CN110642881A - Bortezomib crystal form M and preparation method and application thereof - Google Patents
Bortezomib crystal form M and preparation method and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of pharmaceutical chemistry, in particular to a bortezomib crystal form M and a preparation method and application thereof. The X-ray powder diffraction pattern of the crystal form M has a characteristic peak at a2 theta +/-0.2 DEG position, and the 2 theta is 4.4, 6.2, 8.6, 9.1, 10.1, 11.8, 12.4, 14.5, 18.1, 19.7, 20.9 and 21.9, so that the crystal form M has the advantages of high stability, simplicity in preparation, low cost and high purity.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a bortezomib crystal form M and a preparation method and application thereof.
Background
Bortezomib, formerly PS-341(Velcade, Millennium Pharmaceuticals, Inc, Cambridge, MA), is a dipeptidyl boronic acid compound, white or off-white in mass or powder, chemically named [ (1R) -3-methyl-1- [ [ (2S) -1-oxo-3-phenyl-2- [ (pyrazinecarboxyl) amino group]Propyl radical]Amino group]Butyl radical]Boric acid of formula C19H25BN4O4The structural formula is shown as formula I:
multiple Myeloma (MM) is a malignant plasmacytosis in which the tumor cells originate from plasma cells in the bone marrow, which are cells of the B-lymphocyte development to the final functional stage. Multiple myeloma can therefore be classified in the range of B-lymphocyte lymphomas. WHO currently attributes it as one of the B cell lymphomas, called plasma cell myeloma/plasmacytoma. It is characterized by myelodysplasia with overproduction of monoclonal immunoglobulin or light chains (M protein), and very few patients may be non-secreted MM that does not produce M protein. Multiple myeloma is often associated with multiple osteolytic lesions, hypercalcemia, anemia, and kidney damage. Because of the suppressed production of normal immunoglobulins, various bacterial infections are readily apparent.
Mantle cell lymphoma accounts for 6% of all Non-Hodgkin lymphomas (NHL). Differential diagnosis of mantle cell lymphoma includes other small cell B cell lymphomas. The most common manifestation of mantle cell lymphoma is lymphadenectasis, often accompanied by systemic symptoms. The hematopathologist morphologically found the tumor to be a B cell lymphoma and made the correct diagnosis of mantle cell lymphoma. As with other subtypes of lymphoma, proper biopsy is important. The treatment efficacy of the mantle cell lymphoma CHOP regimen was unsatisfactory, with only a few patients achieving complete remission.
Bortezomib is a highly selective, potent, reversible proteasome inhibitor. FDA approval was obtained on day 19/5 of 2003 for the sale as lyophilized powder for injection for use in multiple myeloma that had previously received at least two therapies and had progressed after the last treatment. The medicine is a proteasome inhibitor, can specifically inhibit the activity of chymotryptase (chymotryptin-like) of 26S proteasome in mammalian cells, has influence on a series of signal transmission in the cells, and finally leads to cancer cell death. Proteasome inhibitors have been found to have the following effects: 1) has selective killing effect on malignant tumor cells; 2) has synergistic effect when used in combination with other anticancer drugs; 3) has radiotherapy sensitization effect; 4) can induce Bcl-2 over-expression cell to die.
WO2009/036281 discloses a method for synthesizing two crystal forms of bortezomib: the crystal form A is recrystallized by mixing two solvents of methanol and water, and the water content of the crystal form A is about 5 percent; form B was prepared by recrystallization from a mixture of toluene and methylene chloride, and had a moisture content of about 3%.
WO2011/107912 discloses two bortezomib a1 and a2 crystal forms, wherein characteristic absorption peaks at XRPD 2 θ of the crystal form a1 are: 7.1, 8.5, 10.1, 12.2, 13.2, 14.6, 15.9, 16.7, 18.4, 18.9, 19.5, 21.3, 25.3(± 0.2 °); the characteristic absorption peaks at XRPD 2 θ of form a2 are: 6.9, 7.2, 8.5, 10.1, 10.7, 12.2, 13.3, 14.6, 16.0, 16.6, 18.4, 19.1, 19.5, 21.4, 25.4, 26.4(± 0.2 °).
