CN117586334B - Dexamethasone sodium phosphate-nicotinamide co-amorphous substance and preparation method thereof - Google Patents
Dexamethasone sodium phosphate-nicotinamide co-amorphous substance and preparation method thereof Download PDFInfo
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- CN117586334B CN117586334B CN202311582279.4A CN202311582279A CN117586334B CN 117586334 B CN117586334 B CN 117586334B CN 202311582279 A CN202311582279 A CN 202311582279A CN 117586334 B CN117586334 B CN 117586334B
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- 229960003957 dexamethasone Drugs 0.000 title claims abstract description 71
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 title claims abstract description 71
- -1 sodium phosphate-nicotinamide Chemical compound 0.000 title claims abstract description 71
- 239000000126 substance Substances 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims abstract description 130
- 229960002344 dexamethasone sodium phosphate Drugs 0.000 claims abstract description 84
- PLCQGRYPOISRTQ-FCJDYXGNSA-L dexamethasone sodium phosphate Chemical compound [Na+].[Na+].C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COP([O-])([O-])=O)(O)[C@@]1(C)C[C@@H]2O PLCQGRYPOISRTQ-FCJDYXGNSA-L 0.000 claims abstract description 84
- 229960003966 nicotinamide Drugs 0.000 claims abstract description 65
- 235000005152 nicotinamide Nutrition 0.000 claims abstract description 65
- 239000011570 nicotinamide Substances 0.000 claims abstract description 65
- 239000002904 solvent Substances 0.000 claims abstract description 52
- 238000000227 grinding Methods 0.000 claims abstract description 25
- 238000005303 weighing Methods 0.000 claims abstract description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 35
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 10
- 238000001291 vacuum drying Methods 0.000 claims description 9
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 5
- 238000002390 rotary evaporation Methods 0.000 claims description 5
- 230000007704 transition Effects 0.000 claims description 4
- 239000000178 monomer Substances 0.000 abstract description 22
- 238000004090 dissolution Methods 0.000 abstract description 13
- 239000006069 physical mixture Substances 0.000 abstract description 11
- 238000010521 absorption reaction Methods 0.000 abstract description 9
- 239000007787 solid Substances 0.000 abstract description 7
- 230000002195 synergetic effect Effects 0.000 abstract description 4
- 230000000052 comparative effect Effects 0.000 description 26
- 238000002441 X-ray diffraction Methods 0.000 description 14
- 239000000463 material Substances 0.000 description 10
- 230000006872 improvement Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010041277 Sodium retention Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 208000018631 connective tissue disease Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 210000003635 pituitary gland Anatomy 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- YGSFNCRAZOCNDJ-UHFFFAOYSA-N propan-2-one Chemical compound CC(C)=O.CC(C)=O YGSFNCRAZOCNDJ-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000005464 sample preparation method Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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Abstract
The invention provides a dexamethasone sodium phosphate-nicotinamide co-amorphous substance and a preparation method thereof. The preparation method comprises the following steps: weighing dexamethasone sodium phosphate and nicotinamide according to a preset molar ratio; fully grinding the weighed dexamethasone sodium phosphate and nicotinamide under the assistance of a solvent, or dissolving the dexamethasone sodium phosphate and nicotinamide in the solvent to obtain a co-amorphous system; the resulting co-amorphous system was dried to remove the solvent from the sample. Through the mode, the dexamethasone sodium phosphate-nicotinamide co-amorphous substance can be simply, conveniently and efficiently prepared. The co-amorphous substance is a solid form which is completely different from dexamethasone sodium phosphate and nicotinamide monomer and physical mixture of the dexamethasone sodium phosphate and nicotinamide monomer, and effectively improves the moisture absorption stability, dissolution rate and storage stability of the dexamethasone sodium phosphate. And the mode of combining dexamethasone sodium phosphate and nicotinamide can also generate a synergistic effect, so that the dexamethasone sodium phosphate and nicotinamide have good application prospect.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a dexamethasone sodium phosphate-nicotinamide co-amorphous substance and a preparation method thereof.
