Crystal form of fruquintinib and preparation method therefor
By preparing a new crystal form of fruquintinib, AZT-III, the problem of instability of the existing crystal form under high temperature and high humidity was solved, achieving excellent stability and flowability, making it suitable for drug formulation development and industrial production.
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- ANLITE SHANGHAI PHARMA TECH CO LTD
- Filing Date
- 2026-01-09
- Publication Date
- 2026-07-16
AI Technical Summary
The existing fruquintinib crystal form is unstable under high temperature, high humidity and light, has poor fluidity, low water solubility, low dissolution rate, and is difficult to stably obtain a single crystal form, which affects the industrial production and application of the drug.
A novel crystalline form of fruquintinib, AZT-III, is provided. It is a monohydrate that is dissolved and crystallized at 50°C to 70°C using a specific preparation method. A crystalline form with excellent stability and fluidity is prepared by using a mixture of water and a water-miscible organic solvent.
Crystalline AZT-III is stable under high temperature and high humidity conditions, does not easily transform into crystals, has good flowability and almost no hygroscopicity, making it suitable for pharmaceutical formulation development and industrial production, thus improving drug stability and therapeutic efficacy.
Smart Images
Figure CN2026071736_16072026_PF_FP_ABST
Abstract
Description
A crystal form of fruquintinib and its preparation method 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, with the molecular formula C21H19N3O5, a molecular weight of 393.39, and the CAS number 1194506-26-7. Its chemical structure is shown in formula (I).
[0004] Currently, existing technologies disclose different crystal forms, preparation methods, and application methods for fruquintinib. For example, WO2016037550A1 discloses three amorphous crystal forms of fruquintinib: crystal form I, crystal form III, and crystal form VII, as well as a semi-ethanol solvate crystal form II, an acetic acid solvate crystal form IV, and a 1,4-dioxane solvate crystal form VIII. 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. As another example, WO2024245409A1 reports a trihydrate crystal form α of fruquintinib. This crystal form α is prone to dehydration and crystal transformation, requires low-temperature storage, and exhibits poor flowability and high static electricity.
[0005] Therefore, there is still a need in this field to develop new solid forms of fruquintinib compounds that are more suitable for industrial production. Summary of the Invention
[0006] In view of the problems in the prior art, the purpose of this invention is to provide a crystal form of fruquintinib, AZT-III, to better meet the needs of drug development and application.
[0007] In a first aspect, the present invention provides a polymorph of a compound of formula (I), characterized in that the polymorph is a hydrate:
[0008] In another preferred embodiment, the polymorph is a monohydrate.
[0009] In another preferred embodiment, the monohydrate crystal form is AZT-III, and the X-ray powder diffraction (XRPD) pattern of the AZT-III crystal form includes two or more 2θ values selected from the group consisting of: 10.8°±0.2°, 12.6°±0.2°, 14.0°±0.2°, 15.3°±0.2°, 22.4°±0.2°, 24.6°±0.2°, and 25.2°±0.2°.
[0010] In another preferred embodiment, the X-ray powder diffraction pattern of the AZT-III crystal form includes three or more 2θ values selected from the group consisting of: 7.1°±0.2°, 10.8°±0.2°, 12.6°±0.2°, 14.0°±0.2°, 15.3°±0.2°, 18.3°±0.2°, 19.5°±0.2°, 19.8°±0.2°, 20.9°±0.2°, 22.4°±0.2°, 24.6°±0.2°, 25.2°±0.2°, 28.2°±0.2°, 28.5°±0.2°, and 29.5°±0.2°.
[0011] In another preferred embodiment, the diffraction angle 2θ values of the X-ray powder diffraction pattern of the AZT-III crystal form are in the ranges of 7.1°±0.2°, 10.8°±0.2°, 11.5°±0.2°, 12.6°±0.2°, 14.0°±0.2°, 15.3°±0.2°, 18.3°±0.2°, 19.5°±0.2°, and 19.8°±0.2°. Characteristic peaks are present at 0.2°, 20.9°±0.2°, 21.6°±0.2°, 22.4°±0.2°, 24.6°±0.2°, 25.2°±0.2°, 27.0°±0.2°, 28.2°±0.2°, 28.5°±0.2°, 29.5°±0.2°, 32.8°±0.2°, and 34.3°±0.2°.
[0012] In another preferred embodiment, the crystal form AZT-III has XRPD data as shown in Table 1.
