CN114437130A - Method for refining cyclophosphamide - Google Patents
Method for refining cyclophosphamide Download PDFInfo
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- CN114437130A CN114437130A CN202210148935.9A CN202210148935A CN114437130A CN 114437130 A CN114437130 A CN 114437130A CN 202210148935 A CN202210148935 A CN 202210148935A CN 114437130 A CN114437130 A CN 114437130A
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- cyclophosphamide
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- molecular sieve
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- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 229960004397 cyclophosphamide Drugs 0.000 title claims abstract description 43
- 238000000034 method Methods 0.000 title claims abstract description 22
- 238000007670 refining Methods 0.000 title claims abstract description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 82
- 238000003756 stirring Methods 0.000 claims abstract description 80
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- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 7
- 229910052782 aluminium Inorganic materials 0.000 claims description 7
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- 239000012043 crude product Substances 0.000 claims description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052593 corundum Inorganic materials 0.000 claims description 2
- 229910001845 yogo sapphire Inorganic materials 0.000 claims description 2
- BYFGZMCJNACEKR-UHFFFAOYSA-N aluminium(i) oxide Chemical compound [Al]O[Al] BYFGZMCJNACEKR-UHFFFAOYSA-N 0.000 claims 2
- KKCBUQHMOMHUOY-UHFFFAOYSA-N Na2O Inorganic materials [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 claims 1
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- SLLDUURXGMDOCY-UHFFFAOYSA-N 2-butyl-1h-imidazole Chemical compound CCCCC1=NC=CN1 SLLDUURXGMDOCY-UHFFFAOYSA-N 0.000 description 1
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
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- CSDREXVUYHZDNP-UHFFFAOYSA-N alumanylidynesilicon Chemical compound [Al].[Si] CSDREXVUYHZDNP-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
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- KAKQVSNHTBLJCH-UHFFFAOYSA-N trifluoromethanesulfonimidic acid Chemical class NS(=O)(=O)C(F)(F)F KAKQVSNHTBLJCH-UHFFFAOYSA-N 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
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Classifications
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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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
- C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
- C07F9/65846—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a six-membered ring which may be condensed with another ring system
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
The invention provides a cyclophosphamide refining method which comprises the steps of adding crude cyclophosphamide into water for dissolving, adding diethyl ether and a molecular sieve, stirring, removing the molecular sieve, cooling, crystallizing, carrying out vacuum filtration, carrying out microwave vacuum low-temperature drying, and obtaining a product with the particle size of less than or equal to 10 mu m and improved water solubility and stability.
Description
Technical Field
The invention relates to the field of a preparation method of cyclophosphamide, in particular to a specific method for crystallizing, purifying and drying a crude cyclophosphamide product to obtain a stable refined product.
Background
Cyclophosphamide (Cyclophosphane) which has a chemical composition of P- [ N, N-bis (β -chloroethyl) ] -1-oxo-3-aza-2-phosphacyclohexane-P-oxide-hydrate according to the description in chinese pharmacopoeia 2015 edition, contains not less than 98.0% of C7H15Cl2N2O2P and has a molecular formula of C7H15Cl2N2O2P · H2O as white crystals or crystalline powder, calculated as anhydride; the crystal water is lost to liquefy; the medicine is soluble in water but not very soluble, the water solution is unstable, and the medicine is originally developed by Baite International Co., Ltd, and is suitable for treating malignant lymphoma, multiple myeloma, lymphocytic leukemia, cervical cancer, prostatic cancer, colon cancer, bronchial cancer, solid tumors such as neuroblastoma, ovarian cancer, breast cancer, various sarcomas, lung cancer and the like. Can also be used for treating rheumatoid arthritis, children nephrotic syndrome and autoimmune diseases, has no antitumor activity in vitro, and is converted into aldehyde phosphoramide by microsomal functional oxidase in liver after entering into body. The aldehydic amide is unstable and is decomposed into amide nitrogen mustard and acrolein in tumor cells, and the amide nitrogen mustard has cytotoxic effect on the tumor cells.
