CN107260698B - A kind of preparation method of maleic acid Afatinib piece - Google Patents
A kind of preparation method of maleic acid Afatinib piece Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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Abstract
The present invention discloses a kind of preparation method of maleic acid Afatinib piece, and it is comprised the steps of：1) by weight, each raw material is weighed respectively, 2) maleic acid Afatinib, diluent, polyethylene glycol and Nei Jia calcium sulfate are well mixed, are heated to 60~70 DEG C, 10~15min is incubated after reaching predetermined temperature, room temperature cools down, add disintegrant, additional sulfuric acid calcium, magnesium stearate, silica after whole grain to be well mixed, tabletting, 3) tablet is coated produced, gained tablet steady quality, content are uniform, have good In Vitro Dissolution behavior.
Description
Technical field
The invention belongs to technical field of medicine, and in particular to a kind of preparation method of maleic acid Afatinib piece.
Background technology
Maleic acid Afatinib was researched and developed by Boehringer Ingelheim (Boehringer-Ingelheim), July 12 in 2013
Huo FDA (Food and Drug Adminstration)s (FDA) approval listing, obtain within 25th European FAD (EMA) after September in 2013
Approval listing, Japanese pharmaceutical product medicine equipment comprehensive organ (PMDA) approval listing is obtained on January 17th, 2014, by Bo Linge Yin
Lattice writing brush list marketing, commodity are
The chemical name of maleic acid Afatinib is：4- [(the chloro- 4- fluorophenyls of 3-) amino] -6- { [4- (N, N- dimethyl
Amino) -1- oxos -2- butene-1s-yl] amino } -7- ((S)-tetrahydrofuran -3- bases epoxide)-quinazoline 2-maleate, knot
Structure formula is：
Molecular formula：C32H33ClFN5O11, molecular weight：718.1, it is readily soluble in water for white to brownish-yellow powder, in ethanol
Middle slightly soluble, it is insoluble in acetonitrile.The formulation sold at present on American market is tablet, is mainly used in treating EGF
(EGFR) acceptor 1 is mutated the non-small cell lung cancer (NSCLC) of the positive.
Research has shown that oxidation reaction may occur under the high temperature conditions for maleic acid Afatinib, oxidation impurities 12 are produced,
Therefore antioxidant 2 need to be often added in prescription, and 6- di-tert-butyl-4-methy phenols (BHT), prevent oxidation reaction from producing, it is described
The structural formula of oxidation impurities 12 be：
On the other hand, maleic acid Afatinib easily hydrolyzes under conditions of high humidity, and chemical stability is poor, is also easy to produce impurity
A so that active component is reduced, hydrolytic degradation products increase, and described impurity A structural formula is：
Therefore, the common preparation technology of Afatinib tablet has：Direct powder compression or compressing dry granulation, it is such as public
The number of opening is：CN 105456222A Chinese patent application " maleic acid Afatinib piece and preparation method thereof " uses powder vertical compression
The method of piece prepares tablet, and technique is simple, easy to operate, but maleic acid Afatinib salt is in fine acicular form, causes spicule
Random alignment and length and caused by bulk density smaller and mobility it is poor, prepared using direct compression method, easily
Cause during directly compression processing procedure the capping of tablet or it is laminated, compressibility is poor, while reduce the content uniformity of tablet.
Separately there is Publication No.：The A of CN 106074427 Chinese patent application " a kind of maleic acid Afatinib tablet and its
Preparation method ", tablet is prepared using compressing dry granulation, improve mobility, but dry granulation is the effect in mechanical force
Lower granulation, pelletization quality control is relatively difficult, particle properties it is repeated poor, be also easy to produce fine powder, obtained particle
General harder and irregular, compacting tablet friability is also very high, pitted skin phenomenon easily occurs.
It is a kind of emerging granulation technique of Abroad in Recent Years to heat pelleting method, is that will make after the relatively low solid melts of fusing point
Make a kind of technology of powder granulation for liquid adhesive.Pelletization need not use water or organic solvent, can avoid drug hydrolysis
And organic solvent residual；Exempt drying steps, energy- and time-economizing, one-step palletizing, greatly shorten the production cycle.Currently without on
The relevant report of maleic acid Afatinib piece is prepared using hot melt pelleting method.
The content of the invention
The purpose of the present invention is overcome the deficiencies in the prior art and provides a kind of preparation method of maleic acid Afatinib piece,
Gained tablet steady quality, content are uniform, have good In Vitro Dissolution behavior.
