Patent Application
20210332014
The present disclosure relates to the field of pharmaceutical chemistry, particularly relates to crystalline forms of cabozantinib malate, processes for preparing and use thereof.
Cabozantinib is an anticancer drug developed by Exelixis, and it was approved by FDA in November 2012 and April 2016 for the treatment of metastatic medullary thyroid cancer and renal cell carcinoma, respectively. In addition, the indications for the treatment of liver cancer was also approved by FDA in January 2019. Cabozantinib is marketed as (S)-malate.
The chemical name of cabozantinib (S)-malate is N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (S)-malate (hereinafter referred to as “Compound I” or cabozantinib (S)-malate). Its structural formula is as follows:
A crystalline form is a solid material whose constituents are arranged in a highly ordered microscopic structure, forming a crystal lattice that extends in all directions. Polymorphism is the ability of a compound to exist in two or more than two crystalline forms. Different crystalline forms have different physicochemical properties and can affect drug's in vivo dissolution and absorption, which will further affect drug's clinical efficacy and safety to some extent. In particular, for poorly soluble drugs, the above effects of the crystalline form will be greater. Therefore, drug polymorphism is an important part of drug research and an important part of drug quality control.
At present, although there are reports on the crystalline forms of Compound I, the properties of the crystalline forms that have been reported are not good, and there are still some problems. For example, CN102388024A disclosed the crystalline form N-1, crystalline form N-2, and amorphous of Compound I. CN102388024A shows that crystalline form N-2 has better stability than amorphous and crystalline form N-1. However, the solubility of crystalline form N-2 is low, and the flowability, compressibility, tensile strength, and adhesion are poor. WO2015177758A1 disclosed crystalline form M1, crystalline form M2, crystalline form M3 and crystalline form M4 of Compound I, wherein crystalline form M4 is better. However, crystalline form M4 has low solubility, poor fluidity, poor compressibility, poor tensile strength, and poor adhesion. Therefore, a large number of experimental studies are still needed to provide more crystal forms with better properties to support the development of Compound I drugs.
In order to overcome the disadvantages of prior art, the inventors of the present disclosure surprisingly discovered crystalline form CSI and crystalline form CSIII of Compound I, which has advantages in physiochemical properties, formulation processability and bioavailability, for example, crystalline form CSI and crystalline form CSIII have advantages in at least one aspect of melting point, solubility, hygroscopicity, purification ability, stability, adhesiveness, compressibility, flowability, in vitro and in vivo dissolution, and bioavailability, etc. Particularly, crystalline form CSI and crystalline form CSIII have high solubility and good fluidity, tensile strength and adhesion, which provides new and better choices for the development of drugs containing Compound I, and is of great significance.
In addition, when the inventors studied the crystal forms of the prior art, it was found that the preparation method of the crystalline form M2 disclosed by WO2015177758 A1 (hereinafter referred to as “Form M2”) has poor repeatability and it is difficult to control the process.
Therefore, developing a robust and controllable preparation method of crystalline form M2 is also of great value for the development of Compound I drugs.
The main objective of the present disclosure is to provide novel crystalline forms of Compound I and processes for preparation and use thereof.
According to the objective of the present disclosure, crystalline form CSI of Compound I is provided (hereinafter referred to as Form CSI).
According to one aspect of the present disclosure, the X-ray powder diffraction pattern of Form CSI shows characteristic peaks at 2 theta values of 8.5°±0.2°, 12.7°±0.2°, 13.9°±0.2° using CuKα radiation.
Furthermore, the X-ray powder diffraction pattern of Form CSI shows one or two or three characteristic peaks at 2 theta values of 12.1°±0.2°, 17.9°±0.2°, 19.9°±0.2°. Preferably, the X-ray powder diffraction pattern of Form CSI shows three characteristic peaks at 2 theta values of 12.1°±0.2°, 17.9°±0.2°, 19.9°±0.2°.
