CN107582528B - Method and products thereof for wet granulation - Google Patents
Method and products thereof for wet granulation Download PDFInfo
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- CN107582528B CN107582528B CN201710952109.9A CN201710952109A CN107582528B CN 107582528 B CN107582528 B CN 107582528B CN 201710952109 A CN201710952109 A CN 201710952109A CN 107582528 B CN107582528 B CN 107582528B
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Abstract
The present invention relates to a kind of for insufficient method of excessively pelletizing or pelletize to be reduced or avoided in pelletization comprising: active pharmaceutical ingredient and the pharmaceutically acceptable auxiliary material that is optionally present are subjected to cold air drying by the granulation solution wet granular obtained that pelletize.The invention further relates to the products obtained by the method.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, more particularly to the method and thus obtained production for wet granulation
Product.
Background technique
Tablet is the solid pharmaceutical preparation of sheet made of drug is suppressed after evenly mixing with auxiliary material or special-shaped sheet.Due to taking
Convenient, quality is stablized, low in cost, easy to carry and transport, is widely applied.In order to improve material compressibility and
Mobility increases the homogeneity of material, usually to use granulation technique in the preparation process of tablet.Wet granulation (Wet
It Granulation is) using granulation technique earlier, because its equipment is simple, manufactured particle wearability is strong, compact property
It is good, it is still widely adopted now.Common wet granulation is can pharmaceutically to connect the active constituent that measure ratio with what is be optionally present
The auxiliary material mixing received mixes, and adds the solution of adhesive, is stirred by certain external force or shearing formation has certain grain
The wet granular of diameter.Wet whole grain is then carried out, it is dry, it finally carries out dry whole grain and obtains the dry particl for being suitable for tabletting.
The influence factor of wet granulation is very more.For material itself, the partial size, crystal form of active constituent itself, bonding
Type, dosage, concentration and the adding manner of agent and the property of other auxiliary materials have a certain impact to wet granulation.It is general next
Say, active constituent, auxiliary material viscosity is bigger or the dosage of adhesive is bigger, concentration is higher, the bonding of active constituent and auxiliary material
Property it is stronger, pelletize it is more abundant, grain diameter obtained and hardness are bigger.In addition, for technological parameter, wet granulator
Rotating speed of agitator, granulating cutter revolving speed, Granulation time also have a significant impact to granulation.Rotating speed of agitator is bigger, and Granulation time is longer,
It pelletizes more abundant.It may due to binder dosage, excessive, rotating speed of agitator be too fast or Granulation time in wet-granulation process
There is excessively granulation phenomenon in the reasons such as too long, it is also possible to since binder dosage is insufficient, rotating speed of agitator is too slow or Granulation time
There is insufficient phenomenon of pelletizing in too short etc. reasons.
If there is excessive granulation phenomenon in wet-granulation process, wet granulation stage and/or wet whole grain rank may cause
There is large crumb in material in section, and subsequent drying is insufficient, and material fluidity is poor, easily occurs filling difference in tableting processes, leads
Slice weight is caused to be difficult to control and tabletting is made to be difficult to carry out.If there is insufficient phenomenon of pelletizing in wet-granulation process, object will cause
Expect that fine powder is excessive, tableting processes may can not be carried out because of the serious sticking of material.In addition, the excessive granulation in wet-granulation process
Phenomenon is not noticeable, often seems very uniform wet granular in granulator, just will appear agglomerate in the wet whole grain stage
Block.It then has no idea excessively to pelletize by adjusting factor controllings such as binder dosage, rotating speed of agitator or Granulation times at this time existing
The generation of elephant.
Therefore, a kind of new method of granulating is needed, to solve the activity of granulation end point window narrows existing in the prior art
Easily there is insufficient problem of excessively pelletizing and/or pelletize in wet-granulation process in ingredient.
Summary of the invention
On the one hand, the present invention relates to it is a kind of for be reduced or avoided in pelletization excessively pelletize or pelletize it is insufficient
Method comprising: active pharmaceutical ingredient and the pharmaceutically acceptable auxiliary material being optionally present are pelletized by granulation solution
And the wet granular obtained carries out cold air drying.
On the other hand, the invention further relates to a kind of wet granulation methods comprising:
(a) by active pharmaceutical ingredient and the pharmaceutically acceptable auxiliary material that is optionally present by granulation solution pelletize with
Obtain wet granular；
(b) wet granular is subjected to cold air drying；
(c) wet granular after cold air drying is subjected to wet whole grain；
(d) particle after wet whole grain is dried；With
(e) particle after drying is subjected to dry whole grain, to obtain the dry particl for being suitable for tabletting.
In another aspect, the invention further relates to a kind of methods for preparing tablet comprising by wet process through the invention
Tabletting after the dry particl that method of granulating obtains is mixed with the pharmaceutically acceptable auxiliary material being optionally present, to obtain described
Agent.
Detailed description of the invention
Fig. 1 is the appearance of wet granular 3-1.
Fig. 2 is the appearance of the wet granular 3-1-1 after direct wet whole grain.
Fig. 3 be cold air drying after carry out again wet whole grain wet granular 3-1-2 appearance.
Specific embodiment
The present invention is described in more detail below, it should be appreciated that the term is intended to describe purpose, rather than limits this hair
It is bright.
Definition
Unless otherwise indicated, the technical and scientific term used herein has and those skilled in the art of the invention
The identical meaning being generally understood.Contradiction if it exists, then be subject to definition provided by the present application.When with range, preferred scope,
Or the form of preferred numerical upper limits and preferred numerical lower limits state some amount, concentration or other values or parameter when
It waits, it should be understood that be equivalent to and specifically disclose by by any pair of range limit or preferred value and any range lower limit or excellent
Any range that numerical value combines is selected, without considering whether the range specifically discloses.Unless otherwise indicated, listed herein
The endpoint and all integers and score (decimal) within the scope of this that numberical range is intended to include range.
Term " about ", " about " are when being often referred to the numerical value of the variable and all numbers of the variable with numerical variable and the used time
Value is in experimental error (such as in the confidence interval of average value 95%) or in ± the 10% of specified numerical value or wider model
In enclosing.
Term " optional " or " being optionally present " refer to that the event then described or situation may occur or may not occur, should
Description includes that the event or situation occurs and the event or situation does not occur.For example, statement " by active pharmaceutical ingredient and
The pharmaceutically acceptable auxiliary material being optionally present is fed into granulator " in, cover pharmaceutically acceptable auxiliary material and exists or do not deposit
The case where.When pharmaceutically acceptable auxiliary material is not present, active pharmaceutical ingredient can be fed directly in granulator；When
There are when pharmaceutically acceptable auxiliary material, active pharmaceutical ingredient and auxiliary material can be fed directly in granulator together, or
The two can be mixed to rear feeding into granulator.Equally, term " optional " or " being optionally present " also cover the member described thereafter
Element can be according to requiring the meaning for being subject to selection.