WO2012/131707 discloses a crystalline form of bortezomib AL having characteristic absorption peaks at XRPD 2 Θ: 6.0, 8.5, 12.2, 13.3, 14.1, 17.3, 18.8, 19.0, 19.6, 20.0, 21.6, 22.4, 23.2, 24.2, 24.6, 26.0, 26.8, 27.3(± 0.2 °), and has a water content of between 7% and 9%.
Chinese patent CN103613640A discloses that bortezomib form J has peaks at approximately 3.12, 4.66, 6.18, 8.58, 9.44, 10.33, 11.95, 12.29, 14.68, 16.28, 17.84, 20.25, 21.33, 22.57, 23.38, 24.71, 26.85, 28.05, 28.81, 37.45 ± 0.2 ° in the X-ray powder diffraction pattern. The bortezomib crystal form J solves the problems of poor solubility, weak oxidation resistance and inconvenience for liquid preparation of the bortezomib crystal form to a certain extent, but a crystallization system of the bortezomib crystal form J is a mixed solvent of toluene and esters, the toluene toxicity is high, and the bortezomib crystal form J is not conducive to green industrial mass production.
The bortezomib crystal form prepared and obtained as disclosed in the above documents is low in stability, and from the perspective of industrial production, there is a certain technical difficulty in preparing a stable bortezomib crystal form, so that a process for obtaining a stable bortezomib crystal form is very urgent and necessary.
Therefore, it is very necessary to develop a bortezomib crystal form M, a preparation method and a use thereof, which can solve the above technical problems.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide the bortezomib crystal form M with high stability, simple preparation, low cost and high purity, and the preparation method and the application thereof.
The invention is realized by the following technical scheme:
a bortezomib crystal form M, wherein an X-ray powder diffraction pattern of the crystal form M has a characteristic peak at a2 theta +/-0.2 DEG position, and the 2 theta is 4.4, 6.2, 8.6, 9.1, 10.1, 11.8, 12.4, 14.5, 18.1, 19.7, 20.9 and 21.9.
The invention also relates to a preparation method of the bortezomib crystal form M, which comprises the following steps: and adding the bortezomib crude product into a benign solvent and a non-benign solvent in sequence for crystallization to obtain the bortezomib.
Preferably, the preparation method comprises the following steps: and adding the bortezomib crude product into a benign solvent to obtain a mixed solution, and then diffusing by using a non-benign solvent or adding the mixed solution into the mixed solution for crystallization to obtain the bortezomib.
Preferably, the crude bortezomib is at least one of amorphous or other literature reported crystalline forms.
The benign solvent is a general term for compound recrystallization, and specifically includes: the solvent can dissolve or dissolve bortezomib, or can quickly dissolve bortezomib in the solvent, or can dissolve bortezomib by using a small amount of solvent, or can reach higher solubility, such as: lower aliphatic hydrocarbons or polar solvents are generally used.
More preferably, the benign solvent is one or more of dichloromethane, tetrahydrofuran, methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide and dimethylsulfoxide.
More preferably, the benign solvent is tetrahydrofuran.
The non-benign solvent is a general term for compound recrystallization, and specifically includes: the solvent is difficult to dissolve or dissolve bortezomib, or the bortezomib is slowly dissolved in the solvent, or a large amount of solvent is used to dissolve a small amount or trace amount of bortezomib, or mechanical force is used to dissolve a small amount or trace amount of bortezomib.
More preferably, the non-benign solvent is one or more of n-heptane, methyl tert-butyl ether, isopropyl ether and toluene.
More preferably, the non-benign solvent is methyl tert-butyl ether.
More preferably, the mass to volume ratio of the crude bortezomib to the benign solvent is 0.1-0.3 g/mL.
More preferably, the mass to volume ratio of the crude bortezomib to the non-benign solvent is 0.02-0.06 g/mL.
