CN103239415A - Preparation method of pemetrexed disodium freeze-dried formulation for injection - Google Patents
Preparation method of pemetrexed disodium freeze-dried formulation for injection Download PDFInfo
- Publication number
- CN103239415A CN103239415A CN2012101559413A CN201210155941A CN103239415A CN 103239415 A CN103239415 A CN 103239415A CN 2012101559413 A CN2012101559413 A CN 2012101559413A CN 201210155941 A CN201210155941 A CN 201210155941A CN 103239415 A CN103239415 A CN 103239415A
- Authority
- CN
- China
- Prior art keywords
- pemetrexed disodium
- preparation
- temperature
- freeze
- speed
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of a pemetrexed disodium freeze-dried formulation for injection, and the preparation method comprises the following steps of: A, pre-freezing: firstly reducing the temperature of a pemetrexed disodium solution to -10+/-2 DEG C, then reducing the temperature of heat-conducting oil to -40+/-2 DEG C at the speed of 1 DEG C/5 minutes, and preserving heat for 3-4 hours; B, sublimation drying: vacuumizing to 8-12 Pa in a box body, raising the temperature of the heat-conducting oil at the speed of 1-2 DEG C/hour, preserving heat after the temperature of the heat-conducting oil is raised to 0+/-2 DEG C, wherein the total time is not less than 24 hours, and the temperature difference of a sample and the heat-conducting oil is ought to be less than 15-20 DEG C; and C, separation drying: raising the temperature of the heat-conducting oil at the speed of 1 DEG C/10 minutes, raising the temperature of a product to 35+/-2 DEG C, and preserving heat for 3-5 hours. The freeze-dried formulation prepared through the method disclosed by the invention has the characteristics of product looseness, stability in quality, fast redissolution, good clarity, and the like.
Description
Technical field
The present invention relates to a kind of preparation method of pemetrexed disodium freeze-dried injection, can obtain stay-in-grade pemetrexed disodium preparation by the method.
Background technology
Pemetrexed is to also have core to be the folic acid resisting preparation of pyrroles's pyrimidine group on a kind of structure, by destroying the dependent homergy process of folic acid in the cell, suppresses cellular replication, thereby suppresses growth of tumor.
The pemetrexed disodium less stable is easily degraded under high temperature, oxidation and illumination condition, and generation can cause the impurity of toxic and side effects, so pemetrexed disodium is prepared into lyophilized injectable powder usually.
Prepare injection pemetrexed disodium lyophilized formulations according to conventional method, processing step includes pre-freeze, distillation, drying, and concrete grammar is A, pre-freeze: goods are cooled to-40 ℃ earlier, are incubated 3 hours.B, distillation and parsing-desiccation: after pre-freeze is finished, open vacuum system, 3 ℃/h rises to 35 ℃ of insulations 2 hours with products temperature; C, charge into nitrogen, tamponade, outlet.Prepare the injection pemetrexed disodium according to conventional method, because when pre-freeze, the pemetrexed disodium solution concentration is higher, the fill amount is bigger, products temperature and baffle temperature differ bigger, cillin bottle splits bottle and the phenomenon that breaks off the base is serious, therefore develops the generation that new freeze drying process reduces this phenomenon.
Summary of the invention
The purpose of this invention is to provide a kind of preparation method of improving injection pemetrexed disodium lyophilized formulations product yield, improving the pemetrexed disodium freeze-dried injection of its output and minimizing loss.
