CN105078905B - A kind of preparation method of doxycycline hydrochloride for injection freeze drying powder injection - Google Patents
A kind of preparation method of doxycycline hydrochloride for injection freeze drying powder injection Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of doxycycline hydrochloride for injection freeze drying powder injection, it includes the steps such as dispensing, freeze-drying, wherein pre-freeze technique is carried out in three steps, i.e. first by temperature of charge prompt drop to 20 DEG C or so, 20 DEG C or so are evenly down to again, and finally prompt drop is to 40 DEG C or so insulations again, and sublimation step is carried out in two steps, temperature of charge is first incubated 5~10 hours to being increased to 20 DEG C or so, then temperature of charge is increased to 5 DEG C or so and 1~3 hour is incubated.The present invention is by using special lyophilized technique, solve concentrated hydrochloric acid Doxycycline decoction and be difficult to lyophilized technical barrier, the solid content of decoction can reach more than 50%, so as to improve lyophilized efficiency, shorten lyophilization cycle, obtained product appearance is full, no atrophy, collapse, the phenomenon such as tomography, solubility and quality stability are good.
Description
Technical field
The invention belongs to technical field of medicine, and in particular to a kind of doxycycline hydrochloride for injection freeze drying powder injection
Preparation method.
Background technology
Doxycycline Hyclate, chemical name is 6- methyl -4- (dimethylamino) -3,5,10,12,12a- penta hydroxy groups -1,11-
Dioxo-Isosorbide-5-Nitrae, 4a, 5,5a, 6,11,12a- octahydro -2- aphthacene carboxamide hydrochlorides, are faint yellow or yellow crystalline powder
End；It is smelly, bitter.Readily soluble in water or in methanol, the slightly soluble in ethanol or acetone is insoluble in chloroform.Its structural formula is as follows：
Doxycycline Hyclate preparation is used to treat asthma, and to respiratory tract, the urinary tract bacterium and mycoplasma infection have one
Fixed curative effect.Compared with tetracycline, it has antibacterial action strong, and persister is few, the advantages of long half time and adverse reaction are lacked.
The Doxycycline Hyclate formulation listed at present has solid pharmaceutical preparation and injection.Solid pharmaceutical preparation is mainly tablet, dry-mixed
Suspension and capsule, injection are predominantly parenteral solution and freeze-dried powder, and Doxycycline Hyclate solid pharmaceutical preparation has action slow, taken
Not the shortcomings of aspect.Doxycycline Hyclate injection and freeze-dried powder prepared by common process, physics and chemical property are stable
Property it is poor, easily degraded, occur discoloration etc. phenomenon.Long-term storage drug quality can decline but also can generate some impurity, bring
Toxic side effect, hidden danger is left to Clinical practice.
CN 101555215A disclose a kind of preparation method of doxycycline hydrochloride for injection freeze drying powder injection, it be by
After Doxycycline Hyclate dissolves with vitamin C, mannitol and sodium pyrosulfite water, through decolouring, bacteria removing, then carry out cold
Lyophilized dry, lyophilized program is：- 28 DEG C of pre-freezing temperature, 2.5 hours；The temperature of distillation is less than -20 DEG C, 2 days；The temperature of re-dry
Degree is less than 30 DEG C, 3 hours.
CN 1868460A disclose the preparation method of another doxycycline hydrochloride for injection freeze drying powder injection, it be by
After Doxycycline Hyclate dissolves with vitamin C, glycine, Tween 80 water, decolourized successively, degerming, freeze-drying, its
In, -50 DEG C of lyophilized pre-freezing temperature, 3.5 hours；The temperature of distillation is -20 DEG C, 3 hours；The temperature of re-dry is 30 DEG C.
Conventional freeze drying technology, typically requires that solid contents is in 8%~25% (such as CN 1868460A jelly in liquid
Solid content is 20%), when concentration is too high, freeze-dried products, which are difficult to be completely dried, causes loss on drying unqualified or freeze-dried products before dry
Outward appearance be likely to occur atrophy, collapse, the phenomenon such as tomography.To obtain qualified doxycycline hydrochloride for injection, generally using increasing
Quantity of solvent, reduces the mode of solid content in order to lyophilized.But the increase of the amount due to solvent, causes lyophilization cycle to extend, increase
Man-hour, energy consumption, reduce production efficiency.Simultaneously as the increase of quantity of solvent, it is necessary to use container (XiLin that volume is larger
Bottle), cause the finished product number freezed under unit volume seldom, be unfavorable for actual production.