More preferably, the crystallization is carried out under a specific temperature condition, and the temperature is-10 to 50 ℃.
More preferably, the temperature is 15-35 ℃.
More preferably, the preparation method comprises the following steps: adding the bortezomib crude product into a benign solvent according to the mass-volume ratio of 0.1-0.3g/mL to obtain a mixed solution, then diffusing or adding a non-benign solvent into the mixed solution, wherein the mass-volume ratio of the bortezomib crude product to the non-benign solvent is 0.02-0.06g/mL, and crystallizing at the temperature of-10-50 ℃ to obtain the bortezomib crystal.
More preferably, the preparation method comprises the following steps: adding the bortezomib crude product into a benign solvent according to the mass-volume ratio of 0.2g/mL to obtain a mixed solution, then diffusing or adding a non-benign solvent into the mixed solution, wherein the mass-volume ratio of the bortezomib crude product to the non-benign solvent is 0.04g/mL, and crystallizing at 25 ℃ to obtain the bortezomib.
The invention also relates to a composition which comprises the bortezomib crystal form M or the bortezomib crystal form M prepared by the preparation method.
The invention also relates to a pharmaceutical preparation which comprises the composition and pharmaceutically acceptable auxiliary materials thereof.
The auxiliary materials can be the ones conventionally used in various preparations, such as: but are not limited to, isotonic agents, buffers, flavoring agents, excipients, fillers, binders, disintegrating agents, lubricants, and the like; it may also be selected for use in accordance with the substance, such as: the auxiliary materials can effectively improve the stability and solubility of the compounds contained in the composition or change the release rate, absorption rate and the like of the compounds, thereby improving the metabolism of the compounds in organisms and further enhancing the administration effect. In addition, specific administration purposes or modes may be achieved, such as: sustained release administration, controlled release administration, pulse administration, and the like, and used auxiliary materials such as: but are not limited to, gelatin, albumin, chitosan, polyether and polyester-based polymeric materials, such as: but are not limited to, polyethylene glycol, polyurethane, polycarbonate, copolymers thereof, and the like.
The formulation is a dosage form that facilitates administration, and the main expression of so-called "facilitating administration" is: but not only improving the treatment effect, improving the bioavailability, reducing the toxic and side effects, improving the compliance of patients and the like.
Preferably, the pharmaceutical preparation is one of aqueous solution injection, powder injection, pill, powder, tablet, patch, suppository, emulsion, cream, gel, granule, capsule, aerosol, spray, powder spray, sustained release agent and controlled release agent.
The invention also relates to an application of the bortezomib crystal form M or the bortezomib crystal form M prepared by the preparation method or the composition or the pharmaceutical preparation in preparing medicines for treating multiple myeloma and mantle cell lymphoma.
As used herein, "treating" or "treatment" refers to inhibiting, suppressing, reducing, ameliorating, slowing, stopping, delaying or reversing the progression or exacerbation of a disease or condition in order to arrest or reduce the occurrence or progression of the disease, and the various indications of the disease, disorder or pathological condition described as remaining or taking the drug include alleviating or reducing symptoms or complications, or curing or eliminating the disease, disorder or condition.
The invention has the beneficial effects that:
1. the stability is high: in long-term stability experiments under the freezing condition, the results show that the crystal forms are not changed, the purity is basically unchanged, the oxidation resistance is high, the impurity increase is less during long-term storage, the crystal transformation is not easy, and the use of patients is safer.
2. The crystal form M has good solubility in common solvents, high dissolution speed, improved absorption rate of active ingredients, high bioavailability of the preparation, and good clarity and visible foreign matters after freeze-drying, and is an advantageous new crystal form for preparing medicinal preparations for treating multiple myeloma and mantle cell lymphoma.
3. The preparation method of the crystal form has the advantages of low price of the used reagent, low toxicity, few crystallization steps, mild crystallization conditions, low cost and high product purity, and is suitable for green industrial mass production.
The invention obviously improves the stability and purity of the crystal form M by limiting the type of the solvent, the mass-volume ratio of the raw materials and the crystallization temperature.