Statement "comprising" or with its synonymous similar statement " comprising ", " containing " and " having " etc. be it is open, do not arrange
Except additional unlisted element, step or ingredient.State " Consists of " exclude unspecified any element, step or at
Point.Statement "consisting essentially of ..." how is limited in specified element, step or ingredient, in addition what is be optionally present will not be real
Element, step or the ingredient of the basic and new feature of theme claimed are influenced in matter.It should be appreciated that statement "comprising"
Cover statement "consisting essentially of ..." and " Consists of ".
Term " one or more " can indicate a kind of, two kinds, three kinds, four kinds, five kinds, six kinds, seven kinds, eight kinds, nine kinds
Or more.
Term " wet granulation " refers to be added in active pharmaceutical ingredient powder and the pharmaceutically acceptable auxiliary material being optionally present
Enter granulation solution, by the gantry or cementation of granulation solution make powder coalesce together to preparation have certain shapes and
The shot-like particle of size.The method of wet granulation include squeeze granulation, rotation granulation, fluidized bed granulation, high shear granulation and by spraying
Drying and granulating etc..Traditional wet granulation mainly includes softwood wet granular, wet whole grain, drying and dry whole grain processed.
The pharmaceutically acceptable auxiliary material that term " wet granular " refers to active pharmaceutical ingredient and is optionally present is molten by pelletizing
Liquid is pelletized and the wet granular that obtains.Such process, such as can be carried out in granulator.The example has can be through the present invention
The particle that obtains afterwards of wet granulation method step (a).
Term " cold wind " refers to without using heating operation, to be performed corresponding processing using air at room temperature.Accordingly
Ground, " cold air drying " refer to being dried under cold wind state.Herein, " cold air drying " can for example pass through fluidized bed
It carries out.In such embodiments, the air inlet heating system of fluidized bed is closed, to enter the wind using air at room temperature.
Term " room temperature " refers to environment temperature, usually 18-26 DEG C.
Term " wet whole grain " refers to the sieve by predetermined size in pelletizing machine, by wet after wet granular/cold air drying
Grain passes through sieve under defined revolving speed.The size of sieve for example can be 4 × 4mm, 5 × 5mm, 8 × 8mm or 9 × 9mm.Turn
Speed can be, for example, 900 ± 250rpm.
Term " dry whole grain " refers in the sieve by predetermined size in pelletizing machine, by the dry particl after drying defined
Pass through sieve under revolving speed.The size of sieve for example can be 0.813mm, 1.016mm, 1.270mm, 1.575mm or 2.007mm.
Revolving speed can be, for example, 750 ± 250rpm.
Term " granulation end point " refers to the end point that wet-granulation process stops.
Statement " wet granulation endpoint window is narrow " refers to when minor change occurs for material or wet granulation technology parameter
It is easy to produce insufficient phenomenon of excessively pelletizing or pelletize, and avoids the hair of this phenomenon without suitable End point indication
It is raw.Such situation, which is common in, contains a large amount of (such as accounting is higher than 50% to active constituent in tablets) water soluble ingredients or inorganic
Salt, and lack the prescription with water suction/water holding capacity auxiliary material, being also common in material properties, (such as adhesive is used to grain made parameter
Amount, Granulation time etc.) variation than more sensitive prescription.
Term " excessively granulation " or " granulation is excessive " refer to that excess is added in adhesive or Granulation time is too long, cause pelletizing
It is formed in machine compared with large crumb or is formed during wet whole grain compared with large crumb.It in the drying process can not be completely dry compared with large crumb
Thoroughly, cause the material of final tabletting tacky, mobility is very poor, makes tableting processes be difficult to carry out because slice weight is unable to control.
Term " granulation is insufficient " or " granulation is insufficient " refer to that deficiency is added in adhesive or Granulation time is too short, lead to wet
Grain is unable to fully to be formed, and material fine powder is excessive.Serious sticking occurs in tableting processes and tableting processes is made to be difficult to carry out.
Term " pharmaceutically acceptable ", which refers to, to be contacted without in normal medical judgment scope with the tissue of patient
There are inappropriate toxicity, irritation, allergic reaction etc., there is reasonable pros and cons ratio and can be effective for purpose purposes.
Term " active pharmaceutical ingredient ", " active constituent ", " therapeutic agent ", " active material " or " activating agent " refers to a kind ofization
Entity is learned, target disease or illness can be effectively treated or prevent.
Active pharmaceutical ingredient used in the present invention is not particularly limited, such as can be adapted for the medicine with various properties
Object active constituent, such as the various particles size and distributions of wide scope, water solubility.For example, active constituent used in the present invention
Particle size range can be those of common in formulation art, such as D90 partial size is to hundreds of microns or bigger a few micrometers, such as 1-
1000 μm, 2-500 μm or 10-200 μm.But the active constituent narrow for wet granulation endpoint window, it is especially water-soluble strong,
Weight ratio in tablets is more than 50% active constituent, and method of the invention is particularly suitable.
The example of active constituent includes but is not limited to that Bupropion or its pharmaceutically acceptable salt, especially hydrochloric acid are pacified
His non-ketone.It should be appreciated that active constituent can cover its salt, ester, polymorph, solvate (including such as hydrate and mixed
The solvate of conjunction and the hydrate of salt), eutectic, unformed and anhydrous form and its mixture.In preferred embodiment
In, above-mentioned form is pharmaceutically acceptable.
BUPROPIONE HCl (Bupropion) is that a kind of norepinephrine, serotonin, dopamine reuptake inhibit
Agent, is usually used in the treatment of depression, also can be used as smoking cessation ancillary drug.Chemical name is 1- (3- chlorphenyl) -2- [(1,1- bis-
Methylethyl) amino] -1- acetone, shown in chemical structural formula such as formula (I).
Term " BUPROPIONE HCl " include 1- (3- chlorphenyl) -2- [(1,1- dimethyl ethyl) amino] -1- acetone, its
Enantiomter, diastereoisomer or their mixture." BUPROPIONE HCl " of this paper also includes BUPROPIONE HCl
Salt, polymorph, solvate (hydrate including such as hydrate and mixed solvate and salt), eutectic, nothing
Sizing and anhydrous form and its mixture.In preferred embodiments, above-mentioned form is pharmaceutically acceptable.
