CN105616362B - A kind of injection SC 69124 sodium pharmaceutical composition and preparation method thereof - Google Patents
A kind of injection SC 69124 sodium pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN105616362B CN105616362B CN201610086769.9A CN201610086769A CN105616362B CN 105616362 B CN105616362 B CN 105616362B CN 201610086769 A CN201610086769 A CN 201610086769A CN 105616362 B CN105616362 B CN 105616362B
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- injection
- sodium
- pharmaceutical composition
- freeze
- parecoxib sodium
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- 238000002347 injection Methods 0.000 title claims abstract description 36
- 239000007924 injection Substances 0.000 title claims abstract description 36
- TZRHLKRLEZJVIJ-UHFFFAOYSA-N parecoxib Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 TZRHLKRLEZJVIJ-UHFFFAOYSA-N 0.000 title claims abstract description 31
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000011734 sodium Substances 0.000 title claims abstract description 27
- 229910052708 sodium Inorganic materials 0.000 title claims abstract description 27
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 26
- 229960003925 parecoxib sodium Drugs 0.000 claims abstract description 54
- ICJGKYTXBRDUMV-UHFFFAOYSA-N trichloro(6-trichlorosilylhexyl)silane Chemical compound Cl[Si](Cl)(Cl)CCCCCC[Si](Cl)(Cl)Cl ICJGKYTXBRDUMV-UHFFFAOYSA-N 0.000 claims abstract description 54
- 239000013078 crystal Substances 0.000 claims abstract description 23
- 238000004108 freeze drying Methods 0.000 claims abstract description 23
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims abstract description 15
- 238000001816 cooling Methods 0.000 claims abstract description 14
- 239000007788 liquid Substances 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 30
- 239000008215 water for injection Substances 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 16
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 12
- 238000013019 agitation Methods 0.000 claims description 11
- 238000010792 warming Methods 0.000 claims description 11
- 239000004695 Polyether sulfone Substances 0.000 claims description 10
- 238000011049 filling Methods 0.000 claims description 10
- 229920006393 polyether sulfone Polymers 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 9
- 239000003610 charcoal Substances 0.000 claims description 8
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 6
- 238000011068 loading method Methods 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 13
- 238000005516 engineering process Methods 0.000 abstract description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 8
- 238000004821 distillation Methods 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 4
- 239000011148 porous material Substances 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 235000015424 sodium Nutrition 0.000 description 22
- 239000000047 product Substances 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 229960002004 valdecoxib Drugs 0.000 description 12
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 12
- 238000009472 formulation Methods 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 8
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 229910052698 phosphorus Inorganic materials 0.000 description 6
- 239000011574 phosphorus Substances 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 208000013038 Hypocalcemia Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 230000000705 hypocalcaemia Effects 0.000 description 3
- 238000012423 maintenance Methods 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 238000004904 shortening Methods 0.000 description 3
- 239000000872 buffer Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 229960004662 parecoxib Drugs 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000000859 sublimation Methods 0.000 description 2
- 230000008022 sublimation Effects 0.000 description 2
- 241001466460 Alveolata Species 0.000 description 1
- 241000208340 Araliaceae Species 0.000 description 1
- 206010014418 Electrolyte imbalance Diseases 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000002456 anti-arthritic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- VDQQXEISLMTGAB-UHFFFAOYSA-N chloramine T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- -1 disodium hydrogen Chemical class 0.000 description 1
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 description 1
- PYLIXCKOHOHGKQ-UHFFFAOYSA-L disodium;hydrogen phosphate;heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O PYLIXCKOHOHGKQ-UHFFFAOYSA-L 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 238000013178 mathematical model Methods 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of injection SC 69124 sodium pharmaceutical composition and preparation method thereof.The injection SC 69124 sodium pharmaceutical composition that the present invention is provided, prescription is simple, and the consumption of disodium hydrogen phosphate greatly reduces compared with prior art, more meets the requirement of injection drug safety；Parecoxib Sodium is crystal form, and dissolving is rapider, liquid preparation time is shortened, it is ensured that steady quality, while improving production efficiency；In preparation process by the way of snap frozen cooling so that freeze-drying thing maintains preferable pore structure, and forms highly uniform granularity, is conducive to the abundant distillation of moisture；Nitrogen charging operation is eliminated, production technology is simplified, reduces cost, be more beneficial for the big production of socialization.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of injection SC 69124 sodium pharmaceutical composition and its preparation
Method.