The refining method of cyclophosphamide in the prior art comprises 1) dissolving crude cyclophosphamide in butylimidazole ionic solution, dissolving at 35-40 deg.C, adding water, cooling to precipitate crystal product, and recovering ionic liquid (CN 107501327); 2) adopting water or acetone as solvent, heating to dissolve, cooling to crystallize, air drying, vacuum drying or freeze drying to obtain crystal (CN107936061, CN107540711, CN 109535201);
the prior art processes all give cyclophosphamide crystals with improved purity, however, the common problem is that cyclophosphamide is unstable, and the unstable state is caused by the transition of anhydrous and monohydrate cyclophosphamide at room temperature. When the humidity is high, the anhydrous form can absorb water to form monohydrate, and the water is lost under the dry condition to cause liquefaction, so that the preparation of the stable medicament is difficult, the medicament is usually required to be in a sealed state in the process of storage and transportation, and when the medicament is clinically used, the water solubility is insufficient, the incomplete dissolution is easy to cause clinical problems such as phlebitis and the like. Foreign researchers keep the crystallization stable by low-temperature freeze drying, induce the crystallization by annealing the frozen solution, reduce the escape of water molecules in crystal lattices after primary drying and pressure adjustment, and prevent the dehydration of the crystal lattices. The process is complicated and requires frozen solution induction, the cost of this process is very expensive, and the collapsed structure caused by the escape of crystal water is difficult to obtain uniformity of crystal particles. The product obtained by repeated tests of the freezing process generally has larger grain diameter, the water solubility is not improved, and the product contains impurities of a freezing inducer and does not reach the pharmacopoeia standard in purity.
Disclosure of Invention
Aiming at the problems in the prior art, the invention passes through systematic research and experiments, uses diethyl ether and water mixed solvent for crystallization, carries out crystallization through diethyl ether evaporation effect and stirring speed change, and adds a molecular sieve, thereby unexpectedly obtaining small-particle cyclophosphamide crystals.
The technical scheme of the invention is as follows:
step 2: and cooling, adding diethyl ether and a molecular sieve, stirring, removing the molecular sieve, continuously stirring, cooling, crystallizing, and performing vacuum filtration to obtain a filter cake, wherein the weight ratio of the cyclophosphamide crude product to the diethyl ether is 1: 5-9, wherein the weight ratio of the crude cyclophosphamide product to the molecular sieve is 5-30: 1;
and step 3: washing the molecular sieve and the suction filtration device with ether, combining the filtrates, removing ether from the filtrate, combining the obtained precipitate and the filter cake obtained in the step 2, and performing microwave vacuum low-temperature drying to obtain the product;
compared with the prior art, the invention has the advantages that the particle size of the product is smaller and more uniform, the stability can be kept to a certain degree at normal temperature and in the humidity range of 30-50 percent, and higher-quality raw materials are provided for clinical dosage and medicine preparation. Compared with the product obtained by a freezing process, the product of the invention has the advantages of single crystal, no inducer, obviously improved solubility and stability, no collapse of internal structure caused by excessive evaporation due to lower microwave drying temperature, no excessive expansion and pore problems, compact and stable particles, and capability of forming a non-critical body convenient for drying again.
As a further improvement of the invention, in the step 1, water is added in two parts, 2/3 water is added initially for dissolution, the temperature is heated to 50-55 ℃, and the rest 1/3 normal temperature water is added when the temperature is heated to above 50 ℃; as a preferred option, the dissolution process can be accelerated by stirring; as a preferable scheme, the weight ratio of the crude cyclophosphamide to water is 1: 5-18, further 1: 8-15, most preferably 1: 9-10;
as a further improvement of the invention, the molecular sieve of the step 2 is a 4A molecular sieve, preferably Na2O·Al2O3·2SiO2·9/2H2O; furthermore, the pore diameter is preferably less than or equal to 10nm, and the silicon-aluminum ratio is 2: 1 (SiO)2：Al2O3) Preferably, the particle size of the molecular sieve particles is more than or equal to 1 mm; the weight ratio of the cyclophosphamide crude product to the molecular sieve is preferably 10-20: 1, most preferably 10-15: 1;
as a further improvement of the invention, the weight ratio of the crude phosphoramide product and the diethyl ether in the step 2 is 1: 6-8; further, the step 2 comprises cooling the solution to 30 ℃, adding ether and a molecular sieve, stirring, removing the molecular sieve, continuing stirring, heating the solution to 35 ℃, naturally cooling to room temperature when white turbid substances appear along the wall of the container, continuing cooling to 5-10 ℃, stirring for 0.5-1h, and then carrying out vacuum filtration to obtain a filter cake; wherein the optimal removing time of the molecular sieve is to remove the molecular sieve when the solution is observed to be turbid and the turbidity is reduced to the bottle bottom and clear state; the preferred stirring speed is 40-45rpm when the temperature is 40-55 ℃, and 30-35rpm when the temperature is 25-40 ℃; when the temperature is 10-25 ℃, the stirring speed is 20-25rpm, and when the temperature is below 10 ℃, the stirring speed is reduced to 10-15 rpm;
as a further improvement of the invention, the method for removing the diethyl ether from the filtrate in the step 3 is to heat the filtrate to 35-40 ℃ to volatilize the diethyl ether;
as a further improvement of the invention, the method for removing the diethyl ether from the filtrate in the step 3 is filtration.
