Crystal form of furaquitinib and preparation method thereof

Abstract

The invention provides a furaquitinib crystal form and a preparation method thereof. Specifically, the invention provides a crystal form IIIa, a crystal form NX-I and a crystal form NX-II of furaquitinib. The furaquitinib crystal form IIIa is good in stability, is a thermodynamically stable crystal form in water, is free of spontaneous crystal transformation in a high-humidity environment, is convenient to store and transport, has relatively good solubility, dissolution rate and fluidity, is beneficial to preparation development, is simple in preparation process and high in yield, is suitable for large-scale production, and is suitable for industrial production. And a better choice is provided for the development of furaquinib-containing medicines.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and more specifically, to the crystal form of fruquintinib and its preparation method. Background Technology

[0002] Fruquintinib is a novel, oral, highly selective vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI). On November 8, 2023, it received marketing approval from the U.S. Food and Drug Administration (FDA) for patients with metastatic colorectal cancer who have previously received fluorouracil-based, oxaliplatin-based, and irinotecan-based chemotherapy, or who have previously received or are not suitable for anti-VEGF therapy or anti-EGFR therapy (RAS wild-type).

[0003] The chemical name of fruquintinib is 6-(6,7-dimethoxyquinazoline-4-oxo)-N,2-dimethylbenzofuran-3-carboxamide, and its molecular formula is: C 21 H 19 N3O5, with a molecular weight of 393.39 and CAS number 1194506-26-7, has the chemical structural formula shown in formula (I):

[0004]

[0005] Currently, existing technologies disclose different crystal forms, preparation methods, and application methods for fruquintinib. For example, WO2016037550A1 discloses three amorphous crystal forms I, III, and VII of fruquintinib, as well as crystal forms II (a half-ethanol solvate), IV (an acetic acid solvate), and VIII (a 1,4-dioxane solvate). Crystal form I exhibits good stability under high temperature, high humidity, and light exposure, but studies have found that it suffers from poor flowability, low water solubility, and low dissolution rate. Furthermore, it can transform into crystal form II in a mixed solvent of ethanol and n-heptane. The preparation methods for crystal forms III and VII are similar, but both suffer from the problem of difficulty in consistently obtaining a single crystal form. None of the three solvates are suitable as pharmaceutical crystal forms. Therefore, there is still a need in the field to develop new solid forms of fruquintinib compounds. Summary of the Invention

[0006] In view of the problems in the prior art, the purpose of this invention is to provide crystal forms IIIa, NX-I, and NX-II of fruquintinib to meet the needs of drug development and application.

[0007] In a first aspect of the invention, a polymorph of a compound of formula (I) is provided, said polymorph being a hydrate, anhydrous form, or a solvate:

[0008]

[0009] In another embodiment, the polymorph is a trihydrate.

[0010] In another preferred embodiment, the polymorph is crystal form IIIa, and the X-ray powder diffraction pattern of crystal form IIIa includes two or more 2θ values ​​selected from the group consisting of: 7.2°±0.2°, 8.6°±0.2°, 12.0°±0.2°, 14.4°±0.2°, 15.2°±0.2°, 20.4°±0.2°, 22.3°±0.2°, 26.1°±0.2°, and 29.1°±0.2°.

[0011] In another preferred embodiment, the X-ray powder diffraction (XRPD) pattern of crystal form IIIa includes three or more 2θ values ​​selected from the group consisting of: 7.2°±0.2°, 8.6°±0.2°, 12.0°±0.2°, 14.4°±0.2°, 15.2°±0.2°, 16.2±0.2°, 20.4°±0.2°, 22.3°±0.2°, 24.0°±0.2°, 26.1°±0.2°, 26.4°±0.2°, and 29.1°±0.2°.

[0012] In another preferred embodiment, the XRPD pattern diffraction angle 2θ values ​​of the crystal form IIIa are 4.8°±0.2°, 7.2°±0.2°, 8.6°±0.2°, 9.7°±0.2°, 12.0°±0.2°, 14.4°±0.2°, 15.1°±0.2°, 16.1°±0.2°, 17.3°±0.2°, 20.4°±0.2°, 20.7°±0.2°, and 2... Characteristic peaks are present at 2.3°±0.2°, 24.0°±0.2°, 24.4°±0.2°, 25.4°±0.2°, 26.1°±0.2°, 26.4°±0.2°, 28.3°±0.2°, 28.6°±0.2°, 29.1°±0.2°, 29.6°±0.2°, 30.2°±0.2°, 30.8°±0.2°, and 32.7°±0.2°.

