CN103271883B - Preparation method for pazufloxacin mesilate for injection - Google Patents
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- CN103271883B CN103271883B CN201310215346.9A CN201310215346A CN103271883B CN 103271883 B CN103271883 B CN 103271883B CN 201310215346 A CN201310215346 A CN 201310215346A CN 103271883 B CN103271883 B CN 103271883B
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Abstract
The invention provides a preparation method for pazufloxacin mesilate for injection. The preparation method comprises the following steps of: preparing the pazufloxacin mesilate and mannitol according to a prescription, and regulating pH values to be 3.0-4.0; adding a proper amount of needle active carbon, heating the mixture to be 70-80 DEG C, and carrying out decoloring after stirring for 15-20 minutes; putting an encapsulated semi-finished product into a freezing vacuum drier, controlling the temperature to be below -30 DEG C and carrying out prefreezing for 1-1.5 hours; when the temperature of a cold trap of the drier is lower than -40 DEG C, vacuumizing until the pressure is 20 Pa, and carrying out constant-temperature drying for 0.5-1 hour; raising the temperature of a separation board of the drier to be -10 DEG C, carrying out the constant-temperature drying for 0.5-1 hour; and raising the temperature of the separation board to be 0 DEG C, carrying out the constant-temperature drying until the waterline of the product reaches the bottom, raising the temperature to be 10 DEG C in a temperature manner, after carrying out the constant-temperature drying until the temperature of the product approximates to 0 DEG C, raising the temperature of the separation board to be 35 DEG C, and judging that the product is qualified after carrying out the constant-temperature drying until reaching the end point. The preparation method has the advantages that the production cost is lowered and the product quality is improved and is more suitable for industrial production.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, relate to a kind of preparation method of Pazufloxacin Mesilate for Injection.
Background technology
Pazufloxacin Mesilate is forth generation Comprecin, is widely used in respiratory tract infection, urogenital infections, surgical infection etc.Its curative effect of Pazufloxacin Mesilate clinical studies show is better than the kinds such as levofloxacin, ofloxacin and ciprofloxacin on domestic market, the carbostyril family antibacterial drugs of Pazufloxacin Mesilate more domestic normal use clinically all in antimicrobial spectrum, antibacterial activity, drug resistance, safety makes moderate progress, and potential applicability in clinical practice is boundless.
Pazufloxacin Mesilate for Injection (Pazufloxacin Mesilate for Injection), chemical structural formula is as follows:
。
The aseptic freeze-dried powder of Pazufloxacin Mesilate for Injection, has not oxidizable, is beneficial to the feature of long storage periods, obtains a wide range of applications in practice.
At present, in process of production, the sublimation time of freeze-dry process is oversize for Pazufloxacin Mesilate for Injection production technology, and cost waste is excessive.How to solve this technical barrier, become the focus of research.
Summary of the invention
The object of the invention is for the deficiencies in the prior art, a kind of preparation method of Pazufloxacin Mesilate for Injection is provided.This preparation method is by the optimization to technological parameters such as temperature, achieve the shortening of freeze-dry process process time, shorten the production cycle, to reduce low, the obtained product inspection quality of production run cost high, can be used for the suitability for industrialized production of Pazufloxacin Mesilate for Injection.
For achieving the above object, the technical solution adopted for the present invention to solve the technical problems is:
The preparation method of Pazufloxacin Mesilate for Injection, comprises following steps:
A, get the Pazufloxacin Mesilate of recipe quantity, inject dissolving of blunging, add the mannitol of recipe quantity, stirring and dissolving, regulate between medicinal liquid pH value to 3.0 ~ 4.0, add to the full amount of water for injection;
B, add appropriate needle-use activated carbon, heating medicinal liquid to 70 ~ 80 DEG C, stirs decolouring in 15 minutes, coarse filtration removes charcoal, filtration sterilization, detection intermediate, embedding;
C, later half for fill semi-finished product of jumping a queue are placed in lyophilizer, products temperature are controlled below-30 DEG C, be incubated pre-freeze 1 hour;
D, when exsiccator condenser temperature is lower than less than-40 DEG C, carry out evacuation, to case, vacuum is at 20Pa, and baffle temperature is risen to-20 DEG C, and-20 DEG C of freeze-day with constant temperature 0.5 hour;
E, exsiccator baffle temperature is risen to-10 DEG C, and freeze-day with constant temperature 0.5 hour at this temperature; Continue baffle temperature to be increased to 0 DEG C, after freeze-day with constant temperature to goods waterline sees the bottom, gradient increased temperature to 10 DEG C, and freeze-day with constant temperature to products temperature close to after 0 DEG C, baffle temperature is risen to 35 DEG C, it is qualified that freeze-day with constant temperature judges to terminal.
