CN118440147A - Carfilzomib eutectic crystal and preparation method thereof - Google Patents
Carfilzomib eutectic crystal and preparation method thereof Download PDFInfo
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- CN118440147A CN118440147A CN202410902962.XA CN202410902962A CN118440147A CN 118440147 A CN118440147 A CN 118440147A CN 202410902962 A CN202410902962 A CN 202410902962A CN 118440147 A CN118440147 A CN 118440147A
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- 108010021331 carfilzomib Proteins 0.000 title claims abstract description 98
- 229960002438 carfilzomib Drugs 0.000 title claims abstract description 97
- BLMPQMFVWMYDKT-NZTKNTHTSA-N carfilzomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)[C@]1(C)OC1)NC(=O)CN1CCOCC1)CC1=CC=CC=C1 BLMPQMFVWMYDKT-NZTKNTHTSA-N 0.000 title claims abstract description 96
- 239000013078 crystal Substances 0.000 title claims abstract description 67
- 230000005496 eutectics Effects 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title abstract description 25
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 claims abstract description 64
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 22
- 239000000126 substance Substances 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 51
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 10
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 239000012535 impurity Substances 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 12
- 239000008186 active pharmaceutical agent Substances 0.000 abstract description 7
- 238000000746 purification Methods 0.000 abstract description 5
- 238000001228 spectrum Methods 0.000 abstract description 5
- 239000003446 ligand Substances 0.000 abstract description 3
- 230000001681 protective effect Effects 0.000 abstract description 2
- 238000003860 storage Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 25
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 14
- 238000012360 testing method Methods 0.000 description 13
- 238000001914 filtration Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 7
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 7
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000002411 thermogravimetry Methods 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- -1 carfilzomib malonic acid salt Chemical class 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 235000021317 phosphate Nutrition 0.000 description 4
- 238000007670 refining Methods 0.000 description 4
- 238000001757 thermogravimetry curve Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 230000004580 weight loss Effects 0.000 description 3
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 229940049920 malate Drugs 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 150000002689 maleic acids Chemical class 0.000 description 2
- 150000004701 malic acid derivatives Chemical class 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 241000600871 Euryale <brittle star> Species 0.000 description 1
- 235000006487 Euryale ferox Nutrition 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
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- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229940000764 kyprolis Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a carfilzomib eutectic crystal and a preparation method thereof, wherein the eutectic crystal is the carfilzomib D-dibenzoyl tartaric acid eutectic crystal. Comparing the XRPD spectrum characteristics of the carfilzomib D-dibenzoyltartaric acid eutectic with the XRPD spectrum characteristics of the API carfilzomib crystal form A and the ligand D-dibenzoyltartaric acid, the eutectic is found to have clear and independent novel crystal form characteristics, and is not simply mixed with the two substances. The carfilzomib D-dibenzoyl tartaric acid eutectic provided by the invention has the advantages of good purification effect, low impurity, high stability, high yield and good scalability, is suitable for long-time storage without any protective measures, and is suitable for large-scale preparation of high-purity API carfilzomib.
Description
Technical Field
The invention belongs to the technical field of drug crystal forms, and particularly relates to a carfilzomib D-dibenzoyl tartaric acid eutectic and a preparation method thereof.
Background
Carfilzomib (formula I) is chemically named (2S) -N- ((S) -1- ((S) -4-methyl-1- ((R) -2-methyl oxiran-2-yl) -1-oxopentan-2-ylcarbamoyl) -2-phenethyl) -2- ((S) -2 (2-morpholinoacetamido) -4-phenylbutyrylamino) -4-methylpentanamide, and has a structural formula represented by formula I:
I is a kind of
Carfilzomib was developed by the company of treatment with euryales, 9 in 2012, on the us, with the commercial product being an intravenous lyophilized powder injection, trade name Kyprolis, for patients with multiple myeloma who were treated with at least 2 drugs previously (including bortezomib and an immunomodulator), and who developed disease progression within 60 days after treatment.
Patent CN105985409B discloses the crystalline forms of various salts of carfilzomib, such as crystals of maleic acid salt of carfilzomib. However, the maleate crystals have almost only good refining effect for removing the isomer impurities shown in the formula II in the specification. And the crystal form refining effect of other salts than maleate is not ideal.
Patent CN107548400a discloses oxalate, maleate, succinate, and citrate of carfilzomib, but only describes the purification effect of acetamide impurity shown in formula II in the specification.