Background technology
Parecoxib Sodium, chemical name is：N- [[4- (5- methyl -3- phenyl -4- isoxazolyls) phenyl] sulfonyl] third
Chlorseptol, chemical structural formula is：
Parecoxib Sodium is a kind of cox 2 inhibitor of high selectivity, the former times dry goods antalgesic belonged in anti-arthritic,
Short available for postoperative pain.Parecoxib Sodium is easily hydrolyzed to Valdecoxib, and Valdecoxib dissolves in water
Property is poor, and difficulty is brought to injection is made.Parecoxib Sodium as Valdecoxib pro-drug, with higher dissolving
Degree, in order to avoid it is quickly converted to Valdecoxib in aqueous, Parecoxib Sodium is mainly made into lyophilized formulations.
Although SC 69124 changes into Valdecoxib rapidly in vivo and played a role, due to the water solubility of Valdecoxib
Difference, if just changing into more Valdecoxib in vitro, will make it that solution forms insoluble particulate matter, influences the performance of drug effect
Also result in potential safety hazard.Therefore, before human body is entered as far as possible, it should be ensured that product all exists or protected in the form of Parecoxib Sodium
The content of Valdecoxib is held in extremely low level.Chinese patent (application number CN 02810765.9) is used and had been freeze-dried
Cheng Zhong, the mode using headroom of the sterile nitrogen full of bottle enters to completely cut off moisture in air, prevents Parecoxib Sodium
It is converted into Valdecoxib too early.But the operation is cumbersome, and it is higher to production equipment requirement, add cost input.
In addition, it is during preparation is produced the problems such as the performance of Parecoxib Sodium, solubility and higher water content
Difficult point.Chinese patent (application number CN 02810765.9) is kept using dropping to -50 DEG C from room temperature in freezing stage 1.75h
7.0h, the frozen cooling time is longer, and solute is unable to snap frozen shaping, is unfavorable for moisture and fully distils.Further, since main ingredient
Dosage is small, and concentration is low, and the rigidity of freeze-drying prods sublimation stage is relatively low, if drying temperature is too high, and the rigidity of solid matrix is not enough to
Alveolate texture is maintained, the solid content matrix of walls in hole will be collapsed；And temperature is too low, water content is higher, and influence product is steady
Qualitative and solubility.Therefore find in suitable preparation prescription and technique, especially lyophilized technique to cooling rate and heating speed
The control of the key factors such as degree, is to solve prior art key of problems.
The content of the invention
The present invention provides a kind of injection SC 69124 sodium pharmaceutical composition, at the same provide that a kind of technique is simple, quality can
The preparation method of the injection Parecoxib Sodium of control.
It is an object of the present invention to provide a kind of injection SC 69124 sodium pharmaceutical composition, every 1000 bottles of drug regimens
Thing is composed of the following components：
| Parecoxib Sodium | 21.18~42.36g |
| Disodium hydrogen phosphate | 1.03~2.84g |
| NaOH or phosphoric acid | In right amount |
| Water for injection | Add to 1~2L |
Wherein, Parecoxib Sodium counts content as 20mg or 40mg using SC 69124 in per unit preparation.
Further, every 1000 bottles of pharmaceutical compositions are composed of the following components：
| Parecoxib Sodium | 21.18g |
| Disodium hydrogen phosphate | 1.42g |
| NaOH or phosphoric acid | In right amount |
| Water for injection | Add to 1L |
Or, every 1000 bottles of pharmaceutical compositions are composed of the following components：
| Parecoxib Sodium | 21.18g |
| Disodium hydrogen phosphate | 1.03g |
| NaOH or phosphoric acid | In right amount |
| Water for injection | Add to 1L |
Or, every 1000 bottles of pharmaceutical compositions are composed of the following components：
| Parecoxib Sodium | 21.18g |
| Disodium hydrogen phosphate | 1.58g |
| NaOH or phosphoric acid | In right amount |
| Water for injection | Add to 1L |
Or, every 1000 bottles of pharmaceutical compositions are composed of the following components：
| Parecoxib Sodium | 42.36g |
| Disodium hydrogen phosphate | 2.84g |
| NaOH or phosphoric acid | In right amount |
| Water for injection | Add to 2L |
Or, every 1000 bottles of pharmaceutical compositions are composed of the following components：
| Parecoxib Sodium | 42.36g |
| Disodium hydrogen phosphate | 2.06g |
| NaOH or phosphoric acid | In right amount |
| Water for injection | Add to 2L |
Or, every 1000 bottles of pharmaceutical compositions are composed of the following components：
| Parecoxib Sodium | 42.36g |
| Disodium hydrogen phosphate | 2.65g |
| NaOH or phosphoric acid | In right amount |
| Water for injection | Add to 2L |
Disodium hydrogen phosphate provided by the present invention can also be used as buffer as pH adjusting agent；Selected from anhydrous phosphorus
Sour disodium hydrogen, sodium phosphate dibasic heptahydrate or disodium hydrogen phosphate dodecahydrate, preferably ADSP.