As optimal way, in described step C, the insulation pre-freeze time is 1 hour.
As optimal way, in described step D, the freeze-day with constant temperature time is 0.5 hour.
As optimal way, in described step e, at-10 DEG C of these temperature, the freeze-day with constant temperature time is 0.5 hour.
Inventor has carried out large quantifier elimination to the preparation method of Pazufloxacin Mesilate for Injection, has done improvement many times to existing method, but does not finally solve its technical problem.Afterwards, by experiment many times, inventor finds unexpectedly, improve freeze-dry process and adopt the method described in the present invention, the shortening of freeze-dry process process time, shorten the production cycle, to reduce low, the obtained product inspection quality of production run cost high, achieve unexpected technique effect.
The present invention is under the prerequisite not changing product property, only existing Pazufloxacin Mesilate for Injection freeze-dry process is improved, all the other each processes are all produced by former technique, and product quality prepared by the inventive method is better than existing product and freeze-dry process is repeated, good stability.
The freeze-drying curve of existing Pazufloxacin Mesilate for Injection preparation method can be found out, whole freeze-drying process takes 36.83 hours, the whole freeze-drying process of freeze-drying curve of the present invention only takes 25 hours, in the optimization of products temperature, condenser temperature, vacuum in the optimization of rate of temperature fall and pre-freezing temperature in pre-freeze process, primary drying, redrying, final flaggy temperature controls, whole freeze-drying process time shorten, production cost reduces, product quality is more excellent, is more suitable for Pazufloxacin Mesilate for Injection suitability for industrialized production.
Beneficial effect of the present invention is: the present invention is by the optimization to technological parameters such as temperature, achieve the shortening of freeze-dry process process time, shorten the production cycle, to reduce low, the obtained product inspection quality of production run cost high, can be used for the suitability for industrialized production of Pazufloxacin Mesilate for Injection.
Accompanying drawing explanation
Examples of the present invention will be described by way of reference to the accompanying drawings, wherein:
Fig. 1 is prior art freeze-dry process curve;
Fig. 2 is freeze-dry process curve of the present invention.
Detailed description of the invention
All features disclosed in this description, or the step in disclosed all methods or process, except mutually exclusive feature and/or step, all can combine by any way.
Arbitrary feature disclosed in this description, unless specifically stated otherwise, all can be replaced by other equivalences or the alternative features with similar object.That is, unless specifically stated otherwise, each feature is an example in a series of equivalence or similar characteristics.
Comparative example: the preparation method of Pazufloxacin Mesilate for Injection, its prescription is as follows:
Pazufloxacin Mesilate (in Pazufloxacin): 390.6g
Mannitol: 60g
0.1mol/L hydrochloric acid pH regulator to 3.0 ~ 4.0
Water for injection adds to 2000ml
Make 1000 bottles altogether
Preparation method is as follows:
1, precision takes the principal agent Pazufloxacin Mesilate of recipe quantity 390.6g, injects by water 2000ml stirring and dissolving.
2, the mannitol of recipe quantity 60g is added, stirring and dissolving;
3, regulate between medicinal liquid pH value to 3.0 ~ 4.0 with 0.1mol/LHCl solution, add to the full amount of water for injection;
4, add appropriate needle-use activated carbon, be heated to 70 ~ 80 DEG C and stir decolouring in 15 minutes, coarse filtration removes charcoal;
5, degerming with 0.22 μm of filtering with microporous membrane;
6, intermediate character, pH and content is detected;
7, detect qualified rear beginning subpackage, lyophilizing, wherein step of freeze drying is:
Later half for fill semi-finished product of jumping a queue are placed on the shelf of frozen vacuum dryer by a on request, carry out refrigeration to-40-45 DEG C to shelf, ensure that product temperature to freeze to eutectic point lower about 20 DEG C, and make product at such a temperature pre-freeze within 2 hours, make product fully charge;
B freezes to cold-trap in good time, after condenser temperature is lower than-40 DEG C, start evacuation;
C, after vacuum arrives below 20Pa, starts distillation; Slowly be warming up to-10 DEG C, and be slowly warming up to 2 DEG C, constant temperature about 550 minutes-10 DEG C of constant temperature distillations, once distil end;
D is slowly warming up to 15 DEG C, and constant temperature is slowly warming up to 30 DEG C after being about 1-2 hour again, constant temperature to product temperature close to the highest platform temperature 30 DEG C, vacuum reach zero load under end vacuum after terminate redrying according to endpoint; Endpoint raises according to pressure in vacuum 3 minutes and is less than 5Pa.Tamponade, rolls lid, lamp inspection, packaging.
