CN103864819B - A kind of ceftazidime compound and pharmaceutical composition thereof - Google Patents
A kind of ceftazidime compound and pharmaceutical composition thereof Download PDFInfo
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- CN103864819B CN103864819B CN201410126071.6A CN201410126071A CN103864819B CN 103864819 B CN103864819 B CN 103864819B CN 201410126071 A CN201410126071 A CN 201410126071A CN 103864819 B CN103864819 B CN 103864819B
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- 229960000484 ceftazidime Drugs 0.000 title claims abstract description 152
- -1 ceftazidime compound Chemical class 0.000 title claims abstract description 50
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 16
- NMVPEQXCMGEDNH-TZVUEUGBSA-N ceftazidime pentahydrate Chemical compound O.O.O.O.O.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 NMVPEQXCMGEDNH-TZVUEUGBSA-N 0.000 claims description 113
- 238000000034 method Methods 0.000 claims description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- 239000013078 crystal Substances 0.000 claims description 37
- 239000012043 crude product Substances 0.000 claims description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 28
- 238000002360 preparation method Methods 0.000 claims description 27
- 230000008569 process Effects 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- 239000008367 deionised water Substances 0.000 claims description 10
- 229910021641 deionized water Inorganic materials 0.000 claims description 10
- 239000012046 mixed solvent Substances 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 9
- 239000012065 filter cake Substances 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 3
- 230000001133 acceleration Effects 0.000 claims description 2
- 238000013019 agitation Methods 0.000 claims description 2
- 238000001228 spectrum Methods 0.000 claims 1
- 239000000243 solution Substances 0.000 description 41
- 238000012360 testing method Methods 0.000 description 25
- KGWHMDCQVDMTNZ-UHFFFAOYSA-N 2-(butylcarbamoylamino)acetic acid Chemical compound CCCCNC(=O)NCC(O)=O KGWHMDCQVDMTNZ-UHFFFAOYSA-N 0.000 description 22
- 229960003547 ceftazidime pentahydrate Drugs 0.000 description 22
- 239000000203 mixture Substances 0.000 description 19
- 229920000642 polymer Polymers 0.000 description 19
- 239000000523 sample Substances 0.000 description 18
- 238000009472 formulation Methods 0.000 description 16
- 239000003814 drug Substances 0.000 description 15
- 239000007924 injection Substances 0.000 description 14
- 238000002347 injection Methods 0.000 description 14
- 239000012535 impurity Substances 0.000 description 10
- DZBUGLKDJFMEHC-UHFFFAOYSA-N benzoquinolinylidene Natural products C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000033228 biological regulation Effects 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000003115 biocidal effect Effects 0.000 description 4
- 229940000406 drug candidate Drugs 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000002932 luster Substances 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000006116 polymerization reaction Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000000151 deposition Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002270 exclusion chromatography Methods 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 230000000391 smoking effect Effects 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000013638 trimer Substances 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- ZUMCDPDQGVRFAA-UHFFFAOYSA-N N1=CC(=CC=C1)C.CC=CCCCCC Chemical compound N1=CC(=CC=C1)C.CC=CCCCCC ZUMCDPDQGVRFAA-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241001122767 Theaceae Species 0.000 description 1
- VXJPCEOTZNHHOA-UHFFFAOYSA-N [K].OC Chemical compound [K].OC VXJPCEOTZNHHOA-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 238000009534 blood test Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000009535 clinical urine test Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- SEGLCEQVOFDUPX-UHFFFAOYSA-N di-(2-ethylhexyl)phosphoric acid Chemical compound CCCCC(CC)COP(O)(=O)OCC(CC)CCCC SEGLCEQVOFDUPX-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000013595 supernatant sample Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
- C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of ceftazidime compound and pharmaceutical composition thereof.The structural formula of described ceftazidime compound is as shown in formula I, and this compound powder X-ray diffraction algoscopy measures, and the X-ray powder diffraction pattern represented with the 2 θ ± 0.2 ° angles of diffraction is as shown in Figure 1.This compound not only has preferable heat stability, and has extraordinary mobility, and is tested by pharmacokinetics and surprisingly find, the ceftazidime compound of the present invention has preferable bioavailability.
Description
Technical field
The invention belongs to field of medicaments, relate in particular to a kind of ceftazidime compound, its preparation method and aseptic
The pharmaceutical composition of mixed powder form.