The consumption of disodium hydrogen phosphate is more existing in injection SC 69124 sodium pharmaceutical composition provided by the present invention, prescription
Technology greatly reduces, according to《Excipient substance handbook》" phosphate intake is excessive (especially by vein, rectum for fourth edition record
Administration), hyperphospheremia may be caused, cause hypocalcemia or other serious electrolyte imbalances ".The present invention is substantially reduced
The consumption of disodium hydrogen phosphate, it is to avoid the generation of adverse events, more meets the safety requirements of injecting medicine-feeding form.
It is a further object of the present invention to provide a kind of injection SC 69124 sodium pharmaceutical composition, included in said composition
Parecoxib Sodium be crystal habit, carry out x-ray powder measure using Cu-ka rays, its collection of illustrative plates has diffraction shown in following table
Angle, interplanar distance and relative intensity：
| Characteristic peak sequence number | 2θ(°) | D (angstrom) | Relative intensity % |
| 1 | 6.1912 | 14.2638 | 1.98 |
| 2 | 8.3750 | 10.5488 | 3.30 |
| 3 | 10.9145 | 8.0994 | 4.76 |
| 4 | 12.1060 | 7.3048 | 16.05 |
| 5 | 14.5531 | 6.0815 | 6.37 |
| 6 | 17.0537 | 5.1950 | 15.82 |
| 7 | 18.0569 | 4.9086 | 100.00 |
| 8 | 20.5835 | 4.3114 | 12.06 |
| 9 | 22.7235 | 3.9100 | 9.83 |
| 10 | 23.9818 | 3.7076 | 61.29 |
| 11 | 25.5648 | 3.4815 | 3.96 |
| 12 | 29.9764 | 2.9784 | 9.27 |
Further, the SC 69124 sodium crystal that the present invention is provided has X-ray powder diffraction figure as shown in Figure 1
Spectrum.
The measure of X-ray powder diffraction (XRPD) of the present invention is acquired using powder diffractometer, specific ginseng
Number such as following table：
The SC 69124 sodium crystal that the present invention is provided is prepared using following methods：Parecoxib Sodium crude product is added to and is selected from
In acetone, ethanol or methanol, preferably acetone, mechanical agitation is warming up to backflow, and acetonitrile or methyl tertiary butyl ether(MTBE) is added dropwise, and insulation is stirred
Mix after 1h, be cooled to room temperature, filter, filter cake acetonitrile or methyl tertiary butyl ether(MTBE) elution are dried under reduced pressure, obtain Parecoxib Sodium knot
It is brilliant.
Another object of the present invention there is provided a kind of preparation method of injection SC 69124 sodium pharmaceutical composition, specifically
Comprise the following steps：
(1) liquid is matched somebody with somebody：The water for injection of total amount 50% is prepared in injection in Agitation Tank, and cooling makes at a temperature below 40
DEG C, add the Parecoxib Sodium and disodium hydrogen phosphate of recipe quantity, stirring to dissolving；With NaOH or phosphoric acid solution adjust pH to
7.5~8.5,0.05% (W/V) medical charcoal is added, stirring and adsorbing 20min is filtered with 0.22 μm of PES (polyether sulfone) filter,
Mend and add to the full amount of water for injection again, it is standby；
(2) it is filling：It is filling by every bottle of 1ml~2ml loading amount；
(3) it is freeze-dried；
(4) tamponade, roll lid.
