An axitinib oxalate crystal form and a method for preparing the same

Abstract

The application belongs to the technical field of crystal form drug molecules, and particularly relates to an axitinib oxalate crystal form and a preparation method and application thereof. The axitinib oxalate crystal form provided by the application is composed of one molecule of axitinib, one molecule of oxalic acid and two molecules of water as a basic unit of the crystal form, has high solubility, good stability, a simple preparation method, good reproducibility and is suitable for industrialized production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of crystal form drug molecules, in particular to an axitinib oxalate crystal form and a preparation method thereof. BACKGROUND

[0002] Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptor (VEGFR) / platelet-derived growth factor (PDGFR) receptor tyrosine kinase (RTK) for inhibiting early to late stage cancer, developed by Pfizer, USA. It was approved for marketing by FDA on January 27, 2012, and the trade name is On April 29, 2015, axitinib was approved by CFDA for use in adult patients with advanced renal cell carcinoma (RCC) who have failed one tyrosine kinase inhibitor or cytokine therapy. Its chemical name is N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indol-6-ylsulfonyl]-benzamide, and the structural formula is as follows:

[0003]

[0004] Due to the photosensitivity and poor solubility of axitinib, people in the field are trying to develop different crystal forms to obtain axitinib crystal forms more suitable for drug use. Patent WO2006048751A1 attempts to study axitinib crystal forms, and discloses a plurality of crystal forms of axitinib, such as crystal form I, crystal form II, crystal form III, crystal form IV, crystal form VI, crystal form VII and crystal form VIII. However, the solubility of axitinib crystal form IV is not greatly improved, for example, the solubility of axitinib crystal form IV in water solution at pH about 1 is about 0.55 mg / ml, the solubility in water solution at pH about 2 is only 0.157 mg / ml, and the solubility in water solution at pH about 6.5 is only 2 μg / ml. In order to improve the water solubility of axitinib, seven axitinib acid salt compounds are prepared, and the solubility is improved, but they are all photosensitive axitinib salts which are significantly degraded when exposed to high intensity light. Patent CN200880016453.6 discloses a plurality of crystal forms, such as crystal form XXV, crystal form XVI, crystal form XLI, crystal form IX, crystal form XII and crystal form XV. The solubility and bioavailability of crystal form XXV and crystal form XLI are not greatly improved.

[0005] Due to the photosensitivity and poor solubility of axitinib itself, many people in the field are trying to develop different crystal forms to obtain a more suitable pharmaceutical axitinib crystal form. However, according to the current reports, considering the bioavailability, stability and manufacturability, among the many axitinib crystal forms disclosed, only crystal form IV and crystal form XLI are available. Due to the extreme instability of crystal form IV under light exposure, the original research company Pfizer ultimately selected crystal form XLI with relatively less light exposure degradation as the marketed crystal form (see CHMP assessment report). However, as reported by the patent CN200880016453.6, the potency of the marketed crystal form XLI after light exposure decreased to 89%, and the use of light shielding process in the preparation process is still unavoidable to achieve safe and effective drug use. Subsequent development and research of a series of axitinib solvate crystal forms, axitinib salt crystal forms and new axitinib crystal forms still have defects in terms of drug safety, solubility, bioavailability or light stability.

[0006] Based on the 7 acid salts of axitinib disclosed in patent WO2006048751A1, 7 axitinib acid salts were further characterized by powder diffraction data in patent WO2015067224A1. Patent CN201510509413.7 discloses the preparation of a crystalline axitinib fumarate crystal form A, in which the molar ratio of axitinib to fumaric acid is 1:1. After light exposure, axitinib fumarate degrades by 0.13%. CN202010787156.4 discloses a crystal form B of axitinib fumarate, in which the molar ratio of axitinib to fumaric acid is 1:1.5. The axitinib fumarate crystal form B powder sample did not change significantly in appearance and drug content after 10 days of light exposure. However, the water adsorption rate under 95% RH was 1.5%. CN202011575325.4 provides an axitinib maleate crystal form, in which the molar ratio of axitinib to maleic acid is 1:1, and two molecules of axitinib, two molecules of maleic acid and two molecules of water constitute the basic unit of the crystal form. CN202011585244.2 provides an axitinib malate crystal form, in which the basic unit of the malate crystal form is composed of one molecule of axitinib, one molecule of malic acid and one molecule of water. CN202011575299.5 provides an axitinib salicylate crystal form, in which the basic unit of the salicylate crystal form is composed of two molecules of axitinib and two molecules of salicylic acid. CN202011573595.1 provides an axitinib citrate crystal form, in which the basic unit of the citrate crystal form is composed of one molecule of axitinib, one molecule of citric acid and one molecule of water. These axitinib salts have achieved beneficial effects in terms of stability, solubility and permeability.