Background technology
Ceftazidime, chemistry entitled (6R, 7R)-7-[[(2-amino-4-thiazolyl)-[(1-carboxyl-1-methyl ethoxy)
Imino group] acetyl group] amino]-2-carboxyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-3-picoline
Inner salt pentahydrate, for applying wide cephalosporin clinically, its structural formula is:
In order to ensure human administration's safety, state-promulgated pharmacopoeia specifies, for ceftazidime antibiotic, it is desirable to ceftazidime five water
The content of compound is not less than 95%, and the content of polymer is not higher than 0.3%, and its color and luster is not higher than No. 6 colors.Ceftazidime antibiotic
During depositing, in the case of particularly suffering high temperature (＞ 50 DEG C), tend to occur degraded and polyreaction, generate cephalo he
Pyridine dimer, trimer and polymer etc. polymer, thus cause active constituents of medicine content to reduce, color and luster is strengthened, polymerization
Thing impurity content raises.It addition, expired ceftazidime antibiotic, owing to the resting period is long, pharmaceutically active is the most usually made to become
Dividing content to reduce, darken, polymer content raises.Further, in some cases, owing to controlling of production process is improper, institute
The ceftazidime pentahydrate obtained, ceftazidime dimer, trimer and polymer etc. polymer content is the highest.And gather
During compound content height, human body is easily made to produce anaphylaxis.So for high ceftazidime five water of this kind of polymeric impurities content
Compound or ceftazidime pharmaceutical preparation, it is necessary to be purified further, ceftazidime five water that obtain high-quality, that purity is high
Solvate crystal.
GB2063871 discloses the preparation method of ceftazidime pentahydrate crystal, and the method is regulation ceftazidime acid
The pH of salt or alkali salt aqueous solution is 3.3-4.0, makes ceftazidime pentahydrate crystal structure separate out.Above-mentioned polymeric impurities content
Higher ceftazidime pentahydrate or ceftazidime pharmaceutical preparation, such as, when polymeric impurities content is higher than 4%, according to
The method crystallization purifying of GB2063871, polymeric impurities is usually associated with ceftazidime pentahydrate crystal and separates out together, institute
With, in obtained ceftazidime pentahydrate crystal, the content of polymeric impurities remains unchanged the highest.
GB2157682 discloses the recovery method of a kind of ceftazidime, and the method is to use non-functional large hole mesh resin,
Be that 2.0-5.5 ceftazidime aqueous solution releases with pH, thus absorb ceftazidime, then carry out eluting, isolate ceftazidime or
Its salt or its hydrate.According to the method, end product may be ceftazidime or its salt or its hydrate, impurity polymer
Content reduces, and product color shoals, but the method needs to use non-functional large hole mesh resin, then carries out eluting, separation, operation
Many, complex operation, cost is high.
US4659813 discloses the preparation method of a kind of ceftazidime pentahydrate crystal, and the method is, about 5～15
At a temperature of DEG C, pH is about the ceftazidime aqueous solution of 5.5～about 6.5, regulates its pH with acid and is about 4.0～about 4.7, and at knot
By controlling the addition of acid during crystalline substance, make pH be maintained at about 4.0～about 4.7, thus separate out ceftazidime pentahydrate crystal.
Although this method is to improving product purity, reducing polymer content has certain help, but, color and luster the highest for polymer content
Very poor ceftazidime preparation, in this way, still can not get the ceftazidime pentahydrate crystal of high-quality.Meanwhile, this side
Material is first dissolved in the higher system of pH by method, causes ceftazidime to degrade, and such response rate reduces.
CN1775784A discloses the purification process of a kind of ceftazidime, more particularly, it relates to by impure, containing polymerization
The ceftazidime that thing impurity is high prepares the method for the ceftazidime pentahydrate of high-quality by crystallization.Impure, polymer contains
Measure high ceftazidime pentahydrate, ceftazidime hydrochlorate, ceftazidime ambroxol salt or expired or from reclaiming on the market
The ceftazidime preparation come, is configured to ceftazidime aqueous solution, then with the pH of alkali or acid regulation ceftazidime aqueous solution is
1.5-2.5, now impurity, ceftazidime polymer separate out together with a small amount of ceftazidime, are filtered to remove these precipitates,
Obtained filtrate alkali regulation pH is 3.5-4.8, and ceftazidime pentahydrate crystal structure separates out.The method is easy and simple to handle,
Low cost, safety is good, and yield is high, and obtained ceftazidime pentahydrate crystal purity is high, and polymer content is low, reaches medicine
Allusion quotation regulation requirement.
