CN115215797A - Novel crystal form of cabozantinib malate and preparation method thereof - Google Patents

Novel crystal form of cabozantinib malate and preparation method thereof Download PDF

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CN115215797A
CN115215797A CN202210219963.5A CN202210219963A CN115215797A CN 115215797 A CN115215797 A CN 115215797A CN 202210219963 A CN202210219963 A CN 202210219963A CN 115215797 A CN115215797 A CN 115215797A
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cabozantinib
malate
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王磊鑫
谷慧科
王颖
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Sichuan Qingmu Pharmaceutical Co ltd
Chengdu Easton Biopharmaceuticals Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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Abstract

The invention provides a novel crystal form of L-malic acid cabozantinib and a preparation method thereof, belonging to the field of medicine crystal forms. Aiming at the problems of low solubility, poor stability and the like in the prior art, the application develops a new crystal form FormA of the L-malic acid cabozantinib. The novel crystal form is an L-malic acid cabozantinib anhydrous crystal form, and compared with the prior art, the crystal form has the advantages of high solubility in water, better stability and the like, and the preparation method is simple, environment-friendly and good in repeatability, and is suitable for industrial scale-up production.

Description

Novel crystal form of cabozantinib malate and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical crystal forms, and particularly relates to a novel cabozantinib malate crystal form and a preparation method thereof.
Background
Cabozantinib malate (cabozantinib mallate) with chemical name: n- [4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] phenyl ] -N' - (4-fluorophenyl) -1, 1-cyclopropane dicarboxamide (S) -malate, having the structure shown in (I):
Figure BDA0003536640900000011
the malic acid is L-malic acid and has the following structure:
Figure BDA0003536640900000012
the malic acid cabozantinib capsule is approved to be marketed in the United states at 11/29 of 2012, cabozantinib is a multi-target small-molecule tyrosine kinase inhibitor developed by Exelixis in the United states, and has a good treatment effect on medullary thyroid cancer, kidney cancer, non-small cell lung cancer, liver cancer, prostate cancer, breast cancer, ovarian cancer and other solid tumors.
The medicine crystal form refers to the state of two or more different crystal forms of the medicine, and the different crystal forms of the same medicine have different melting points, crystal appearances, solubility, fluidity, hygroscopicity, stability and other properties.
Patent CN105503717A discloses a cabozantinib malate compound in a new crystal form and a preparation method thereof. The cabozantinib malate compound in the new crystal form has diffraction peaks at the following interplanar spacings in X-ray powder diffraction: 13.30, 11.44, 10.22, 9.42, 8.11, 7.57, 6.62, 5.83. Stability influence factor tests are carried out on the cabozantinib malate compound in the new crystal form according to Chinese pharmacopoeia, and the results show that the cabozantinib malate compound in the new crystal form has good stability under the conditions of high temperature (40 ℃), high humidity and illumination, and the highest single impurity and total impurity content have no obvious change. Meanwhile, under the conditions of high temperature, high humidity and illumination, the cabozantinib malate compound in the new crystal form provided by the invention slightly increases the absorbed moisture, has slight hygroscopicity and meets the medicinal requirements.