As the preferred scheme of the invention, the microwave drying temperature is 36-45 ℃, and the vacuum degree is 0.004-0.09 MPa; more preferably, the temperature is 38-42 ℃, the vacuum degree is 0.005-0.075MPa, and the microwave drying device is provided with a vacuum drying box and an automatic control system; the power is 200-.
Preferably, after drying at the power of 300-; the air humidity in the vacuum box is set between 15 and 39 percent; most preferably between 20 and 35%.
The average particle size of the cyclophosphamide (hydrate) crystal is less than or equal to 10 mu m, preferably less than or equal to 5 mu m, and most preferably less than or equal to 3 mu m.
The invention carries out microwave drying at lower temperature, ether is evaporated at boiling point first, the steam pressure of internal water vapor is in a passive drying state under the condition of low microwave power, partial aggregation is formed on the surface of the particles, particle pore channels are blocked, the balance of the crystallization state of cyclophosphamide monohydrate is achieved under the conditions of specific time, temperature and vacuum degree, the critical state is slightly changed by expansion along with the increase of microwave power to form radial driving force, internal water molecules are pushed to further evaporate, partial water molecules are directly extruded and evaporated in a liquid state, and relatively compact particles can be formed by shortening the drying time, meanwhile, the surface of the structure is sealed by crystal water, and water molecules are not easy to get into the structure from the air, so that the collapse condition of the internal structure is avoided, thereby forming solid powder which has stable structure and is not easy to liquefy in a certain humidity/temperature range.
The automatic control system can set corresponding programs for heating power and adjusting the microwave drying time to perform automatic adjustment within a certain range, pulse type drying can be performed, and the drying equipment can be assisted by adding a hot air exchanger or a reflux device to realize accurate control on the temperature, humidity and vacuum degree in the drying chamber; meanwhile, the device has a disinfection effect. The present invention does not require any terminal sterilization or sterile filtration.
The granules prepared by the invention are dried at low temperature, do not cause the problems of expansion or frozen collapse, have a non-critical stable state, and can be further dried to remove surface crystal water, so that the granules have finer gaps and surface areas, but the anhydrous hydrate needs stricter drying sealing in transportation packaging, including but not limited to nitrogen-filled sealing.
The solvent of the invention needs to be added with the molecular sieve, the molecular sieve has the effect which is not the effect of traditional drying and impurity removal, the crystallization speed is obviously improved after the addition, the solution has the dynamic change of turbid bottle bottom and clarification under the stirring state, the particle size of the final product is more uniform, the water solubility is improved, and the side effect of intravenous injection inflammation caused by insufficient water solubility is reduced.
Unless otherwise specified in the specification, the cyclophosphamide in the invention is cyclophosphamide monohydrate, g is weight unit 'g', h is time unit 'h', min is time unit 'min', ml is volume unit 'ml', mm is length unit 'mm', and the room temperature is 23-25 ℃, and the room temperature is 20 ℃.