Although patent CN111153964B discloses phosphates, malates, malonates of carfilzomib, the preparation method shows that the preparation time is longer, 1-2 days are required, the production efficiency is low, and the yield is lower. Although it is described that the isomer impurity of formula II has a good removal effect, the purification effect which is not detected is not achieved.
II (II)
In view of the above, there is an urgent need in the art for a new method for preparing high-purity, stable carfilzomib, and the method needs to have the advantages of simple preparation method, good repeatability, and suitability for large-scale industrial production.
Disclosure of Invention
The invention aims to provide a carfilzomib eutectic crystal and a preparation method thereof, so as to solve the problems in the prior art.
In order to achieve the above purpose, the invention adopts the following technical scheme:
A co-crystal which is a co-crystal of carfilzomib D-dibenzoyltartaric acid.
Preferably, the co-crystal of carfilzomib D-dibenzoyltartaric acid comprises carfilzomib and D-dibenzoyltartaric acid in a molar ratio of 1:1.
Preferably, the X-ray powder diffraction pattern of the carfilzomib D-dibenzoyltartaric acid co-crystal has a characteristic peak at diffraction angle 2θ：9.9±0.2°,20.9±0.2°,21.6±0.2°,21.8±0.2°,22.9±0.2°,23.6±0.2°,24.5±0.2°,30.5±0.2°,31.8±0.2°,33.5±0.2°.
Preferably, the X-ray powder diffraction pattern of the carfilzomib D-dibenzoyltartaric acid co-crystal has a characteristic peak at diffraction angle 2θ：9.9±0.2°,15.7±0.2°,18.4±0.2°,18.5±0.2°,20.9±0.2°,21.6±0.2°,21.8±0.2°,22.9±0.2°,23.6±0.2°,24.5±0.2°,25.2±0.2°,27.5±0.2°,29.4±0.2°,30.0±0.2°,30.5±0.2°,31.8±0.2°,32.1±0.2°,33.5±0.2°,34.0±0.2°,37.4±0.2°.
Preferably, the X-ray powder diffraction pattern of the carfilzomib D-dibenzoyltartaric acid co-crystal has a characteristic peak at diffraction angle 2θ：9.9±0.2°,13.5±0.2°,15.7±0.2°,18.4±0.2°,18.5±0.2°,19.0±0.2°,19.5±0.2°,20.9±0.2°,21.6±0.2°,21.8±0.2°,22.9±0.2°,23.6±0.2°,24.5±0.2°,25.2±0.2°,26.8±0.2°,27.0±0.2°,27.5±0.2°,28.8±0.2°,29.4±0.2°,30.0±0.2°,30.5±0.2°,31.8±0.2°,32.1±0.2°,32.4±0.2°,33.5±0.2°,34.0±0.2°,36.5±0.2°,36.9±0.2°,37.4±0.2°,39.2±0.2°.
Preferably, the X-ray powder diffraction pattern of the carfilzomib D-dibenzoyltartaric acid co-crystal is substantially as shown in figure 1.
Preferably, the differential scanning calorimetry endotherm temperature of the carfilzomib D-dibenzoyltartaric acid co-crystal is 185.3±3 ℃.
Preferably, the Differential Scanning Calorimetry (DSC) curve of the co-crystal of carfilzomib D-dibenzoyltartaric acid is substantially as shown in figure 2.
Preferably, the carfilzomib D-dibenzoyltartaric acid eutectic thermogravimetric analysis (TGA) profile has a weight loss of 0.02% in the temperature range of 30-100 ℃.
Preferably, the carfilzomib D-dibenzoyltartaric acid co-crystal is an anhydrate.
Preferably, the thermogravimetric analysis curve (TGA) of the carfilzomib D-dibenzoyltartaric acid co-crystal is substantially as shown in figure 3.
A method of preparing a co-crystal comprising the steps of: d-dibenzoyl tartaric acid and carfilzomib are dissolved in a solvent, and after the D-dibenzoyl tartaric acid and carfilzomib are completely dissolved, solids are stirred and separated out, stirred, filtered and dried.
The feeding mole ratio of the D-dibenzoyl tartaric acid to the carfilzomib is (1-3): 1, preferably 1-1.5:1; stirring for 1-3 h at room temperature; the solvent is selected from one or more of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran and methyl tertiary butyl ether, preferably any one of methanol, ethanol and tetrahydrofuran.