The content of the invention
It is an object of the invention to provide a kind of preparation method of doxycycline hydrochloride for injection freeze drying powder injection, it is right that it passes through
Lyophilized technique is improved, and it is disposably freezed the liquid of high solids, while can improve the quality of freeze-drying prods again.
Above-mentioned purpose is achieved through the following technical solutions：
A kind of preparation method of doxycycline hydrochloride for injection freeze drying powder injection, it comprises the following steps：
(1) Doxycycline Hyclate, vitamin C, mannitol are dissolved in water for injection, then add medicinal carbon and take off
Color, through filtering with microporous membrane take off charcoal, it is degerming after be sub-packed in cillin bottle；
(2) it is freeze-dried, including pre-freeze, once distillation and re-dry three phases, the operating procedure in each stage is as follows：
Pre-freeze：Temperature of charge is first rapidly decreased to -22~-18 DEG C, is kept for 20~60 minutes, was then dropped by every 3~6 minutes
Temperature of charge is evenly down to -35~-28 DEG C by low 1 DEG C of speed, is all freezed to material, then temperature of charge is dropped rapidly
To -45~-38 DEG C, 2~5 hours are incubated；
Once distil：Vacuum is controlled below 15 handkerchiefs, temperature of charge is first increased to -25~-15 DEG C and insulation 5~10
Hour, then temperature of charge is increased to -8~-2 DEG C and 1~3 hour is incubated；
Re-dry：Temperature of charge is raised to 30~40 DEG C, 8~15 hours are incubated；
(3) compaction plug, rolls aluminium lid, and full inspection is packed,
The weight proportion of each raw material is：
Preferably, the pre-freeze, once distillation and re-dry three phases operating procedure it is as follows：
Pre-freeze：Temperature of charge is first rapidly decreased to -20 DEG C, kept for 30 minutes, then by the speed of 1 DEG C of reduction in every 5 minutes
Temperature of charge is evenly down to -30 DEG C, all freezed to material, then temperature of charge is rapidly decreased to -40 DEG C, insulation 3.5 is small
When；
Once distil：Vacuum is controlled below 15 handkerchiefs, temperature of charge is first increased to -20 DEG C and 6 hours are incubated, then will
Temperature of charge is increased to -5 DEG C and is incubated 2 hours；
Re-dry：Temperature of charge is raised to 35 DEG C, 10 hours are incubated.
It is further preferred that the weight proportion of each raw material is：
The beneficial effects of the invention are as follows：
1) present invention, by using special lyophilized technique, is thoroughly solved according to the physical property of Doxycycline Hyclate
Concentrated hydrochloric acid Doxycycline decoction is difficult to lyophilized technical problem, and the solid content of decoction can be with when using present invention process lyophilized
More than 50% is reached, so that lyophilized efficiency greatly improved, lyophilization cycle is shortened, whole lyophilization cycle can be tied in 24 hours
Beam, reduces energy consumption, improves the medicament contg of single dose.
2) it is full using product appearance produced by the present invention, no atrophy, collapse, the phenomenon such as tomography, solubility is good, and quality is steady
It is qualitative good.
Embodiment
The present invention is described in detail with reference to embodiments.
Embodiment 1
A kind of preparation method of doxycycline hydrochloride for injection freeze drying powder injection, comprises the following steps：
(1) Doxycycline Hyclate 5g, vitamin C 24.8g, mannitol 20g are dissolved in 50g waters for injection, then added
0.2g medicinal carbons, are then sufficiently stirred for 15 minutes, stand 15 minutes and decolourize, and take off charcoal through 0.45 μm of filtering with microporous membrane, remove
After bacterium, intermediates content is detected, is sub-packed in by the dosage of every Doxycycline containing 0.1g in 10ml cillin bottles.
(2) it is freeze-dried, including pre-freeze, once distillation and re-dry three phases, the operating procedure in each stage is as follows：
Pre-freeze：Temperature of charge is first rapidly decreased to -20 DEG C, kept for 30 minutes, then by the speed of 1 DEG C of reduction in every 5 minutes
Temperature of charge is evenly down to -30 DEG C, all freezed to material, then temperature of charge is rapidly decreased to -40 DEG C, insulation 3.5 is small
When；
Once distil：Vacuum is controlled below 15 handkerchiefs, temperature of charge is first increased to -20 DEG C and 6 hours are incubated, then will
Temperature of charge is increased to -5 DEG C and is incubated 2 hours；
Re-dry：Temperature of charge is raised to 35 DEG C, 10 hours are incubated.
(3) compaction plug, rolls aluminium lid, full inspection, packaging.
