CN105640958B - A kind of avocin and the pharmaceutical composition of sulbactam - Google Patents
A kind of avocin and the pharmaceutical composition of sulbactam Download PDFInfo
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- CN105640958B CN105640958B CN201610001023.3A CN201610001023A CN105640958B CN 105640958 B CN105640958 B CN 105640958B CN 201610001023 A CN201610001023 A CN 201610001023A CN 105640958 B CN105640958 B CN 105640958B
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- 229960005256 sulbactam Drugs 0.000 title claims abstract description 135
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical group O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 title claims abstract description 135
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 claims abstract description 36
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 170
- BVHLGVCQOALMSV-JEDNCBNOSA-N L-lysine hydrochloride Chemical compound Cl.NCCCC[C@H](N)C(O)=O BVHLGVCQOALMSV-JEDNCBNOSA-N 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 53
- 238000002156 mixing Methods 0.000 claims description 50
- 229960005337 lysine hydrochloride Drugs 0.000 claims description 48
- 238000003756 stirring Methods 0.000 claims description 48
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 44
- 239000013078 crystal Substances 0.000 claims description 40
- 238000013019 agitation Methods 0.000 claims description 36
- 239000000706 filtrate Substances 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 18
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 18
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 18
- 238000010792 warming Methods 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 14
- 229960002292 piperacillin Drugs 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 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 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 230000005855 radiation Effects 0.000 claims description 2
- IVBHGBMCVLDMKU-GXNBUGAJSA-N piperacillin Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 IVBHGBMCVLDMKU-GXNBUGAJSA-N 0.000 claims 2
- 238000005516 engineering process Methods 0.000 abstract description 6
- 238000005457 optimization Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 53
- 238000000034 method Methods 0.000 description 20
- 239000000463 material Substances 0.000 description 15
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 12
- 238000013112 stability test Methods 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 239000011812 mixed powder Substances 0.000 description 7
- 239000012467 final product Substances 0.000 description 6
- 150000002576 ketones Chemical class 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 229960005264 piperacillin sodium Drugs 0.000 description 5
- 229960000614 sulbactam sodium Drugs 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 241000588624 Acinetobacter calcoaceticus Species 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000588656 Neisseriaceae Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- NKZMPZCWBSWAOX-IBTYICNHSA-M Sulbactam sodium Chemical compound [Na+].O=S1(=O)C(C)(C)[C@H](C([O-])=O)N2C(=O)C[C@H]21 NKZMPZCWBSWAOX-IBTYICNHSA-M 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/86—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with only atoms other than nitrogen atoms directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the pharmaceutical composition of a kind of avocin and sulbactam, the specific rotation of avocin and 1 weight portion including 24 weight portions is+230 ° to+235 ° of sulbactam.Preparation technology of the present inventor by optimization sulbactam, prepares the sulbactam that specific rotation is+230 ° to+235 °, optimizes avocin preparation technology, is conducive to the stability for improving pharmaceutical composition, using safer.
Description
Technical field
A kind of the invention belongs to field of pharmaceutical preparations, in particular it relates to the drug regimen of avocin and sulbactam
Thing.
Background technology
Avocin belongs to PCs broad-spectrum antibiotic, mainly plays sterilized work by disturbing the synthesis of bacteria cell wall
With, the infection caused by being mainly used in pseudomonas aeruginosa and various gram negative bacillis, but easily by bacteriogenic beta-lactam
Enzyme hydrolysis and produce drug resistance；Sulbactam in addition to Neisseriaceae and acinetobacter calcoaceticus, to other bacteriums without antibacterial activity, but
Sulbactam has irreversible suppression to the most important beta-lactamase that beta-lactam antibiotic antibody-resistant bacterium is produced
Effect.Sulbactam can prevent destruction of the drug-fast bacteria to PCs and cephalosporins, sulbactam and penicillin
Class and cephalosporins have significantly synergy.
Piperacillin-sulbactam sodium combination preparation quantity is big, and determined curative effect, market prospects are good, but the storage of existing preparation
Less stable is deposited, clinical efficacy has been had a strong impact on.And make to overcome piperacillin-sulbactam sodium to combine in prior art
New defect is stablized in agent, proposes multiple solutions, and such as Chinese patent literature CN200610015440.X discloses a kind of anti-
Raw element compound, is made up of avocin, sulbactam and at least one ion chelating agent for suppressing particles generation, not enough
Part is that ion chelating agent is particularly the use of EDTA and easily causes sodium in bone, potassium, calcium ion loss.
Content of the invention
The technical problem to be solved is to provide the pharmaceutical composition of a kind of avocin and sulbactam, storage
Deposit good stability, it is ensured that the efficacy and saferry of Clinical practice.