Specifically, the present invention is achieved through the following technical solutions object above：
A kind of preparation method of maleic acid Afatinib piece, it is characterised in that comprise the steps of：
(1) by weight, 25~40 parts of maleic acid Afatinib, 100~150 parts of diluent, poly- second two are weighed respectively
It is 30~40 parts of alcohol, 10~20 parts of calcium sulfate, 3~5 parts of disintegrant, 0.1~0.5 part of magnesium stearate, silica 1~2 part, soluble in the stomach
5~6 parts of type film coating pre-mix dose, it is standby；
(2) maleic acid Afatinib, diluent, polyethylene glycol and Nei Jia calcium sulfate are well mixed, are heated to 60~70
DEG C, 10~15min is incubated after reaching predetermined temperature, room temperature is cooled down, and disintegrant, additional sulfuric acid calcium, stearic acid are added after whole grain
Magnesium, silica are well mixed, tabletting；
(3) plain piece is subjected to film coating using stomach dissolved film coating pre-mix dose, obtains maleic acid Afatinib piece.
Further, the mass ratio of described interior plus calcium sulfate and additional sulfuric acid calcium is 1:2~4.
Preferably, the mass ratio of described interior plus calcium sulfate and additional sulfuric acid calcium is 1:3.
Further, described diluent is mannitol and microcrystalline cellulose PH101 with 4~6:1 mass ratio composition.
Preferably, described diluent is mannitol and microcrystalline cellulose PH101 with 5:1 mass ratio composition.
Further, described polyethylene glycol is polyethylene glycol PEG4000, polyethylene glycol PEG6000, polyethylene glycol
At least one of PEG8000, polyethylene glycol PEG10000, polyethylene glycol PEG20000.
Preferably, described polyethylene glycol is polyethylene glycol PEG6000.
Further, described disintegrant be Ac-Di-Sol, it is PVPP, more methyl starch sodium, low
Substitute at least one of hydroxypropylcellulose.
Preferably, described disintegrant is PVPP.
Further, described stomach dissolved film coating pre-mix dose is295B680002。
Specifically, the hot melt pelletization in above-mentioned steps (2) is carried out in fluid bed, and specific parameter is：Set
Blower fan frequency is 30~50Hz, and temperature of charge is 60~70 DEG C, and the heat time is 10~15min.
The present inventor carries out the system of particle using hot melt granulating process in the preparation process of maleic acid Afatinib piece
It is standby, have been surprisingly found that using the poor mannitol combination microcrystalline cellulose of mobility as diluent, obtained tablet has preferable
Performance, smooth appearance, hardness is preferable, and friability is relatively low, and tablet weight variation is few, and content is uniform, and with the lactose of more flowability
Or the analog sorbierite of mannitol replaces mannitol, and microcrystalline cellulose is combined as diluent, tablet each side is made
It can substantially reduce, especially be used using sorbierite combination microcrystalline cellulose as diluent, obtained tablet various aspects of performance reduces
It is the most obvious.Speculate mannitol occur to be changed into unbodied change by crystalline solid in reflow process, further with maleic acid
Afatinib, interior plus calcium sulfate and polyethylene glycol interaction, form the higher particle of sphericity.
In addition, the present inventor will be applied to the preparation of maleic acid Afatinib piece within calcium sulfate plus with additional mode,
As a result find, interior plus calcium sulfate can significantly improve the integrality of particle made from hot melt granulating process, and additional sulfuric acid calcium can show
Writing improves the compressibility of tablet, obtained tablet is had preferable uniformity of dosage units and In Vitro Dissolution performance, and steady quality,
Impurity is formed less, achieves unexpected technique effect.
On the other hand, present inventors have shown that using the hot melt granulating process shown in the present invention, obtained tablet finished product is external
Dissolving out capability grinds tablet with originalSimilar, stripping property is good, and its hydrolysis impurity A (refers to accompanying drawing without growth trend
2), it is significantly better than and maleic acid Afatinib piece is prepared using wet granulation technology (hydrolysis impurity A refers in rising appreciably trend
Accompanying drawing 1), show that there is preferable stability using maleic acid Afatinib piece made from hot melt granulating process, can effectively suppress
Hydrolysis impurity A generation.Meanwhile use the prescription of the present invention to be prepared with compressing dry granulation technique, obtained Malaysia
Sour Afatinib piece dissolution RSD% is larger, hence it is evident that is ground more than using maleic acid Afatinib piece made from present invention process and original
TabletShow that there is preferable dissolving out capability using maleic acid Afatinib piece made from hot melt granulating process.