[0013] In another preferred embodiment, the crystal form IIIa has essentially the following characteristics: Figure 1 The X-ray powder diffraction pattern shown is shown.

[0014] In another preferred embodiment, the crystal form IIIa has essentially the following characteristics: Figure 2 The thermogravimetric analysis (TGA) spectrum shown indicates that crystal form IIIa exhibits significant weight loss of 11% or more, preferably 12% or more, at room temperature to 110°C.

[0015] In another preferred embodiment, the crystal form IIIa has essentially the following characteristics: Figure 3 The DSC spectrum shown indicates that crystal form IIIa has an endothermic peak at 98.25℃ and 243.53℃, and the peak temperature of dehydration of crystal form IIIa is 98.25℃±5℃; the melting point of crystal form IIIa after dehydration is 243.53℃±5℃.

[0016] In another preferred embodiment, the purity of crystal form IIIa is at least 99%, preferably 99.5%.

[0017] In another embodiment, the polymorph is NX-I, and the XRPD plot of NX-I includes two or more 2θ values ​​selected from the group consisting of: 6.4°±0.2°, 8.6°±0.2°, 13.0°±0.2°, 13.8°±0.2°, 15.0°±0.2°, 22.1°±0.2°, and 25.8°±0.2°.

[0018] In another preferred embodiment, the XRPD plot of the NX-I crystal form includes three or more 2θ values ​​selected from the group consisting of: 6.4°±0.2°, 8.6°±0.2°, 13.0°±0.2°, 13.8°±0.2°, 15.0°±0.2°, 17.2°±0.2°, 19.5°±0.2°, 21.1°±0.2°, 22.1°±0.2°, and 25.8°±0.2°.

[0019] In another preferred embodiment, the XRPD pattern of the NX-I crystal form has characteristic peaks at diffraction angles 2θ at 6.4°±0.2°, 8.6°±0.2°, 13.0°±0.2°, 13.8°±0.2°, 15.0°±0.2°, 17.2°±0.2°, 19.5°±0.2°, 19.8°±0.2°, 21.1°±0.2°, 22.1°±0.2°, 24.5°±0.2°, 25.8°±0.2°, 27.6°±0.2°, 30.9°±0.2°, 32.7°±0.2°, 33.6°±0.2°, and 34.1°±0.2°.

[0020] In another preferred embodiment, the crystal form NX-I has essentially the following characteristics: Figure 4 The XRPD spectrum shown.

[0021] In another preferred embodiment, the crystal form NX-I has essentially the following characteristics: Figure 5 The TGA spectrum shown indicates that the NX-I crystal form does not exhibit significant weight loss.

[0022] In another preferred embodiment, the crystal form NX-I is an anhydrous form.

[0023] In another preferred embodiment, the crystal form NX-I has essentially the following characteristics: Figure 6The DSC spectrum shown indicates that the melting point of the NX-I crystal form is 245.54℃±5℃.

[0024] In another preferred embodiment, the purity of the crystal form NX-I is at least 99%, preferably 99.3%.

[0025] In another embodiment, the polymorph is NX-II, wherein the XRPD diagram of NX-II includes two or more 2θ values ​​selected from the group consisting of: 5.8°±0.2°, 9.2°±0.2°, 11.5°±0.2°, 21.0°±0.2°, 23.0°±0.2°, and 27.0±0.2°.

[0026] In another preferred embodiment, the XRPD plot of the NX-II crystal form includes three or more 2θ values ​​selected from the group consisting of: 4.7°±0.2°, 5.8°±0.2°, 9.2°±0.2°, 11.5°±0.2°, 21.0°±0.2°, 22.3°±0.2°, 26.9°±0.2°, and 27.0°±0.2°.

[0027] In another preferred embodiment, the XRPD pattern of the NX-II crystal form has characteristic peaks at diffraction angles 2θ at 4.7°±0.2°, 5.8°±0.2°, 8.8°±0.2°, 9.2°±0.2°, 11.5°±0.2°, 16.0°±0.2°, 17.3°±0.2°, 21.0°±0.2°, 23.0°±0.2°, 26.9°±0.2°, and 27.0°±0.2°.

[0028] In another preferred embodiment, the NX-II crystal form has essentially the following characteristics: Figure 7 The XRPD spectrum shown.

[0029] In another preferred embodiment, the NX-II crystal form has essentially the following characteristics: Figure 8 The TGA spectrum shown.

[0030] In another preferred embodiment, the crystal form NX-II is a formic acid solvate.