[0013] In another preferred embodiment, the crystal form AZT-III has an X-ray powder diffraction pattern substantially as shown in Figure 1.
[0014] In another preferred embodiment, the crystal form AZT-III has a thermogravimetric analysis TAG diagram as shown in Figure 2.
[0015] In another preferred embodiment, the crystalline form AZT-III exhibits significant weight loss of 4.5% at temperatures ranging from 50°C to 180°C.
[0016] In another preferred embodiment, the crystal form AZT-III has a DSC spectrum essentially as shown in Figure 3.
[0017] In another preferred embodiment, the AZT-III crystal form has an endothermic peak at a peak temperature of 136.32°C and an onset temperature of 245.92°C.
[0018] In another preferred embodiment, the dehydration temperature of the AZT-III crystal form is 136.32℃±5℃.
[0019] In another preferred embodiment, the melting point of the AZT-III crystal form after dehydration is 245.92℃±5℃.
[0020] In another preferred embodiment, the purity of the AZT-III crystal form is 99%.
[0021] In another preferred embodiment, the purity of the AZT-III crystal form is 99.5%.
[0022] In another preferred embodiment, the purity of the AZT-III crystal form is 99.9%.
[0023] In a second aspect of the invention, a method for preparing the hydrate crystal form AZT-III of the compound of formula (I) as described in the first aspect of the invention is provided.
[0024] (i) The method includes the following steps:
[0025] (a1) Disperse the raw material of compound (I) in a solvent, heat it to 50℃~70℃, and keep the solution clear to obtain a clear solution;
[0026] (a2) Cool the solution obtained in step (a1) to 20℃~45℃, stir, cool and crystallize, and filter to obtain the crystal form AZT-III.
[0027] In another preferred embodiment, step (a2) includes slowly cooling the solution obtained in step (a1) to 40°C to 45°C; optionally, adding AZT-III seed crystals; then continuing to slowly cool to 20°C to 30°C and stirring at a constant temperature, filtering, and drying to obtain the crystalline form AZT-III.
[0028] Or (ii) the method includes the steps of:
[0029] (b1) Disperse the raw material of compound (I) in a solvent to obtain a suspension;
[0030] (b2) The suspension obtained in step (b1) is stirred at a constant temperature of 30℃ to 60℃ and filtered to obtain the crystal form AZT-III.
[0031] In another preferred embodiment, the solvent is selected from a mixture of water and a water-miscible organic solvent.
[0032] In another preferred embodiment, the water-miscible organic solvent in the mixed solvent is selected from tetrahydrofuran, acetonitrile, phenylacetonitrile, and acrylonitrile.
[0033] In another preferred embodiment, the volume ratio of water and water-miscible organic solvent in the mixed solvent is 1:0.5 to 1:6.
[0034] In another preferred embodiment, the mass (g) / volume (mL) ratio of the raw material to the solvent of the compound of formula (I) is 1:1 to 1:100, and preferably, the mass (g) / volume (mL) ratio of the raw material to the solvent of the compound of formula (I) is 1:1 to 1:50.
[0035] 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.
[0036] In a fourth aspect of the invention, a pharmaceutical composition is provided, the pharmaceutical composition comprising: 1) the polymorph described in the first aspect of the invention; and 2) a pharmaceutically acceptable carrier.
[0037] 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
[0038] Figure 1 is the XRPD spectrum of the crystal form AZT-III of fruquintinib described in this invention.
[0039] Figure 2 is the TGA spectrum of the crystal form AZT-III of fruquintinib described in this invention.
[0040] Figure 3 is the DSC spectrum of the AZT-III crystal form of fruquintinib described in this invention.
[0041] Figure 4 is the DVS spectrum of the crystalline form AZT-III of fruquintinib described in this invention.
[0042] Figure 5 is a microscopic photograph of the crystal form AZT-III of fruquintinib described in this invention.
[0043] Figure 6 is a microscope photograph of crystal form I of fruquintinib described in this invention.
[0044] Figure 7 is a microscope photograph of crystal form VII of fruquintinib described in this invention.
[0045] Figure 8 is a microscopic photograph of the crystal form α of fruquintinib described in this invention. Detailed Implementation
[0046] Through extensive and in-depth research, the inventors have, for the first time, provided a novel crystal form of fruquintinib. This crystal form, AZT-III, exhibits excellent stability, is virtually hygroscopic, and possesses good flowability, which is beneficial for subsequent drug formulation development. Furthermore, the preparation process of AZT-III is simple, and the solvent system is convenient and economical, making it suitable for industrial-scale production and providing a superior option for the development of drugs containing fruquintinib. Based on these findings, the inventors have completed this invention.