Drawings
FIG. 1: example 1 cyclophosphamide detection profile;
FIG. 2: electron microscopy scan of the particles of example 1;
FIG. 3: electron microscopy scan of the particles of example 3;
FIG. 4: an electron micrograph of example 5;
FIG. 5: electron microscopy scan of example 8;
FIG. 6: an electron micrograph of example 9.
Detailed Description
HPLC using Agilent1200 high performance liquid chromatograph (Agilent corporation, USA), the HPLC involved in the present invention example detects the following conditions:
chromatographic column C18, flow rate 1.0ml/min, column temperature 30 deg.C, detection wavelength 210nm, mobile phase 0.05mol/l water-acetonitrile (30:70)
The microwave vacuum low-temperature drying equipment adopts an RD-MXT type drying box; the other reagents were purchased from Hangzhou Kund chemical technology, Inc. or commercially available products.
Example 1:
adding 10g of crude cyclophosphamide into a three-necked bottle containing 60ml of water, stirring and heating to 50 ℃, continuously adding 30ml of normal temperature water, stirring and continuously maintaining at 50 ℃ until the crude cyclophosphamide is dissolved, and filtering out insoluble impurities at the bottom of the bottle; stirring at 45rpm, cooling to below 40 deg.C, reducing the rotation speed to 35rpm, cooling to 30 deg.C, adding 60g diethyl ether solutionAnd 1g of Na2O·Al2O3·2SiO2·9/2H2O (wherein the aperture is less than or equal to 10nm, the ratio of silicon to aluminum is 2: 1, and the particle size is more than or equal to 1mm), and the temperature is maintained for continuous stirring until the solution is no longer clear and the bottom of the bottle is clearer than the upper part, or the solution is slightly turbid until the bottom of the bottle becomes clearer; stopping stirring, quickly removing the molecular sieve, keeping the solution, continuously stirring, slightly heating to 35 ℃, stopping heating when white turbidity appears along the bottle wall, naturally cooling to room temperature, reducing the stirring speed to 25rpm, continuously cooling to below 10 ℃, reducing the stirring speed to 15rpm, continuously cooling to keep the temperature within the range of 5-10 ℃, stirring for 1h, and carrying out vacuum filtration to obtain a filter cake; washing the molecular sieve and the suction filtration port with ether, filtering the filtrate, mixing the obtained precipitate and the filter cake, naturally airing for 1h, placing in a vacuum drying oven of a microwave vacuum drying device, setting the temperature at 40 ℃, the humidity in the oven at 30%, the power at 300w and the vacuum degree at 0.07MPa, vacuum drying for 10min, adjusting the power to 600w and the vacuum degree at 0.01MPa, and continuously drying for 10min to obtain the product.
The purity (calculated by anhydrous cyclophosphamide) is 99.97% by HPLC (detection by HPLC), see detection attached figure 1. The yield is 81%; the scanning electron microscope is shown in figure 2.
Example 2:
adding 15g of crude cyclophosphamide into a three-necked bottle containing 100ml of water, stirring and heating to 55 ℃, continuously adding 50ml of normal temperature water, stirring until the mixture is dissolved, and filtering out impurities insoluble at the bottom of the bottle; stirring at 40rpm, cooling to below 40 deg.C, reducing the rotation speed to 30rpm, cooling to 30 deg.C, adding 120g diethyl ether solution and 1g Na2O·Al2O3·2SiO2·9/2H2O (wherein the aperture is less than or equal to 10nm, the ratio of silicon to aluminum is 2: 1, and the particle size is more than or equal to 1mm), continuously stirring at the temperature until the solution is not clarified any more, the bottom of the bottle is clarified than the upper part of the bottle, stopping stirring, quickly removing the molecular sieve, continuously stirring the solution, slightly heating the solution to 35 ℃, stopping heating when white turbidity appears along the wall of the bottle, naturally cooling the solution to room temperature, reducing the stirring speed to 20rpm, continuously cooling the solution to below 10 ℃, reducing the stirring speed to 10rpm, continuously cooling the solution to be kept within the range of 5-10 ℃, stirring for 40min, and performing vacuum filtration to obtain the productA filter cake; washing a molecular sieve and a suction filtration port with diethyl ether, heating to evaporate the diethyl ether, mixing the obtained precipitate and the filter cake, naturally airing for 1h, placing in a microwave vacuum drying device, setting the temperature at 39 ℃, the humidity in the box at 20%, the power at 500w, the vacuum degree at 0.08MPa, carrying out vacuum drying for 20min, adjusting the power to 1000w and the vacuum degree at 0.008MPa, and continuously drying for 10min to obtain a white powdery crystal.
