CN106109421B - A kind of bromhexine hydrochloride granule and its preparation technology - Google Patents
A kind of bromhexine hydrochloride granule and its preparation technology Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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- C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
- C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
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Abstract
The invention belongs to pharmaceutical technology field, more particularly to a kind of bromhexine hydrochloride granule, described bromhexine hydrochloride granule is prepared from by following composition：1~8mg of bromhexine hydrochloride, 145~165mg of lactose, 280~330mg of sorbierite, 2~6mg of silica, 0.2~1mg of essence, appropriate amount of water.The medicine of described bromhexine hydrochloride granule point stable content, dissolution rate are high, it is simple to be not likely to produce impurity, preparation technology, easily storage, are particularly suitable for use in the patient or infant with aphetite disorder, general applicability is good.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of bromhexine hydrochloride particle and its preparation technology.
Background technology
Bromhexine hydrochloride, its chemical name is：N- methyl-N- cyclohexyl -2- amino -3,5- dibromobenzene methylamine hydrochlorides,
For white or the crystalline powder of off-white color；Odorless, it is tasteless.Bromhexine hydrochloride is slightly molten in ethanol or chloroform, atomic in water
Dissolving.Bronchus body of gland is can be done directly on, promotes the lysosome of mucous secreting cell to disengage, makes the viscous sugared fiber point in phlegm
Change cracking；The synthesis of acidoglycoprotein in muccus gland and goblet cell is may also suppress, is allowed to secrete the relatively low small molecule of viscosity
Glycoprotein, so that the viscosity reduction of sputum, it is easy to expectoration.In addition, causing respiratory tract with can also stimulating gastric mucosa reflectivity
Glandular secretion increase, dilutes sputum.Since 1960s, bromhexine hydrochloride is that a kind of wide variety of mucus is molten
Agent is solved, it also has the property and antibacterial activity in vitro for removing free radical.The open bromhexine hydrochloride used is generally note at present
Penetrate agent or injection freeze-dried powder or oral liquid or tablet or capsule.
Bromhexine hydrochloride solvability in water is extremely weak, although dissolubility is preferable in acid condition, but less stable,
Impurity is also easy to produce, European Pharmacopoeia 7.0 editions has recorded 5 kinds of impurity (A, B, C, D, E), wherein most commonly seen with impurity E.In order to ensure
The quality and stability of medicine, are preparing the injection or oral liquid of bromhexine hydrochloride or are also needing predissolve using preceding
Freeze dried injection, it usually needs add more auxiliary material to improve stability, and it is more harsh to preparation technology requirement.Such as
This, necessarily causes the increase of cost of drugs, and selling price is high.It is well known that the disease such as chronic bronchitis and asthma belongs to week
Phase longer chronic disease, in order to dispel the symptom that mucus adjoint therewith is difficult expectoration, it is necessary to take larger amount of eliminating the phlegm
Medicine, therefore drug price is high, is unfavorable for the utilization and extention of medicine, it is impossible to meet the basic healthy need of general public well
Ask.In addition, such bromhexine hydrochloride has higher requirement to storage and traffic condition.And for injection, patient also needs to
The assistance of special medical professional, it is inconvenient for use and need increase extra-pay.
The tablet or capsule of bromhexine hydrochloride need patient to be swallowed, and suffer with chronic bronchitis with asthma etc.
The patient of disease generally entails phlegmatic disease shape, and dysphagia is made troubles to patient, therefore compliance is poor.In addition, infant
Patient generally takes tablet or capsule, therefore lacks general applicability.And tablet and capsule are in preparation, it is difficult precisely
The content of active ingredient is controlled, each batch medicine point stable content is difficult to ensure that.
The content of the invention
It is an object of the invention to overcome above-described defect, there is provided one kind is convenient to take, medicament contg is stable, be difficult
Produce the bromhexine hydrochloride granule that impurity, preparation technology are simple, easily store, transport.In addition, the hydrochloric acid bromine for preparing of the present invention oneself
New granule is easy to carry, and dissolution rate is high, and medicine bioavailability is high, and compliance is good, and mouthfeel is good, has been especially suitable for aphetite disorder
Patient or infant patient, universal adaptability is good.