[0047] the term
[0048] In this document, unless otherwise specified, all abbreviations have their conventional meanings as understood by those skilled in the art.
[0049] As used herein, unless otherwise specified, the term “fruquintinib raw material” refers to the various solid forms of the 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).
[0050] Preferably, the fruquintinib raw material used in this invention is fruquintinib prepared by the preparation method provided in the embodiments of this invention.
[0051] As used herein, “the crystal form of the present invention” refers to the fruquintinib crystal form AZT-III as described herein.
[0052] As used in this article, the “slow addition” method includes, but is not limited to: adding drop by drop, or adding slowly along the container wall.
[0053] As used in this article, the term "room temperature" generally refers to 4℃ to 30℃, and preferably 20℃ ± 5℃.
[0054] The crystal form of the present invention
[0055] As used herein, “polymorph of the invention” refers to the polymorph of fruquintinib as described herein, the polymorph being the monohydrate polymorph AZT-III.
[0056] The XRPD pattern of the AZT-III crystal form shows characteristic peaks at diffraction angles 2θ at 7.1°±0.2°, 10.8°±0.2°, 11.5°±0.2°, 12.6°±0.2°, 14.0°±0.2°, 15.3°±0.2°, 18.3°±0.2°, 19.5°±0.2°, 19.8°±0.2°, 20.9°±0.2°, 21.6°±0.2°, 22.4°±0.2°, 24.6°±0.2°, 25.2°±0.2°, 27.0°±0.2°, 28.2°±0.2°, 28.5°±0.2°, 29.5°±0.2°, 32.8°±0.2°, and 34.3°±0.2°.
[0057] In another preferred embodiment, the crystal form AZT-III has an XRPD spectrum that is essentially as shown in Figure 1.
[0058] In another preferred embodiment, the crystal form AZT-III has a TGA spectrum as shown in Figure 2.
[0059] In another preferred embodiment, the crystal form AZT-III has a DSC spectrum as shown in Figure 3.
[0060] In another preferred embodiment, the crystal form AZT-III has a DVS spectrum as shown in Figure 4.
[0061] In another preferred embodiment, the crystal form AZT-III has a basic microscopic image as shown in FIG5.
[0062] Preparation method
[0063] The crystalline form AZT-III provided by this invention can be prepared by the following method, including the following steps:
[0064] (i) The method includes the following steps:
[0065] (a1) Disperse the raw material of compound (I) in a solvent, heat it to 50℃~70℃, and keep the solution clear to obtain a clear solution;
[0066] (a2) Cool the solution obtained in step (a1) to 20℃~45℃, stir, cool and crystallize, and filter to obtain the crystal form AZT-III.
[0067] In another preferred embodiment, step (a2) includes slowly cooling the solution obtained in step (a1) to 40°C to 45°C; optionally, adding AZT-III seed crystals; then continuing to slowly cool to 20°C to 30°C and stirring at a constant temperature, filtering, and drying to obtain the crystalline form AZT-III.
[0068] Or (ii) the method includes the steps of:
[0069] (b1) Disperse the raw material of compound (I) in a solvent to obtain a suspension;
[0070] (b2) The suspension obtained in step (b1) is stirred at a constant temperature of 30℃ to 60℃ and filtered to obtain the crystal form AZT-III.
[0071] In another preferred embodiment, the solvent is selected from a mixture of water and a water-miscible organic solvent.
[0072] In another preferred embodiment, the water-miscible organic solvent in the mixed solvent is selected from tetrahydrofuran, acetonitrile, phenylacetonitrile, and acrylonitrile.
[0073] In another preferred embodiment, the volume ratio of water and water-miscible organic solvent in the mixed solvent is 1:0.5 to 1:6.
[0074] In another preferred embodiment, the mass (g) / volume (mL) ratio of the raw material to the solvent of the compound of formula (I) is 1:1 to 1:100, and preferably, the mass (g) / volume (mL) ratio of the raw material to the solvent of the compound of formula (I) is 1:1 to 1:50.
[0075] Pharmaceutical Composition
[0076] The pharmaceutical compositions of the present invention comprise fruquintinib crystal form, namely crystal form AZT-III or a pharmacologically acceptable salt thereof, within a safe and effective range, and a pharmacologically acceptable excipient or carrier. Here, "safe and effective range" means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
[0077] "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.