The object of the present invention is achieved like this:
Injection pemetrexed disodium lyophilized formulations preparation method provided by the present invention equally includes steps such as pre-freeze, sublimation drying, parsing-desiccation with the preparation method of conventional lyophilized injectable powder, and its innovative point is:
A, pre-freeze: at first pemetrexed disodium solution is cooled to-12 ℃～-14 ℃, then conduction oil is down to-20 ℃ with the speed of 1 ℃/10min, the insulation 2～3h, treat that products temperature is down to-16～-20 ℃ after, be cooled to-40 ± 2 ℃ rapidly, the insulation 4～5h;
B, sublimation drying: be evacuated to 7～12 handkerchiefs in the casing, with the speed of 1～2 ℃/h conduction oil heated up, insulation after the conduction oil temperature rises to 0 ℃, insulation should be no less than 30h at total time, and the temperature difference of sample and conduction oil should be less than 15～20 ± 2 ℃;
C, parsing-desiccation: the speed with per 1 ℃/10min heats up to conduction oil, and goods are warming up to 40 ± 2 ℃, insulation 3～5h.
The eutectic point of described pemetrexed disodium solution is at-7～-9 ℃.
Cooling in the described pre-freeze step is gradient cooling.
Beneficial effect of the present invention:
Pre-freeze presents the purpose of gradient cooling among the present invention, is to freeze the time in order to slow down pemetrexed disodium solution, reduces liquid and is converted into the active force that produces when solid-state, and anti-crack arrest bottle phenomenon occurs.The purpose of the insulation in the pre-freeze process is in order to dwindle the temperature difference between conduction oil and the lyophilizing sample, to prevent the phenomenon that breaks off the base.
In order to make pre-freeze reach better effect, the control of the final temperature of pre-freeze is at-40 ± 2 ℃ among the present invention, and insulation 4-5h guarantees that goods freeze fully, prevents from occurring in vacuum the lyophilizing sample phenomenon that breaks off the base that causes of cooling rapidly.
Adopt that the injection pemetrexed disodium lyophilized formulations of the present invention's preparation has that the goods pine is dredged, steady quality, characteristics such as redissolution is fast, clarity good, yield rate height.
The specific embodiment
The present invention is further elaborated below in conjunction with embodiment, but embodiment imposes any restrictions the present invention absolutely not.Those skilled in the art will drop in the scope of claims any change that the present invention does under the enlightenment of this description.
Embodiment 1 in following examples and embodiment 2 are the methods that prepare preparation routinely, embodiment 3 adopts the present invention to prepare the method for preparation, preparation performance with the preparation of two class methods compares then, thereby can find out that the present invention prepares the advantage of formulation method:
Embodiment 1
Be example with 100 bottles of injection pemetrexed disodium lyophilized formulations, concrete preparation method is:
Take by weighing 50.0g mannitol and 6.3g sodium acetate, water-soluble 600ml, take by weighing in the 60.4g pemetrexed disodium adding solution and dissolve, take by weighing the 0.6g active carbon and add in the medicinal liquid, stir 30min, medicinal liquid is with 2 0.45 μ m membrane filtration decarburizations, again the medicinal liquid after the decarburization is removed Mycoderma by 0.22 μ m, measure pH value, the qualified back packing of content, then by following program frozen drying:
A, pre-freeze: goods are cooled to-40 ℃ earlier, are incubated 3 hours.
B, distillation and parsing-desiccation: after pre-freeze is finished, open vacuum system, 3 ℃/h rises to 35 ℃ of insulations 2 hours with products temperature.
C, charge into nitrogen, tamponade, outlet.
Embodiment 2
Prepare 1.0g pemetrexed disodium solution according to a conventional method, carry out frozen drying by following operation then:
A, pre-freeze: at first pemetrexed disodium solution is cooled to-10 ℃ ± 2 ℃, then conduction oil is down to-40 ± 2 ℃ with the speed of 1 ℃/5min, insulation 2h.
B, sublimation drying: be evacuated to 8～12 handkerchiefs in the casing, with the speed of 2 ℃/h conduction oil heated up, be incubated 5h after the conduction oil temperature rises to-7 ℃, the temperature difference of sample and conduction oil should be less than 15～20 ℃.
C, parsing-desiccation: heat up to conduction oil with the speed of per 1 ℃/10min in sublimation drying knot back, goods are warming up to 35 ± 2 ℃, insulation 4～6h.
