CN104540820A - Afatinib acid addition salts and crystal forms thereof, preparation method and pharmaceutical composition thereof - Google Patents

Afatinib acid addition salts and crystal forms thereof, preparation method and pharmaceutical composition thereof Download PDF

Info

Publication number
CN104540820A
CN104540820A CN201480002096.3A CN201480002096A CN104540820A CN 104540820 A CN104540820 A CN 104540820A CN 201480002096 A CN201480002096 A CN 201480002096A CN 104540820 A CN104540820 A CN 104540820A
Authority
CN
China
Prior art keywords
afatinib
preparation
solvent
diffraction
preferred
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201480002096.3A
Other languages
Chinese (zh)
Other versions
CN104540820B (en
Inventor
沈涛
盛晓霞
盛晓红
Original Assignee
Hangzhou Pushai Pharmaceutical Technology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hangzhou Pushai Pharmaceutical Technology Co ltd filed Critical Hangzhou Pushai Pharmaceutical Technology Co ltd
Priority to CN201610664357.9A priority Critical patent/CN106279127B/en
Priority to CN201480002096.3A priority patent/CN104540820B/en
Priority to CN201610659418.2A priority patent/CN106279126B/en
Publication of CN104540820A publication Critical patent/CN104540820A/en
Application granted granted Critical
Publication of CN104540820B publication Critical patent/CN104540820B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/34—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfuric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C307/02—Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/05—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing at least two sulfo groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/33—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems
    • C07C309/34—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems formed by two rings
    • C07C309/35—Naphthalene sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/45—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/46—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/08—Malonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
    • C07C59/06—Glycolic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
    • C07C59/10—Polyhydroxy carboxylic acids
    • C07C59/105—Polyhydroxy carboxylic acids having five or more carbon atoms, e.g. aldonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to novel afatinib acid addition salts and crystal forms thereof. Compared with the prior art, the afatinib acid addition salts and crystal forms thereof of the present invention have one or more improved properties. The present invention also relates to a preparation method of the novel afatinib acid addition salts and crystal forms thereof, a pharmaceutical composition thereof, and the use thereof in preparing drugs for treating and/or preventing advanced non-small cell lung cancer and HER2-positive advanced breast cancer.

Description

Afatinib acid addition salts and crystal forms thereof, preparation method and pharmaceutical composition thereof
Afatinib acid-addition salts and its crystal formation, its preparation method and Yao Wu Group compound technical fields
The invention belongs to pharmaceutical chemistry crystallization technique field, in particular to new Afatinib acid-addition salts and its crystal formation, its preparation method, and its medicine thing Group compound and purposes.
Background technology
The chemical name of Afatinib is N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- [[(3S)-four Hydrogen -3- furyls] epoxide] -6- quinazolyls] -4- (dimethylaminos；) -2- crotonamides, English name is AFATINIB, also known as BIBW 2992, molecular formula C24H25C1FN503, its structural formula is such as
Afatinib is researched and developed by German Boehringer Ingelheim company, it is adaptable to advanced Non-small cell lung（NSCLC) and the positive advanced breast cancer patients of HER2, oral tablet, standard dose is 40mg once a day.Listing license application is submitted by existing positive European drug administration of Boehringer Ingelheim company, is expected to list with Tovok.Afatinib is EGF-R ELISA（EGFR is also known as ErbBl) and human epidermal growth factor receptor-2 (HER2/neu is also known as ErbB2) EGFR-TK potent and selective double inhibitor.Different from first generation tyrosine kinase inhibitor, Afatinib be designed as with EGFR and HER2 covalent bonds so that its combine the irreversible inactivation of acceptor molecule.
Patent document WO2002/50043A1 discloses afatinib compound, and WO2007/054550A1 and WO2007/054551A1 disclose the indication of Afatinib.
Patent document WO2005/037824A2 (patent families document CN1867564B) discloses the preparation method of the Afatinib 2-maleate of crystalline state.
WO2012121764 A1 disclose Afatinib 2-maleate crystal formation B, DSC figure and show that it has exothermic peak at 125.9 °C, illustrate the crystal formation to thermally labile, it may occur that turn brilliant and even decompose.
WO2013052157A1 discloses Afatinib 2-maleate crystal formation C, D, E, and the document claims crystal formation C, D to be probably anhydride, but without positive evidence；Crystal formation C DSC figures, which are shown in 40 °C -95 °C, endothermic peak, it is likely that be solvate；Crystal formation E be hydrate, aqueous 5.9%-8.1%, higher water content is to humidity sensitive.
There is more serious hygroscopicity through the above-mentioned Afatinib 2-maleate crystal formation 8 of the present inventor's studies have shown that, C, D, E, be unsuitable for storage and formulation application.
The Afatinib 2-maleate that patent document WO2009/147238 A1 disclose described in WO2005/037824 A2 is fine acicular form, so its mobility can be made poor, differing greatly between different batches, machinability is also poor, and easy sticking, can not vertical compression.Therefore patent document WO2009/147238 A1 improved using roll-in method brought due to the needle-like pattern of raw material the problem of being difficult to, but using roll-in method can increase roll-in crushing unit operation, so as to increase production cost.For convenience, the Afatinib 2-maleate described in WO2005/037824 A2 is referred to as " Afatinib 2-maleate prior art crystal formation " in this application.
Patent document WO 2012121764A1 disclose the preparation method of the Afatinib acid-addition salts of solid-state form, include 2-maleate, diphenyl sulfonate, fumarate, dithionate, dihydrochloride, dioxalic acid salt, mesylate, diphosphate, two L MALIC ACID salt, citrate, two succinates, L-Aspartic acid salt and two fumarates of Afatinib.The document is generally to refer to that above-mentioned Afatinib acid-addition salts have some beneficial properties for being adapted to tablet applications, but without the specific data of offer.
Patent document CN1867564B, which discloses Afatinib 2-maleate prior art crystal formation, certain hygroscopicity, but without specific data, studies have shown that Afatinib 2-maleate prior art crystal formation crystal formation through the present inventor weight change in 10%-80% RH ranges is 2.6%.It is preferred that medicinal activity material should only have limited hygroscopicity, higher hygroscopicity often brings detrimental effect.For example, during manufacture, the absorption of moisture reduces the content of pharmaceutically active substance, preparation process is influenceed, the homogeneity of preparation is influenceed；Moisture preventive measure must be taken in storage, for example, adds drier or is stored in moistureproof environment, Add cost, the risk that also extended storage stability is deteriorated.
Therefore, it need to develop with more superior functions, especially can be using powder direct pressure closing and the Afatinib acid-addition salts and its crystal formation that are difficult moisture absorption.
The content of the invention
In view of the shortcomings of the prior art, the invention provides new pharmaceutically useful Afatinib acid-addition salts and its crystal formation, including its ethanedisulphonate, 1,5- napadisilates, malonate, two malonates, two 2- naphthalene sulfonates, diamino sulfonic acid salt, two D-Glucose hydrochlorates, glycol hydrochlorate, bicyclohexane sulfamate, the crystal formation of two 4- amino phenyl sulfonyls hydrochlorates and above-mentioned new salt, further comprises a kind of novel crystal forms of Afatinib 2-maleate.Compared with the Afatinib acid-addition salts or its crystal formation of prior art, Afatinib acid-addition salts of the invention and its crystal formation have one or more improvement performances.Invention further provides preparation method, its Yao Wu Group compound and the purposes of the Afatinib acid-addition salts of the present invention and its crystal formation.
One of present disclosure is to provide Afatinib ethanedisulphonate and its crystal formation and their preparation method.
Detected through HPLC, the actual content of Afatinib free alkali (disregards the amount of solvent for 71.4% in the Afatinib ethanedisulphonate）, Afatinib and ethionic acid are with 1:1 mol ratio formation compound in Afatinib theoretical content 71.9%, therefore in Afatinib ethanedisulphonate of the present invention Afatinib and ethionic acid with 1:1 mol ratio is into salt, and its structural formula is as follows：
The preparation method of the Afatinib ethanedisulphonate, comprises the following steps：The mol ratio 1 of the solution system of Afatinib and ethionic acid in soluble solvent, Afatinib and ethionic acid is formed respectively: 1-1 :2, two System forming slurries are mixed, soluble solvent is then removed.It is preferred that the soluble solvent is nitrile, alcohols, ketone, esters, alkanes, ethers or its mixture；The soluble solvent is more preferably acetonitrile, methanol, acetone, ethyl acetate, normal heptane or methyl tertiary butyl ether(MTBE).It is preferred to use the method that is spin-dried for and removes soluble solvent.
Preferably, the Afatinib ethanedisulphonate is E1 crystal formation Afatinib ethanedisulphonates, is radiated using Cu- Κ α, and its X-ray powder diffraction pattern is 6.3 ± 0.2 in the Θ of the angle of diffraction 2.、 7.0±0.2.、 17.6±0.2.、 17.8±0.2.、 21.7±0.2., there is characteristic peak at 22.8 ± 0.2 ° and 24.6 ± 0.2 °.
Further, the E1 crystal formations Afatinib ethanedisulphonate, its X-ray powder diffraction pattern is 6.3 ± 0.2 in the Θ of the angle of diffraction 2.、7.0±0.2.、 12.6±0.2.、 14.5±0.2.、 17.6±0.2.、 17.8±0.2.、 18.3±0.2.、 19.0±0.2.、 21.7±0.2.、 22.8±0.2.、 24.6±0.2.、 26.3±0.2.With 28.6 ± 0.2.Place has characteristic peak.
Further, the E1 crystal formations Afatinib ethanedisulphonate, the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure is as follows：
The Θ relative intensities % of the angle of diffraction 2
6.3±0.2° 26.9
7.0±0.2° 47.3
12.6±0.2° 16.8
14.1±0.2° 10.2
14.5±0.2° 15.2
16.4±0.2° 10.8
17.6±0.2° 62.8
17.8±0.2° 100.0
18.3±0.2° 21.8
19.0±0.2° 23.9
21.3±0.2° 12.7
21.7±0.2° 49.9
22.5±0.2° 17.8 22.8±0.2° 65.3
23.0±0.2° 40.5
24.1±0.2° 18.0
24.6±0.2° 91.5
25.4±0.2° 13.6
26.3±0.2° 16.9
27.6±0.2° 15.8
28.6±0.2° 39.8
29.0±0.2° 17.5
29.4±0.2° 10.9
36.7±0.2° 13.0
Without limitation, a representative instance of the El crystal formations Afatinib ethanedisulphonate has X-ray powder diffraction pattern as shown in Figure 6.
The E1 crystal formations Afatinib ethanedisulphonate, its FTIR spectrum is 1501,1454,1227,1206,1168,1023 and 767cm " in wave number1Place has characteristic peak.
The E1 crystal formations Afatinib ethanedisulphonate, its Raman spectrum is 1661,1610,1551,1406,1379,1297 and 1207 cm " in wave number1Place has characteristic peak.
A kind of preparation method of the E1 crystal formations Afatinib ethanedisulphonate, comprises the following steps：The mol ratio 1 of the solution system of Afatinib and ethionic acid in soluble solvent, Afatinib and ethionic acid is formed respectively:1-1 :2, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, then remove solvent, wherein the soluble solvent is selected from C2-C4Nitrile, d-C4Alcohol, C3-C5Ketone, C4-C5Ester, C6-C9Alkane, C4-C6Ether or its mixture.The C2-C4Nitrile includes but is not limited to acetonitrile, the d-C4Alcohol includes but is not limited to methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol and sec-butyl alcohol, the C3-C5Ketone includes but is not limited to acetone and butanone, the C4-C5Ester includes but is not limited to ethyl acetate and isopropyl acetate, the C6-C9Alkane includes but is not limited to n-hexane, normal heptane and hexahydrotoluene, the C4-C6Ether includes but is not limited to ether, methyl tertiary butyl ether(MTBE) and isopropyl ether；It is preferred that the soluble solvent is acetonitrile, methanol, acetone, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture, more preferably acetonitrile.It is preferred that concentration of the Afatinib in soluble solvent is the saturated solution of Afatinib under 10 mg/mls to the solvent.It is preferred that Afatinib and ethionic acid mole is 1:1-1:2.It is preferred that the operation temperature of the preparation method is room temperature.
Another preparation method of the E1 crystal formations Afatinib ethanedisulphonate, comprises the following steps：The Afatinib ethanedisulphonate that preceding method is prepared forms slurries and stirred in organic solvent, slurries are kept 1 72 hours under -10-50 °C, and then solvent is removed, wherein the organic solvent is selected from acetonitrile, methanol, acetone, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture.It is preferred that the operation temperature of the preparation method is room temperature.
Compared with the prior art, especially compared with the Afatinib 2-maleate or its crystal formation of prior art, Afatinib ethanedisulphonate or E1 crystal formation Afatinib ethanedisulphonates have one or more improved characteristics, for example：Higher crystallinity, preferable solubility, preferably dissolution velocity, crystal habit, preferable heat endurance and bin stability, relatively low hygroscopicity, preferable flowable and favourable processing and treatment characteristic.
Particularly E1 crystal formations Afatinib ethanedisulphonate has following beneficial property：
1) solubility is 55.7mg/ml in water at room temperature, relative to the mg/ml of solubility 7.5 of Afatinib 2-maleate prior art crystal formation under the same conditions, with higher dissolubility；
2) moisture absorption 1.4% in 10%-80% RH ranges at room temperature, relative to Afatinib 2-maleate prior art crystal formation moisture absorption 2.6% under the same conditions, with smaller hygroscopicity；
3) decomposition temperature is 261.8 °C, relative to 164.1 °C of the decomposition temperature of Afatinib 2-maleate prior art crystal formation, with higher heat endurance；
4) it is granular crystals, is acicular crystal relative to Afatinib 2-maleate prior art crystal formation, with more preferable mobility, compressibility and machinability.