[0078] 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.
[0079] Preferably, the excipient includes one or more of fillers, disintegrants, binders, and lubricants.
[0080] Preferably, the filler includes one or more of starch, lactose, microcrystalline cellulose, dextrin, mannitol, oxidase, and calcium sulfate.
[0081] Preferably, the disintegrant includes one or more of carboxymethyl cellulose and its salts, croscarmellose and its salts, croscarmellose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose.
[0082] Preferably, the adhesive comprises one or more of polyvinylpyrrolidone, hydroxypropyl methylcellulose, starch paste, and pregelatinized starch.
[0083] Preferably, the lubricant comprises one or more of sodium stearate fumarate, magnesium stearate, and calcium stearate.
[0084] Compared with the prior art, the main advantages of the present invention include:
[0085] (1) The crystal form AZT-III of the present invention has obvious advantages in terms of stability, including good thermal stability, pressure stability and chemical stability; especially in high temperature and high humidity environments, it will not spontaneously transform into crystals.
[0086] (2) The crystal form AZT-III of the present invention is almost non-hygroscopic, which facilitates the storage and transportation of the formulation.
[0087] (3) The crystal form AZT-III of the present invention has good fluidity, which can enable the drug to exert better therapeutic effects and is of great significance for formulation development.
[0088] (4) The preparation process of the crystal form AZT-III of the present invention is simple and the solvent system is convenient and economical, making it suitable for industrial scale-up production.
[0089] 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.
[0090] 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.
[0091] General Method
[0092] All test methods in this invention are general methods, and the test parameters are as follows:
[0093] XRPD spectrum determination method:
[0094] 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.
[0095] TGA spectral determination method:
[0096] 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.
[0097] DSC spectrum determination method:
[0098] 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℃.
[0099] DVS spectrum determination method:
[0100] Dynamic Moisture Adsorption (DVS) Instrument: TA Instruments Q5000 SA model, USA; Temperature: 25℃; Relative Humidity Range: 0%~90%~0%; Stepped Relative Humidity Adjustment, Humidity Gradient 10%, Maximum Stay at Each Humidity Level for 2 Hours; If the Weight Change is Less Than 0.01% Within 10 Minutes During the Humidity Adjustment Process, Move to the Next Humidity Level.
[0101] Polarizing microscope observation method:
[0102] Polarizing microscope instrument: BH200P model from Ningbo Sunny Optical Co., Ltd. Sample preparation: Disperse the powder in silicone oil, take 1-2 drops, and observe under 40x or 100x magnification.
[0103] Example 1: Preparation of fruquintinib crystal form AZT-III
[0104] 3g of fruquintinib raw material was added to a mixed solvent of 40mL tetrahydrofuran and 20mL water, and the mixture was heated to 62℃~65℃ and refluxed until dissolved. The temperature was slowly lowered to 45℃ for 3 hours, and a large amount of solid precipitated out. The temperature was then slowly lowered to 20℃~30℃ for 2 hours. After reaching 20℃~30℃, the mixture was stirred at a constant temperature for 0.5~1 hour. The mixture was filtered and washed with 15mL of room temperature water. The resulting wet solid was dried overnight in a vacuum drying oven at 50℃ to obtain 2.1g of solid, i.e., crystal form AZT-III.
[0105] XRPD testing was performed on the obtained fruquintinib crystal form AZT-III, and the results are shown in Figure 1. The spectral data are shown in Table 1 below. TGA testing was performed on the obtained solid, and the results are shown in Figure 2. The results show that the fruquintinib crystal form AZT-III has a weight loss of approximately 4.5%, indicating that this crystal form is a monohydrate (theoretical water content is 4.4%). DSC testing was performed on the obtained solid, and the results are shown in Figure 3. The results show that its DSC dehydration peak temperature is 136.32℃, and the melting point after dehydration is 245.92℃.
[0106] Table 1
[0107] Example 2: Preparation of fruquintinib crystal form AZT-III
[0108] 3g of fruquintinib raw material was added to a mixed solvent of 80mL tetrahydrofuran and 40mL water, and heated to 50℃~60℃ to dissolve. The solution was then slowly cooled to 35℃~45℃ for 1~3 hours, resulting in a clear solution. 0.03g of crystalline AZT-III obtained in Example 1 was added, and the solution was stirred at a constant temperature for 1~2 hours, resulting in the precipitation of a significant amount of solid. The solution was then slowly cooled to 20℃~30℃ for 1~2 hours, and stirred at a constant temperature for 0.5~1 hour after reaching 20℃~30℃. The solution was filtered, washed with 15mL of room temperature water, and the resulting wet solid was dried overnight in a vacuum drying oven at 50℃ to obtain 2.4g of solid, which is crystalline AZT-III.