The present invention the adopted technical scheme that solves the above problems is：
A kind of avocin and the pharmaceutical composition of sulbactam, the avocin and 1 weight including 2-4 weight portions
The specific rotation of amount part is+230 ° to+235 ° of sulbactam.
Sulbactam of the applicant by the selection specific rotation scope, avocin in obtained pharmaceutical composition
And the content reduction amplitude of sulbactam is slower, relevant content of material is relatively low, and relevant content of material elevation amplitude is slower, and
When sulbactam specific rotation not in the scope required by the application when, in obtained pharmaceutical composition avocin and relax
The content of Batan sodium reduces amplitude comparatively fast, and relevant content of material is higher, and relevant content of material elevation amplitude is also very fast.
Wherein, the preparation method of the sulbactam is：（1）Under the conditions of 0-5 DEG C, lysine hydrochloride is added to Sulbactam
In sour acetone soln, and reacting solution pH value is controlled in 6.3-6.8；（2）After lysine hydrochloride completion of dropping, then by reaction solution
10-25 degree Celsius is warming up to, sodium bicarbonate solution is added in sulbactam acetone soln, control reacting solution pH value is in 6.4-
6.9；（3）After reaction finishes filtration, in three stages, the first stage, agitation and dropping entered acetone by filtrate temperature control at 18-20 DEG C, drop
Plus 5-10min；Second stage, 18-20 DEG C of stirring 30-60min, after crystal is separated out, continue agitation and dropping and enter acetone, be added dropwise third
The time of ketone is 10-15min；Crystal is finally cleaned by phase III, 10-15 DEG C of stirring 30-60min；Wherein, hydrochloric acid
Lysine adds 5-8 times that quality is sulbactam quality.Wherein, the step（3）Middle first stage mixing speed is 300-
350r/min, second stage mixing speed are 200-250r/min, and phase III mixing speed is 100-150r/min.
The application adopts above-mentioned technique to prepare the sulbactam that specific rotation is for+230 ° to+235 °, is drawn with piperazine with improving
The stability of pharmaceutical composition prepared by XiLin sodium.
Wherein, the specific rotation is that the preparation method of+232 ° to+235 ° of sulbactam is：（1）Under the conditions of 0-5 DEG C,
Lysine hydrochloride is added in sulbactam acetone soln, and reacting solution pH value is controlled in 6.5-6.8；（2）Lysine hydrochloride
After completion of dropping, then reaction solution is warming up to 10-25 degree Celsius, sodium bicarbonate solution is added to sulbactam acetone soln
In, control reacting solution pH value is in 6.6-6.9；（3）After reaction finishes filtration, in three stages, filtrate temperature control is existed by the first stage
19-20 DEG C, agitation and dropping enters acetone, and mixing speed is 300-330r/min, and 5-8min is added dropwise；Second stage, 18-19 DEG C of stirring
42-60min, mixing speed are 320-350r/min, after crystal is separated out, continue agitation and dropping and enter acetone, be added dropwise acetone when
Between be 10-13min；Phase III, 10-13 DEG C of stirring 42-60min, mixing speed is 100-130r/min, finally washes crystal
Net；Wherein, lysine hydrochloride adds 5-7 times that quality is sulbactam quality.
Wherein, the specific rotation is that the preparation method of+233 ° of sulbactam is：（1）Under the conditions of 0-5 DEG C, by hydrochloric acid
Lysine is added in sulbactam acetone soln, and controls reacting solution pH value 6.6；（2）After lysine hydrochloride completion of dropping,
Reaction solution is warming up to 10-25 degree Celsius again, sodium bicarbonate solution is added in sulbactam acetone soln, control reaction is molten
Liquid pH value is 6.7；（3）After reaction finishes filtration, in three stages, the first stage, agitation and dropping entered third by filtrate temperature control at 19 DEG C
Ketone, mixing speed are 320r/min, and 7min is added dropwise；Second stage, 19 DEG C of stirring 48min, mixing speed is 330r/min, treats crystalline substance
After body is separated out, continue agitation and dropping and enter acetone, the time that acetone is added dropwise is 12min；Phase III, 12 DEG C of stirring 48min, stirring
Speed is 120r/min, finally cleans crystal；Wherein, lysine hydrochloride adds quality for the 6.5 of sulbactam quality
Times.The sulbactam prepared using above-mentioned technique, then prepared pharmaceutical composition after powder is mixed with avocin, its stability is most
Good, and relevant content of material is minimum.