Drawings
Figure 1 is an X-ray powder diffraction pattern of crystalline form M of bortezomib of example 1.
Fig. 2 is a high performance liquid chromatogram of bortezomib form M of example 1.
Fig. 3 is a partially enlarged view of fig. 2.
Detailed Description
The invention will be further described with reference to specific embodiments, and the advantages and features of the invention will become apparent as the description proceeds. These examples are illustrative only and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
Example 1
A preparation method of bortezomib crystal form M comprises the following steps:
adding the bortezomib crude product into a test tube containing tetrahydrofuran according to the mass volume ratio of 0.3g/mL to obtain a tetrahydrofuran mixed solution, then placing the test tube into a beaker containing methyl tert-butyl ether with the opening of the test tube facing upwards and sealing the beaker, wherein the mass volume ratio of the bortezomib crude product to the methyl tert-butyl ether is 0.04g/mL, the test tube opening is higher than the height of the methyl tert-butyl ether in the beaker, the methyl tert-butyl ether is diffused into the tetrahydrofuran mixed solution through a solvent, and crystallizing at 25 ℃ to obtain the bortezomib.
Example 2
A preparation method of bortezomib crystal form M comprises the following steps:
adding the bortezomib crude product into a test tube containing methyl tetrahydrofuran according to the mass-volume ratio of 0.1g/mL to obtain a methyl tetrahydrofuran mixed solution, then placing the test tube into a beaker containing isopropyl ether in an open manner with the opening of the test tube facing upwards, sealing the beaker, wherein the mass-volume ratio of the bortezomib crude product to the isopropyl ether is 0.02g/mL, the opening of the test tube is higher than the height of the isopropyl ether in the beaker, and the isopropyl ether is diffused into the methyl tetrahydrofuran mixed solution through a solvent and crystallized at the temperature of-10 ℃ to obtain the bortezomib-N-methyl tetrahydrofuran mixed solution.
Example 3
A preparation method of bortezomib crystal form M comprises the following steps:
adding the bortezomib crude product into a three-necked flask containing tetrahydrofuran according to the mass-volume ratio of 0.2g/mL for nitrogen protection, slowly adding methyl tert-butyl ether while stirring until a solid is separated out and then dissolved immediately, adding 3% (relative to the mass fraction of the bortezomib crude product) of seed crystals M (prepared in example 1) and continuously stirring, and continuously adding the methyl tert-butyl ether until the mass-volume ratio of the bortezomib crude product to the methyl tert-butyl ether is 0.04g/mL after obvious solid is separated out. Cooling to 15 ℃, stirring for 4h, filtering, and washing a filter cake with a methyl tert-butyl ether/tetrahydrofuran mixed solution (volume ratio is 5:1) to obtain the filter cake.
Test example 1
X-ray powder diffraction of Bortezomib form M
The parameters of the X-ray powder diffraction method are as follows:
CuKa target
The tube voltage is 40KV, and the tube current is 40 mA.
Example 1X-ray powder diffraction of bortezomib form M is shown in figure 1, with specific data shown in table 1.
TABLE 1 Bortezomib form M XRPD data summarization
As can be seen from table 1, the new form M of bortezomib has the following characteristic peaks measured in 2 θ in the X-ray powder diffraction pattern: characteristic peaks at 4.4, 6.2, 8.6, 9.1, 10.1, 11.8, 12.4, 14.5, 18.1, 19.7, 20.9 and 21.9(± 0.2 °).
Test example 2
Purity test of new crystal form M sample of bortezomib
Through detection of high performance liquid chromatography, the purity of the novel crystal form M prepared in the embodiment 1 is 99.75% in 0 month, and the novel crystal form M is placed under the refrigeration condition of-20 ℃ for sealed storage for 6 months to obtain the purity of 99.67%.