The HPLC detection purity (calculated by anhydrous cyclophosphamide) is 99.89%, and the detection pattern is the same as that of example 1 and is cyclophosphamide monohydrate.
Example 3:
adding 10g of crude cyclophosphamide into a three-necked bottle containing 60ml of water, stirring and heating to 50 ℃, continuously adding 30ml of normal temperature water, stirring and continuously maintaining at 50 ℃ until the crude cyclophosphamide is dissolved, and filtering out insoluble impurities at the bottom of the bottle; stirring at 45rpm, cooling to below 40 deg.C, reducing the rotation speed to 35rpm, cooling to 30 deg.C, adding 60g diethyl ether solution and 1g Na2O·Al2O3·2SiO2·9/2H2O (wherein the aperture is less than or equal to 10nm, the ratio of silicon to aluminum is 2: 1, and the particle size is more than or equal to 1mm), and the temperature is maintained for continuous stirring until the solution is not clarified any more, and the bottom of the bottle is clearer than the upper part, or the solution is slightly turbid until the bottom of the bottle becomes clear; stopping stirring, quickly removing the molecular sieve, keeping the solution, continuously stirring, slightly heating to 35 ℃, stopping heating when white turbidity appears along the bottle wall, naturally cooling to room temperature, reducing the stirring speed to 25rpm, continuously cooling to below 10 ℃, reducing the stirring speed to 15rpm, continuously cooling to keep the temperature within the range of 5-10 ℃, stirring for 1h, and performing vacuum filtration to obtain a filter cake; washing molecular sieve and suction filtration port with diethyl ether, filtering the filtrate, mixing the obtained precipitate with the above filter cake, air drying for 1 hr, heating to 40 deg.C, vacuum drying, and volatilizing diethyl ether.
The HPLC detection purity (calculated by anhydrous cyclophosphamide) is 99.59%, and the detection pattern is the same as that of example 1 and is cyclophosphamide monohydrate. The electron microscope scan is shown in FIG. 3.
Example 4:
adding 15g of crude cyclophosphamide into a three-necked bottle containing 100ml of water, stirring and heating to 55 ℃, continuously adding 50ml of normal temperature water, stirring until the mixture is dissolved, and filtering out impurities insoluble at the bottom of the bottle; stirring at 40rpm for cooling to below 40 deg.C, reducing the rotation speed to 30rpm, cooling to 30 deg.C, adding 120g diethyl ether solution, maintaining the temperature, stirring, maintaining the solution turbid, keeping the solution, stirring, slightly heating to 35 deg.C, clarifying the solution, stopping heating, naturally cooling to room temperature, reducing the stirring speed to 20rpm, cooling to below 10 deg.C, reducing the stirring speed to 10rpm, continuously cooling to 5-10 deg.C, suspending oily substance, and no crystal precipitation.
Example 5:
adding 15g of crude cyclophosphamide into a three-necked bottle containing 100ml of water, stirring and heating to 45 ℃, continuously adding 50ml of normal temperature water, stirring until the mixture is dissolved, and filtering out impurities insoluble at the bottom of the bottle; stirring at 40rpm, cooling to below 40 deg.C, reducing the rotation speed to 30rpm, cooling to 30 deg.C, adding 120g acetone solution and 1g Na2O·Al2O3·2SiO2·9/2H2O (wherein the aperture is less than or equal to 10nm, the ratio of silicon to aluminum is 2: 1, and the particle size is more than or equal to 1mm), continuously stirring at the temperature until the solution is not clarified any more, the bottom of the bottle is clearer than the upper part of the bottle, stopping stirring, quickly removing the molecular sieve, continuously stirring the retained solution, slightly heating the solution to 35 ℃, gradually clarifying the solution, naturally cooling the solution to room temperature, reducing the stirring speed to 20rpm, continuously cooling the solution to below 10 ℃, reducing the stirring speed to 10rpm, continuously cooling the solution to 5 ℃, gradually turbidity and generating precipitates, cooling the solution to about 0 ℃, stirring for 240min, and performing vacuum filtration to obtain a filter cake; washing a molecular sieve and a suction filtration port with acetone, combining a precipitate obtained by filtering with the filter cake, naturally airing for 1h, placing in a microwave vacuum drying device, setting the temperature at 39 ℃, setting the humidity in the box to be 20%, the power to be 500w, the vacuum degree to be 0.08MPa, carrying out vacuum drying for 20min, increasing the power to be 1000w, and the vacuum degree to be 0.008MPa, and continuously drying for 10min to obtain a white powdery crystal.
