TWI632133B - Crystalline forms of 3-z-[1-(4-(n-((4-methyl-piperazin-1-yl)-methylcarbonyl)-n-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone - Google Patents

Abstract

The present invention provides 3-Z-[1-(4-(N-((4-methyl-pyridazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1 a novel free base crystal form of phenyl-methylene]-6-methoxycarbonyl-2-indolone and a process for the preparation thereof, and a pharmaceutical preparation containing the crystal form and its use for treating diseases It is used for the treatment of angiogenic eye diseases.

Description

3-Z-[1-(4-(N-((4-methyl-pyridazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl- Crystal form of methylene]-6-methoxycarbonyl-2-indololinone

The present invention relates to 3-Z-[1-(4-(N-((4-methyl-pyridazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1 a novel free base crystal form of phenyl-methylene]-6-methoxycarbonyl-2-indolone and a process for preparing the same, a pharmaceutical preparation containing the same, and use thereof as a medicament.

3-Z-[1-(4-(N-((4-methyl-pyridazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl- Methylene]-6-methoxycarbonyl-2-indolone, the drug name Nintedanib, is a potent inhibitor of the receptor tyrosine kinase family (RTK). Nidanib is capable of inhibiting platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR) and Fms-like tyrosine kinase-3 (FLT3). FGFR, PDGFR and VEGFR have been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), and by blocking these signal transduction pathways involved in the progression of fibrosis, nidanib can be reduced by Less lung function declines, thereby slowing the progression of IPF disease. WO 2016/209555 discloses ophthalmic formulations for the treatment of ocular surface diseases comprising nidanib.

An object of the present invention is to provide nidanib (chemical name: 3-Z-[1-(4-(N-((4-methyl-pyridazin-1-yl)-methylcarbonyl)-N-) A new crystalline form of benzyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolone).

Another object of the present invention is to provide a process for the preparation of the crystal form of the nidanib.

Another object of the present invention is to provide a pharmaceutical preparation containing the crystalline form of the nidanib.

Another object of the invention is to provide a crystalline form of the nidanib and the use of the formulation.

In one aspect, the invention provides a 3-Z-[1-(4-(N-((4-methyl-pyridazin-1-yl)-methylcarbonyl)-N-methyl-amino)-aniline The free base form of -1-phenyl-methylene]-6-methoxycarbonyl-2-indolone, ie the crystalline form of nidanib. The crystal form of nidanib provided by the present invention includes: Form B, Form C, Form D, Form E, Form F.

In some embodiments of the present invention, the crystal form of nidanib of the present invention has an X-ray powder diffraction (XRPD) pattern having a characteristic diffraction peak at a 2θ value of 6.4 ± 0.2, and is selected There are characteristic diffraction peaks from at least one of the following 2θ values: 16.6 ± 0.2, 17.4 ± 0.2, 17.8 ± 0.2, and 19.9 ± 0.2. Such crystal forms include Form C, Form D, Form E, Form F.

In some embodiments of the present invention, the crystal form of nidanib of the present invention has an XRPD pattern having a characteristic diffraction peak at a correspondence of the following 2θ values: 6.4 ± 0.2, 16.6 ± 0.2, 17.4 ± 0.2, 17.8 ± 0.2 and 19.9 ± 0.2. Such crystal forms include Form C, Form E, Form F.

In some embodiments of the invention, the crystal form of nidanib of the present invention has an XRPD pattern having characteristic diffraction peaks at the corresponding 2θ values: 6.4 ± 0.2, 12.0 ± 0.2, 16.6 ± 0.2, 17.4 ±0.2, 17.8±0.2 and 19.9±0.2. Such crystal forms include Form E and Form F.

In some embodiments of the invention, the crystal form of nidanib of the present invention has an XRPD pattern having characteristic diffraction peaks at the corresponding 2θ values: 6.4 ± 0.2, 12.0 ± 0.2, 16.6 ± 0.2, 17.4 ± 0.2, 17.8 ± 0.2 and 19.9 ± 0.2; and the crystalline form has a melting point temperature of 245 ° C ± 5 ° C. This crystal form is named crystal form E in the present invention.