The specific test method comprises the following steps: taking 20mg of the product, placing the product in a 20ml measuring flask, adding 7ml of acetonitrile, adding 0.5ml of water, performing ultrasonic treatment for about 1 minute, shaking to dissolve the product, adding water to dilute the product to a scale, and shaking up to obtain a sample solution. Measuring by high performance liquid chromatography (0512 in the fourth division of the pharmacopoeia of China 2015), using octadecylsilane chemically bonded silica as filler (Waters symmetry C18, 4.6mm × 250mm, 5 μm column); mobile phase a was water-formic acid (100:0.1) and mobile phase B was acetonitrile-formic acid (100:0.1) with a flow rate of 1.0ml per minute for gradient elution. The sample amount is 20 mul; the column temperature was 25 ℃; the detection wavelength was 270 nm.
Example 1 the HPLC test results are shown in fig. 2, and the specific data are shown in table 2.
TABLE 2 high Performance liquid chromatography purity test results
The comparison of the purity of the new form M obtained in example 2 and example 3 measured by the above method between 0 day and 6 months in a sealed storage is shown in Table 3:
table 3 comparison of purity of samples of example 2 and example 3 between 0 day and 6 months
The results show that the purity of the novel crystal form M prepared by the method is higher and is more than 99.7%, the purity change is extremely small after the novel crystal form M is frozen and stored for 6 months, crystal transformation is not easy to occur, and the novel crystal form M is safer for patients to use.
The technical scheme of the invention is not limited to the technical means disclosed by the technical means, and also comprises the technical scheme formed by any combination of the technical features. While the foregoing is directed to embodiments of the present invention, it will be appreciated by those skilled in the art that various changes may be made in the embodiments without departing from the principles of the invention, and that such changes and modifications are intended to be included within the scope of the invention.
Claims (10)
1. Bortezomib form M, characterized in that the X-ray powder diffraction pattern of form M has a characteristic peak at 2 theta +/-0.2 degrees, wherein 2 theta is 4.4, 6.2, 8.6, 9.1, 10.1, 11.8, 12.4, 14.5, 18.1, 19.7, 20.9 and 21.9.
2. A process for preparing bortezomib form M according to claim 1, comprising the steps of: and (3) adding the bortezomib crude product into a benign solvent and a non-benign solvent in sequence, and crystallizing to obtain the bortezomib.
3. The method of claim 2, comprising the steps of: and adding the bortezomib crude product into a benign solvent to obtain a mixed solution, and then diffusing or adding a non-benign solvent into the mixed solution for crystallization to obtain the bortezomib compound.
4. The production method according to claim 3, characterized in that the benign solvent is one or more of dichloromethane, tetrahydrofuran, methyltetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, and dimethylsulfoxide, preferably tetrahydrofuran; the non-benign solvent is one or more of n-heptane, methyl tert-butyl ether, isopropyl ether and toluene, preferably methyl tert-butyl ether.
5. The preparation method according to claim 3, wherein the mass-to-volume ratio of the bortezomib crude product to the benign solvent is 0.1-0.3 g/mL; the mass-to-volume ratio of the bortezomib crude product to the non-benign solvent is 0.02-0.06 g/mL.
6. The method according to claim 3, wherein the crystallization is carried out at a temperature of-10 to 50 ℃, preferably 15 to 35 ℃.
7. A composition comprising the crystalline form M of bortezomib according to claim 1 or prepared by the preparation process according to any one of claims 2 to 6.
8. A pharmaceutical formulation comprising the composition of claim 7 and a pharmaceutically acceptable excipient.
9. The pharmaceutical preparation of claim 8, wherein the pharmaceutical preparation is one of an aqueous solution injection, a powder injection, a pill, a powder, a tablet, a patch, a suppository, an emulsion, a cream, a gel, a granule, a capsule, an aerosol, a spray, a powder spray, a sustained release agent, and a controlled release agent.
10. Use of the crystalline form M of bortezomib according to claim 1, or the crystalline form M of bortezomib prepared by the preparation method according to any one of claims 2 to 6, or the composition according to claim 7, or the pharmaceutical preparation according to any one of claims 8 to 9 for the preparation of a medicament for the treatment of multiple myeloma or mantle cell lymphoma.
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