Insufficient method of excessively pelletizing or pelletize is reduced or avoided
On the one hand, the present invention relates to it is a kind of for be reduced or avoided in pelletization excessively pelletize or pelletize it is insufficient
Method comprising: active pharmaceutical ingredient and the pharmaceutically acceptable auxiliary material being optionally present are pelletized by granulation solution
And the wet granular obtained carries out cold air drying.
As described above, method of the invention is not particularly limited active pharmaceutical ingredient, such as can be adapted for having
There are the active pharmaceutical ingredient of various properties, such as the various particles size and distributions of wide scope, water solubility.But for wet granulation
The narrow active constituent of endpoint window, especially water-soluble strong, weight ratio in tablets is more than 50% active constituent, above-mentioned side
Method is particularly suitable.
In one embodiment, active pharmaceutical ingredient is Bupropion or its pharmaceutically acceptable salt.At another
In preferred embodiment, active constituent is BUPROPIONE HCl.
In another embodiment, pharmaceutically acceptable auxiliary material includes but is not limited to filler, adhesive, antioxygen
One of agent, stabilizer are a variety of.
In yet another embodiment, filler can be for selected from microcrystalline cellulose, starch, pregelatinized starch, lactose, sweet dew
One of alcohol, calcium monohydrogen phosphate are a variety of.
In yet another embodiment, adhesive can be for selected from modified starch, gelatin, polyvinyl alcohol, carboxymethyl cellulose
In sodium, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, polyvinylpyrrolidone (PVP) or hydroxypropyl methyl cellulose
It is one or more.In a preferred embodiment, adhesive is in polyvinylpyrrolidone, polyvinyl alcohol
It is one or more.
Polyvinylpyrrolidone is also known as povidone (Povidone), such as can be by vinyl pyrrolidone in water
In or the free radical polymerization in 2- propyl alcohol and prepared.The K value of polyvinylpyrrolidone is in about 10- about 95, preferably 20-
95.The K value is also known as Fikentscher K value, refers to commonly used in the art to comprising vinyl pyrrolidone units
Or mixtures thereof polymer molecular weight measurement, and can if H.Fikentscher is in Cellulose-Chemie,
Method described in 1932,13:58-64/71-74 is measured with 1 weight % aqueous solution.
More specifically, in an especially preferred embodiment, adhesive polyethylene base pyrrolidones can be for for example
The product of International Specialty Products companies market OrAnd the commercial product of BASF AG OrOne of or it is a variety of, but not limited to this.
In an especially preferred embodiment, polyvinyl pyrrolidone can beOrOne of or it is a variety of.
In yet another embodiment, antioxidant can be for selected from butylhydroxy anisole (BHA), dibutyl hydroxy toluene
(BHT), one of propylgallate (PG), tert-butyl hydroquinone (TBHQ), anhydrous sodium sulfate or sodium hydrogensulfite or
It is a variety of.
In yet another embodiment, stabilizer can be for selected from hydrochloric acid, L- cysteine hydrochloride, glycine hydrochloride, apple
Acid, sodium pyrosulfite, citric acid, acetic acid, fumaric acid, maleic acid, tartaric acid, succinic acid, oxalic acid, malonic acid, benzene
One of formic acid, mandelic acid, L-cysteine, ascorbic acid or arabo-ascorbic acid are a variety of.It is particularly preferred at one
In embodiment, stabilizer is selected from one of hydrochloric acid, L- cysteine hydrochloride or tartaric acid or a variety of.
It should be noted that above-mentioned cited pharmaceutically acceptable auxiliary material is illustrative and representative.Therefore,
Pharmaceutical preparation of the invention is not limited to cited pharmaceutically acceptable auxiliary material herein above.Those skilled in the art can root
Various changes, adjustment or equivalent replacement are carried out to above-mentioned auxiliary material according to routine techniques, without departing from protection scope of the present invention.
In one embodiment, granulation solution can be selected from pure water, ethanol water, dehydrated alcohol, isopropanol and its mix
Close object.It respectively can optionally contain pharmaceutically acceptable auxiliary material in these granulation solutions, such as optionally contain and pharmaceutically may be used
Water or ethanol water of the auxiliary material of receiving etc..In a preferred embodiment, it is water-soluble to can be selected from pure water, ethyl alcohol for granulation solution
Liquid, the optionally water containing pharmaceutically acceptable auxiliary material and the ethanol water for optionally containing pharmaceutically acceptable auxiliary material.
Pharmaceutically acceptable auxiliary material such as those described above.In a more preferred, granulation solution
In the pharmaceutically acceptable auxiliary material that contains can be one of adhesive, antioxidant or stabilizer or a variety of.
In the method for the invention, it after pelletize by granulation solution and obtaining wet granular, is carried out by cold air drying
Processing.In a preferred embodiment, cold air drying is carried out by fluidized bed.In another preferred embodiment, cold wind
Dry inlet air temperature is room temperature.
After carrying out cold air drying to wet granular, subsequent working process step optionally can be carried out according to actual needs.
For example, the wet granular after cold air drying can be carried out to wet whole grain, drying, dry whole grain, tabletting etc..It will be into if should be appreciated that
The processing of row subsequent step, then wind cold drying should carry out before carrying out these steps.It is obtained for example, being pelletized by granulation solution
After wet granular, cold air drying is carried out, then carries out wet whole grain, drying, dry whole grain, tabletting again.
It is also understood that conflict unless otherwise specified or obviously, below with respect to being referred to such as in the description of wet granulation
The example (such as to described in step (a) and (b)) of various parameters be readily applicable to method as discussed above corresponding steps or
Stage.
Wet granulation method
On the other hand, the invention further relates to a kind of wet granulation methods comprising:
(a) by active pharmaceutical ingredient and the pharmaceutically acceptable auxiliary material that is optionally present by granulation solution pelletize with
Obtain wet granular；
(b) wet granular is subjected to cold air drying；
(c) wet granular after cold air drying is subjected to wet whole grain；
(d) particle after wet whole grain is dried；With
(e) particle after drying is subjected to dry whole grain, to obtain the dry particl for being suitable for tabletting.
Step (a):
In step (a), granulation can carry out in granulator.It can be by active pharmaceutical ingredient and the pharmacy being optionally present
Upper acceptable auxiliary material, which is fed directly in granulator, pelletizes, without mixing in advance.Alternatively, can also be by pharmaceutical activity
Ingredient and the pharmaceutically acceptable auxiliary material being optionally present are uniformly mixed, and are then fed into granulator and are pelletized.When not depositing
Pharmaceutically when acceptable auxiliary material, directly active pharmaceutical ingredient can be fed into granulator and pelletized.