In addition, the present inventor has been unexpectedly discovered that, by strictly controlling maleic acid Afatinib heat exposure condition, (temperature is not
More than 70 DEG C, and heated time (after reaching predetermined temperature) is no more than 15 minutes, hereafter rapid to cool at room temperature), carry out Malaysia
The preparation of sour Afatinib piece, without adding BHT, you can the total amount of impurity is effectively reduced, it is miscellaneous compared with the tablet containing BHT
Matter total amount difference is not notable, and stability is preferable, achieves preferable effect.
Compared with prior art, advantage of the invention is that：
(1) using the present invention shown in maleic acid Afatinib piece smooth appearance made from technique, hardness is preferable, friability compared with
Low, tablet weight variation is few, and content is uniform, has good In Vitro Dissolution behavior, and it is similar to grind tablet to original, and steady quality, can
Effectively suppress impurity generation, reduce total impurities, improve Drug safety.
(2) present invention is used to prepare maleic acid Afatinib piece by the way of Nei Jia and additional sulfuric acid calcium, can significantly change
The integrality of particle made from kind hot melt granulating process, improves the compressibility of tablet, obtained tablet is had preferable content
The uniformity and In Vitro Dissolution performance, and tablet stability can be improved, reduce impurity generation.
(3) the problem of dissolvent residual being not present using technique shown in the present invention, and exempt drying, energy- and time-economizing, a step system
Grain, greatly shortens the production cycle.
Brief description of the drawings
Fig. 1 maleic acid Afatinib pieces of the present invention grind tablet stripping curve figure with original.
Fig. 2 uses the chromatogram of maleic acid Afatinib piece made from wet granule compression tablet technique.
Fig. 3 uses the chromatogram of maleic acid Afatinib piece made from technique shown in the present invention.
Embodiment
The present invention is further described below by way of embodiment, but the present invention is not limited only to following examples.
Embodiment 1-3 and comparative example 1-10 maleic acid Afatinib pieces preparation
Embodiment 1-3The composition of maleic acid Afatinib piece see the table below shown：
Comparative example 1-7The composition of maleic acid Afatinib piece see the table below shown：
Comparative example 8-10The composition of maleic acid Afatinib piece see the table below shown：
Embodiment 1The preparation of maleic acid Afatinib piece：
(1) by weight, maleic acid Afatinib 29.56g, mannitol 118g, microcrystalline cellulose are weighed respectively
PH10124g, polyethylene glycol PEG6000 30g, calcium sulfate 10g, PVPP 3.6g, magnesium stearate 0.5g, silica
2g, stomach dissolved film coating pre-mix dose (295B680002) 5.4g, it is standby；
(2) by maleic acid Afatinib, mannitol, microcrystalline cellulose PH101, polyethylene glycol PEG6000 and Nei Jia sulfuric acid
Calcium (2.5g) is well mixed, is heated to 70 DEG C, is incubated 15min after reaching predetermined temperature, room temperature is cooled down, and crosslinking is added after whole grain
PVP, additional sulfuric acid calcium (7.5g), magnesium stearate, silica are well mixed, tabletting；
(3) by plain piece using stomach dissolved film coating pre-mix dose (Film coating 295B680002) is carried out, is obtained
Maleic acid Afatinib piece.
Shown in the preparation reference implementation example 1 of the maleic acid Afatinib piece of embodiment 2 and 3.
Shown in the preparation reference implementation example 1 of comparative example 1-7 maleic acid Afatinib pieces.
Comparative example 8The preparation of maleic acid Afatinib piece：
(1) by weight, maleic acid Afatinib 29.56g, mannitol 118g, microcrystalline cellulose are weighed respectively
PH10124g, polyethylene glycol PEG6000 30g, calcium sulfate 10g, PVPP 3.6g, magnesium stearate 0.5g, silica
2g, stomach dissolved film coating pre-mix dose (295B680002) 5.4g, it is standby；
(2) maleic acid Afatinib, mannitol, microcrystalline cellulose PH101, polyethylene glycol PEG6000 and calcium sulfate are mixed
Close uniform, be heated to 70 DEG C, reach and 15min is incubated after predetermined temperature, room temperature cooling, PVPP, hard is added after whole grain
Fatty acid magnesium, silica are well mixed, tabletting；
(3) by plain piece using stomach dissolved film coating pre-mix dose (Film coating 295B680002) is carried out, is obtained
Maleic acid Afatinib piece.