CN101607966A discloses the preparation method of a kind of ceftazidime pentahydrate, carries out as steps described below: step
Rapid one, in a dissolving tank, inject water for injection, add ceftazidime hydrochlorate, after dissolving, put into activated carbon decolorizing, filter,
Filtrate is stand-by；Step 2, in another dissolving tank inject water for injection, add ceftazidime hydrochlorate, after dissolving, put into live
Property charcoal, decolouring, filter, filtrate proceeds to crystallizer；Step 3, drips aqueous slkali in the crystallizer in second step, regulation pH arrives
4.0-6.0, then drip the filtrate in the first step and make pH value pull back to 3.6, keep temperature 0-10 DEG C, stirring, crystallization；Step 4,
Growing the grain filtered after 3-4 hour, and filter cake cold water and acetone wash respectively, was vacuum dried 2-3 hour, obtained ceftazidime five hydration
Thing crystal.Its advantage is: save fund, Simplified flowsheet, minimizing waste gas discharge of wastewater；Easy and simple to handle, it is suitable for industrialized production；Pure
Degree is high, yield is high.
Visible, the method for prior art is mostly from improving stability, improving head with minimizing polyreaction as far as possible
The quality of his pyridine product of spore.But, ceftazidime poor fluidity prepared by the method for prior art, have a strong impact on its subpackage accurate
Really property and uniformity, be not suitable for commercial production.
In view of this, the special proposition present invention.
Summary of the invention
The primary and foremost purpose of the present invention is to provide a kind of ceftazidime compound, and this not only has preferable heat stability,
And mobility is preferable.
For achieving the above object, the present invention adopts the following technical scheme that
A kind of ceftazidime compound, it is characterised in that the structural formula such as formula I institute of described ceftazidime compound
Showing, this compound powder X-ray diffraction algoscopy measures, the X-ray powder diffraction pattern represented with the 2 θ ± 0.2 ° angles of diffraction
As shown in Figure 1.
The inside solid-state structure of compound has the biggest impact, same compound to its physicochemical property, and its crystal formation is not
With, cause its lattice energy different, thus cause its physical property the most different.
The invention provides a kind of ceftazidime unlike the prior art, have compared with the ceftazidime of prior art
Higher lattice energy, lattice is higher to the binding force of ceftazidime molecule, thus improves the stability of ceftazidime compound.
Inventor is by thermally-stabilised new test, and result shows that the special crystal form of ceftazidime compound provided by the present invention is with existing
The solid form having the ceftazidime of technology is compared, and has higher heat stability, which greatly improves the medication peace of patient
Entirely.It addition, present inventors have surprisingly found that, ceftazidime compound provided by the present invention has extraordinary mobility, easily
In subpackage.
Meanwhile, the present invention tests also by pharmacokinetics, surprisingly finds that the ceftazidime of the present invention has more preferable biology
Availability.
The present invention also aims to provide the preparation method of above-mentioned ceftazidime compound, the method to include walking as follows
Rapid:
1) crude product solution is prepared: ceftazidime crude product is added the mixed solvent formulated by dimethyl sulfoxide and methanol
In, control temperature 20～30 DEG C, add activated carbon decolorizing, filter, obtain ceftazidime crude product solution, standby；
2) nucleus generate process: control ceftazidime crude product solution temperature in the range of 20～30 DEG C, under agitation to
In this solution, stream adds deionized water, has muddy appearance, obtains turbid solution；
3) crystal growing process: by step 2) turbid solution of gained is placed under ultrasonic field, controls solution temperature 20～30
DEG C, drip chloroform wherein, separate out crystal；Closing ultrasonic field, be cooled to 0～5 DEG C, filter, filter cake is washed with deionized water
Washing, vacuum drying obtains described ceftazidime compound.
In the present invention, described ceftazidime crude product can be the method such as CN102391289A institute public affairs using prior art
The ceftazidime pentahydrate that the synthetic method of the ceftazidime opened prepares, it is also possible to be commercially available ceftazidime five hydration
Raw material medicine.
Crystallization is a complicated process, and in different environments, the change of the either step of crystallization process all can be formed
Different crystallization effects.In the present invention, first for ensureing effective crystallize, step 1) purify former by activated carbon decolorizing, filtration
Material；Step 2) and step 3) it is that nucleus generates and crystal growing process.Wherein step 3) after nucleus is formed, introduce ultrasonic
, and in crystallization process introduce ultrasonic field have change crystal morphology, regulate crystal size, improve particle size distribution and shorten knot
The effect of brilliant time etc..In the present invention, by prepared ceftazidime compound crystal form XRD is characterized, obtained by discovery
Ceftazidime compound is a kind of ceftazidime being different from prior art crystal formation.
As the preferred version of the present invention, wherein, step 1) described in ceftazidime crude product and described mixed solvent
Amount ratio be 1g:5～8ml.
In described mixed solvent, dimethyl sulfoxide is 3～7:1 with the volume ratio of methanol.
Step 2) described in deionized water and step 1) described in the volume ratio of mixed solvent be 5:1～10:1.
Step 3) described in ultrasonic field be frequency be 3.5～6.5kHz, intensity be 0.6W cm-2～4W cm-2Super
Sound field.