The primary and foremost purpose of the present invention is to provide a kind of bromhexine hydrochloride granule, described bromhexine hydrochloride granule
Component and content are as follows：
Described essence is that the one or more in edible essence are combined.
On the basis of technical problem of the present invention is solved, in order to further optimize bromhexine hydrochloride granule
Stability, as much as possible reduction produce the content of impurity, and the present inventor has carried out substantial amounts of experiment, obtained more excellent again
Bromhexine hydrochloride granule prescription.
Preferably, the bromhexine hydrochloride used in described bromhexine hydrochloride granule is brilliant for a kind of new bromhexine hydrochloride
Body compound, measures the X-ray powder diffraction figure that the crystal obtains as shown in Figure 1 using Cu-K alpha rays.It is spread out with 2 θ ± 0.2
The X-ray powder diffraction figure that firing angle is represented 6.3 °, 9.7 °, 10.2 °, 11.5 °, 13.6 °, 17.8 °, 20.1 °, 21.2 °,
Characteristic peak is shown at 21.7 °, 22.8 °, 23.1 °, 25.0 °, 26.5 °.
Described bromhexine hydrochloride crystalline compounds are prepared by following method：
(1) bromhexine hydrochloride crude product is ground, crosses 200~300 mesh sieves, be then added to acetic acid：Ethyl acetate body
Product is than being 3~5：In 1 mixed solution, stirring and dissolving；
(2) methanol is added while stirring：Water volume ratio is 1：3~4 mixed solution, while being warming up to 40~45 DEG C；
(3) after mixed solution is added, stand, be cooled to 5~10 DEG C, growing the grain 8~10 hours is washed, and is dried, is obtained hydrochloric acid
Bromhexine crystal.
Using the new crystalline compounds of above-described bromhexine hydrochloride as bulk drug, can effectively improve hydrochloric acid bromine oneself
The stability of new granule, the impurity content of generation is few.
Preferably, described bromhexine hydrochloride granule is prepared from by following composition：
It is highly preferred that described bromhexine hydrochloride granule is prepared from by following composition：
It is highly preferred that described bromhexine hydrochloride granule is prepared from by following composition：
Another free-revving engine of the present invention is to provide a kind of technique for preparing described bromhexine hydrochloride particle, including under
Row step：(1) bromhexine hydrochloride bulk drug, lactose, sorbierite, silica are crossed into 80 mesh sieves respectively, it is standby；
(2) bromhexine hydrochloride and lactose of recipe quantity are well mixed by the method for equal increments, add recipe quantity
Sorbierite is well mixed, and obtains mixed powder；
(3) in the state of mixed powder is stirred continuously, using water as wetting agent softwood, the granulation of 16 mesh sieves is crossed；
(4) obtained wet granular is dried, less loss weight must not cross 1.5%, crosses 10 mesh sieve whole grains；
(5) silica and essence of recipe quantity are added in the particle after whole grain, is well mixed；
(6) investigate particle appearance uniform, determine the actual content of bromhexine hydrochloride in particle；
(7) according to the actual content measurement result of bromhexine hydrochloride, sample-loading amount is calculated, particle is fitted into film bag, rapidly
Seal sack.
Further, the uniformity of the mixed powder in described step (2) reaches following standard：A+2.2s≤10.
Further, described step (7) also includes leakage sampling observation, every sampling observation in 30 minutes once.Prepared by the present invention
Bromhexine hydrochloride granule stability is good, and the impurity content of generation is low, and it is good to take compliance, be especially suitable for aphetite disorder or
The patient of inconvenience.In addition, its preparation technology is simple, do not need the storage of harshness and traffic condition, cost is reduced.
Brief description of the drawings
The X-ray powder diffraction pattern of bromhexine hydrochloride crystalline compounds prepared by Fig. 1 embodiment of the present invention 1.