Cabotinib malate discloses the N-1 crystal form, the N-2 crystal form and amorphous form in patent CN 102388024A. The powder X-ray powder diffraction pattern of the N-1 crystal form comprises 4 or more 2 theta values selected from 12.8 +/-0.2 degrees, 13.5 +/-0.2 degrees, 16.9 +/-0.2 degrees, 19.4 +/-0.2 degrees, 21.5 +/-0.2 degrees, 22.8 +/-0.2 degrees, 25.1 +/-0.2 degrees and 27.6 +/-0.2 degrees. Its N-2 crystalline powder x-ray diffraction pattern comprises 2 theta values at 20.9 + -0.2 DEG and 21.9 + -0.2 DEG and 2 or more 2 theta values selected from 6.4 + -0.2 DEG, 9.1 + -0.2 DEG, 12.0 + -0.2 DEG, 12.8 + -0.2 DEG, 13.7 + -0.2 DEG, 17.1 + -0.2 DEG, 22.6 + -0.2 DEG, 23.7 + -0.2 deg.
Disclosure of Invention
The invention relates to a new crystal Form A of L-cabozantinib malate, and the new crystal Form is an anhydrous crystal Form of the L-cabozantinib malate.
Compared with the prior art, the new crystal Form A of the L-malic acid cabozantinib has the advantages of high solubility in water, good stability and the like, and the preparation method is simple, environment-friendly and good in repeatability, and is suitable for industrial scale-up production.
The invention provides a Cabotinib L-malate crystal Form A, wherein the 2 theta angle of a characteristic peak in an X-ray powder diffraction pattern is as follows: 13.680 +/-0.2 degrees, 14.339 +/-0.2 degrees, 15.000 +/-0.2 degrees, 16.758 +/-0.2 degrees, 20.098 +/-0.2 degrees, 21.240 +/-0.2 degrees, 22.161 +/-0.2 degrees, 22.959 +/-0.2 degrees and 25.640 +/-0.2 degrees.
Preferably, the cabozantinib L-malate crystal Form a has a characteristic peak 2 theta angle in an X-ray powder diffraction pattern as follows: 10.276 +/-0.2 degrees, 11.140 +/-0.2 degrees, 12.661 +/-0.2 degrees, 13.680 +/-0.2 degrees, 14.339 +/-0.2 degrees, 15.000 +/-0.2 degrees, 16.758 +/-0.2 degrees, 18.241 +/-0.2 degrees, 20.098 +/-0.2 degrees, 20.540 +/-0.2 degrees, 21.240 +/-0.2 degrees, 22.161 +/-0.2 degrees, 22.959 +/-0.2 degrees, 24.436 +/-0.2 degrees, 25.640 +/-0.2 degrees, 28.121 +/-0.2 degrees, 30.443 +/-0.2 degrees and 34.459 +/-0.2 degrees.
Preferably, the cabozantinib L-malate crystal Form a has an X-ray powder diffraction pattern shown in fig. 1.
Preferably, the cabozantinib L-malate crystal Form a has endothermic peaks at 159.86 ℃ and 173.69 ℃ in a differential scanning calorimetry spectrum.
Preferably, the cabozantinib L-malate crystal Form a has a differential scanning calorimetry spectrum as shown in fig. 2.
Preferably, the cabozantinib L-malate crystal Form a has a thermogravimetric graph showing a weight loss of about 0.81%, as shown in fig. 3.
Preferably, the crystal Form A of the cabozantinib L-malate has a nuclear magnetic spectrum shown in figure 4.
The invention also provides a preparation method of the L-malic acid cabozantinib crystal Form A, and the preparation method of the new crystal Form comprises the steps of dissolving a certain amount of L-malic acid cabozantinib in a solvent at a certain temperature, stirring for a period of time, cooling to a certain temperature, filtering and drying to obtain a white-like solid.
The preparation method of the cabozantinib malate crystal Form A specifically comprises the following steps: adding L-cabozantinib malate into a solvent at the temperature of 20-60 ℃, wherein the volume of the solvent is 10-50 times of the mass of the L-cabozantinib malate, and stirring; cooling to 0-30 ℃, and continuing stirring; filtering, and drying for 24h at 55-65 ℃ by blowing.
Preferably, the solvent is one or more of water, ethanol, methanol, acetone, butanone and 2-pentanone.
More preferably, the solvent is acetone and water.
Preferably, the volume of the solvent is 30 times of the feeding mass of the cabozantinib L-malate.
Preferably, the suspension temperature of the L-cabozantinib malate in the solvent is 50 DEG C
Preferably, the temperature reduction is 15 ℃.
Preferably, the drying temperature is 65 ℃, and the drying time is 24h.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of cabozantinib L-malate crystal Form A.
FIG. 2 is a differential scanning calorimetry thermogram of the crystalline Form A of cabozantinib L-malate.
FIG. 3 is a thermogravimetric plot of cabozantinib L-malate Form A.
FIG. 4 is a nuclear magnetic spectrum of cabozantinib L-malate crystal Form A.