[0031] In a second aspect of the present invention, a method for preparing a polymorph as described in the first aspect of the present invention is provided, wherein the polymorph is of crystal form IIIa, and the method comprises the following preparation steps:

[0032] (a) Optionally, the starting material of the compound of formula (I) is dispersed in a solvent under stirring and / or heating to 40°C to 80°C to obtain a dispersion;

[0033] (b1) The dispersion obtained in step (a) is allowed to evaporate at room temperature to obtain crystal form IIIa; or

[0034] (b2) Introduce an antisolvent into the dispersion obtained in step (a), stir, and filter to obtain the crystal form IIIa.

[0035] In another preferred embodiment, the solvent is selected from the group consisting of tetrahydrofuran, acetonitrile, dimethyl sulfoxide, or combinations thereof.

[0036] In another preferred embodiment, the antisolvent is selected from the group consisting of water, or a mixture of water and water-miscible organic solvents.

[0037] In another preferred embodiment, the water-miscible organic solvent is selected from one or more of acetone, methanol, ethanol, and acetonitrile.

[0038] In another preferred embodiment, the mass (g) / volume (mL) ratio of the raw material of the compound of formula (I) to the solvent is 1:5 to 1:100.

[0039] In another preferred embodiment, the volume ratio of the solvent to the antisolvent is 1:3 to 1:20.

[0040] In another preferred embodiment, the method of introducing the antisolvent into the dispersion includes directly adding the antisolvent to the dispersion, or placing a container containing the dispersion into a container containing the antisolvent to perform gas-liquid diffusion.

[0041] In another preferred embodiment, in step (b1) or (b2), the time for placing, evaporating, or stirring is preferably 1 day.

[0042] In a third aspect of the invention, there is provided the use of the polymorph as described in the first aspect of the invention for preparing a medicament for the prevention and / or treatment of rectal cancer.

[0043] In a fourth aspect of the invention, a pharmaceutical composition is provided comprising: a polymorph of a compound of formula (I) as described in the first aspect of the invention and a pharmaceutically acceptable carrier.

[0044] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0045] Figure 1 This is the XRPD spectrum of crystal form IIIa of fruquintinib as described in this invention.

[0046] Figure 2 This is the TGA spectrum of crystal form IIIa of fruquintinib as described in this invention.

[0047] Figure 3 This is the DSC spectrum of crystal form IIIa of fruquintinib as described in this invention.

[0048] Figure 4 This is the XRPD spectrum of the NX-I crystal form of fruquintinib described in this invention.

[0049] Figure 5 This is the TGA spectrum of the NX-I crystal form of fruquintinib described in this invention.

[0050] Figure 6 This is the DSC spectrum of the NX-I crystal form of fruquintinib described in this invention.

[0051] Figure 7 This is the XRPD spectrum of the NX-II crystal form of fruquintinib described in this invention.

[0052] Figure 8 This is the TGA spectrum of the NX-II crystal form of fruquintinib described in this invention. Detailed Implementation

[0053] Through extensive and in-depth research, the inventors have, for the first time, provided a polymorph of fruquintinib, and the trihydrate form IIIa provided by this invention exhibits excellent stability. Based on this, the inventors completed this invention.

[0054] the term

[0055] In this document, unless otherwise specified, all abbreviations have their conventional meanings as understood by those skilled in the art.

[0056] As used herein, unless otherwise specified, the term “raw material of formula (I) compound” refers to the various solid forms of the formula fruquintinib compound (including the various crystalline or amorphous forms mentioned herein, and the crystalline or amorphous forms mentioned in various published or unpublished documents or patents).

[0057] Preferably, the fruquintinib raw material used in this invention is fruquintinib prepared by the preparation method provided in the embodiments of this invention.

[0058] As used herein, “polymorph of the present invention” refers to polymorph IIIa, polymorph NX-I, and polymorph NX-II of fruquintinib as described herein.

[0059] As used in this article, the term "room temperature" generally refers to 4–30°C, and preferably 20±5°C.

[0060] As used in this article, the term "optionally" means optional or not optional.

[0061] As used herein, the term "pharmaceuticalally acceptable" means a substance that is suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), i.e., a reasonable benefit / risk ratio.

[0062] As used in this article, the solvent or solution is added by pouring it directly or adding it at a constant rate.

[0063] The crystal form of the present invention

[0064] As used herein, “polyform of the invention” refers to the crystalline form of fruquintinib as described herein, including polyform IIIa, polyform NX-I and polyform NX-II.

[0065] The crystal form IIIa of the present invention has an X-ray powder diffraction (XRPD) pattern including two or more 2θ values ​​selected from the group consisting of: 7.2°±0.2°, 8.6°±0.2°, 12.0°±0.2°, 14.4°±0.2°, 15.2°±0.2°, 20.4°±0.2°, 22.3°±0.2°, 26.1°±0.2°, and 29.1°±0.2°.