Wherein, the specific rotation is that the preparation method of+234 ° of sulbactam is：（1）Under the conditions of 0-5 DEG C, by hydrochloric acid
Lysine is added in sulbactam acetone soln, and controls reacting solution pH value 6.7；（2）After lysine hydrochloride completion of dropping,
Reaction solution is warming up to 10-25 degree Celsius again, sodium bicarbonate solution is added in sulbactam acetone soln, control reaction is molten
Liquid pH value is 6.8；（3）After reaction finishes filtration, in three stages, the first stage, agitation and dropping entered third by filtrate temperature control at 20 DEG C
Ketone, mixing speed are 310r/min, and 6min is added dropwise；Second stage, 18 DEG C of stirring 54min, mixing speed is 340r/min, treats crystalline substance
After body is separated out, continue agitation and dropping and enter acetone, the time that acetone is added dropwise is 11min；Phase III, 11 DEG C of stirring 54min, stirring
Speed is 110r/min, finally cleans crystal；Wherein, lysine hydrochloride adds 6 times that quality is sulbactam quality.
Wherein, the specific rotation is that the preparation method of+235 ° of sulbactam is：（1）Under the conditions of 0-5 DEG C, by hydrochloric acid
Lysine is added in sulbactam acetone soln, and controls reacting solution pH value 6.8；（2）After lysine hydrochloride completion of dropping,
Reaction solution is warming up to 10-25 degree Celsius again, sodium bicarbonate solution is added in sulbactam acetone soln, control reaction is molten
Liquid pH value is 6.9；（3）After reaction finishes filtration, in three stages, the first stage, agitation and dropping entered third by filtrate temperature control at 20 DEG C
Ketone, mixing speed are 300r/min, and 5min is added dropwise；Second stage, 18 DEG C of stirring 60min, mixing speed is 350r/min, treats crystalline substance
After body is separated out, continue agitation and dropping and enter acetone, the time that acetone is added dropwise is 10min；Phase III, 10 DEG C of stirring 60min, stirring
Speed is 100r/min, finally cleans crystal；Wherein, lysine hydrochloride adds 5 times that quality is sulbactam quality.
Wherein, the specific rotation is that the preparation method of+232 ° of sulbactam is：（1）Under the conditions of 0-5 DEG C, by hydrochloric acid
Lysine is added in sulbactam acetone soln, and controls reacting solution pH value 6.5；（2）After lysine hydrochloride completion of dropping,
Reaction solution is warming up to 10-25 degree Celsius again, sodium bicarbonate solution is added in sulbactam acetone soln, control reaction is molten
Liquid pH value is 6.6；（3）After reaction finishes filtration, in three stages, the first stage, agitation and dropping entered third by filtrate temperature control at 19 DEG C
Ketone, mixing speed are 330r/min, and 8min is added dropwise；Second stage, 19 DEG C of stirring 42min, mixing speed is 320r/min, treats crystalline substance
After body is separated out, continue agitation and dropping and enter acetone, the time that acetone is added dropwise is 13min；Phase III, 13 DEG C of stirring 42min, stirring
Speed is 130r/min, finally cleans crystal；Wherein, lysine hydrochloride adds 7 times that quality is sulbactam quality.
Wherein, the preparation method of the avocin is：（One）At 20-25 DEG C, sodium acid carbonate is added Piperacillin
Be stirred continuously in acid, and reaction solution pH is controlled for 5.5-6.0；（Two）After reaction terminates, add ethanol and be stirred continuously 10min
Afterwards, while using infrared radiation 3-5min, continue stirring 30-60min and obtain crystal.
Wherein, the preferred 2.5-3.5 weight portions of the avocin, further preferred 3.5 weight portion.
Wherein, described pharmaceutical composition is injectable drug.One skilled in the art will appreciate that injecting drug use, is directly to note
The formulation in human body is injected, its security is most important.And the effect and security for how improving injecting drug use always is
Pharmaceutical producing enterprise wishes that the problem for solving, the effect of injecting drug use and safety are mainly solved in terms of two, and one is that prescription sets
Meter guarantees medication effect and safety, and two is that the process for producing of medicine guarantees medication effect and safety.The application is by optimizing
The preparation technology of sulbactam, prepares the sulbactam that specific rotation is+230 ° to+235 °, except being effectively improved medicine
Outside storage stability, additionally it is possible to which effectively improve the piperacillin-sulbactam sodium combination preparation as injecting drug use uses peace
Quan Xing.
Relative to prior art, the invention has the beneficial effects as follows：Preparation technology of the present inventor by optimization sulbactam
The sulbactam that specific rotation is+230 ° to+235 ° is prepared, optimizes avocin preparation technology, be conducive to improving existing piperazine drawing
The stability of XiLin sodium and sulbactam sodium combination preparation, and use as ejection preparation safer.
Specific embodiment
For making the object, technical solutions and advantages of the present invention become more apparent, with reference to embodiment, to present invention work
Further detailed description, the exemplary embodiment of the present invention and its explanation are only used for explaining the present invention, are not intended as to originally
The restriction of invention.
Embodiment 1
Preparation method is as follows：
Prepare avocin：（One）At 20-25 DEG C, sodium acid carbonate is added and is stirred continuously in Piperacillin acid, and controlled
Reaction solution pH processed is 5.5-6.0；（Two）After reaction terminates, after adding ethanol and being stirred continuously 10min, while being shone with infrared ray
3-5min is penetrated, is continued stirring 30-60min and is obtained crystal.