Product quality data are in table 1.
Embodiment 1: the preparation method of Pazufloxacin Mesilate for Injection, its prescription is as follows:
Pazufloxacin Mesilate (in Pazufloxacin): 390.6g
Mannitol: 60g
0.1mol/L hydrochloric acid pH regulator to 3.0 ~ 4.0
Water for injection adds to 2000ml
Make 1000 bottles altogether
Its preparation method is as follows:
1, precision takes the principal agent Pazufloxacin Mesilate of recipe quantity 390.6g, injects by water 2000ml stirring and dissolving.
2, the mannitol of recipe quantity 60g is added, stirring and dissolving;
3, regulate between medicinal liquid pH value to 3.0 ~ 4.0 with 0.1mol/LHCl solution, add to the full amount of water for injection;
4, add appropriate needle-use activated carbon, be heated to 70 ~ 80 DEG C and stir decolouring in 15 minutes, coarse filtration removes charcoal;
5, degerming with 0.22 μm of filtering with microporous membrane;
6, intermediate character, pH and content is detected;
7, detect qualified rear beginning subpackage, lyophilizing, wherein step of freeze drying is:
Later half for fill semi-finished product of jumping a queue are placed in lyophilizer by a, and baffle temperature is cooled to-40 DEG C, are incubated pre-freeze 1 hour after products temperature is below-30 DEG C;
B is in good time to cold-trap refrigeration, and when condenser temperature is lower than less than-40 DEG C, carry out evacuation, to case, vacuum is at about 20Pa, and baffle temperature is risen to-20 DEG C, and at-20 DEG C of freeze-day with constant temperature 0.5 hours;
Baffle temperature is risen to-10 DEG C by c again, and freeze-day with constant temperature 0.5 hours at this temperature; Continue baffle temperature to be increased to 0 DEG C, and after freeze-day with constant temperature to goods waterline sees the bottom at such a temperature, gradient increased temperature to 10 DEG C, and at 10 DEG C freeze-day with constant temperature to products temperature close to after 0 DEG C, baffle temperature is risen to 35 DEG C, freeze-day with constant temperature judge to terminal qualified after, tamponade, roll lid, lamp inspection, packaging.
Product quality data are in table 1.
Embodiment 2: the preparation method of Pazufloxacin Mesilate for Injection, its prescription is as follows:
Pazufloxacin Mesilate (in Pazufloxacin): 390.6g
Mannitol: 60g
0.1mol/L hydrochloric acid pH regulator to 3.0 ~ 4.0
Water for injection adds to 2000ml
Make 1000 bottles altogether
Its preparation method is as follows:
1, precision takes the principal agent Pazufloxacin Mesilate of recipe quantity 390.6g, injects by water 2000ml stirring and dissolving.
2, the mannitol of recipe quantity 60g is added, stirring and dissolving;
3, regulate between medicinal liquid pH value to 3.0 ~ 4.0 with 0.1mol/LHCl solution, add to the full amount of water for injection;
4, add appropriate needle-use activated carbon, be heated to 70 ~ 80 DEG C and stir decolouring in 20 minutes, coarse filtration removes charcoal;
5, degerming with 0.22 μm of filtering with microporous membrane;
6, intermediate character, pH and content is detected;
7, detect qualified rear beginning subpackage, lyophilizing, wherein step of freeze drying is:
Later half for fill semi-finished product of jumping a queue are placed in lyophilizer by a, and baffle temperature is cooled to-40 DEG C, are incubated pre-freeze 1.5 hours after products temperature is below-30 DEG C;
B is in good time to cold-trap refrigeration, and when condenser temperature is lower than less than-40 DEG C, carry out evacuation, to case, vacuum is at about 20Pa, and baffle temperature is risen to-20 DEG C, and at-20 DEG C of freeze-day with constant temperature 1 hours;
Baffle temperature is risen to-10 DEG C by c again, and freeze-day with constant temperature 1 hours at this temperature; Continue baffle temperature to be increased to 0 DEG C, and after freeze-day with constant temperature to goods waterline sees the bottom at such a temperature, gradient increased temperature to 10 DEG C, and at 10 DEG C freeze-day with constant temperature to products temperature close to after 0 DEG C, baffle temperature is risen to 35 DEG C, freeze-day with constant temperature judge to terminal qualified after, tamponade, roll lid, lamp inspection, packaging.