In one embodiment, active pharmaceutical ingredient is Bupropion or its pharmaceutically acceptable salt.At another
In preferred embodiment, active constituent is BUPROPIONE HCl.
In another embodiment, pharmaceutically acceptable auxiliary material includes but is not limited to filler, adhesive, antioxygen
One of agent, stabilizer are a variety of.
In yet another embodiment, filler can be for selected from microcrystalline cellulose, starch, pregelatinized starch, lactose, sweet dew
One of alcohol, calcium monohydrogen phosphate are a variety of.
In yet another embodiment, adhesive can be for selected from modified starch, gelatin, polyvinyl alcohol, carboxymethyl cellulose
In sodium, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, polyvinylpyrrolidone (PVP) or hydroxypropyl methyl cellulose
It is one or more.In a preferred embodiment, adhesive is in polyvinylpyrrolidone, polyvinyl alcohol
It is one or more.
Polyvinylpyrrolidone is also known as povidone (Povidone), such as can be by vinyl pyrrolidone in water
In or the free radical polymerization in 2- propyl alcohol and prepared.The K value of polyvinylpyrrolidone is in about 10- about 95, preferably 20-
95.The K value is also known as Fikentscher K value, refers to commonly used in the art to comprising vinyl pyrrolidone units
Or mixtures thereof polymer molecular weight measurement, and can if H.Fikentscher is in Cellulose-Chemie,
Method described in 1932,13:58-64/71-74 is measured with 1 weight % aqueous solution.
More specifically, in an especially preferred embodiment, adhesive polyethylene base pyrrolidones can be for for example
The product of International Specialty Products companies market OrAnd the commercial product of BASF AG OrOne of or it is a variety of, but not limited to this.
In an especially preferred embodiment, polyvinyl pyrrolidone can beOrOne of or it is a variety of.
In yet another embodiment, antioxidant can be for selected from butylhydroxy anisole (BHA), dibutyl hydroxy toluene
(BHT), one of propylgallate (PG), tert-butyl hydroquinone (TBHQ), anhydrous sodium sulfate or sodium hydrogensulfite or
It is a variety of.
In yet another embodiment, stabilizer can be for selected from hydrochloric acid, L- cysteine hydrochloride, glycine hydrochloride, apple
Acid, sodium pyrosulfite, citric acid, acetic acid, fumaric acid, maleic acid, tartaric acid, succinic acid, oxalic acid, malonic acid, benzene
One of formic acid, mandelic acid, L-cysteine, ascorbic acid or arabo-ascorbic acid are a variety of.It is particularly preferred at one
In embodiment, stabilizer is selected from one of hydrochloric acid, L- cysteine hydrochloride or tartaric acid or a variety of.
In one embodiment, the amount for the pharmaceutically acceptable auxiliary material being optionally present is not particularly limited, Ke Yigen
It is adjusted according to actual conditions.For example, the pharmaceutically acceptable auxiliary material being optionally present is based on active pharmaceutical ingredient and optionally
The amount of the about 2-20% (w/w) of the total weight of existing pharmaceutically acceptable auxiliary material exists, preferably from about 5-15% (w/w), more
Preferably from about 5-10% (w/w), even more preferably about 9% (w/w), for example including but be not limited to 2.5% (w/w), 6% (w/w),
9% (w/w) and 12% (w/w) etc..
It should be noted that above-mentioned cited pharmaceutically acceptable auxiliary material is illustrative and representative.Therefore,
Pharmaceutical preparation of the invention is not limited to cited pharmaceutically acceptable auxiliary material herein above.Those skilled in the art can root
Various changes, adjustment or equivalent replacement are carried out to above-mentioned auxiliary material according to routine techniques, without departing from protection scope of the present invention.
In the method for the invention, the mode that granulation solution is added is not particularly limited, such as can be sprayed using pressurized tank
Enter or peristaltic pump input mode.
In pelletization, the mode of stirring and/or shearing can be taken.For example, can open and stir in pelletization
Mix paddle and/or granulating cutter.Agitating paddle and/or the revolving speed of granulating cutter can be constantly adjusted according to the character of material in granulator,
It can also remain uniform revolving speed.In a preferred embodiment, agitating paddle and/or granulating cutter maintain uniform revolving speed.Example
Such as, the revolving speed of agitating paddle is about 50-250rpm, preferably from about 100-200rpm, more preferably from about 150rpm.For example, granulating cutter turns
Speed is about 500-2500rpm, preferably from about 1000-2000rpm, more preferable 1500rpm.
In one embodiment, granulation solution can be selected from pure water, ethanol water, dehydrated alcohol, isopropanol and its mix
Close object.It respectively can optionally contain pharmaceutically acceptable auxiliary material in these granulation solutions, such as optionally contain and pharmaceutically may be used
Water or ethanol water of the auxiliary material of receiving etc..In a preferred embodiment, it is water-soluble to can be selected from pure water, ethyl alcohol for granulation solution
Liquid, the optionally water containing pharmaceutically acceptable auxiliary material and the ethanol water for optionally containing pharmaceutically acceptable auxiliary material.
Pharmaceutically acceptable auxiliary material such as those described above.In a more preferred, granulation solution
In the pharmaceutically acceptable auxiliary material that contains can be one of adhesive, antioxidant or stabilizer or a variety of.
In a preferred embodiment, granulation solution is ethanol water, and concentration is that the ethyl alcohol of 0-95% (w/w) is water-soluble
Liquid, preferably 30-95% (w/w), more preferable 50-95% (w/w), even more preferably 70-95% (w/w), most preferably 80% (w/
w)。
The amount of granulation solution is not particularly limited, and can be adjusted according to the actual situation.In one embodiment, it makes
The amount of grain solution is based on the total of granulation dry material (i.e. active pharmaceutical ingredient and the pharmaceutically acceptable auxiliary material being optionally present)
The amount of the about 5-20% (w/w) of weight exists, such as from about 8-17% (w/w), preferably from about 10-15% (w/w), more preferably from about 11-
14% (w/w), even more preferably about 14% (w/w), for example including but be not limited to 12% (w/w), 12.5% (w/w), 13% (w/
W), 14% (w/w) and 15% (w/w) etc..
Step (b):
In step (b), handled by wet granular of the cold air drying to acquisition.That is, to acquisition before wet whole grain
Wet granular carry out cold air drying.If carrying out cold air drying after wet whole grain, can not solve the problems, such as excessively to pelletize.
In a preferred embodiment, cold air drying is carried out by fluidized bed.In another preferred embodiment, cold
Air-drying dry inlet air temperature is room temperature.
