CN114341112A - Novel crystal form of acetylated eltrombopag and preparation method thereof - Google Patents
Novel crystal form of acetylated eltrombopag and preparation method thereof Download PDFInfo
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- CN114341112A CN114341112A CN202080060751.6A CN202080060751A CN114341112A CN 114341112 A CN114341112 A CN 114341112A CN 202080060751 A CN202080060751 A CN 202080060751A CN 114341112 A CN114341112 A CN 114341112A
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- 239000013078 crystal Substances 0.000 title claims abstract description 92
- XDXWLKQMMKQXPV-QYQHSDTDSA-N eltrombopag Chemical compound CC1=NN(C=2C=C(C)C(C)=CC=2)C(=O)\C1=N/NC(C=1O)=CC=CC=1C1=CC=CC(C(O)=O)=C1 XDXWLKQMMKQXPV-QYQHSDTDSA-N 0.000 title claims abstract description 90
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- 238000002360 preparation method Methods 0.000 title abstract description 16
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 31
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 31
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- 238000000034 method Methods 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 230000005855 radiation Effects 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 206010043554 thrombocytopenia Diseases 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 10
- 238000001757 thermogravimetry curve Methods 0.000 claims description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 8
- 238000004090 dissolution Methods 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000012296 anti-solvent Substances 0.000 claims description 6
- 230000004580 weight loss Effects 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
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- 238000000113 differential scanning calorimetry Methods 0.000 description 16
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- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 10
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- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 10
- 208000032467 Aplastic anaemia Diseases 0.000 description 5
- 208000006154 Chronic hepatitis C Diseases 0.000 description 5
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- 238000010911 splenectomy Methods 0.000 description 5
- DJMJHIKGMVJYCW-UHFFFAOYSA-N 2-aminoethanol 3-[3-[[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]diazenyl]-2-hydroxyphenyl]benzoic acid Chemical compound CC1=C(C=C(C=C1)N2C(=O)C(=C(N2)C)N=NC3=CC=CC(=C3O)C4=CC(=CC=C4)C(=O)O)C.C(CO)N.C(CO)N DJMJHIKGMVJYCW-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
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- 229960001827 eltrombopag olamine Drugs 0.000 description 1
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D231/08—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen or sulfur atoms directly attached to ring carbon atoms
Abstract
The invention provides a novel crystal form of acetylated eltrombopag and a preparation method thereof, belonging to the field of pharmaceutical chemistry. The crystal form has better stability, is beneficial to operation in storage, transfer and production processes, can be well released in an animal body, and can be used for preparing a preparation.
Description
The invention belongs to the field of pharmaceutical chemistry, and relates to a novel crystal form of acetylated eltrombopag and a preparation method thereof.
Eltrombopag diethanolamine salt (Eltrombopag olamine), CAS: 496775-62-3, is a thrombopoietin receptor agonist used to treat certain conditions that result in thrombocytopenia. The structure of eltrombopag diethanolamine salt is shown in the following formula (1).
The structure of the acetylated eltrombopag is shown as the following formula (2).
Eltrombopag has a food effect, and acetylated eltrombopag is a prodrug of eltrombopag and can be used to overcome the food effect of eltrombopag.
Drug polymorphism is a common phenomenon in drug development and is an important factor affecting drug quality. Different crystal forms of the same medicament may have obvious difference in physicochemical properties such as appearance, fluidity, solubility, storage stability, bioavailability and the like, may have great difference, and may have different influences on storage transfer, application, stability, curative effect and the like of the medicament; in order to obtain a crystal form that is effective for production or for pharmaceutical preparations, the crystallization behavior of the drug needs to be comprehensively examined to obtain a crystal form that meets production requirements.
The invention is prepared by the following steps of: a large number of experimental researches are carried out on acetylated eltrombopag to obtain a new crystal form of the compound, and the new crystal form has the advantages of good stability, good release in animal bodies, simple preparation process, easy operation and the like.
Disclosure of Invention
Summary of The Invention
The invention provides an acetylated eltrombopag new crystal form and a preparation method thereof, wherein the crystal form has good stability, and the preparation method of the crystal form is simple and easy to operate.
