CN105078907B - The freeze-drying method of hydrochloride for injection ligustrazine lyophilized preparation - Google Patents
The freeze-drying method of hydrochloride for injection ligustrazine lyophilized preparation Download PDFInfo
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Abstract
The present invention provides a kind of hydrochloride for injection ligustrazine lyophilized preparation freeze-drying method, which is characterized in that this method includes a c following steps in sequence：Step a, pre-freeze；Step b, 0 DEG C of distillation below, the moisture of 83% or more removal；With step c, 0 DEG C~30 DEG C of sublimation process, the time was no more than 2 hours.The method of the present invention can effectively solve the problems, such as to split during quick freezing bottle, and can control Ligustrazine Hydrochloride volatile quantity during vacuum freezedrying, keep stable content, improve rate of sublimation.
Description
Technical field
The present invention relates to a kind of freeze-drying methods of hydrochloride for injection ligustrazine lyophilized preparation, belong to pharmaceutical preparation neck
Domain.
Background technology
Hydrochloride for injection ligustrazine has platelet aggregation-against, and has depolymerisation to the blood platelet assembled.In addition originally
Product still have expansion parteriole, improve microcirculation and increase cerebral blood flow (CBF), to generate the effect of antithrombotic and thrombus dissolving.Clinically
For treating ischemic angiocardiopathy and cerebrovascular disease such as cerebral insufficiency, cerebral thrombosis, cerebral embolism and other ischemic angiopathies such as
Coronary atherosclerotic heart disease, vasculitis etc..
Ligustrazine Hydrochloride is active ingredient of the extraction with function promoting blood circulation and removing blood stasis from chuanxiong at first, is a kind of biology
The hydrochloride of alkali monomer, chemical constitution are Tetramethylpyrazine, now have been carried out artificial synthesized, and ligustrazine has to having assembled
Blood platelet has depolymerisation.Parteriole can be expanded, microcirculation is improved and increases coronary artery, cerebral blood flow (CBF), improves myocardium resist oxygen lack
Ability etc., Ligustrazine Hydrochloride classification in Chinese Pharmacopoeia is vasodilator agent.
Ligustrazine Hydrochloride is curative for effect, safe, successively has tablet and injection listing in last century the eighties, uses extensively
In clinic, various ischemic angiocardiopathy and cerebrovascular diseases are treated, microcirculation can be improved, improve hemorheology etc., in addition also have
Treat various effects such as renal failure, the high disease of gestation, retinopathy.
Chinese Pharmacopoeia has just recorded the raw material and small-volume injection of Ligustrazine Hydrochloride at 1977 editions；Specification is 2ml；
40mg, with the gradual maturation for freezing dry drying process, the advantages of lyophilized preparation, is more and more prominent, and hydrochloride for injection ligustrazine is cold
Freeze-drying drying process can preferably ensure product stability.Therefore Freeze Drying Technique is produced on Ligustrazine Hydrochloride preparation obtains extensively
General application.
Invention content
It is an object of the present invention to provide the freeze-drying methods of hydrochloride for injection ligustrazine lyophilized preparation.
Second object of the present invention is to provide the preparation method of hydrochloride for injection ligustrazine lyophilized preparation.
The purpose of the present invention is what is be achieved through the following technical solutions：
A kind of hydrochloride for injection ligustrazine lyophilized preparation freeze-drying method, this method include a-c following steps in sequence：
Step a, pre-freeze；
Step b, 0 DEG C of distillation below, the moisture of 83% or more removal；
Step c, 0 DEG C~30 DEG C of distillation, soaking time was no more than 2 hours.
Further, the step a pre-freeze processes include fast cooling and heating and keep the constant step of temperature；More into one
Step, the step a pre-freeze processes include first fast cooling, are then heated up, then the process to cool down, which repeats 1~3 time；Its
In preferably, during primary cooling, heating cool down again, for the first time temperature-fall period be temperature by be down between 50 DEG C to 20 DEG C-
Between 30 DEG C to -50 DEG C, rate of temperature fall is 0.2~1 DEG C/min；Temperature-rise period is temperature by being warming up between -30 DEG C to -50 DEG C
- 24 DEG C are risen to, heating rate is 1~2 DEG C/min；Second temperature-fall period be temperature by -24 DEG C be down to -30 DEG C to -50 DEG C it
Between, rate of temperature fall is 0.2~1 DEG C/min, and 20~40min is kept the temperature after still more preferably heating up, 180 are kept the temperature after second of cooling
~300min.