Step 3) described in chloroform and step 1) described in the volume ratio of mixed solvent be 7:1～12:1.
Step 2) described in mixing speed be 130～200r/min.
Step 2) described in stream rate of acceleration be 10～15ml/min；Step 3) described in drop rate be 5～8ml/
min。
The present invention furthermore provides a kind of pharmaceutical composition, and described pharmaceutical composition contains head provided by the present invention
His acridine compound of spore.
In the present invention, described pharmaceutical composition can be prepared as any applicable various dosage forms of prior art, described
Various dosage forms are referred to prior art and are similar to dosage form and are prepared, and pay more creativeness without those skilled in the art
Work, can realize the purpose of the present invention.
The preferred injectable sterile powder of the present invention.
It is furthermore preferred that injectable sterile powder of the present invention is possibly together with natrium carbonicum calcinatum.
Most preferably, in described pharmaceutical composition, the consumption of natrium carbonicum calcinatum is the consumption of ceftazidime compound
11.2wt%, wherein the consumption of ceftazidime compound presses ceftazidime (C22H22N6O7S2) meter.
Described pharmaceutical composition is through nothing after ceftazidime crystalline compounds is mixed by described consumption with natrium carbonicum calcinatum
Aseptic powder injection is made after bacterium subpackage.
The sterilized powder of the present invention can carry out subpackage by the specification of 0.5g/ bottle, 1.0g/ bottle, 2.0g/ bottle etc..Here rule
Lattice are with ceftazidime (C22H22N6O7S2) meter.
Compared with prior art, present invention have the advantage that
(1) ceftazidime compound provided by the present invention has preferable heat stability, and polymer content change is little；
(2) ceftazidime provided by the present invention has preferable mobility, is conducive to improving the accuracy of subpackage, and
It is easily mixed when mixing with other composition uniformly；
(3) ceftazidime provided by the present invention has preferable bioavailability.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction figure of the ceftazidime compound of the present invention；
Fig. 2 be 24 healthy volunteers take ceftazidime for injection investigational agent and comparison medicine after mean blood plasma concentration-
Time graph.
Detailed description of the invention
Be below the detailed description of the invention of the present invention, described embodiment be in order to further describe the present invention rather than
Limit the present invention.
The preparation of [embodiment 1] ceftazidime compound
1) crude product solution is prepared: 20g ceftazidime crude product is added 110ml by formulated the mixing of dimethyl sulfoxide and methanol
In bonding solvent (wherein the volume ratio of dimethyl sulfoxide and methanol is 6:1), control temperature 22 DEG C, add ceftazidime crude product weight
The activated carbon decolorizing of 0.01%, filters, obtains ceftazidime crude product solution, standby；
2) nucleus generates process: the temperature of control ceftazidime crude product solution is in the range of 22 DEG C, and low whipping speed is
Under the stirring of 150r/min, in this solution, speed stream with 11ml/min adds deionized water, has muddy appearance, obtains muddy molten
Liquid；
3) nucleus crystal growing process: by step 2) turbid solution of gained be placed in frequency be 4kHz, intensity be 3W cm-2
Ultrasonic field under, control solution temperature 22 DEG C, drip 1210ml chloroform with the speed of 8ml/min wherein, separate out crystal；
Closing ultrasonic field, be cooled to 1 DEG C, filter, filter cake is washed with deionized 3 times, and vacuum drying obtains described ceftazidime
Compound.Purity 99.8%, loss on drying 14.1%.
The ceftazidime crystalline compounds powder X-ray diffraction algoscopy obtained is measured, with the 2 θ ± 0.2 ° angles of diffraction
The X-ray powder diffraction pattern represented is as shown in Figure 1.
The preparation of [embodiment 2] ceftazidime compound
1) crude product solution is prepared: 20g ceftazidime crude product is added 150ml by formulated the mixing of dimethyl sulfoxide and methanol
In bonding solvent (wherein the volume ratio of dimethyl sulfoxide and methanol is 4:1), control temperature 28 DEG C, add ceftazidime crude product weight
The activated carbon decolorizing of 0.01%, filters, obtains ceftazidime crude product solution, standby；
2) nucleus generates process: the temperature of control ceftazidime crude product solution is in the range of 28 DEG C, and low whipping speed is
Under the stirring of 180r/min, in this solution, speed stream with 14ml/min adds 1050ml deionized water, has muddy appearance, obtains
Turbid solution；
3) nucleus crystal growing process: by step 2) turbid solution of gained be placed in frequency be 4.8kHz, intensity be 1W
cm-2Ultrasonic field under, control solution temperature 28 DEG C, drip 1500ml chloroform with the speed of 7ml/min wherein, separate out crystalline substance
Body；Closing ultrasonic field, be cooled to 3 DEG C, filter, filter cake is washed with deionized 3 times, and vacuum drying obtains described ceftazidime
Compound.Purity 99.7%, loss on drying 14.0%.