In some embodiments of the invention, the crystal form of nidanib of the present invention has an XRPD pattern having characteristic diffraction peaks at the corresponding 2θ values: 6.4 ± 0.2, 12.0 ± 0.2, 16.6 ± 0.2, 17.4 ± 0.2, 17.8 ± 0.2 and 19.9 ± 0.2; and the crystalline form has a melting point temperature of 255 ° C ± 5 ° C. This crystal form is named as Form F in the present invention.

In some embodiments of the invention, the crystal form of nidanib of the present invention has an XRPD pattern having characteristic diffraction peaks at the corresponding 2θ values: 6.4 ± 0.2, 16.6 ± 0.2, 17.4 ± 0.2, 17.8 ±0.2,19.9±0.2 and 23.3±0.2. In the present invention, a crystal form having a diffraction peak of these characteristics is named as Form C.

In some embodiments of the present invention, the crystal form of nidanib of the present invention has an XRPD pattern having characteristic diffraction peaks at the corresponding 2θ values: 4.8 ± 0.2, 5.6 ± 0.2, 6.4 ± 0.2, 17.4 ±0.2 and 19.9±0.2. In the present invention, a crystal form having a diffraction peak of these characteristics is named as Form D.

The present invention also provides another crystal form of nidanib having an XRPD spectrum having characteristic diffraction peaks at the corresponding 2θ values: 11.2 ± 0.2, 14.8 ± 0.2, 16.4 ± 0.2, 17.0 ± 0.2 And 21.0 ± 0.2. In the present invention, a crystal form having a diffraction peak of these characteristics is named as Form B.

In some embodiments of the invention, the crystal form of the nidanib of the present invention is Form E, the XRPD pattern of which is substantially as shown in Figures 12, 14, 19, 20, 21 or 22. In the present invention, "substantially as shown in Figure n" means having a characteristic diffraction peak at a corresponding position of a specific 2θ value of ± 0.2 as indicated in Figure n.

In some embodiments of the invention, the crystal form of the nidanib of the present invention is Form E, and the differential scanning calorimetry (DSC) pattern of the crystal form is substantially as shown in FIG.

In some embodiments of the invention, the crystalline form of nidanib of the present invention is Form F, the XRPD pattern of which is substantially as shown in Figure 15 or Figure 23.

In some embodiments of the invention, the crystalline form of nidanib of the present invention is Form F, the DSC pattern of which is substantially as shown in FIG.

In some embodiments of the present invention, the crystal form of the nidanib of the present invention is a crystalline form C, and the XRPD pattern of the crystalline form is substantially as shown in FIGS. 3, 4, 5, 6, 7, and 8. Figure 9, Figure 10, Figure 17, or Figure 18.

In some embodiments of the invention, the crystal form of nidanib of the present invention is Form D, the XRPD pattern of which is substantially as shown in FIG.

In some embodiments of the invention, the crystal form of nidanib of the present invention is Form B, the XRPD pattern of which is substantially as shown in FIG.

In another aspect, the present invention also provides a process for the preparation of the crystal form of nidanib of the present invention, wherein a commercially available free base crystal form or a specific salt of nidanib can be used as a starting material in different solvent systems. Various crystal forms of nidanib as described in the present invention are obtained by suspension stirring, slow evaporation, and the like. In some embodiments of the invention, the crystal form of the nidanib of the invention The preparation method comprises the following steps: adding nidanib ethanesulfonate to a saturated aqueous solution of sodium carbonate, extracting with dichloromethane, then washing with water to neutrality, drying the organic layer with anhydrous sodium sulfate, and evaporating the solvent to prepare nidani. Cloth crystal type B.

In some embodiments of the present invention, the method for preparing the nedanib of the present invention comprises: adding nidanib to acetone, vortexing for several minutes, and then passing through a 0.22 μm organic filter to obtain a filtrate. The solid after the filtrate was subjected to a volatile solvent was nidanib form C.