Above-mentioned beneficial property shows, compared with the Afatinib 2-maleate or its crystal formation of prior art, the Afatinib ethanedisulphonate or E1 crystal formation Afatinib ethanedisulphonates of the present invention has a variety of advantage performances, and application effect can be more preferable, is suitable as medicine The active component of thing preparation.The higher dissolubility of active component is conducive to improving the bioavilability of medicine, and then produces actively impact to drug effect；The crystallization shape of active component is good, good to the suitability of preparation process with more preferable mobility, compressibility and machinability；Active component has the heat endurance of lower hygroscopicity and Geng Gao, the problems such as active component content as caused by the factors such as environment temperature, humidity during medicine manufacture and/or storage etc. uneven, purity reduction and impurity increase can preferably be resisted, the curative effect downside risk thus brought and security risk are reduced, and is conducive to accurate quantitative analysis, raising preparation homogeneity and the storage and transport in later stage in medicine manufacture.
The two of present disclosure are to provide Afatinib 1,5- napadisilates and its crystal formation and their preparation method.Detected through HPLC, the Afatinib 1, the actual content of Afatinib free alkali (disregards the amount of solvent for 63.3% in 5- napadisilates）, Afatinib and 1,5- naphthalenedisulfonic acid are with 1:The theoretical content of Afatinib is Afatinib in 62.8%, therefore Afatinib 1,5- napadisilates of the present invention and 1,5- naphthalenedisulfonic acids with 1 in the compound of 1 mol ratio formation:1 mol ratio is into salt, and its structural formula is as follows：
The Afatinib 1, the preparation method of 5- napadisilates comprises the following steps：Form solution system in soluble solvent of Afatinib and 1,5- naphthalenedisulfonic acid respectively, the mol ratio of Afatinib and 1,5- naphthalenedisulfonic acid is 1: 1-1 :2, two System forming slurries are mixed, soluble solvent is then removed.It is preferred that the soluble solvent is nitrile, alcohols, ketone, esters, alkanes, ethers or its mixture；The soluble solvent is more preferably acetonitrile, methanol, acetone, ethyl acetate, normal heptane or methyl tertiary butyl ether(MTBE).It is preferred to use the method that is spin-dried for and removes soluble solvent.
Preferably, the Afatinib 1,5- napadisilates are N1 crystal formations Afatinib 1, and 5- napadisilates are radiated using Cu-Ka, its X-ray powder diffraction pattern the Θ of the angle of diffraction 2 be 6.6 ± 0.2 °, 13.4 ± 0.2.、 16.6±0.2.、 17.5±0.2.、 20.8±0.2.With 24.2 ± 0.2.Place has characteristic peak.
Further, the N1 crystal formations Afatinib 1,5- napadisilates, its X-ray powder diffraction pattern is 6.6 ± 0.2 in the Θ of the angle of diffraction 2.、8.1±0.2.、 13.4±0.2.、 14.8±0.2.、 16.3±0.2.、 16.6±0.2.、 17.5±0.2.、 18.3±0.2.、20.8±0.2.、 22.0±0.2.、 22.7±0.2.With 24.2 ± 0.2.Place has characteristic peak.
Further, the N1 crystal formations Afatinib 1,5- napadisilates, the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure is as follows：
The Θ relative intensities % of the angle of diffraction 2
6.6±0.2° 100.0
8.1±0.2° 16.1
1 1. .2±0. .2° 12.2
13. .4±0. .2° 75.6
14. .8±0. .2° 21.2
16. .3±0. .2° 13.4
16. .6±0. .2° 53.5
17. .5±0. .2° 27.1
17. .9±0. .2° 13.0
18. .3±0. .2° 23.1
19. .2±0. .2° 20.7
19. .5±0. .2° 22.5
20. .5±0. .2° 29.9
20. .8±0. .2° 38.0
21. .8±0. .2° 24.5
22. .0±0. .2° 24.8
22. .4±0. .2° 26.4 22.7±0.2° 28.9
23.2±0.2° 14.3
23.5±0.2° 15.4
24.2±0.2° 62.3
24.7±0.2° 15.6
26.5±0.2° 15.3
30.2±0.2° 19.5
Without limitation, the Nl crystal formations Afatinib 1 a, representative instance of 5- napadisilates has X-ray powder diffraction pattern as shown in fig. 13 that.
The N1 crystal formations Afatinib 1,5- napadisilates, its FTIR spectrum is 1639,1577,1524,1500,1452,1216,1155,1028 and 765cm in wave number_1Place has characteristic peak.
The N1 crystal formations Afatinib 1,5- napadisilates, its Raman spectrum is to have characteristic peak at 1704,1661,1613,1543,1403,1365,1205,1068,999 and 780 cm in wave number.
A kind of N1 crystal formations Afatinib 1, preparation method of 5- napadisilates comprises the following steps：Form solution system in soluble solvent of Afatinib and 1,5- naphthalenedisulfonic acid respectively, the mol ratio of Afatinib and 1,5- naphthalenedisulfonic acid is 1: 1-1 :2, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, then remove solvent, wherein the soluble solvent is selected from C2-C4Nitrile, d-C4Alcohol, C3-C5Ketone, C4-C5Ester, C6-C9Alkane, C4-C6Ether or its mixture.The C2-C4Nitrile includes but is not limited to acetonitrile, the d-C4Alcohol includes but is not limited to methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol and sec-butyl alcohol, the C3-C5Ketone includes but is not limited to acetone and butanone, the C4-C5Ester includes but is not limited to ethyl acetate and isopropyl acetate, the C6-C9Alkane includes but is not limited to n-hexane, normal heptane and hexahydrotoluene, the C4-C6Ether includes but is not limited to ether, methyl tertiary butyl ether(MTBE) and isopropyl ether；It is preferred that the soluble solvent is acetonitrile, methanol, ethanol, acetone, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；The acetonitrile solution of Afatinib and the ethanol solution of 1,5- naphthalenedisulfonic acids are more preferably formed respectively.It is preferred that concentration of the Afatinib in soluble solvent is the saturated solution of Afatinib under 10 mg/mls to the solvent.It is preferred that Afatinib and the mol ratio of 1,5- naphthalenedisulfonic acids are 1: 1-1 : 1.5.It is preferred that the operation temperature of the preparation method is room temperature.
The N1 crystal formations Afatinib 1, another preparation method of 5- napadisilates comprises the following steps：Will be according to Afatinib 1 made from aforementioned preparation process, 5- napadisilates form slurries and stirred in organic solvent, the slurries are kept 1 72 hours under -10-50 °C, and then solvent is removed, wherein the organic solvent is selected from methanol, ethanol, acetonitrile, acetone, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture.It is preferred that the operation temperature of the preparation method is room temperature.
Preferably, the Afatinib 1,5- napadisilates are N2 crystal formations Afatinib 1,5- naphthalenedisulfonic acid salt hydrates.Radiated using Cu- Κ α, the N2 crystal formations Afatinib 1, the X-ray powder diffraction patterns of 5- naphthalenedisulfonic acid salt hydrates is 6.7 ± 0.2 in the Θ of the angle of diffraction 2.、 8.1±0.2.、 9.3±0.2.、 14.9±0.2., there is characteristic peak at 20.9 ± 0.2 ° and 23.0 ± 0.2 °.
Further, the N2 crystal formations Afatinib 1,5- naphthalenedisulfonic acid salt hydrates, its X-ray powder diffraction pattern is 6.7 ± 0.2 in the Θ of the angle of diffraction 2.、 8.1±0.2.、 9.3±0.2.、 13.9±0.2.、 14.9±0.2°、 15.8±0.2.、 16.7±0.2.、 17.5±0.2.、 20.5±0.2.、 20.9±0.2.、 21.7±0.2.、 23.0±0.2., there is characteristic peak at 24.1 ± 0.2 ° and 24.3 ± 0.2 °.
Further, the N2 crystal formations Afatinib 1,5- naphthalenedisulfonic acid salt hydrates, the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure is as follows：
The Θ relative intensities % of the angle of diffraction 2
5.9±0.2° 12.1
6.7±0.2° 25.2
8.1±0.2° 36.7
9.3±0.2° 27.4
12.0±0.2° 13.9
13.5±0.2。 12.6
13.9±0.2° 26.8
14.9±0.2° 93.0
15.8±0.2° 39.0
16.3±0.2° 14.7
16.7±0.2° 28.6 17 5±0 2° 26.8
18 1±0 2° 19.8
19 4±0 2° 12.1
20 0±0 2° 30.1
20 5±0 2° 47.9
20 9±0 2° 53.1
21 7±0 2° 45.9
22 2±0 2° 15.3
23 0±0 2° 100.0
24 1±0 2° 43.3
24 3±0 2° 47.5
24 8±0 2° 18.9
25 7±0 2° 15.9
26 1±0 2° 28.0
27 6±0 2° 26.6
Without limitation, the N2 crystal formations Afatinib 1 a, representative instance of 5- naphthalenedisulfonic acid salt hydrates has the X-ray powder diffraction pattern as shown in Figure 20.
The N2 crystal formations Afatinib 1,5- naphthalenedisulfonic acid salt hydrates, its thermogravimetric analysis（TGA) collection of illustrative plates shows the weightlessness for having 5.97% before 100 °C, is about combined into trihydrate.
The N2 crystal formations Afatinib 1,5- naphthalenedisulfonic acid salt hydrates, its FTIR spectrum is to have characteristic peak at 1641,1578,1500,1451,1219,1155,1028 and 764cm in wave number.
The N2 crystal formations Afatinib 1,5- naphthalenedisulfonic acid salt hydrates, its Raman spectrum is 1654,1610,1549,1400,1371,1297,1216,997 and 781cm in wave number-1Place has characteristic peak.
The N2 crystal formations Afatinib 1, the preparation method of 5- naphthalenedisulfonic acid salt hydrates comprises the following steps：By N1 types Afatinib 1,5- napadisilates are placed in the room temperature environment of 75%-100% relative humidity, 17 days standing times.In the room temperature environment for being preferably positioned at 75%-85% relative humidity, 13 days standing times.
Compared with the prior art, especially compared with the Afatinib 2-maleate or its crystal formation of prior art, Afatinib 1,5- napadisilates or N1 crystal formations Afatinib 1,5- napadisilates or N2 crystal formations Afatinib 1,5- naphthalenedisulfonic acid salt hydrates have one or more improved characteristics, for example：Higher crystallinity, preferable solubility, preferably dissolution velocity, crystal habit, preferable heat endurance and bin stability, relatively low hygroscopicity, preferable flowable and favourable processing and treatment characteristic.
Particularly N1 crystal formations Afatinib 1,5- napadisilates have following beneficial property：
1) decomposition temperature is 276.3 °C, relative to 164.1 °C of the decomposition temperature of Afatinib 2-maleate prior art crystal formation, with higher heat endurance；
2) it is more regular granular crystals, relative to the acicular crystal of Afatinib 2-maleate prior art crystal formation, with more preferable mobility, compressibility and machinability；
Particularly N2 crystal formations Afatinib 1,5- naphthalenedisulfonic acid salt hydrates have following beneficial property：
1) moisture absorption 1.80% under 30-80% relative humidity at room temperature, relative to Afatinib 2-maleate prior art crystal formation moisture absorption 2.2% under the same conditions, with lower hygroscopicity；
2) decomposition temperature is 275.4 °C, relative to 164.1 °C of the decomposition temperature of Afatinib 2-maleate prior art crystal formation, with higher heat endurance；
3) it is more regular granular crystals, relative to the acicular crystal of Afatinib 2-maleate prior art crystal formation, with more preferable mobility, compressibility and machinability.
Above-mentioned beneficial property shows, compared with the Afatinib 2-maleate or its crystal formation of prior art, the Afatinib 1 of the present invention, 5- napadisilates or N1 crystal formations Afatinib 1,5- napadisilates or N2 crystal formations Afatinib 1,5- naphthalenedisulfonic acid salt hydrates have a variety of advantage performances, and application effect can be more preferable, is suitable as the active component of pharmaceutical preparation.The crystallization shape of active component is good, good to the suitability of preparation process with more preferable mobility, compressibility and machinability；Active component have lower hygroscopicity and Geng Gao heat endurance, can preferably resist medicine manufacture and/or storage etc. during drawn by factors such as environment temperature, humidity The active component content that rises is uneven, purity reduction and the problems such as impurity increase, reduces the curative effect downside risk thus brought and security risk, and be conducive to medicine manufacture in accurate quantitative analysis, improve preparation homogeneity and the storage and transport in later stage.
The three of present disclosure are to provide the malonate of Afatinib one and its crystal formation and their preparation method.
Detected through HPLC, the actual content of Afatinib free alkali (disregards the amount of solvent for 83.0% in the malonate of Afatinib one）, Afatinib and malonic acid are with 1:The theoretical content of Afatinib is that Afatinib and malonic acid are with 1 in 82.4%, therefore the malonate of Afatinib of the present invention one in the compound of 1 mol ratio formation:1 mol ratio is into salt, and its structural formula is as follows：
HOOCCH COOH
The preparation method of the malonate of Afatinib one, comprises the following steps：The mol ratio 1 of the solution system of Afatinib and malonic acid in soluble solvent, Afatinib and malonic acid is formed respectively: 1-1 :1.5, two System forming slurries are mixed, solvent is then removed.It is preferred that the soluble solvent is ether solvent；More preferably C4-C5Ether, the C4-C5Ether includes but is not limited to ether, methyl tertiary butyl ether(MTBE) and isopropyl ether；Most preferably methyl tertiary butyl ether(MTBE).It is preferred to use the method that is spin-dried for and removes solvent.