The preparation of comparative example 8 is similar to preparing for embodiment 1, and difference is, calcium sulfate only within plus mode carry out piece
The preparation of agent.
Comparative example 9The preparation (wet granule compression tablet method) of maleic acid Afatinib piece
(1) by weight, maleic acid Afatinib 29.56g, mannitol 118g, microcrystalline cellulose are weighed respectively
It is PH10124g, the 30g of 30 POVIDONE K 30 BP/USP 90, calcium sulfate 10g, PVPP 3.6g, magnesium stearate 0.5g, silica 2g, soluble in the stomach
Type film coating pre-mix dose (295B680002) 5.4g, it is standby；
(2) maleic acid Afatinib, mannitol, microcrystalline cellulose PH101,30 POVIDONE K 30 BP/USP 90 and calcium sulfate are well mixed,
Using purified water softwood, it is equal to be put into 60 DEG C of dryings in baking oven, whole grain, and the mixing of PVPP, silica, magnesium stearate
It is even, tabletting；
(3) by plain piece using stomach dissolved film coating pre-mix dose (Film coating 295B680002) is carried out, is obtained
Maleic acid Afatinib piece.
Comparative example 10The preparation (compressing dry granulation) of maleic acid Afatinib piece
(1) by weight, maleic acid Afatinib 29.56g, lactose 118g, microcrystalline cellulose PH101 are weighed respectively
24g, PVPP 3.6g, magnesium stearate 0.5g, silica 2g, stomach dissolved film coating pre-mix dose (
295B680002) 5.4g, it is standby；
(2) maleic acid Afatinib, lactose, microcrystalline cellulose PH101 are well mixed, pelletized using dry granulating machine,
Add PVPP, magnesium stearate, silica to be well mixed, tabletting；
(3) by plain piece using stomach dissolved film coating pre-mix dose (Film coating 295B680002) is carried out, is obtained
Maleic acid Afatinib piece.
The quality testing of test example one, maleic acid Afatinib piece
Outward appearance, hardness, friability are carried out to maleic acid Afatinib piece made from embodiment 1-3 and comparative example 1-10 respectively
Degree, tablet weight variation, accumulation stripping quantity (using water as dissolution medium) detection, and tablet is ground with originalAccumulation dissolution
Amount is compared (as reference preparation), as a result see the table below shown in 1 and 2.
Outward appearance, hardness, friability, the tablet weight variation testing result of the maleic acid Afatinib piece of table 1
| Group | Outward appearance | Hardness | Friability | Tablet weight variation |
| Embodiment 1 | It is unilateral bright and clean | 126N | Loss of weight 0.2% | ＜ ± 2% |
| Embodiment 2 | It is unilateral bright and clean | 125N | Loss of weight 0.2% | ＜ ± 2% |
| Embodiment 3 | It is unilateral bright and clean | 127N | Loss of weight 0.2% | ＜ ± 2% |
| Comparative example 1 | It is unilateral bright and clean | 132N | Loss of weight 0.5% | ＜ ± 4% |
| Comparative example 2 | Occasionally there is pitted skin | 118N | Loss of weight 0.7% | ＜ ± 5% |
| Comparative example 3 | There is pitted skin | 113N | Loss of weight 1.1%, there is sliver | ＜ ± 6% |
| Comparative example 4 | There is pitted skin | 110N | Loss of weight 1.3%, there is sliver | ＜ ± 6% |
| Comparative example 5 | It is unilateral bright and clean | 122N | Loss of weight 0.3% | ＜ ± 4% |
| Comparative example 6 | Occasionally there is pitted skin | 118N | Loss of weight 0.4% | ＜ ± 4% |
| Comparative example 7 | It is unilateral bright and clean | 128N | Loss of weight 0.2% | ＜ ± 2% |
| Comparative example 8 | Occasionally there is pitted skin | 130N | Loss of weight 0.5% | ＜ ± 4% |
| Comparative example 9 | It is unilateral bright and clean | 126N | Loss of weight 0.4% | ＜ ± 3% |
| Comparative example 10 | Occasionally there is pitted skin | 128N | Loss of weight 1.5%, there is sliver | ＜ ± 6% |
The accumulation stripping quantity of the maleic acid Afatinib piece of table 2 (using water as dissolution medium)
From upper table 1, maleic acid Afatinib piece is unilateral bright and clean made from 1-3 of the embodiment of the present invention, and it is suitable to have
Hardness, friability detection loss of weight be 0.2%, there is not sliver phenomenon, tablet weight variation ＜ ± 2%, be significantly better than comparative example
Maleic acid Afatinib piece made from 1-10.