The HPLC detection purity (calculated by anhydrous cyclophosphamide) is 97.89%, and the detection pattern is the same as that of example 1 and is cyclophosphamide monohydrate. The electron microscope scan is shown in FIG. 4.
Example 6
Dissolving 15g of cyclophosphamide in 150ml of water, heating and stirring the solution at 50 ℃ for dissolution, continuously cooling the solution to below-10 ℃, stirring the solution at a rotating speed of 60rpm for crystallization for 2 hours, heating the solution to above 0 ℃, and filtering and drying the solution to obtain cyclophosphamide crystals.
The HPLC detection purity (calculated by anhydrous cyclophosphamide) is 99.67%, and the detection pattern is the same as that of example 1 and is cyclophosphamide monohydrate.
Example 7
Dissolving 10g of crude cyclophosphamide product in 40ml of 1-methyl-3N-butylimidazole trifluoromethanesulfonamide salt at 35 ℃, adding 2ml of water, cooling to room temperature until the system becomes turbid, adding 0.1g of cyclophosphamide monohydrate seed crystal, cooling to 10 ℃, controlling the time to be 2h, stirring for 30min, carrying out suction filtration, washing a filter cake twice with ice water, and carrying out vacuum drying on the combined filtrate by a water pump at 20-25 ℃ to obtain the cyclophosphamide compound.
The HPLC detection purity (calculated by anhydrous cyclophosphamide) is 99.19%, and the detection pattern is the same as that of example 1 and is cyclophosphamide monohydrate.
Example 8:
adding 100g of crude cyclophosphamide into a three-necked bottle containing 600ml of water, stirring and heating to 50 ℃, continuously adding 300ml of normal-temperature water, stirring and continuously maintaining at 50 ℃ until the crude cyclophosphamide is dissolved, and filtering out insoluble impurities at the bottom of the bottle; stirring at 45rpm, cooling to below 40 deg.C, reducing the rotation speed to 35rpm, cooling to 30 deg.C, adding 600g diethyl ether solution and 10g Na2O·Al2O3·2SiO2·9/2H2O (wherein the aperture is less than or equal to 10nm, the ratio of silicon to aluminum is 2: 1, and the particle size is more than or equal to 1mm), and the temperature is maintained for continuous stirring until the solution is not clarified any more, and the bottom of the bottle is clearer than the upper part, or the solution is slightly turbid until the bottom of the bottle becomes clear; stopping stirring, quickly removing the molecular sieve, keeping the solution, continuously stirring, slightly heating to 35 ℃, stopping heating when white turbidity appears along the bottle wall, naturally cooling to room temperature, reducing the stirring speed to 25rpm, continuously cooling to below 10 ℃, reducing the stirring speed to 15rpm, continuously cooling to keep the temperature within the range of 5-10 ℃, stirring for 1h, and performing vacuum filtration to obtain a filter cake; washing the molecular sieve and the suction filtration port with diethyl ether, filtering the filtrate to obtain a precipitate and the aboveMixing the filter cakes, placing in a flat chassis, keeping the height of 1-2cm, naturally drying for 1h, freeze-drying, adding a freeze-inducing solution, drying for 1-2h at a set temperature of-5 to-10 ℃ under a pressure of 8-10Pa, reducing the pressure to 1Pa, and vacuum-drying for 1-2h to obtain the final product.
The HPLC detection purity (calculated by anhydrous cyclophosphamide) is 97.97%, the detection pattern is the same as that of example 1, and the detection pattern is cyclophosphamide monohydrate, and an electron microscope scanning image is shown in figure 5.