Prepare sulbactam：（1）Under the conditions of 0-5 DEG C, lysine hydrochloride is added in sulbactam acetone soln, and is controlled
Reacting solution pH value processed is 6.6；（2）After lysine hydrochloride completion of dropping, then reaction solution is warming up to 10-25 degree Celsius, will
Sodium bicarbonate solution is added in sulbactam acetone soln, controls reacting solution pH value 6.7；（3）After reaction finishes filtration, point
In three stages, the first stage, agitation and dropping entered acetone by filtrate temperature control at 19 DEG C, and mixing speed is 320r/min, and 7min is added dropwise；The
Two-stage, 19 DEG C of stirring 48min, mixing speed is 330r/min, after crystal is separated out, continues agitation and dropping and enters acetone, be added dropwise
The time of acetone is 12min；Phase III, 12 DEG C of stirring 48min, mixing speed is 120r/min, finally cleans i.e. crystal
Can；Wherein, lysine hydrochloride adds 6.5 times that quality is sulbactam quality.
Automatic polarimeter is adopted to determine the specific rotation of sulbactam prepared by said method for+233 °.
The avocin of above-mentioned preparation is aseptically carried out mixed powder according to weight portion shown in table 1 with sulbactam
Process, obtain final product the pharmaceutical composition of avocin and sulbactam.
Embodiment 2
Avocin and sulbactam are prepared using technique same as Example 1, difference is, mix powder
When, avocin is different from the part by weight of sulbactam, concrete as shown in table 1.
Embodiment 3
Avocin and sulbactam are prepared using technique same as Example 1, difference is, mix powder
When, avocin is different from the part by weight of sulbactam, concrete as shown in table 1.
Embodiment 4
Avocin and sulbactam are prepared using technique same as Example 1, difference is, mix powder
When, avocin is different from the part by weight of sulbactam, concrete as shown in table 1.
Embodiment 5
Preparation method is as follows：
Prepare avocin：（One）At 20-25 DEG C, sodium acid carbonate is added and is stirred continuously in Piperacillin acid, and controlled
Reaction solution pH processed is 5.5-6.0；（Two）After reaction terminates, after adding ethanol and being stirred continuously 10min, while being shone with infrared ray
3-5min is penetrated, is continued stirring 30-60min and is obtained crystal.
Prepare sulbactam：（1）Under the conditions of 0-5 DEG C, lysine hydrochloride is added in sulbactam acetone soln, and is controlled
Reacting solution pH value processed is 6.8；（2）After lysine hydrochloride completion of dropping, then reaction solution is warming up to 10-25 degree Celsius, will
Sodium bicarbonate solution is added in sulbactam acetone soln, controls reacting solution pH value 6.9；（3）After reaction finishes filtration, point
In three stages, the first stage, agitation and dropping entered acetone by filtrate temperature control at 20 DEG C, and mixing speed is 300r/min, and 5min is added dropwise；The
Two-stage, 18 DEG C of stirring 60min, mixing speed is 350r/min, after crystal is separated out, continues agitation and dropping and enters acetone, be added dropwise
The time of acetone is 10min；Phase III, 10 DEG C of stirring 60min, mixing speed is 100r/min, finally cleans i.e. crystal
Can；Wherein, lysine hydrochloride adds 5 times that quality is sulbactam quality.
Automatic polarimeter is adopted to determine the specific rotation of sulbactam prepared by said method for+235 °.
The avocin of above-mentioned preparation is aseptically carried out mixed powder according to weight portion shown in table 1 with sulbactam
Process, obtain final product the pharmaceutical composition of avocin and sulbactam.
Embodiment 6
Preparation method is as follows：
Prepare avocin：（One）At 20-25 DEG C, sodium acid carbonate is added and is stirred continuously in Piperacillin acid, and controlled
Reaction solution pH processed is 5.5-6.0；（Two）After reaction terminates, after adding ethanol and being stirred continuously 10min, while being shone with infrared ray
3-5min is penetrated, is continued stirring 30-60min and is obtained crystal.
Prepare sulbactam：（1）Under the conditions of 0-5 DEG C, lysine hydrochloride is added in sulbactam acetone soln, and is controlled
Reacting solution pH value processed is 6.7；（2）After lysine hydrochloride completion of dropping, then reaction solution is warming up to 10-25 degree Celsius, will
Sodium bicarbonate solution is added in sulbactam acetone soln, controls reacting solution pH value 6.8；（3）After reaction finishes filtration, point
In three stages, the first stage, agitation and dropping entered acetone by filtrate temperature control at 20 DEG C, and mixing speed is 310r/min, and 6min is added dropwise；The
Two-stage, 18 DEG C of stirring 54min, mixing speed is 340r/min, after crystal is separated out, continues agitation and dropping and enters acetone, be added dropwise
The time of acetone is 11min；Phase III, 11 DEG C of stirring 54min, mixing speed is 110r/min, finally cleans i.e. crystal
Can；Wherein, lysine hydrochloride adds 6 times that quality is sulbactam quality.