Further, what step (3) was freeze-dried concretely comprises the following steps：
A) pre-freeze：10min-30min flaggies are down to -40 DEG C from room temperature, maintain 3~6 hours, make sample fully charge, open
Condenser is played, when condenser temperature is down to below -45 DEG C, vavuum pump is opened and vacuumizes, forvacuum is less than 0.2mbar, opens
Begin to heat up；
B) first stage heats up：Shelf is heated, -5 DEG C are warming up within 3 hours, maintained 2~3.5 hours；
C) second stage heats up：5 DEG C are continuously heating in 2.5h, is maintained 1~2 hour, maintains vacuum to be less than 0.2mbar；
40 DEG C are heated in 2h to shelf, is maintained 1~6 hour, terminates lyophilized.
Freeze drying process disclosed in prior art typically using 2h or so frozen cooling to design temperature, rate of temperature fall compared with
Slowly.Solute is difficult Quick-forming in refrigerating process, is unfavorable for the abundant distillation of moisture.The injection handkerchief auspicious former times that the present invention is provided
In the preparation method of cloth sodium, because snap frozen cools within the very short time, freeze-drying thing is set to maintain preferable hole
Gap structure, is conducive to moisture fully to distil, and leaves tubular conduit, greatly reduces mathematical models resistance, rate of sublimation
Significantly improve；Snap frozen makes solute form highly uniform granularity simultaneously, it is ensured that freeze-dried products are when long during storage
Between remain stable；And the pore structure formed also make it that this product dissolves rapidly in the process for preparation of clinical practice with granularity
Clarification, solubility significantly improves.
Injection SC 69124 sodium pharmaceutical composition prepared by the present invention has advantages below：
(1) prescription is simple, and the consumption of disodium hydrogen phosphate buffer greatly reduces compared with prior art, and other are not used
What freeze-dried excipient or freeze drying protectant, obtained product quality is stable, it is rapid to redissolve, it is to avoid because phosphate was taken in
Hypocalcemia caused by many, more meets the requirement of injection drug safety；
(2) by the way of snap frozen cooling so that freeze-drying thing maintains preferable pore structure, and forms non-
Often uniform granularity, is conducive to the abundant distillation of moisture, it is ensured that product appearance is good, steady quality, redissolve it is rapid；
(3) nitrogen charging operation is eliminated compared with prior art, simplifies production technology, reduce cost, be more beneficial for socialization
Big production.
(4) the SC 69124 sodium crystal that the present invention is provided, crystal formation dissolving more known in the art is rapider, shortens with liquid
Time, it is ensured that steady quality, while improving production efficiency.
Brief description of the drawings
Accompanying drawing 1：SC 69124 sodium crystal X-ray powder diffraction pattern prepared by embodiment 1
Embodiment
Below in conjunction with test example and embodiment, the present invention is described in further detail, but the not limit to the present invention
System, the equivalent of all any this areas made according to the disclosure of invention belongs to protection scope of the present invention.
Freeze-drying curve screening test
The present invention is investigated to the temperature fall time in freezing dry process, it is ensured that obtain optimal freeze-drying bar
Part, and evaluated by moisture, dissolution time, stability indicator, testing program is as shown in table 1 below, investigates result such as table 2 below
It is shown：
Table 1 is freeze-dried curve screening test
The freeze-drying curve screening experiment investigation result of table 2
| Inspection target | Moisture % | Dissolution time | Valdecoxib amount % | Total miscellaneous amount % |
| The sample of freeze-drying curve 1 | 0.5 | 11s | 0.02 | 0.02 |
| The sample of freeze-drying curve 2 | 0.6 | 13s | 0.03 | 0.03 |
| The sample of freeze-drying curve 3 | 0.6 | 14s | 0.03 | 0.03 |
| The sample of freeze-drying curve 4 | 1.2 | 27s | 0.09 | 0.09 |
| The sample of freeze-drying curve 5 | 1.5 | 35s | 0.15 | 0.15 |
| The sample of freeze-drying curve 6 | 1.7 | 42s | 0.22 | 0.22 |
From the above it can be seen that：Rate of temperature fall is faster, and dissolution time is shorter, and moisture and impurity content are lower.Especially
When pre-freeze temperature fall time is in the range of 10-30min, product redissolves rapidly, and moisture and impurity content are very low, and product is steady
It is fixed.
SC 69124 sodium crystal rate of dissolution is investigated
Valdecoxib is easily converted into water and under hot conditions due to Parecoxib Sodium, therefore when preparing solution,
Reduction should be tried one's best with liquid temperature degree and shortening liquid preparation time.But in the big production of socialization, because batch is larger, if Parecoxib Sodium
Rate of dissolution it is slower, then need improve with liquid temperature degree or extension liquid preparation time, be unfavorable for the stabilization of Parecoxib Sodium.Cause
This, rate of dissolution of the Parecoxib Sodium in water has material impact to product quality and production efficiency.Tests below will be contrasted
Investigate SC 69124 sodium crystal and dissolution velocities of the crystal formation B known in the art in water for injection that the present invention is provided.