[0007] It is well known that the crystal form of a drug has a great influence on the stability, dissolution, permeability, bioavailability, etc. of the solid preparation of the drug, and an excellent crystal form suitable for the preparation of a solid preparation generally needs to meet the requirements of stability, dissolution, bioavailability, etc. A new salt form of a drug refers to a new co-crystal former (CCF) introduced through proton transfer, which self-assembles with a drug active effective component (APT) under the action of hydrogen bond force to form a supramolecular crystal with a fixed stoichiometric ratio. In the preclinical research and development stage of a drug, a new drug research and development company usually improves the solubility, dissolution rate, permeability, hygroscopicity, stability, bioavailability and other physicochemical properties of a drug active effective component (APT) through salt formation. Compared with nanocrystals, solid dispersions and new drug dosage forms, the salt form of a drug has obvious advantages in improving the solubility, dissolution rate, permeability, hygroscopicity, stability and bioavailability of a drug.

[0008] In order to better play the role of axitinib salt crystal form in drug synergistic therapy and better application, the present application provides a simple and easy-to-operate method for preparing high-purity axitinib oxalate salt crystal, so as to more efficiently play the medicinal value of axitinib. SUMMARY

[0009] In view of the deficiencies of the prior art, one object of the present application is to provide an axitinib oxalate salt crystal and a preparation method thereof; the salt has definite crystallographic main parameters and atomic spatial positions; and great improvements have been achieved in stability, solubility, permeability, etc.

[0010] The specific technical content of the present application is as follows:

[0011] In a first aspect, the present application provides an axitinib oxalate salt crystal, wherein one molecule of axitinib combines one molecule of oxalic acid and two molecules of water to form a basic unit of the crystal form.

[0012] Preferably, the axitinib oxalate salt crystal has characteristic peaks at 7.17±0.2°, 17.21±0.2°, 18.07±0.2°, 20.47±0.2°, 24.76±0.2° in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0013] Preferably, the X-ray diffraction spectrum of the axitinib oxalate crystal form, using Cu-Ka radiation, has characteristic peaks at 7.17±0.2°, 11.25±0.2°, 12.42±0.2°, 14.13±0.2°, 17.21±0.2°, 18.07±0.2°, 18.52±0.2°, 20.47±0.2°, 21.60±0.2°, 23.45±0.2°, 24.76±0.2°, 27.32±0.2°, 28.16±0.2°, 30.39±0.2°.

[0014] Preferably, the X-ray diffraction spectrum of the axitinib oxalate crystal form, using Cu-Ka radiation, has characteristic peaks at 7.17±0.2°, 11.25±0.2°, 12.42±0.2°, 14.13±0.2°, 17.21±0.2°, 18.07±0.2°, 18.52±0.2°, 20.47±0.2°, 21.60±0.2°, 23.45±0.2°, 24.76±0.2°, 27.32±0.2°, 28.16±0.2°, 30.39±0.2°. Figure 3

[0015] Preferably, the crystallographic parameters of the axitinib oxalate crystal form are: triclinic system, space group P-1; cell parameters are: α = 66.9690(10)°, β = 76.9010(10)°, γ = 84.3290(10)°, cell volume

[0016] The second aspect of the present application provides a preparation method of the axitinib oxalate crystal form, and the specific preparation steps include: dissolving axitinib and oxalic acid in solvent A, heating and dissolving to obtain a transparent solution, cooling and standing to crystallize, filtering, washing, and vacuum drying to obtain the axitinib oxalate crystal form.

[0017] Preferably, the solvent A is selected from the mixed solvents of acetic acid-methanol-water, acetic acid-ethanol-water, acetic acid-acetone-water, acetic acid-isopropanol-water, formic acid-methanol-water, formic acid-ethanol-water, formic acid-acetone-water, and formic acid-isopropanol-water.

[0018] Further preferably, the solvent A is selected from the mixed solvents of formic acid-ethanol-water, formic acid-methanol-water, formic acid-acetone-water, and formic acid-isopropanol-water.

[0019] Preferably, the volume ratio of the acid, alcohol or acetone, and water in the solvent A mixed solvent is 1:1 to 5:0.5 to 5, preferably 1:2.5:1.