Further, 90% or more moisture is removed during step b；
Further, inert gas is added in step b sublimation processes；
Further, step b includes the multiple step to heat up and keep temperature constant using the temperature of pre-freeze step as starting point,
It can also include the process to cool down again；Still more preferably it is first to be warming up to -20 DEG C with the speed of 1~2 DEG C/min, heat preservation
30~40min, then -10 DEG C are warming up to the speed of 2~5 DEG C/min, 10~12h is kept the temperature, finally with 0.01~0.1 DEG C/min's
Speed is warming up to -6 DEG C, and distillation terminates.Wherein, step b vacuum degrees are 10~30pa；The inert gas can be nitrogen.
Further, the distillation that step c is 0 DEG C~25 DEG C, soaking time was no more than 1 hour；
Further, step c is added without inert gas.
The Ligustrazine Hydrochloride lyophilized preparation had included previously following preparation process in freeze-drying：
Step 1, Ligustrazine Hydrochloride and auxiliary material are taken, water for injection is added, stirs evenly；
Step 2, solution made from step 1 is filtered, obtains intermediate, adjust pH to acidity, degerming is filling.
A kind of preparation method of hydrochloride for injection ligustrazine lyophilized preparation, this method comprises the following steps：
Step 1, Ligustrazine Hydrochloride and auxiliary material are taken, water for injection is added, stirs evenly；
Step 2, solution made from step 1 is filtered, obtains intermediate, adjust pH to acidity, degerming is filling；With
Step 3, it is freeze-dried after step 2 is filling, hydrochloride for injection ligustrazine lyophilized preparation is made；
Wherein freeze-drying should include a-c following steps in sequence：
Step a, pre-freeze；
Step b, 0 DEG C of distillation below, the moisture of 83% or more removal；
Step c, 0 DEG C~30 DEG C of distillation, soaking time was no more than 2 hours；
Further, the step a pre-freeze processes include fast cooling and heating and keep the constant step of temperature；More into one
Step, the step a pre-freeze processes include first fast cooling, are then heated up, then the process to cool down, which repeats 1~3 time；Its
In preferably, during primary cooling, heating cool down again, for the first time temperature-fall period be temperature by be down between 50 DEG C to 20 DEG C-
Between 30 DEG C to -50 DEG C, rate of temperature fall is 0.2~1 DEG C/min；Temperature-rise period is temperature by being warming up between -30 DEG C to -50 DEG C
- 24 DEG C are risen to, heating rate is 1~2 DEG C/min；Second temperature-fall period be temperature by -24 DEG C be down to -30 DEG C to -50 DEG C it
Between, rate of temperature fall is 0.2~1 DEG C/min, and 20~40min is kept the temperature after still more preferably heating up, 180 are kept the temperature after second of cooling
~300min.
Further, 90% or more moisture is removed during step b；
Further, inert gas is added in the step b sublimation processes；
Further, step b includes the multiple step to heat up and keep temperature constant using the temperature of pre-freeze step as starting point,
It can also include the process to cool down again；Still more preferably it is first to be warming up to -20 DEG C with the speed of 1~2 DEG C/min, heat preservation
30~40min, then -10 DEG C are warming up to the speed of 2~5 DEG C/min, 10~12h is kept the temperature, finally with 0.01~0.1 DEG C/min's
Speed is warming up to -6 DEG C, and distillation terminates.Wherein, step b vacuum degrees are 10~30pa；The inert gas can be nitrogen.
Further, step c is 0 DEG C -- 25 DEG C of distillation, soaking time was no more than 2 hours；
Further, step c is added without inert gas.
Further, auxiliary material described in step 1 is selected from sodium hydroxide, hydrochloric acid, mannitol, glucosides, lactose, sodium carbonate, bicarbonate
It is one or more of in sodium；
Further, the temperature that water for injection is added in step 1 is 50~70 DEG C；Further, it is 55~65 DEG C；
Further, step 2 is carried out by medical charcoal, and the dosage of step 2 medical charcoal is 0.1~0.5% (W/V)；Adjust pH
It is worth to 2.0~3.0.
The beneficial effects of the present invention are：1. pre-freeze process is using cooling repeatedly, the technique to cool down again that heats up and controls drop
Warm rate, the specific ice crystal structure formed want larger compared with the ice crystal of simple fast cooling, after the distillation of top ice crystal
Larger channel is left, the spilling of lower part distillation steam is conducive to, improves an entire rate of sublimation, is removed preferably, faster
Moisture；And the step can effectively change solute and solvent ice crystal structure, product is made to lose rigidly, during solution quick freezing
Split a bottle problem；2. it is volatile during vacuum freezedrying since Ligustrazine Hydrochloride has volatility, cause content to decline,
Specifically distillation and drying steps can control Ligustrazine Hydrochloride volatile quantity during vacuum freezedrying to the present invention, keep containing
Amount is stablized；3. inert gas is added in sublimation process, aeration process forms convection current, overcomes lacking without convective heat exchange under vacuum condition
Point makes heat distribution evenly, can improve rate of sublimation, increases product homogeneity and stability.