According to one aspect of the invention, the invention provides a novel crystalline form of acetylated eltrombopag: form D, form J.
The new crystal form is researched, and the crystal form D and the crystal form J have good performances in the aspects of stability and the like, and can be used for preparing pharmaceutical preparation production.
Said form D is characterized by having diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by an X-ray powder diffractometer using Cu-Ka radiation: 6.7,8.8,13.4,14.6,16.2,18.9,21.4,26.4 and 30.6.
The Differential Scanning Calorimetry (DSC) curve of the crystal form D has endothermic peaks in the range of 167-169 ℃, 211-213 ℃ and 225-227 ℃.
Said form J is characterized by having diffraction peaks at the following 2 theta (units: degrees, error. + -. 0.2 degrees) angles by means of an X-ray powder diffractometer using Cu-Ka radiation: 5.8,8.8,12,14.5,16.5,22.8 and 25.7.
The Differential Scanning Calorimetry (DSC) curve of the crystal form J has an endothermic peak in the range of 165-167 ℃.
The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of acetylated eltrombopag form D or form J and a pharmaceutically acceptable adjuvant or excipient. The pharmaceutical composition contains acetylated eltrombopag, wherein at least 80% of the acetylated eltrombopag is in a crystal form D or a crystal form J of the acetylated eltrombopag according to the mass ratio.
The pharmaceutical composition can be used for treating thrombocytopenia of patients with chronic Idiopathic Thrombocytopenic Purpura (ITP) after glucocorticoid medicaments, immunoglobulin ineffective treatment or splenectomy, thrombocytopenia of patients with chronic hepatitis C, severe aplastic anemia with insufficient response to immunosuppressive treatment and the like.
The invention also provides a method for preparing the acetylated eltrombopag crystal form D or the acetylated eltrombopag crystal form J.
A method of preparing acetylated eltrombopag form D comprising: mixing the acetylated eltrombopag with tetrahydrofuran, after complete dissolution, dropwise adding an anti-solvent into the tetrahydrofuran solution, stirring to separate out crystals, collecting the crystals, and removing the solvent to obtain the crystal form D.
A method of preparing acetylated eltrombopag form J comprising: mixing the acetylated eltrombopag with a good solvent, heating to dissolve, reducing the temperature to 0-30 ℃ after complete dissolution, separating out crystals, collecting the crystals, and removing the solvent to obtain a crystal form J.
The crystal form D and the crystal form J provided by the invention have good stability, are favorable for operation in storage, transfer and production processes, and can be used for preparing preparations.
Detailed Description
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention aims to provide an acetylated eltrombopag new crystal form and a preparation method thereof, wherein the crystal form has good stability, and the preparation method of the crystal form is simple and easy to operate.
According to one aspect of the invention, the invention provides a novel crystalline form of acetylated eltrombopag: form D and form J.
The new crystal form is researched, and the crystal form D and the crystal form J have good performances in the aspects of stability, in-vivo release and the like, and can be used for preparing pharmaceutical preparation production.
Form D is characterized by having diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by an X-ray powder diffractometer using Cu-Ka radiation: 6.7,8.8,13.4,14.6,16.2,18.9,21.4,26.4 and 30.6.
In some embodiments, form D has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by X-ray powder diffractometer using Cu-K α radiation: 7.1,14.2,16.9,19.9,26.0 and 28.6.
In some embodiments, form D has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by X-ray powder diffractometer using Cu-K α radiation: 6.7,7.1,8.8,13.4,14.2,14.6,16.2,16.9,18.9,19.9,21.4,26.0,26.4,28.6 and 30.6.
In some embodiments, the acetylated eltrombopag form D has an X-ray powder diffraction pattern with a relative intensity of diffraction peak at 8.8 degrees 2 Θ of greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.
In some embodiments, the crystalline form D has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in figure 1.
In some embodiments, the form D has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak in the range of 167 ℃ to 169 ℃, 211 ℃ to 213 ℃, 225 ℃ to 227 ℃.
In some embodiments, the form D has a differential scanning calorimetry curve (DSC profile) as shown in figure 2.