Product quality data are in table 1.
Embodiment 3: the preparation method of Pazufloxacin Mesilate for Injection, its prescription is as follows:
Pazufloxacin Mesilate (in Pazufloxacin): 390.6g
Mannitol: 60g
0.1mol/L hydrochloric acid pH regulator to 3.0 ~ 4.0
Water for injection adds to 2000ml
Make 1000 bottles altogether
Its preparation method is as follows:
1, precision takes the principal agent Pazufloxacin Mesilate of recipe quantity 390.6g, injects by water 2000ml stirring and dissolving.
2, the mannitol of recipe quantity 60g is added, stirring and dissolving;
3, regulate between medicinal liquid pH value to 3.0 ~ 4.0 with 0.1mol/LHCl solution, add to the full amount of water for injection;
4, add appropriate needle-use activated carbon, be heated to 70 ~ 80 DEG C and stir decolouring in 18 minutes, coarse filtration removes charcoal;
5, degerming with 0.22 μm of filtering with microporous membrane;
6, intermediate character, pH and content is detected;
7, detect qualified rear beginning subpackage, lyophilizing, wherein step of freeze drying is:
Later half for fill semi-finished product of jumping a queue are placed in lyophilizer by a, and baffle temperature is cooled to-40 DEG C, are incubated pre-freeze 1.2 hours after products temperature is below-30 DEG C;
B is in good time to cold-trap refrigeration, and when condenser temperature is lower than less than-40 DEG C, carry out evacuation, to case, vacuum is at about 20Pa, and baffle temperature is risen to-20 DEG C, and at-20 DEG C of freeze-day with constant temperature 0.8 hours;
Baffle temperature is risen to-10 DEG C by c again, and freeze-day with constant temperature 0.8 hours at this temperature; Continue baffle temperature to be increased to 0 DEG C, and after freeze-day with constant temperature to goods waterline sees the bottom at such a temperature, gradient increased temperature to 10 DEG C, and at 10 DEG C freeze-day with constant temperature to products temperature close to after 0 DEG C, baffle temperature is risen to 35 DEG C, freeze-day with constant temperature judge to terminal qualified after, tamponade, roll lid, lamp inspection, packaging.
Product quality data are in table 1.
The product quality contrast table of comparative example and embodiment sees the following form:
Table 1 product quality contrast table
Can be found out by the product quality contrast table of comparative example and embodiment, Pazufloxacin Mesilate for Injection product prepared by the inventive method is every all meets related request, and significantly better than comparative example on the key index such as impurity content, active constituent content, achieve beyond thought technique effect.
The present invention is not limited to aforesaid detailed description of the invention.The present invention expands to any new feature of disclosing in this manual or any combination newly, and the step of the arbitrary new method disclosed or process or any combination newly.
Claims (1)
1. the preparation method of Pazufloxacin Mesilate for Injection, is characterized in that, comprises following steps:
A, get 390.6g Pazufloxacin Mesilate, inject dissolving of blunging, add 60g mannitol, stirring and dissolving, regulate between medicinal liquid pH value to 3.0 ~ 4.0, inject water to 2000ml;
B, add appropriate needle-use activated carbon, heating medicinal liquid to 70 ~ 80 DEG C, stirs decolouring in 15-20 minute, coarse filtration removes charcoal, filtration sterilization, detection intermediate, embedding;
C, later half for fill semi-finished product of jumping a queue are placed in lyophilizer, products temperature are controlled below-30 DEG C, be incubated pre-freeze 1 hour;
D, when exsiccator condenser temperature is lower than less than-40 DEG C, carry out evacuation, to case, vacuum is at 20Pa, and baffle temperature is risen to-20 DEG C, and-20 DEG C of freeze-day with constant temperature 0.5 hour;
E, exsiccator baffle temperature is risen to-10 DEG C, and freeze-day with constant temperature 0.5 hour at this temperature, baffle temperature is continued to be increased to 0 DEG C, after freeze-day with constant temperature to goods waterline sees the bottom, gradient increased temperature to 10 DEG C, and freeze-day with constant temperature to products temperature close to after 0 DEG C, baffle temperature is risen to 35 DEG C, it is qualified that freeze-day with constant temperature judges to terminal.
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