Freeze-drying method of the present invention is equally applicable to easily split bottle in freezing dry process and since volatility is led
The drug for causing content to decline.
1 pre-freeze technique of experimental example is investigated
1, experiment purpose：Investigate the pre-freeze process in freezing dry process
2, experimental method：
(1) hydrochloride for injection ligustrazine freeze-dried powder sample preparation procedure：Filling, half tamponade production prepared by Example 1
Article unit three batches is labeled as sample 1,2,3, is respectively placed in freeze drier, is freeze-dried, waited after being lyophilized, portion
Point inflated with nitrogen, total head plug under micro-vacuum roll lid sealing after outlet, obtain hydrochloride for injection ligustrazine freeze-dried powder.
(2) pre-freeze process：Present invention freeze-drying includes three steps, step a pre-freezes process, step b sublimation processes, step
Rapid c drying processes.(sample 1,2,3 presses scheme to the case where different temperature control schemes that step a is investigated in this experiment influence finished product respectively
One, two, three pre-freeze is carried out)；Step b, c conditions remain unchanged.Step b is sublimation process：Use inert gas aeration, vacuum degree
Control 20pa；Temperature control program is：In 15 minutes, temperature increases -20 DEG C from -40 DEG C, keeps the temperature 40 minutes；In 5 minutes, temperature from-
20 DEG C rise to -10 DEG C, keep the temperature 12 hours；In 120 minutes, temperature rises to -6 DEG C from -10 DEG C, and distillation terminates；Step c is dried
Journey：Inert gas is mixed in stopping, and temperature rises to 25 DEG C from -6 DEG C in 30 minutes, keeps the temperature 60 minutes, and drying terminates.
Step a pre-freeze processes：
Scheme one：In 105 minutes, -40 DEG C are down to by room temperature；Heat preservation 240 minutes；
Scheme two：In 30 minutes, -40 DEG C are down to by room temperature；In 15 minutes, -24 DEG C are risen to by -40 DEG C, keeps the temperature 30 minutes；
In 30 minutes, temperature is down to -40 DEG C, keeps the temperature 240 minutes；
Scheme three：In 105 minutes, -40 DEG C are down to by room temperature；In 15 minutes, -24 DEG C are risen to by -40 DEG C, keeps the temperature 30 points
Clock；In 30 minutes, temperature is down to -40 DEG C, keeps the temperature 240 minutes.
Each sample measures moisture and Ligustrazine Hydrochloride content after step b, and measure after step c moisture and
Ligustrazine Hydrochloride content and lyophilized preparation molding effect.Experimental result is shown in Table 1.
3, experimental result：
It is shown in Table 1.
Influence of the different pre-freeze processes of table 1 to product quality
It is above-mentioned the experimental results showed that：
Scheme one：500 samples have 20 to split bottle, and product content meets regulation, and moisture does not meet rule 5%~10%
It is fixed；
Scheme two：500 samples have 2 to split bottle, and product content meets regulation, and moisture meets regulation 3%~5%；
Scheme three：500 samples meet regulation without bottle, content is split, and moisture meets regulation 1%~3%.
The result shows that scheme three can faster, more remove moisture removal, and preferably ensured without splitting a bottle situation.
2 sublimation process of experimental example is investigated
1, experiment purpose：Investigate the sublimation process condition in freezing dry process
2, experimental method：
(1) filling, each 2 batches of half tamponade product unit prepared by Example 1,2,3 is labeled as sample 1~6, sets respectively
It in freeze drier, is freeze-dried, is waited after being lyophilized, part inflated with nitrogen, total head plug under micro-vacuum rolls lid after outlet
Sealing, obtains hydrochloride for injection ligustrazine freeze-dried powder.
(2) sublimation process：Present invention freeze-drying includes three steps, step a pre-freezes process, step b sublimation processes, step
Rapid c drying processes.The case where different condition that step b sublimation processes are investigated in this experiment influences finished product (press respectively by sample 1~6
Scheme one~six distils)；Step a, c conditions remain unchanged.Step a pre-freeze processes：In 105 minutes, -40 are down to by room temperature
℃；In 15 minutes, -24 DEG C are risen to by -40 DEG C, keeps the temperature 30 minutes；In 90 minutes, temperature is down to -40 DEG C, keeps the temperature 240 minutes；Step
Rapid c drying processes：Inert gas is mixed in stopping, is that starting point rises to 25 DEG C in 30 minutes using step b outlet temperatures, heat preservation 60 minutes.