[0020] Preferably, the molar ratio of axitinib to oxalic acid is 1:1.0 to 1.4; preferably, the molar ratio of axitinib to oxalic acid is 1:1.0 to 1.2.

[0021] Preferably, the mass-volume ratio of axitinib to solvent A in the system is 3 to 6:1, wherein the mass is in mg and the volume is in mL.

[0022] ​Preferably, the temperature of the solution heating is 55-70℃.

[0023] Preferably, the temperature of the temperature-lowering crystallization is 0-30℃, preferably 10-20℃.

[0024] Preferably, the crystallization time is 36-72 hours.

[0025] Preferably, the drying temperature is 55-60℃, and the drying time is 5-10 hours.

[0026] Preferably, the solvent for washing the filter cake is selected from one of ethanol, methanol, acetone, and isopropanol.

[0027] The third aspect of the present application provides a pharmaceutical composition comprising the prepared axitinib oxalate crystal form and other components.

[0028] Preferably, the preparation method of the pharmaceutical composition of the present application is as follows: using standard and conventional techniques, the compound of the present application is combined with a pharmaceutically acceptable solid or liquid carrier, and optionally combined with a pharmaceutically acceptable excipient to prepare a dosage form.

[0029] Preferably, the other components include other active ingredients that can be used in combination, fillers, diluents, binders, disintegrants, lubricants, etc.

[0030] Preferably, the diluent is selected from one or more of starch, sucrose, dextrin, lactose, microcrystalline cellulose, mannitol, and sorbitol; the binder is selected from one or more of methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium hydroxymethyl cellulose, ethyl cellulose, and povidone; the disintegrant is selected from one or more of sodium carboxymethyl starch, low-substitution hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and cross-linked povidone; and the lubricant is selected from one or more of magnesium stearate, microfine silica, talc, and sodium dodecyl sulfate.

[0031] Preferably, the pharmaceutical composition is a tablet, a capsule, a granule, a pill, etc.

[0032] The fourth aspect of the present application provides the use of axitinib oxalate crystal form as an active ingredient for preparing an anti-cancer drug.

[0033] Confirmation of crystal structure

[0034] The application provides an axitinib oxalate crystal form which is subjected to X-ray single crystal diffraction test analysis. The X-ray single crystal diffraction instrument and test conditions involved in the application are as follows: XtaLAB Synergy X-ray single crystal diffraction instrument of Rigaku, test temperature 293(2) K, CuKa radiation, data collection by ω scanning mode and Lp correction. The structure is analyzed by a direct method, all non-hydrogen atoms are found by difference Fourier method, all hydrogen atoms on carbon and nitrogen are obtained by theoretical hydrogenation, and the structure is refined by a least square method.

[0035] The crystallographic data of the axitinib oxalate crystal form prepared in the application is (Table 1): the crystallographic parameters are as follows: triclinic crystal system, space group P-1; cell parameters are as follows: α = 66.9690 (10) °, β = 76.9010 (10) °, γ = 84.3290 (10) °, cell volume The ORTEP of the axitinib oxalate crystal form of the application Figure 1 indicates that one molecule of axitinib is combined with one molecule of oxalic acid and two molecules of water. The packing diagram of the axitinib oxalate crystal form of the application is shown in FIG. 2. Figure 2

[0036] Table 1 Main crystallographic data of the axitinib oxalate crystal form

[0037]

[0038]

[0039] The X-ray powder diffraction test instrument and test conditions involved in the application are as follows: X-ray powder diffraction instrument: PANalytical E; Cu-Ka; sample table: flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage: 45 kv, current: 40 mA; divergence slit: 1 / 4; anti-scattering slit: 1; soller slit: 0.04 rad; step length: 0.5 s; scanning range: 3-50 °.

[0040] According to the above crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Ka) are shown in FIG. 1 and Table 2. Figure 3

[0041] Table 2 PXRD peak data of the axitinib oxalate crystal form

[0042]

[0043] All the samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction spectrum as described above.

[0044] ​​The axitinib oxalate crystal form provided by this invention has achieved significant improvements in stability, solubility, and permeability. After long-term photostability testing, the eutectic exhibits good photostability. This axitinib oxalate crystal form is regular, with uniform particle size, well-defined crystallographic parameters, and precise atomic spatial positions. Furthermore, the preparation method is simple, making it suitable for industrial production and large-scale application. Attached Figure Description

[0045] Figure 1 ORTEP diagram of axitinib oxalate crystal form.

[0046] Figure 2 Packing diagram of axitinib oxalate crystal form.