FIG. 5 is an XRD spectrum of influence factor tests of the crystal Form A of the L-malic acid cabozantinib.
FIG. 6 is an XRD spectrum of accelerated stability test of the crystal Form A of the L-cabozantinib malate.
FIG. 7 is an XRD pattern of amorphous influencing factor test of cabozantinib L-malate.
FIG. 8 is a graph of the average drug concentration versus time for the L-malic acid cabozantinib Form A, form N-2, and Form N-1.
Detailed Description
In the invention, the related powder X-diffraction test instrument is as follows: powder diffractometer DANDONHUAN DX-2700B; and (3) testing conditions: radiation of Cu K instrument, 40kV,40mA,
Figure BDA0003536640900000031
3-40°。
differential Scanning Calorimeter (DSC): mettler-toledo DSC1; and (3) testing conditions: 25-250 ℃ and 10 ℃/min; n2 (50 mL/min).
Thermogravimetric analyzer (TGA): mettler-tolliduo TGA2; and (3) testing conditions are as follows: 30-300 ℃ and 10 ℃/min; n2 (50 mL/min).
Bruker as nuclear magnetic resonance apparatus; and (3) testing conditions are as follows: 400MHz, solvent deuterated DMSO, hydrogen spectrum.
Example 1
Weighing 50mg L-cabozantinib malate, adding 0.5ml acetone and 1ml water at 50 ℃, stirring for a period of time, cooling to 15 ℃, continuing stirring for 24h at 15 ℃, filtering, and drying by air blowing at 65 ℃ for 24h to obtain 41.5mg off-white solid, wherein the XRD pattern is consistent with that of figure 1.
Example 2
Weighing 200mg of L-cabozantinib malate, adding 2ml of acetone and 4ml of water at 50 ℃, stirring for a period of time, cooling to 15 ℃, continuously stirring for 24h at 15 ℃, filtering, and drying by air blowing at 65 ℃ for 24h to obtain 171.5mg of off-white solid, wherein an XRD (X-ray diffraction) pattern is consistent with that of figure 1.
Example 3
Weighing 1.0g of L-cabozantinib malate, adding 10ml of acetone and 20ml of water at 50 ℃, stirring for a period of time, cooling to 15 ℃, continuously stirring for 24h at 15 ℃, filtering, and performing forced air drying at 65 ℃ for 24h to obtain 0.83g of off-white solid, wherein the XRD pattern is consistent with that of figure 1, and the yield is 83.0%.
Example 4
Weighing 1.0g of L-cabozantinib malate, adding 10ml of butanone and 20ml of water at 50 ℃, stirring for a period of time, cooling to 15 ℃, continuously stirring for 24 hours at 15 ℃, filtering, and performing forced air drying for 24 hours at 65 ℃ to obtain 0.74g of off-white solid, wherein an XRD (X-ray diffraction) pattern is consistent with that of figure 1, and the yield is 74.0%.
Example 5
Weighing 1.0g of L-cabozantinib malate, adding 10ml of acetone and 20ml of water at 20 ℃, stirring for a period of time, cooling to 15 ℃, continuously stirring for 48h at 15 ℃, filtering, and performing forced air drying at 65 ℃ for 24h to obtain 0.82g of off-white solid, wherein an XRD (X-ray diffraction) pattern is consistent with that of figure 1, and the yield is 82.0%.
Example 6
Weighing 1.0g of L-cabozantinib malate, adding 10ml of acetone and 20ml of water at 50 ℃, stirring for a period of time, cooling to 30 ℃, continuously stirring for 4h at 30 ℃, filtering, and performing forced air drying at 65 ℃ for 24h to obtain 0.71g of off-white solid, wherein the XRD pattern is consistent with that of figure 1, and the yield is 71.0%.
Example 7
Weighing 10.0g of L-cabozantinib malate, adding 100ml of acetone and 200ml of water at 50 ℃, stirring for a period of time, cooling to 15 ℃, continuing stirring for 24h at 15 ℃, filtering, and performing forced air drying for 24h at 65 ℃ to obtain 8.56g of off-white solid, wherein the XRD pattern is consistent with that of figure 1.
Example 8
Weighing 0.5kg of L-cabozantinib malate, adding 5.0L of acetone and 10.0L of water at 50 ℃, stirring for a period of time, cooling to 15 ℃, continuing stirring for 24h at 15 ℃, filtering, and performing forced air drying at 65 ℃ for 24h to obtain 0.42kg of off-white solid, wherein the XRD spectrum is consistent with that of figure 1.
Example 9
The solubility of cabozantinib Form a, form N-2 and Form N-1L-malate in water at 25 ℃ and 50 ℃ respectively was tested and the results are given in the following table:
Figure BDA0003536640900000041
Figure BDA0003536640900000051
the results show that cabozantinib Form a L-malate has higher solubility in water at both 25 ℃ and 50 ℃ than Form N-2 and Form N-1.
Example 10
The L-cabozantinib malate Form A is placed at 60 ℃ under the illumination condition for 15 days, and the experimental result shows that the crystal Form of the L-cabozantinib malate Form A is not converted, and is shown in figure 5.
Example 11
The L-malic acid cabozantinib Form A is placed at the conditions of 25 ℃/RH60% and 40 ℃/RH75% for 6 months, the experimental result shows that the crystal Form of the L-malic acid cabozantinib Form A is not transformed, and the experimental result is shown in figure 6.
Example 12
The L-cabozantinib malate is placed in an amorphous state at 60 ℃ under the illumination condition for 15 days, the experimental result shows that crystal transformation of the L-cabozantinib malate in an amorphous state occurs, the crystal form is unstable under the condition, and the experimental result is shown in figure 7.
Test example in vivo pharmacokinetic test in rats
1. Purpose of the experiment
The concentration level of cabozantinib in plasma and the pharmacokinetic characteristics thereof after rats are orally administered with cabozantinib Form A, form N-1 and Form N-2L-malate in a single time under the same administration dose are inspected.
2. Materials and methods
2.1 test drugs
L-malic acid cabozantinib Form N-1, provided by the institute of crystalline Form, chengdouyuan Tombycis, inc., as a white-like solid, lot number B-20130-47-01, purity: 99.35 percent
L-malic acid cabozantinib Form N-2, provided by shanghai pacho biotechnology ltd, as a white-like solid, lot No. 20191015, purity: 99.76 percent;
l-malic acid cabozantinib Form A, provided by the institute of crystalline Form, chengdouyuan Toyobo biopharmaceutical GmbH, white-like solid, lot number B-20130-43-01, purity: 99.81 percent.
2.2 test animals
9 SD rats, female, weighing 220-240g, purchased from Schleickanda laboratory animals, inc., hunan by Cheng Dus Vill Biotech, inc., license number: SCXK (Xiang) 2019-0004.
2.3 test methods
After the tested medicine is prepared into 1.25mg/kg uniform suspension by corn oil, the uniform suspension is immediately orally administered to rats according to the volume of 4mL/kg, 0.1mL of blood is taken from jugular veins 15min, 30min, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 24h, 32h and 48h before and after administration, the jugular veins are placed in an EDTA-K2 tube for 3000r/min, centrifuged for 10min, blood plasma is separated, and the mixture is frozen and stored in a refrigerator at the temperature of 80 ℃ below zero.
2.4LC/MS/MS biological sample analysis:
mixing 50 μ L of plasma with 5 μ L of working solution or blank diluent, adding 150 μ L of internal standard acetonitrile-containing precipitant, vortex shaking for 2min, centrifuging at 12000r/min for 10min, mixing supernatant 2 μ L with 200 μ L of pure water: after mixing acetonitrile (1.
2.5 test results:
the L-malic acid cabozantinib Form A, form N-1 and Form N-2 are respectively subjected to animal experiments, namely, the average concentration (ng. ML-1) of API in plasma of female rats at different time is tested after single oral administration, the result is shown in figure 8 as the average drug concentration-time curve in plasma of female rats after single oral administration, and the main pharmacokinetic parameters are as follows:
parameter(s) Form N-1 Form N-2 Form A
T 1/2 (h) 74.88±53.78 15.25±1.65 17.95±10.29
T max (h) 4.00±1.00 18.67±9.27 7.33±1.15
C max (ng·mL -1 ) 3007±543 2703±856 3913±1218
AUC last (h·ng·mL -1 ) 72030±12157 77621±28495 105046±19633
Cl_F_obs(mL/hr/kg) 37.18±20.36 58.74±22.23 40.83±10.56
MRT(h) 17.65±2.21 21.22±2.48 19.41±1.30
The experimental result shows that the AUC of the L-malic acid cabozantinib Form A last AUC greater than Form N-1 and Form N-2 last Therefore, form A is superior to Form N-1 and Form N-2 in bioavailability.