Step b sublimation processes：
Scheme one：- 30 DEG C of sublimation processes below：Use inert gas aeration, vacuum degree control 20pa；Temperature control journey
Sequence is：In 15 minutes, temperature increases -30 DEG C from -40 DEG C, keeps the temperature 40 minutes；In 5 minutes, temperature rises to -10 DEG C from -30 DEG C, protects
Temperature 12 hours；In 120 minutes, temperature rises to -6 DEG C from -10 DEG C, until watermark completely disappears on to bottom of bottle, distillation terminates.
Scheme two：- 20 DEG C of sublimation processes below：Use inert gas aeration, vacuum degree control 20pa；Temperature control journey
Sequence is：In 15 minutes, temperature increases -20 DEG C from -40 DEG C, keeps the temperature 40 minutes；In 5 minutes, temperature rises to -10 DEG C from -20 DEG C, protects
Temperature 12 hours；In 120 minutes, temperature rises to -6 DEG C from -10 DEG C, until watermark completely disappears on to bottom of bottle, distillation terminates.
Scheme three：- 10 DEG C of sublimation processes below：Use inert gas aeration, vacuum degree control 20pa；Temperature control journey
Sequence is：In 15 minutes, temperature increases -10 DEG C from -40 DEG C, keeps the temperature 12 hours；In 120 minutes, temperature rises to -6 DEG C from -10 DEG C,
It is completely disappeared to watermark to bottom of bottle on, distillation terminates.
Scheme four：5 DEG C of sublimation processes below：Use inert gas aeration, vacuum degree control 20pa；Temperature control program
For：In 15 minutes, temperature increases 5 DEG C from -40 DEG C, keeps the temperature 12 hours；In 120 minutes, temperature rises to 10 DEG C from 5 DEG C, until watermark
It is completely disappeared to bottom of bottle on, distillation terminates.
Scheme five：10 DEG C of sublimation processes below：Use inert gas aeration, vacuum degree control 20pa；Temperature control journey
Sequence is：In 15 minutes, temperature increases 10 DEG C from -40 DEG C, keeps the temperature 12 hours；In 120 minutes, temperature rises to 15 DEG C from 10 DEG C, until
Watermark completely disappears on to bottom of bottle, and distillation terminates；Step 3 is drying process.
Scheme six：15 DEG C of sublimation processes below：Use inert gas aeration, vacuum degree control 20pa；Temperature control journey
Sequence is：In 15 minutes, temperature increases 15 DEG C from -40 DEG C, keeps the temperature 12 hours；In 120 minutes, temperature rises to 20 DEG C from 15 DEG C, until
Watermark completely disappears on to bottom of bottle, and distillation terminates.
Each sample measures moisture and Ligustrazine Hydrochloride content after step b, and measure after step c moisture and
Ligustrazine Hydrochloride content and lyophilized preparation molding effect.
3 experimental results
It is shown in Table 2.
Influence of the different sublimation processes of table 2 to product quality
It is above-mentioned the experimental results showed that：Step b control a sublimation temperature 0 DEG C or less, remove 83% or more moisture can
Ensure that final products water content and content conform to quality requirements.
3 drying process of experimental example is investigated
1, experiment purpose：Investigate the drying process condition in freezing dry process
2, experimental method：
(1) filling, each 2 batches of half tamponade product unit prepared by Example 1,2,3 is labeled as sample 1~6, sets respectively
It in freeze drier, is freeze-dried, is waited after being lyophilized, part inflated with nitrogen, total head plug under micro-vacuum rolls lid after outlet
Sealing, obtains hydrochloride for injection ligustrazine freeze-dried powder.
(2) drying process：Present invention freeze-drying includes three steps, step a pre-freezes process, step b sublimation processes, step
Rapid c drying processes.The case where different condition that step c drying processes are investigated in this experiment influences finished product (press respectively by sample 1~6
Scheme one~six is dried)；Step a, b conditions remain unchanged.Step a pre-freeze processes：In 105 minutes, -40 are down to by room temperature
℃；In 15 minutes, -24 DEG C are risen to by -40 DEG C, keeps the temperature 30 minutes；In 90 minutes, temperature is down to -40 DEG C, keeps the temperature 240 minutes；Step
Rapid b is sublimation process：Use inert gas aeration, vacuum degree control 20pa；Temperature control program is：In 15 minutes, temperature is from -40 DEG C
- 20 DEG C are increased, keeps the temperature 40 minutes；In 5 minutes, temperature rises to -10 DEG C from -20 DEG C, keeps the temperature 12 hours；In 120 minutes, temperature
- 6 DEG C are risen to from -10 DEG C, distillation terminates.