In some embodiments of the present invention, the method for preparing the nedanib of the present invention comprises: adding nidanib to a solvent, suspending, magnetically stirring, and then centrifuging the supernatant, and drying and drying. The solid obtained was a nidanib crystal form C. Specifically, the solvent is selected from the group consisting of acetonitrile, isopropanol, n-propanol, 2-butanone, 1,4-dioxane/water mixed solvent, heptane, methanol/water mixed solvent, and acetone/water mixed solvent. One or more.

In some embodiments of the present invention, the method for preparing the nedanib of the present invention comprises: adding nidanib to dichloromethane, vortexing for several minutes, and then passing through a 0.22 μm organic filter. The solid of the filtrate and the filtrate after the volatile solvent is the nedanib form D.

In some embodiments of the present invention, the method for preparing the nedanib of the present invention comprises: adding nidanib form A to water or acetone/water (9/1, v/v), Vortex, pass 0.22μm filter, the filtrate is added to nidanib form B, vortex, pass 0.22μm filter, the filtrate is added to nidanib form C, vortex, pass 0.22μm filter, filtrate is added to Nepal Danibu Form A, Form B and Form C, magnetically stirred, centrifuged to discard the supernatant, and evaporated to dryness. The obtained solid was Nidanib Form E.

In some embodiments of the present invention, the method for preparing the nedanib of the present invention comprises: adding nidanib ethanesulfonate to water and adjusting with a saturated sodium carbonate solution. The pH of the solution is about 10, methylene chloride is added to the suspension solution, stirred, and the mixture is allowed to stand for separation. The aqueous layer is further extracted with dichloromethane, and the organic phase is combined. The organic phase is washed with water, separated, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the nidanib free base was dried. The nidanib free base was added to ethanol, suspended and stirred, filtered, and dried to give crystal form F.

In some embodiments of the present invention, the method for preparing the nedanib of the present invention comprises: adding nidanib form F to water, and uniformly stirring magnetically, adding a small amount of crystal form E as a seed crystal, the chamber The magnetic stirring was carried out under temperature, and the solid was centrifuged to obtain a nidanib crystal form E.

In some embodiments of the present invention, the method for preparing the nedanib of the present invention comprises: mixing nidanib form F with a 0.2% tyloxapol solution, and using nidanib The mixture of tyloxapol and the 200 micron zirconia grinding beads were ground, ground, separated and centrifuged and dried to obtain a nedanib crystal form E.

The crystalline form of nidanib of the present invention possesses valuable pharmacological properties and can be used in the pharmaceutical industry for the production of pharmaceutical compositions for use in human medicine.

In another aspect, the invention also provides the use of the crystalline form of nidanib of the invention for the preparation of a medicament, in particular for the manufacture of a medicament for the treatment and/or prevention of an ocular condition.

In another aspect, the invention also provides a pharmaceutical composition comprising a crystalline form of nidanib of the invention.

In some embodiments of the present invention, the present invention provides an ophthalmic formulation comprising: a crystalline form of nidanib of the present invention (including Form B, Form C, Form D, Form E, One or more of Form F), and one or more pharmaceutically acceptable carriers.

In another aspect, the present invention provides the use of the ophthalmic preparation for the preparation of a medicament for treating an ocular disease selected from the group consisting of age-related macular degeneration (AMD), eyes Anterior angiogenesis such as keratitis, corneal transplantation or keratoplasty, corneal angiogenesis, atrophy of retinal pigment epithelium (RPE), choroidal neovascularization (CNV), chorioretinal occlusion (choroidal retinal vein occlusion), slow proliferative conjunctival degeneration (cleavage plaque), conjunctival papilloma, corneal angiogenesis caused by hypoxic retinal detachment, diabetic macular edema, diabetic retinopathy, ocular congestion (hyperremeia), hyperemeia associated with pterygium, hyperthyroidism-induced hyperremia, hypertrophic pigment epithelial (RPE) hypertrophy, immune or surgery-related dry eye , retinal edema, macular edema, macular edema of retinal vein occlusion, neovascular glaucoma (NVG), eye cancer, pterygium conjunctivae, pterygium recurrence, Steven Johnson syndrome (Steven Johnson syndrome), sty (stye) and visual network Submucosal edema.