The ceftazidime crystalline compounds powder X-ray diffraction algoscopy obtained is measured, with the 2 θ ± 0.2 ° angles of diffraction
The X-ray powder diffraction pattern represented is consistent with embodiment 1.
The preparation of [embodiment 3] ceftazidime compound
1) crude product solution is prepared: 20g ceftazidime crude product is added 130ml by formulated the mixing of dimethyl sulfoxide and methanol
In bonding solvent (wherein the volume ratio of dimethyl sulfoxide and methanol is 5:1), control temperature 25 DEG C, add ceftazidime crude product weight
The activated carbon decolorizing of 0.01%, filters, obtains ceftazidime crude product solution, standby；
2) nucleus generates process: the temperature of control ceftazidime crude product solution is in the range of 25 DEG C, and low whipping speed is
Under the stirring of 160r/min, in this solution, speed stream with 12ml/min adds 1040ml deionized water, has muddy appearance, obtains
Turbid solution；
3) nucleus crystal growing process: by step 2) turbid solution of gained be placed in frequency be 5.0kHz, intensity be 2W
cm-2Ultrasonic field under, control solution temperature 25 DEG C, drip 1170ml chloroform with the speed of 6ml/min wherein, separate out crystalline substance
Body；Closing ultrasonic field, be cooled to 2 DEG C, filter, filter cake is washed with deionized 3 times, and vacuum drying obtains described ceftazidime
Compound.Purity 99.8%, loss on drying 14.2%.
The ceftazidime crystalline compounds powder X-ray diffraction algoscopy obtained is measured, with the 2 θ ± 0.2 ° angles of diffraction
The X-ray powder diffraction pattern represented is consistent with embodiment 1.
The preparation of [embodiment 4] ceftazidime compound
1) crude product solution is prepared: 20g ceftazidime crude product is added 160ml by formulated the mixing of dimethyl sulfoxide and methanol
In bonding solvent (wherein the volume ratio of dimethyl sulfoxide and methanol is 7:1), control temperature 30 DEG C, add ceftazidime crude product weight
The activated carbon decolorizing of 0.01%, filters, obtains ceftazidime crude product solution, standby；
2) nucleus generates process: the temperature of control ceftazidime crude product solution is in the range of 30 DEG C, and low whipping speed is
Under the stirring of 200r/min, in this solution, speed stream with 15ml/min adds 1600ml deionized water, has muddy appearance, obtains
Turbid solution；
3) nucleus crystal growing process: by step 2) turbid solution of gained be placed in frequency be 6.5kHz, intensity be 4W
cm-2Ultrasonic field under, control solution temperature 30 DEG C, drip 1920ml chloroform with the speed of 8ml/min wherein, separate out crystalline substance
Body；Closing ultrasonic field, be cooled to 5 DEG C, filter, filter cake is washed with deionized 3 times, and vacuum drying obtains described ceftazidime
Compound.Purity 99.7%, loss on drying 14.0%.
The ceftazidime crystalline compounds powder X-ray diffraction algoscopy obtained is measured, with the 2 θ ± 0.2 ° angles of diffraction
The X-ray powder diffraction pattern represented is consistent with embodiment 1.
The preparation of [embodiment 5] ceftazidime compound
1) crude product solution is prepared: 20g ceftazidime crude product is added 100ml by formulated the mixing of dimethyl sulfoxide and methanol
In bonding solvent (wherein the volume ratio of dimethyl sulfoxide and methanol is 3:1), control temperature 20 DEG C, add ceftazidime crude product weight
The activated carbon decolorizing of 0.01%, filters, obtains ceftazidime crude product solution, standby；
2) nucleus generates process: the temperature of control ceftazidime crude product solution is in the range of 20 DEG C, and low whipping speed is
Under the stirring of 130r/min, in this solution, speed stream with 10ml/min adds 500ml deionized water, has muddy appearance, obtains muddy
Turbid solution；
3) nucleus crystal growing process: by step 2) turbid solution of gained be placed in frequency be 3.5kHz, intensity be
0.6W·cm-2Ultrasonic field under, control solution temperature 20 DEG C, drip 700ml chloroform with the speed of 5ml/min wherein,
Separate out crystal；Closing ultrasonic field, be cooled to 0 DEG C, filter, filter cake is washed with deionized 3 times, and vacuum drying obtains described head
His acridine compound of spore.Purity 99.8%, loss on drying 14.2%.
The ceftazidime crystalline compounds powder X-ray diffraction algoscopy obtained is measured, with the 2 θ ± 0.2 ° angles of diffraction
The X-ray powder diffraction pattern represented is consistent with embodiment 1.