Preferably, the malonate of Afatinib one be the malonate of Ml crystal formations Afatinib one, using Cu- Κ α radiate, its X-ray powder diffraction pattern the Θ of the angle of diffraction 2 be 6.6 ± 0.2 °, 7.2 ± 0.2.、 13.2±0.2.、 13.4±0.2.、 17.3±0.2., there is characteristic peak at 20.8 ± 0.2 ° and 25.1 ± 0.2 °.
Further, the malonate of Ml crystal formations Afatinib one, its X-ray powder diffraction pattern is 6.6 ± 0.2 in the Θ of the angle of diffraction 2.、 7.2±0.2.、 8.7±0.2.、 13.2±0.2.、 13.4±0.2.、 14.3±0.2.、 17.3±0.2.、 18.0±0.2.、 19.7±0.2.、 20.8±0.2.、 21.4±0.2., there is characteristic peak at 25.1 ± 0.2 ° and 26.1 ± 0.2 °.
Further, the malonate of Ml crystal formations Afatinib one, the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure is as follows：
The Θ relative intensities % of the angle of diffraction 2
6.6±0.2° 92.8
7.2±0.2° 31.1
8.7±0.2° 12.4
13. .2±0. .2° 29.7
13. .4±0. .2° 32.2
14. .3±0. .2° 15.0
17. .3±0. .2° 30.8
18. .0±0. .2° 25.5
19. .3±0. .2° 15.7
19. .7±0. .2° 22.2
20. .8±0. .2° 42.1
21. .4±0. .2° 18.7
22. .3±0. .2° 10.7
22. .7±0. .2° 16.6
23. .6±0. .2° 18.5
25. .1±0. .2° 100.0
26. .0±0. .2° 32.2
Without limitation, a representative instance of the malonate of Ml crystal formations Afatinib one has X ray powder diffractions as shown in figure 25.
The malonate of Ml crystal formations Afatinib one, its FTIR spectrum is 1693,1628,1499,1454,1363,1213,1155,1063 and 749cm in wave number_1Place has characteristic peak. The malonate of Ml crystal formations Afatinib one, its Raman spectrum is to have characteristic peak at 1657,1609,1544,1397,1369,1343,1301,1204 and 780 cm in wave number.
A kind of preparation method of the malonate of Ml crystal formations Afatinib one, comprises the following steps：Afatinib and malonic acid are formed respectively in C4-C5The mol ratio 1 of solution system in ether, Afatinib and malonic acid: 1-1 :1.5, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, then remove solvent.The C4-C5Ether includes but is not limited to ether, methyl tertiary butyl ether(MTBE) and isopropyl ether, preferably methyl tertiary butyl ether(MTBE).It is preferred that Afatinib is in C4-C5Concentration in ether is the saturated solution of Afatinib under 10 mg/mls to the solvent.It is preferred that the operation temperature of the preparation method is room temperature,
Another preparation method of the malonate of Ml crystal formations Afatinib one, comprises the following steps：The malonate of Afatinib one that preceding method is made forms slurries and stirred in organic solvent, the slurries are kept 1 72 hours under -10-50 °C, and then the solvent is removed, wherein the organic solvent is selected from methanol, acetone, acetonitrile, methyl tertiary butyl ether(MTBE), ethyl acetate, normal heptane or its mixture.It is preferred that the operation temperature of the preparation method is room temperature.
Compared with the prior art, especially compared with known Afatinib 2-maleate or its crystal formation, the malonate of Afatinib one or the malonate of Ml crystal formations Afatinib one have one or more improved characteristics, for example：Higher crystallinity, preferable solubility, preferably dissolution velocity, crystal habit, preferable heat endurance and bin stability, relatively low hygroscopicity, preferable flowable and favourable processing and treatment characteristic.
The particularly malonate of Ml crystal formations Afatinib one has following beneficial property：
1) solubility at room temperature in water is 40.8mg/ml, relative to the solubility 7.5mg/ml of Afatinib 2-maleate prior art crystal formation under the same conditions, with higher dissolubility；
2) it is more regular graininess, relative to the acicular crystal of Afatinib 2-maleate prior art crystal formation, with more preferable mobility, compressibility and machinability.
Above-mentioned beneficial property shows, compared with the Afatinib 2-maleate or its crystal formation of prior art, the malonate of Afatinib one or the malonate of Ml crystal formations Afatinib one of the present invention has a variety of advantage performances, and application effect can be more preferable, is suitable as the active component of pharmaceutical preparation.The higher dissolubility of active component is conducive to improving the bioavilability of medicine, and then produces actively impact to drug effect；The crystallization shape of active component is good, good to the suitability of preparation process with more preferable mobility, compressibility and machinability.
The four of present disclosure are to provide the malonate of Afatinib two and its crystal formation and their preparation method.
Detected through HPLC, the actual content of Afatinib free alkali (disregards the amount of solvent for 70.2% in the malonate of Afatinib two）, Afatinib and malonic acid are with 1:The theoretical content of Afatinib is 70.0% in the compound of 2 mol ratios formation, therefore Ah method of the present invention, into salt, its structural formula is as follows：
The preparation method of the malonate of Afatinib two, comprises the following steps：The mol ratio 1 of the solution system of Afatinib and malonic acid in soluble solvent, Afatinib and malonic acid is formed respectively:2-1 :4, two System forming slurries are mixed, solvent is then removed.It is preferred that the soluble solvent is esters solvent；The further preferred soluble solvent is C4-C5Ester, the C4-C5Ester includes but is not limited to ethyl acetate, isopropyl acetate；More preferably ethyl acetate.It is preferred to use the method that is spin-dried for and removes solvent.
Preferably, the malonate of Afatinib two is the malonate of M2 crystal formations Afatinib two, is radiated using Cu- Κ α, and its X-ray powder diffraction pattern is 6.5 ± 0.2 in the Θ of the angle of diffraction 2.、 8.1±0.2.、 13.1±0.2.、 16.1±0.2.、 20.8±0.2.With 25.8 ± 0.2 ° at have characteristic peak.
Further, the malonate of M2 crystal formations Afatinib two, its X-ray powder diffraction pattern is 6.5 ± 0.2 in the Θ of the angle of diffraction 2.、 8.1±0.2.、 9.7±0.2.、 10.9±0.2.、 13.1±0.2.、 14.0±0.2.、 16.1±0.2.、 18.3±0.2.、 19.0±0.2.、 20.8±0.2.、 25.8±0.2.With 27.0 ± 0.2.Place has characteristic peak. Further, the malonate of M2 crystal formations Afatinib two, the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure is as follows：
The Θ relative intensities % of the angle of diffraction 2
5.8±0.2° 12.3
6.5±0.2° 58.7
8.1±0.2° 24.1
9.7±0.2° 14.2
10. .9±0. .2° 14.9
13. .1±0. .2° 42.9
13. .6±0. .2° 16.0
14. .0±0. .2° 31.9
15. .1±0. .2° 14.7
16. .1±0. .2° 35.0
16. .4±0. .2° 18.8
18. .3±0. .2° 15.9
19. .0±0. .2° 19.9
19. .8±0. .2° 18.0
20. .4±0. .2° 14.7
20. .8±0. .2° 41.7
21. .5±0. .2° 10.5
22. .2±0. .2° 19.9
23. .6±0. .2° 1 1.3
25. .8±0. .2° 100.0
26. .5±0. .2° 13.3
27. .0±0. .2° 39.3
27. .7±0. .2° 1 1.8
29. .3±0. .2° 12.0
Without limitation, a representative instance of the malonate of M2 crystal formations Afatinib two has X ray powder diffractions as shown in figure 31.
The malonate of M2 crystal formations Afatinib two, its FTIR spectrum is 1694,1630,1501,1455,1364,1262,1214,1064,892 and 749cm in wave number-1Place has characteristic peak.
The malonate of M2 crystal formations Afatinib two, its Raman spectrum is to have characteristic peak at 1658,1621,1607,1545,1491,1397,1301,1205 and 781 cm in wave number.
A kind of preparation method of the malonate of M2 crystal formations Afatinib two, comprises the following steps：Afatinib and malonic acid are formed respectively in C4-C5The mol ratio 1 of solution system in ester, Afatinib and malonic acid:2-1 :4, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, then remove solvent；Or, the malonate of Afatinib one is formed respectively in C4-C5Suspension liquid system and malonic acid in ester is in C4-C5The mol ratio of solution system in ester, the malonate of Afatinib one and malonic acid is 1: 1-1 :2, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, then remove solvent.The C4-C5Ester includes but is not limited to ethyl acetate, isopropyl acetate, preferably described C4-C5Ester is ethyl acetate.It is preferred that Afatinib is in C4-C5The saturated solution of Afatinib under the mg/ml of concentration 10 to solvent in ester.It is preferred that Afatinib and the mol ratio of malonic acid are 1:2-1 :3.It is preferred that the mol ratio of the malonate of Afatinib one and malonic acid is 1: 1-1 : 1.5.It is preferred that the operation temperature of the preparation method is room temperature.
Another preparation method of the malonate of M2 crystal formations Afatinib two, comprises the following steps：The malonic acid hydrochlorate of Afatinib two that aforementioned preparation process is obtained is in organic solvent formation slurries and stirs, the slurries are kept 1 72 hours under -10-50 °C, and then solvent is removed, the organic solvent is selected from methanol, acetone, acetonitrile, methyl tertiary butyl ether(MTBE), ethyl acetate, normal heptane or its mixture.It is preferred that the operation temperature of the preparation method is room temperature.
Compared with the prior art, especially compared with the Afatinib 2-maleate or its crystal formation of prior art, the malonate of Afatinib two or the malonate of M2 crystal formations Afatinib two have one or more improved characteristics, for example：Higher crystallinity, preferable solubility, dissolution velocity, preferably crystal habit, preferable heat endurance and bin stability, relatively low hygroscopicity, compared with Good flowable and favourable processing and treatment characteristic.
The particularly malonate of M2 crystal formations Afatinib two has following beneficial property：
1) solubility at room temperature in water is 26.2mg/ml, relative to the mg/ml of solubility 7.5 of Afatinib 2-maleate prior art crystal formation under the same conditions, with higher dissolubility.
2) moisture absorption under room temperature, 10-80% relative humidity is 1.1%, relative to Afatinib 2-maleate prior art crystal formation moisture absorption 2.6% under the same conditions, with lower hygroscopicity.
Above-mentioned beneficial property shows, compared with the Afatinib 2-maleate or its crystal formation of prior art, the malonate of Afatinib two or the malonate of M2 crystal formations Afatinib two of the present invention has a variety of advantage performances, and application effect can be more preferable, is suitable as the active component of pharmaceutical preparation.The higher dissolubility of active component is conducive to improving the bioavilability of medicine, and then produces actively impact to drug effect；Active component has lower hygroscopicity, the problems such as active component content as caused by ambient humidity during medicine manufacture and/or storage etc. uneven, purity reduction and impurity increase can preferably be resisted, the curative effect downside risk thus brought and security risk are reduced, and is conducive to accurate quantitative analysis, raising preparation homogeneity and the storage and transport in later stage in medicine manufacture.
The five of present disclosure are to provide the 2- naphthalene sulfonates of Afatinib two and its crystal formation and their preparation method.Detected through HPLC, the actual content of Afatinib free alkali (disregards the amount of solvent for 55.0% in the 2- naphthalene sulfonates of Afatinib two）, Afatinib and 2- naphthalene sulfonic acids are with 1:The theoretical content of Afatinib is Afatinib in 53.9%, therefore the 2- naphthalene sulfonates of Afatinib of the present invention two and 2- naphthalene sulfonic acids with 1 in the compound of 2 mol ratios formation:2 mol ratios are into salt, and its structural formula is as follows：
The preparation method of the 2- naphthalene sulfonates of Afatinib two, comprises the following steps：Form solution system in soluble solvent of Afatinib and 2- naphthalene sulfonic acids respectively, the mol ratio of Afatinib and 2- naphthalene sulfonic acids is 1:2-1 :4, two System forming slurries are mixed, solvent is then removed.It is preferred that the soluble solvent is alcohols, ketone, esters, alkanes, ethers or its mixture；More preferably methanol, acetone, ethyl acetate, normal heptane or methyl tertiary butyl ether(MTBE).It is preferred to use the method that is spin-dried for and removes solvent.
Preferably, the 2- naphthalene sulfonates of Afatinib two are the 2- naphthalene sulfonates of Nsl crystal formations Afatinib two, radiated using Cu-Ka, its X-ray powder diffraction pattern is to have characteristic peak at 5.6 ± 0.2 °, 24.0 ± 0.2 ° and 26.8 ± 0.2 ° in the Θ of the angle of diffraction 2.
Further, the 2- naphthalene sulfonates of Nsl crystal formations Afatinib two, the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure is as follows：
The Θ relative intensities % of the angle of diffraction 2
5.6±0.2° 26.0
24.0±0.2° 100.0
26.8±0.2° 54.3
Without limitation, a representative instance of the 2- naphthalene sulfonates of Nsl crystal formations Afatinib two has X-ray powder diffraction pattern as shown in figure 37.
The 2- naphthalene sulfonates of Nsl crystal formations Afatinib two, its FTIR spectrum is 1627,1536,1498,1427,1211,1090,1030 and 675cm in wave number-1Place has characteristic peak.