Automatic polarimeter is adopted to determine the specific rotation of sulbactam prepared by said method for+234 °.
The avocin of above-mentioned preparation is aseptically carried out mixed powder according to weight portion shown in table 1 with sulbactam
Process, obtain final product the pharmaceutical composition of avocin and sulbactam.
Embodiment 7
Preparation method is as follows：
Prepare avocin：（One）At 20-25 DEG C, sodium acid carbonate is added and is stirred continuously in Piperacillin acid, and controlled
Reaction solution pH processed is 5.5-6.0；（Two）After reaction terminates, after adding ethanol and being stirred continuously 10min, while being shone with infrared ray
3-5min is penetrated, is continued stirring 30-60min and is obtained crystal.
Prepare sulbactam：（1）Under the conditions of 0-5 DEG C, lysine hydrochloride is added in sulbactam acetone soln, and is controlled
Reacting solution pH value processed is 6.5；（2）After lysine hydrochloride completion of dropping, then reaction solution is warming up to 10-25 degree Celsius, will
Sodium bicarbonate solution is added in sulbactam acetone soln, controls reacting solution pH value 6.6；（3）After reaction finishes filtration, point
In three stages, the first stage, agitation and dropping entered acetone by filtrate temperature control at 19 DEG C, and mixing speed is 330r/min, and 8min is added dropwise；The
Two-stage, 19 DEG C of stirring 42min, mixing speed is 320r/min, after crystal is separated out, continues agitation and dropping and enters acetone, be added dropwise
The time of acetone is 13min；Phase III, 13 DEG C of stirring 42min, mixing speed is 130r/min, finally cleans i.e. crystal
Can；Wherein, lysine hydrochloride adds 7 times that quality is sulbactam quality.
Automatic polarimeter is adopted to determine the specific rotation of sulbactam prepared by said method for+232 °.
The avocin of above-mentioned preparation is aseptically carried out mixed powder according to weight portion shown in table 1 with sulbactam
Process, obtain final product the pharmaceutical composition of avocin and sulbactam.
Embodiment 8
Preparation method is as follows：
Prepare avocin：（One）At 20-25 DEG C, sodium acid carbonate is added and is stirred continuously in Piperacillin acid, and controlled
Reaction solution pH processed is 5.5-6.0；（Two）After reaction terminates, after adding ethanol and being stirred continuously 10min, while being shone with infrared ray
3-5min is penetrated, is continued stirring 30-60min and is obtained crystal.
Prepare sulbactam：（1）Under the conditions of 0-5 DEG C, lysine hydrochloride is added in sulbactam acetone soln, and is controlled
Reacting solution pH value processed is 6.4；（2）After lysine hydrochloride completion of dropping, then reaction solution is warming up to 10-25 degree Celsius, will
Sodium bicarbonate solution is added in sulbactam acetone soln, controls reacting solution pH value 6.5；（3）After reaction finishes filtration, point
In three stages, the first stage, agitation and dropping entered acetone by filtrate temperature control at 18 DEG C, and mixing speed is 340r/min, and 9min is added dropwise；The
Two-stage, 20 DEG C of stirring 36min, mixing speed is 310r/min, after crystal is separated out, continues agitation and dropping and enters acetone, be added dropwise
The time of acetone is 14min；Phase III, 14 DEG C of stirring 36min, mixing speed is 140r/min, finally cleans i.e. crystal
Can；Wherein, lysine hydrochloride adds 7.5 times that quality is sulbactam quality.
Automatic polarimeter is adopted to determine the specific rotation of sulbactam prepared by said method for+231 °.
The avocin of above-mentioned preparation is aseptically carried out mixed powder according to weight portion shown in table 1 with sulbactam
Process, obtain final product the pharmaceutical composition of avocin and sulbactam.
Embodiment 9
Preparation method is as follows：
Prepare avocin：（One）At 20-25 DEG C, sodium acid carbonate is added and is stirred continuously in Piperacillin acid, and controlled
Reaction solution pH processed is 5.5-6.0；（Two）After reaction terminates, after adding ethanol and being stirred continuously 10min, while being shone with infrared ray
3-5min is penetrated, is continued stirring 30-60min and is obtained crystal.