[example of formulations 1] ceftazidime for injection
Specification: 0.5g is (by ceftazidime C22H22N6O7S2Meter)
Preparation method:
1, interior packaging material processes
The cleaning of antibiotic glass bottle, plug, aluminium lid technique routinely, drying, sterilizing, standby；
2, concrete steps
(1) the ceftazidime compound prepared by the natrium carbonicum calcinatum of recipe quantity and embodiment 1 is weighed, in sterile chamber
Mix homogeneously；
(2) in the middle of, product examine is tested；
(3) carry out aseptic subpackaged by specification；
(4) evacuation, tamponade, lid is rolled；
(5) packaging, Quan Jian, warehouse-in.
[example of formulations 2] ceftazidime for injection
Specification: 1.0g is (by ceftazidime C22H22N6O7S2Meter)
Preparation method: with example of formulations 1, except that ceftazidime used is the cephalo prepared by embodiment 2
His acridine compound.
[example of formulations 3] ceftazidime for injection
Specification: 2.0g is (by ceftazidime C22H22N6O7S2Meter)
Preparation method: with example of formulations 1, except that ceftazidime used is the cephalo prepared by embodiment 3
His acridine compound.
[example of formulations 4] ceftazidime for injection
Specification: 0.5g is (by ceftazidime C22H22N6O7S2Meter)
Preparation method: with example of formulations 1, except that ceftazidime used is the cephalo prepared by embodiment 4
His acridine compound.
[example of formulations 5] ceftazidime for injection
Specification: 1.0g is (by ceftazidime C22H22N6O7S2Meter)
Preparation method: with example of formulations 1, except that ceftazidime used is the cephalo prepared by embodiment 5
His acridine compound.
[example of formulations 6] ceftazidime for injection
Specification: 2.0g is (by ceftazidime C22H22N6O7S2Meter)
Preparation method: with example of formulations 1, except that ceftazidime used is the cephalo prepared by embodiment 2
His acridine compound.
[example of formulations 7] ceftazidime for injection
Specification: 0.5g is (by ceftazidime C22H22N6O7S2Meter)
Preparation method: with example of formulations 1, except that ceftazidime used is the cephalo prepared by embodiment 3
His acridine compound.
Test example 1
Heat stabilization test
Ceftazidime is during depositing, and particularly under conditions of high temperature (＞ 50 DEG C), tends to occur degraded and polymerization
Reaction, thus cause active constituents of medicine content to reduce, color and luster is strengthened, and polymeric impurities content raises.This test example is used for examining
Examine the thermal stability difference of the ceftazidime crystalline compounds prepared by the present invention and ceftazidime of the prior art.
In this test example, each sample is numbered:
Trial target 1: the ceftazidime crystalline compounds prepared by the embodiment of the present invention 1；
Trial target 2: the ceftazidime crystalline compounds prepared by the embodiment of the present invention 5；
Reference substance 1: obtain after ceftazidime pentahydrate being purified according to the method for CN1775784A embodiment 1
Ceftazidime pentahydrate；
Reference substance 2: the ceftazidime pentahydrate crystal obtained according to the method for CN101607966A embodiment 1.
Each sample is respectively exposed to relative humidity be 75%, in the environment of temperature is 60 DEG C, use molecular-exclusion chromatography
Method measures the content of high molecular polymer, and (molecular exclusion chromatography is according to pharmacopeia in 2005 second, the relevant bar of annex VH
Part is measured), the results are shown in Table 1.
Table 1, heat stabilization test result
| Time | Content | Trial target 1 | Trial target 2 | Reference substance 1 | Reference substance 2 |
| 0 day | The content (%) of polymer | 0.01 | 0.02 | 0.09 | 0.03 |
| 7 days | The content (%) of polymer | 0.02 | 0.02 | 0.18 | 0.19 |
| 14 days | The content (%) of polymer | 0.02 | 0.03 | 0.22 | 0.27 |
| 21 days | The content (%) of polymer | 0.03 | 0.04 | 0.30 | 0.31 |
| 28 days | The content (%) of polymer | 0.03 | 0.03 | 0.33 | 0.36 |
As can be seen from the above table, the heat stability of the ceftazidime compound that the method for the employing present invention prepares is significantly better than
The ceftazidime pentahydrate crystal that the method using prior art obtains after being purified.
The ceftazidime compound of other embodiments of the present invention has been also carried out above-mentioned test, and its result obtained is similar.
Test example 2
Fluidity test
This test example has investigated the mobility of the ceftazidime compound of the present invention and prior art.