In the preparation method, the dissolution temperature of the D-dibenzoyltartaric acid and the carfilzomib is 20-60 ℃.
Comparing the XRPD spectrum characteristics of the carfilzomib D-dibenzoyltartaric acid eutectic with the XRPD spectrum characteristics of the API carfilzomib crystal form A and the ligand D-dibenzoyltartaric acid, the eutectic is found to have clear and independent novel crystal form characteristics, and is not simply mixed with the two substances.
The beneficial effects are that: the carfilzomib D-dibenzoyl tartaric acid eutectic provided by the invention has the advantages of good purification effect, low impurity, high stability, high yield and good scalability, is suitable for long-time storage without any protective measures, and is suitable for large-scale preparation of high-purity API carfilzomib.
Drawings
FIG. 1 shows the XRPD patterns of the carfilzomib D-dibenzoyltartaric acid co-crystal of example 1;
FIG. 2 shows DSC curves of the Carfilzomib D-dibenzoyltartaric acid co-crystal of example 1;
FIG. 3 shows the TGA curve of the co-crystal of carfilzomib D-dibenzoyltartaric acid of example 1;
Figure 4 shows a comparison of XRPD pattern features of carfilzomib D-dibenzoyltartaric acid co-crystals of example 1 with API crystalline forms a and D-dibenzoyltartaric acid.
Detailed Description
The invention will be further explained with reference to the drawings and examples.
The terms used in the present application are explained as follows:
The term "co-crystal" or "co-crystal" refers to a composition of two or more phases; the phase refers to a substance having the same composition, crystal structure, and properties.
The term XRD refers to X-ray powder diffraction. In the invention, the powder X-ray diffraction test instrument comprises: a bruk D8 Advance powder diffractometer; test conditions: cuK alpha instrument rays, 40kV,40mA,3-40 degrees.
The term DSC refers to a differential scanning calorimeter. In the present invention, the differential scanning calorimeter is: U.S. TA DSC2500; test conditions: 20-250 ℃,10 ℃/min; n2 (50 mL/min).
The term TGA refers to thermogravimetric analyzer. In the present invention, the thermogravimetric analyzer is: U.S. TA TGA5500; test conditions: 30-300 ℃,10 ℃/min; n 2 (50 mL/min).
In the context of the present invention, the values of the diffraction angles 2theta (also known as 2theta or diffraction peaks) in the X-ray powder diffraction pattern are all in degrees (°).
When referring to a spectrum and/or data in a graph, the term "diffraction peak" refers to a feature that one skilled in the art would not attribute to background noise.
The X-ray powder diffraction peak of the crystal, the measurement of 2 theta or diffraction peak of the X-ray powder diffraction pattern thereof has experimental error, and the measurement of 2 theta or diffraction peak of the X-ray powder diffraction pattern 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 + -0.2 units, so that the value of 2 theta or diffraction peak cannot be regarded as absolute.
The differential scanning calorimetric curve (DSC) of the crystal has experimental errors, and 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 experimental error or difference may have a value of 5 ℃ or less, or 4 ℃ or less, or 3 ℃ or less, or 2 ℃ or less, or 1 ℃ or less, so the peak position or peak value of the endothermic peak of the DSC cannot be regarded as absolute.
The thermogravimetric analysis curve (TGA) of the crystal has experimental errors, and the endothermic curve or the weight loss ratio may slightly differ between one machine and another machine and between one sample and another sample, and the experimental error or the difference may have a value of 0.4% or 0.3% or 0.2% or 0.1% or less, so the thermogravimetric analysis curve or the weight loss ratio thereof cannot be regarded as absolute.
The crude carfilzomib product used in the examples had a high performance liquid color purity of 95.1%, a content of 94.3% and a mono-hetero HPLC content of 2.51% as shown in formula II. The crude carfilzomib product can be prepared according to a method in the prior art.
Example 1: preparation of carfilzomib D-dibenzoyl tartaric acid eutectic
Example 1-1
50G of carfilzomib and 24.88g of D-dibenzoyl tartaric acid are weighed, dissolved in 200mL of absolute ethanol at 40 ℃, stirred until the mixture is completely dissolved, a large amount of solids are separated out, stirred continuously for 1h at room temperature, filtered and dried to obtain 66.8g of carfilzomib D-dibenzoyl tartaric acid eutectic product, and the molar yield is 94.95% and the purity is 99.98%. The XRPD, DSC, TGA diagrams are respectively consistent with the diagrams of fig. 1,2 and 3, and related data are shown in table 1; the XRPD pattern characteristics of which are shown in figure 4 for the crystalline form pair of API carfilzomib with the ligand D-dibenzoyltartaric acid.