In some embodiments, the thermogravimetric analysis curve (TGA) of form D shows a weight loss of about 3.66% between 30 ℃ and 120 ℃.
In some embodiments, the crystalline form D has a thermogravimetric analysis curve (TGA profile) substantially as shown in figure 3.
In some embodiments, the form D has a purity of at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99%. In some embodiments, the form D has a purity of at least 85%, or at least 90%, or at least 95%, or at least 99%.
Form J is characterized by having diffraction peaks at the following 2 θ (units: degrees, error. + -. 0.2 degrees) angles by an X-ray powder diffractometer using Cu-Ka radiation: 5.8,8.8,12,14.5,16.5,22.8 and 25.7.
In some embodiments, form J has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by X-ray powder diffractometer using Cu-ka radiation: 7.9,10.5,12.9,14.8,18.4,20.8 and 23.8.
In some embodiments, form J has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by X-ray powder diffractometer using Cu-ka radiation: 5.8,7.9,8.8,10.5,12,12.9,14.5,14.8,16.5,18.4,20.8,22.8,23.8 and 25.7.
In some embodiments, form J has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by X-ray powder diffractometer using Cu-ka radiation: 7.0, 7.9,10.5,12.9,13.5, 14.0, 14.8,16.0, 17.2, 17.7, 18.4,19.3,20.0,20.8,23.8, 24.7 and 27.1.
In some embodiments, form J has diffraction peaks at the following 2 θ (units: degrees, error ± 0.2 degrees) angles by X-ray powder diffractometer using Cu-ka radiation: 5.8,7.0, 7.9,8.8,10.5,12,12.9,13.5, 14.0, 14.5,14.8,16.0, 16.5,17.2, 17.7, 18.4,19.3,20.0,20.8,22.8,23.8, 24.7 and 27.1.
In some embodiments, the acetylated eltrombopag form J has a relative intensity in an X-ray powder diffraction pattern of a peak at 14.8 degrees 2 Θ of greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.
In some embodiments, the crystalline form J has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in figure 4.
In some embodiments, the form J has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak in the range of 165 ℃ to 167 ℃.
In some embodiments, the form J has a differential scanning calorimetry curve (DSC profile) as shown in figure 5.
In some embodiments, the thermogravimetric analysis curve (TGA) of form J shows a weight loss of about 4.56% between 30 ℃ and 160 ℃.
In some embodiments, the crystalline form J has a thermogravimetric analysis curve (TGA profile) substantially as shown in figure 6.
In some embodiments, the form J has a purity of at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99%.
The acetylated eltrombopag crystal form D and the acetylated eltrombopag crystal form J can be used for treating thrombocytopenia of patients suffering from chronic Idiopathic Thrombocytopenic Purpura (ITP) after glucocorticoid medicaments and immunoglobulin ineffective treatment or splenectomy, thrombocytopenia of patients suffering from chronic hepatitis C, severe aplastic anemia with insufficient response to immune suppression treatment and other symptoms.
Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of acetylated eltrombopag form D or form J and a pharmaceutically acceptable adjuvant or excipient. In general, a therapeutically effective amount of acetylated eltrombopag form D or/and form J is mixed or contacted with one or more pharmaceutical excipients to make a pharmaceutical composition or formulation, which is prepared in a manner well known in the pharmaceutical art. The pharmaceutical composition or the preparation can be used for treating thrombocytopenia of patients suffering from chronic Idiopathic Thrombocytopenic Purpura (ITP) after glucocorticoid medicaments, immunoglobulin treatment ineffectiveness or splenectomy, thrombocytopenia of patients suffering from chronic hepatitis C, severe aplastic anemia with insufficient response to immunosuppressive treatment and the like.
The invention provides a pharmaceutical composition, which contains at least 0.1-10% of the crystal form D or the crystal form J by weight of the total composition. The invention provides a pharmaceutical composition, which contains at least 0.1-5% of the crystal form D or the crystal form J by weight of the total composition. The invention provides a pharmaceutical composition, which contains at least 0.1-1% of the crystal form D or the crystal form J by weight of the total composition. The invention provides a pharmaceutical composition, which contains at least 0.1-0.5% of the crystal form D or the crystal form J based on the total weight of the composition.