Testing program：Two conical flasks are taken, each water for injection 1000ml for adding 40 DEG C is separately added into the embodiment of the present invention
The 1 SC 69124 sodium crystal prepared and SC 69124 sodium crystal B (prepare crystalline substance according to Chinese patent CN03806088.4 embodiments 2
Type B) each 21.18g, be placed in constant-temperature table vibration, design temperature be 40 DEG C, oscillation rate be 100 times/min, respectively at 1min,
The content (in terms of SC 69124) of Parecoxib Sodium in the aqueous solution is measured by sampling in 3min, 5min, 10min, 20min, 30min, surveys
Determine result as shown in table 3 below：
Assay result (the unit of the crystal formation of 3 embodiment of table 1 and known crystal formation B：mg/ml)
| The investigation time | 1min | 3min | 5min | 8min | 10min | 30min |
| The crystal formation of embodiment 1 | 17.54 | 19.98 | 20.01 | 20.00 | 19.98 | 19.99 |
| Crystal formation B | 12.32 | 15.61 | 18.34 | 19.65 | 20.01 | 20.02 |
It is seen from the above data that the SC 69124 sodium crystal that the present invention is provided has dissolved completely in 3min, and it is brilliant
Type B needs the 10min to be just completely dissolved, it is seen that rate of dissolution of the SC 69124 sodium crystal that the present invention is provided in water is substantially fast
In crystal formation B known in the art, the generation of conversion can be avoided, it is ensured that product quality, while shortening liquid preparation time, improve production
Efficiency.
Embodiment 1：Parecoxib Sodium preparation method 1
100g Parecoxib Sodium crude products are added in 100ml acetone, mechanical agitation, are warming up to backflow, 1000ml is added dropwise
After acetonitrile, insulated and stirred 1h, room temperature is cooled to, is filtered, filter cake is eluted with acetonitrile, is dried under reduced pressure, and obtains 94.4g Parecoxib Sodiums
Crystallization, yield 94.4%.Relevant material uses HPLC methods, and always miscellaneous is 0.02%；X-ray powder survey is carried out using Cu-ka rays
It is fixed, with X-ray powder diffraction pattern as shown in the accompanying drawings 1.
Embodiment 2：Parecoxib Sodium preparation method 2
100g Parecoxib Sodium crude products are added in 100ml ethanol, mechanical agitation, are warming up to backflow, 1000ml is added dropwise
After methyl tertiary butyl ether(MTBE), insulated and stirred 1h, room temperature is cooled to, is filtered, filter cake is eluted with methyl tertiary butyl ether(MTBE), is dried under reduced pressure, obtained
To the crystallization of 94.8g Parecoxib Sodiums, yield 94.8%.Relevant material uses HPLC methods, and always miscellaneous is 0.02%；Penetrated using Cu-ka
Line carries out x-ray powder measure, and its X-ray powder diffraction pattern is consistent with accompanying drawing 1.
Example 3 below~embodiment 8 is prepared using Parecoxib Sodium made from embodiment 1.
Embodiment 3：Injection Parecoxib Sodium (in terms of 1000 bottles, unit：g)
| Parecoxib Sodium | 21.18 |
| ADSP | 1.42 |
| NaOH or phosphorus acid for adjusting pH are extremely | 8.0 |
| Water for injection is added to | 1000ml |
Preparation technology：The water for injection of total amount 50% is prepared in injection in Agitation Tank, and cooling makes at a temperature below 40
DEG C, add the Parecoxib Sodium and ADSP of recipe quantity, stirring to dissolving；Adjusted with NaOH or phosphoric acid solution
PH to 8.0, adds 0.05% (W/V) medical charcoal, and stirring and adsorbing 20min is filtered, then add note with 0.22 μm of PES filter
Penetrate with water to full dose；It is filling in cillin bottle by every bottle of 1ml；It is placed in freeze drying box and is freezed, 30min flaggies is from room temperature
- 40 DEG C are down to, is maintained 4 hours, is made sample fully charge, open condenser, when condenser temperature is down to below -45 DEG C, open
Open vavuum pump to vacuumize, forvacuum is less than 0.2mbar, starts to warm up；Shelf is heated, -5 DEG C are warming up within 3 hours, 3 are maintained
Hour；5 DEG C are continuously heating in 2.5h, is maintained 1 hour, maintains vacuum to be less than in 0.2mbar, 2h and 40 is heated to shelf
DEG C, maintain 5 hours, terminate lyophilized；Tamponade, lid is rolled, produce sterile cryo dry product.