The 2- naphthalene sulfonates of Nsl crystal formations Afatinib two, its Raman spectrum is 1650,1628,1610,1581,1501,1386,1355,1211,1021 and 771 cm in wave number_1Place has characteristic peak.
A kind of preparation method of the 2- naphthalene sulfonates of Nsl crystal formations Afatinib two, comprises the following steps：Form solution system in soluble solvent of Afatinib and 2- naphthalene sulfonic acids respectively, the mol ratio of Afatinib and 2- naphthalene sulfonic acids is 1:2-1 :4, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, then remove solvent, wherein the soluble solvent is selected from d-C4Alcohol, C3-C5Ketone, C4-C5Ester, C6-C9Alkane, C4-C6Ether or its mixture.The d-C4Alcohol includes but is not limited to methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol and sec-butyl alcohol, the C3-C5Ketone includes but is not limited to acetone and butanone, the C4-C5Ester includes but is not limited to ethyl acetate and isopropyl acetate, the C6-C9Alkane includes but is not limited to n-hexane, normal heptane and hexahydrotoluene, the C4-C6Ether includes but is not limited to ether, isopropyl ether and methyl tertiary butyl ether(MTBE)；It is preferred that described can Solvent is methanol, acetone, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；More preferably ethyl acetate.It is preferred that concentration of the Afatinib in soluble solvent is the saturated solution of Afatinib under 10 mg/mls to the solvent.It is preferred that Afatinib and the mol ratio of 2- naphthalene sulfonic acids are 1:2-1 :3.It is preferred that the operation temperature of the preparation method is room temperature.
Another preparation method of the 2- naphthalene sulfonates of Nsl crystal formations Afatinib two, comprises the following steps：The 2- naphthalene sulfonates of Afatinib two that aforementioned preparation process is obtained form slurries and stirred in organic solvent, the slurries are kept 1 72 hours under -10-50 °C, and then solvent is removed, wherein the organic solvent is selected from methanol, acetone, acetonitrile, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture.It is preferred that the operation temperature of the preparation method is room temperature.
Compared with the prior art, especially compared with the Afatinib 2-maleate or its crystal formation of prior art, the 2- Nai Shuo hydrochlorates of Afatinib two or the 2- Nai Shuo hydrochlorates of Nsl crystal formations Afatinib two have one or more improved characteristics, for example：Higher crystallinity, preferable solubility, preferably dissolution velocity, crystal habit, preferable heat endurance and bin stability, relatively low hygroscopicity, preferable flowable and favourable processing and treatment characteristic.
The particularly 2- naphthalene sulfonic acids of Nsl crystal formations Afatinib two has following beneficial property：Its decomposition temperature is 249.1 °C, relative to 164.1 °C of the decomposition temperature of Afatinib 2-maleate prior art crystal formation, with higher heat endurance.Above-mentioned beneficial property shows, compared with the Afatinib 2-maleate or its crystal formation of prior art, the 2- naphthalene sulfonic acids of Afatinib two or the 2- naphthalene sulfonic acids of Nsl crystal formations Afatinib two of the present invention has a variety of advantage performances, and application effect can be more preferable, is suitable as the active component of pharmaceutical preparation.Active component has higher heat endurance, the problems such as active component content as caused by the factors such as environment temperature during medicine manufacture and/or storage etc. uneven, purity reduction and impurity increase can preferably be resisted, the curative effect downside risk thus brought and security risk are reduced, and is conducive to accurate quantitative analysis, raising preparation homogeneity and the storage and transport in later stage in medicine manufacture.
The six of present disclosure are to provide Afatinib diamino sulfonic acid salt and its crystal formation and their preparation method.
Detected through HPLC, the actual content of Afatinib free alkali (disregards the amount of solvent for 70.9% in the Afatinib diamino sulfonic acid salt）, Afatinib and sulfamic acid are with 1:The theoretical content of Afatinib is Afatinib in 71.5%, therefore Afatinib diamino sulfonic acid salt of the present invention and sulfamic acid with 1 in the compound of 2 mol ratios formation:2 mol ratios are into salt, and its structural formula is as follows：
The preparation method of the Afatinib diamino sulfonic acid salt, comprises the following steps：The mol ratio of the suspension liquid system of the solution system and sulfamic acid formed respectively in Afatinib soluble solvent in organic solvent, Afatinib and ammonia base Shuo acid is 1:2-1 :4, two System forming slurries are mixed, solvent is then removed.It is preferred that the soluble solvent or organic solvent are nitrile, alcohols, ketone, esters, alkanes, ethers or its mixture；More preferably acetonitrile, methanol, acetone, ethyl acetate, normal heptane or methyl tertiary butyl ether(MTBE).It is preferred to use the method that is spin-dried for and removes solvent.
Preferably, the Afatinib diamino sulfonic acid salt is the Afatinib diamino sulfonic acid salt of S1 crystal formations, is radiated using Cu-Ka, and its X-ray powder diffraction pattern is 5.3 ± 0.2 in the Θ of the angle of diffraction 2.、 10.7±0.2.、 13.2±0.2.、 21.5±0.2°、 22.3±0.2.、 25.5±0.2.With 26.1 ± 0.2.Place has characteristic peak.
Further, the S1 crystal formations Afatinib diamino sulfonic acid salt, its X-ray powder diffraction pattern is 5.3 ± 0.2 in the Θ of the angle of diffraction 2.、 10.7±0.2.、 11.0±0.2.、 12.3±0.2.、 13.2±0.2.、 13.6±0.2.、 17.1±0.2.、 20.2±0.2.、 21.5±0.2.、 22.3±0.2., there is characteristic peak at 25.5 ± 0.2 ° and 26.1 ± 0.2 °.
Further, the S1 crystal formations Afatinib diamino sulfonic acid salt, the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure is as follows：
The Θ relative intensities % of the angle of diffraction 2
5.3±0.2° 65.4
10.7±0.2° 42.4
1 1.0±0.2° 15.7
12.3±0.2° 13.5
12.9±0.2° 10.1 13.2±0.2° 26. 1
13.6±0.2° 12.0
17. 1±0.2° 17.0
19.0±0.2° 10. 1
20.2±0.2° 19.3
21.5±0.2° 22.4
22.3±0.2° 22.2
23.0±0.2° 1 1.2
25.5±0.2° 100.0
26. 1±0.2° 53.2
Without limitation, a representative instance of the S I crystals Afatinib diamino sulfonic acid salt has X ray powder diffractions as shown in figure 42.
The crystal formation Afatinib diamino sulfonic acid salt of S 1, its FTIR spectrum is 1640,1575,1528,1497,1450,1233,1159,1042 and 776cm in wave number_1Place has characteristic peak.
The crystal formation Afatinib diamino sulfonic acid salt of S 1, its Raman spectrum is 1656,1606,1548,1490,1401,1374,1297,1215 and 782cm in wave number-1Place has characteristic peak.
A kind of preparation method of the crystal formation Afatinib diamino sulfonic acid salt of S 1, comprises the following steps：Form solution system and sulfamic acid suspension liquid system in organic solvent of the Afatinib in soluble solvent respectively, the mol ratio of Afatinib and sulfamic acid is 1:2-1 :4, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, and then solvent is removed, wherein the soluble solvent or organic solvent are selected from C2-C4Nitrile, d-C4Alcohol, C3-C5Ketone, C4-C5Ester, C6-C9Alkane, C4-C6Ether or its mixture.The C2-C4Nitrile includes but is not limited to acetonitrile, the d-C4Alcohol includes but is not limited to methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol and sec-butyl alcohol, the C3-C5Ketone includes but is not limited to acetone and butanone, the C4-C5Ester includes but is not limited to ethyl acetate and isopropyl acetate, the C6-C9Alkane includes but is not limited to n-hexane, normal heptane and hexahydrotoluene, the C4-C6Ether includes but is not limited to ether, isopropyl ether and methyl tertiary butyl ether(MTBE)；It is preferred that the soluble solvent or organic solvent are acetonitrile, methanol, acetone, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；More preferably acetonitrile or ethyl acetate.It is preferred that concentration of the Afatinib in soluble solvent is the saturated solution of Afatinib under 10 mg/mls to the solvent.It is preferred that Afatinib and the mol ratio of sulfamic acid are 1:2-1 :3.It is preferred that the operation temperature of the preparation method is room temperature.
Another preparation method of the crystal formation Afatinib diamino sulfonic acid salt of S 1, comprises the following steps：The Afatinib diamino sulfonic acid salt that preceding method is made forms slurries and stirred in organic solvent, the slurries are kept 1 72 hours under -10-50 °C, and then solvent is removed, wherein the organic solvent is selected from methanol, acetone, acetonitrile, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture.It is preferred that the operation temperature of the preparation method is room temperature.
Compared with the prior art, especially compared with known Afatinib 2-maleate or its crystal formation, Afatinib diamino sulfonic acid salt or the crystal formation Afatinib diamino sulfonic acid salt of S 1 have one or more improved characteristics, for example：Higher crystallinity, preferable solubility, preferably dissolution velocity, crystal habit, preferable heat endurance and bin stability, relatively low hygroscopicity, preferable flowable and favourable processing and treatment characteristic.
The particularly crystal formation Afatinib diamino sulfonic acid salt of S 1 has following beneficial property：
1) solubility at room temperature in water is 138.3mg/ml, relative to the solubility 7.5mg/ml of Afatinib 2-maleate prior art crystal formation under the same conditions, with higher dissolubility；
2) decomposition temperature is 246.3 °C, relative to 164.1 °C of the decomposition temperature of Afatinib 2-maleate prior art crystal formation, with more preferable heat endurance.
Above-mentioned beneficial property shows, compared with prior art Afatinib 2-maleate or its crystal formation, the Afatinib diamino sulfonic acid salt or the crystal formation Afatinib diamino sulfonic acid salt of S 1 of the present invention has a variety of advantage performances, application effect can be more preferable, is suitable as the active component of pharmaceutical preparation.The higher dissolubility of active component is conducive to improving the bioavilability of medicine, and then produces actively impact to drug effect；Active component has higher heat endurance, the problems such as active component content as caused by the factors such as environment temperature during medicine manufacture and/or storage etc. uneven, purity reduction and impurity increase can preferably be resisted, the curative effect downside risk thus brought and security risk are reduced, and is conducive to accurate quantitative analysis, raising preparation homogeneity and the storage and transport in later stage in medicine manufacture. The seven of present disclosure are to provide the D-Glucose hydrochlorate of Afatinib two and its crystal formation and their preparation method.Detected through HPLC, the actual content of Afatinib free alkali (disregards the amount of solvent for 54.4% in the D-Glucose hydrochlorate of Afatinib two）, Afatinib and maltonic acid are with 1:The theoretical content of Afatinib is Afatinib in 55.3%, therefore the D-Glucose hydrochlorate of Afatinib of the present invention two and maltonic acid with 1 in the compound of 2 mol ratios formation:2 mol ratios are into salt, and its structural formula is as follows：
The preparation method of the D-Glucose hydrochlorate of Afatinib two, comprises the following steps：The mol ratio of solution of the formation Afatinib in soluble solvent, Afatinib and maltonic acid is 1:2-1 :4, solution of the Afatinib in soluble solvent and D- aqueous gluconic acids are mixed to form slurries, solvent is then removed.It is preferred that the soluble solvent is nitrile, alcohols, ketone, esters, alkanes, ethers or its mixture；More preferably acetonitrile, methanol, acetone, ethyl acetate, normal heptane or methyl tertiary butyl ether(MTBE).It is preferred to use the method that is spin-dried for and removes solvent.It is preferred that the concentration of D-Glucose aqueous acid is 50%.
Preferably, the D-Glucose hydrochlorate of Afatinib two is the D-Glucose hydrochlorate of Afatinib two of G1 crystal formations, is radiated using Cu- Κ α, and its X-ray powder diffraction pattern is 4.9 ± 0.2 in the Θ of the angle of diffraction 2.、 5.5±0.2.、 10.0±0.2.、 13.0±0.2.、 25.3±0.2.With 25.9 ± 0.2.Place has characteristic peak.
Further, the D-Glucose hydrochlorate of G1 crystal formations Afatinib two, its X-ray powder diffraction pattern is 4.9 ± 0.2 in the Θ of the angle of diffraction 2.、 5.5±0.2.、 6.1±0.2.、 9.6±0.2.、 10.0±0.2.、 13.0±0.2.、 17.1±0.2.、 19.6±0.2.、 20.0±0.2.、 20.3±0.2.、 25.3±0.2.With 25.9 ± 0.2.Place has characteristic peak.
Further, the D-Glucose hydrochlorate of G1 crystal formations Afatinib two, the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure is as follows：
The Θ relative intensities % of the angle of diffraction 2
4.9±0.2° 60.6
5.5±0.2° 23.8
6. 1±0.2° 17.4
8.5±0.2° 14. 1
9.6±0.2° 18.5
10. .0±0. .2° 44.4
12. . 1±0. .2° 14.7
13. .0±0. .2° 26.8
15. .2±0. .2° 10.3
17. . 1±0. .2° 29.4
18. .8±0. .2° 15.6
19. .6±0. .2° 21.8
20. .0±0. .2° 33.5
20. .3±0. .2° 33.8
22. .3±0. .2° 1 1.2
25. .3±0. .2° 100.0
25. .9±0. .2° 53.2
26. .6±0. .2° 1 1.8
27. .3±0. .2° 13.8
27. .7±0. .2° 1 1.8
Without limitation, a representative instance of the D-Glucose hydrochlorate of G1 crystal formations Afatinib two has X-ray powder diffraction pattern as shown in figure 47. The D-Glucose hydrochlorate of Gl crystal formations Afatinib two, its FTIR spectrum is 1626,1578,1538,1497,1453,1237,1209,1050 and 777cm in wave number-1Place has characteristic peak.