In a preferred embodiment, cold air drying (as by fluidized bed progress) intake volume be about 1000- about
3000m3/ h, preferably from about 1200- about 2800m3/ h, preferably from about 1500- about 2500m3/ h, more preferably from about 1800- about 2200m3/
H, most preferably 2000m3/ h, for example including but be not limited to 1500m3/h、1800m3/h、2000m3/h、2200m3/ h and 2500m3/h
Deng.
In a preferred embodiment, carry out cold air drying (as by fluidized bed progress) time be about 3- about
15min, preferably from about 3-12min, more preferably from about 3-10min, even more preferably about 3-8min, most preferably 5min, for example including but
It is not limited to 3min, 4min, 5min, 6min, 7min, 8min, 9min and 10min.
Step (c):
In step (c), wet whole grain will be carried out obtained from the particle of step (b).
The sieve of wet whole grain is not particularly limited, including but not limited to square mesh or circular screen mesh.Of the invention one
In a preferred embodiment, it having a size of 4 × 4-9 × 9mm, such as can be 4 × 4mm, 5 that the sieve of wet whole grain, which is square mesh,
× 5mm, 8 × 8mm or 9 × 9mm, preferably 9 × 9mm.The revolving speed of wet whole grain is also not particularly limited, preferably at of the invention one
In embodiment, the revolving speed of wet whole grain is 600-1200rpm, preferably 800-1000rpm, more preferable 900rpm.
Step (d):
In step (d), the particle after the wet whole grain of step (c) is dried.
The mode that particle after wet whole grain is dried is not particularly limited, including but not limited to fluidized bed drying, baking
Case drying etc..In an especially preferred embodiment, the mode that the particle after wet whole grain is dried is done for fluidized bed
It is dry.In an especially preferred embodiment, the particle after wet whole grain is carried out the inlet air temperature of fluidized bed drying is about 50-
About 80 DEG C, intake volume is about 1000- about 3000m3/ h, time are about 30-150min.
Step (e):
In step (e), dry whole grain will be carried out obtained from the dry particle of step (d).
The sieve of dry whole grain is not particularly limited, including but not limited to fish scale shape sieve or circular screen mesh.Of the invention
In one preferred embodiment, the sieve for doing whole grain is fish scale shape sieve, having a size of from about 0.8- about 2.1mm, such as can be
0.813mm, 1.016mm, 1.270mm, 1.575mm or 2.007mm, preferably 1.575mm.The revolving speed of dry whole grain is also without special limit
System, in a preferred embodiment of the invention, do whole grain revolving speed be 500-1000rpm, preferably 650-850rpm, it is more excellent
Select 750rpm.By doing whole grain, the dry particl for being suitable for tabletting can be obtained.
Correspondingly, the invention further relates to a kind of dry particls for being suitable for tabletting, wet granulation method through the invention
It obtains.
In one embodiment, particle of the partial size less than 125 microns is no more than dry particl total weight in dry particl
50%.
The invention further relates to a kind of methods for preparing tablet comprising obtains wet granulation method through the invention
Dry particl tabletting, to obtain the tablet.
In one embodiment, tabletting method include by the dry particl be optionally present it is pharmaceutically acceptable auxiliary
Tabletting after material (such as one of pH adjusting agent, filler, disintegrating agent, lubricant or corrigent or a variety of) mixing.
Correspondingly, the invention further relates to a kind of tablets of dry particl preparation through the invention.
In one embodiment, tablet is 50-240N, preferably 90-240N according to the hardness that USP method measures.Another
In one embodiment, tablet is no more than 1% according to the friability that USP method measures.In yet another embodiment, tablet root
Disintegration time according to the measurement of USP method is no more than 30min.In preferred embodiments, the tablet has one or more
Following characteristics (measure) according to USP method: hardness 50-240N, preferably 90-240N；Friability is no more than 1%；Disintegration time
No more than 30min.
Beneficial effect
The active constituent narrow for wet granulation endpoint window, it is upper using existing method of granulating commercially producing, it may
Lead to following problems: (1) in the wet granulation stage since binder dosage is insufficient, rotating speed of agitator is too slow or Granulation time is too short
Etc. reasons there is the insufficient phenomenon of pelletizing, cause material fine powder excessive, tableting processes may can not be into due to material serious sticking
Row；(2) in the wet granulation stage occurring due to binder dosage is excessive, rotating speed of agitator is too fast or Granulation time is too long etc.
Excessively granulation phenomenon, may cause material in wet granulation stage and/or wet whole grain stage and large crumb occurs, subsequent drying is not
Sufficiently, material fluidity is poor, easily occurs filling difference in tableting processes, slice weight is caused to be difficult to control and tabletting is made to be difficult to carry out.
The unexpected discovery of the present inventor, in pelletization, after obtaining wet granular, by one section of its cold air drying
Time can effectively solve insufficient phenomenon of excessively pelletizing or pelletize because of material properties or technological parameter difference bring.It will be through
The wet granular for crossing cold air drying carries out subsequent processing and can get the dry particl for being suitable for tabletting.
Compared with prior art, by carrying out cold air drying before wet whole grain, to remove the excessive solvent in wet granular,
It can avoid the formation of the agglomerate block material in wet granulation stage and/or wet whole grain stage.Due to not having to worry excessively granulation
Risk, in pelletization can suitably by granulation end point instruction limit set height, enough adhesives are added so that granulation foot
It is enough abundant, so as to the insufficient problem of pelletizing for avoiding the amount deficiency because of adhesive from generating.
Further, as described in embodiments herein, in the production of pharmaceutical business metaplasia, it is very difficult to which control is such as former
Expect the nature difference of partial size etc. between medicine is criticized, and meeting is so that the differences between batches of raw material are further magnified in pelletization.Such as this
Demonstrated in the embodiment of text, by means of the present invention, it can be avoided various problems caused by such difference and its draw
The loss on time and cost risen.Therefore, for the active pharmaceutical ingredient of wide scope property, method of the invention is all applicable
's.
In short, compared with prior art, wet granulation method of the invention provides height technology stability, reduce because of material
Differences between batches caused by property or technological parameter difference are more suitable for being commercialized mass production.
Embodiment
Hereinafter technical solution of the present invention will be further described by specific embodiment.It should be noted that the embodiment is only
To be exemplary, rather than limiting the scope of the invention.The active pharmaceutical ingredient and other groups enumerated in the embodiments herein
The property divided is only used for example the solution of the present invention, is not intended to limit the scope of the present invention.Those skilled in the art answer
Work as understanding, the present invention can also there are other embodiments, or can be practiced or carried out in many ways.Unless otherwise indicated, herein
In all percentage, number, ratio etc. be by weight.
Medicine material and auxiliary material used herein are commercially available.For example, BUPROPIONE HCl is purchased from Supor company,
Povidone is purchased from ISP company, and magnesium stearate is purchased from Mallinckrodt company.