Furthermore, the X-ray powder diffraction pattern of Form CSI shows one or two or three characteristic peaks at 2 theta values of 14.9°±0.2°, 16.7°±0.2°, 25.5°±0.2°. Preferably, the X-ray powder diffraction pattern of Form CSI shows three characteristic peaks at 2 theta values of 14.9°±0.2°, 16.7°±0.2°, 25.5°±0.2°.
According to another aspect of the present disclosure, the X-ray powder diffraction pattern of Form CSI shows three or four or five or six or seven or eight or nine characteristic peaks at 2 theta values of 8.5°±0.2°, 12.7°±0.2°, 13.9°±0.2°, 12.1°±0.2°, 17.9°±0.2°, 19.9°±0.2°, 14.9°±0.2°, 16.7°±0.2°, 25.5°±0.2° using CuKα radiation.
Furthermore, Form CSI is an acetic acid solvate.
Without any limitation being implied, the X-ray powder diffraction pattern of Form CSI is substantially as depicted in
According to the objective of the present disclosure, a process for preparing Form CSI is also provided. The process includes the following methods:
Method 1: dissolving Compound I in acetic acid or a solvent mixture of acetic acid and an aromatic hydrocarbon, then fast evaporating at 50-80° C.;
Method 2: dissolving the Compound I solid in acetic acid, a mixture of acetic acid and an aromatic, a mixture of acetic acid and an alkane, or a mixture of acetic acid and water, then adding an aromatic hydrocarbon, an alkane, an ester or a ketone into the solution with stirring. The obtained solid is crystalline form CSI.
Furthermore, said aromatic hydrocarbons in method 1 is toluene; the volume ratio of said acetic acid and toluene is 2:1-1:3, preferably 1:1.
Furthermore, the volume ratios of said acetic acid and aromatic hydrocarbon, said acetic acid and alkane, or said acetic acid and water in method 2 are 2:1-1:3, preferably 1:1.
Furthermore, in method 2, said aromatic hydrocarbon is toluene, said alkane is n-heptane, said ester is isopropyl acetate, and said ketone is methyl isobutyl ketone.
Furthermore, said stirring in method 2 is performed at 0-5° C.
According to the objective of the present disclosure, crystalline form CSIII of Compound I is provided (hereinafter referred to as Form CSIII).
According to one aspect of the present disclosure, the X-ray powder diffraction pattern of Form CSIII shows characteristic peaks at 2 theta values of 8.5°±0.2°, 21.3°±0.2°, 23.0°±0.2° using CuKα radiation.
Furthermore, the X-ray powder diffraction pattern of Form CSIII shows one or two or three characteristic peaks at 2 theta values of 14.4°±0.2°, 17.8°±0.2°, 12.6°±0.2°. Preferably, the X-ray powder diffraction pattern of Form CSIII shows three characteristic peaks at 2 theta values of 14.4°±0.2°, 17.8°±0.2°, 12.6°±0.2°. Furthermore, the X-ray powder diffraction pattern of Form CSIII shows one or two or three characteristic peaks at 2 theta values of 20.5°±0.2°, 24.0°±0.2°, 16.4°±0.2°. Preferably, the X-ray powder diffraction pattern of Form CSIII shows three characteristic peaks at 2 theta values of 20.5°±0.2°, 24.0°±0.2°, 16.4°±0.2°.
According to another aspect of the present disclosure, the X-ray powder diffraction pattern of Form CSIII shows three or four or five or six or seven or eight or nine characteristic peaks at 2 theta values of 8.5°±0.2°, 21.3°±0.2°, 23.0°±0.2°, 14.4°±0.2°, 17.8°±0.2°, 12.6°±0.2°, 20.5°±0.2°, 24.0°±0.2°, 16.4°±0.2° using CuKα radiation.