Prepare sulbactam：（1）Under the conditions of 0-5 DEG C, lysine hydrochloride is added in sulbactam acetone soln, and is controlled
Reacting solution pH value processed is 6.3；（2）After lysine hydrochloride completion of dropping, then reaction solution is warming up to 10-25 degree Celsius, will
Sodium bicarbonate solution is added in sulbactam acetone soln, controls reacting solution pH value 6.4；（3）After reaction finishes filtration, point
In three stages, the first stage, agitation and dropping entered acetone by filtrate temperature control at 18 DEG C, and mixing speed is 350r/min, and 10min is added dropwise；
Second stage, 20 DEG C of stirring 30min, mixing speed is 300r/min, after crystal is separated out, continues agitation and dropping and enters acetone, drip
Plus the time of acetone is 15min；Phase III, 15 DEG C of stirring 30min, mixing speed is 150r/min, finally cleans crystal
?；Wherein, lysine hydrochloride adds 8 times that quality is sulbactam quality.
Automatic polarimeter is adopted to determine the specific rotation of sulbactam prepared by said method for+230 °.
The avocin of above-mentioned preparation is aseptically carried out mixed powder according to weight portion shown in table 1 with sulbactam
Process, obtain final product the pharmaceutical composition of avocin and sulbactam.
For verifying performance impact of the sulbactam of different specific rotations to pharmaceutical composition, selection is several not to exist the applicant
The sulbactam in the range of specific rotation required by the application makes pharmaceutical composition with the mixed powder of avocin（In table 1
Shown in comparative example 1-7）, and keep sulbactam identical with the part by weight of avocin, pharmaceutical composition is carried out stable
Property and the related experiment about material.
Performance detection：Instruct according to two annex of Chinese Pharmacopoeia version in 2010, Ⅺ Ⅹ С pharmaceutical preparations stability test former
The related request of Ⅺ Ⅹ F medicine impurity analysis guidelines of related request and annex then, investigates pharmaceutical composition at 25 DEG C
Place 12 months, 40 DEG C of stability for placing 6 months and relevant content of material.
Table 1 is filled a prescription
2 25 DEG C of stability tests of table, sulbactam content（%）
3 25 DEG C of stability tests of table, Piperacillin sodium content（%）
4 25 DEG C of stability tests of table, relevant content of material（%）
5 40 DEG C of stability tests of table, sulbactam content（%）
6 40 DEG C of stability tests of table, Piperacillin sodium content（%）
7 40 DEG C of stability tests of table, relevant content of material（%）
Content in above-mentioned table 2 and table 5 is to add the amount of sulbactam raw material to be calculated as radix, such as adds
Measure as 1g, the amount for measuring sulbactam after 3 months is 0.994g, then after March, sulbactam content is 994%；In the same manner, table 3 and
Content in table 6 is to add the amount of Piperacillin sodium raw materials to be calculated as radix.Test data in above-mentioned each table
In, the test value of partial data is more than 100%, but still in effective error scope, therefore, is considered as valid data.
By above-described embodiment 1-9, it can be seen that piperacillin-sulbactam sodium medicine prepared by technique of the present invention
Composition storage stability is good, and injection is safe to use, and 25 DEG C of stability test shows, after storing 12 months, Shu Ba
Smooth sodium content is about 98.5-99.6%, and Piperacillin sodium content is about 99.2-99.5%, and relevant content of material is less than 0.59%, miscellaneous
Matter content is relatively low；40 DEG C of stability tests show that, after storing 6 months, sulbactam content is about 98.6-99.8%, Piperacillin
Sodium content is about 97.8-99.0%, and relevant content of material is less than 0.61%, and impurity content is still relatively low.Compared with comparative example 1-7, no
Pipe is storage stability or impurity content, and the pharmaceutical composition in scope required by the application is respectively provided with more preferably effect.
By contrasting above-described embodiment 4-9 and comparative example 1-7, the applicant's fixation avocin is added with sulbactam
Dosage, contrasts the sulbactam of different specific rotations prepared by different process, the impact to medicine stability and impurity content.When easypro
When the specific rotation of Batan sodium is in the scope required by the application, avocin and sulbactam in obtained pharmaceutical composition
Content reduce that amplitude is slower, relevant content of material is relatively low, and relevant content of material elevation amplitude is slower, and works as sulbactam
Specific rotation not in the scope required by the application when, in obtained pharmaceutical composition, avocin and sulbactam contains
Amount reduction amplitude is very fast, and relevant content of material is higher, and relevant content of material elevation amplitude is also very fast.
The performance of pharmaceutical composition obtained in filling a prescription from above-described embodiment 1-9 as can be seen that shown in embodiment 4-6 is more
Good, especially obtained in formula shown in embodiment 4, the performance of pharmaceutical composition is optimal.
Above-described specific embodiment, has been carried out further to the purpose of the present invention, technical scheme and beneficial effect
Describe in detail, the be should be understood that specific embodiment that the foregoing is only the present invention is not intended to limit the present invention
Protection domain, all any modification, equivalent substitution and improvements that within the spirit and principles in the present invention, is done etc. all should include
Within protection scope of the present invention.