Step c drying processes：
Scheme one：25 DEG C are risen to from -6 DEG C, keep the temperature 60 minutes；
Scheme two：25 DEG C are risen to from -6 DEG C, keep the temperature 90 minutes；
Scheme three：25 DEG C are risen to from -6 DEG C, keep the temperature 120 minutes；
Scheme four：30 DEG C are risen to from -6 DEG C, keep the temperature 90 minutes；
Scheme five：30 DEG C are risen to from -6 DEG C, keep the temperature 120 minutes；
Scheme six：35 DEG C are risen to from -6 DEG C, keep the temperature 140 minutes.
Each sample measures moisture and Ligustrazine Hydrochloride content after step c.
3, experimental result
It is shown in Table 3.
Influence of the different drying processes of table 3 to product quality
| Content | Moisture | |
| Sample 1 | 105% | 2%~3% |
| Sample 2 | 103% | 2%~3% |
| Sample 3 | 99% | 1%~2% |
| Sample 4 | 97% | 1%~2% |
| Sample 5 | 93% | ﹤ 1% |
| Sample 6 | 75% | ﹤ 1% |
The above results show：When needing stringent control drying process outlet temperature and heat preservation when controlling product moisture and content
Between；Product quality can be ensured when outlet temperature is no more than two hours less than 30 DEG C, soaking time.
Specific implementation mode
Embodiment 1
Prescription：
Preparation method：
Step 1：Ligustrazine Hydrochloride and auxiliary material are accurately weighed by recipe quantity, appropriate injection is taken to be added to the container control water temperature
60 DEG C, auxiliary material is first added and is completely dissolved, then adds the dissolving of raw material Ligustrazine Hydrochloride completely, adds a certain amount of injection
Water is stirred evenly to total amount；
Step 2：0.1% (W/V) medical charcoal, the stirring and adsorbing 20 under the conditions of 50 DEG C are added into solution made from step 1
Minute, it is filtered by 1.0 μm of stud filters and 0.5 μm of prefilter, obtains intermediate；Solution is taken to measure pH value (measured concentration
The 8mg/ml in terms of Ligustrazine Hydrochloride), solution ph is adjusted to 2.0, then with bacterial filter to centre with the HCl solution of 0.1mol/L
Body carries out aseptic filtration (filter sizes 0.22um), then presses aseptic processing and carries out filling, half tamponade.
Embodiment 2
Prescription：
Preparation method：
Step 1：Ligustrazine Hydrochloride and auxiliary material are accurately weighed by recipe quantity, appropriate injection is taken to be added to the container control water temperature
65 DEG C, auxiliary material is first added and is completely dissolved, then adds the dissolving of raw material Ligustrazine Hydrochloride completely, adds a certain amount of injection
Water is stirred evenly to total amount；
Step 2：0.3% (W/V) medical charcoal, the stirring and adsorbing 20 under the conditions of 55 DEG C are added into solution made from step 1
Minute, it is filtered by 1.0 μm of stud filters and 0.5 μm of prefilter, obtains intermediate；Solution is taken to measure pH value (measured concentration
The 8mg/ml in terms of Ligustrazine Hydrochloride), solution ph is adjusted to 3.0, then with bacterial filter to centre with the HCl solution of 0.1mol/L
Body carries out aseptic filtration (filter sizes 0.22um), then presses aseptic processing and carries out filling, half tamponade.
Embodiment 3
Prescription：
Preparation method：
Step 1：Ligustrazine Hydrochloride and auxiliary material are accurately weighed by recipe quantity, appropriate injection is taken to be added to the container control water temperature
70 DEG C, auxiliary material is first added and is completely dissolved, then adds the dissolving of raw material Ligustrazine Hydrochloride completely, adds a certain amount of injection
Water is stirred evenly to total amount；
Step 2：0.5% (W/V) medical charcoal, the stirring and adsorbing 20 under the conditions of 45 DEG C are added into solution made from step 1
Minute, it is filtered by 1.0 μm of stud filters and 0.5 μm of prefilter, obtains intermediate；Solution is taken to measure pH value (measured concentration
The 8mg/ml in terms of Ligustrazine Hydrochloride), solution ph is adjusted to 2.5, then with bacterial filter to centre with the HCl solution of 0.1mol/L
Body carries out aseptic filtration (filter sizes 0.22um), then presses aseptic processing and carries out filling, half tamponade.