The D-Glucose hydrochlorate of G1 crystal formations Afatinib two, its Raman spectrum is 1656,1608,1546,1400,1370,1300,1215 and δ η in wave number1Place has characteristic peak.
A kind of preparation method of the D-Glucose hydrochlorate of G1 crystal formations Afatinib two, comprises the following steps：The mol ratio of solution of the formation Afatinib in soluble solvent, Afatinib and maltonic acid is 1:2-1:4, solution of the Afatinib in soluble solvent and D-Glucose aqueous acid are mixed to form slurries and stirred, is kept for 1-48 hour under -10-50 °C, and then solvent is removed, wherein the soluble solvent is selected from C2-C4Nitrile, d-C4Alcohol, C3-C5Ketone, C4-C5Ester, C6-C9Alkane, the d-C of nitro substitution3Alkane, C4-C6Ether or its mixture.The C2-C4Nitrile includes but is not limited to acetonitrile, the d-C4Alcohol includes but is not limited to methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol and sec-butyl alcohol, the C3-C5Ketone includes but is not limited to acetone and butanone, the C4-C5Ester includes but is not limited to ethyl acetate and isopropyl acetate, the C6-C9Alkane includes but is not limited to n-hexane, normal heptane and hexahydrotoluene, the d-C of the nitro substitution3Alkane includes but is not limited to nitromethane, the C4-C6Ether includes but is not limited to ether, isopropyl ether and methyl tertiary butyl ether(MTBE)；It is preferred that the soluble solvent is ethyl acetate, acetonitrile, nitromethane, methanol, acetone, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；More preferably ethyl acetate.It is preferred that concentration of the Afatinib in soluble solvent is the saturated solution of Afatinib under 10 mg/mls to the solvent.It is preferred that Afatinib and the mol ratio of maltonic acid are 1:2-1:3.It is preferred that the operation temperature of the preparation method is room temperature.It is preferred that the concentration of D-Glucose aqueous acid is 50%.
Another preparation method of the D-Glucose hydrochlorate of G1 crystal formations Afatinib two, comprises the following steps：The D-Glucose hydrochlorate of Afatinib two that aforementioned preparation process is obtained forms slurries and stirred in organic solvent, the slurries are kept 1 72 hours under -10-50 °C, and then solvent is removed, wherein the organic solvent is selected from methanol, acetonitrile, ethyl acetate, nitromethane, acetone, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture.It is preferred that the operation temperature of the preparation method is room temperature.
Compared with the prior art, especially compared with the Afatinib 2-maleate or its crystal formation of prior art, the D- gluconates of Afatinib two or the D-Glucose hydrochlorate of G1 crystal formations Afatinib two have one or more improved characteristics, for example：Higher crystallinity, preferable solubility, preferably dissolution velocity, crystal habit, preferable heat endurance and bin stability, relatively low hygroscopicity, preferable flowable and favourable processing and treatment characteristic.
The particularly D-Glucose hydrochlorate of G1 crystal formations Afatinib two has following beneficial property：
1) its fusing point is 101.3 °C, and less than 166.2 °C of the fusing point of Afatinib 2-maleate prior art crystal formation, amorphous substance can be prepared at quite low temperatures, and amorphous substance has preferable dissolubility；
2) according to document《Handbook of Pharmaceutical Salts properties, Selection,and use》Introduce, D- gluconic acids have lower toxicity compared with maleic acid.
Above-mentioned beneficial property shows, compared with the Afatinib 2-maleate or its crystal formation of prior art, the D-Glucose hydrochlorate of Afatinib two or the D-Glucose hydrochlorate of G1 crystal formations Afatinib two of the present invention has a variety of advantage performances, application effect can be more preferable, is suitable as the active component of pharmaceutical preparation.The higher dissolubility of active component is conducive to improving the bioavilability of medicine, and then produces actively impact to drug effect；Active component has lower toxicity so that the manufacturing process of preparation and the clinical practice of medicine are safer.
The eight of present disclosure are to provide Afatinib bicyclohexane An Ji Shuo hydrochlorates and its crystal formation and their preparation method.Detected through HPLC, the actual content of Afatinib free alkali (disregards the amount of solvent for 58.3% in the Afatinib bicyclohexane sulfamate）, Afatinib and cyclohexane sulfamic acid are with 1:The theoretical content of Afatinib is Afatinib in 57.6%, therefore Afatinib bicyclohexane sulfamate of the present invention and cyclohexane sulfamic acid with 1 in the compound of 2 mol ratios formation:2 mol ratios are into salt, and its structural formula is as follows：
The preparation method of the Afatinib bicyclohexane sulfamate, comprises the following steps：Form solution system and cyclohexane sulfamic acid suspension system in organic solvent of the Afatinib in soluble solvent respectively, the mol ratio of Afatinib and cyclohexane sulfamic acid is 1:2-1 :4, two System forming slurries are mixed, solvent is then removed.It is preferred that the soluble solvent or organic solvent are nitrile, alcohols, ketone, esters, alkanes, ethers or its mixture；More preferably acetonitrile, methanol, acetone, ethyl acetate, normal heptane or methyl tertiary butyl ether(MTBE).It is preferred to use the method that is spin-dried for and removes solvent.
Preferably, the Afatinib bicyclohexane sulfamate is the Afatinib bicyclohexane sulfamate of C1 crystal formations, is radiated using Cu- Κ α, and its X-ray powder diffraction pattern is 5.0 ± 0.2 in the Θ of the angle of diffraction 2.、 6.0±0.2.、 16.5±0.2.、 17.9±0.2.、 18.6±0.2.With 20.2 ± 0.2.Place has characteristic peak.
Further, the C1 crystal formations Afatinib bicyclohexane sulfamate, its X-ray powder diffraction pattern is 5.0 ± 0.2 in the Θ of the angle of diffraction 2.、 6.0±0.2.、 12.5±0.2.、 14.9±0.2.、 16.5±0.2.、 17.9±0.2.、 18.4±0.2.、 18.6±0.2.、 20.2±0.2.、 21.3±0.2.、 21.6±0.2.With 24.2 ± 0.2.Place has characteristic peak.
Further, the C1 crystal formations Afatinib bicyclohexane sulfamate, the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure is as follows：
The Θ relative intensities % of the angle of diffraction 2
5.0±0.2° 100.0
6.0±0.2° 27.1
12.5±0.2° 9.6
14.9±0.2° 9.9
16.5±0.2° 13.6
17.9±0.2° 15.3
18.4±0.2° 17.6
18.6±0.2° 31.3
19.5±0.2° 9.6
20.2±0.2° 27.9
21.3±0.2° 12.2
21.6±0.2° 13.1
24.2±0.2° 12.9
27.8±0.2° 10.2
Without limitation, a representative instance of the C1 crystal formations Afatinib bicyclohexane sulfamate has X-ray powder diffraction pattern as shown in figure 50.
The C1 crystal formations Afatinib bicyclohexane sulfamate, its FTIR spectrum is 1637,1577,1540,1498,1453,1204,1157,1029,866 and 775cm in wave number_1Place has characteristic peak.
The C1 crystal formations Afatinib bicyclohexane sulfamate, its Raman spectrum is to have characteristic peak at 1662,1609,1543,1401,1372,1291,1209 and 778cm in wave number.
A kind of preparation method of the C1 crystal formations Afatinib bicyclohexane sulfamate, comprises the following steps：Form the suspension system of solution system of the Afatinib in soluble solvent and cyclohexane sulfamic acid in organic solvent respectively, the mol ratio of Afatinib and cyclohexane sulfamic acid is 1:2-1 :4, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, then remove solvent, wherein the soluble solvent or organic solvent are selected from C2-C4Nitrile, d-C4Alcohol, C3-C5Ketone, C4-C5Ester, C6-C9Alkane, C4-C6Ether or its mixture.The C2-C4Nitrile includes but is not limited to acetonitrile, the d-C4Alcohol includes but is not limited to methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol and sec-butyl alcohol, the C3-C5Ketone includes but is not limited to acetone and butanone, the C4-C5Ester includes but is not limited to ethyl acetate and isopropyl acetate, the C6-C9Alkane includes but is not limited to n-hexane, normal heptane and hexahydrotoluene, the C4-C6Ether includes but is not limited to ether, isopropyl ether and methyl tertiary butyl ether(MTBE)；It is preferred that the soluble solvent or organic solvent are acetonitrile, methanol, acetone, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；More preferably acetonitrile.It is preferred that concentration of the Afatinib in soluble solvent is the saturated solution of Afatinib under 10 mg/mls to the solvent.It is preferred that Afatinib and the mol ratio of the own alkylamino Shuo acid of ring are 1:2-1 :3.It is preferred that the operation temperature of the preparation method is room temperature.
Another preparation method of the C1 crystal formations Afatinib bicyclohexane sulfamate, comprises the following steps：The Afatinib bicyclohexane An Ji Shuo hydrochlorates that aforementioned preparation process is obtained form slurries and stirred in organic solvent, the slurries are kept 1 72 hours under -10-50 °C, and then remove solvent, wherein the organic solvent be selected from methanol, acetone, acetonitrile, ethyl acetate, normal heptane, Methyl tertiary butyl ether(MTBE) or its mixture.It is preferred that the operation temperature of the preparation method is room temperature.
Compared with the prior art, especially compared with the Afatinib 2-maleate or its crystal formation of prior art, Afatinib bicyclohexane sulfamate or C1 crystal formation Afatinib bicyclohexane An Ji Shuo hydrochlorates have one or more improved characteristics, for example：Higher crystallinity, preferable solubility, preferably dissolution velocity, crystal habit, preferable heat endurance and bin stability, relatively low hygroscopicity, preferable flowable and favourable processing and treatment characteristic.
Particularly C1 crystal formations Afatinib bicyclohexane sulfamate has following beneficial property：
1) solubility at room temperature in water is 63.1mg/ml, relative to the mg/ml of solubility 7.5 of Afatinib 2-maleate prior art crystal formation under the same conditions, with higher dissolubility；
2) decomposition temperature is 246.1 °C, relative to 164.1 °C of the decomposition temperature of Afatinib 2-maleate prior art crystal formation, with higher heat endurance.
Above-mentioned beneficial property shows, compared with prior art Afatinib 2-maleate or its crystal formation, the Afatinib bicyclohexane sulfamate or C1 crystal formation Afatinib bicyclohexane ammonia base Shuo hydrochlorates of the present invention has a variety of advantage performances, application effect can be more preferable, is suitable as the active component of pharmaceutical preparation.The higher dissolubility of active component is conducive to improving the bioavilability of medicine, and then produces actively impact to drug effect；Active component has higher heat endurance, the problems such as active component content as caused by the factors such as environment temperature during medicine manufacture and/or storage etc. uneven, purity reduction and impurity increase can preferably be resisted, the curative effect downside risk thus brought and security risk are reduced, and is conducive to accurate quantitative analysis, raising preparation homogeneity and the storage and transport in later stage in medicine manufacture.
The nine of present disclosure are to provide the 4- amino phenyl sulfonyls hydrochlorate of Afatinib two and its crystal formation and their preparation method.Detected through HPLC, the actual content of Afatinib free alkali (disregards the amount of solvent for 59.1% in the 4- amino phenyl sulfonyl hydrochlorates of Afatinib two）, Afatinib and 4- aminobenzenesulfonic acids are with 1:The theoretical content of Afatinib is Afatinib in 58.4%, therefore the 4- amino phenyl sulfonyl hydrochlorates of Afatinib of the present invention two and 4- aminobenzenesulfonic acids with 1 in the compound of 2 mol ratios formation:2 mol ratios are into salt, its structural formula
The preparation method of the 4- amino phenyl sulfonyl hydrochlorates of Afatinib two, comprises the following steps：Form solution system and 4- aminobenzenesulfonic acid suspension system in organic solvent of the Afatinib in soluble solvent respectively, the mol ratio of Afatinib and 4- aminobenzenesulfonic acids is 1:2-1 :4, two System forming slurries are mixed, solvent is then removed.It is preferred that the soluble solvent or organic solvent are nitrile, alcohols, ketone, alkanes, ethers or its mixture；More preferably acetonitrile, methanol, acetone, ethyl acetate, normal heptane or methyl tertiary butyl ether(MTBE).It is preferred to use the method that is spin-dried for and removes solvent.
Preferably, the 4- amino phenyl sulfonyls hydrochlorate of Afatinib two is the 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations Afatinib two, is radiated using Cu- Κ α, and its X-ray powder diffraction pattern is 12.9 ± 0.2 in the Θ of the angle of diffraction 2.、17.1±0.2.、18.2±0.2.、23.8±0.2.、 24.5±0.2.With 25.7 ± 0.2.Place has characteristic peak.
Further, the 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations Afatinib two, its X-ray powder diffraction pattern is 5.6 ± 0.2 in the Θ of the angle of diffraction 2.、 12.9±0.2.、 17.1±0.2.、 18.2±0.2.、 21.3±0.2°、 23.8±0.2.、 24.5±0.2.、 25.7±0.2., there is characteristic peak at 27.6 ± 0.2 ° and 34.3 ± 0.2 °.