From upper table 2, maleic acid Afatinib piece made from 1-3 of the embodiment of the present invention has preferable dissolution in water
Performance, the dissolving out capability between tablet is stable, and difference is small, is significantly better than maleic acid Afatinib piece made from comparative example 1-10 and exists
Dissolving out capability in water, it is especially poor with maleic acid Afatinib piece dissolving out capability in water made from compressing dry granulation,
Dissolution RSD% larger (comparative example 10) between tablet.In addition, by maleic acid Afatinib piece made from embodiment 1 in water
The accumulation stripping quantity of different time grinds tablet accumulation stripping quantity of different time in water with original and is fitted, it is known that both have
Similar dissolved corrosion (see Fig. 1), but the dissolution RSD% of maleic acid Afatinib piece grinds tablet better than original made from embodiment 1.
Result above shows, preferable using maleic acid Afatinib tablet quality made from technique shown in the present invention.
The influence that test example two, Different Preparation generate to maleic acid Afatinib piece hydrolysis impurity A
Respectively to using maleic acid Afatinib piece (embodiment 1) made from technique shown in the present invention, using wet granulation
Maleic acid Afatinib piece (comparative example 9) made from pressed disc method, using maleic acid Afatinib made from compressing dry granulation
Piece (comparative example 10) carries out the measure of impurity A and total impurities content, as a result see the table below shown in 3, Fig. 2 and 3.
The impurity content of maleic acid Afatinib piece made from the Different Preparation of table 3
| Impurity (%) | Embodiment 1 | Comparative example 9 | Comparative example 10 |
| Hydrolysis impurity A | 0.07 | 0.09 | 0.06 |
| Total impurities | 0.23 | 0.28 | 0.24 |
From upper table 3, using the hydrolysis impurity A of maleic acid Afatinib piece made from technique shown in the present invention and total miscellaneous
The content of matter is relatively low, and close with the impurity content using tablet made from compressing dry granulation, stability is preferable.
From Fig. 2 and Fig. 3, maleic acid Afatinib piece is prepared using wet granulation technology, hydrolysis impurity A increases in obvious
Long trend (Fig. 2), hence it is evident that higher than maleic acid Afatinib piece (Fig. 3) made from technique shown in the present invention.
The influence detection of test example three, high temperature accelerated test to maleic acid Afatinib piece impurity
Respectively to maleic acid Afatinib piece made from embodiment 1 and comparative example 1-10 under high temperature acceleration environment (40 DEG C,
75%RH) detected, as a result see the table below shown in 4.
The defects inspecting (high temperature accelerated test) of the maleic acid Afatinib piece of table 4
From upper table 4, maleic acid Afatinib piece is carried out using technique shown in the present invention and prepared, can effectively suppress tablet
Impurity generates under the high temperature conditions, containing BHT (comparative example 7) and does not contain BHT (embodiment 1) in prescription, obtained tablet into
Product carry out high temperature accelerated test, and maximum single impurity content and total impurities content difference be not notable, shows to use institute of the present invention
Show that technique carries out maleic acid Afatinib piece and prepared, can effectively suppress the generation of impurity, it is not necessary to which extra addition is anti-in prescription
Oxidant BHT.In addition, from comparative example 1-2 and comparative example 5-6, the composition of diluent tries tablet at high temperature in prescription
The stability tool tested has a certain impact.From comparative example 3,4 and 8, the addition of calcium sulfate and its feed postition are to tablet
Stability equally tool have a certain impact.From comparative example 9, compared with wet granule compression tablet method, produced by the present invention
Agent stability is preferable.From comparative example 10, using tablet made from technique shown in the present invention and compressing dry granulation is used
Obtained tablet has same good stability.
Maleic acid Afatinib tablet stability detects in test example four, long term test
Long-term stable experiment (25 is carried out to maleic acid Afatinib piece made from embodiment 1 and comparative example 1-10 respectively
DEG C, 65%RH), as a result it see the table below shown in 5.