Embodiment 4
Prescription：
The preparation method is the same as that of Example 1.
Embodiment 5
Embodiment 1-4 is filling through aseptic processing, half tamponade product unit is placed in freeze drier, and it is dry to carry out freezing
Dry, the freeze drying process includes the following steps：
Step a, pre-freeze process：
In 105 minutes, -40 DEG C are down to by room temperature；
In 15 minutes, -24 DEG C are risen to by -40 DEG C, keeps the temperature 30 minutes；
In 90 minutes, temperature is down to -40 DEG C, keeps the temperature 240 minutes；
Step b, sublimation process：Use inert gas aeration, vacuum degree control 20pa；Temperature control program is：
In 15 minutes, temperature increases -20 DEG C from -40 DEG C, keeps the temperature 40 minutes；
In 5 minutes, temperature rises to -10 DEG C from -20 DEG C, keeps the temperature 12 hours；
In 120 minutes, temperature rises to -6 DEG C from -10 DEG C, and distillation terminates；
Step c, drying process：Inert gas is mixed in stopping, and temperature rises to 25 DEG C from -6 DEG C in 30 minutes, keeps the temperature 60 minutes,
Drying terminates.
Embodiment 6
Embodiment 1-4 is filling through aseptic processing, half tamponade product unit is placed in freeze drier, and it is dry to carry out freezing
Dry, the freeze drying process includes the following steps：
Step a, pre-freeze process：Temperature control program is：
In 60 minutes, -40 DEG C are down to by room temperature；
In 50 minutes, -24 DEG C are risen to by -40 DEG C, keeps the temperature 30 minutes；
In 140 minutes, temperature is down to -40 DEG C, keeps the temperature 240 minutes；
Step b, sublimation process：Use inert gas aeration, vacuum degree control 10pa；Temperature control program is：
In 15 minutes, temperature increases -20 DEG C from -40 DEG C, keeps the temperature 40 minutes；
In 5 minutes, temperature rises to -10 DEG C from -20 DEG C, keeps the temperature 12 hours；
In 120 minutes, temperature rises to -6 DEG C from -10 DEG C, and distillation terminates；
Step c, drying process：Inert gas is mixed in stopping, and temperature rises to 25 DEG C from -6 DEG C in 10 minutes, keeps the temperature 90 minutes,
Drying terminates.
Embodiment 7
Embodiment 1-4 is filling through aseptic processing, half tamponade product unit is placed in freeze drier, and it is dry to carry out freezing
Dry, the freeze drying process includes the following steps：
Step a, pre-freeze process：Temperature control program is：
In 90 minutes, -40 DEG C are down to by room temperature；
In 30 minutes, -24 DEG C are risen to by -40 DEG C, keeps the temperature 30 minutes；
In 60 minutes, temperature is down to -40 DEG C, keeps the temperature 240 minutes；
Step b, sublimation process：Use inert gas aeration, vacuum degree control 10pa；Temperature control program is：
In 15 minutes, temperature increases -10 DEG C from -40 DEG C, keeps the temperature 12 hours；
In 120 minutes, temperature rises to -6 DEG C from -10 DEG C, keeps the temperature 12 hours, distillation terminates；
Step c, drying process：Inert gas is mixed in stopping, and temperature rises to 30 DEG C from -6 DEG C in 60 minutes, keeps the temperature 60 minutes,
Drying terminates.
Embodiment 8
Embodiment 1-4 is filling through aseptic processing, half tamponade product unit is placed in freeze drier, and it is dry to carry out freezing
Dry, the freeze drying process includes the following steps：
Step a, pre-freeze process：Temperature control program is：
In 140 minutes, -40 DEG C are down to by room temperature；
In 40 minutes, -24 DEG C are risen to by -40 DEG C, keeps the temperature 30 minutes；
In 105 minutes, temperature is down to -40 DEG C, keeps the temperature 240 minutes；
Step b, sublimation process：Use inert gas aeration, vacuum degree control 10pa；Temperature control program is：
In 30 minutes, temperature increases -20 DEG C from -40 DEG C, keeps the temperature 40 minutes；
In 10 minutes, temperature rises to -10 DEG C from -20 DEG C, keeps the temperature 12 hours；
In 140 minutes, temperature rises to -6 DEG C from -10 DEG C, and distillation terminates；
Step c, drying process：Inert gas is mixed in stopping, and temperature rises to 25 DEG C from -6 DEG C in 50 minutes, keeps the temperature 120 minutes,
Drying terminates.