[0066] In a preferred embodiment, the XRPD pattern of crystal form IIIa includes three or more 2θ values ​​selected from the group consisting of: 7.2°±0.2°, 8.6°±0.2°, 12.0°±0.2°, 14.4°±0.2°, 15.2°±0.2°, 16.2±0.2°, 20.4°±0.2°, 22.3°±0.2°, 24.0°±0.2°, 26.1°±0.2°, 26.4°±0.2°, and 29.1°±0.2°.

[0067] In another preferred embodiment, the XRPD pattern of crystal form IIIa includes four or more 2θ values ​​selected from the group consisting of: 4.8°±0.2°, 7.2°±0.2°, 8.6°±0.2°, 9.7°±0.2°, 12.0°±0.2°, 14.4°±0.2°, 15.1°±0.2°, 16.1°±0.2°, 17.3°±0.2°, 20.4°±0.2°, 20 0.7°±0.2°, 22.3°±0.2°, 24.0°±0.2°, 24.4°±0.2°, 25.4°±0.2°, 26.1°±0.2°, 26.4°±0.2°, 28.3°±0.2°, 28.6°±0.2°, 29.1°±0.2°, 29.6°±0.2°, 30.2°±0.2°, 30.8°±0.2° and 32.7°±0.2°.

[0068] In another preferred embodiment, the crystal form IIIa is a trihydrate crystal form, and the hydrate in the crystal form originates from water vapor in the environment.

[0069] In another preferred embodiment, the crystal form IIIa has XRPD characteristic peaks as shown in Table 1.

[0070] In another preferred embodiment, the crystal form IIIa has essentially the following characteristics: Figure 1 The XRPD spectrum shown.

[0071] In another preferred embodiment, the crystal form IIIa has essentially the following characteristics: Figure 2 The thermogravimetric analysis (TGA) spectrum shown indicates that crystal form IIIa exhibits significant weight loss of 11% or more, preferably 12% or more, at room temperature to 110°C.

[0072] In another preferred embodiment, the crystal form IIIa has essentially the following characteristics: Figure 3 The DSC spectrum shown indicates that crystal form IIIa has an endothermic peak at 98.25℃ and 243.53℃, and the peak temperature of dehydration of crystal form IIIa is 98.25℃±5℃; the melting point of crystal form IIIa after dehydration is 243.53℃±5℃.

[0073] In another preferred embodiment, the purity of crystal form IIIa is at least 99%, preferably 99.5%.

[0074] The NX-I crystal form of the present invention has an XRPD diagram comprising four or more 2θ values ​​selected from the following group: 6.4°±0.2°, 8.6°±0.2°, 13.0°±0.2°, 13.8°±0.2°, 15.0°±0.2°, 17.2°±0.2°, 19.5°±0.2°, 19.8°±0.2°, 21.1°±0.2°, 22.1°±0.2°, 24.5°±0.2°, 25.8°±0.2°, 27.6°±0.2°, 30.9°±0.2°, 32.7°±0.2°, 33.6°±0.2°, and 34.1°±0.2°.

[0075] In a preferred embodiment, the crystal form NX-I has XRPD characteristic peaks as shown in Table 2.

[0076] In another preferred embodiment, the crystal form NX-I has essentially the following characteristics: Figure 4 The XRPD spectrum shown.

[0077] In another preferred embodiment, the crystal form NX-I has essentially the following characteristics: Figure 5 The TGA spectrum shown.

[0078] In another preferred embodiment, the crystal form NX-I has essentially the following characteristics: Figure 6 The DSC spectrum shown.

[0079] The NX-II crystal form of the present invention has an XRPD diagram comprising four or more 2θ values ​​selected from the following group: 4.7°±0.2°, 5.8°±0.2°, 8.8°±0.2°, 9.2°±0.2°, 11.5°±0.2°, 16.0°±0.2°, 17.3°±0.2°, 21.0°±0.2°, 23.0°±0.2°, 26.9°±0.2°, and 27.0°±0.2°.

[0080] In a preferred embodiment, the NX-II crystal form has XRPD characteristic peaks as shown in Table 3.

[0081] In another preferred embodiment, the NX-II crystal form has essentially the following characteristics: Figure 7 The XRPD spectrum shown.

[0082] In another preferred embodiment, the NX-II crystal form has essentially the following characteristics: Figure 8 The TGA spectrum shown.