This test example is by measuring the mobility evaluating sample angle of repose of sample, and concrete grammar is as follows: take sample
Grain, flows in the surface plate of circle from fixing little funnel, until obtain the highest cone, measure cone height H and
Radius R, calculates α angle of repose by tan α==H/R, the results are shown in Table 2, and angle of repose is the biggest, and mobility is the poorest.Refer to table 2.
Table 2, fluidity test result
| Sample 1 | Sample 2 | Sample 3 | Sample 4 | |
| Angle of repose (°) | 45° | 46° | 62° | 64° |
Wherein: sample 1 is the product of the embodiment of the present invention 1；
Sample 2 is the product of the embodiment of the present invention 2；
Sample 3 is the ceftazidime pentahydrate prepared according to the method for CN102391289A embodiment 8；
Sample 4 is the ceftazidime pentahydrate prepared according to the method for CN1775784A embodiment 1.
As known from Table 2, compared with ceftazidime of the prior art, the ceftazidime compound prepared by the present invention has
Preferably mobility, is conducive to improving the accuracy of subpackage, and is easily mixed when mixing with other composition uniformly.
Test example 3
Pharmacokinetics is tested
1, instrument and reagent
Agilent 1100Series high performance liquid chromatograph, Agilent company of the U.S. produces, including: G1310A HPLC
Pump, G1313A automatic sampler, G1314A ultraviolet wavelengthtunable detector, G1310A chromatographic work station.
Ceftazidime for injection investigational agent (ceftazidime for injection that invention formulation embodiment 2 prepares)；Injection head
His pyridine of spore comparison medicine (ceftazidime for injection prepared according to prescription and the method for invention formulation embodiment 2, except that
Ceftazidime used is the ceftazidime pentahydrate prepared according to the method for CN1775784A embodiment 1).Used by test
Acetonitrile be chromatographically pure, other reagent are analytical pure, and test water is distilled water.Blank plasma is that Beijing Red Cross blood station carries
The Healthy Human Serum of confession.
2, method and result
2.1 chromatographic condition
Chromatographic column: A lltin a C18(53mm × 7mm, 3 μm, Alltech company of the U.S.)；Chromatograph pre-column: Aichram-
Bond AQ C18(2.1mm × 10mm, 5 μm, Abel Industrise company of the U.S.)；Flowing phase: 0.02mol L-1Di(2-ethylhexyl)phosphate
Hydrogen potassium-methanol (85:15, v/v)；Flow velocity: 2mL min-1, detect wavelength: 254nm；Column temperature: room temperature；Sample size: 20 μ L.
2.2 sample pretreatment
Serum specimen processing method: accurate absorption blood serum sample 500 μ L, puts in 5mL centrifuge tube, adds perchloric acid
(0.5mol·L-1) 500 μ L, vortex oscillation 1min, in 10000r min-1Centrifugal 5min, Aspirate supernatant sample introduction measures.
2.3 pharmacokinetic studies
24 selected healthy male volunteers are university students, the mean age of experimenter be (21.7 ±
1.6) in year, height is (173.9 ± 2.8) cm, and body weight is (65.9 ± 4.4) kg, and Body Mass Index BMI is 21.8 ± 1.5, health check-up,
It is normal before electrocardiogram, blood biochemistry, routine blood test and routine urine test.Experimenter tests first 1 week and does not takes any medicine, without medicine
Thing allergies and habits of smoking and alcohol drinking.This test is ratified through Ethics Committee of institute, and the experimenter participating in test all signs written in the know
Letter of consent.
24 experimenters are randomly divided into two groups, test group and matched group, and often group 12, eats light respectively at the previous day of taking medicine
Fasting 12h after dinner, continued fasting to 4h after being administered tested morning on the same day, upon administration 4,10h fed standard meal, the most tested
Period can drink water, it is impossible to drinks tea, coffee and Other Drinks.Experimenter, can only be movable in special ward during testing, it is impossible to
Carry out aggravating activities.Can not drink during test, smoking.Test group and matched group give ceftazidime investigational agent and cephalo respectively
His pyridine comparison medicine, ceftazidime investigational agent and comparison medicine respectively with after a small amount of physiological saline solution, addition 250mL normal saline
In, constant rate intravenous drop 30min.Take a blood sample before being arranged to instil during test, the 5min during drop, drop 30min terminate
Can and be administered terminate after 5,15,30,45,60,90,120,180,240,360,480,720min extracting vein blood 5mL, be subject to
After examination person's blood sampling, can leave away.4000r·min-1Centrifugal 10min, separates serum, and the blood specimen after administration measures immediately,
The specimen do not surveyed is in-20 DEG C of preservations, and measures complete in the stable phase of sample.The mean blood plasma concentration curve recorded is shown in
Fig. 2.
From the mean blood plasma concentration-time graph of ceftazidime it can be seen that the C of investigational agentmaxIt is better than compareing medicine, uses
Trapezoidal method calculates AUC, result show by reagent AUC also superior to comparison medicine.