Embodiment 2
A kind of preparation method of doxycycline hydrochloride for injection freeze drying powder injection, comprises the following steps：
(1) Doxycycline Hyclate 3g, vitamin C 20g, mannitol 25g are dissolved in 51.9g waters for injection, then added
0.1g medical active carbon decolorings, charcoal is taken off through filtering with microporous membrane, after aseptic filtration, detects intermediates content, contains 0.1g by every
The dosage of Doxycycline is sub-packed in 10ml cillin bottles.
(2) it is freeze-dried, including pre-freeze, once distillation and re-dry three phases, the operating procedure in each stage is as follows：
Pre-freeze：Temperature of charge is first rapidly decreased to -18 DEG C, kept for 60 minutes, then by the speed of 1 DEG C of reduction in every 3 minutes
Temperature of charge is evenly down to -28 DEG C, all freezed to material, then temperature of charge is rapidly decreased to -38 DEG C, 5 hours are incubated；
Once distil：Control vacuum below 15 handkerchiefs, first by temperature of charge to be increased to -15 DEG C and insulation 5 hours, then
Temperature of charge is increased to -8 DEG C and 3 hours are incubated；
Re-dry：Temperature of charge is raised to 30 DEG C, 15 hours are incubated.
(3) compaction plug, rolls aluminium lid, full inspection, packaging.
Embodiment 3
A kind of preparation method of doxycycline hydrochloride for injection freeze drying powder injection, comprises the following steps：
(1) Doxycycline Hyclate 8g, vitamin C 30g, mannitol 15g are dissolved in 46.5g waters for injection, then added
0.5g medical active carbon decolorings, charcoal is taken off through filtering with microporous membrane, after aseptic filtration, detects intermediates content, contains 0.1g by every
The dosage of Doxycycline is sub-packed in 10ml cillin bottles.
(2) it is freeze-dried, including pre-freeze, once distillation and re-dry three phases, the operating procedure in each stage is as follows：
Pre-freeze：Temperature of charge is first rapidly decreased to -22 DEG C, kept for 20 minutes, then by the speed of 1 DEG C of reduction in every 6 minutes
Temperature of charge is evenly down to -35 DEG C, all freezed to material, then temperature of charge is rapidly decreased to -45 DEG C, 2 hours are incubated；
Once distil：Vacuum is controlled in 15 handkerchiefs, temperature of charge is first increased to -25 DEG C and 10 hours are incubated, then by thing
Material temperature degree is increased to -2 DEG C and is incubated 1 hour；
Re-dry：Temperature of charge is raised to 40 DEG C, 8 hours are incubated.
(3) compaction plug, rolls aluminium lid, full inspection, packaging.
Test example：
1. the effect assessment of pre-freeze technique
The pre-freeze technique of the present invention is carried out in three steps, i.e., first by temperature of charge prompt drop to -20 DEG C or so, then evenly drop
To -30 DEG C or so, finally extremely -40 DEG C or so insulations of prompt drop again.With common quick-frozen, slow jelly and repeatedly compared with pre-freeze method, freezing
Material afterwards is not stratified, and no atrophy, solubility, clarity are good, not only reduces the difficulty of later sublimation, drying process, and
Significantly improve the quality of finished product.
Concrete outcome is shown in Table 1.
The effect assessment of the pre-freeze technique of table 1
2. the effect assessment of sublimation process
The method that the present invention is distilled using two steps is that is, first small to -20 DEG C or so insulations 5~10 are increased to by temperature of charge
When, then by temperature of charge be increased to -5 DEG C and be incubated 1~3 hour, compared with a common step sublimation method, the present invention first -
20 DEG C by the water sublimed in material, now because temperature is relatively low, it is ensured that rate of sublimation too fast will not cause spray bottle, material temperature
Degree ensures under eutectic point, will not melt.When moisture distils completely substantially, rise temperature accelerates residual moisture to -5 DEG C
Distillation, to save freeze-drying time.