TABLE 1 XRPD data for Carfilzomib D-dibenzoyltartaric acid Co-crystals
| Sequence number | 2θ（o） | I/Io(%) |
| 1 | 9.9 | 45.2 |
| 2 | 13.5 | 23.9 |
| 3 | 15.7 | 38.9 |
| 4 | 18.4 | 11.7 |
| 5 | 18.5 | 20.0 |
| 6 | 19.0 | 5.9 |
| 7 | 19.5 | 3.5 |
| 8 | 20.9 | 42.8 |
| 9 | 21.6 | 91.1 |
| 10 | 21.8 | 100.0 |
| 11 | 22.9 | 1.3 |
| 12 | 23.6 | 15.7 |
| 13 | 24.5 | 90.0 |
| 14 | 25.2 | 22.1 |
| 15 | 26.8. | 20.4 |
| 16 | 27.0 | 15.4 |
| 17 | 27.5 | 16.2 |
| 18 | 28.8 | 13.5 |
| 19 | 29.4 | 12.7 |
| 20 | 30.0 | 17.8 |
| 21 | 30.5 | 19.2 |
| 22 | 31.8 | 11.3 |
| 23 | 32.1 | 14.2 |
| 24 | 32.4 | 15.6 |
| 25 | 33.5 | 9 |
| 26 | 34.0 | 3.5 |
| 27 | 36.5 | 6.7 |
| 28 | 36.9 | 7.8 |
| 29 | 37.4 | 8.3 |
| 30 | 39.2 | 6.7 |
Examples 1 to 2
50G of carfilzomib and 24.88g of D-dibenzoyltartaric acid are weighed, dissolved in 150mL of methanol at 50 ℃, stirred until the carfilzomib and 24.88g of D-dibenzoyltartaric acid are completely dissolved, a large amount of solids are separated out, stirred continuously for 1h at 4 ℃ for filtering and drying to obtain 65.5g of carfilzomib D-dibenzoyltartaric acid eutectic product, the molar yield is 92.74%, and the purity is 99.97%.
Examples 1 to 3
50G of carfilzomib and 24.88g of D-dibenzoyl tartaric acid are weighed, dissolved in 300mL of tetrahydrofuran at 50 ℃, stirred until the mixture is completely dissolved, a large amount of solids are separated out, stirred continuously for 1h at 4 ℃ for filtering and drying to obtain 66.1g of carfilzomib D-dibenzoyl tartaric acid eutectic product, wherein the molar yield is 93.60%, and the purity is 99.95%.
Examples 1 to 4
50G of carfilzomib and 24.88g of D-dibenzoyl tartaric acid are weighed, dissolved in 300mL of acetone at 40 ℃, stirred until the mixture is completely dissolved, a large amount of solids are separated out, stirred continuously for 1h at room temperature, filtered and dried to obtain 65.0g of carfilzomib D-dibenzoyl tartaric acid eutectic product, wherein the molar yield is 92.04%, and the purity is 99.96%.
Examples 1 to 5
50G of carfilzomib and 24.88g of D-dibenzoyltartaric acid were weighed out, dissolved in 150mL of absolute ethanol at 40 ℃ and stirred until complete dissolution, and a large amount of solids were precipitated. 50mL of methyl tertiary butyl ether is added, stirring is continued for 1h at room temperature, filtering and drying are carried out, and 68.2g of carfilzomib D-dibenzoyl tartaric acid eutectic product is obtained, the molar yield is 96.57%, and the purity is 99.90%.
Examples 1 to 6
50G of carfilzomib and 24.88g of D-dibenzoyltartaric acid were weighed out, dissolved in 150mL of acetone at 50℃and stirred until complete dissolution, and a large amount of solids were precipitated. 50mL of methyl tertiary butyl ether is added, stirring is continued for 1h at room temperature, filtering and drying are carried out, and 66.9g of carfilzomib D-dibenzoyl tartaric acid eutectic product is obtained, the molar yield is 94.73%, and the purity is 99.83%.