A pharmaceutical composition comprises acetylated eltrombopag, wherein at least 80% of the acetylated eltrombopag is in form D or form J, by mass. In some embodiments, a pharmaceutical composition comprises acetylated eltrombopag, wherein at least 90% of the acetylated eltrombopag is the acetylated eltrombopag form D or form J, by mass ratio. In some embodiments, a pharmaceutical composition comprises acetylated eltrombopag, wherein at least 95% of the acetylated eltrombopag is the acetylated eltrombopag form D or form J, by mass ratio. In some embodiments, a pharmaceutical composition comprises acetylated eltrombopag, wherein at least 97% of the acetylated eltrombopag is the acetylated eltrombopag form D or form J, by mass ratio. In some embodiments, a pharmaceutical composition comprising acetylated eltrombopag, wherein at least 99% of the acetylated eltrombopag is said acetylated eltrombopag form D or form J, by mass ratio.
In some embodiments, the pharmaceutical composition is form D having a purity of at least 80%. In some embodiments, the purity of form D in the pharmaceutical composition is at least 85%, or at least 90%, or at least 95%, or at least 99%.
In some embodiments, the pharmaceutical composition is form J at least 80% pure. In some embodiments, the purity of form J in the pharmaceutical composition is at least 85%, or at least 90%, or at least 95%, or at least 99%.
The pharmaceutical composition containing the acetylated eltrombopag crystal form D or the crystal form J can be used for preparing pharmaceutical preparations for treating thrombocytopenia of patients with chronic Idiopathic Thrombocytopenic Purpura (ITP) after ineffective treatment or splenectomy by glucocorticoid medicaments and immunoglobulin, thrombocytopenia of patients with chronic hepatitis C and severe aplastic anemia with insufficient response to immune suppression treatment. The pharmaceutical composition containing the acetylated eltrombopag crystal form D or the crystal form J can be used for treating thrombocytopenia of patients suffering from chronic Idiopathic Thrombocytopenic Purpura (ITP) after glucocorticoid medicaments and immunoglobulin treatment ineffectiveness or splenectomy, thrombocytopenia of patients suffering from chronic hepatitis C and severe aplastic anemia with insufficient response to immune suppression treatment.
The crystal form D or the crystal form J provided by the invention has better stability, and the more stable crystal form has important significance for improving the quality of the medicine.
The crystal form D and the crystal form J provided by the invention have good stability, are not easy to deliquesce under a high-humidity condition, and are convenient for long-term storage and placement of the medicine. The crystal form provided by the invention has good stability, can well avoid crystal transformation in the processes of medicine storage and development, thereby avoiding the change of bioavailability and medicine effect, and has strong economic value.
According to a second aspect of the invention, the invention proposes a process for preparing the aforementioned acetylated eltrombopag form D or form J.
A method of preparing acetylated eltrombopag form D comprising: mixing the acetylated eltrombopag with tetrahydrofuran, after complete dissolution, dropwise adding an anti-solvent into the tetrahydrofuran solution, stirring to separate out crystals, collecting the crystals, and removing the solvent to obtain the crystal form D. In some embodiments, a method of preparing acetylated eltrombopag form D comprises: mixing the acetylated eltrombopag with tetrahydrofuran, after complete dissolution, dropwise adding an anti-solvent into the tetrahydrofuran solution, separating out crystals, collecting the crystals, and removing the solvent to obtain the crystal form D. The anti-solvent is water or methanol, or a combination thereof. When the mass is calculated by grams (g) and the volume of the solvent is calculated by milliliters (mL), the mass-volume ratio of the acetylated eltrombopag to the tetrahydrofuran solvent is 1: 2-1: 20; more preferably 1:3 to 1: 5.