The effect assessment of the sublimation process of table 2
3. the quality measurements of embodiment 1-3 finished products
The quality examination of 3 embodiment of table 1~3
Claims (3)
1. a kind of preparation method of doxycycline hydrochloride for injection freeze drying powder injection, it is characterised in that comprise the following steps：
(1) Doxycycline Hyclate, vitamin C, mannitol are dissolved in water for injection, then add medical active carbon decoloring, warp
Filtering with microporous membrane takes off charcoal, it is degerming after be sub-packed in cillin bottle；
(2) it is freeze-dried, including pre-freeze, once distillation and re-dry three phases, the operating procedure in each stage is as follows：
Pre-freeze：Temperature of charge is first rapidly decreased to -22~-18 DEG C, kept for 20~60 minutes, then by reduction by 1 in every 3~6 minutes
DEG C speed temperature of charge is evenly down to -35~-28 DEG C, all freeze to material, then temperature of charge is rapidly decreased to -45
~-38 DEG C, it is incubated 2~5 hours；
Once distil：Vacuum is controlled below 15 handkerchiefs, temperature of charge is first increased to -25~-15 DEG C and insulation 5~10 is small
When, then temperature of charge is increased to -8~-2 DEG C and 1~3 hour is incubated；
Re-dry：Temperature of charge is raised to 30~40 DEG C, 8~15 hours are incubated；
(3) compaction plug, rolls aluminium lid, and full inspection is packed,
The weight proportion of each raw material is：
2. the preparation method of doxycycline hydrochloride for injection freeze drying powder injection as claimed in claim 1, it is characterised in that described
Pre-freeze, the once operating procedure of distillation and re-dry three phases are as follows：
Pre-freeze：Temperature of charge is first rapidly decreased to -20 DEG C, is kept for 30 minutes, then reduced by 1 DEG C of speed at the uniform velocity by every 5 minutes
Temperature of charge is down to -30 DEG C by ground, is all freezed to material, then temperature of charge is rapidly decreased into -40 DEG C, is incubated 3.5 hours；
Once distil：Vacuum is controlled below 15 handkerchiefs, temperature of charge is first increased to -20 DEG C and 6 hours are incubated, then by material
Temperature is increased to -5 DEG C and is incubated 2 hours；
Re-dry：Temperature of charge is raised to 35 DEG C, 10 hours are incubated.
3. the preparation method of doxycycline hydrochloride for injection freeze drying powder injection as claimed in claim 1 or 2, it is characterised in that institute
The weight proportion for stating each raw material is：
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| CN201510495924.8A CN105078905B (en) | 2015-08-13 | 2015-08-13 | A kind of preparation method of doxycycline hydrochloride for injection freeze drying powder injection |
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| CN201510495924.8A CN105078905B (en) | 2015-08-13 | 2015-08-13 | A kind of preparation method of doxycycline hydrochloride for injection freeze drying powder injection |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107638395B (en) * | 2017-10-10 | 2021-02-02 | 济南康和医药科技有限公司 | Doxycycline hydrochloride freeze-dried powder for injection and preparation method thereof |
| CN108815124A (en) * | 2018-09-12 | 2018-11-16 | 海南通用康力制药有限公司 | A kind of doxycycline hydrochloride for injection freeze drying powder injection and preparation method thereof |
| CN110354003B (en) * | 2019-07-08 | 2022-05-27 | 广州贝研生物科技有限公司 | Application of tranexamic acid as freeze-dried powder excipient and freeze-drying process |
| CN110227038B (en) * | 2019-07-08 | 2022-03-08 | 珠海贝美生物科技有限公司 | Freeze-dried powder with whitening activity and preparation method and application thereof |
| CN112361726B (en) * | 2020-10-27 | 2022-09-02 | 北京诺康达医药科技股份有限公司 | Freeze-dried preparation water control method and application thereof |
| CN113230216B (en) * | 2021-05-26 | 2023-04-07 | 海南通用康力制药有限公司 | Piracetam freeze-dried powder injection for injection and preparation method thereof |
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|---|---|---|---|---|
| CN1868460A (en) * | 2006-04-19 | 2006-11-29 | 汕头市健信药品有限公司 | Doxycycline hydrochloride freeze-dried power prepn. for injection, and process for preparing same |
| CN101555215A (en) * | 2009-05-12 | 2009-10-14 | 海口奇力制药股份有限公司 | Preparation technology of doxycycline hydrochloride for injection |
| CN103446067A (en) * | 2013-09-16 | 2013-12-18 | 石药集团欧意药业有限公司 | Oxiracetam freeze-drying preparation for injection and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000064479A1 (en) * | 1999-04-27 | 2000-11-02 | Antibody Systems, Inc. | Compositions containing tetracyclines for treating hemorrhagic virus infections and other disorders |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1868460A (en) * | 2006-04-19 | 2006-11-29 | 汕头市健信药品有限公司 | Doxycycline hydrochloride freeze-dried power prepn. for injection, and process for preparing same |
| CN101555215A (en) * | 2009-05-12 | 2009-10-14 | 海口奇力制药股份有限公司 | Preparation technology of doxycycline hydrochloride for injection |
| CN103446067A (en) * | 2013-09-16 | 2013-12-18 | 石药集团欧意药业有限公司 | Oxiracetam freeze-drying preparation for injection and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| Doxycycline;Mylan Institutional LLC;《Med Library.org》;20140624;第1-5页，尤其是第1页第2、4段 * |
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