Embodiment
The preparation of the bromhexine hydrochloride crystal of embodiment 1
(1) bromhexine hydrochloride crude product is ground, crosses 200~300 mesh sieves, be then added to acetic acid：Ethyl acetate body
Product is than being 3：In 1 mixed solution, stirring and dissolving；
(2) methanol is added while stirring：Water volume ratio is 1：3 mixed solution, while being warming up to 40 DEG C；
(3) after mixed solution is added, stand, be cooled to 5 DEG C, growing the grain 8 hours is washed, and is dried, and obtains bromhexine hydrochloride brilliant
Body.
X-ray powder diffraction spectrum obtained by preparation is as shown in Figure 1.
The preparation of the bromhexine hydrochloride crystal of embodiment 2
(1) bromhexine hydrochloride crude product is ground, crosses 300 mesh sieves, be then added to acetic acid：Ethyl acetate volume ratio is
5：In 1 mixed solution, stirring and dissolving；
(2) methanol is added while stirring：Water volume ratio is 1：4 mixed solution, while being warming up to 45 DEG C；
(3) after mixed solution is added, stand, be cooled to 10 DEG C, growing the grain 10 hours is washed, and is dried, is obtained bromhexine hydrochloride
Crystal.
X-ray powder diffraction spectrum obtained by preparation is as shown in Figure 1.
The preparation of the bromhexine hydrochloride crystal of embodiment 3
(1) bromhexine hydrochloride crude product is ground, crosses 250 mesh sieves, be then added to acetic acid：Ethyl acetate volume ratio is
4：In 1 mixed solution, stirring and dissolving；
(2) methanol is added while stirring：Water volume ratio is 1：3 mixed solution, while being warming up to 42 DEG C；
(3) after mixed solution is added, stand, be cooled to 7 DEG C, growing the grain 9 hours is washed, and is dried, and obtains bromhexine hydrochloride brilliant
Body.
X-ray powder diffraction spectrum obtained by preparation is as shown in Figure 1.
The preparation of the bromhexine hydrochloride granule of embodiment 4
Prescription：
Preparation method：
(1) bromhexine hydrochloride bulk drug, lactose, sorbierite, silica are crossed into 80 mesh sieves respectively, it is standby；
(2) bromhexine hydrochloride and lactose of recipe quantity are well mixed by the method for equal increments, add recipe quantity
Sorbierite is well mixed, and obtains mixed powder；
(3) in the state of mixed powder is stirred continuously, using water as wetting agent softwood, the granulation of 16 mesh sieves is crossed；
(4) obtained wet granular is dried, less loss weight must not cross 1.5%, crosses 10 mesh sieve whole grains；
(5) silica and essence of recipe quantity are added in the particle after whole grain, is well mixed；
(6) investigate particle appearance uniform, determine the actual content of bromhexine hydrochloride in particle；
(7) according to the actual content measurement result of bromhexine hydrochloride, sample-loading amount is calculated, particle is fitted into film bag, rapidly
Seal sack.
The preparation of the bromhexine hydrochloride granule of embodiment 5
Prescription：
Preparation method：
(1) bromhexine hydrochloride bulk drug, lactose, sorbierite, silica are crossed into 80 mesh sieves respectively, it is standby；
(2) bromhexine hydrochloride and lactose of recipe quantity are well mixed by the method for equal increments, add recipe quantity
Sorbierite is well mixed, and obtains mixed powder；
(3) in the state of mixed powder is stirred continuously, using water as wetting agent softwood, the granulation of 16 mesh sieves is crossed；
(4) obtained wet granular is dried, less loss weight 1%, crosses 10 mesh sieve whole grains；
(5) silica and essence of recipe quantity are added in the particle after whole grain, is well mixed, the uniformity reaches A+2.2s
≤10；
(6) investigate particle appearance uniform, determine the actual content of bromhexine hydrochloride in particle；
(7) according to the actual content measurement result of bromhexine hydrochloride, sample-loading amount is calculated, particle is fitted into film bag, rapidly
Sack is sealed, every leakage sampling observation in 30 minutes once.