Background
Dexamethasone sodium phosphate (dexamethasone sodium phosphate) is an adrenocortical hormone medicine, has the functions of resisting inflammation, resisting allergy, resisting rheumatism and inhibiting immunity, is clinically used for treating allergic and autoimmune diseases, including connective tissue diseases, active rheumatism, rheumatoid arthritis, lupus erythematosus, severe bronchial asthma, severe dermatitis ulcerative colitis, acute leukemia and the like, and is also used for comprehensively treating certain severe infections, poisoning and malignant lymphomas. The anti-inflammatory effect and the effect of controlling skin allergy are more remarkable than those of prednisone, but the effects of water sodium retention and potassium discharge promotion are slight, and the inhibition effect on pituitary gland and adrenal cortex is strong, so that the anti-inflammatory agent is widely applied. Clinically, the dissolution performance and stability of dexamethasone sodium phosphate still need to be improved.
Co-amorphous is a special solid form that lacks regularity and ordering among molecules, but remains as a single phase. There is a weak but discrete intermolecular interaction between the components forming the co-amorphous. The thermodynamic functions (such as energy and entropy) of the monomer components can be remarkably improved by preparing the active pharmaceutical ingredient and one or more auxiliary materials or another active pharmaceutical ingredient into a co-amorphous substance, so that the solubility, dissolution rate, moisture absorption stability and storage stability of the substance are improved. However, it is unpredictable under what conditions it is possible to form co-amorphous forms, and how to prepare dexamethasone sodium phosphate with other excipients or active agents into co-amorphous forms remains a current problem to be solved.
In view of this, it is necessary to design a co-amorphous based on dexamethasone sodium phosphate to solve the above-mentioned problems.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a dexamethasone sodium phosphate-nicotinamide co-amorphous substance and a preparation method thereof, which can effectively improve the moisture absorption stability, dissolution rate and storage stability of the dexamethasone sodium phosphate.
In order to achieve the above purpose, the invention provides a preparation method of dexamethasone sodium phosphate-nicotinamide co-amorphous substance, comprising the following steps:
S1, weighing dexamethasone sodium phosphate and nicotinamide according to a preset molar ratio;
S2, preparing a co-amorphous system by adopting a grinding method or a solvent volatilization method;
wherein the grinding method comprises the following steps: fully grinding the dexamethasone sodium phosphate and nicotinamide weighed in the step S1 under the assistance of a solvent to obtain a co-amorphous system;
The solvent volatilization method comprises the following steps: dissolving the dexamethasone sodium phosphate and nicotinamide weighed in the step S1 in a solvent to obtain a co-amorphous system;
S3, drying the co-amorphous system, and removing the solvent to obtain the dexamethasone sodium phosphate-nicotinamide co-amorphous.
As a further improvement of the invention, in the step S1, the molar ratio of the dexamethasone sodium phosphate to the nicotinamide is 1:1-5.
As a further improvement of the present invention, in step S2, the grinding method includes: mixing dexamethasone sodium phosphate and nicotinamide, grinding for 4-6 min, adding solvent, and grinding for 8-12 min; wherein the addition amount of the solvent accounts for 3.3-33% of the total mass of the dexamethasone sodium phosphate and the nicotinamide.
As a further improvement of the present invention, when the grinding method is used for preparing the co-amorphous system, the solvent is methanol or ethanol.
As a further improvement of the present invention, when the solvent evaporation method is used to prepare the co-amorphous system, the solvent comprises one of methanol, ethanol, a mixture of acetone and water, and a mixture of acetonitrile and water.
As a further improvement of the invention, the volume fraction of the acetone in the mixture of the acetone and the water is 10-66.7%; in the mixture of acetonitrile and water, the volume fraction of acetonitrile is 10% -75%.
As a further improvement of the invention, in the step S2, when the solvent evaporation method is adopted to prepare a co-amorphous system, the ratio of the total mass of dexamethasone sodium phosphate and nicotinamide to the volume of the solvent is 50-200 mg/5 mL.
As a further improvement of the present invention, in step S3, the drying treatment includes one of reduced pressure rotary evaporation and vacuum drying.
The invention also provides a dexamethasone sodium phosphate-nicotinamide co-amorphous substance, which is prepared by the preparation method according to any one of the technical schemes, and comprises dexamethasone sodium phosphate and nicotinamide.
As a further improvement of the invention, the endothermic transition point of the dexamethasone sodium phosphate-nicotinamide co-amorphous substance is 80-90 ℃.