D, fill nitrogen and handle: fill nitrogen under the vacuum state, tamponade, outlet.
Embodiment 3
Prepare 1.0g pemetrexed disodium solution according to a conventional method, carry out frozen drying by following operation then:
A, pre-freeze: at first pemetrexed disodium solution is cooled to-10 ℃ ± 2 ℃, then conduction oil is down to-40 ± 2 ℃ with the speed of 1 ℃/5min, insulation 3～4h.
B, sublimation drying: be evacuated to 8～12 handkerchiefs in the casing, with the speed of 1～2 ℃/h conduction oil heated up, insulation after the conduction oil temperature rises to 0 ± 2 ℃, total time should be no less than 24h, and the temperature difference of sample and conduction oil should be less than 15～20 ℃.
C, parsing-desiccation: the speed with per 1 ℃/10min heats up to conduction oil, and goods are warming up to 35 ± 2 ℃, insulation 3～5h.
D, fill nitrogen and handle: fill nitrogen under the vacuum state, tamponade, outlet.
The comparison that experimentizes of the injection pemetrexed disodium lyophilized formulations (embodiment 3) that adopts the inventive method preparation and injection pemetrexed disodium lyophilized formulations (embodiment 1 and the embodiment 2) properties of product of routine techniques preparation, its result sees following table for details:
Annotate: clarity＞No. 0.5 is defective
25 ℃ of table 1 temperature and relative humidity 65% condition test result
| Outward appearance | Redissolution speed (s) | Clarity | Split bottle | Break off the base | |
| Embodiment 1 | Loose full | 4 | Clarification | 5 | 10 |
| Embodiment 2 | Loose full | 6 | Clarification | / | / |
| Embodiment 3 | Loose full | 5 | Clarification | / | / |
Proof by experiment: the injection pemetrexed disodium lyophilized formulations of the inventive method preparation can reduce effectively and splits bottle and the phenomenon that breaks off the base, and has overcome the existing great drawback of prior preparation method.
If the content that is not described in detail is arranged, should be those skilled in the art's technique known in this description, repeat no more herein.
Claims (3)
1. the preparation method of an injection pemetrexed disodium lyophilized formulations includes pre-freeze, sublimation drying, parsing-desiccation processing step, it is characterized in that:
A, pre-freeze: at first pemetrexed disodium solution is cooled to-12 ℃～-14 ℃, then conduction oil is down to-20 ℃ with the speed of 1 ℃/10min, the insulation 2～3h, treat that products temperature is down to-16～-20 ℃ after, be cooled to-40 ± 2 ℃ rapidly, the insulation 4～5h;
B, sublimation drying: be evacuated to 7～12 handkerchiefs in the casing, with the speed of 1～2 ℃/h conduction oil heated up, insulation after the conduction oil temperature rises to 0 ℃, insulation should be no less than 30h at total time, and the temperature difference of sample and conduction oil should be less than 15～20 ± 2 ℃;
C, parsing-desiccation: the speed with per 1 ℃/10min heats up to conduction oil, and goods are warming up to 40 ± 2 ℃, insulation 3～5h.
2. the preparation method of pemetrexed disodium lyophilized formulations according to claim 1, it is characterized in that: the cooling in the described pre-freeze technology is gradient cooling.