Further, the 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations Afatinib two, the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure is as follows：
The Θ relative intensities % of the angle of diffraction 2
5.6±0.2° 10.5
12.9±0.2° 23.9
17.1±0.2° 1 1.9
18.2±0.2° 100.0 21.3±0.2° 12.9
23.8±0.2° 19.1
24.5±0.2° 29.6
25.7±0.2° 23.1
27.6±0.2° 18.3
34.3±0.2° 16.1
Without limitation, a representative instance of the 4- amino phenyl sulfonyl hydrochlorates of Al crystal formations Afatinib two has X-ray powder diffraction pattern as shown in figure 50.
The 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations Afatinib two, its FTIR spectrum is to have characteristic peak at 1637,1599,1525,1498,1451,1206,1158,1118,1027 and 694cm in wave number.
The 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations Afatinib two, its Raman spectrum is to have characteristic peak at 1657,1644,1546,1499,1400,1371,1297,1208,1122 and 781cm in wave number.
A kind of preparation method of the 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations Afatinib two, comprises the following steps：Form solution system and 4- aminobenzenesulfonic acid suspension system in organic solvent of the Afatinib in soluble solvent respectively, the mol ratio of Afatinib and 4- aminobenzenesulfonic acids is 1:2-1 :4, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, then remove solvent, wherein the soluble solvent or organic solvent are selected from C2-C4Nitrile, d-C4Alcohol, C3-C5Ketone, C6-C9Alkane, C4-C6Ether or its mixture.The C2-C4Nitrile includes but is not limited to acetonitrile, the d-C4Alcohol includes but is not limited to methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol and sec-butyl alcohol, the C3-C5Ketone includes but is not limited to acetone and butanone, the C6-C9Alkane includes but is not limited to n-hexane, normal heptane and hexahydrotoluene, the C4-C6Ether includes but is not limited to ether, isopropyl ether and methyl tertiary butyl ether(MTBE)；It is preferred that the soluble solvent or organic solvent are acetonitrile, methanol, acetone, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；More preferably acetonitrile.It is preferred that concentration of the Afatinib in soluble solvent is the saturated solution of Afatinib under 10 mg/mls to the solvent.It is preferred that Afatinib and the mol ratio of 4- aminobenzenesulfonic acids are 1:2-1 :3.It is preferred that the operation temperature of the preparation method is room temperature.
Another preparation method of the 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations Afatinib two, comprises the following steps：The 4- amino phenyl sulfonyls hydrochlorate of Afatinib two that aforementioned preparation process is obtained forms slurries and stirred in organic solvent, the slurries are kept 1 72 hours under -10-50 °C, and then solvent is removed, wherein the organic solvent is selected from methanol, acetone, acetonitrile, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture.It is preferred that the operation temperature of the preparation method is room temperature.
Compared with the prior art, especially compared with prior art Afatinib 2-maleate or its crystal formation, the 4- An Ji Ben Shuo hydrochlorates of Afatinib two or the 4- An Ji Ben Shuo hydrochlorates of A1 crystal formations Afatinib two have one or more improved characteristics, for example：Higher crystallinity, preferable solubility, preferably dissolution velocity, crystal habit, preferable heat endurance and bin stability, relatively low hygroscopicity, preferable flowable and favourable processing and treatment characteristic.
The particularly 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations Afatinib two have following beneficial property：
1) solubility at room temperature in water is 123.8mg/ml, relative to the mg/ml of solubility 7.5 of Afatinib 2-maleate prior art crystal formation under the same conditions, with higher dissolubility.
2) decomposition temperature is 261.7 °C, relative to 164.1 °C of the decomposition temperature of Afatinib 2-maleate prior art crystal formation, with higher heat endurance.
Above-mentioned beneficial property shows, compared with prior art Afatinib 2-maleate or its crystal formation, the Afatinib bicyclohexane ammonia base Shuo hydrochlorates or C1 crystal formation Afatinib bicyclohexane ammonia base Shuo hydrochlorates of the present invention has a variety of advantage performances, application effect can be more preferable, is suitable as the active component of pharmaceutical preparation.The higher dissolubility of active component is conducive to improving the bioavilability of medicine, and then produces actively impact to drug effect；Active component has higher heat endurance, can preferably resist during medicine manufacture and/or storage etc. that the active component content as caused by the factors such as environment temperature is uneven, purity reduction and the problems such as impurity increase, the curative effect downside risk thus brought and security risk are reduced, and is conducive to accurate quantitative analysis, raising preparation homogeneity and the storage and transport in later stage in medicine manufacture.
The ten of present disclosure are to provide Afatinib glycol hydrochlorate and its crystal formation and their preparation method.
Detected through HPLC, the actual content of Afatinib free alkali (disregards the amount of solvent for 85.4% in the Afatinib glycol hydrochlorate）, Afatinib and Glycolic acid are with 1：The theoretical content of Afatinib is Afatinib in 86.5%, therefore the Afatinib glycol hydrochlorate and Glycolic acid with 1 in the compound of 1 mol ratio formation:1 mol ratio is into salt, and its structural formula is as follows：
The preparation method of the Afatinib glycol hydrochlorate, comprises the following steps：Form solution system in soluble solvent of Afatinib and Glycolic acid respectively, the mol ratio of Afatinib and Glycolic acid is 1: 1-1 :2, two System forming slurries are mixed, solvent is then removed.It is preferred that the soluble solvent is alcohols, ketone, esters, alkanes, ethers or its mixture；More preferably methanol, acetone, ethyl acetate, normal heptane or methyl tertiary butyl ether(MTBE).It is preferred to use the method that is spin-dried for and removes solvent.
Preferably, the Afatinib glycol hydrochlorate be G1-1 crystal formations Afatinib glycol hydrochlorate, using Cu- Κ α radiate, its X-ray powder diffraction pattern the Θ of the angle of diffraction 2 be 5.1 ± 0.2 °, 6.4 ± 0.2.、 13.0±0.2.、 13.3±0.2., there is characteristic peak at 20.8 ± 0.2 ° and 25.0 ± 0.2 °.
Further, the G1-1 crystal formations Afatinib glycol hydrochlorate, its X-ray powder diffraction pattern is 5.1 ± 0.2 in the Θ of the angle of diffraction 2.、 6.4±0.2.、 7.0±0.2.、 13.0±0.2.、 13.3±0.2.、 17.2±0.2.、 17.9±0.2.、 19.7±0.2.、 20.8±0.2., 22.4 ± 0.2 °, there is characteristic peak at 25.0 ± 0.2 ° and 25.9 ± 0.2 °.
Further, the G1-1 crystal formations Afatinib glycol hydrochlorate, the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure is as follows：
The Θ relative intensities % of the angle of diffraction 2
5.1±0.2° 28.9
6.4±0.2° 100.0
7.0±0.2° 1 1.5
13.0±0.2° 21.7
13.3±0.2° 19.0
17.2±0.2° 14.7
17.9±0.2° 13.9
19.0±0.2° 1 1.2
19.7±0.2° 1 1.5
20.8±0.2° 24.7
21.2±0.2° 12.0
22.4±0.2° 14.8
23.5±0.2° 12.6
25.0±0.2° 67.5
25.9±0.2° 20.1
Without limitation, a representative instance of the G1-1 crystal formations Afatinib glycol hydrochlorate has X-ray powder diffraction pattern as shown in Figure 63.
The G1-1 crystal formations Afatinib glycol hydrochlorate, its FTIR spectrum is 1625,1577,1536,1497,1452,1427,1234,1212,1081 and 777cm in wave number-1Place has characteristic peak.
The G1-1 crystal formations Afatinib glycol hydrochlorate, its Raman spectrum is 1650,1629,1610,1536,1398,1344,1304,1215 and δ η in wave number1Place has characteristic peak.
A kind of preparation method of the G1-1 crystal formations Afatinib glycol hydrochlorate, comprises the following steps：Form solution system in soluble solvent of Afatinib and Glycolic acid respectively, the mol ratio of Afatinib and Glycolic acid is 1: 1-1 :2, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, and then solvent is removed, wherein the soluble solvent is selected from d-C4Alcohol, C3-C5Ketone, C4-C5Ester, C6-C9Alkane, the d-C of nitro substitution3Alkane, C4-C6Ether or its mixture.The d-C4Alcohol includes but is not limited to methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol and sec-butyl alcohol, the C3-C5Ketone includes but is not limited to acetone and butanone, the C4-C5Ester includes but is not limited to ethyl acetate and isopropyl acetate, the C6-C9Alkane includes but is not limited to n-hexane, normal heptane and hexahydrotoluene, the d-C of the nitro substitution3Alkane includes but is not limited to nitromethane, described C4-C6Ether includes but is not limited to ether, isopropyl ether and methyl tertiary butyl ether(MTBE)；It is preferred that the soluble solvent is ethyl acetate or nitromethane.It is preferred that concentration of the Afatinib in soluble solvent is the saturated solution of Afatinib under 10 mg/mls to the solvent.It is preferred that Afatinib and the mol ratio of Glycolic acid are 1: 1-1 : 1.5.It is preferred that the operation temperature of the preparation method is room temperature.
Another preparation method of the crystal formation Afatinib glycol hydrochlorates of G1- 1, comprises the following steps：The Afatinib glycol hydrochlorate that aforementioned preparation process is obtained forms slurries and stirred in organic solvent, the slurries are kept 1 72 hours under -10-50 °C, and then solvent is removed, wherein the organic solvent is selected from methanol, acetone, acetonitrile, ethyl acetate, nitromethane, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture.It is preferred that the operation temperature of the preparation method is room temperature.
Compared with the prior art, especially compared with the Afatinib 2-maleate or its crystal formation of prior art, Afatinib glycol hydrochlorate or the crystal formation Afatinib glycol hydrochlorates of G1- 1 have one or more improved characteristics, for example：Higher crystallinity, preferable solubility, preferably dissolution velocity, crystal habit, preferable heat endurance and bin stability, relatively low hygroscopicity, preferable flowable and favourable processing and treatment characteristic.
The particularly crystal formation Afatinib glycol hydrochlorates of G1- 1 have following beneficial property：
1) fusing point is 83.5 °C, and less than 166.2 °C of the fusing point of Afatinib 2-maleate prior art crystal formation, amorphous substance can be prepared at quite low temperatures, and amorphous substance has preferable dissolubility.
2) according to document《Handbook of Pharmaceutical Salts properties,selection,and use》Introduce, Glycolic acid has lower toxicity compared with maleic acid.
Above-mentioned beneficial property shows, compared with the Afatinib 2-maleate or its crystal formation of prior art, the Afatinib glycol hydrochlorate or G1-1 crystal formation Afatinib glycol hydrochlorates of the present invention has a variety of advantage performances, and application effect can be more preferable, is suitable as the active component of pharmaceutical preparation.The higher dissolubility of active component is conducive to improving the bioavilability of medicine, and then produces actively impact to drug effect；Active component has lower toxicity so that the manufacturing process of preparation and the clinical practice of medicine are safer.
The 11 of present disclosure are to provide a kind of new Afatinib 2-maleate crystal formation N and preparation method thereof.Radiated using Cu- Κ α, the X-ray powder diffraction pattern of the Afatinib 2-maleate crystal formation N is 4.8 ± 0.2 in the Θ of the angle of diffraction 2.、 9.7±0.2.、 14.5±0.2.、 17.0±0.2.、 19.5±0.2.、 20.1±0.2、 25.6±0.2.Place has characteristic peak.
Further, the Afatinib 2-maleate crystal formation N, the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure is as follows：
The Θ relative intensities % of the angle of diffraction 2
4.8±0.2° 100.0
9.7±0.2° 7.5
14.5±0.2° 3.6
17.0±0.2° 2.2
19.5±0.2° 5.7
20. 1±0.2° 2.3
25.5±0.2° 5.0 。
Without limitation, a representative instance of the Afatinib 2-maleate crystal formation N has X-ray powder diffraction pattern as shown in Figure 66.
The Afatinib 2-maleate crystal formation N, its FTIR spectrum is to have characteristic peak at 1684,1576,1542,1496,1449,1351,1088,891 and 859cm in wave number.
The Afatinib 2-maleate crystal formation N, its Raman spectrum is to have characteristic peak at 1657,1607,1546,1494,1404,1374,1302,1217 and 783cm in wave number.
The preparation method of the Afatinib 2-maleate crystal formation N, comprises the following steps：Form solution system in nitromethane of Afatinib and maleic acid respectively, the mol ratio of Afatinib and maleic acid is 1:2-1 :4, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, then remove solvent.It is preferred that concentration of the Afatinib in nitromethane is saturated solution of 10 mg/mls to Afatinib in nitromethane；It is preferred that Afatinib and the mol ratio of maleic acid are 1:2-1 :3 ;It is preferred that the operation temperature of the preparation method is room temperature.
Compared with the prior art, especially compared with Afatinib 2-maleate prior art crystal formation, Afatinib 2-maleate crystal formation N of the invention has one or more improved characteristics, for example：Higher crystallinity, preferable solubility, dissolving Speed, preferably crystal habit, preferable heat endurance and bin stability, relatively low hygroscopicity, preferable flowable and favourable processing and treatment characteristic.
Particularly Afatinib 2-maleate crystal formation N has following beneficial property：Its solubility at room temperature in water is 12.7mg/ml, relative to the mg/ml of solubility 7.5 of Afatinib 2-maleate prior art crystal formation under the same conditions, with higher dissolubility.Above-mentioned beneficial property shows, compared with Afatinib 2-maleate prior art crystal formation, and Afatinib 2-maleate crystal formation N of the invention has advantage performance, and application effect can be more preferable, is suitable as the active component of pharmaceutical preparation.The higher dissolubility of active component is conducive to improving the bioavilability of medicine, and then produces actively impact to drug effect.