[0083] Preparation method of crystal form IIIa

[0084] In one embodiment, the method for preparing crystal form IIIa includes the following steps:

[0085] (a) Optionally, the starting material of the compound of formula (I) is dispersed in a solvent under stirring and / or heating to 40°C to 80°C to obtain a dispersion;

[0086] (b) The dispersion obtained in step (a) is allowed to evaporate at room temperature to obtain the crystal form IIIa;

[0087] Alternatively, an antisolvent may be introduced into the dispersion obtained in step (a), stirred, and filtered to obtain the crystal form IIIa.

[0088] In another preferred embodiment, the solvent is selected from tetrahydrofuran, acetonitrile, and dimethyl sulfoxide.

[0089] In another preferred embodiment, the antisolvent is selected from water, or a mixture of water and a water-miscible organic solvent.

[0090] In another preferred embodiment, the water-miscible organic solvent is selected from one or more of acetone, methanol, ethanol, and acetonitrile.

[0091] In another preferred embodiment, the mass (g) / volume (mL) ratio of the raw material of the compound of formula (I) to the solvent is 1:5 to 1:100.

[0092] In another preferred embodiment, the volume ratio of the solvent to the antisolvent is 1:3 to 1:20.

[0093] In another preferred embodiment, the method of introducing the antisolvent into the dispersion includes directly adding the antisolvent to the dispersion, or placing a container containing the dispersion into a container containing the antisolvent to perform gas-liquid diffusion.

[0094] In another preferred embodiment, in step (b), the time for placing, evaporating, or stirring is preferably 1 day.

[0095] Pharmaceutical Composition

[0096] The pharmaceutical compositions of the present invention comprise polymorphs of fruquintinib within a safe and effective range, namely crystal form IIIa, crystal form NX-I, and crystal form NX-II, or pharmacologically acceptable salts thereof, and pharmacologically acceptable excipients or carriers. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects.

[0097] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the polymorphs of the present invention without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0098] The polymorphs of the present invention are typically mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0099] Preferably, the excipient includes one or more of the following: filler, disintegrant, binder, and lubricant.

[0100] Preferably, the filler is any one or a mixture of several of the following: starch, lactose, microcrystalline cellulose, dextrin, mannitol, oxidase, and calcium sulfate.

[0101] Preferably, the disintegrant includes any one or more of carboxymethyl cellulose and its salts, croscarmellose and its salts, croscarmellose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose.

[0102] Preferably, the adhesive includes any one or more of polyvinylpyrrolidone, hydroxypropyl methylcellulose, starch paste, and pregelatinized starch.

[0103] Preferably, the lubricant includes any one or more of sodium stearate fumarate, magnesium stearate, and calcium stearate.

[0104] Compared with the prior art, the main advantages of the present invention include:

[0105] (1) The crystal forms IIIa and NX-I of the present invention have good stability, including good thermal stability, pressure stability and chemical stability. In particular, crystal form IIIa is a thermodynamically stable crystal form in water, and other crystal forms will transform into crystal form IIIa in water. At the same time, crystal form IIIa will not spontaneously transform into crystal in a high humidity environment.

[0106] (2) The crystal form IIIa of the present invention is almost non-hygroscopic, making it convenient for storage and transportation.

[0107] (3) The crystal forms IIIa and NX-I of the present invention have good solubility, dissolution rate and flowability, which can enable the drug to exert better therapeutic effects and are of great significance for formulation development and storage.

[0108] (4) The preparation process of the crystal forms IIIa and NX-I of the present invention is simple, has high yield and high repeatability, and is suitable for large-scale production.

[0109] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0110] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0111] General Method

[0112] All test methods in this invention are general methods, and the test parameters are as follows:

[0113] 1. XRPD spectral determination method:

[0114] X-ray powder diffraction instrument: Bruker D2 Phaser X-ray powder diffractometer; radiation source Cu Generator kV: 30kV; Generator mA: 10mA; Initial 2θ: 2.0°; Scan range: 2.0~35.0°; Scan speed: 0.1s / step; Step size: 0.02° / step.

[0115] 2. TGA spectral determination method:

[0116] Thermogravimetric analysis (TGA) instrument: TGA55 from TA Instruments, USA, with a temperature range of 20–300°C, a heating rate of 10°C / min, and a nitrogen flow rate of 40 mL / min.

[0117] 3. DSC spectral determination method:

[0118] Differential scanning calorimetry (DSC) instrument: DISCOVERY DSC 250 from TA Instruments, USA, with a heating rate of 10℃ / min and a nitrogen flow rate of 50mL / min in the range of 25 to 300℃.

[0119] Example 1

[0120] At room temperature, 20 mg of fruquintinib raw material was dissolved in 1 mL of tetrahydrofuran and allowed to evaporate slowly at room temperature. After evaporation for 1 day, 18.2 mg of white solid, i.e. crystal form IIIa, was obtained.