Embodiment 9
Embodiment 1-4 is filling through aseptic processing, half tamponade product unit is placed in freeze drier, and it is dry to carry out freezing
Dry, the freeze drying process includes the following steps：
Step a, pre-freeze process：Temperature control program is：
In 70 minutes, -40 DEG C are down to by room temperature；
In 60 minutes, -24 DEG C are risen to by -40 DEG C, keeps the temperature 30 minutes；
In 120 minutes, temperature is down to -40 DEG C, keeps the temperature 240 minutes；
Step b, sublimation process：Use inert gas aeration, vacuum degree control 10pa；Temperature control program is：
In 60 minutes, temperature increases -20 DEG C from -40 DEG C, keeps the temperature 40 minutes；
In 25 minutes, temperature rises to -10 DEG C from -20 DEG C, keeps the temperature 12 hours；
In 80 minutes, temperature rises to -6 DEG C from -10 DEG C, and distillation terminates；
Step c, drying process：Inert gas is mixed in stopping, and temperature rises to 25 DEG C from -6 DEG C in 20 minutes, keeps the temperature 60 minutes,
Drying terminates.
Embodiment 10
By the product after embodiment 5-9 freeze-drying, part inflated with nitrogen, total head plug under micro-vacuum rolls lid sealing after outlet,
Obtain hydrochloride for injection ligustrazine freeze-dried powder.
Specification：80mg/ branch
Product inspection result：It is examined by 2010 editions Chinese Pharmacopoeia third addendum hydrochloride for injection ligustrazine quality standards
It tests.
Character：For white or the loose block of off-white color or powder.
Differentiate：(1) it takes this product appropriate (being approximately equivalent to Ligustrazine Hydrochloride 40mg), after adding water 10ml to dissolve, adds bismuth potassium iodide
Test solution 2 drips, that is, generates Chinese red precipitation.
(2) take this product, being dissolved in water and diluting is made in every 1ml containing about the solution of Ligustrazine Hydrochloride 0.02mg, according to it is ultraviolet-
Visible spectrophotometry (two IV A of annex of Chinese Pharmacopoeia version in 2010) measures, and has absorption maximum at 295nm wavelength.
(3) in the chromatogram recorded under assay item, the retention time and reference substance solution of test solution main peak
The retention time of main peak is consistent.
(4) aqueous solution of this product shows the identification (two annex III of Chinese Pharmacopoeia version in 2010) of chloride.
The clarity and color of solution：5 bottles of this product is taken, respectively plus water 10ml dissolvings, solution answer clear, colorless.
It checks：PH value 2.3~2.5；
Content：It is the 98%~102% of labelled amount；
Other indexs comply with relevant regulations.
Effect experiment：
Compare the effect of the freeze-drying method and prior art freeze-drying method of " pre-freeze, secondary distillation repeatedly " of the invention
Fruit.
Experimental group：Using the embodiment of the present invention 1 prepare half tamponade product, respectively press embodiment 5~9 freeze drying process into
Row freeze-drying.
Control group 1：Freeze-drying method：- 55 DEG C are down to by room temperature, keeps the temperature 1 hour；It vacuumizes and reaches 8.0 × 10- 2Mbar, heating rate are 5 DEG C/h, when being warming up to -15 DEG C, maintain this temperature 6h；When being warming up to 20 DEG C with 5 DEG C/h speed, heat preservation
5h。
Control group 2：Freeze-drying method：- 55 DEG C are down to by room temperature, keeps the temperature 1 hour；It vacuumizes and reaches 8.0 × 10- 2Mbar, heating rate are 5 DEG C/h, when being warming up to -5 DEG C, maintain this temperature 10h；When being warming up to 35 DEG C with 5 DEG C/h speed, heat preservation
2h。
It is 500 that each group, which tests number, counts and splits bottle number in freezing dry process and calculate finished product Ligustrazine Hydrochloride content.As a result
It see the table below.
| Product | Test number | Split a bottle number | Ligustrazine Hydrochloride content |
| The embodiment of the present invention 5 | 500 | Nothing | 102% |
| The embodiment of the present invention 6 | 500 | Nothing | 100% |
| The embodiment of the present invention 7 | 500 | Nothing | 101% |
| The embodiment of the present invention 8 | 500 | Nothing | 98% |
| The embodiment of the present invention 9 | 500 | Nothing | 102% |
| Control group 1 | 500 | 10 | 87% |
| Control group 2 | 500 | 20 | 90% |
The experimental results showed that the method for the present invention solves the problems, such as easily to occur splitting in prior art freezing dry process bottle,
And Ligustrazine Hydrochloride volatile quantity during vacuum freezedrying can be effectively controlled, stable content is kept.