In any of the above described preparation method of the present invention, alternatively, solution system and the solution system of acid or the hybrid mode of suspension system of the Afatinib are：I) solution system of Afatinib is added into the solution system or suspension system of acid；Or ii) added into the solution system of Afatinib acid solution system or suspension system；Or iii) add the solution system or suspension system of the solution system of Afatinib and acid into reaction vessel simultaneously.
" stirring " described in any of the above described preparation method of the present invention can be completed with routine techniques, such as magnetic agitation and mechanical agitation.Mixing speed is 50 1800 revs/min, preferably 300 900 revs/min.
" removing solvent " step described in any of the above described preparation method of the present invention can be completed with routine techniques, for example, filter, centrifuge, dry or evaporate.The concrete operations of revolving are：The container that will be equipped with solution is placed in revolving instrument, under the bath temperature of room temperature to solvent boiling point（It is preferred that 30 ~ 50 °C), less than under the pressure of atmospheric pressure（It is preferred that pressure is less than 0.08MPa), with 10 180 revs/min of rotary speed（It is preferred that 50 ~ 100 revs/min）, solvent is eliminated.
Afatinib acid-addition salts and its crystal formation that any of the above described preparation method of the present invention is obtained, can be further dried using routine techniques.Dry and carried out in the case where depressurizing or not depressurizing, preferably pressure is less than 0.09MPa, about 30-50 °C of drying temperature, drying time 10-72 hour, preferably 10-48 hour, more preferably 10-24 hour.Drying can be carried out in fume hood, convection oven or vacuum drying oven.
In the present invention, initiation material Afatinib can be prepared according to method disclosed in embodiment 1 in document CN1867564B, and the document is incorporated into the application by way of quoting its full text.
In the present invention, " room temperature " refers to 10-25 °C of c
According to the purpose of the present invention, the present invention provides a kind of Yao Wu Group compounds, one or more of the present invention Afatinib acid-addition salts or its crystal formation of the Yao Wu Group compounds comprising treatment and/or prevention effective dose or the Afatinib acid-addition salts or its crystal formation that are prepared by the inventive method, and at least one pharmaceutically acceptable excipient.Wherein, Afatinib acid-addition salts or its crystal formation of the present invention are selected from the ethanedisulphonate of Afatinib, E1 crystal formation ethanedisulphonates, 1, 5- napadisilates, N1 crystal formations 1, 5- napadisilates, N2 crystal formations 1, 5- naphthalenedisulfonic acid salt hydrates, malonate, Ml crystal formation malonates, two malonates, the malonate of M2 crystal formations two, two 2- naphthalene sulfonates, the 2- naphthalene sulfonates of Nsl crystal formations two, diamino sulfonic acid salt, S1 crystal formation diamino sulfonic acid salt, two D-Glucose hydrochlorates, the D-Glucose hydrochlorate of G1 crystal formations two, bicyclohexane sulfamate, C1 crystal formation bicyclohexane sulfamates, two 4- amino phenyl sulfonyl hydrochlorates, the 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations two, glycol hydrochlorate, G1-1 crystal formation glycol hydrochlorates or 2-maleate crystal formation N, in addition, the Yao Wu Group compounds can also include Afatinib or its pharmaceutically useful other salt, and their crystal formation or amorphous substance.
Excipient in the Yao Wu Group compounds includes carbohydrate, Xian Victoria elements and its derivative, starch or modified starch, solid inorganic thing such as calcium phosphate, phosphoric acid Hydrogen dicalcium, hydroxyapatite, calcium sulfate, calcium carbonate, semi-solid such as lipid or paraffin, adhesive such as Wei Jing Xian Victoria elements, Yi Ji Xian Victoria elements, Qiang Jia Ji Xian Victoria elements, Qiang hydroxypropyl methyl Xian Victoria elements, Qiang Yi Ji Xian Victoria elements, glidant such as colloidal silica, light anhydrous silicic acid, crystallize Xian Victoria elements, talcum powder or stearic acid town, disintegrant such as Sodium Carboxymethyl Starch, Jiao Ju Victoria ketone, Jiao connection Suo Jia Ji Xian Victoria elements, Suo Jia Ji Xian Victoria element sodium, dried corn starch, lubricant such as stearic acid, magnesium stearate, sodium stearyl fumarate, polyethylene glycol.
The Yao Wu Group compounds can be solid-state or liquid, and method of administration includes oral, intravenous injection, hypodermic injection, Group and knits interior administration, cutaneous penetration, rectally, intranasal administration etc..For example, solid oral dosage form, including tablet, granule, capsule, powder, pill and lozenge, can be conventional, dispersible, masticable, Orally dissolving or rapid melting preparation；Liquid oral dosage form, including solution, syrup, supensoid agent, dispersant and emulsion；Injectable formulation, including solution, dispersant and freeze-dried；Suitable for inhalant aerosol preparations；Suppository suitable for rectally.Formula may be adapted to the quick-release of active component, Slow and release or adjust release. The Yao Wu Group compounds can be used to be prepared well known to a person skilled in the art method.When preparing Yao Wu Group compounds, the Afatinib acid-addition salts or its crystal formation of the present invention are mixed with one or more pharmaceutically acceptable excipient, crystal formation or amorphous substance optionally with the other salt of pharmaceutically useful Afatinib are mixed, and are optionally mixed with one or more other active constituents of medicine.Solid pharmaceutical preparation can be prepared by the technique such as directly mixing, pelletizing.
The Afatinib acid-addition salts or its crystal formation of the present invention are applied to treat benign or malignant tumour, for preventing and treating respiratory tract and PUD D, and for treating intestines and stomach, bile duct and gallbladder disease.
Further, it is used to prepare treatment and/or prevention advanced Non-small cell lung the invention provides the foregoing Afatinib acid-addition salts of the present invention or its crystal formation（) and the purposes in the medicine of the positive advanced breast cancer diseases of HER2 NSCLC.
Further, the present invention provides a kind for the treatment of and/or prevention advanced Non-small cell lung（NSCLC) and the positive advanced breast cancers of HER2 method, methods described includes giving patient's treatment of needs and/or foregoing Afatinib acid-addition salts of the invention of prevention effective dose or its crystal formation or the Yao Wu Group compounds comprising foregoing Afatinib acid-addition salts of the invention or its crystal formation.The patient is usually homoiothermy Vertebrate, particularly people.The dosage used as medicine is 0.01 100 mg kg of body weight, preferably 0.1 15 mg kg of body weight.
Brief description of the drawings
Fig. 1 is the XRPD figures of Afatinib 2-maleate prior art crystal formation disclosed in CN1867564B
Fig. 2 is the XRPD figures of Afatinib 2-maleate prior art crystal formation prepared by preparation example 1
Fig. 3 is the TGA figures of Afatinib 2-maleate prior art crystal formation prepared by preparation example 1
Fig. 4 is the DSC figures of Afatinib 2-maleate prior art crystal formation prepared by preparation example 1
Fig. 5 is the DVS figures of Afatinib 2-maleate prior art crystal formation prepared by preparation example 1
Fig. 6 is the XRPD figures of E1 crystal formation Afatinib ethanedisulphonates prepared by embodiment 3
Fig. 7 is the PLM figures of E1 crystal formation Afatinib ethanedisulphonates prepared by embodiment 3
Fig. 8 is the TGA figures of E1 crystal formation Afatinib ethanedisulphonates prepared by embodiment 3
Fig. 9 is the DVS figures of E1 crystal formation Afatinib ethanedisulphonates prepared by embodiment 3
Figure 10 is the IR figures of E1 crystal formation Afatinib ethanedisulphonates prepared by embodiment 3
Figure 11 is the Raman figures of E1 crystal formation Afatinib ethanedisulphonates prepared by embodiment 3
Figure 12 is the NMR figures of E1 crystal formation Afatinib ethanedisulphonates prepared by embodiment 3
Figure 13 is the XRPD figures of N1 crystal formation Afatinib 1,5- napadisilates prepared by embodiment 12
Figure 14 is the PLM figures of N1 crystal formation Afatinib 1,5- napadisilates prepared by embodiment 12
Figure 15 is the TGA figures of N1 crystal formation Afatinib 1,5- napadisilates prepared by embodiment 12
Figure 16 is the DVS figures of N1 crystal formation Afatinib 1,5- napadisilates prepared by embodiment 12
Figure 17 is the IR figures of N1 crystal formation Afatinib 1,5- napadisilates prepared by embodiment 12
Figure 18 is the Raman figures of N1 crystal formation Afatinib 1,5- napadisilates prepared by embodiment 12
Figure 19 is the NMR figures of N1 crystal formation Afatinib 1,5- napadisilates prepared by embodiment 12
Figure 20 is the XRPD figures of N2 crystal formation Afatinib 1,5- naphthalenedisulfonic acid salt hydrates prepared by embodiment 20
Figure 21 is the PLM figures of N2 crystal formation Afatinib 1,5- naphthalenedisulfonic acid salt hydrates prepared by embodiment 20
Figure 22 is the TGA figures of N2 crystal formation Afatinib 1,5- naphthalenedisulfonic acid salt hydrates prepared by embodiment 20
Figure 23 is the IR figures of N2 crystal formation Afatinib 1,5- naphthalenedisulfonic acid salt hydrates prepared by embodiment 20
Figure 24 is the Raman figures of N2 crystal formation Afatinib 1,5- naphthalenedisulfonic acid salt hydrates prepared by embodiment 20
Figure 25 is the XRPD figures of the malonate of Ml crystal formations Afatinib one prepared by embodiment 24
Figure 26 is the PLM figures of the malonate of Ml crystal formations Afatinib one prepared by embodiment 24
Figure 27 is the TGA figures of the malonate of Ml crystal formations Afatinib one prepared by embodiment 24
Figure 28 is the IR figures of the malonate of Ml crystal formations Afatinib one prepared by embodiment 24
Figure 29 is the Raman figures of the malonate of Ml crystal formations Afatinib one prepared by embodiment 24
Figure 30 is the NMR figures of the malonate of Ml crystal formations Afatinib one prepared by embodiment 24
Figure 31 is the XRPD figures of the malonate of M2 crystal formations Afatinib two prepared by embodiment 31
Figure 32 is the TGA figures of the malonate of M2 crystal formations Afatinib two prepared by embodiment 31 Figure 33 is embodiment 31
Figure 34 is embodiment 31
Figure 35 is embodiment 31
Figure 36 is embodiment 31
Figure 37 is embodiment 38
Figure 38 is embodiment 38
Figure 39 is embodiment 38
Figure 40 is embodiment 38
Figure 41 is embodiment 38
Figure 42 is embodiment 46
Figure 43 is embodiment 46
Figure 44 is embodiment 46
Figure 45 is embodiment 46
Figure 46 is embodiment 46
Figure 47 is embodiment 54
Figure 48 is embodiment 54
Figure 49 is embodiment 54
Figure 50 is embodiment 54
Figure 51 is embodiment 54
Figure 52 is embodiment 54
Figure 53 is embodiment 63
Figure 54 is embodiment 63
Figure 55 is embodiment 63
Figure 56 is embodiment 63
Figure 57 is embodiment 63
Figure 58 is embodiment 72
Figure 59 is embodiment 72
Figure 60 is embodiment 72
Figure 61 is embodiment 72
Figure 62 is embodiment 72
Figure 63 is embodiment 81
Figure 64 is embodiment 81
Figure 65 is embodiment 81
Figure 66 is embodiment 81
Figure 67 is embodiment 81
Figure 68 is embodiment 81
Figure 69 is embodiment 88
Figure 70 is embodiment 88
Figure 71 is embodiment 88
Figure 72 is embodiment 88
Embodiment
The present invention is with further reference to following examples, and the preparation and application of the salt and crystal formation of the present invention is described in detail in the embodiment.It can implement without departing from the present invention it will be apparent for a person skilled in the art that changing for both material and method many of which.
Detecting instrument and method：
X-ray powder diffraction（XPRD the instrument used in) is Bruker D8 Advance diffractometer, using copper target ripple A length of 1.54nm Κ α X-rays, under 40kV and 40mA operating condition, Θ -2 Θ angular instruments, Mo monochromators, Lynxeye detectors.Instrument is correcting peak position using the preceding standard sample carried with instrument.Acquisition software is that Diffrac Plus XRD Commander samples are tested at room temperature, and sample is placed on organic slide.Testing conditions：Angular range： 3~4.2Θ ;Step-length： 0.02°2Θ ;Speed：0.2s/ is walked.
Polarization light microscope（PLM) collection of illustrative plates is picked up from XP-500E polarization microscopes（The rectangular optical instrument Co., Ltd in Shanghai）.A small amount of powder sample is taken to be placed on slide, a small amount of mineral oil is added dropwise with preferably dispersion powders sample, sample, is then placed on the objective table of XP-500E polarization microscopes by covered, select the pattern of suitable multiplication factor observing samples and clap it is clear,
Thermogravimetric analysis（TGA) data are picked up from TA Instruments Q500 TGA, instrument control software Thermal Advantage, analysis software Universal Analysis generally take 5 ~ 15mg samples to be placed in platinum crucible, using segmentation high resolution detection mode, N is dried in 50mL/min with 10 °C/min programming rates2Protection under sample from room temperature is risen to 300 °C, while the weight change in TA software records sample temperature-rise periods.
Dynamic moisture content adsorption analysis（DVS) data are picked up from TA Instruments Q5000 TGA, and instrument control software is Thermal Advantage, and analysis software is Universal Analysis.1 ~ 10 mg samples are generally taken to be positioned in platinum crucible, TA software records sample is in relative humidity from the weight change in 0% to 80% to 0% change procedure.According to the concrete condition of sample, can also different absorption and De contamination step be used to sample.