A method of preparing acetylated eltrombopag form J comprising: mixing the acetylated eltrombopag with a good solvent, heating to dissolve, reducing the temperature to 0-30 ℃ after complete dissolution, separating out crystals, collecting the crystals, and removing the solvent to obtain a crystal form J. In some embodiments, a method of preparing acetylated eltrombopag form J comprises: mixing the acetylated eltrombopag with a good solvent, heating to dissolve, reducing the temperature to 0-20 ℃ after complete dissolution, separating out crystals, collecting the crystals, and removing the solvent to obtain a crystal form J.
The good solvent is ethylene glycol dimethyl ether, acetone, tetrahydrofuran, a mixed solvent of acetone and ethyl acetate, a mixed solvent of acetone and butanone, and a mixed solvent of acetone and acetonitrile. When the good solvent is a mixed solvent, the volume ratio of acetone to ethyl acetate, butanone or acetonitrile is 1: 1.
When the mass is calculated by grams (g) and the volume of the solvent is calculated by milliliters (mL), the mass-volume ratio of the acetylated eltrombopag to the good solvent is 1: 20-1: 50; more preferably 1:25 to 1: 40.
The "crystal form" of the present invention may be present in a sample at 0.0001% to 100%, and therefore, as long as the sample contains even a trace amount of the "crystal form" of the present invention, for example, more than 0.0001%, more than 0.001%, or more than 0.01%, should be understood to fall within the scope of the present invention. In order to describe the parameters of the "crystal form" of the present invention more clearly, the present invention is characterized and identified by testing the parameters of a sample containing a substantially pure "crystal form".
In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. The numerical value of each number may differ by 1%, 2%, or 5%.
The Differential Scanning Calorimetry (DSC) of the crystal form has experimental errors and is slightly affected by the dryness of the sample, the position and peak value of the endothermic peak may slightly differ between one machine and another machine and between one sample and another sample, and the value of the experimental error or difference may be 10 ℃ or less, 5 ℃ or less, 4 ℃ or less, 3 ℃ or less, 2 ℃ or less, or 1 ℃ or less, so the value of the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.
In the present invention, mass to volume ratio is calculated in grams and ml.
In the present invention, "RH" is relative humidity.
FIG. 1: an X-ray powder diffraction (XRPD) pattern of crystalline form D of acetylated eltrombopag.
FIG. 2: differential Scanning Calorimetry (DSC) profile of form D of acetylated eltrombopag.
FIG. 3: thermogravimetric analysis (TGA) profile of crystalline form D of acetylated eltrombopag.
FIG. 4: an X-ray powder diffraction (XRPD) pattern of crystalline form J of acetylated eltrombopag.
FIG. 5: differential Scanning Calorimetry (DSC) profile of crystalline form J of acetylated eltrombopag.
FIG. 6: thermogravimetric analysis (TGA) profile of crystalline form J of acetylated eltrombopag.
Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like or similar reference numerals refer to the same or similar elements or elements having the same or similar function throughout. The embodiments described below with reference to the drawings are illustrative and intended to be illustrative of the invention and are not to be construed as limiting the invention.
In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
Example 1 preparation of acetylated eltrombopag form D
1g of acetylated eltrombopag was added to tetrahydrofuran (2ml), and after heating to 55 ℃ and stirring to obtain a clear solution, water (20ml) was added dropwise to the tetrahydrofuran solution of acetylated eltrombopag. The yellow solid product was precipitated by stirring and stirred for 12 hours. Filtering, placing in a drying oven, and vacuum drying at 50 deg.C to constant weight to obtain yellow powder 0.46 g; XPRD detection proves that the crystal form D of the acetylated eltrombopag is the crystal form D; the X-ray powder diffraction pattern is basically consistent with that of figure 1, the DSC pattern is basically consistent with that of figure 2, and the TGA pattern is basically consistent with that of figure 3.
Example 2 preparation of acetylated eltrombopag form D
5g of acetylated eltrombopag was added to tetrahydrofuran (15ml), and after heating to 55 ℃ and stirring to obtain a clear solution, water (210ml) was added dropwise to the tetrahydrofuran solution of acetylated eltrombopag. The yellow solid product was precipitated by stirring and stirred for 12 hours. Suction filtered and placed in a drying oven for vacuum drying at 50 ℃ to constant weight to obtain 3.09g of yellow powder. XPRD detection proves that the crystal form D of the acetylated eltrombopag is the crystal form D; the X-ray powder diffraction pattern is basically consistent with that of figure 1, the DSC pattern is basically consistent with that of figure 2, and the TGA pattern is basically consistent with that of figure 3.