Embodiment 4：Injection Parecoxib Sodium (in terms of 1000 bottles, unit：g)
| Parecoxib Sodium | 21.18 |
| ADSP | 1.58 |
| NaOH or phosphorus acid for adjusting pH are extremely | 7.5 |
| Water for injection is added to | 1000ml |
Preparation technology：The water for injection of total amount 50% is prepared in injection in Agitation Tank, and cooling makes at a temperature below 40
DEG C, add the Parecoxib Sodium and ADSP of recipe quantity, stirring to dissolving；Adjusted with NaOH or phosphoric acid solution
PH to 7.5, adds 0.05% (W/V) medical charcoal, and stirring and adsorbing 20min is filtered, then add note with 0.22 μm of PES filter
Penetrate with water to full dose；It is filling in cillin bottle by every bottle of 1ml；It is placed in freeze drying box and is freezed, 10min flaggies is from room temperature
- 40 DEG C are down to, is maintained 5 hours, is made sample fully charge, open condenser, when condenser temperature is down to below -45 DEG C, open
Open vavuum pump to vacuumize, forvacuum is less than 0.2mbar, starts to warm up；Shelf is heated, -5 DEG C are warming up within 3 hours, 3 are maintained
Hour；5 DEG C are continuously heating in 2.5h, is maintained 1.5 hours, maintains vacuum to be less than in 0.2mbar, 2h and shelf is heated to
40 DEG C, maintain 1 hour, terminate lyophilized；Tamponade, lid is rolled, produce sterile cryo dry product.
Embodiment 5：Injection Parecoxib Sodium (in terms of 1000 bottles, unit：g)
| Parecoxib Sodium | 21.18 |
| ADSP | 1.03 |
| NaOH or phosphorus acid for adjusting pH are extremely | 8.2 |
| Water for injection is added to | 1000ml |
Preparation technology：The water for injection of total amount 50% is prepared in injection in Agitation Tank, and cooling makes at a temperature below 40
DEG C, add the Parecoxib Sodium and ADSP of recipe quantity, stirring to dissolving；Adjusted with NaOH or phosphoric acid solution
PH to 8.2, adds 0.05% (W/V) medical charcoal, and stirring and adsorbing 20min is filtered, then add note with 0.22 μm of PES filter
Penetrate with water to full dose；It is filling in cillin bottle by every bottle of 1ml；It is placed in freeze drying box and is freezed, 20min flaggies is from room temperature
- 40 DEG C are down to, is maintained 6 hours, is made sample fully charge, open condenser, when condenser temperature is down to below -45 DEG C, open
Open vavuum pump to vacuumize, forvacuum is less than 0.2mbar, starts to warm up；Shelf is heated, -5 DEG C are warming up within 3 hours, 3 are maintained
Hour；5 DEG C are continuously heating in 2.5h, is maintained 2 hours, maintains vacuum to be less than in 0.2mbar, 2h and 40 is heated to shelf
DEG C, maintain 2 hours, terminate lyophilized；Tamponade, lid is rolled, produce sterile cryo dry product.
Embodiment 6：Injection Parecoxib Sodium (in terms of 1000 bottles, unit：g)
| Parecoxib Sodium | 42.36 |
| ADSP | 2.84 |
| NaOH or phosphorus acid for adjusting pH are extremely | 8.5 |
| Water for injection is added to | 2000ml |
Preparation technology：The water for injection of total amount 50% is prepared in injection in Agitation Tank, and cooling makes at a temperature below 40
DEG C, add the Parecoxib Sodium and ADSP of recipe quantity, stirring to dissolving；Adjusted with NaOH or phosphoric acid solution
PH to 8.5, adds 0.05% (W/V) medical charcoal, and stirring and adsorbing 20min is filtered, then add note with 0.22 μm of PES filter
Penetrate with water to full dose；It is filling in cillin bottle by every bottle of 2ml；It is placed in freeze drying box and is freezed, 30min flaggies is from room temperature
- 40 DEG C are down to, is maintained 3 hours, is made sample fully charge, open condenser, when condenser temperature is down to below -45 DEG C, open
Open vavuum pump to vacuumize, forvacuum is less than 0.2mbar, starts to warm up；Shelf is heated, -5 DEG C, maintenance are warming up within 3 hours
3.5 hours；5 DEG C are continuously heating in 2.5h, is maintained 2 hours, maintains vacuum to be less than in 0.2mbar, 2h to shelf heat temperature raising
To 40 DEG C, maintain 4 hours, terminate lyophilized；Tamponade, lid is rolled, produce sterile cryo dry product.