Comparative example 1: preparation of citrate of patent CN105985409B
10G of carfilzomib and 2.71g of citric acid were dissolved in 75mL of tetrahydrofuran and 50mL of acetonitrile at room temperature, and after dissolution, the mixture was stirred at room temperature for 2 hours, and a large amount of white solid was precipitated. The reaction flask was cooled to-10 ℃, stirred overnight, the solid filtered off and washed with 100mL acetonitrile to give 8.37g of carfilzomib citrate product with a molar yield of 70.00% and a purity of 97.77%.
Comparative example 2: preparation of maleic acid salt of patent CN105985409B
20G of carfilzomib was dissolved in 400mL of tetrahydrofuran at room temperature, 3.60g of maleic acid was added, and the mixture was stirred at room temperature for 2 hours, and a large amount of white solid was precipitated. The solid was filtered off, washed with tetrahydrofuran and dried under reduced pressure to give 18.20g of carfilzomib maleate product with a molar yield of 83.10% and a purity of 98.31%.
Comparative example 3: preparation of oxalate of patent CN107548400A
10G of carfilzomib and 1.30g of oxalic acid were dissolved in a mixture of 70mL of tetrahydrofuran and 50mL of acetonitrile, and stirred at 20-25℃for 1 hour, and a large amount of white solid was precipitated. After 1h cooling to 0-10 ℃ and stirring for 3h, the solid was filtered off to give 9.29g of carfilzomib oxalate product with a molar yield of 87.56% and a purity of 96.82%.
Comparative example 4: preparation of maleate salt by THF/acetonitrile System
At room temperature, 20g of carfilzomib crude product is dissolved in 100mL of tetrahydrofuran, 3.90g of maleic acid is added, stirring is carried out at room temperature for 1h, 400mL of acetonitrile is added, stirring is carried out at room temperature for 1h, filtering is carried out, filter cakes are washed by acetonitrile, 18.91g of carfilzomib maleate product is obtained by vacuum drying, and the yield is 86.35% and the purity is 98.27%.
Comparative example 5: preparation of oxalate by THF/acetonitrile System
20G of crude carfilzomib product is dissolved in 100mL of tetrahydrofuran at room temperature, 3.12g of oxalic acid is added, stirring is carried out at room temperature for 1h, 400mL of acetonitrile is added, stirring is carried out at room temperature for 1h, filtering is carried out, filter cakes are washed by acetonitrile, vacuum drying is carried out, 19.05g of carfilzomib oxalate product is carried out, the molar yield is 89.77%, and the purity is 98.01%.
Comparative example 6: preparation of phosphate of patent CN111153964B
20G of crude carfilzomib product is dissolved in 100mL of tetrahydrofuran at room temperature, 2.5mL of phosphoric acid is added, stirring is carried out for 1h at room temperature, 400mL of acetonitrile is added, stirring is carried out for 2h at room temperature, filtering is carried out, filter cakes are washed by acetonitrile, 18.52g of carfilzomib phosphate product is obtained by vacuum drying, and the molar yield is 86.42% and the purity is 99.10%.
Comparative example 7: preparation of malate salt of patent CN111153964B
20G of crude carfilzomib product is dissolved in 100mL of tetrahydrofuran at room temperature, 4.5g of malic acid is added, stirring is carried out for 1h at room temperature, 400mL of acetonitrile is added, stirring is carried out for 7 days at room temperature, filtering is carried out, filter cakes are washed by acetonitrile, and drying under reduced pressure is carried out to obtain 9.15g of carfilzomib malate product, the molar yield is 40.90%, and the purity is 98.91%.
Comparative example 8: preparation of patent CN111153964B malonate crystalline form AZT-I
Dissolving 20g of crude carfilzomib product in 100mL of tetrahydrofuran at room temperature, adding 3.5g of malonic acid, stirring for 1h at room temperature, adding 400mL of acetonitrile, stirring for 1 day at room temperature, filtering, washing a filter cake with acetonitrile, and drying under reduced pressure to obtain 18.03g of carfilzomib malonate crystal form AZT-I product, wherein the molar yield is 83.51%, and the purity is 98.56%.
Comparative example 9: preparation of patent CN111153964B malonate crystalline form AZT-II
20G of carfilzomib crude product is dissolved in 600mL of acetone, 3.5g of malonic acid is added, stirring is carried out for 1 day at room temperature, filtering is carried out, a filter cake is washed by acetone, and 18.19g of carfilzomib malonic acid salt crystal form AZT-II product is obtained by vacuum drying, wherein the molar yield is 84.25%, and the purity is 98.23%.