The influence of 1 conventional wet method of granulating of embodiment-technological parameter
1, method and step
Using particle diameter distribution in table 1-1, (determining instrument is the active constituent 1- of pulp classifier Sympatek Helos/Rodos)
Grain made parameter in 1 and 1-2 and table 1-2 carries out wet granulation with step as follows:
(1) will about 80kg active ingredient hydrochloric acid Bupropion and about 2kg povidone in granulator (400L Aeromatic
Fielder High Shear Mixer) in carry out dry-mixing
(2) after dry-mixing, a certain proportion of 80% ethanol water (w/w) is sprayed by pressurized tank, opens stirring
Paddle and granulating cutter carry out wet granulation and obtain corresponding wet granular 1-1 and 1-2, and wherein the revolving speed of agitating paddle is 150 ± 50rpm,
The revolving speed of granulating cutter is 1500 ± 250rpm；Agitating paddle power full-scale reading is recorded simultaneously, passes through agitating paddle power full-scale reading
The additional amount and Granulation time of value control granulation solution
(3) wet granular 1-1 and 1-2 are passed through into wet pelletizing machine (Aeromatic Fielder Sirocco NPS250 Wet
Mill wet whole grain) is carried out, the size of square mesh is 9 × 9mm, and revolving speed is 900 ± 250rpm
(4) wet granular after wet whole grain is transferred in fluidized bed (Fluid bed dryer Dfi 400) dry about 30-
150min (until the loss on drying of particle is not more than 1%), fluidized bed inlet air temperature is about 65 ± 5 DEG C, and intake volume is about
2000±500m3/h
(5) particle after drying is subjected to dry whole grain, fish scale shape shape sieve by dry pelletizing machine (Quadro Comil U20)
The size of net be 1.016mm, revolving speed be 750 ± 250rpm to get arrive corresponding dry particl 1-1 and 1-2
(6) by the magnesium stearate of dry particl and 1%, (amount of magnesium stearate is the weight based on dry particl and magnesium stearate total amount
Amount percentage) be added to hopper mixing machine (300L Bin Blender) carry out after mixing, use tablet press machine (Manesty
XPress 500) tabletting to get arrive corresponding tablet 1-1 and 1-2
Table 1-1 active constituent particle diameter distribution
Table 1-2 wet granulation technology parameter
* granulation solution amount is the weight hundred based on granulation dry material (active constituent and pharmaceutically acceptable auxiliary material) total amount
Score.
2, particle proterties are evaluated
1) wet granular conglobation property
It is found in pelletization, wet granular 1-1 is generated after whole grain overly moist without obvious large crumb.And wet granular 1-2 is passed through
Occur obvious large crumb after whole grain overly moist, illustrates that excessive granulation phenomenon occurs in wet granular 1-2.
2) dry particl compressibility
It is found in tableting processes, using dry particl 1-1 tabletting, slice weight is controllable, and tableting processes are normal.Tablet root obtained
It is measured according to USP method, hardness 90-240N, friability is no more than 1%, and disintegration time is no more than 30min.In contrast, it uses
Dry particl 1-2 tabletting, material fluidity is very poor, and filling inaccuracy, slice weight is uncontrollable, and tableting processes can not carry out.
From the above results, it can be seen that, although used active constituent partial size is essentially identical when preparing dry particl 1-1 and 1-2,
When granulation solution only occurs small variation (increasing to 13% from 12.5%), also gap is very small (from 7min drop for mixing time
When for 6.5min), very big change can occur for the character of the dry particl finally obtained.It means that passing through conventional granulation
Method, it is very difficult to the final properties of control granulation product.
The influence of 2 conventional wet method of granulating of embodiment-active constituent partial size
1, method and step
Using particle diameter distribution in table 2-1, (determining instrument is the active constituent 2- of pulp classifier Sympatek Helos/Rodos)
Grain made parameter in 1 and 2-2 and table 2-2 carries out wet granulation according to the conventional wet method of granulating in embodiment 1, can obtain
Obtain corresponding dry particl 2-1 and 2-2.
Table 2-1 active constituent particle diameter distribution
Table 2-2 wet granulation technology parameter
*Granulation solution amount is the weight hundred based on granulation dry material (active constituent and pharmaceutically acceptable auxiliary material) total amount
Score.
2, particle proterties are evaluated
1) wet granular conglobation property
Wet granular 2-1 and 2-2 is generated without obvious large crumb after whole grain overly moist.
2) dry particl particle diameter distribution
Pulp classifier (Sympatek Helos/Rodos) is used to measure its particle diameter distribution after obtaining dry particl, as a result such as following table
Shown in 2-3.
Table 2-3 dry particl particle diameter distribution
The results show that the fine powder amount (< 125 μm) in dry particl 2-2 is apparently higher than dry particl 2-1 (60%v.s.47%),
Illustrate the insufficient phenomenon of granulation occurred.
3) dry particl compressibility
Using dry particl 2-1 tabletting, sticking phenomenon does not occur, tableting processes are normally carried out.Tablet obtained is according to the side USP
Method measurement, hardness 90-240N, friability are no more than 1%, and disintegration time is no more than 30min.In contrast, using dry particl
2-2 tabletting, occurs serious sticking phenomenon, and tableting processes can not carry out.
From the above results, it can be seen that used granulation solution is consistent when preparation dry particl 2-1 is with 2-2, and Granulation time
Unanimously, the only slightly difference of the particle diameter distribution between active constituent results in particle proterties obtained that very big change has occurred.
In fact, in the production of pharmaceutical business metaplasia, it is very difficult to control bulk pharmaceutical chemicals batch between partial size, and in pelletization
Middle meeting is so that the differences between batches of raw material are further magnified.Different API partial sizes is different to technological parameters such as binder dosages
Requirement, for example, partial size reduce, adhesive requirement increase；Partial size increases, and adhesive requirement reduces.For window of pelletizing
For narrow prescription, even if when using the same materials medicine of identical producer's different batches, the granulating process parameter of each batch
It requires to do intense adjustment, it is slightly improper, it will lead to the failure of entire batch.This unstable technique gives business metaplasia
It produces and brings greatly inconvenient and resource waste.
Wet granulation method-the cold air drying of the invention of embodiment 3
1, method and step
According to the active constituent and technological parameter in table 3-1, according in embodiment 1 method and step (1) and (2) carry out it is wet
Method granulation, can be obtained wet granular 3-1.Wet granular 3-1 is divided into two parts to get wet granular 3-1-1 and wet granular 3-
1-2.Wet granular 3-1 has large crumb in granulator and is formed, and excessively granulation phenomenon occurs, as shown in Figure 1.