[0121] XRPD testing was performed on the obtained fruquintinib crystal form IIIa, and the results are as follows: Figure 1 As shown in Table 1, the spectral data are presented below. The obtained solid was subjected to TGA testing, and the results are as follows: Figure 2 As shown, the results indicate that the TGA spectrum of fruquintinib crystal form IIIa shows a weight loss of approximately 11.7%, indicating that this crystal form is a trihydrate (theoretical water content is 12.07%). DSC analysis of the obtained solid yielded the following results: Figure 3 As shown in the figure, the peak temperature of its DSC dehydration is 98.25℃, and the melting point after dehydration is 243.53℃.

[0122] Table 1

[0123]

[0124]

[0125] Example 2: Preparation of fruquintinib crystal form IIIa

[0126] At room temperature, 20 mg of fruquintinib raw material was suspended in 2 mL of acetonitrile and heated to 40 °C–80 °C with stirring to dissolve the solid. The solution was then allowed to evaporate slowly at room temperature. After one day of evaporation, 17.5 mg of white solid, i.e. crystal form IIIa, was obtained.

[0127] Example 3: Preparation of fruquintinib crystal form IIIa

[0128] At room temperature, 0.2 g of fruquintinib raw material was suspended in 1 mL of dimethyl sulfoxide and heated to 40℃~80℃ to dissolve it completely. 10 mL of water was slowly added dropwise to the dimethyl sulfoxide solution. After the addition was completed, a large amount of white solid precipitated. The solution was stirred at room temperature for 1 day, filtered, and dried to obtain 0.16 g of white solid, i.e. crystal form IIIa.

[0129] Example 4: Preparation of fruquintinib crystal form IIIa

[0130] At room temperature, 20 mg of fruquintinib raw material was dissolved in 1 mL of tetrahydrofuran. A 5 mL glass vial containing 1 mL of fruquintinib tetrahydrofuran solution was placed in a 20 mL glass vial containing 8 mL of purified water. The 20 mL vial was placed at room temperature to allow gas-liquid diffusion. After the solid precipitated, it was filtered to obtain a white solid, i.e., crystal form IIIa.

[0131] Example 5: Preparation of fruquintinib crystal form IIIa

[0132] The raw materials for fruquintinib, specifically 1.0 g of fruquintinib crystal form I, 1.0 g of crystal form II and 1.0 g of crystal form VII, were suspended in 30 mL of purified water, stirred at room temperature for 10 hours, and then filtered to obtain a white solid, namely crystal form IIIa.

[0133] In this embodiment, fruquintinib crystal forms I, II and VII correspond to fruquintinib crystal forms I, II and VII disclosed in WO2016037550A1, respectively, and their preparation methods can also refer to WO2016037550A1.

[0134] Example 6: Preparation of fruquintinib crystal form NX-I

[0135] 1.2g of fruquintinib raw material solid was suspended in 50mL of a mixed solvent of tetrahydrofuran and water (volume ratio 1:1), and heated to 65℃~70℃ under stirring and refluxed to dissolve the solid. The solution was then slowly cooled to room temperature, filtered, and a 20mL glass bottle containing the crystal form was placed open in a 60℃ oven. After 15 days, a white solid, namely crystal form NX-I, was obtained.

[0136] XRPD testing was performed on the obtained fruquintinib compound crystal form NX-I, and the results are as follows: Figure 4 As shown in Table 2, the spectral data are presented; the obtained solid was subjected to TGA testing, and the results are as follows. Figure 5 As shown, the results indicate that the TGA spectrum of fruquintinib NX-I crystal form showed no significant weight loss, indicating that this crystal form is anhydrous; DSC analysis of the obtained solid yielded the following results. Figure 6 As shown in the figure, the results indicate that its melting point is 245.54℃.

[0137] Table 2

[0138] 2θ / ° relative strength 6.40±0.2 27.50％ 8.61±0.2 7.90％ 12.95±0.2 8.10％ 13.83±0.2 100.00％ 14.99±0.2 7.70％ 17.24±0.2 5.40％ 19.48±0.2 5.60％ 19.84±0.2 4.70％ 21.11±0.2 3.60％ 22.09±0.2 8.70％ 24.45±0.2 0.90％ 25.82±0.2 6.30％ 27.55±0.2 1.70％ 30.87±0.2 1.20％ 32.74±0.2 0.70％ 33.61±0.2 0.60％ 34.10±0.2 0.70％

[0139] Example 7: Preparation of fruquintinib crystal form NX-I

[0140] 1.7 g of fruquintinib solid was suspended in 70 mL of a mixed solvent of tetrahydrofuran and water (volume ratio 3:1), and heated to 65 °C–70 °C under stirring and refluxed to dissolve the solid. The solution was then slowly cooled to room temperature, filtered, and placed open in a 60 °C oven for 10 days to obtain a white solid, i.e., crystal form NX-I.