Example 3 preparation of acetylated eltrombopag form J
Adding 500mg of acetylated eltrombopag into acetone (20ml), heating to 50 ℃, stirring to obtain a clear solution, then placing the reaction system in a low-temperature tank at 0 ℃ for overnight crystallization, stirring to separate out a yellow solid product, and stirring for 12 hours. Suction filtered and placed in a drying oven for vacuum drying at 50 ℃ to constant weight to obtain 320mg of yellow powder. XPRD detection proves that the crystal form J of the acetylated eltrombopag is formed; the X-ray powder diffraction pattern is basically consistent with that of figure 4, the DSC pattern is basically consistent with that of figure 5, and the TGA pattern is basically consistent with that of figure 6.
Example 4 preparation of acetylated eltrombopag form J
Adding 1.5g of acetylated eltrombopag into acetone (55ml), heating to 50 ℃, stirring to obtain a clear solution, placing the reaction system in a low-temperature tank at 0 ℃, crystallizing for 4 hours, and stirring to separate out a yellow solid product. Suction-filtered and placed in a drying oven for vacuum drying at 50 ℃ to constant weight to obtain 990mg of yellow powder. XPRD detection proves that the crystal form J of the acetylated eltrombopag is formed; the X-ray powder diffraction pattern is basically consistent with that of figure 4, the DSC pattern is basically consistent with that of figure 5, and the TGA pattern is basically consistent with that of figure 6.
Example 5 stability experiment of acetylated eltrombopag form D
The acetylated eltrombopag crystal form D sample is respectively placed in the conditions of 60 ℃ (temperature deviation +/-2 ℃) and 75% relative humidity, 25 ℃/60% relative humidity/4500 lux and 25 ℃/92.5% relative humidity after being opened, and the XRPD is measured after 10 days of sampling, and the experimental results are shown in the following table 1.
TABLE 1 stability study of form D
The above results show that: after the sample is respectively placed for 10 days under the conditions of 60 ℃ (temperature deviation +/-2 ℃), 75% relative humidity, 25 ℃, 60% relative humidity, 4500 lux, 25 ℃ and 92.5% relative humidity, the crystal form is not changed, and the stability is good.
Example 6 stability experiment of acetylated Eltrombopag form J
The acetylated eltrombopag crystal form J sample is taken and respectively placed under the conditions of 60 ℃ (temperature deviation +/-2 ℃)/75% relative humidity, 25 ℃/60% relative humidity/4500 lux and 25 ℃/92.5% relative humidity in an open manner, the sample is sampled after 10 days, the XRPD is measured, and the experimental results are shown in the following table 2.
TABLE 2 study of Crystal form J stability
The above results show that: the crystal form J is kept unchanged and has good stability after being respectively placed for 10 days under the conditions of illumination at 25 ℃/60% relative humidity/4500 lux and high humidity at 25 ℃/92.5% relative humidity.
In the present invention, a test apparatus and method
(1) Powder X-ray diffraction (XRPD) study
X-ray powder diffraction (XRPD) patterns were collected on a PANalytical Empyrean X-ray diffractometer in the netherlands equipped with a transmission-reflection sample stage with an automated 3X 15 zero background sample holder. The radiation source used is (Cu, K alpha, K alpha 1)
1.540598；Kα2 
1.544426, respectively; the K alpha 2/K alpha 1 intensity ratio: 0.50) with the voltage set at 45KV and the current set at 40 ma.the beam divergence of the X-rays, i.e. the effective size of the X-ray confinement on the sample, is 10 mm.a theta-theta continuous scanning mode is used to obtain an effective 2 theta range of 3 deg. -40 deg.. Taking a proper amount of sample at the position of the circular groove of the zero-background sample rack under the environmental condition (about 18-32 ℃), lightly pressing the sample by using a clean glass slide to obtain a flat plane, and fixing the zero-background sample rack. The sample was scanned at a scan step of 0.0168 ° in the range of 3-40 ° 2 θ to produce a conventional XRPD pattern. The software used for Data collection was a Data Collector, and Data was analyzed and presented using Data Viewer and HighScore Plus.