[0109] Example 3: Preparation of fruquintinib crystal form AZT-III
[0110] 0.5g of fruquintinib crystal form I, 0.5g of crystal form AZT-III and 0.5g of crystal form α were added to 5mL of a mixed solvent of tetrahydrofuran / water = 1 / 2. The suspension was placed in a biochemical incubator at 50℃ and magnetically stirred for 24h. After cooling, a solid, namely crystal form AZT-III, precipitated out.
[0111] Example 1: Comparison of stability of different crystal forms
[0112] Crystal forms I and VII from WO2016037550A1, crystal form α from WO2024245409A1, and crystal form AZT-III of this invention were left exposed at 50°C, 25°C / 60%RH, and 40°C / 75%RH for 0–3 months, respectively. Samples were then taken and their XRPD and HPLC results were analyzed. The crystal form stability results are shown in Table 2. Crystal forms I and VII from WO2016037550A1, and crystal form AZT-III of this invention were left exposed at 60°C / 92.5%RH for 0–10 days, respectively. The samples were then ground, and samples were taken after grinding. The XRPD and HPLC results of the relevant samples were analyzed. The crystal form stability results are shown in Table 3.
[0113] Table 2. Stability of different crystal forms at 50℃, 25℃ / 60%RH and 40℃ / 75%RH.
[0114] Table 3. Stability of different crystal forms at 60℃ / 92.5% RH
[0115] As can be seen from the above embodiments, fruquintinib crystal form VII transforms into crystal form α under humid conditions, and transforms into a mixed crystal containing crystal forms α, VII, and I at 50°C. Fruquintinib crystal form α retains its original crystal form α in a humid environment, but transforms into a mixed crystal of crystal forms I and VII at 50°C. Fruquintinib crystal form I does not exhibit crystal transformation under varying humidity and temperature conditions. The AZT-III crystal form of the present invention remains stable as AZT-III and maintains a purity of over 99.9% after being stored at 50°C, 60°C / 92.5%RH, 40°C / 75%RH, and 25°C / 60%RH for 10 days to 3 months, respectively, demonstrating its stable existence under different temperature and humidity conditions. Furthermore, no crystal transformation was observed in the AZT-III crystal form of the present invention during grinding under high temperature and high humidity conditions. In summary, the crystalline AZT-III of the present invention has good thermal stability, physical stability and chemical stability. The good stability makes the crystalline AZT-III beneficial for drug transport and transfer and the development of formulation processes under different conditions.
[0116] Example 2: Comparison of hygroscopicity of different crystal forms
[0117] Hygroscopicity tests were conducted on crystal forms I and VII in the prior art WO2016037550A1 and crystal form AZT-III of the present invention according to the methods in the Chinese Pharmacopoeia. The results are shown in Table 4 below.
[0118] Table 4 Comparison of hygroscopicity test data for different crystal forms
[0119] The hygroscopicity test results show that crystal form VII has a large hygroscopicity, while the hygroscopicity of crystal form AZT-III and crystal form I of the present invention is only 0.12% and 0.11%, respectively; indicating that crystal form AZT-III of the present invention has almost no hygroscopicity, which is convenient for storage and transportation.
[0120] Example 3: Comparison of fluidity of different crystal forms
[0121] Based on the polarized light microscope images in Figures 5, 6, 7, and 8, crystal forms I, VII, and α are all needle-like crystals, while crystal form AZT-III is a bulk crystal. Generally, bulk particles have a small contact area with each other and thus better fluidity; needle-like particles have a large number of planar contact points on their surface, resulting in poorer fluidity. According to the fixed mass method and tap density determination method in the Chinese Pharmacopoeia, the bulk density and tap density of crystal forms I and VII in the prior art WO2016037550A1 and crystal form AZT-III of this invention were tested, and the Hausner ratio was calculated. The results are shown in Table 5 below.