The ceftazidime for injection preparing other example of formulations of the present invention has been also carried out above-mentioned test, its knot obtained
The most similar.
Claims (10)
1. a ceftazidime compound crystal, it is characterised in that the structural formula such as formula of described ceftazidime compound crystal
(I), shown in, this compound crystal powder X-ray diffraction algoscopy measures, the x-ray powder represented with the 2 θ ± 0.2 ° angles of diffraction
Diffracting spectrum as it is shown in figure 1,
2. the preparation method of the ceftazidime compound crystal described in a claim 1, it is characterised in that the method include as
Lower step:
1) crude product solution is prepared: add ceftazidime crude product by the formulated mixed solvent of dimethyl sulfoxide and methanol, control
Temperature 20 processed～30 DEG C, add activated carbon decolorizing, filters, obtains ceftazidime crude product solution, standby；
2) nucleus generates process: the temperature of control ceftazidime crude product solution is in the range of 20～30 DEG C, under agitation molten to this
In liquid, stream adds deionized water, has muddy appearance, obtains turbid solution；
3) crystal growing process: by step 2) turbid solution of gained is placed under ultrasonic field, controls solution temperature 20～30 DEG C, to
Wherein drip chloroform, separate out crystal；Closing ultrasonic field, be cooled to 0～5 DEG C, filter, filter cake is washed with deionized, very
Sky is dried to obtain described ceftazidime compound crystal.
Preparation method the most according to claim 2, it is characterised in that step 1) described in ceftazidime crude product with described
The amount ratio of mixed solvent be 1g:5～8ml.
Preparation method the most according to claim 3, it is characterised in that dimethyl sulfoxide and methanol in described mixed solvent
Volume ratio is 3～7:1.
Preparation method the most according to claim 2, it is characterised in that step 2) described in deionized water and step 1) in
The volume ratio of described mixed solvent is 5:1～10:1.
Preparation method the most according to claim 2, it is characterised in that step 3) described in ultrasonic field be frequency be 3.5
～6.5kHz, intensity are 0.6W cm-2～4W cm-2Ultrasonic field.
Preparation method the most according to claim 2, it is characterised in that step 3) described in chloroform and step 1) in
The volume ratio of described mixed solvent is 7:1～12:1.
Preparation method the most according to claim 2, it is characterised in that step 2) described in mixing speed be 130～200r/
min。
Preparation method the most according to claim 2, it is characterised in that step 2) described in stream rate of acceleration be 10～
15ml/min；Step 3) described in drop rate be 5～8ml/min.
10. the pharmaceutical composition containing the ceftazidime compound crystal described in claim 1.
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| CN105560194B (en) * | 2014-10-17 | 2018-09-04 | 林立东 | Cefotaxime powder-injection of high-purity and preparation method thereof |
| CN106167498A (en) * | 2016-06-23 | 2016-11-30 | 石药集团中诺药业（石家庄）有限公司 | A kind of new ceftazidime compound |
| CN106317081B (en) * | 2016-08-22 | 2018-08-31 | 山东罗欣药业集团恒欣药业有限公司 | A kind of anti-infectives cefotaxime crystalline compounds and its pharmaceutical composition |
| CN106397458A (en) * | 2016-09-23 | 2017-02-15 | 临沂草之美医药科技有限公司 | Ceftazidime crystal compound as drug for treating infection during surgical operation |
| CN106432281A (en) * | 2016-09-23 | 2017-02-22 | 临沂草之美医药科技有限公司 | Preparation method of pharmaceutical ceftazidime crystal compound for treating surgical infection |
| CN106432280A (en) * | 2016-09-23 | 2017-02-22 | 临沂草之美医药科技有限公司 | Medicine ceftazidime crystalline compound for treating surgical operation infection |
| CN109096309B (en) * | 2017-06-20 | 2019-10-01 | 陕西顿斯制药有限公司 | One kind 43/4His acridine compound of head spore and its pharmaceutical composition |
| CN111116611B (en) * | 2019-11-21 | 2021-05-07 | 华北制药河北华民药业有限责任公司 | Preparation method of ceftazidime powder injection preparation for injection |
| CN116731041A (en) * | 2023-06-13 | 2023-09-12 | 烟台大学 | Ceftazidime crystal and preparation method and application thereof |
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| CN101607966A (en) * | 2008-06-19 | 2009-12-23 | 上海新先锋药业有限公司 | The preparation method of ceftazidime pentahydrate |
| CN102391289B (en) * | 2011-12-03 | 2013-09-18 | 齐鲁安替制药有限公司 | Synthetic methods of ceftazidime intermediate and ceftazidime |
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