Embodiment 7：Injection Parecoxib Sodium (in terms of 1000 bottles, unit：g)
| Parecoxib Sodium | 42.36 |
| ADSP | 2.65 |
| NaOH or phosphorus acid for adjusting pH are extremely | 7.8 |
| Water for injection is added to | 2000ml |
Preparation technology：The water for injection of total amount 50% is prepared in injection in Agitation Tank, and cooling makes at a temperature below 40
DEG C, add the Parecoxib Sodium and ADSP of recipe quantity, stirring to dissolving；Adjusted with NaOH or phosphoric acid solution
PH to 7.8, adds 0.05% (W/V) medical charcoal, and stirring and adsorbing 20min is filtered, then add note with 0.22 μm of PES filter
Penetrate with water to full dose；It is filling in cillin bottle by every bottle of 2ml；It is placed in freeze drying box and is freezed, 20min flaggies is from room temperature
- 40 DEG C are down to, is maintained 4 hours, is made sample fully charge, open condenser, when condenser temperature is down to below -45 DEG C, open
Open vavuum pump to vacuumize, forvacuum is less than 0.2mbar, starts to warm up；Shelf is heated, -5 DEG C, maintenance are warming up within 3 hours
2.5 hours；5 DEG C are continuously heating in 2.5h, is maintained 1 hour, maintains vacuum to be less than in 0.2mbar, 2h to shelf heat temperature raising
To 40 DEG C, maintain 3 hours, terminate lyophilized；Tamponade, lid is rolled, produce sterile cryo dry product.
Embodiment 8：Injection Parecoxib Sodium (in terms of 1000 bottles, unit：g)
Preparation technology：The water for injection of total amount 50% is prepared in injection in Agitation Tank, and cooling makes at a temperature below 40
DEG C, add the Parecoxib Sodium and ADSP of recipe quantity, stirring to dissolving；Adjusted with NaOH or phosphoric acid solution
PH to 8.0, adds 0.05% (W/V) medical charcoal, and stirring and adsorbing 20min is filtered, then add note with 0.22 μm of PES filter
Penetrate with water to full dose；It is filling in cillin bottle by every bottle of 2ml；It is placed in freeze drying box and is freezed, 10min flaggies is from room temperature
- 40 DEG C are down to, is maintained 3 hours, is made sample fully charge, open condenser, when condenser temperature is down to below -45 DEG C, open
Open vavuum pump to vacuumize, forvacuum is less than 0.2mbar, starts to warm up；Shelf is heated, -5 DEG C, maintenance are warming up within 3 hours
3.5 hours；5 DEG C are continuously heating in 2.5h, is maintained 1 hour, maintains vacuum to be less than in 0.2mbar, 2h to shelf heat temperature raising
To 40 DEG C, maintain 6 hours, terminate lyophilized；Tamponade, lid is rolled, produce sterile cryo dry product.Comparative formulation 1：According to patent (Shen
Please number：CN02810765.9) formulation and technology of the formulation C of embodiment 1 prepares Comparative formulation 1, and specification is 1ml：20mg.
Test example 1：Quality research is tested
The sample and each 50 bottles of the sample of Comparative formulation 1 for taking the embodiment of the present invention 3,8 to prepare, (60 under the conditions of accelerated test
DEG C, RH75%) place 3 months, respectively at the 0th day, January, 2 months, March sampling carry out character, redissolve speed, clarity of solution,
Moisture, about material, the measure of content, investigate the quality change situation of sample under these conditions, the result of the test such as institute of table 4
Show.
The embodiment of the present invention of table 4 is compared with Comparative formulation influence factor test mass
It can be seen from the results above that embodiment of the present invention sample (60 DEG C, RH75%) under the conditions of accelerated test places 3
After individual month, indices are held essentially constant, and quality is highly stable.And after the sample of Comparative formulation 1 is placed 3 months, moisture contains
Amount and Valdecoxib amount are significantly increased, and the redissolution time is far longer than embodiment of the present invention sample, and clarity of solution is also gradually reduced.