Without any limitation being implied, the X-ray powder diffraction pattern of Form CSIII is substantially as depicted in
According to the objective of the present disclosure, a process for preparing Form CSIII is also provided. The process includes the following methods:
Method 1: dissolving Compound I in an acid, a mixture of an acid and an aromatic hydrocarbon, a mixture of an acid and an alkane, or a mixture of an acid and water, adding aromatic hydrocarbon, alkane, ester or ketone into the solution with stirring to precipitate a solid. Filtrating to get the solid. The obtained solid was slurred in a solvent mixture of an aromatic hydrocarbon and water, separating the solid again to get Form CSIII;
Method 2:
step 1: dissolving Compound I in an acid, stirring and heating until the solid was completely dissolved, then naturally cooling to room temperature and filtering.
step 2: adding an aromatic hydrocarbon dropwise to the clear solution, transferring the mixture to an environment at 0-10° C. with continuous stirring, then filtering the mixture to separate the solid, and drying;
Step 3: heating the solid to 50-100° C. under nitrogen purging, and then cooling to 30° C., the obtained solid is Form CSIII.
Furthermore, the volume ratio of said acid and aromatic hydrocarbon, acid and alkane, or acid and water in Method 1 are 2:1-1:3, preferably, the volume ratio is 1:1.
Furthermore, in method 1, said acid is acetic acid, said aromatic hydrocarbon is toluene, said alkane is n-heptane, said ester is isopropyl acetate, and said ketone is methyl isobutyl ketone.
Furthermore, in method 2, said acid is acetic acid, said aromatic hydrocarbon is toluene.
Furthermore, in method 2, said stirring of step 1 is at 80° C.; said stirring of step 2 is at 5° C., the time of said stirring of step 2 is 10-20 hours, and said heating of step 3 is up to 100° C.
Further, in method 2, the time of said stirring of step 2 is 15 hours.
Form CSI of the present disclosure has the following advantages:
(1) Compared with prior art, Form CSI has higher solubility. In a specific embodiment, the solubility of Form CSI in water is twice of that of Form N-2 and over five times more than that of Form M4.
Cabozantinib is a poorly water-soluble drug and belongs to BCS class II. Higher solubility is beneficial to improve drug's in vivo absorption and bioavailability, thus improving drug efficacy. In addition, drug dose reduction without affecting efficacy is possible due to higher solubility, thereby reducing the drug's side effects and improving drug safety.
(2) Form CSI of the present disclosure has good purification effect. The purity is significantly increased after the raw material is converted to Form CSI of the present disclosure. In a specific embodiment, after Form CSI is prepared from the raw material using the crystallization process, the purity is significantly increased and the content of each impurity is reduced.
Chemical purity is of great significance for ensuring drug efficacy, safety and preventing the occurrence of adverse effects. If the drug contains impurities higher than limit, its physicochemical properties and drug appearance may change, and the stability will be affected. The increase in impurities will lead to significantly lowered active ingredient content or reduced drug activity, and will also lead to significantly increased toxicity and side effects of the drug products. Therefore, different drug regulations have strict requirements on impurity content. Crystalline forms with good purification effect are excellent in removing impurities in the crystallization process, thus drug substances with high purity can be obtained through crystallization, which effectively overcome the disadvantages of poor stability, poor efficacy and high toxicity caused by the low purity drug substances.
Form CSIII of the present disclosure has the following advantages:
Compared with prior art, Form CSIII has higher solubility. Especially in FeSSIF and water, the solubility of Form CSIII is twice of that of Form N-2 and Form M4.
Cabozantinib is a poorly water-soluble drug and belongs to BCS class II. Higher solubility is beneficial to improve drug's in vivo absorption and bioavailability, thus improving drug efficacy.
In addition, drug dose reduction without affecting efficacy is possible due to higher solubility, thereby reducing the drug's side effects and improving drug safety.