Example 9:
adding 10g of crude cyclophosphamide into a three-necked bottle containing 60ml of water, stirring and heating to 50 ℃, continuously adding 30ml of normal temperature water, stirring and continuously maintaining at 50 ℃ until the crude cyclophosphamide is dissolved, and filtering out insoluble impurities at the bottom of the bottle; stirring at 90rpm, cooling to below 40 deg.C, maintaining stirring speed, cooling to 30 deg.C, adding 60g diethyl ether solution and 1g Na2O·Al2O3·2SiO2·9/2H2O (wherein the aperture is less than or equal to 10nm, the ratio of silicon to aluminum is 2: 1, and the particle size is more than or equal to 1mm), and the temperature is maintained for continuous stirring until the solution is not clarified any more, and the bottom of the bottle is clearer than the upper part, or the solution is slightly turbid until the bottom of the bottle becomes clear; stopping stirring, quickly removing the molecular sieve, keeping the solution, continuously stirring, slightly heating to 35 ℃, stopping heating when white turbidity appears along the wall of the bottle, continuously stirring at the stirring speed of 90rpm, naturally cooling to room temperature, continuously cooling to below 10 ℃, keeping the temperature within the range of 5-10 ℃, stirring at 90rpm for 1h, and performing vacuum filtration to obtain a filter cake; washing the molecular sieve and the suction filtration port with ether, filtering the filtrate, mixing the obtained precipitate and the filter cake, naturally airing for 1h, placing in a vacuum drying oven of a microwave vacuum drying device, setting the temperature at 40 ℃, the humidity in the oven at 30%, the power at 300w and the vacuum degree at 0.07MPa, vacuum drying for 10min, adjusting the power to 600w and the vacuum degree at 0.02MPa, and continuously drying for 10min to obtain the product.
The HPLC detection purity (calculated by anhydrous cyclophosphamide) is 99.45%, and the detection pattern is the same as that of example 1. Are cyclophosphamide monohydrate; the electron microscope scan is shown in FIG. 6.
Test 1: physical property detection
The commercial product was used as a control, which was not used because the inventive example 4 did not form crystal precipitation within 2 hours.
1) Moisture absorption: evaluating the hygroscopicity of the products of each example under the condition of room temperature by using a water vapor adsorption analyzer, testing the products in the relative humidity range of 20-80%, and calculating the moisture absorption weight gain conditions of the products in 5min, 10min, 30min and 2h (expressed by the mass percentage of the moisture absorption weight gain); see table 1 for results;
2) solubility: tabletting by a conventional process, adding the pure cyclophosphamide monohydrate obtained in the above embodiment, adding 20% of an excipient, 10% of a filler and 5% of a lubricant, mixing, tabletting by a tabletting machine, and sealing and storing the tablets; wherein the excipient is microcrystalline cellulose, the filler is starch, and the lubricant is magnesium stearate. The dissolution rate of the tablets of the product of examples in a phosphoric acid buffer solution of sodium lauryl sulfate at room temperature was measured using a Distek dissolution apparatus (DISTEK Co., 2100A) and the dissolution surface area was 1cm2
See table 2 for results;
3) crystal appearance and particle size, uniformity of crystal morphology of examples was observed using an electron lens and average particle size was measured, and the results are shown in table 1.
TABLE 1
According to the results of the above table 1, the stability of examples 1-2 is high, the shape can be kept stable for a certain time in the humidity range of 20-40%, and the hygroscopicity is not high even under the high humidity condition, thereby providing convenience for the preparation and clinical configuration and use of the drug. And in the embodiment 5, acetone is used as a solvent, so that the product purity is not high, and the hygroscopicity is slightly poor. The control and example 6 were relatively dry, and the crystal water was unstable and liquefied. Examples 3, 7-8 are less stable, and example 7 has a hysteresis effect on moisture absorption in a drier environment, possibly related to microstructure. The particles of the examples 1-2 are small and compact, and the penetration of water molecules is difficult, which may result in high stability, while the stability of the example 9 is only good at 60% humidity, and the regulation range is narrow.