XRPD detection was performed on the crystalline forms prepared in the examples, respectively, using the conditions described above.
(2) Differential Scanning Calorimetry (DSC) analysis
DSC measurements in TA InstrumentsTMModel Q2000 was performed using a sealed disk apparatus. Samples (approximately 1-3 mg) were weighed in aluminum pans, capped with Tzero, precision recorded to one hundredth of a milligram, and transferred to the instrument for measurement. The instrument was purged with nitrogen at 50 mL/min. Data were collected between room temperature and 300 ℃ at a heating rate of 10 ℃/min. The endothermic peak was plotted downward, and the data was analyzed and displayed using TA Universal Analysis.
(3) Thermogravimetric analysis (TGA) analysis
TGA measurements in TA InstrumentsTMIn model Q500. The operation steps are that the empty crucible is peeled, about 10mg of solid sample is taken and put in the peeled empty crucible, and the solid sample is spread evenly. After the instrument runs stably, data are collected at a heating rate of 10 ℃/min between room temperature and 300 ℃ under nitrogen purging, and a spectrum is recorded.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (18)
- A crystalline form of acetylated eltrombopag, said crystalline form being form D or form J; characterized in that Cu-Kalpha radiation is used, and an X-ray powder diffraction spectrum is expressed by 2 theta (error +/-0.2 degrees), wherein the X-ray powder diffraction pattern of the crystal form D has diffraction peaks at the positions of 6.7,8.8,13.4,14.6,16.2,18.9,21.4,26.4 and 30.6 degrees of 2 theta; form J has diffraction peaks at 5.8,8.8,12,14.5,16.5,22.8, and 25.7 degrees 2 theta in its X-ray powder diffraction pattern.
- The crystalline form of claim 1, wherein form D has an X-ray powder diffraction pattern having diffraction peaks at 7.1,14.2,16.9,19.9,26.0, and 28.6 degrees 2 Θ; or form D has diffraction peaks in the X-ray powder diffraction pattern at 6.7,7.1,8.8,13.4,14.2,14.6,16.2,16.9,18.9,19.9,21.4,26.0,26.4,28.6, and 30.6 degrees 2 Θ; or form D, as shown in figure 1.
- The crystalline form of claim 1, wherein the thermogravimetric analysis curve of form D shows a weight loss between 30 ℃ and 120 ℃.
- The crystalline form of claim 1, wherein the thermogravimetric analysis curve of form D shows a weight loss of about 3.66% over a temperature range of 30 ℃ to 120 ℃.
- The crystalline form of claim 1, wherein the purity of form D is at least 70%.
- The crystalline form of claim 1, wherein form J has an X-ray powder diffraction pattern having diffraction peaks at 7.9,10.5,12.9,14.8,18.4,20.8, and 23.8 degrees 2 Θ; or form J has diffraction peaks at positions 5.8,7.9,8.8,10.5,12,12.9,14.5,14.8,16.5,18.4,20.8,22.8,23.8, and 25.7 degrees 2 Θ in its X-ray powder diffraction pattern; or form J has diffraction peaks at positions 7.0, 7.9,10.5,12.9,13.5, 14.0, 14.8,16.0, 17.2, 17.7, 18.4,19.3,20.0,20.8,23.8, 24.7, and 27.1 degrees 2 Θ in its X-ray powder diffraction pattern; or form J has diffraction peaks at positions 5.8,7.0, 7.9,8.8,10.5,12,12.9,13.5, 14.0, 14.5,14.8,16.0, 16.5,17.2, 17.7, 18.4,19.3,20.0,20.8,22.8,23.8, 24.7, and 27.1 degrees 2 Θ in an X-ray powder diffraction pattern; or form J, as shown in FIG. 4.
- The crystalline form of claim 1 or 6, wherein the thermogravimetric analysis curve of form J shows a weight loss between 30 ℃ and 160 ℃.