In some embodiments of the invention, the ophthalmic formulation of the invention comprising the nedanib crystalline form is for use in the treatment of an angiogenic ocular disorder.

The desired form of pharmacological effect can be achieved by administering to the individual in need a crystalline form of the nidanib. For the purposes of the present invention, the individual is preferably a mammal or human in need of treatment for a particular condition or disease.

Advantageous Effects of the Crystal Form of Nidanib of the Invention: The crystalline form of Nidanib of the present invention has enhanced thermodynamic stability.

Figure 1 is an XRPD pattern of the nedanib in Form B of the present invention.

Figure 2 is an XRPD pattern of Form A of a commercially available nidanib.

3 to 10 are XRPD patterns of the nidanib form C of Experiment Nos. 0227-05-A01 to 0227-05-A08, respectively.

Figure 11 is an XRPD pattern of the nidanib form D of the present invention.

Figure 12 is an XRPD pattern of Nidanib Form E (Experiment No. 0271-71-A04) of the present invention.

Figure 13 is a DSC spectrum of the nidanib crystal form E (experiment No. 0271-101-A04) of the present invention, and the information of the endothermic peak on the DSC spectrum curve is as follows: the integral value is -158.08 mJ (mJ); The integral value was -69.95 Jg ^-1 (Joules / gram); the starting temperature was 243.44 ° C; the peak temperature was 247.08 ° C.

Figure 14 is an XRPD pattern of Nidanib Form E (Experiment No. 0271-71-A05) of the present invention.

Figure 15 is an XRPD pattern of the nidanib form F of the present invention.

Figure 16 is a DSC spectrum of the nidanib form F of the present invention, the information of the endothermic peak on the DSC spectrum curve is as follows: the integral value is -274.70 mJ (mJ); the normalized integral value is -105.25 Jg ^-1 ( Joules per gram; starting temperature is 253.38 ° C; peak temperature is 254.15 ° C.

Figure 17 is an XRPD pattern of Nidanib Form C (Experiment No. 0227-06-A01) of the present invention.

Figure 18 is an XRPD pattern of Nidanib Form C (Experiment No. 0227-06-A02) of the present invention.

Figure 19 is an XRPD pattern of Nidanib Form E of Example 7 of the present invention.

Figure 20 is an XRPD pattern of the nidanib form E of Example 8 of the present invention.

Figure 21 is a Nidanib crystal form E of Example 8 of the present invention placed in a 60 ° C incubator XRPD pattern after 28 days.

Figure 22 is an XRPD pattern of the Nidanib Form E of Example 8 of the present invention after being placed in a 4 ° C incubator for 28 days.

Figure 23 is an XRPD pattern of Nidanib Form F after standing at room temperature for three months in accordance with another embodiment of the present invention.

The invention is further described in detail below by way of specific examples, but the invention is not limited to the following examples.

In each case, X-ray powder diffraction experiment: using a Bruker D8 advance diffractometer, using a Cu Ka (wavelength 1.54056 Å) filled tube (40 kV, 40 mA) as an X-ray source with a wide-angle goniometer at room temperature, 0.6 Mm divergence slit, 2.5° primary cable slit, 2.5° secondary cable slit, 8mm anti-scatter slit, 0.1mm detector slit and LynxEye detector. In the 2θ continuous scan mode, data acquisition was performed at a scan speed of 2.4°/min and a scan step of 0.02° in the range of 3°-40°.

DSC experiment: Data acquisition was accomplished using TA Q200, Mettler DSC 1+ and Mettler DSC 3+ under N ₂ protection at a flow rate of 50 mL/min, before ramping from room temperature to degradation temperature at 10 C/min.

Nidanib various crystal forms and preparation methods thereof

Example 1 Nidanib Form B and preparation method thereof

22 g of nidanib ethanesulfonate (Shanghai Haote Pharmaceutical Technology Co., Ltd.) was added to a saturated aqueous solution of sodium carbonate to adjust the pH to 9, extracted three times with 20 ml of dichloromethane, and washed three times with 30 ml of water to neutral, organic layer. It was dried over anhydrous sodium sulfate. After drying for 0.5 h, the solvent was evaporated under reduced pressure. The solvent was rotary evaporated to give 20 g of nidanib.