The preparation of the bromhexine hydrochloride granule of embodiment 6
Prescription：
Preparation method：
(1) bromhexine hydrochloride bulk drug, lactose, sorbierite, silica are crossed into 80 mesh sieves respectively, it is standby；
(2) bromhexine hydrochloride and lactose of recipe quantity are well mixed by the method for equal increments, add recipe quantity
Sorbierite is well mixed, and obtains mixed powder；
(3) in the state of mixed powder is stirred continuously, using water as wetting agent softwood, the granulation of 16 mesh sieves is crossed；
(4) obtained wet granular is dried, less loss weight 0.5%, crosses 10 mesh sieve whole grains；
(5) silica and essence of recipe quantity are added in the particle after whole grain, is well mixed, the uniformity reaches A+2.2s
≤10；
(6) investigate particle appearance uniform, determine the actual content of bromhexine hydrochloride in particle；
(7) according to the actual content measurement result of bromhexine hydrochloride, sample-loading amount is calculated, particle is fitted into film bag, rapidly
Sack is sealed, every leakage sampling observation in 30 minutes once.
The preparation of the bromhexine hydrochloride granule of embodiment 7
Prescription：
Preparation method：
(1) bromhexine hydrochloride bulk drug, lactose, sorbierite, silica are crossed into 80 mesh sieves respectively, it is standby；
(2) bromhexine hydrochloride and lactose of recipe quantity are well mixed by the method for equal increments, add recipe quantity
Sorbierite is well mixed, and obtains mixed powder；
(3) in the state of mixed powder is stirred continuously, using water as wetting agent softwood, the granulation of 16 mesh sieves is crossed；
(4) obtained wet granular is dried, less loss weight 0.8%, crosses 10 mesh sieve whole grains；
(5) silica and essence of recipe quantity are added in the particle after whole grain, is well mixed, the uniformity reaches A+2.2s
≤10；
(6) investigate particle appearance uniform, determine the actual content of bromhexine hydrochloride in particle；
(7) according to the actual content measurement result of bromhexine hydrochloride, sample-loading amount is calculated, particle is fitted into film bag, rapidly
Sack is sealed, every leakage sampling observation in 30 minutes once.
The preparation of the bromhexine hydrochloride granule of embodiment 8
Prescription：
Preparation method：
(1) bromhexine hydrochloride bulk drug, lactose, sorbierite, silica are crossed into 80 mesh sieves respectively, it is standby；
(2) bromhexine hydrochloride and lactose of recipe quantity are well mixed by the method for equal increments, add recipe quantity
Sorbierite is well mixed, and obtains mixed powder；
(3) in the state of mixed powder is stirred continuously, using water as wetting agent softwood, the granulation of 16 mesh sieves is crossed；
(4) obtained wet granular is dried, less loss weight 0.4%, crosses 10 mesh sieve whole grains；
(5) silica and essence of recipe quantity are added in the particle after whole grain, is well mixed, the uniformity reaches A+2.2s
≤10；
(6) investigate particle appearance uniform, determine the actual content of bromhexine hydrochloride in particle；
(7) according to the actual content measurement result of bromhexine hydrochloride, sample-loading amount is calculated, particle is fitted into film bag, rapidly
Sack is sealed, every leakage sampling observation in 30 minutes once.
The preparation of the bromhexine hydrochloride granule of embodiment 9
The prescription and embodiment 4 that the embodiment is used are identical, only difference is that bromhexine hydrochloride used is this
The bromhexine hydrochloride crystalline compounds with new crystal structure prepared are invented, the method for preparation is same as Example 4.
The preparation of the bromhexine hydrochloride granule of embodiment 10
The prescription and embodiment 5 that the embodiment is used are identical, only difference is that bromhexine hydrochloride used is this
The bromhexine hydrochloride crystalline compounds with new crystal structure prepared are invented, the method for preparation is same as Example 5.
The preparation of the bromhexine hydrochloride granule of embodiment 11
The prescription and embodiment 6 that the embodiment is used are identical, only difference is that bromhexine hydrochloride used is this
The bromhexine hydrochloride crystalline compounds with new crystal structure prepared are invented, the method for preparation is same as Example 6.