Wet granular 3-1-1 is directly carried out wet whole grain (according to (3) the step of embodiment 1), forms large crumb after wet whole grain,
Uniform wet granular can not be obtained (see Fig. 2).Large crumb wet granular after wet whole grain is used into fluidized bed cold air drying, wet granular
Large crumb is remained as, does not obtain uniform particle.And the large crumb after these wet whole grains will be unable in subsequent drying process
Absolutely dry, material can be tacky after doing whole grain, and loadings inaccuracy, tableting processes can not be normally carried out when eventually resulting in tabletting.
Wet granular 3-1-2 is first used into fluidized bed (Fluid bed dryer Dfi 400) cold air drying, is then carried out again
Wet whole grain (according to (3) the step of embodiment 1), obtains uniform wet granular (see Fig. 3).
Cold air drying technique parameter is as follows:
| Inlet air temperature | Room temperature |
| Intake volume | About 2000 ± 500m3/h |
| Time | About 5min |
Table 3-1 active constituent partial size and wet granulation technology parameter
*Granulation solution amount is the weight hundred based on granulation dry material (active constituent and pharmaceutically acceptable auxiliary material) total amount
Score.
As can be seen from Figure 2, obtained excessively to have pelletized using the active constituent and technological parameter in table 3-1
There is large crumb after the directly wet whole grain of wet granular 3-1, i.e., excessively granulation phenomenon can not be retrieved.However, before wet whole grain, it will
The wet granular excessively pelletized carries out cold air drying processing, can effectively solve the excessive system having already appeared in wet-granulation process
Grain phenomenon.But first carry out wet whole grain, then by the wet granular for large crumb occur carry out cold air drying processing, to large crumb without
Improvement result.This means that carrying out cold air drying processing only before wet whole grain, it just can solve in wet-granulation process and occur
Excessive granulation problem.
The influence of the wet granulation method of the invention of embodiment 4-active constituent partial size
1, method and step
Use following particle diameter distribution in table 4-1 (determining instrument for the activity of pulp classifier Sympatek Helos/Rodos) at
Divide grain made parameter in 4-1 and 4-2 and table 4-2, carry out wet granulation with step as follows:
(1) will about 80kg active ingredient hydrochloric acid Bupropion and about 2kg povidone in granulator (400L Aeromatic
Fielder High Shear Mixer) in carry out dry-mixing
(2) after dry-mixing, a certain proportion of 80% ethanol water (w/w) is sprayed by pressurized tank, opens stirring
Paddle and granulating cutter carry out wet granulation and obtain corresponding wet granular 4-1 and 4-2, and wherein the revolving speed of agitating paddle is 150 ± 50rpm,
The revolving speed of granulating cutter is 1500 ± 250rpm；Agitating paddle power full-scale reading is recorded simultaneously, passes through agitating paddle power full-scale reading
The additional amount and Granulation time of value control granulation solution
(3) wet granular being transferred in fluidized bed (Fluid bed dryer Dfi 400), inlet air temperature is room temperature, into
Wind air quantity is about 2000 ± 500m3/ h, time are about 5min
(4) wet granular after cold air drying is passed through into wet pelletizing machine (Aeromatic Fielder Sirocco
NPS250Wet mill) wet whole grain is carried out, the size of square mesh is 9 × 9mm, and revolving speed is 900 ± 250rpm
(5) wet granular after wet whole grain is transferred in fluidized bed (Fluid bed dryer Dfi 400) to dry, fluidisation
Bed inlet air temperature is about 65 ± 5 DEG C, and intake volume is about 2000 ± 50m3/h
(6) particle after drying is subjected to dry whole grain, fish scale shape sieve by dry pelletizing machine (Quadro Comil U20)
Size be 1.016mm, revolving speed be 750 ± 250rpm to get arrive corresponding dry particl 4-1 and 4-2
(7) by the magnesium stearate of dry particl and 2%, (amount of magnesium stearate is the weight based on dry particl and magnesium stearate total amount
Amount percentage) it is added to hopper mixing machine (300L Bin Blender) after mixing, use tablet press machine (Manesty
XPress 500) tabletting to get arrive corresponding tablet 4-1 and 4-2
Table 4-1 active constituent particle diameter distribution
Table 4-2 wet granulation technology parameter
*Granulation solution amount is the weight hundred based on granulation dry material (active constituent and pharmaceutically acceptable auxiliary material) total amount
Score.
2, particle proterties
1) wet granular conglobation property
Wet granular 4-1 is generated in granulator without obvious large crumb.Wet granular 4-2 has a small amount of agglomerate in granulator and produces
Raw, then there is obvious large crumb in direct wet whole grain, shows excessive granulation phenomenon occurred.It is wet but even if there is excessively granulation
As long as particle 4-2 is first after cold air drying, then carries out wet whole grain, then occur without large crumb.
2) dry particl particle diameter distribution
Pulp classifier (Sympatek Helos/Rodos) is used to measure its particle diameter distribution after obtaining dry particl, as a result such as following table
Shown in 4-3.
Table 4-3 dry particl particle diameter distribution
The results show that the fine powder amount (< 125 μm) in dry particl 4-1 and 4-2 is no more than 50%, illustrate not pelletize
Insufficient phenomenon.
3) compressibility is evaluated
Using dry particl 4-1 and 4-2 tabletting, do not occur sticking phenomenon, slice weight is controllable, and tableting processes are normally carried out.System
The tablet obtained is measured according to USP method, hardness 90-240N, and friability is no more than 1%, and disintegration time is no more than 30min.
It can be seen that using (D90=48.19 μm of different-grain diameter；D90=62.77 μm) active constituent, using the present invention
Wet granulation method, can get suitable for tabletting dry particl.Further, the excessive granulation for occurring in pelletization
Phenomenon is handled by cold air drying, and during subsequent wet whole grain, phenomenon of excessively pelletizing can be solved, i.e., large crumb disappears
It loses.Continue subsequent technique, still can get the dry particl suitable for tabletting.
Therefore, by means of the present invention, so that granulating process can opereating specification and stability greatly improve.
It will be clear for a person skilled in the art that many modifications and variations of the present invention can be carried out without departing from its spirit and model
It encloses.Specific embodiment as described herein is only provided by way of example, is not meant to limit in any way.The present invention
True scope and spirit shown by the appended claims, description and embodiments are merely exemplary.