The beneficial effects of the invention are as follows:
According to the dexamethasone sodium phosphate-nicotinamide co-amorphous substance and the preparation method thereof, the dexamethasone sodium phosphate and nicotinamide are mixed according to a specific molar ratio, a co-amorphous substance system is prepared by adopting a liquid auxiliary grinding method or a solvent volatilizing method based on a specific type of solvent system, and the solvent is removed by drying treatment, so that the dexamethasone sodium phosphate-nicotinamide co-amorphous substance can be simply, conveniently and efficiently obtained. The dexamethasone sodium phosphate-nicotinamide co-amorphous substance is a solid form completely different from dexamethasone sodium phosphate and nicotinamide monomers and physical mixtures thereof, effectively improves the moisture absorption stability, dissolution rate and storage stability of the dexamethasone sodium phosphate, and has good application prospect in the field of preparation of powder-liquid double-chamber bag transfusion systems. In addition, the nicotinamide has better anti-inflammatory activity, and the nicotinamide can be combined with dexamethasone sodium phosphate to prepare the co-amorphous substance successfully under specific conditions, and can also generate synergistic pharmacological action to improve clinical curative effect.
Drawings
FIG. 1 is an X-ray diffraction pattern of dexamethasone sodium phosphate-nicotinamide co-amorphous compound prepared in example 1.
FIG. 2 is a DSC chart of dexamethasone sodium phosphate-nicotinamide co-amorphous prepared in example 1.
FIG. 3 is an infrared spectrum of dexamethasone sodium phosphate-nicotinamide co-amorphous that was prepared in example 1.
FIG. 4 is an X-ray diffraction pattern of dexamethasone sodium phosphate-nicotinamide co-amorphous compound prepared in example 1 under different conditions.
FIG. 5 is a powder X-ray diffraction pattern comparison of dexamethasone sodium phosphate, nicotinamide, and dexamethasone sodium phosphate-nicotinamide co-amorphous.
FIG. 6 is a DSC chart comparing dexamethasone sodium phosphate, nicotinamide, and dexamethasone sodium phosphate-nicotinamide co-amorphous.
FIG. 7 is a graph comparing infrared spectra of dexamethasone sodium phosphate, nicotinamide, dexamethasone sodium phosphate-nicotinamide mixture, and dexamethasone sodium phosphate-nicotinamide co-amorphous compound.
FIG. 8 is an X-ray diffraction pattern of dexamethasone sodium phosphate and nicotinamide co-amorphous form of dexamethasone sodium phosphate-nicotinamide prepared at different molar ratios.
FIG. 9 is an X-ray diffraction pattern of dexamethasone sodium phosphate-nicotinamide co-amorphous that was prepared in a different solvent system.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in detail with reference to the accompanying drawings and specific embodiments.
It should be noted that, in order to avoid obscuring the present invention due to unnecessary details, only structures and/or processing steps closely related to aspects of the present invention are shown in the drawings, and other details not greatly related to the present invention are omitted.
In addition, it should be further noted that the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Based on the problem that the dissolution performance and stability of dexamethasone sodium phosphate are to be improved, the invention discovers in the research process that: dexamethasone sodium phosphate and nicotinamide are mixed according to a specific molar ratio, and under the action of a specific solvent, co-amorphous matters can be formed. Therefore, the invention provides a preparation method of dexamethasone sodium phosphate-nicotinamide co-amorphous substance, which comprises the following steps:
S1, weighing dexamethasone sodium phosphate and nicotinamide according to a preset molar ratio;
S2, preparing a co-amorphous system by adopting a grinding method or a solvent volatilization method;
wherein the grinding method comprises the following steps: fully grinding the dexamethasone sodium phosphate and nicotinamide weighed in the step S1 under the assistance of a solvent to obtain a co-amorphous system;
The solvent volatilization method comprises the following steps: dissolving the dexamethasone sodium phosphate and nicotinamide weighed in the step S1 in a solvent to obtain a co-amorphous system;
S3, drying the co-amorphous system, and removing the solvent to obtain the dexamethasone sodium phosphate-nicotinamide co-amorphous.
In the step S1, the molar ratio of the dexamethasone sodium phosphate to the nicotinamide is 1:1-5.
In step S2, when the co-amorphous system is prepared by a grinding method, the specific steps include: mixing dexamethasone sodium phosphate and nicotinamide, grinding for 4-6 min, adding solvent, and grinding for 8-12 min; wherein the addition amount of the solvent accounts for 3.3% -33% of the total mass of the dexamethasone sodium phosphate and the nicotinamide; the solvent is preferably methanol or ethanol.