3. the preparation method of pemetrexed disodium lyophilized formulations according to claim 1, it is characterized in that: the eutectic point of described pemetrexed disodium solution is at-7～-9 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101559413A CN103239415A (en) | 2012-05-18 | 2012-05-18 | Preparation method of pemetrexed disodium freeze-dried formulation for injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101559413A CN103239415A (en) | 2012-05-18 | 2012-05-18 | Preparation method of pemetrexed disodium freeze-dried formulation for injection |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103239415A true CN103239415A (en) | 2013-08-14 |
Family
ID=48919522
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012101559413A Pending CN103239415A (en) | 2012-05-18 | 2012-05-18 | Preparation method of pemetrexed disodium freeze-dried formulation for injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103239415A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EA038700B1 (en) * | 2018-04-26 | 2021-10-07 | Тютор С.А.С.И.Ф.И.А. | Method of producing a pharmaceutical composition of disodium pemetrexed |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101411710A (en) * | 2008-11-25 | 2009-04-22 | 江苏奥赛康药业有限公司 | Pemetrexed disodium freeze-dried injection and preparation method thereof |
| WO2010030598A2 (en) * | 2008-09-11 | 2010-03-18 | Dr. Reddy's Laboratories Limited | Pharmaceutical formulations comprising pemetrexed |
| CN102106833A (en) * | 2011-02-12 | 2011-06-29 | 海南锦瑞制药股份有限公司 | Pemetrexed disodium freeze-dried powder injection and preparation method thereof |
-
2012
- 2012-05-18 CN CN2012101559413A patent/CN103239415A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010030598A2 (en) * | 2008-09-11 | 2010-03-18 | Dr. Reddy's Laboratories Limited | Pharmaceutical formulations comprising pemetrexed |
| CN101411710A (en) * | 2008-11-25 | 2009-04-22 | 江苏奥赛康药业有限公司 | Pemetrexed disodium freeze-dried injection and preparation method thereof |
| CN102106833A (en) * | 2011-02-12 | 2011-06-29 | 海南锦瑞制药股份有限公司 | Pemetrexed disodium freeze-dried powder injection and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EA038700B1 (en) * | 2018-04-26 | 2021-10-07 | Тютор С.А.С.И.Ф.И.А. | Method of producing a pharmaceutical composition of disodium pemetrexed |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107034149B (en) | Preparation method and application of kluyveromyces marxianus freeze-dried microbial inoculum | |
| CN106754525B (en) | Lactobacillus paracasei N1115 freeze-dried powder leavening agent and preparation method thereof | |
| CN110915987A (en) | Method for producing feed by comprehensively utilizing tea leaves | |
| CN102641248B (en) | Preparation method for gemcitabine hydrochloride lyophilized preparation for injection | |
| CN103054818B (en) | High-quality high-efficiency freeze drying technology | |
| CN103239415A (en) | Preparation method of pemetrexed disodium freeze-dried formulation for injection | |
| CN105640899A (en) | Tedizolid pharmaceutical composition for injection | |
| CN104094924A (en) | Cryoprotectant for human sperm | |
| CN103371980A (en) | Dexamethasone sodium phosphate freeze-dried powder injection | |
| CN104814932B (en) | A kind of frozen dried method of Calcium Folinate for injection freeze drying powder injection | |
| CN106106910A (en) | A kind of preparation method of tea concentrated solution | |
| Nguyen et al. | Using high pitching rate for improvement of yeast fermentation performance in high gravity brewing | |
| JP2015519069A5 (en) | ||
| CN103230371B (en) | Preparation method of injection-use oxaliplatin freeze-dried preparation | |
| CN103371978A (en) | Freeze-dried powder injection prepared from ethanol-containing solvent | |
| CN104336574A (en) | Method for preparing yeast microcapsule by biology-low temperature freeze-drying method | |
| CN104585397A (en) | Gamma-amino butyric acid instant tea preparation method | |
| JPH07138178A (en) | Composition for improving hyperglycemia | |
| CN112715875A (en) | Preparation method of fermented phyllanthus emblica | |
| CN101343620A (en) | Ultra low temperature freezing-storage method for onosma paniculatum cell | |
| CN106035802A (en) | Method for increasing dissolution rate of effective components of Liu Pao tea | |
| CN103271883B (en) | Preparation method for pazufloxacin mesilate for injection | |
| CN102727450A (en) | Preparation method of Schisandrin C freeze-dried powder injection | |
| LU501648B1 (en) | Preparation method of homologous micro-emulsified coffee polyphenols | |
| CN106389402B (en) | Application of convection heat transfer mode in preparation process of dianhydrogalactitol freeze-dried powder |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130814 |