- The crystalline form of claim 1 or 6 wherein the thermogravimetric analysis curve of form J shows a weight loss of about 4.56% between 30 ℃ and 160 ℃.
- The crystalline form of claim 1 or 6, wherein form J is at least 70% pure.
- A method of preparing the acetylated eltrombopag crystalline form of any of claims 1-5 comprising: mixing the acetylated eltrombopag with tetrahydrofuran, after complete dissolution, dropwise adding an anti-solvent into a tetrahydrofuran solution of the acetylated eltrombopag, stirring to separate out crystals, collecting the crystals, and removing the solvent to obtain a crystal form D; wherein the anti-solvent is at least one of water and methanol.
- The method according to claim 10, characterized in that the mass to volume ratio of acetylated eltrombopag to tetrahydrofuran is between 1g:2ml and 1g:20 ml.
- A method of preparing the acetylated eltrombopag crystalline form of any of claims 1 or 6-9 comprising: mixing the acetylated eltrombopag with a good solvent, heating to dissolve, reducing the temperature to 0-30 ℃ after complete dissolution, separating out crystals, collecting the crystals, and removing the solvent to obtain a crystal form J; wherein the good solvent is at least one selected from ethylene glycol dimethyl ether, acetone, tetrahydrofuran, a mixed solvent of acetone and ethyl acetate, a mixed solvent of acetone and butanone and a mixed solvent of acetone and acetonitrile.
- The method according to claim 12, wherein the mass to volume ratio of the acetylated eltrombopag to the good solvent is from 1g:20ml to 1g:50 ml.
- The process according to claim 12, wherein the volume ratio of acetone to ethyl acetate is 1:1, the volume ratio of acetone to butanone is 1:1, or the volume ratio of acetone to acetonitrile is 1: 1.
- A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of any one of claims 1-9 and a pharmaceutically acceptable excipient.
- The pharmaceutical composition according to claim 15, wherein at least 80% of the acetylated eltrombopag is form D or form J, by mass ratio.
- The pharmaceutical composition of claim 15 or 16, wherein the crystalline form is at least 0.1% to 10% of the total weight of the composition.
- Use of a pharmaceutical composition according to any one of claims 15 to 17 in the manufacture of a medicament for the treatment of thrombocytopenia.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1444477A (en) * | 2000-05-25 | 2003-09-24 | 史密丝克莱恩比彻姆公司 | Thrombopoietin mimetics |
| WO2013072921A2 (en) * | 2011-09-13 | 2013-05-23 | Glenmark Generics Limited | Process for preparation of substituted 3'-hydrazino-biphenyl-3-carboxylic acid compounds |
| US20170275255A1 (en) * | 2014-09-05 | 2017-09-28 | Hetero Research Foundation | Crystalline form of eltrombopag free acid |
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| CA2724881C (en) * | 2008-05-20 | 2016-09-27 | Neurogesx, Inc. | Carbonate prodrugs and methods of using the same |
| US7956048B2 (en) * | 2009-04-01 | 2011-06-07 | Pliva Hrvatska D.O.O. | Polymorphs of eltrombopag and eltrombopag salts and processes for preparation thereof |
| US9561285B2 (en) * | 2010-01-22 | 2017-02-07 | Ascendis Pharma As | Carrier-linked carbamate prodrug linkers |
| EP3692021A1 (en) * | 2017-10-06 | 2020-08-12 | Assia Chemical Industries Ltd | Solid state forms of eltrombopag choline |
| CN109096195A (en) * | 2018-09-27 | 2018-12-28 | 上海雅本化学有限公司 | A kind of preparation method of eltrombopag olamine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1444477A (en) * | 2000-05-25 | 2003-09-24 | 史密丝克莱恩比彻姆公司 | Thrombopoietin mimetics |
| WO2013072921A2 (en) * | 2011-09-13 | 2013-05-23 | Glenmark Generics Limited | Process for preparation of substituted 3'-hydrazino-biphenyl-3-carboxylic acid compounds |
| US20170275255A1 (en) * | 2014-09-05 | 2017-09-28 | Hetero Research Foundation | Crystalline form of eltrombopag free acid |
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