When a solvent volatilization method is adopted to prepare a co-amorphous system, the ratio of the total mass of dexamethasone sodium phosphate to nicotinamide to the volume of the solvent is 50-200 mg/5 ml; the solvent comprises one of methanol, ethanol, a mixture of acetone and water, and a mixture of acetonitrile and water. Wherein, in the mixture of the acetone and the water, the volume fraction of the acetone is 10 percent to 66.7 percent; in the mixture of acetonitrile and water, the volume fraction of acetonitrile is 10% -75%.
Through the mode, the existence of the dexamethasone sodium phosphate and the nicotinamide in the form of co-amorphous substances can be ensured, so that the moisture absorption stability, the dissolution rate and the storage stability of the dexamethasone sodium phosphate are effectively improved.
More specifically, in step S3, the drying treatment includes one of reduced pressure rotary evaporation and vacuum drying.
Among them, the conditions of reduced pressure rotary evaporation are preferably: vacuum rotary steaming for 15-30 min at 30-60 ℃; the conditions for vacuum drying are preferably: drying under reduced pressure at 30-60 ℃ for 12h.
The dexamethasone sodium phosphate-nicotinamide co-amorphous substance obtained by the technical scheme comprises dexamethasone sodium phosphate and nicotinamide, can generate a synergistic pharmacological effect by using the combination of the two groups of medicaments, and improves the clinical curative effect. In addition, the dexamethasone sodium phosphate-nicotinamide co-amorphous substance is a solid form which is completely different from dexamethasone sodium phosphate and nicotinamide monomers and physical mixtures thereof, has an endothermic transition point of 80-90 ℃, has excellent moisture absorption stability, dissolution rate and storage stability, and has good application prospect in the field of preparation of powder-liquid double-chamber bag transfusion systems.
The dexamethasone sodium phosphate-nicotinamide co-amorphous substance and the preparation method thereof provided by the invention are described in detail below with reference to specific examples.
Example 1
The embodiment provides a preparation method of dexamethasone sodium phosphate-nicotinamide co-amorphous substance, which comprises the following steps:
s1, weighing 51.6mg (0.1 mmol) of dexamethasone sodium phosphate and 12.2mg (0.1 mmol) of nicotinamide according to a molar ratio of 1:1;
S2, dissolving the dexamethasone sodium phosphate and nicotinamide weighed in the step S1 in 5mL of methanol, and stirring for 30min to fully dissolve the dexamethasone sodium phosphate and nicotinamide to obtain a co-amorphous system;
S3, performing rotary evaporation on the co-amorphous substance system obtained in the step S2 under reduced pressure at 60 ℃ for 15min, then placing the mixture in a vacuum drying oven for vacuum drying, and performing vacuum drying at 30 ℃ for 12h to obtain the dexamethasone sodium phosphate-nicotinamide co-amorphous substance.
The dexamethasone sodium phosphate-nicotinamide co-amorphous substance prepared in the embodiment is detected to obtain an X-ray diffraction pattern, a DSC spectrogram and an infrared spectrogram, which are respectively shown in figures 1,2 and 3.
The test conditions for X-ray diffraction are as follows:
instrument: d8FOCUS powder X-ray diffractometer (bruk, germany);
And (3) target: cu-K alpha radiation;
Measurement range: 3-60 degrees;
X-ray tube voltage: 40kV;
x-ray light pipe current: 40mA;
Step size: 0.02 °;
the steps are as follows: 0.5 s/step.
As can be seen from the X-ray diffraction pattern measured in FIG. 1, typical diffraction peaks are not seen in the pattern.
The test conditions for determining the DSC profile using differential scanning calorimetry are as follows:
Instrument: DSC3500 differential scanning calorimeter (Germany, resistant Chi Co.);
Temperature range: 30-300 ℃;
heating rate: 10 ℃/min.
From the DSC profile measured in FIG. 2, it can be seen that the endothermic transition point of dexamethasone sodium phosphate-nicotinamide co-amorphous form is at 85.8 ℃.
The conditions for the infrared test are as follows:
instrument: nigaoli iS5 infrared spectrometer (sammer, usa);
4000-400 cm -1;
The sample preparation method comprises the following steps: potassium bromide tabletting method.