It can be seen that, embodiment of the present invention sample is significantly increased compared with the stability of the sample of Comparative formulation 1, is conducive to the curative effect and peace of Clinical practice
Entirely.
In summary, in the injection SC 69124 sodium pharmaceutical composition that the present invention is provided, prescription is simple, disodium hydrogen phosphate
The consumption of buffer greatly reduces compared with prior art, and other any freeze-dried excipients or freeze drying protectant are not used, made
Product quality it is stable, redissolve it is rapid, it is to avoid due to phosphate intake it is excessive caused by hypocalcemia, more meet injection
The requirement of drug safety；Parecoxib Sodium is crystal form, and crystal formation dissolving more known in the art is rapider, when shortening with liquid
Between, it is ensured that steady quality, while improving production efficiency.In preparation process by the way of snap frozen cooling so that freezing
Dried object maintains preferable pore structure, and forms highly uniform granularity, is conducive to the abundant distillation of moisture；It need not use
Nitrogen charging is operated, and product is maintained low-down moisture, be simplified production technology, reduce cost, be more beneficial for society
Big production can be changed.
Claims (5)
1. a kind of injection SC 69124 sodium pharmaceutical composition, it is characterised in that every 1000 bottles of pharmaceutical compositions are by following components
Composition：
Wherein, Parecoxib Sodium is crystal form in described pharmaceutical composition, and x-ray powder measure is carried out using Cu-ka rays,
Its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
2. a kind of injection SC 69124 sodium pharmaceutical composition, it is characterised in that every 1000 bottles of pharmaceutical compositions are by following components
Composition：
Wherein, Parecoxib Sodium is crystal form in described pharmaceutical composition, and x-ray powder measure is carried out using Cu-ka rays,
Its collection of illustrative plates has the angle of diffraction shown in following table, interplanar distance and relative intensity：
3. injection SC 69124 sodium pharmaceutical composition according to claim 1 or 2, it is characterised in that the medicine group
Parecoxib Sodium has X-ray powder diffraction pattern as shown in Figure 1 in compound.
4. a kind of preparation method of the injection SC 69124 sodium pharmaceutical composition described in any one of claims 1 to 3, its feature
It is to comprise the following steps：
(1) liquid is matched somebody with somebody：The water for injection of total amount 50% is prepared in injection in Agitation Tank, and cooling makes at a temperature below 40 DEG C, plus
Enter the Parecoxib Sodium and disodium hydrogen phosphate of recipe quantity, stirring to dissolving；With NaOH or phosphoric acid solution regulation pH to 7.5~
8.5,0.05% (W/V) medical charcoal is added, stirring and adsorbing 20min is filtered, then mend with 0.22 μm of PES (polyether sulfone) filter
Add to the full amount of water for injection, it is standby；
(2) it is filling：It is filling by every bottle of 1ml or 2ml loading amount；
(3) it is freeze-dried；
(4) tamponade, roll lid.
5. preparation method according to claim 4, it is characterised in that step (3) freeze-drying comprises the following steps：
A) pre-freeze：10min-30min flaggies are down to -40 DEG C from room temperature, maintain 3~6 hours, make sample fully charge, open cold
Condenser, when condenser temperature is down to below -45 DEG C, opens vavuum pump and vacuumizes, forvacuum is less than 0.2mbar, start to rise
Temperature；
B) first stage heats up：Shelf is heated, -5 DEG C are warming up within 3 hours, maintained 2~3.5 hours；
C) second stage heats up：5 DEG C are continuously heating in 2.5h, is maintained 1~2 hour, maintains vacuum to be less than 0.2mbar；In 2h
40 DEG C are heated to shelf, is maintained 1~6 hour, terminates lyophilized.
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| CN107011279A (en) * | 2017-06-04 | 2017-08-04 | 宁夏康亚药业股份有限公司 | A kind of SC 69124 sodium novel crystal form and preparation method thereof |
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| CN109985040A (en) * | 2019-05-15 | 2019-07-09 | 南京正大天晴制药有限公司 | A kind of injection Parecoxib Sodium Pharmaceutical composition and preparation method thereof for preemptive analgesia |
| CN113456597B (en) * | 2020-03-30 | 2023-02-14 | 石药集团欧意药业有限公司 | Parecoxib sodium for injection and preparation method thereof |
| CN113730362A (en) * | 2021-10-21 | 2021-12-03 | 上药东英（江苏）药业有限公司 | Parecoxib sodium freeze-dried powder injection and preparation method thereof |
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