Claims (10)

  1. The crystal Form A of the L-malic acid cabozantinib is characterized in that the 2 theta angle of a characteristic peak in an X-ray powder diffraction pattern is as follows: 13.680 +/-0.2 degrees, 14.339 +/-0.2 degrees, 15.000 +/-0.2 degrees, 16.758 +/-0.2 degrees, 20.098 +/-0.2 degrees, 21.240 +/-0.2 degrees, 22.161 +/-0.2 degrees, 22.959 +/-0.2 degrees and 25.640 +/-0.2 degrees.
  2. 2. The cabozantinib L-malate crystalline Form a according to claim 1, characterized in that the 2 Θ angle of the characteristic peaks in the X-ray powder diffraction pattern is: 10.276 +/-0.2 degrees, 11.140 +/-0.2 degrees, 12.661 +/-0.2 degrees, 13.680 +/-0.2 degrees, 14.339 +/-0.2 degrees, 15.000 +/-0.2 degrees, 16.758 +/-0.2 degrees, 18.241 +/-0.2 degrees, 20.098 +/-0.2 degrees, 20.540 +/-0.2 degrees, 21.240 +/-0.2 degrees, 22.161 +/-0.2 degrees, 22.959 +/-0.2 degrees, 24.436 +/-0.2 degrees, 25.640 +/-0.2 degrees, 28.121 +/-0.2 degrees, 30.443 +/-0.2 degrees and 34.459 +/-0.2 degrees.
  3. 3. The cabozantinib L-malate crystalline Form a of claim 1, having an X-ray powder diffraction pattern as shown in figure 1.
  4. 4. The cabozantinib L-malate crystalline Form a of any one of claims 1-3, having endothermic peaks at 159.86 ℃ and 173.69 ℃ in differential scanning calorimetry.
  5. 5. The crystalline Form A of cabozantinib L-malate according to any one of claims 1 to 3, characterized by a differential scanning calorimetry trace as shown in figure 2.
  6. 6. The cabozantinib malate crystalline Form a according to any one of claims 1 to 3, having a thermogravimetric profile as shown in figure 3.
  7. 7. The cabozantinib L-malate crystalline Form a according to any one of claims 1 to 3, characterized in that its nuclear magnetic spectrum is shown in figure 4.
  8. 8. A method of preparing cabozantinib L-malate Form a Form according to claim 1, comprising the steps of: adding L-cabozantinib malate into a solvent at the temperature of 20-60 ℃, wherein the volume of the solvent is 10-50 times of the mass of the L-cabozantinib malate, and stirring; cooling to 0-30 ℃, and continuing stirring; filtering, and drying for 24h at 55-65 ℃ by blowing.
  9. 9. The method of claim 8, wherein the solvent is one or more of water, ethanol, methanol, acetone, butanone, and 2-pentanone.
  10. 10. The method of claim 8 or 9, comprising the steps of: adding the L-cabozantinib malate into a solvent at 50 ℃, wherein the volume of the solvent is 30 times of the mass of the L-cabozantinib malate, and stirring; cooling to 15 ℃, and continuing stirring; filtering, and oven drying at 65 deg.C for 24 hr.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102388024A (en) * 2009-01-16 2012-03-21 埃克塞里艾克西斯公司 Malate salt of n- (4- { [ 6, 7-bis (methyloxy) quin0lin-4-yl] oxy}phenyl-n' - (4 -fluorophenyl) cyclopropane-1-dicarboxamide, and crystalline forms therof for the treatment of cancer
CN104109124A (en) * 2013-04-19 2014-10-22 正大天晴药业集团股份有限公司 Crystal of cabozantinib*0.5 malate
CN105503717A (en) * 2014-09-24 2016-04-20 江苏奥赛康药业股份有限公司 Cabozantinib malate compound and medicine composition therewith
US20170096395A1 (en) * 2014-05-23 2017-04-06 Mylan Labs Limited Novel polymorphs of cabozantinib (s)-malate and cabozantinib free base
CN108341773A (en) * 2017-01-21 2018-07-31 南京华威医药科技开发有限公司 The rich crystal form II for Buddhist nun's malate of card

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102388024A (en) * 2009-01-16 2012-03-21 埃克塞里艾克西斯公司 Malate salt of n- (4- { [ 6, 7-bis (methyloxy) quin0lin-4-yl] oxy}phenyl-n' - (4 -fluorophenyl) cyclopropane-1-dicarboxamide, and crystalline forms therof for the treatment of cancer
CN104109124A (en) * 2013-04-19 2014-10-22 正大天晴药业集团股份有限公司 Crystal of cabozantinib*0.5 malate
US20170096395A1 (en) * 2014-05-23 2017-04-06 Mylan Labs Limited Novel polymorphs of cabozantinib (s)-malate and cabozantinib free base
CN105503717A (en) * 2014-09-24 2016-04-20 江苏奥赛康药业股份有限公司 Cabozantinib malate compound and medicine composition therewith
CN108341773A (en) * 2017-01-21 2018-07-31 南京华威医药科技开发有限公司 The rich crystal form II for Buddhist nun's malate of card

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