FIG. 3 is an infrared spectrum of the measured dexamethasone sodium phosphate-nicotinamide co-amorphous form (potassium bromide tablet).
To examine the moisture absorption stability and storage stability of the dexamethasone sodium phosphate-nicotinamide co-amorphous prepared in this example, they were dispensed into different clean dishes and placed under different conditions, respectively, for stability studies. Wherein the X-ray diffraction pattern was measured under various conditions, as shown in FIG. 4, under high humidity conditions (25 ℃ C./92.5% RH) for 15 days, under accelerated stability study conditions (40 ℃ C./75% RH) for 15 days, and under long-term stability study conditions (25 ℃ C./60% RH) for 90 days.
As can be seen from FIG. 4, the X-ray diffraction patterns of the dexamethasone sodium phosphate-nicotinamide co-amorphous substance under different conditions are not obviously different, which shows that the dexamethasone sodium phosphate-nicotinamide co-amorphous substance has better moisture absorption stability and storage stability.
Comparative examples 1 to 2
Comparative example 1 provides dexamethasone sodium phosphate monomer and comparative example 2 provides nicotinamide monomer.
To compare the difference between the dexamethasone sodium phosphate-nicotinamide co-amorphous form prepared in example 1 and the dexamethasone sodium phosphate monomer and nicotinamide monomer, the X-ray diffraction pattern and DSC profile of the dexamethasone sodium phosphate monomer and nicotinamide monomer were measured according to the test method provided in example 1, and compared with the dexamethasone sodium phosphate-nicotinamide co-amorphous form prepared in example 1, and the results are shown in fig. 4 and 5.
As can be seen from fig. 4 and 5, the X-ray diffraction pattern of the dexamethasone sodium phosphate-nicotinamide co-amorphous material prepared in example 1 is significantly different from that of the dexamethasone sodium phosphate monomer and the nicotinamide monomer, and the dexamethasone sodium phosphate-nicotinamide co-amorphous material has significantly different melting peaks from that of the dexamethasone sodium phosphate monomer and the nicotinamide monomer, indicating that the dexamethasone sodium phosphate-nicotinamide co-amorphous material prepared in example 1 is in a solid form completely different from that of the dexamethasone sodium phosphate monomer and the nicotinamide monomer.
Comparative example 3
The comparative example provides a physical mixture of dexamethasone sodium phosphate and nicotinamide, which is obtained by simply mixing dexamethasone sodium phosphate and nicotinamide according to a molar ratio of 1:1.
The physical mixture of dexamethasone sodium phosphate and nicotinamide as provided in this comparative example, and the monomers provided in comparative examples 1-2, were infrared tested according to the test method provided in example 1 and compared to the co-amorphous of dexamethasone sodium phosphate and nicotinamide prepared in example 1, the results are shown in fig. 6.
As can be seen from fig. 6, the infrared spectrum of the dexamethasone sodium phosphate-nicotinamide co-amorphous material prepared in example 1 is significantly different from that of the dexamethasone sodium phosphate monomer, nicotinamide monomer and dexamethasone sodium phosphate-nicotinamide physical mixture, indicating that the dexamethasone sodium phosphate-nicotinamide co-amorphous material prepared in example 1 and the dexamethasone sodium phosphate-nicotinamide physical mixture belong to different solid forms.
To examine the difference in solubility between the physical mixture of dexamethasone sodium phosphate and nicotinamide provided in comparative example 3 and the co-amorphous substance of dexamethasone sodium phosphate and nicotinamide prepared in example 1, the physical mixture of dexamethasone sodium phosphate and nicotinamide provided in comparative example 3 was dissolved in 1mL of physiological saline, respectively, and the time required for complete dissolution was tested; the dexamethasone sodium phosphate-nicotinamide co-amorphous prepared in example 1 was dissolved in 1mL of pure water in physiological saline under the same conditions, and the time required for complete dissolution was measured, and the results are shown in table 1.
Table 1 comparison of solubility of substances provided in example 1 and comparative example 3
As can be seen from table 1, the dissolution rate of dexamethasone sodium phosphate-nicotinamide co-amorphous substance prepared in example 1 in pure water and physiological saline was 1.46 times and 1.81 times faster, respectively, than that of the physical mixture provided in comparative example 3, and an effective increase in dissolution rate was achieved.