[0047] Figure 3 X-ray powder diffraction pattern of axitinib oxalate crystal form. Detailed Implementation

[0048] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0049] Materials used in the experiment: Axitinib can be purchased or prepared according to the method disclosed in patent WO2006048745. The axitinib crystal form required for the comparative experiment can be prepared according to existing technology or purchased; other materials used in this experiment whose source and specifications are not specified are all commercially available analytical grade or chemically pure.

[0050] Example 1

[0051] 399 mg of axitinib and 101 mg of oxalic acid were added to a mixed solvent of 20 mL formic acid, 50 mL ethanol and 10 mL water. The mixture was heated to 70 °C and stirred to dissolve. The mixture was refluxed for 3 hours, then slowly cooled to 10–20 °C and allowed to stand for crystallization for 36 hours. The crystals were filtered, washed with ethanol, and dried under vacuum at 55 °C for 6 hours to obtain axitinib oxalate crystals with a yield of 98.00% and a purity of 99.80%.

[0052] Example 2

[0053] 451 mg of axitinib and 154 mg of oxalic acid were added to a mixed solvent of 20 mL formic acid, 50 mL methanol and 10 mL water. The mixture was heated to 65 °C and stirred to dissolve. The mixture was refluxed for 3 hours, then slowly cooled to 10–20 °C and allowed to stand for crystallization for 36 hours. The crystals were filtered, washed with methanol, and dried under vacuum at 55 °C for 6 hours to obtain axitinib oxalate crystals with a yield of 97.26% and a purity of 99.75%.

[0054] Example 3

[0055] Add 351 mg axitinib, 82 mg oxalic acid into 20 mL formic acid, 40 mL acetone and 20 mL water mixed solvent, heat to 60℃, stir to dissolve, reflux for 3 hours, slowly cool to 10-20℃, control temperature and stand for crystallization for 36 hours, filter, wash the filter cake with acetone, vacuum dry at 55℃ for 6h, to obtain axitinib oxalate crystal form, yield 95.11%, purity 99.81%.

[0056] Example 4

[0057] Add 383 mg axitinib, 95 mg oxalic acid into 20 mL formic acid, 40 mL isopropyl alcohol and 20 mL water mixed solvent, heat to 65℃, stir to dissolve, reflux for 3 hours, slowly cool to 10-20℃, control temperature and stand for crystallization for 36 hours, filter, wash the filter cake with isopropyl alcohol, vacuum dry at 55℃ for 6h, to obtain axitinib oxalate crystal form, yield 94.95%, purity 99.74%.

[0058] Verification example:

[0059] The axitinib crystal form prepared above is investigated in terms of stability, hygroscopicity, solubility, permeability, etc. The specific implementation content is as follows:

[0060] 1. Light stability test

[0061] Take the crystal form obtained in Example 1, store it at 25℃ (RH 45%) under strong light irradiation (4500Lx±500Lx), take samples at 5 days and 10 days respectively, and detect the purity by HPLC. The results are shown in Table 3.

[0062] Table 3 Light stability test results of axitinib crystal form

[0063]

[0064] The light stability test results show that the axitinib oxalate crystal form prepared in the present application has good light stability after 10 days under strong light irradiation. It is found that Examples 1-4 have similar stability test results.

[0065] 2. Hygroscopicity test

[0066] Take the axitinib oxalate crystal form obtained in Example 1, the crystal form B of axitinib fumarate in CN202010787156.4 (repeat Example 1 to prepare it), and the axitinib maleate crystal form in CN202011575325.4 (repeat Example 1 to prepare it) to conduct hygroscopicity test.

[0067] The test method and conditions refer to the guidance principles of drug hygroscopicity test in Chinese Pharmacopoeia 2020 edition part 4 9103

[0068] Among them, the hygroscopicity characteristic description and the definition of hygroscopic weight gain are as follows:

[0069] Deliquescence: Absorbing sufficient moisture to form a liquid.

[0070] Highly hygroscopic: hygroscopic weight gain is not less than 15%.

[0071] Hygroscopic: hygroscopic weight gain is less than 15% but not less than 2%.

[0072] Slightly hygroscopic: hygroscopic weight gain is less than 2% but not less than 0.2%.

[0073] No or almost no hygroscopicity: hygroscopic weight gain is less than 0.2%.

[0074] The hygroscopicity test results are shown in Table 4.