[0141] Example 8: Preparation of fruquintinib crystal form NX-II

[0142] Weigh 6.2 mg of fruquintinib solid and dissolve it in 0.1 mL of formic acid at room temperature. Allow it to evaporate at room temperature for 5 days to obtain a light yellow solid, i.e., NX-II crystal form.

[0143] The obtained NX-II crystal form was subjected to XRPD testing, and the results are as follows: Figure 7 As shown, the spectral data are presented in Table 3. The obtained solid was subjected to TGA testing, and the results are as follows: Figure 8 As shown, the results indicate that the TGA spectrum of fruquintinib NX-II crystal form shows significant weight loss, indicating that this crystal form is a solvate.

[0144] Table 3

[0145] 2θ / ° relative strength 4.70±0.2 14.40％ 5.82±0.2 100.00％ 8.75±0.2 9.70％ 9.22±0.2 27.60％ 11.53±0.2 91.80％ 15.97±0.2 13.70％ 17.26±0.2 18.20％ 21.01±0.2 24.40％ 22.95±0.2 42.20％ 26.91±0.2 35.00％ 27.02±0.2 36.90％

[0146] Example 9: Preparation of fruquintinib crystal form NX-II

[0147] Weigh 2.0 g of fruquintinib solid and dissolve it in 1 mL of formic acid at 50 °C. Allow it to cool in the open at room temperature overnight to obtain the NX-II crystal form.

[0148] Example 1: Comparison of stability of different crystal forms

[0149] Crystal forms I and VII in the prior art WO2016037550A1 and crystal forms IIIa and NX-I of the present invention were ground, or placed in the open at 25℃ / 60%RH, 40℃ / 75%RH and 60℃ / 92.5%RH respectively; samples were taken after grinding for 10 minutes or after being placed under different temperature and humidity conditions, and XRPD and HPLC were tested. The results of crystal form stability are shown in Tables 4 to 6.

[0150] Table 4. Stability data of different crystal forms under conditions of 25℃ / 60%RH and 40℃ / 75%RH.

[0151]

[0152]

[0153] Table 5. Stability data of different crystal forms at 60℃ / 92.5%RH.

[0154]

[0155] Table 6. Stability data after grinding different crystal forms

[0156] Initial crystal form Grind for 10 minutes Crystal form I Crystal form I Crystal form VII Crystal form IIIa Crystal form IIIa Crystal form IIIa Crystal form NX-I Crystal form NX-I

[0157] The results in Tables 4-6 show that crystal form VII transforms into crystal form IIIa under all investigated conditions, while crystal forms I, IIIa, and NX-I do not exhibit crystal transformation. Crystal forms IIIa and NX-I of this invention remain stable for 10 days to 3 months under conditions of 60℃ / 92.5%RH, 40℃ / 75%RH, and 25℃ / 60%RH, with no significant change in crystal purity; furthermore, no crystal transformation is observed after grinding, demonstrating that crystal forms IIIa and NX-I are stable under different temperature and humidity environments, exhibiting good thermal, physical, and chemical stability. Crystal form IIIa, in particular, shows good stability in water and does not spontaneously transform under high temperature and humidity conditions. This excellent stability makes crystal forms IIIa and NX-I more advantageous for drug transport and the development of formulation processes.

[0158] Example 2: Comparison of hygroscopicity of different crystal forms

[0159] Hygroscopicity tests were conducted on crystal forms I and VII in existing technology WO2016037550A1 and crystal form IIIa of this invention, according to the methods in the Chinese Pharmacopoeia. Dry, stoppered glass weighing bottles (outer diameter 50 mm, height 15 mm) were placed in a 25°C constant temperature desiccator (with a saturated ammonium sulfate solution at the bottom) one day before the test, and their weight was accurately measured (m1). Appropriate amounts of crystal forms I, VII, and IIIa were spread evenly in three of the aforementioned weighing bottles, with a sample thickness generally about 1 mm. The weighing bottles and caps were then accurately weighed together (m2). The weighing bottles were left open and placed under the same constant temperature and humidity conditions as the caps for 24 hours. The weighing bottles were then capped and accurately weighed (m3). The percentage increase in weight was calculated (percentage increase = [(m3-m2) / (m2-m1)] x 100%), and the results are shown in Table 7 below.