[0122] Table 5 Comparison of fluidity data for different crystal forms
[0123] Flowability results showed that AZT-III exhibited superior flowability compared to existing crystal forms I, VII, and α. Given that fruquintinib is marketed as a small-capsule formulation, providing a crystal form with good flowability is more conducive to the uniform mixing of fruquintinib active pharmaceutical ingredient and excipients. Therefore, the AZT-III crystal form provided by this invention is of great significance in the development of this drug formulation.
[0124] In summary, the AZT-III crystal form of this invention exhibits significant advantages in stability, including excellent thermal stability, pressure stability, and chemical stability. Even under conditions of constantly changing temperature and humidity, the AZT-III crystal form of this invention not only does not spontaneously transform into crystals but also maintains a purity of over 99.9%. Furthermore, the AZT-III crystal form of this invention is virtually non-hygroscopic, facilitating the storage and transportation of the drug. The AZT-III crystal form of this invention also possesses excellent flowability, which is beneficial for the uniform mixing of fruquintinib active pharmaceutical ingredient and excipients, thereby facilitating the development of small-sized fruquintinib capsules. The preparation method of the AZT-III crystal form of this invention is simple to operate, and the solvent system is economical and convenient, making it suitable for large-scale industrial production.
[0125] 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 in that, The polymorph is a monohydrate:
2. The polymorph of the compound of formula (I) as described in claim 1, characterized in that, The polymorph is AZT-III, and the X-ray powder diffraction pattern of AZT-III includes two or more 2θ values selected from the group consisting of: 10.8°±0.2°, 12.6°±0.2°, 14.0°±0.2°, 15.3°±0.2°, 22.4°±0.2°, 24.6°±0.2°, and 25.2°±0.2°.
3. The polymorph of the compound of formula (I) as described in claim 2, characterized in that, The crystalline form AZT-III loses 4.5% of its weight at temperatures ranging from 50°C to 180°C; And / or the dehydration temperature of the crystal form AZT-III is 136.32℃±5℃; And / or the melting point of the AZT-III crystal form after dehydration is 245.92℃±5℃.
4. The polymorph of the compound of formula (I) as described in claim 2 or 3, characterized in that, The crystal form AZT-III has a basic X-ray powder diffraction pattern as shown in Figure 1; And / or the crystal form AZT-III has a thermogravimetric analysis spectrum as shown in Figure 2; And / or the crystal form AZT-III has a differential scanning calorimetry profile as shown in Figure 3; And / or the crystal form AZT-III has a dynamic water vapor adsorption pattern as shown in Figure 4.
5. A method for preparing a polymorph of the compound of formula (I) according to claim 1, characterized in that, The polymorph is AZT-III, and the process includes the following steps: (a1) Disperse the raw material of compound (I) in a solvent, heat it to 50℃~70℃, and keep the solution clear to obtain a clear solution; (a2) Cool the solution obtained in step (a1) to 20℃~45℃, stir, cool and crystallize, and filter to obtain the crystal form AZT-III.
6. The preparation method according to claim 5, characterized in that, Step (a2) includes slowly cooling the solution obtained in step (a1) to 40°C to 45°C; optionally, adding AZT-III seed crystals; then continuing to slowly cool to 20°C to 30°C and stirring at a constant temperature, filtering, and drying to obtain the crystalline form AZT-III.
7. A method for preparing a polymorph of the compound of formula (I) according to claim 1, characterized in that, The polymorph is AZT-III, and the process includes the following steps: (b1) Disperse the raw material of compound (I) in a solvent to obtain a suspension; (b2) The suspension obtained in step (b1) is stirred at a constant temperature of 30℃ to 60℃ and filtered to obtain the crystal form AZT-III.
8. A method for preparing a polymorph of the compound of formula (I) as described in any one of claims 5 to 7, characterized in that, The solvent is selected from a mixture of water and water-miscible organic solvents; And / or, the organic solvent miscible with water in the mixed solvent is selected from one of tetrahydrofuran, acetonitrile, phenylacetonitrile and acrylonitrile; And / or, the volume ratio of water to a water-miscible organic solvent in the mixed solvent is 1:0.5 to 1:6; And / or, the mass (g) / volume (mL) ratio of the raw material to the solvent of the compound of formula (I) is 1:1 to 1:
100.
9. Use of a polymorph of the compound of formula (I) as described in claim 1, characterized in that, This is used to prepare a drug for the prevention and / or treatment of metastatic colorectal cancer.
10. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a polymorph of the compound of formula (I) as claimed in claim 1 and a pharmaceutically acceptable carrier.