Furthermore, Form CSIII of the present disclosure also has the following advantages:
(1) Compared with prior art, Form CSIII of the present disclosure has better flowability. Flowability evaluation results indicate that the flowability of Form CSIII is remarkably better than that of prior art forms. Better flowability can prevent clogging of production equipment and increase manufacturing efficiency. Better flowability of Form CSIII ensures the blend uniformity and content uniformity of the drug product, and reduces the weight variation of the drug product and improves product quality
(2) Compared with prior art, Form CSIII of the present disclosure has better compressibility. Failure in hardness/friability test and tablet crack issue can be avoided due to better compressibility, making the preparation process more reliable, improving product appearance and product quality. Better compressibility can increase the compression rate, thus further increases the efficiency of process and reduces the cost of compressibility improving excipients.
(3) Compared with prior art, Form CSIII of the present disclosure shows superior adhesiveness. Adhesiveness evaluation results indicate that adhesion quantity of Form CSIII is remarkably lower than that of prior art forms. Due to superior adhesiveness of Form CSIII, adhesion to roller and tooling during dry-granulation and compression process can be reduced, which is also beneficial to improve product appearance and weight variation. In addition, Superior adhesiveness of Form CSIII can reduce the agglomeration of drug substance, which is beneficial to the dispersion of drug substance and reduce the adhesion between drug substance and other instruments, and improve the blend uniformity and content uniformity of drug product.
According to the objective of the present disclosure, a pharmaceutical composition is provided. Said pharmaceutical composition comprises a therapeutically effective amount of Form CSI or Form CSIII or combinations thereof and pharmaceutically acceptable carrier, dilution agents or excipients.
Furthermore, Form CSI or Form CSIII or combinations thereof can be used for preparing drugs inhibiting MET, VEGFR1/2/3, ROS1, RET, AXL, NTRK and KIT.
Furthermore, Form CSI or Form CSIII or combinations thereof can be used for preparing drugs treating thyroid cancer, lung cancer, gastric cancer, and liver cancer.
According to the objective of the present disclosure, a process for preparing Form M2 of Compound I is provided. The process comprises: dissolving the solid of Compound I or a solid mixture of cabozantinib and (S)-malic acid in solvent and then adding an anti-solvent to precipitate a solid, then drying the solid under a condition of more than 30% relative humidity (RH) to obtain Form M2. Said solvent is an organic acid or a solvent mixture of an organic acid and an aromatic hydrocarbon; said anti-solvent is an aromatic hydrocarbon, an ester, an alcohol, a ketone or a solvent mixture of an aromatic hydrocarbon and an ester or an aromatic hydrocarbon and a ketone; the X-ray powder diffraction pattern of said Form M2 shows characteristic peaks at 2 theta values of 8.6°±0.2°, 12.6°±0.2°, 20.2°±0.2°, 23.4°±0.2°, 26.1°±0.2.
Furthermore, said organic acid is acetic acid, said aromatic hydrocarbon is toluene, said ester is ethyl acetate or isopropyl acetate, said ketone is methyl isobutyl ketone, and said alcohol isopropanol or n-propanol.
Furthermore, the temperature of the solvent system when adding the anti-solvent is below 15° C.; preferably −5° C. to 10° C.
Furthermore, seed crystals of Form M2 can be added before adding the anti-solvent; the amount of seed crystals are 1 wt % to 10 wt %.
Furthermore, the volume ratio of the solvent and the anti-solvent is 1:1 to 1:10; preferably, the volume ratio is 2: 5.
Compared with the prior art, the process for preparing Form M2 provided by the present disclosure has advantages as it is controllable and can be scaled up easily. It can be seen from the comparative example that crystal form N-1 of CN102388024A instead of Form M2 is obtained by repeating the preparation method of the prior art. In addition, Form M2 obtained by the preparation method provided by the present disclosure has the advantages of high yield, low solvent residue, and uniform particle size distribution. Such a preparation method not only saves costs, but also provides high-quality drug substances, which provides new and better choices for preparation of drug product containing cabozantinib and has significant values for future drug development.
In the present disclosure, said “stirring” is accomplished by using a conventional method in the field such as magnetic stirring or mechanical stirring and the stirring speed is 50 to 1800 r/min, preferably the magnetic stirring speed is 300 to 900 r/min and mechanical stirring speed is 100 to 300 r/min.