The defects inspecting (long-term stable experiment) of the maleic acid Afatinib piece of table 5
From upper table 5, maleic acid Afatinib piece is carried out using technique shown in the present invention and prepared, obtained finished tablet
With preferable stability, long term test, the content of maximum single impurity and the content of total impurities are carried out under normal temperature condition
Change is smaller, and property is stable.From comparative example 1-2 and comparative example 5-6, the composition of diluent is tried for a long time tablet in prescription
The stability tool tested has a certain impact.From comparative example 3,4 and 8, the addition of calcium sulfate and its feed postition are to tablet
Stability equally tool have a certain impact.BHT is added from comparative example 7, in prescription and is not added with BHT (embodiment 1), is made
Tablet be respectively provided with preferable stability, the extra BHT that adds is not significantly increased the stability of tablet.From comparative example 9,
Compared with wet granule compression tablet method, tablet stability produced by the present invention is preferable.From comparative example 10, using shown in the present invention
Tablet made from technique has similar stability to using tablet made from compressing dry granulation, but total after long-term December
Impurity content, which will be less than, uses tablet made from compressing dry granulation.
Test example five, the detection of maleic acid Afatinib piece uniformity of dosage units
Maleic acid Afatinib piece made from embodiment 1-3, comparative example 1-6 and comparative example 8, comparative example 10 is carried out respectively
Uniformity of dosage units detects, and as a result see the table below shown in 6.
The maleic acid Afatinib piece uniformity of dosage units of table 6 detects
From upper table 6, maleic acid Afatinib piece has preferable content uniform made from 1-3 of the embodiment of the present invention
Degree, maleic acid Afatinib piece made from comparative example 1-6 and comparative example 8, comparative example 10 is significantly better than, and is made with comparative example 10
Tablet uniformity of dosage units it is worst, show using compressing dry granulation carry out prepare the uniformity of dosage units of tablet can be caused poor
Different increase.
It the above is only the preferred embodiment of the present invention, it is noted that above-mentioned preferred embodiment is not construed as pair
The limitation of the present invention, protection scope of the present invention should be defined by claim limited range.For the art
For those of ordinary skill, without departing from the spirit and scope of the present invention, some improvements and modifications can also be made, these change
Enter and retouch and also should be regarded as protection scope of the present invention.
Claims (5)
1. a kind of preparation method of maleic acid Afatinib piece, it is characterised in that comprise the steps of：
（1）By weight, 25 ~ 40 parts of maleic acid Afatinib, 100 ~ 150 parts of diluent, polyethylene glycol 30 ~ 40 are weighed respectively
Part, 10 ~ 20 parts of calcium sulfate, 3 ~ 5 parts of disintegrant, 0.1 ~ 0.5 part of magnesium stearate, silica 1 ~ 2 part, stomach dissolution type film coating are pre-
5 ~ 6 parts of mixture, it is standby；
（2）Maleic acid Afatinib, diluent, polyethylene glycol and Nei Jia calcium sulfate are well mixed, 60 ~ 70 DEG C is heated to, reaches
10 ~ 15min is incubated after to predetermined temperature, room temperature is cooled down, and disintegrant, additional sulfuric acid calcium, magnesium stearate, dioxy are added after whole grain
SiClx is well mixed, tabletting；
（3）Plain piece is subjected to film coating using stomach dissolved film coating pre-mix dose, obtains maleic acid Afatinib piece；
Described diluent is mannitol and microcrystalline cellulose PH101 with 4 ~ 6:1 mass ratio composition；
Described polyethylene glycol is polyethylene glycol PEG6000；
Described disintegrant is PVPP.
2. according to the preparation method of claim 1 maleic acid Afatinib piece, it is characterised in that described interior plus calcium sulfate and outer
The mass ratio for adding calcium sulfate is 1:2~4.
3. according to the preparation method of claim 2 maleic acid Afatinib piece, it is characterised in that described interior plus calcium sulfate and outer
The mass ratio for adding calcium sulfate is 1:3.
4. according to the preparation method of claim 1 maleic acid Afatinib piece, it is characterised in that described diluent is mannitol
With microcrystalline cellulose PH101 with 5:1 mass ratio composition.
5. according to the preparation method of claim 1 maleic acid Afatinib piece, it is characterised in that described stomach dissolution type film coating
Pre-mixing agent is Opadry 295B680002.
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