See Figure 1 for the XRPD pattern of Nidanib Form B.

Example 2 Nidanib crystal form C and preparation method thereof

The crystal form of nidanib, which is commercially available (Shanghai Haote Pharmaceutical Technology Co., Ltd.), was determined, and the crystal form was named as crystal form A (see Fig. 2 for XRPD pattern).

Weighed about 30mg of Nidanib from the market (Shanghai Hao Tein Pharmaceutical Technology Co., Ltd.) into 8 high-performance liquid chromatography (HPLC) vials, and added 1mL of the solvent in the table below to each HPLC vial. Medium, suspended, magnetically stirred for 72 hours. After 72 hours, the supernatant was centrifuged, and the solid was placed in a fume hood and evaporated to dryness at room temperature to obtain a nedanib form C. The experimental data and measurement results are shown in the table below. The XRPD patterns of the experimental numbers are shown in Figures 3 to 10.

Example 3 Nidanib Form D Preparation Method

Weighed about 20 mg of Nidanibu (available from Shanghai Haotein Pharmaceutical Technology Co., Ltd.) and added it to a 10 mL vial. 3 mL of dichloromethane was added, vortexed for several minutes, and then passed through a 0.22 μm organic filter to obtain a filtrate into a 10 mL vial. The vials containing the filtrate were sealed with parafilm, and 5-6 small holes were poked and slowly evaporated in a fume hood. The volatilized dry solid is nidanib form D. The experimental data and measurement results are shown in the table below.

See Figure 11 for the XRPD pattern of Nidanib Form D.

Example 4 Nidanib Form E Preparation Method

The nidanib form A in the following experiment was obtained from a commercially available (Shanghai Haote Pharmaceutical Technology Co., Ltd.); the nidanib form B was obtained by the preparation method of Example 1; the nidanib form C was The preparation method of Example 2 was obtained.

Weigh 2-3 mg of nidanib crystal form A, add 1 mL of water, vortex for a few minutes, pass through a 0.22 μm filter, and add the filtrate to a 1.8 mL HPLC vial containing 2-3 mg of nidanib form B. Vortex for a few minutes, pass through a 0.22 μm filter, and add the filtrate to a 1.8 mL HPLC vial containing 2-3 mg of nidanib C, vortex for a few minutes, pass through a 0.22 μm filter, and add the filtrate to Shengni In a 1.8 mL HPLC vial of 10 mg each of Danibu Form A, Form B and Form C, after magnetic stirring for 72 hours, the supernatant was centrifuged, and the obtained solid was placed in a fume hood and evaporated to dryness at room temperature. The solid is nidanib crystal form E. The experimental data and measurement results are shown in the table below.

Weigh 3-5mg nidanib form A, add 1mL acetone / water (9 / 1, v / v), vortex for a few minutes, pass 0.22μm filter, the filtrate is added to hold 3-5mg Nidani In a 1.8 mL HPLC vial of Form B, vortex for a few minutes, pass through a 0.22 μm filter, and add the filtrate to a 1.8 mL HPLC vial containing 3-5 mg of nidanib C, vortex for a few minutes. 0.22 μm filter, the filtrate was added to a 1.8 mL HPLC vial containing 10 mg of each of Nidanib Form A, Form B and Form C. After magnetic stirring for 72 hours, the supernatant was centrifuged to obtain a solid solution. The fume hood is evaporated and dried at room temperature, and the obtained solid is Nidanib crystal form E. The experimental data and measurement results are shown in the table below.

See Figure 12 for the XRPD pattern of nidanib Form E (0227-11-A04) and Figure 13 for the DSC pattern (0227-11-A04).

See Figure 14 for the XRPD pattern of Nidanib Form E (0227-11-A05).