Said “separation” is accomplished by using a conventional method in the field such as centrifugation or filtration. The operation of “centrifugation” is as follows: the sample to be separated is placed into the centrifuge tube, and then centrifuged at a rate of 10000 r/min until the solid all sink to the bottom of the tube.
Said “drying” is accomplished at room temperature or a higher temperature. The drying temperature is from room temperature to about 60° C., or to 40° C., or to 50° C. The drying time can be 2 to 48 hours, or overnight. Drying is accomplished in a fume hood, forced air convection oven or vacuum oven.
Said “evaporating” is accomplished by using a conventional method in the field. Slow evaporation is accomplished in a container covered by sealing film with pinholes. Fast evaporation is accomplished in an open container.
Said “cooling” is accomplished by using conventional methods in the field such as slow cooling and rapid cooling. Slow cooling is usually accomplished at the speed of 0.1° C./min. Rapid cooling is usually accomplished by transferring the sample directly from environment which is no lower than room temperature to refrigerator for cooling.
In the present disclosure, “crystal” or “crystalline form” refers to the crystal or the crystalline form being identified by the X-ray diffraction pattern shown herein. Those skilled in the art are able to understand that physicochemical properties discussed herein can be characterized. The experimental errors depend on the instrument conditions, the sample preparation and the purity of samples. In particular, those skilled in the art generally know that the X-ray diffraction pattern typically varies with the experimental conditions. It is necessary to point out that, the relative intensity of the diffraction peaks in the X-ray diffraction pattern may also vary with the experimental conditions; therefore, the order of the diffraction peak intensities cannot be regarded as the sole or decisive factor. In fact, the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystals, and the diffraction peak intensities shown herein are illustrative and identical diffraction peak intensities are not required. In addition, the experimental error of the diffraction peak position is usually 5% or less, and the error of these positions should also be considered. An error of ±0.2° is usually allowed. In addition, due to experimental factors such as sample thickness, the overall offset of the diffraction peak is caused, and a certain offset is usually allowed. Thus, it will be understood by those skilled in the art that a crystalline form of the present disclosure is not necessarily to have the exact same X-ray diffraction pattern of the example shown herein. Any crystalline forms whose X-ray diffraction patterns have the same or similar characteristic peaks should be within the scope of the present disclosure. Those skilled in the art can compare the patterns shown in the present disclosure with that of an unknown crystalline form in order to identify whether these two groups of patterns reflect the same or different crystalline forms. In some embodiments, crystalline Form CSI and Form CSIII of the present disclosure is pure and substantially free of any other crystalline forms. In the present disclosure, the term “substantially free” when used to describe a novel crystalline form, it means that the content of other crystalline forms in the novel crystalline form is less than 20% (w/w), specifically less than 10% (w/w), more specifically less than 5% (w/w) and further more specifically less than 1% (w/w).
In the present disclosure, the term “about” when referring to a measurable value such as weight, time, temperature, and the like, is meant to encompass variations of ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount.
The present disclosure is further illustrated by the following examples which describe the preparation and use of the crystalline forms of the present disclosure in detail. It is obvious to those skilled in the art that many changes in the materials and methods can be accomplished without departing from the scope of the present disclosure.
The abbreviations used in the present disclosure are explained as follows:
XRPD: X-ray Powder Diffraction
DSC: Differential Scanning calorimetry
TGA: Thermo Gravimetric Analysis
DVS: Dynamic Vapor Sorption
1H NMR: Proton Nuclear Magnetic Resonance
PSD: Particle Size Distribution
HPLC: High Performance Liquid Chromatography
Instruments and methods used for data collection:
X-ray powder diffraction patterns in Example 1-4, 10-11, 13-14 and comparative examples of the present disclosure were acquired by a Bruker D2 PHASER X-ray powder diffractometer. The parameters of the X-ray powder diffraction method of the present disclosure are as follows:
X-ray powder diffraction patterns in Example 12 of the present disclosure were acquired by a Bruker D8 Discover X-Ray powder diffractometer. The parameters of the X-ray powder diffraction method of the present disclosure are as follows:
Differential scanning calorimetry (DSC) data in the present disclosure were acquired by a TA Q2000. The parameters of the DSC method of the present disclosure were as follows:
Thermo gravimetric analysis (TGA) data in the present disclosure were acquired by a TA Q500. The parameters of the TGA method of the present disclosure were as follows:
Proton nuclear magnetic resonance spectrum data (1H NMR) were collected from a Bruker Avance II DMX 400M HZ NMR spectrometer. 1-5 mg of sample was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to obtain a solution with a concentration of 2-10 mg/mL.