Claims (32)
1. a kind of for insufficient method of excessively pelletizing or pelletize to be reduced or avoided in pelletization comprising:
Active pharmaceutical ingredient and the pharmaceutically acceptable auxiliary material that is optionally present pelletize by granulation solution and is obtained
Wet granular carries out cold air drying；
Wherein, the active pharmaceutical ingredient is Bupropion or its pharmaceutically acceptable salt；
The inlet air temperature of the cold air drying is room temperature.
2. a kind of wet granulation method comprising:
(a) active pharmaceutical ingredient and the pharmaceutically acceptable auxiliary material being optionally present are pelletized by granulation solution to obtain
Wet granular；
(b) wet granular is subjected to cold air drying；
(c) wet granular after cold air drying is subjected to wet whole grain；
(d) particle after wet whole grain is dried；With
(e) particle after drying is subjected to dry whole grain, to obtain the dry particl for being suitable for tabletting；
Wherein, the active pharmaceutical ingredient is Bupropion or its pharmaceutically acceptable salt；
The inlet air temperature of the cold air drying is room temperature.
3. the method for claims 1 or 2, which is characterized in that
The active pharmaceutical ingredient is BUPROPIONE HCl.
4. the method for claims 1 or 2, which is characterized in that
The pharmaceutically acceptable auxiliary material is selected from one of filler, adhesive, antioxidant and stabilizer or a variety of.
5. method for claim 4, which is characterized in that
Described adhesive is fine selected from modified starch, gelatin, polyvinyl alcohol, sodium carboxymethylcellulose, hydroxypropyl cellulose, methyl
Tie up one of element, ethyl cellulose, polyvinylpyrrolidone and hydroxypropyl methyl cellulose or a variety of.
6. method for claim 4, which is characterized in that
Described adhesive is selected from one of polyvinyl alcohol and polyvinylpyrrolidone or a variety of.
7. method for claim 4, which is characterized in that
Described adhesive is polyvinylpyrrolidone.
8. method for claim 4, which is characterized in that
The stabilizer be selected from hydrochloric acid, L- cysteine hydrochloride, glycine hydrochloride, malic acid, sodium pyrosulfite, citric acid,
Acetic acid, fumaric acid, maleic acid, tartaric acid, succinic acid, oxalic acid, malonic acid, benzoic acid, mandelic acid, half Guang ammonia of L-
One of acid, ascorbic acid and arabo-ascorbic acid are a variety of.
9. method for claim 4, which is characterized in that
The stabilizer is selected from one of hydrochloric acid, L- cysteine hydrochloride and tartaric acid or a variety of.
10. method for claim 4, which is characterized in that
The stabilizer is tartaric acid.
11. the method for claims 1 or 2, which is characterized in that
The granulation solution is selected from pure water, ethanol water, dehydrated alcohol, isopropanol and its mixture, and above-mentioned granulation solution is each
From optionally contain pharmaceutically acceptable auxiliary material.
12. the method for claim 11, which is characterized in that
The ethanol water is 0-95% (w/w) ethanol water.
13. the method for claim 11, which is characterized in that
The ethanol water is 30-95% (w/w) ethanol water.
14. the method for claim 11, which is characterized in that
The ethanol water is 50-95% (w/w) ethanol water.
15. the method for claim 11, which is characterized in that
The ethanol water is 70-95% (w/w) ethanol water.
16. the method for claim 11, which is characterized in that
The ethanol water is 80% (w/w) ethanol water.
17. the method for claims 1 or 2, which is characterized in that
The intake volume of the cold air drying is 1000-3000m3/h。
18. the method for claims 1 or 2, which is characterized in that
The intake volume of the cold air drying is 1200-2800m3/h。
19. the method for claims 1 or 2, which is characterized in that
The intake volume of the cold air drying is 1500-2500m3/h。
20. the method for claims 1 or 2, which is characterized in that
The intake volume of the cold air drying is 1800-2200m3/h。
21. the method for claims 1 or 2, which is characterized in that
The intake volume of the cold air drying is 2000m3/h。
22. the method for claims 1 or 2, which is characterized in that
The time of the cold air drying is 3-15min.
23. the method for claims 1 or 2, which is characterized in that
The time of the cold air drying is 3-12min.
24. the method for claims 1 or 2, which is characterized in that
The time of the cold air drying is 3-10min.
25. the method for claims 1 or 2, which is characterized in that
The time of the cold air drying is 3-8min.
26. the method for claims 1 or 2, which is characterized in that
The time of the cold air drying is 5min.
27. a kind of method for preparing tablet comprising:
By the dry particl obtained by the method for any one of claim 2-26 be optionally present it is pharmaceutically acceptable auxiliary
Tabletting after material mixing, to obtain the tablet.
28. a kind of dry particl is obtained by the method for any one of claim 1-26.
29. the dry particl of claim 28, which is characterized in that
Particle of the partial size less than 125 μm is no more than the 50% of dry particl total weight in the dry particl.
30. a kind of tablet is obtained by the method for claim 27.
31. the tablet of claim 30, wherein the tablet has one or more following characteristics:
Hardness is 50-240N；
Friability is no more than 1%；
Disintegration time is no more than 30min.
32. the tablet of claim 31, wherein the tablet has the feature that
Hardness is 90-240N.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102836165A (en) * | 2012-09-18 | 2012-12-26 | 沈阳奥吉娜药业有限公司 | Aspirin vitamin C effervescent tablet and preparation technology thereof |
| CN106333023A (en) * | 2015-07-09 | 2017-01-18 | 广东豪爽天然保健食品有限公司 | Ganoderma-linearstripe rabdosia teabag and preparation method thereof |
-
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| CN102836165A (en) * | 2012-09-18 | 2012-12-26 | 沈阳奥吉娜药业有限公司 | Aspirin vitamin C effervescent tablet and preparation technology thereof |
| CN106333023A (en) * | 2015-07-09 | 2017-01-18 | 广东豪爽天然保健食品有限公司 | Ganoderma-linearstripe rabdosia teabag and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| COMPARISON OF BIOAVAILABILITY FOR PHENYTOIN PRODUCTS PREPPARED BY WET GRANULATION IN NORMAL SUBJECTS AND EPILEPTIC PATIENTS;YUKINAO KOHDA，et al;《J.Pharm.Dyn》;19831231;第752-759页 |
| 实验动物饲料化学污染物和微生物控制探讨;金树兴等;《实验动物与比较医学》;20080831;第274-276页 |
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Address after: Room 205 and 207, 515 huanke Road, China (Shanghai) pilot Free Trade Zone, Pudong New Area, Shanghai, 201210 Patentee after: Shanghai xuantai Pharmaceutical Technology Co., Ltd Address before: 201203 1st floor, building 3, 99 Haike Road, Pudong New Area, Shanghai Patentee before: SINOTHERAPEUTICS Inc. |