Test case
Test example 1 effect of preparing crystalline forms using salts/co-crystals of carfilzomib
The crystallization conditions, crystal purity, and yield in the above examples and comparative examples were examined, and the results are shown in Table 2.
TABLE 2 Carfilzomib salt purity (HPLC) results
The results in Table 2 show that in comparative example 6, although the phosphate salt obtained had a certain purification effect, the purity of the main compound was far lower than that of the D-dibenzoyltartaric acid eutectic products obtained in examples 1 to 6. In addition, the molar yields of the D-dibenzoyltartaric acid eutectic products obtained in examples 1-6 are all greater than 90%, and the molar yields of the other salt products are all less than 90%.
Test example 2 effect of Carfilzomib salt/co-crystals in preparation process on removal of isomer impurities
In the process of preparing crude carfilzomib, isomer impurities shown in formula II are inevitably generated, so that the impurities need to be removed before the preparation of subsequent dosage forms. As described above, the crude carfilzomib product adopted by the invention has a purity of 95.1% and an isomer impurity content of 2.51%. Therefore, in order to verify the impurity removing effect of the method for preparing crystals in the present invention, the purity of crystals and the content of impurities of formula II in examples 1-1 and comparative examples 1-9 of the present invention were examined, and the detailed results are shown in table 3 below:
TABLE 3 Table 3
The results in Table 3 show that the carfilzomib D-dibenzoyltartaric acid eutectic of the invention has better refining effect on isomer impurities than other salt type crystals such as citrate, oxalate, phosphate, malate, malonate AZT-I and the like, and can reach undetected level.
Test example 3 solubility investigation test of Carfilzomib salts/Co-crystals
In order to examine the difference in solubility between the co-crystal of carfilzomib D-dibenzoyltartaric acid obtained in the preparation of example 1-1 of the present invention and the pharmaceutically acceptable form a and each salt form disclosed in the patent. The present invention examined the equilibrium solubility (saturated solution) measured by external standard method under the conditions of pure water at 37℃and medium at pH4.5, and the results are shown in Table 4 below:
TABLE 4 Table 4
The solubility test result shows that the D-dibenzoyltartaric acid eutectic phase has obvious advantages compared with the medicinal crystal form A and other salt forms in the equilibrium solubility in two media of pure water and pH4.5 at 37 ℃. The solubility of the D-dibenzoyltartaric acid eutectic is 12.5 times of that of the medicinal crystal form A and 26.0 times of that of the oxalate in a pure water medium; the solubility of the D-dibenzoyltartaric acid eutectic is 16.7 times that of the medicinal crystal form A and 33.4 times that of oxalate in a pH4.5 medium, and the solubility is obviously improved.
Test example 4 stability investigation test of Carfilzomib salts/Co-crystals
And carrying out an influence factor test by referring to the stability test guiding principle of the raw material medicine and the preparation of 2015 edition of the pharmacopoeia of the people's republic of China. The salt forms of examples 1-1 and comparative examples 1-9, API form A, were allowed to stand at 40℃and 60℃under 75% humidity and light, respectively, for a period of time, and the purity and changes of the crystal forms after the standing are shown in Table 5.
TABLE 5
Note that: where "/" indicates the initial state before processing of the various embodiments.
The results in Table 5 show that the crystal forms of the examples of the present invention have better stability, less variation in crystal form purity under high temperature, high humidity and light irradiation conditions, less single impurity generation, and more suitability for refining crude products, as compared with the comparative examples.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (10)
1. A co-crystal, characterized in that: the eutectic is carfilzomib D-dibenzoyl tartaric acid eutectic.
2. The co-crystal of claim 1, wherein: the carfilzomib D-dibenzoyltartaric acid eutectic comprises carfilzomib and D-dibenzoyltartaric acid in a molar ratio of 1:1.
3. The co-crystal of claim 1, wherein: the X-ray powder diffraction pattern of the carfilzomib D-dibenzoyltartaric acid co-crystal has a characteristic peak at diffraction angle 2θ：9.9±0.2°,20.9±0.2°,21.6±0.2°,21.8±0.2°,22.9±0.2°,23.6±0.2°,24.5±0.2°,30.5±0.2°,31.8±0.2°,33.5±0.2°.