[0160] Table 7 Comparison of moisture absorption and weight gain data for different crystal forms

[0161] Crystal form Percentage of weight gain Crystal form IIIa 0.10％ Crystal form I 0.11％ Crystal form VII 12.15％

[0162] The hygroscopic test results in the table above show that crystal form VII has greater hygroscopicity, while crystal form IIIa of the present invention has a weight gain percentage of only 0.10%, with almost no hygroscopicity, making it convenient for storage and transportation.

[0163] In summary, the crystal forms IIIa and NX-I provided by this invention exhibit good stability, including excellent thermal stability, pressure stability, and chemical stability. In particular, crystal form IIIa is thermodynamically stable in water, while other crystal forms will transform into crystal form IIIa in water. Furthermore, crystal form IIIa will not spontaneously transform into crystals in high humidity environments. Moreover, crystal form IIIa of this invention has almost no hygroscopicity, facilitating storage and transportation. In addition, crystal forms IIIa and NX-I of this invention have good solubility, dissolution rate, and flowability, which can enable drugs to exert better therapeutic effects and are of great significance for formulation development and storage. The preparation process of crystal forms IIIa and NX-I of this invention is simple, has high yield, and high reproducibility, making it suitable for scale-up production.

[0164] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A polymorph of a compound of formula (I) characterized by, the polymorph is a hydrate, an anhydrate or a solvate; 2. The polymorph of the compound of formula (I) according to claim 1, characterized by, the polymorph is a trihydrate.

3. The polymorph of the compound of formula (I) according to claim 1, characterized by, the polymorph is Form IIIa, and the X-ray powder diffraction pattern of the Form IIIa includes two or more 2θ values selected from the group consisting of 7.2°±0.2°, 8.6°±0.2°, 12.0°±0.2°, 14.4°±0.2°, 15.2°±0.2°, 20.4°±0.2°, 22.3°±0.2°, 26.1°±0.2° and 29.1°±0.2°.

4. The polymorph of the compound of formula (I) according to claim 3, characterized by, the Form IIIa has an X-ray powder diffraction pattern substantially as shown in Figure 1; and / or the Form IIIa has a thermogravimetric analysis TGA profile substantially as shown in Figure 2.

5. The polymorph of the compound of formula (I) as claimed in claim 1, wherein, the polymorph is Form NX-I, and the X-ray powder diffraction pattern of the Form NX-I includes two or more 2θ values selected from the group consisting of 6.4°±0.2°, 8.6°±0.2°, 13.0°±0.2°, 13.8°±0.2°, 15.0°±0.2°, 22.1°±0.2° and 25.8°±0.2°; or the polymorph is Form NX-II, and the X-ray powder diffraction pattern of the Form NX-II includes two or more 2θ values selected from the group consisting of 5.8°±0.2°, 9.2°±0.2°, 11.5°±0.2°, 21.0°±0.2°, 23.0°±0.2° and 27.0°±0.2°.

6. A process for the preparation of the polymorph of claim 1, characterized in that, the polymorph is Form IIIa, comprising the following preparation steps: (a) optionally, dispersing a raw material of the compound of Formula (I) in a solvent under stirring and / or heating to 40-80°C to obtain a dispersion; (b1) volatilizing the dispersion obtained in step (a) at room temperature to obtain Form IIIa; or (b2) introducing an anti-solvent into the dispersion obtained in step (a), stirring, and filtering to obtain the Form IIIa.

7. The production method according to claim 6, wherein the method comprises one or more of the following features: (i) the solvent is selected from the group consisting of tetrahydrofuran, acetonitrile, dimethyl sulfoxide, or a combination thereof; (ii) the anti-solvent is selected from the group consisting of water, or a mixed solvent of water and a water-miscible organic solvent selected from one or more of acetone, methanol, ethanol and acetonitrile; (iii) the volume ratio of the solvent to the anti-solvent is 1:3-1:20; and / or (iv) the mass (g) of the raw material of the compound of Formula (I) to the volume (mL) of the solvent is 1:5-1:

100.

8. The production method according to claim 6, wherein the way of introducing the anti-solvent into the dispersion comprises the step of adding the anti-solvent directly into the dispersion, or placing a container containing the dispersion into a container containing the anti-solvent for gas-liquid diffusion.

9. Use of a polymorph according to claim 1, characterized in that, a medicament for preventing and / or treating metastatic colorectal cancer.

10. A pharmaceutical composition, characterized by, the pharmaceutical composition comprises the polymorph of claim 1, and a pharmaceutically acceptable carrier.

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