Examples 2 to 5 and comparative example 4
Examples 2 to 5 and comparative example 4 respectively provide a preparation method of dexamethasone sodium phosphate-nicotinamide co-amorphous substance, and compared with example 1, the difference is only that the molar ratio of dexamethasone sodium phosphate to nicotinamide is changed, and specific molar ratios in each example and comparative example are shown in table 2, and the dosage of dexamethasone sodium phosphate and other relevant steps and parameters are the same as those in example 1, and are not repeated here.
Table 2 molar ratio of dexamethasone sodium phosphate to nicotinamide in examples 2-5 and comparative example 4
| Sample preparation | Molar ratio of dexamethasone sodium phosphate to nicotinamide |
| Example 2 | 1:2 |
| Example 3 | 1:3 |
| Example 4 | 1:4 |
| Example 5 | 1:5 |
| Comparative example 4 | 1:6 |
X-ray diffraction tests were performed on the dexamethasone sodium phosphate-nicotinamide co-amorphous material provided in examples 2-5 and comparative example 4 according to the test method provided in example 1, and compared with the dexamethasone sodium phosphate-nicotinamide co-amorphous material prepared in example 1, and the results are shown in fig. 8.
As can be seen from fig. 8, the dexamethasone sodium phosphate-nicotinamide co-amorphous forms prepared in examples 2-5 are identical to example 1, and have no typical diffraction peaks; whereas in comparative example 4 the co-amorphous formation was affected by setting the molar ratio of dexamethasone sodium phosphate to nicotinamide to 1:6. Therefore, the invention can ensure the formation of dexamethasone sodium phosphate-nicotinamide co-amorphous substance by preferably selecting the mol ratio of dexamethasone sodium phosphate to nicotinamide to be 1:1-5.
Examples 6 to 8 and comparative examples 5 to 6
Examples 6 to 8 and comparative examples 5 to 6 respectively provide a preparation method of dexamethasone sodium phosphate-nicotinamide co-amorphous substance, and compared with example 1, the difference is only that the types of solvents are changed, the specific solvent compositions in each example and comparative example are shown in table 3, and the dosage of the solvents and other relevant steps and parameters are the same as those in example 1, and are not repeated here.
TABLE 3 solvent systems in examples 6-8 and comparative examples 5-6
| Sample preparation | Solvent system |
| Example 6 | Ethanol |
| Example 7 | Acetone/water (acetone 50%) |
| Example 8 | Acetonitrile/water (acetonitrile 50%) |
| Comparative example 5 | Acetone (acetone) |
| Comparative example 6 | Acetonitrile |
X-ray diffraction tests were performed on dexamethasone sodium phosphate-nicotinamide co-amorphous material provided in examples 6-8 and comparative examples 5-6 according to the test method provided in example 1, and compared with dexamethasone sodium phosphate-nicotinamide co-amorphous material prepared in example 1, and the results are shown in fig. 9.
As can be seen from fig. 9, the dexamethasone sodium phosphate-nicotinamide co-amorphous forms prepared in examples 6-8 are identical to example 1, and have no typical diffraction peaks; in contrast, in comparative examples 5 to 6, the formation of co-amorphous forms is affected by the use of only acetone or acetonitrile as the solvent. Thus, the present invention can ensure the formation of dexamethasone sodium phosphate-nicotinamide co-amorphous form by preference for the solvent system.
Example 9
The embodiment provides a preparation method of dexamethasone sodium phosphate-nicotinamide co-amorphous substance, which comprises the following steps:
S1, weighing 25.8mg (0.05 mmol) of dexamethasone sodium phosphate and 6.1mg (0.05 mmol) of nicotinamide according to a molar ratio of 1:1;
s2, placing the dexamethasone sodium phosphate and nicotinamide weighed in the step S1 into an agate mortar, grinding and mixing for 5min, and then dropwise adding 5-10 ul of methanol for auxiliary grinding for 10min to obtain a co-amorphous substance system;
S3, placing the co-amorphous substance system obtained in the step S2 into a vacuum drying oven for vacuum drying treatment, and drying under reduced pressure at 30 ℃ for 12 hours to obtain the dexamethasone sodium phosphate-nicotinamide co-amorphous substance.