Claims (9)
1. the pharmaceutical composition of a kind of avocin and sulbactam, it is characterised in that including the Piperacillin of 3.5 weight portions
The specific rotation of sodium and 1 weight portion is+230 ° to+235 ° of sulbactam；The preparation method of the sulbactam is：(1) exist
Under the conditions of 0-5 DEG C, lysine hydrochloride is added in sulbactam acetone soln, and reacting solution pH value is controlled in 6.3-6.8；
(2) after lysine hydrochloride completion of dropping, then reaction solution is warming up to 10-25 degree Celsius, sodium bicarbonate solution is added to Shu Ba
In smooth sour acetone soln, control reacting solution pH value is in 6.4-6.9；(3) after reaction finishes filtration, in three stages, the first stage
By filtrate temperature control at 18-20 DEG C, agitation and dropping enters acetone, and 5-10min is added dropwise；Second stage, 18-20 DEG C of stirring 30-60min,
After crystal is separated out, continue agitation and dropping and enter acetone, the time that acetone is added dropwise is 10-15min；Phase III, 10-15 DEG C of stirring
Crystal is finally cleaned by 30-60min；Wherein, lysine hydrochloride adds 5-8 times that quality is sulbactam quality.
2. pharmaceutical composition according to claim 1, it is characterised in that first stage mixing speed in step (3)
For 300-350r/min, second stage mixing speed is 200-250r/min, and phase III mixing speed is 100-150r/min.
3. pharmaceutical composition according to claim 1, it is characterised in that the preparation method of the avocin is：
(1) at 20-25 DEG C, sodium acid carbonate is added and is stirred continuously in Piperacillin acid, and reaction solution pH is controlled for 5.5-6.0；
(2), after reaction terminates, after adding ethanol and being stirred continuously 10min, while using infrared radiation 3-5min, continue stirring 30-
60min obtains crystal.
4. pharmaceutical composition according to claim 2, it is characterised in that the specific rotation is preferably+232 ° to+235, institute
The preparation method for stating the sulbactam that specific rotation is+232 ° to+235 ° is：(1) under the conditions of 0-5 DEG C, by lysine hydrochloride plus
Into sulbactam acetone soln, and reacting solution pH value is controlled in 6.5-6.8；(2) after lysine hydrochloride completion of dropping, then will
Reaction solution is warming up to 10-25 degree Celsius, and sodium bicarbonate solution is added in sulbactam acetone soln, controls reaction solution pH
Value is in 6.6-6.9；(3), after reaction finishes filtration, in three stages, the first stage, agitation and dropping entered by filtrate temperature control at 19-20 DEG C
Acetone, mixing speed are 300-330r/min, and 5-8min is added dropwise；Second stage, 18-19 DEG C of stirring 42-60min, mixing speed
For 320-350r/min, after crystal is separated out, continue agitation and dropping and enter acetone, the time that acetone is added dropwise is 10-13min；3rd
Stage, 10-13 DEG C of stirring 42-60min, mixing speed is 100-130r/min, finally cleans crystal；Wherein, hydrochloric acid
Lysine adds 5-7 times that quality is sulbactam quality.
5. pharmaceutical composition according to claim 4, it is characterised in that the specific rotation is preferably+233 °, described than rotation
The preparation method for spending the sulbactam for+233 ° is：(1) under the conditions of 0-5 DEG C, lysine hydrochloride is added to sulbactam acetone
In solution, and reacting solution pH value is controlled 6.6；(2) after lysine hydrochloride completion of dropping, then reaction solution is warming up to 10-
, sodium bicarbonate solution is added in sulbactam acetone soln, reacting solution pH value is controlled 6.7 by 25 degrees Celsius；(3) reacted
Finish after filtering, in three stages, the first stage, agitation and dropping entered acetone by filtrate temperature control at 19 DEG C, and mixing speed is 320r/min,
7min is added dropwise；Second stage, 19 DEG C of stirring 48min, mixing speed is 330r/min, after crystal is separated out, continues agitation and dropping
Enter acetone, the time that acetone is added dropwise is 12min；Phase III, 12 DEG C of stirring 48min, mixing speed is 120r/min, finally will
Crystal is cleaned；Wherein, lysine hydrochloride adds 6.5 times that quality is sulbactam quality.