4. The co-crystal of claim 3, wherein: the X-ray powder diffraction pattern of the carfilzomib D-dibenzoyltartaric acid co-crystal has a characteristic peak at diffraction angle 2θ：9.9±0.2°,15.7±0.2°,18.4±0.2°,18.5±0.2°,20.9±0.2°,21.6±0.2°,21.8±0.2°,22.9±0.2°,23.6±0.2°,24.5±0.2°,25.2±0.2°,27.5±0.2°,29.4±0.2°,30.0±0.2°,30.5±0.2°,31.8±0.2°,32.1±0.2°,33.5±0.2°,34.0±0.2°,37.4±0.2°.
5. The co-crystal of claim 4, wherein: the X-ray powder diffraction pattern of the carfilzomib D-dibenzoyltartaric acid co-crystal has a characteristic peak at diffraction angle 2θ：9.9±0.2°,13.5±0.2°,15.7±0.2°,18.4±0.2°,18.5±0.2°,19.0±0.2°,19.5±0.2°,20.9±0.2°,21.6±0.2°,21.8±0.2°,22.9±0.2°,23.6±0.2°,24.5±0.2°,25.2±0.2°,26.8±0.2°,27.0±0.2°,27.5±0.2°,28.8±0.2°,29.4±0.2°,30.0±0.2°,30.5±0.2°,31.8±0.2°,32.1±0.2°,32.4±0.2°,33.5±0.2°,34.0±0.2°,36.5±0.2°,36.9±0.2°,37.4±0.2°,39.2±0.2°.
6. The co-crystal according to any one of claims 1 to 5, wherein: the differential scanning calorimetry endothermic temperature of the carfilzomib D-dibenzoyltartaric acid eutectic is 185.3+/-3 ℃.
7. The co-crystal according to any one of claims 1 to 5, wherein: the carfilzomib D-dibenzoyl tartaric acid eutectic is an anhydrous substance.
8. A method of preparing the co-crystal of claim 1, wherein: the method comprises the following steps: d-dibenzoyl tartaric acid and carfilzomib are dissolved in a solvent, and after the D-dibenzoyl tartaric acid and carfilzomib are completely dissolved, solids are stirred and separated out, stirred, filtered and dried.
9. The method of preparing a co-crystal according to claim 8, wherein: the feeding mole ratio of the D-dibenzoyl tartaric acid to the carfilzomib is (1-3) 1, and the stirring condition is that stirring is carried out for 1-3 hours at room temperature; the solvent is selected from one or more of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran and methyl tertiary butyl ether.
10. The method of preparing a co-crystal according to claim 9, wherein: the feeding mole ratio of the D-dibenzoyl tartaric acid to the carfilzomib is (1-1.5): 1; the solvent is selected from any one of methanol, ethanol and tetrahydrofuran.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103193779A (en) * | 2012-01-05 | 2013-07-10 | 成都弘达药业有限公司 | Eszopiclone preparation method |
| CN105985409A (en) * | 2015-02-12 | 2016-10-05 | 正大天晴药业集团股份有限公司 | Carfilzomib maleate crystal and preparation method thereof |
| CN105985408A (en) * | 2015-02-12 | 2016-10-05 | 正大天晴药业集团股份有限公司 | Purifying method for carfilzomib |
| CN106310221A (en) * | 2016-08-25 | 2017-01-11 | 齐鲁制药有限公司 | Pharmaceutical composition containing carfilzomib and preparation method thereof |
| CN115666579A (en) * | 2020-04-15 | 2023-01-31 | 卡希夫生物科学有限公司 | Stable, ready-to-dilute formulations of carfilzomib |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103193779A (en) * | 2012-01-05 | 2013-07-10 | 成都弘达药业有限公司 | Eszopiclone preparation method |
| CN105985409A (en) * | 2015-02-12 | 2016-10-05 | 正大天晴药业集团股份有限公司 | Carfilzomib maleate crystal and preparation method thereof |
| CN105985408A (en) * | 2015-02-12 | 2016-10-05 | 正大天晴药业集团股份有限公司 | Purifying method for carfilzomib |
| CN106310221A (en) * | 2016-08-25 | 2017-01-11 | 齐鲁制药有限公司 | Pharmaceutical composition containing carfilzomib and preparation method thereof |
| CN115666579A (en) * | 2020-04-15 | 2023-01-31 | 卡希夫生物科学有限公司 | Stable, ready-to-dilute formulations of carfilzomib |
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