High Performance Liquid Chromatography (HPLC) data in the present disclosure were collected from an Agilent 1260 with Variable Wavelength Detector (VWD).
The HPLC method parameters for solubility test in the present disclosure are as follows:
The particle size distribution data in the present disclosure were acquired by an S3500 laser particle size analyzer of Microtrac. Microtrac S3500 is equipped with an SDC (Sample Delivery Controller). The test is carried out in wet mode, and the dispersion medium is Isopar G. The parameters are as follows:
Dynamic Vapor Sorption (DVS) is measured via an SMS (Surface Measurement Systems Ltd.) intrinsic DVS instrument. Its control software is DVS-Intrinsic control software, and its control software is DVS-Intrinsic control software. Typical Parameters for DVS test are as follows:
Unless otherwise specified, the following examples were conducted at room temperature. Said “room temperature” is not a specific temperature, but a temperature range of 10-30° C.
According to the present disclosure, cabozantinib and/or its salt used as a raw material is solid (crystalline and amorphous), oil, liquid form or solution. Preferably, Compound I and/or its salt used as a raw material is a solid.
Raw materials of cabozantinib and/or a salt thereof used in the following examples were prepared by known methods in the prior art, for example, the method disclosed in CN102388024A.
The obtained solid was test, and the chemical purity of the obtained solid was 99.77%. The solvent residues of acetic acid, toluene, isopropyl acetate, and n-heptane were less than 1250 ppm, 325 ppm, 756 ppm, and 2324 ppm, respectively, which meets the requirements of ICH. The particle size distribution diagram of the solid is shown in
5.06 g of compound I was weighed into a 100-mL glass vial, and a mixed solvent of acetic acid and toluene was added to dissolve the solid and obtain a clear solution. The solution was filtered into a 250-mL reactor and cooled to 0-5° C. 52.1 mg of Form M2 seed crystals were added to the system and the system was aged for 0.5 h. Isopropyl acetate was added slowly into the suspension. After a solid was precipitated, the solid was separated by suction filtration. The solid was dried by a forded air convection oven at 30° C. (the humidity was no less than 40% RH). Characterization shows that the obtained solid is Form M2. The XRPD pattern and data are shown in
About 8.00 g of cabozantinib freebase and 2.25 g of (S)-malic acid was weighed in a 100-mL glass vial, and a mixed solvent of acetic acid and toluene was added to dissolve the solid and obtain a clear solution. The solution was filtered into a 500-mL reactor and cooled to −5-15° C. About 200 mg of Form M2 seed crystals were added to the system. Isopropyl acetate and toluene were added slowly into the system. After a solid was precipitated, the solid was separated by suction filtration. The solid was dried by a forded air convection oven at 40° C. (the humidity was no less than 40% RH). And then Form M2 was obtained. The XRPD pattern and XRPD data are shown in
335.4 mg of compound I was weighed into a 20-mL glass vial, and 1 mL of propionic acid was added. A clear solution was obtained by heating. The solution was cooled to room temperature and 10 mL of methyl-tert-butyl ether was added with stirring. After aging for 2 h, the solid was sampled and characterized to be amorphous, and the XRPD pattern is shown in
| Number | Date | Country | Kind |
|---|---|---|---|
| 201811096899.6 | Sep 2018 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2019/106847 | 9/20/2019 | WO | 00 |