6. pharmaceutical composition according to claim 4, it is characterised in that the specific rotation is preferably+234 °, described than rotation
The preparation method for spending the sulbactam for+234 ° is：(1) under the conditions of 0-5 DEG C, lysine hydrochloride is added to sulbactam acetone
In solution, and reacting solution pH value is controlled 6.7；(2) after lysine hydrochloride completion of dropping, then reaction solution is warming up to 10-
, sodium bicarbonate solution is added in sulbactam acetone soln, reacting solution pH value is controlled 6.8 by 25 degrees Celsius；(3) reacted
Finish after filtering, in three stages, the first stage, agitation and dropping entered acetone by filtrate temperature control at 20 DEG C, and mixing speed is 310r/min,
6min is added dropwise；Second stage, 18 DEG C of stirring 54min, mixing speed is 340r/min, after crystal is separated out, continues agitation and dropping
Enter acetone, the time that acetone is added dropwise is 11min；Phase III, 11 DEG C of stirring 54min, mixing speed is 110r/min, finally will
Crystal is cleaned；Wherein, lysine hydrochloride adds 6 times that quality is sulbactam quality.
7. pharmaceutical composition according to claim 4, it is characterised in that the specific rotation is preferably+235 °, described than rotation
The preparation method for spending the sulbactam for+235 ° is：(1) under the conditions of 0-5 DEG C, lysine hydrochloride is added to sulbactam acetone
In solution, and reacting solution pH value is controlled 6.8；(2) after lysine hydrochloride completion of dropping, then reaction solution is warming up to 10-
, sodium bicarbonate solution is added in sulbactam acetone soln, reacting solution pH value is controlled 6.9 by 25 degrees Celsius；(3) reacted
Finish after filtering, in three stages, the first stage, agitation and dropping entered acetone by filtrate temperature control at 20 DEG C, and mixing speed is 300r/min,
5min is added dropwise；Second stage, 18 DEG C of stirring 60min, mixing speed is 350r/min, after crystal is separated out, continues agitation and dropping
Enter acetone, the time that acetone is added dropwise is 10min；Phase III, 10 DEG C of stirring 60min, mixing speed is 100r/min, finally will
Crystal is cleaned；Wherein, lysine hydrochloride adds 5 times that quality is sulbactam quality.
8. pharmaceutical composition according to claim 4, it is characterised in that the specific rotation is preferably+232 °, described than rotation
The preparation method for spending the sulbactam for+232 ° is：(1) under the conditions of 0-5 DEG C, lysine hydrochloride is added to sulbactam acetone
In solution, and reacting solution pH value is controlled 6.5；(2) after lysine hydrochloride completion of dropping, then reaction solution is warming up to 10-
, sodium bicarbonate solution is added in sulbactam acetone soln, reacting solution pH value is controlled 6.6 by 25 degrees Celsius；(3) reacted
Finish after filtering, in three stages, the first stage, agitation and dropping entered acetone by filtrate temperature control at 19 DEG C, and mixing speed is 330r/min,
8min is added dropwise；Second stage, 19 DEG C of stirring 42min, mixing speed is 320r/min, after crystal is separated out, continues agitation and dropping
Enter acetone, the time that acetone is added dropwise is 13min；Phase III, 13 DEG C of stirring 42min, mixing speed is 130r/min, finally will
Crystal is cleaned；Wherein, lysine hydrochloride adds 7 times that quality is sulbactam quality.
9. pharmaceutical composition according to any one of claim 1 to 8, it is characterised in that described pharmaceutical composition is note
Penetrate and use medicine.
Priority Applications (2)
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|---|---|---|---|
| CN201610001023.3A CN105640958B (en) | 2016-01-04 | 2016-01-04 | A kind of avocin and the pharmaceutical composition of sulbactam |
| PCT/CN2016/078923 WO2017117882A1 (en) | 2016-01-04 | 2016-04-11 | Pharmaceutical composition of piperacillin sodium and sulbactam sodium |
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| CN201610001023.3A CN105640958B (en) | 2016-01-04 | 2016-01-04 | A kind of avocin and the pharmaceutical composition of sulbactam |
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| CN101322702A (en) * | 2008-08-01 | 2008-12-17 | 海南百那医药发展有限公司 | Piperacillin sodium and sulbactam sodium for injection and preparation of freeze-dried injection thereof |
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| CN101062032B (en) * | 2006-04-25 | 2011-06-08 | 刘祥华 | Sulbactam sodium bacteriophage complex and the preparing method thereof |
| CN101890014B (en) * | 2010-07-29 | 2012-05-23 | 胡建荣 | Piperacillin-sulbactam sodium medicinal composition liposome injection |
| CN103012429B (en) * | 2012-12-28 | 2014-12-31 | 吴秋萍 | Novel amoxicillin sodium compound and composition of amoxicillin sodium compound and sulbactam sodium compound |
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| CN101322702A (en) * | 2008-08-01 | 2008-12-17 | 海南百那医药发展有限公司 | Piperacillin sodium and sulbactam sodium for injection and preparation of freeze-dried injection thereof |
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| Title |
|---|
| 复方抗生素哌拉西林钠舒巴坦钠的研究进展;王霆等;《医学理论与实践》;20111231;第24卷(第2期);150-152 * |
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