Claims (7)
1. a kind of hydrochloride for injection ligustrazine lyophilized preparation freeze-drying method, which is characterized in that this method includes following sequence
Step a-c：
Step a, pre-freeze；
Step b, 0 DEG C of distillation below, the moisture of 83% or more removal；
Step c, 0 DEG C~30 DEG C of distillation keep temperature Time constant no more than 2 hours after distillation；
Wherein, the step a pre-freeze processes are：Between temperature between 50 DEG C to 20 DEG C by being down to -30 DEG C to -50 DEG C, cooling speed
Rate is 0.2~1 DEG C/min；Temperature-rise period is that temperature rises to -24 DEG C by being warming up between -30 DEG C to -50 DEG C, heating rate 1
~2 DEG C/min；Second temperature-fall period be temperature by -24 DEG C be down to -30 DEG C to -50 DEG C between, rate of temperature fall for 0.2~1 DEG C/
min；
The auxiliary material of the lyophilized preparation is one in sodium hydroxide, hydrochloric acid, mannitol, glucosides, lactose, sodium carbonate, sodium bicarbonate
Kind is several.
2. the method as described in claim 1, which is characterized in that keep the temperature 20~40min, second of drop after the step a heatings
180~300min is kept the temperature after temperature.
3. the method as described in claim 1, which is characterized in that remove 90% or more moisture during the step b.
4. the method as described in claim 1, which is characterized in that inert gas is added during the step b.
5. method as claimed in claim 3, which is characterized in that the step b sublimation processes include the following steps：With step a
Outlet temperature be starting point, be first warming up to -20 DEG C with the speed of 1~2 DEG C/min, keep the temperature 30~40min, continue with 2~5 DEG C/
The speed of min is warming up to -10 DEG C, keeps the temperature 10~12h, is finally warming up to -6 DEG C with the speed of 0.01~0.1 DEG C/min, distillation knot
Beam.
6. the method as described in claim 1, which is characterized in that the distillation that the step c is 0 DEG C~25 DEG C, soaking time is not
It can exceed that 2 hours, which is added without inert gas.
7. a kind of preparation method of hydrochloride for injection ligustrazine lyophilized preparation, which is characterized in that described method includes following steps：
Step 1, Ligustrazine Hydrochloride and auxiliary material are taken, water for injection is added, stirs evenly；
Step 2, solution made from step 1 is filtered, obtains intermediate, adjust pH to acidity, degerming is filling；With
Step 3, it is freeze-dried after step 2 is filling, hydrochloride for injection ligustrazine lyophilized preparation is made；
Wherein, auxiliary material described in step 1 is one in sodium hydroxide, hydrochloric acid, mannitol, glucosides, lactose, sodium carbonate, sodium bicarbonate
Kind is several；The temperature of water for injection is 50~70 DEG C；Step 2 adjusts pH value to 2.0~3.0；
Step 3 freeze-drying should include a-c following steps in sequence：
Step a, pre-freeze；
Step b, 0 DEG C of distillation below, the moisture of 83% or more removal；
Step c, 0 DEG C~30 DEG C of distillation keep temperature Time constant no more than 2 hours after distillation；
Wherein, the step a pre-freeze processes are：Between temperature between 50 DEG C to 20 DEG C by being down to -30 DEG C to -50 DEG C, cooling speed
Rate is 0.2~1 DEG C/min；Temperature-rise period is that temperature rises to -24 DEG C by being warming up between -30 DEG C to -50 DEG C, heating rate 1
~2 DEG C/min；Second temperature-fall period be temperature by -24 DEG C be down to -30 DEG C to -50 DEG C between, rate of temperature fall for 0.2~1 DEG C/
min。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1931139A (en) * | 2006-10-13 | 2007-03-21 | 郭维城 | Freeze dried ligustrazine hydrochloride prepn for injection and its prepn process |
| CN103462911A (en) * | 2013-09-22 | 2013-12-25 | 苏州二叶制药有限公司 | Preparation technique of freeze-dried powder injection |
| CN104173299A (en) * | 2014-08-29 | 2014-12-03 | 湖南科伦制药有限公司 | Freeze-drying method for injection ligustrazine |
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2015
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1931139A (en) * | 2006-10-13 | 2007-03-21 | 郭维城 | Freeze dried ligustrazine hydrochloride prepn for injection and its prepn process |
| CN103462911A (en) * | 2013-09-22 | 2013-12-25 | 苏州二叶制药有限公司 | Preparation technique of freeze-dried powder injection |
| CN104173299A (en) * | 2014-08-29 | 2014-12-03 | 湖南科伦制药有限公司 | Freeze-drying method for injection ligustrazine |
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