The preparation of the bromhexine hydrochloride granule of embodiment 12
The prescription and embodiment 7 that the embodiment is used are identical, only difference is that bromhexine hydrochloride used is this
The bromhexine hydrochloride crystalline compounds with new crystal structure prepared are invented, the method for preparation is same as Example 7.
The preparation of the bromhexine hydrochloride granule of embodiment 13
The prescription and embodiment 8 that the embodiment is used are identical, only difference is that bromhexine hydrochloride used is this
The bromhexine hydrochloride crystalline compounds with new crystal structure prepared are invented, the method for preparation is same as Example 8.
The content uniformity test of test example 1
The purpose of the experiment is the drug content uniformity for investigating bromhexine hydrochloride prepared by the present invention.What is determined is specific
The detection method of the granule uniformity of the method with reference to described in four general rules 0941 of Chinese Pharmacopoeia 2015 edition.
Preparation process (2) mixes the sample of powder different parts in Example 4, and precision weighs 12.5mg (with bromhexine hydrochloride
Content meter), be placed in 25ml measuring bottles, plus appropriate methanol, ultrasound makes bromhexine hydrochloride dissolve and with methanol dilution to scale, shakes
Even, filtration takes filtered fluid as need testing solution；It is another to take bromhexine hydrochloride standard reference material appropriate, it is accurately weighed, plus methanol is molten
Solve and be quantitatively diluted to the solution in every 1ml containing about 0.5mg, be used as reference substance solution；Precision measures reference substance solution and for examination
Each 10 μ l of product solution, inject liquid chromatograph, chromatogram are recorded, by external standard method with bromhexine hydrochloride in calculated by peak area powder
Content.
Each batch sample that this experiment prepares embodiment to bromhexine hydrochloride is tested, the uniformity result of gained
A+2.2s≤10 are satisfied by, the good evenness of bromhexine hydrochloride granule meets pharmacopeia 2015 editions on granule uniformity
It is required that.
The dissolution rate test of test example 2
The method of testing that this test example is used is the method described in two annex XC of pharmacopeia 2015 edition, in 50 revs/min of bars
Tested under part, sample time is 5mim, 10min and 15min, and per sub-sampling 10ml, dissolution result see the table below.
The bromhexine hydrochloride granule that it can be seen from test result prepared by the present invention interior almost all in 15min is molten
Go out, dissolving is fast, content is high, convenient to take quick, good drug efficacy.
Especially, it can be drawn by result of the test：The new bromhexine hydrochloride crystal that embodiment 9-13 is obtained using the present invention
Compound, the bromhexine hydrochloride granule of preparation is implemented with preferably dissolution rate, i.e. embodiment 9 are more excellent than embodiment 4 relatively
Example 10 is more excellent compared with embodiment 5, the like, embodiment 13 is more excellent compared with embodiment 8.Therefore, the new hydrochloric acid bromine that the present invention is obtained
Oneself can further lift the dissolution rate of bromhexine hydrochloride granule by new crystalline compounds.
The accelerated test of test example 3
The bromhexine hydrochloride granule for taking 4-13 of the embodiment of the present invention to prepare, is packed by commercial standard, in temperature 40 ± 2
DEG C, accelerated test is carried out under conditions of relative humidity 75% ± 5%, investigate 6 months, take 1 respectively, 2,3, sampling in June, test production
Raw impurity content (%), it is as a result as shown in the table.
It can be drawn by test result：Bromhexine hydrochloride granule prepared by the present invention places 6 in accelerated test condition
Month, the impurity content of generation is low, and drug quality is stable, good reliability.
In addition, can be drawn by result of the test：The new bromhexine hydrochloride crystal that embodiment 9-13 is obtained using the present invention
Compound, the bromhexine hydrochloride granule of preparation has relatively more excellent stability, i.e. embodiment 9 is more excellent than embodiment 4, implements
Example 10 is more excellent compared with embodiment 5, the like, embodiment 13 is more excellent compared with embodiment 8.Therefore, the new hydrochloric acid bromine that the present invention is obtained
Oneself can further improve the stability of bromhexine hydrochloride granule by new crystalline compounds.