Example 5 Nidanib Form F and preparation method thereof

Add 30 g of nidanib ethanesulfonate to 300 ml of water, adjust the pH of the solution to about 10 with saturated sodium carbonate solution at room temperature, add 200 ml of dichloromethane to the suspension solution, stir for 15 minutes, and stand for separation. The aqueous layer was back-extracted with 50 ml of dichloromethane, and the organic phase was combined. The organic phase was washed twice with 100 ml of water, separated, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and dried at 45 ° C for 8 hours. Nibble free base 27g. 27 g of the above sample was added to 140 ml of ethanol, stirred and stirred for 3 days, filtered, and dried by air drying at 45 ° C for 15-16 hours. Form F is obtained.

See Figure 15 for the XRPD pattern of Form F and Figure 16 for the DSC pattern.

Amplification preparation example of nidanib crystal form

Example 6 Amplification Preparation of Nidanib Form C

Weighed 500 mg of nidanib (commercially available from Shanghai Haotein Pharmaceutical Technology Co., Ltd.), added 15 mL of acetone/water (9/1, v/v), and suspended and stirred at room temperature for 72 hours, then centrifuged to discard the supernatant. The obtained solid was placed in a fume hood and evaporated to dryness at room temperature. The obtained solid was a nidanib form C. The experimental data and measurement results are shown in the table below.

Nidanib form B was obtained by the preparation method of Example 1, 500 mg of nidanib form B was weighed, 15 mL of acetone/water (9/1, v/v) was added, and the mixture was suspended and stirred at room temperature for 72 hours. The supernatant was discarded by centrifugation, and the obtained solid was placed in a fume hood and evaporated to dryness at room temperature. The obtained solid was a nidanib form C. The experimental data and measurement results are shown in the table below.

See Figure 17 for the XRPD pattern of nidanib Form C (0227-06-A01). See Figure 18 for the XRPD pattern of nidanib Form C (0227-06-A02).

Example 7 Amplification Preparation of Nidanib Form E

The nidanib form F in the following experiment was obtained by the preparation method of Example 5.

Weigh about 500mg of Form F into 30ml vial, add 15ml of water, stir evenly after magnetic stirring, add a small amount of Form E as seed crystal, stir magnetically for 72 hours at room temperature, centrifuge to take solid, and dry at 40 °C for 2 days. The solid obtained was Nidanib Form E (the XRPD pattern is shown in Figure 19).

Stability test of nidanib crystal form

Example 8 Stability Test of Nidani Bunet Suspension

About 4.0 g of the nidanib form F obtained by the preparation method of Example 5 was weighed at room temperature, and dispersed and mixed by stirring in 200 ml of a 0.2% tyloxapol solution. Next, a mixture of nidanib and tyloxapol was ground in a 160 ml chamber of NETZSCH® MINICER with 200 micron zirconia beads. The grinding speed and time are adjusted to vary the specific characteristics of the formulation composition, such as the particle size distribution. The exemplary speed and time used was 20 minutes at 3000 revolutions per minute (rpm). After grinding, the particle size distribution of the nidanib particles was evaluated. After separation and centrifugation and drying, the obtained solid was found to be nidanib crystal form E (the XRPD pattern is shown in Fig. 20) after XRPD measurement.

The particle size and composition of an exemplary nidanibone suspension prepared according to the ball milling process described above are shown in the table below.

The stability test of the nidanibone suspension prepared by the above ball milling method was carried out, and the nidanibone suspension sample was placed in a 60 ° C and 4 ° C incubator for 28 days, respectively, and then taken out and centrifuged. The residual auxiliary solution was washed away with water, and the solid was taken and blast dried at 30 ° C for 1-2 days. When the surface of the sample had no obvious residual water, the XRPD was measured. The results show that the above nanosuspension maintains its stability under different storage environments, and its crystal form remains crystal form E. The results of the XRPD pattern after 28 days in a 60 ° C incubator are shown in Fig. 21. The results of the XRPD pattern after 28 days in a 4 ° C incubator are shown in Fig. 22.

Example 9 Stability Test of Nidanibu Form F

The nidanib form F was obtained by the preparation method of Example 5. Place the crystal form F in a polyethylene plastic bag, then place the plastic bag in a humidity-free dryer and leave it at room temperature for three months (April 12 to July 12). The XRPD patterns of April 12 and July 12 were measured (see Figure 15 for the XRPD pattern before placement and Figure 23 for the XRPD pattern after three months). The results are all for Form F.

