of crystal form IV, expressed as a diffraction angle of 2θ ± 0.2°, shows characteristic peaks at 8.651, 9.801, 10.150, 12.669, 13.630, 14.391, 15.371, 17.080, 17.500, 18.370, 18.889, 19.680, 20.169, 20.480, 21.700, 24.250, 26.530, 29.661, 30.040, 32.637, and 36.

280. X-ray powder diffraction pattern of crystal form V, expressed as a diffraction angle of 2θ ± 0.2°, is shown at the following θ values: 9.620, 10.380, 12.860, 13.310, 13.640, 14.871, 15.390, 16.930, 17.640, 19.590, 20.300, 21.270, 21.630, 23.030, 2... Characteristic peaks are found at 3.680, 24.621, 25.090, 25.880, 26.520, 27.320, 27.960, 28.769, 29.460, 30.669, 31.170, 33.269, 33.899, 34.339, 34.659, 35.260, 36.290, and 37.

001. The X-ray powder diffraction pattern of crystal form VII, expressed as a diffraction angle of 2θ±0.2°, shows characteristic peaks at 5.860, 11.700, 13.441, 13.710, 15.270, 15.630, 15.900, 17.381, 17.590, 17.769, 18.260, 20.980, 21.710, 25.020, 25.860, 26.550, 27.140, 29.950, 30.420, 31.590, 35.590, and 36.

020.

6. The polymorph of saffron acid according to claim 1, characterized in that: Crystal forms I, II, and IV have the following characteristics: The DSC curve of crystal form I shows an endothermic melting peak at 275.95±3℃, indicating that the melting process is accompanied by decomposition; the DSC curve of crystal form I shows an exothermic decomposition peak at 283.91±3℃. The DSC curve of crystal form II shows an endothermic melting peak at 291.88±3℃, indicating that the melting process is accompanied by decomposition; the DSC curve of crystal form II shows an exothermic decomposition peak at 296.24±3℃. The DSC curve of crystal form IV shows a melting endothermic peak at 288.34±3℃, indicating that the melting process is accompanied by decomposition; the DSC curve of crystal form IV shows a decomposition exothermic peak at 293.03±3℃.

7. The polymorph of saffron acid according to claim 1, characterized in that: Crystal forms III, V, VI, VII, and VIII have the following characteristics: Crystal form III is triclinic, space group P-1, with cell parameters a=5.0959(2)Å, α=76.064(1)°, b=10.6753(3)Å, β=110.654(6)°, c=12.0174(4)Å, γ=83.802(2)°, and cell volume=630.78(4)Å. 3 ; Crystal form V is a monoclinic crystal system with space group P21 / c. The cell parameters are a = 9.3728(5) Å, α = 90°, b = 10.3669(6) Å, β = 107.825(2)°, c = 14.8907(7) Å, γ = 90°, and the cell volume is 1377.43(13) Å. 3 ; Crystal form VI is a monoclinic crystal system with space group P21 / c. Its cell parameters are a = 8.8923(3) Å, α = 90°, b = 9.8872(4) Å, β = 102.585(1)°, c = 15.4927(5) Å, γ = 90°, and cell volume = 1329.39(8) Å. 3 ; Crystal form VII is a triclinic crystal system with space group P-1. Its cell parameters are a = 6.3204(4) Å, α = 88.851(3)°, b = 7.5677(4) Å, β = 78.330(3)°, c = 15.2230(9) Å, γ = 68.541(2)°, and cell volume = 662.48(7) Å. 3 ; Crystal form VIII is a monoclinic crystal system with space group P21 / n. Its unit cell parameters are a = 9.0256(3) Å, α = 90°, b = 11.2448(4) Å, β = 104.973(2)°, c = 14.8569(7) Å, γ = 90°, and unit cell volume = 1456.65(10) Å. 3 .

8. A method for preparing the polymorph of crocin according to any one of claims 1-7, characterized in that, The polymorphs of crocin were prepared using one of the following methods: Method 1: Add compound I to a good solvent and stir to dissolve. Add the resulting solution to an antisolvent and stir. Filter the solution, wash the filter cake, and dry it to obtain the final product. Method 2: Add compound I to a good solvent, heat and stir to dissolve, allow the resulting saturated solution to stand and cool to crystallize, filter, and obtain the product; Method 3: Add compound I to a solvent and shake for 1-2 days, centrifuge, remove the supernatant, and vacuum dry to obtain the product; Method 4: Add compound I to a solvent, suspend and stir at 0-50℃ for 4-7 days, filter, and vacuum dry to obtain the product; Method 5: Add compound I to an alkaline solution with pH > 9 and stir for 1 hour. Adjust the pH of the solution to < 4 with acid, filter, and vacuum dry to obtain the product. Method 6: Dissolve compound I in a solvent, filter, place the filtrate in an antisolvent environment for gas-liquid diffusion, filter, and vacuum dry to obtain the product; Method 7: Place compound I in a solvent environment for gas-solid diffusion to obtain the product; Method 8: Add compound I to a solvent, suspend and stir at 0-50℃ for 4-7 days, filter, and vacuum dry to obtain the product; Method 9: Add compound I to a solvent, suspend and stir at 0-50℃ for 4-7 days, filter, vacuum dry, and heat treat under nitrogen protection to obtain the final product.

9. The method for preparing polymorphs of crocin according to claim 8, characterized in that, The solvent is one or more of water or organic solvents; the organic solvent is one or more of alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, benzene, sulfoxides, amides, or alkanolamines; the good solvent is one or more of methanol, ethanol, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, ethanolamine, isopropanolamine, and 3-aminopropanol; the antisolvent is one or more of isopropanol, acetone, ethyl acetate, isopropyl acetate, methyl acetate, acetonitrile, methyl tert-butyl ether, toluene, dichloromethane, water, or n-hexane; the alkaline solution contains one or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and ammonia water; the acid used contains one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, and succinic acid with a pKa < 4.

10. An application of any one of the polymorphs of crocin according to claims 1-9, characterized in that, The drug combination includes at least one of crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI, crystal form VII or crystal form VIII and a druggable carrier.

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