The detection shows that the dexamethasone sodium phosphate-nicotinamide co-amorphous substance prepared in the embodiment is basically consistent with the X-ray diffraction pattern, DSC spectrogram and infrared spectrogram of the dexamethasone sodium phosphate-nicotinamide co-amorphous substance prepared in the embodiment 1.
In summary, the invention provides a dexamethasone sodium phosphate-nicotinamide co-amorphous substance and a preparation method thereof. The preparation method comprises the following steps: weighing dexamethasone sodium phosphate and nicotinamide according to a preset molar ratio; fully grinding the weighed dexamethasone sodium phosphate and nicotinamide under the assistance of a solvent, or dissolving the dexamethasone sodium phosphate and nicotinamide in the solvent to obtain a co-amorphous system; drying the obtained co-amorphous system to remove the first solvent or the second solvent. Through the mode, the dexamethasone sodium phosphate-nicotinamide co-amorphous substance can be simply, conveniently and efficiently prepared, is in a solid form completely different from dexamethasone sodium phosphate and nicotinamide monomers and physical mixtures of the dexamethasone sodium phosphate and nicotinamide monomers, and effectively improves the moisture absorption stability, dissolution rate and storage stability of the dexamethasone sodium phosphate. And the mode of combining dexamethasone sodium phosphate and nicotinamide can also generate a synergistic effect, so that the dexamethasone sodium phosphate and nicotinamide have good application prospect.
The above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention.
Claims (6)
1. A method for preparing dexamethasone sodium phosphate-nicotinamide co-amorphous substance, which is characterized by comprising the following steps:
S1, weighing dexamethasone sodium phosphate and nicotinamide according to a molar ratio of 1:1-5;
S2, preparing a co-amorphous system by adopting a grinding method or a solvent volatilization method;
Wherein, the grinding method is as follows: fully grinding the dexamethasone sodium phosphate and nicotinamide weighed in the step S1 under the assistance of a solvent to obtain a co-amorphous system;
the solvent volatilization method comprises the following steps: dissolving the dexamethasone sodium phosphate and nicotinamide weighed in the step S1 in a solvent to obtain a co-amorphous system;
when the grinding method is adopted to prepare a co-amorphous system, the solvent is methanol or ethanol; when the solvent volatilization method is adopted to prepare a co-amorphous substance system, the solvent is one of a mixture of methanol, ethanol, acetone and water and a mixture of acetonitrile and water;
S3, drying the co-amorphous system, and removing the solvent to obtain the dexamethasone sodium phosphate-nicotinamide co-amorphous.
2. The method for preparing dexamethasone sodium phosphate-nicotinamide co-amorphous compound as recited in claim 1, wherein: in step S2, the grinding method is as follows: mixing dexamethasone sodium phosphate and nicotinamide, grinding for 4-6 min, adding a solvent, and grinding for 8-12 min; the addition amount of the solvent accounts for 3.3% -33% of the total mass of the dexamethasone sodium phosphate and the nicotinamide.
3. The method for preparing dexamethasone sodium phosphate-nicotinamide co-amorphous compound as recited in claim 1, wherein: in the mixture of the acetone and the water, the volume fraction of the acetone is 10% -66.7%; in the mixture of acetonitrile and water, the volume fraction of acetonitrile is 10% -75%.
4. The method for preparing dexamethasone sodium phosphate-nicotinamide co-amorphous compound as recited in claim 1, wherein: in the step S2, when the solvent volatilization method is adopted to prepare a co-amorphous system, the ratio of the total mass of dexamethasone sodium phosphate to nicotinamide to the volume of the solvent is 50-200 mg/5 mL.
5. The method for preparing dexamethasone sodium phosphate-nicotinamide co-amorphous compound as recited in claim 1, wherein: in step S3, the drying process is one of reduced pressure rotary evaporation and vacuum drying.
6. A dexamethasone sodium phosphate-nicotinamide co-amorphous compound, characterized in that: the preparation method of any one of claims 1-5, which is prepared from dexamethasone sodium phosphate and nicotinamide; the molar ratio of the dexamethasone sodium phosphate to the nicotinamide is 1:1-5, and the endothermic transition point of the dexamethasone sodium phosphate-nicotinamide co-amorphous substance is 80-90 ℃.
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| CN110025578A (en) * | 2019-04-10 | 2019-07-19 | 深圳市新阳唯康科技有限公司 | A kind of total amorphous powder and preparation method thereof for treating asthma class pulmonary disease |
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