[0075] Table 4 Hygroscopicity test results

[0076]

[0077] Conclusion: The acitretin oxalate crystal form obtained in the application has slight hygroscopicity and needs to be stored in a controlled humidity environment. In addition, the crystal form after hygroscopicity is detected by PXRD, and the stability of each crystal form is tested.

[0078] 3. Solubility test

[0079] Test method: Take the acitretin oxalate crystal form obtained in Example 1 in excess, respectively, and add it to water and 0.01 mol / L hydrochloric acid solution, pH 6.8 PBS buffer as medium, and stir at 37℃ for 72 hours. Repeat sampling three times, filter, take the filtrate, dilute, detect by HPLC, and obtain the solubility in each medium.

[0080] Table 5 Solubility of acitretin in different media (mg / ml)

[0081]

[0082] The solubility test results show that the acitretin oxalate crystal form prepared in the application has made significant progress in solubility compared with the crystal form disclosed in the prior art. Oxalic acid as a strong acid promotes the solubility of acitretin. It is found that Examples 1-4 have similar solubility test results.

[0083] 4. Permeability test

[0084] Test conditions: The permeability test is carried out by Franz diffusion cell method at water temperature of (37±0.5)℃.

[0085] Dialysis membrane (Model: MW 14000 Da, Himedia, India): treated with 10% sodium bicarbonate solution, 10 mM EDTA solution, deionized water at 70 °C for 20 min, respectively; the treated dialysis membrane was loaded into the diffusion cell (effective surface area 4.15 cm 2 ); the donor chamber was suspended with the crystal form B of axitinib fumarate salt in Example 1 and CN202010787156.4 (repeat Example 1 to prepare) (10 mg in terms of axitinib) in 2 ml distilled water, respectively; the receptor chamber was filled with phosphate buffer (pH = 7.4), kept at room temperature, removed the air bubbles, and stirred at 45 ± 5 RPM by magnetic force; the cumulative penetration amount was tested after 24 hours.

[0086] Table 6 Cumulative penetration amount of axitinib (mg / cm 2 )

[0087]

[0088]

Claims

1. A crystal form of axitinib oxalate, characterized in that, The basic unit of the axitinib oxalate crystal form consists of one molecule of axitinib combined with one molecule of oxalic acid and two molecules of water. The axitinib oxalate crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its 2θ X-ray diffraction pattern at 7.17±0.2°, 11.25±0.2°, 12.42±0.2°, 14.13±0.2°, 17.21±0.2°, 18.07±0.2°, 18.52±0.2°, 20.47±0.2°, 21.60±0.2°, 23.45±0.2°, 24.76±0.2°, 27.32±0.2°, 28.16±0.2°, and 30.39±0.2°.

2. The axitinib oxalate crystal form according to claim 1, characterized in that, Using Cu-Kα radiation, its characteristic peaks conform to the X-ray powder diffraction pattern shown in Figure 3.

3. The axitinib oxalate crystal form according to claim 1, characterized in that, Its crystallographic parameters are: triclinic crystal system, space group: P-1 The unit cell parameters are: a = 8.11170(10) Å, b = 12.25710(10)Å, c = 14.6650(2)Å, α =66.9690(10)°, β =76.9010(10)°, γ =84.3290(10)°, cell volume V =1306.86(3)Å 3 .

4. The method for preparing the axitinib oxalate crystal form according to any one of claims 1-3, characterized in that, The steps include: dissolving axitinib and oxalic acid in solvent A, heating to dissolve, obtaining a transparent solution, cooling and allowing to stand to crystallize, filtering, washing, and vacuum drying to obtain axitinib oxalate crystals; The solvent A is selected from the mixed solvents of acetic acid-methanol-water, acetic acid-ethanol-water, acetic acid-acetone-water, acetic acid-isopropanol-water, formic acid-methanol-water, formic acid-ethanol-water, formic acid-acetone-water, and formic acid-isopropanol-water.

5. The preparation method according to claim 4, characterized in that, The molar ratio of axitinib to oxalic acid is 1:1.0 to 1.

4.

6. The preparation method according to claim 4, characterized in that, The molar ratio of axitinib to oxalic acid is 1:1.0 to 1.

2.

7. The preparation method according to claim 4, characterized in that, The melting and heating temperature is 55–70°C; the cooling and crystallization temperature is 0–30°C.

8. The preparation method according to claim 4, characterized in that, The melting and heating temperature is 55–70°C; the cooling and crystallization temperature is 10–20°C.

9. The use of the axitinib oxalate crystal form according to any one of claims 1-3 as an active ingredient in the preparation of antitumor drugs.

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