The bromhexine hydrochloride assay of test example 4
The bromhexine hydrochloride granule for taking 4-13 of the embodiment of the present invention to prepare, is packed by commercial standard, in temperature 40 ± 2
DEG C, accelerated test is carried out under conditions of relative humidity 75% ± 5%, investigate 6 months, take 0 respectively, 2,3, sampling in June, test salt
The actual content of sour bromhexine, it is as a result as shown in the table.
The medicine point content of the own granule of hydrochloric acid bromine prepared from test result, the present invention is highly stable and homogeneous,
Drug effect is reliable, is very suitable for popularization and application.In addition, prepared by the new bromhexine hydrochloride crystalline compounds obtained using the present invention
The medicine of bromhexine hydrochloride particle point content is higher, and more stable, performance is more preferably.
Claims (8)
1. a kind of bromhexine hydrochloride granule, it is characterised in that described bromhexine hydrochloride granule prepared by following composition and
Into：
Described bromhexine hydrochloride is a kind of bromhexine hydrochloride crystalline compounds, and its X- obtained using Cu-K alpha ray measurements is penetrated
Line powder diagram as shown in figure 1, the X-ray powder diffraction figure represented with the angles of diffraction of 2 θ ± 0.2 6.3 °, 9.7 °, 10.2 °,
Characteristic peak is shown at 11.5 °, 13.6 °, 17.8 °, 20.1 °, 21.2 °, 21.7 °, 22.8 °, 23.1 °, 25.0 °, 26.5 °.
2. a kind of bromhexine hydrochloride granule according to claim 1, it is characterised in that described bromhexine hydrochloride crystal
Compound is prepared through the following steps：
(1) bromhexine hydrochloride crude product is ground, crosses 200~300 mesh sieves, be then added to acetic acid：Ethyl acetate volume ratio
For 3~5：In 1 mixed solution, stirring and dissolving；
(2) methanol is added while stirring：Water volume ratio is 1：3~4 mixed solution, while being warming up to 40~45 DEG C；
(3) after mixed solution is added, stand, be cooled to 5~10 DEG C, growing the grain 8~10 hours is washed, and is dried, obtain hydrochloric acid bromine oneself
New crystal.
3. a kind of bromhexine hydrochloride granule according to claim 1~2 any one, it is characterised in that described salt
Sour bromhexine granule is prepared from by following composition：
4. a kind of bromhexine hydrochloride granule according to claim 3, it is characterised in that described bromhexine hydrochloride particle
Agent is prepared from by following composition：
5. a kind of bromhexine hydrochloride granule according to claim 3, it is characterised in that described bromhexine hydrochloride particle
Agent is prepared from by following composition：
6. a kind of preparation technology of bromhexine hydrochloride granule according to claim any one of 1-5, it is characterised in that bag
Include the following steps：
(1) bromhexine hydrochloride bulk drug, lactose, sorbierite, silica are crossed into 80 mesh sieves respectively, it is standby；
(2) bromhexine hydrochloride and lactose of recipe quantity are well mixed by the method for equal increments, add the sorb of recipe quantity
Alcohol is well mixed, and obtains mixed powder；
(3) in the state of mixed powder is stirred continuously, using water as wetting agent softwood, the granulation of 16 mesh sieves is crossed；
(4) obtained wet granular is dried, less loss weight must not exceed 1.5%, crosses 10 mesh sieve whole grains；
(5) particle after whole grain adds the silica and essence of recipe quantity, is well mixed；
(6) particle appearance uniformity is investigated, the actual content of bromhexine hydrochloride in particle is determined；
(7) according to the actual content measurement result of bromhexine hydrochloride, sample-loading amount is calculated, particle is fitted into film bag, rapid sealing
Sack, is produced.
7. preparation technology according to claim 6, it is characterised in that the uniformity of the mixed powder in described step (2) reaches
To following standard：A+2.2s≤10.
8. preparation technology according to claim 6, it is characterised in that described step (7) also includes leakage sampling observation, every
Sampling observation in 30 minutes is once.
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| CN102525949B (en) * | 2012-01-17 | 2013-06-05 | 山东罗欣药业股份有限公司 | Cefaclor composition particles and preparation method thereof |
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