The above tests show the variation of stability of the crystals under different humidity conditions due to the transition from anhydrate-monohydrate, differences in internal structure. The crystallization process is very sensitive to temperature and slight environmental change, and the invention passes through a plurality of tests, so that the uncontrollable factors of the process are more. Particle size was determined by scanning electron microscopy and particle appearance was observed, the results are shown in table 2.
TABLE 2
It should be noted that no devitrification is formed in example 4 of the present invention, and it can be seen that the molecular sieve functions other than drying or adsorption or impurity removal. In fact, the molecular sieve and the ether are added, so that the crystallization speed is increased, the solution is subjected to dynamic change of turbid bottle bottom and clarification under the stirring state, the particle size of the final product is more uniform, and the final product has certain heat absorption efficiency, and the crystallization of the examples 1-3 is faster and the particles are uniform. The lyophilized example product then produced a larger particle size and instability above 40% humidity.
The above embodiments do not limit the scope of the present invention, and those skilled in the art can make various changes and applications of the functional, methodological or structural equivalents or substitutions without departing from the scope of the present invention.
Claims (5)
1. A method for refining cyclophosphamide is characterized by comprising the following steps:
step 1, adding a crude cyclophosphamide product into water, heating and dissolving, wherein the weight ratio of the crude cyclophosphamide product to the water is 1: 4-20, filtering undissolved impurities;
step 2: and cooling, adding diethyl ether and a molecular sieve, stirring, removing the molecular sieve, continuously stirring, cooling, crystallizing, and performing vacuum filtration to obtain a filter cake, wherein the weight ratio of the cyclophosphamide crude product to the diethyl ether is 1: 5-9, wherein the weight ratio of the crude cyclophosphamide product to the molecular sieve is 5-30: 1;
and step 3: washing the molecular sieve and the suction filtration device with ether, combining the filtrates, heating to 35-40 ℃ to volatilize the solvent, combining the obtained precipitate and the filter cake obtained in the step 2, and drying under the low temperature in a microwave vacuum manner to obtain the product.
2. The method of claim 1, wherein: the molecular sieve is Na2O & Al2O3 & 2SiO2 & 9/2H2O, the aperture is less than or equal to 10nm, and the ratio of silicon to aluminum is 2: 1(SiO 2: Al2O 3), wherein the particle size of the molecular sieve particles is more than or equal to 1 mm.
3. The method of claims 1-2, wherein water is added in two parts in step 1, 2/3 water is added initially to dissolve, heated to 50-55 deg.C, and the rest 1/3 water at normal temperature is added when heated to above 50 deg.C.
4. The method of claim 1, wherein the microwave drying temperature is 36-45 ℃ and the vacuum degree is 0.004-0.09 MPa.
5. Cyclophosphamide hydrate, characterized in that it is obtained by the process according to claim 1.
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| JPS54109990A (en) * | 1978-02-14 | 1979-08-29 | Otsuka Pharmaceut Co Ltd | Crystals of cyclophosphamide |
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| DE3805329A1 (en) * | 1987-03-06 | 1988-09-15 | Asta Pharma Ag | Process for the preparation of ifosfamid with improved properties |
| CN107540711A (en) * | 2017-09-26 | 2018-01-05 | 山东印迹生物技术有限公司 | A kind of method for crystallising of endoxan |
| CN109535201A (en) * | 2019-01-25 | 2019-03-29 | 连云港贵科药业有限公司 | A kind of synthetic method of cyclophosphamide |
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2022
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| JPS54109990A (en) * | 1978-02-14 | 1979-08-29 | Otsuka Pharmaceut Co Ltd | Crystals of cyclophosphamide |
| RO84659B (en) * | 1982-05-12 | 1984-09-30 | Ion Neda | Process for purifying 2-(bis-(2-chlorethyle)amino)-tetrahydro-2h, 1, 3, 2-oxazophosphorian-2-monohydrated oxide |
| DE3805329A1 (en) * | 1987-03-06 | 1988-09-15 | Asta Pharma Ag | Process for the preparation of ifosfamid with improved properties |
| CN107540711A (en) * | 2017-09-26 | 2018-01-05 | 山东印迹生物技术有限公司 | A kind of method for crystallising of endoxan |
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