Claims (16)

3-Z-[1-(4-(N-((4-methyl-pyridazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl a free base crystal form of methylene]-6-methoxycarbonyl-2-indolone, the X-ray powder diffraction pattern of the crystal form having a characteristic diffraction peak at a correspondence of 2θ values of 6.4 ± 0.2, And having characteristic diffraction peaks at at least one correspondence selected from the following 2θ values: 16.6 ± 0.2, 17.4 ± 0.2, 17.8 ± 0.2, and 19.9 ± 0.2. According to the crystal form described in claim 1, the X-ray powder diffraction pattern of the crystal form has a characteristic diffraction peak at a position corresponding to the following 2θ values: 6.4 ± 0.2, 16.6 ± 0.2, 17.4 ± 0.2, 17.8 ± 0.2, and 19.9 ± 0.2. According to the crystal form described in claim 1, the X-ray powder diffraction pattern of the crystal form has a characteristic diffraction peak at a correspondence of the following 2θ values: 6.4 ± 0.2, 12.0 ± 0.2, 16.6 ± 0.2, 17.4 ± 0.2, 17.8 ± 0.2 and 19.9 ± 0.2. According to the crystal form described in claim 3, the crystal form has a melting point temperature of 245 ° C ± 5 ° C. According to the crystal form described in claim 3, the crystal form has a melting point temperature of 255 ° C ± 5 ° C. According to the crystal form described in claim 2, the X-ray powder diffraction pattern of the crystal form has a characteristic diffraction peak at a correspondence of the following 2θ values: 6.4 ± 0.2, 16.6 ± 0.2, 17.4 ± 0.2, 17.8 ± 0.2, 19.9 ± 0.2 and 23.3 ± 0.2. According to the crystal form described in claim 1, the X-ray powder diffraction pattern of the crystal form has a characteristic diffraction peak at a position corresponding to the following 2θ values: 4.8±0.2, 5.6±0.2, 6.4±0.2, 17.4±0.2, and 19.9 ± 0.2. According to the crystal form described in claim 1, the X-ray powder diffraction pattern of the crystal form is substantially as shown in Fig. 12, Fig. 14, Fig. 19, Fig. 20, Fig. 21 or Fig. 22. According to the crystal form described in claim 1 or 8, the DSC pattern of the crystal form is substantially as shown in FIG. According to the crystal form described in claim 1, the X-ray powder diffraction pattern of the crystal form is substantially as shown in Fig. 15 or Fig. 23. According to the crystal form described in claim 1 or 10, the DSC pattern of the crystal form is substantially as shown in FIG. According to the crystal form described in claim 1, the X-ray powder diffraction pattern of the crystal form is substantially as shown in Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7, Fig. 8, Fig. 9, Fig. 10, Fig. 17 or Figure 18 shows. According to the crystal form described in claim 1, the X-ray powder diffraction pattern of the crystal form is substantially as shown in FIG. An ophthalmic formulation comprising: the crystalline form of any one of claims 1-13, and one or more pharmaceutically acceptable carriers. Use of an ophthalmic preparation according to claim 14 for the preparation of a medicament for treating an ocular disease selected from the group consisting of age-related macular degeneration (AMD), anterior ocular angiogenesis, and retinal pigment epithelium (RPE) Atrophic changes, choroidal neovascularization (CNV), choroidal retinal vein occlusion, slow proliferative conjunctival degeneration (cleavage plaque), conjunctival papilloma, caused by hypoxic retinal detachment Corneal angiogenesis, diabetic macular edema, diabetic retinopathy, hyperremeia, hyperemeia associated with pterygium, hyperglycemia caused by hyperthyroidism (hyperthyroidism-induced hyperremia), hypertrophy of retinal pigment epithelium (RPE), immune or surgery-related dry eye, retinal edema, macular edema, macular edema of retinal vein occlusion, neovascular glaucoma (NVG), eye cancer, wing Pterygium conjunctivae, pterygium recurrence, Steven Johnson syndrome, stye and subretinal edema. The use according to claim 15, wherein the ophthalmic preparation is for treating an angiogenic ocular disease.