Infrared spectrum analysis (IR) data are picked up from Bruker Tensor 27, and instrument control software and DAS are all OPUS.Generally use ATR equipment, Ο Ο ^ Ο Ο Ο η-1In the range of, infrared absorption spectroscopy is gathered, the sweep time of sample and blank background is 16 seconds, instrumental resolution 4cm-1。
Raman spectrum analysis（Raman) data are picked up from Buddhist nun's high-tensile strength DXR 780, and instrument control software and DAS are all onmic 8.2.Generally under 10 times of mirrors, in the range of wave number SO ^Ocm, exposure frequency 8 times, Raman spectrum collection is carried out to sample at 1 second time for exposure.
Nmr analysis（NMR) data are picked up from Bruker Ascend Tm 500.Excite, spectrum width 30PPM, pulse, 30 ° of angles are excited, scan 16 times usually using full range, digitized quadrature detection, temperature control 298K.
High-efficient liquid phase analysis（HPLC) data are picked up from Agilent 1260, and instrument control software is Agilent chem workstations B.04 version online, and analysis software is Agilent chem workstations B.04 version offline.Using C18 chromatographic columns, 150mmx4.6mm, 40 °C of column temperature, wavelength 254nm, flow velocity 0.3ml/min, sample size 50 μ 1, run time 30min.Mobile phase A is the water containing 0.01% trifluoroacetic acid, and Mobile phase B is the acetonitrile containing 0.01% trifluoroacetic acid, and gradient is shown in Table 1：
Eluent gradient table in HPLC
Tablet hardness detection data are picked up from the YD-1 tablet hardness testers of the new daylight analytical instrumentation techniques Co., Ltd in Tianjin.Tablet is put into testboard, turn clockwise rotation disk, numerical value when being extruded broken to tablet is its hardness.
The preparation of the Afatinib 2-maleate prior art crystal formation of preparation example 1
LOOmg Afatinibs free alkali is taken to add 1.5mL ethanol stirring and dissolvings, it is heated to 70 °C, 50mg maleic acids are taken to add 0.4mL ethanol stirring and dissolvings, the ethanol solution Slow of maleic acid is added dropwise in the ethanol solution of Afatinib free alkali slowly, stirring, is cooled to room temperature by reaction solution after separating out solid, 2-3h is stirred at room temperature, filtering, 40 °C are dried in vacuum overnight to obtain Afatinib 2-maleate.
XRPD is analyzed as shown in Fig. 2 display is consistent with Afatinib 2-maleate prior art crystal formation disclosed in CN1867564B.
TGA collection of illustrative plates is as shown in figure 3, the decomposition temperature for showing the salt is 164.1 °C.
DSC collection of illustrative plates is as shown in figure 4, the fusing point for showing the salt is 166.2 °C.
DVS adsorption isothermal curves are as shown in figure 5, show that salt weight change in 10%-80% RH ranges is 2.6%. The preparation of the Afatinib ethanedisulphonate of embodiment 1
50mg Afatinibs free alkali is taken to add lmL ethyl acetate stirring and dissolvings, 19.6mg ethionic acids are taken to add 2mL ethyl acetate stirring and dissolvings, the ethyl acetate solution Slow of ethionic acid is added dropwise in the ethyl acetate solution of Afatinib free alkali slowly and forms slurries, stirring, there is solid precipitation after room temperature reaction overnight, 40 °C of vacuum are spin-dried for, and obtain 68mg Afatinib ethanedisulphonates, yield 97.7%.
The preparation of the E1 crystal formation Afatinib ethanedisulphonates of embodiment 2
50mg Afatinibs free alkali is taken to add lmL acetonitrile stirring and dissolvings, 19.6mg ethionic acids are taken to add 2mL acetonitrile stirring and dissolvings, the acetonitrile solution Slow of ethionic acid is added dropwise in the acetonitrile solution of Afatinib free alkali slowly and forms slurries, stirring, reaction has solid precipitation overnight at room temperature, filtering, 40 °C are dried in vacuum overnight to obtain 62mg El crystal formation Afatinib ethanedisulphonates, yield 89%.
The preparation of the E1 crystal formation Afatinib ethanedisulphonates of embodiment 3
" the acetonitrile solution Slow of ethionic acid is added dropwise in the acetonitrile solution of Afatinib free alkali slowly " in embodiment 2 is replaced with " being added dropwise to the acetonitrile solution Slow of Afatinib free alkali in the acetonitrile solution of ethionic acid slowly ", other operations are identical with embodiment 2, obtain 63.6mg El crystal formation Afatinib ethanedisulphonates, yield 91.5%.
XRPD analyze as shown in fig. 6,
PLM collection of illustrative plates is as shown in Figure 7.Display：The salt is granular crystals, and more preferable mobility and machinability have been compared with the acicular crystal of Afatinib 2-maleate prior art crystal formation.
TGA collection of illustrative plates is as shown in Figure 8.Display：The salt has 3.4% weightlessness before 150 °C, is hydrate, containing 1.5 mole of water, and decomposition temperature is 261.1 °C, higher than 164.1 °C of the decomposition temperature of Afatinib 2-maleate prior art crystal formation, shows more preferable heat endurance.
DVS adsorption isothermal curves are as shown in Figure 9.Display：The salt in 10%-80% RH ranges weight change be 1.4%, with Afatinib 2-maleate prior art crystal formation under the same conditions 2.6% weight change compare, have lower hygroscopicity.
Infrared spectrum analysis is as shown in Figure 10.
Raman spectrum analysis is as shown in figure 11.
MR collection of illustrative plates is as shown in figure 12.Display：Afatinib and ethionic acid are into salt.
HPLC detections show that the content of Afatinib in the salt is 71.4%, with Afatinib and ethionic acid 1:1 mol ratio is approached into the theoretical content 71.9% of salt, illustrates Afatinib and ethionic acid with 1:1 mol ratio is into salt.
The preparation of the E1 crystal formation Afatinib ethanedisulphonates of embodiment 4
30mg Afatinibs free alkali is taken to add 0.5mL acetonitrile stirring and dissolvings, 19.6mg Yi bis- Shuo acid is taken to add 0.5mL acetonitrile stirring and dissolvings, the acetonitrile solution Slow of ethionic acid is added dropwise in the acetonitrile solution of Afatinib free alkali slowly and forms slurries, stirring, reaction has solid precipitation overnight at room temperature, filtering, 40 °C are dried in vacuum overnight to obtain white solid Afatinib ethanedisulphonate.
The preparation of the E1 crystal formation Afatinib ethanedisulphonates of embodiment 5
The mg of Afatinib ethanedisulphonate 30 prepared by Example 1, is placed in 50ml flasks, adds 2 ml methanol formation slurries, is stirred at room temperature 72 hours, filters, 40 °C are dried in vacuum overnight, and obtain E1 crystal formation Afatinib ethanedisulphonates.
The preparation of the E1 crystal formation Afatinib ethanedisulphonates of embodiment 6
" methanol " in embodiment 5 is replaced with into " methyl tertiary butyl ether(MTBE) ", other operation be the same as Examples 5 obtain brilliant E1 types Afatinib ethanedisulphonate.
The preparation of the E1 crystal formation Afatinib ethanedisulphonates of embodiment 7
" methanol " in embodiment 5 is replaced with into " acetone ", other operation be the same as Examples 5 obtain E1 crystal formation Afatinib ethanedisulphonates.
The preparation of the E1 crystal formation Afatinib ethanedisulphonates of embodiment 8
" methanol " in embodiment 5 is replaced with into " normal heptane ", other operation be the same as Examples 5 obtain E1 crystal formation Afatinib ethanedisulphonates.
The preparation of the E1 crystal formation Afatinib ethanedisulphonates of embodiment 9
" methanol " in embodiment 5 is replaced with into " ethyl acetate ", other operation be the same as Examples 5 obtain E1 crystal formation Afatinib ethanedisulphonates.
The preparation of the E1 crystal formation Afatinib ethanedisulphonates of embodiment 10
" 19.6mg ethionic acids " in embodiment 2 is replaced with into " 39.1mg ethionic acids ", other operation be the same as Examples 2, Obtain El crystal formation Afatinib ethanedisulphonates.
The preparation of the Afatinib 1,5- napadisilates of embodiment 11
50mg Afatinibs free alkali is taken to add lmL acetone stirring and dissolvings, take 37.1mg 1,5- naphthalenedisulfonic acids tetrahydrate adds 2mL acetone stirring and dissolvings, and the acetone soln Slow of 1,5- naphthalenedisulfonic acids is added dropwise in the acetone soln of Afatinib free alkali slowly and forms slurries, stirring, solid is stirred overnight after separating out at room temperature, and 40 °C of vacuum are spin-dried for, and obtain 78mg Afatinibs 1,5- napadisilates, yield 98%.
The preparation of the N1 crystal formation Afatinib 1,5- napadisilates of embodiment 12
50mg Afatinibs free alkali is taken to add lmL acetonitrile stirring and dissolvings, 37.1mg 1 is taken, 5- Nai bis- Shuo acid tetrahydrates add 2mL ethanol stirring and dissolvings, by 1, the ethanol solution Slow of 5- naphthalenedisulfonic acids is added dropwise in the acetonitrile solution of Afatinib free alkali slowly forms slurries, stirring, is stirred overnight after solid precipitation, filters at room temperature, 40 °C are dried in vacuum overnight, obtain 71mg Nl crystal formations Afatinib 1,5- napadisilates, yield 89.2%.
XRPD analyses are as shown in figure 13.
PLM collection of illustrative plates is as shown in figure 14.Display：The salt is granular crystals, more regular, is compared with the acicular crystal of Afatinib 2-maleate prior art crystal formation, there is more preferable mobility and machinability.
TGA collection of illustrative plates is as shown in figure 15.Display：Sample is anhydride, and decomposition temperature is 276.3 °C, and more preferable heat endurance has been compared with 164.1 °C of decomposition temperatures of Afatinib 2-maleate prior art crystal formation.
DVS adsorption isothermal curves are as shown in figure 16.Display：N1 crystal formations Afatinib 1,5- napadisilates are stable below 50% relative humidity, N2 crystal formations Afatinib 1 is initially formed more than 50% relative humidity, 5- naphthalenedisulfonic acid salt hydrates, form N2 crystal formations Afatinib 1, to 80% relative humidity after 5- naphthalenedisulfonic acid salt hydrates, the weight change of water suction is 1.8%;N2 crystal formations Afatinib 1,5- naphthalenedisulfonic acids salt hydrate is stable more than 30% relative humidity, starts to slough the crystallization water below 30% relative humidity.With Afatinib 2-maleate prior art crystal formation under the same conditions（Under 30%-80% relative humidity）Water suction weight change is compared for 2.2%, and N2 crystal formations Afatinib 1,5- naphthalenedisulfonic acid salt hydrates have lower hygroscopicity.
Infrared spectrum analysis is as shown in figure 17.
Raman spectrum analysis is as shown in figure 18.
MR collection of illustrative plates is as shown in figure 19.Display：Afatinib and 1,5- naphthalenedisulfonic acids are into salt.
HPLC detections show that Afatinib content is 63.3% in the salt, and with Afatinib and 1,5- naphthalenedisulfonic acids are with 1:1 mol ratio is approached into the theoretical content 62.8% of salt, illustrates Afatinib and 1,5- naphthalenedisulfonic acids are with 1:1 mol ratio is into salt.
The preparation of the N1 crystal formation Afatinib 1,5- napadisilates of embodiment 13
15mg Afatinibs free alkali is taken to add 0.5mL acetonitrile stirring and dissolvings, take 14.8mg 1,5- Nai bis- Shuo acid tetrahydrates add 0.5mL ethanol stirring and dissolvings, the ethanol solution Slow of 1,5 naphthalenedisulfonic acid is added dropwise in the acetonitrile solution of Afatinib free alkali slowly, stirred, solid is stirred overnight after separating out, filtering, 40 °C are dried in vacuum overnight to obtain white solid Afatinib 1,5- napadisilates.
The preparation of the N1 crystal formation Afatinib 1,5- napadisilates of embodiment 14
The napadisilate 30mg of Afatinib 1,5 prepared by Example 11, is placed in 50ml flasks, adds 2ml methanol formation slurries, stirs 72 hours at room temperature, filtering, 40 °C are dried in vacuo to obtain the napadisilate of N1 crystal formations Afatinib 1,5.
The preparation of the N1 crystal formation Afatinib 1,5- napadisilates of embodiment 15
" methanol " in embodiment 14 is replaced with into " methyl tertiary butyl ether(MTBE) ", other operation be the same as Examples 14 obtain N1 crystal formations Afatinib 1,5- napadisilates.
The preparation of the N1 crystal formation Afatinib 1,5- napadisilates of embodiment 16
" methanol " in embodiment 14 is replaced with into " acetone ", other operation be the same as Examples 14 obtain N1 crystal formations Afatinib 1,5- napadisilates.
The preparation of the N1 crystal formation Afatinib 1,5- napadisilates of embodiment 17
" methanol " in embodiment 14 is replaced with into " normal heptane ", other operation be the same as Examples 14 obtain N1 crystal formations Afatinib 1,5- napadisilates.
The preparation of the N1 crystal formation Afatinib 1,5- napadisilates of embodiment 18
" methanol " in embodiment 14 is replaced with into " ethyl acetate ", other operation be the same as Examples 14 obtain N1 crystal formations Afatinib 1,5- napadisilates. The preparation of the Nl crystal formation Afatinib 1,5- napadisilates of embodiment 19
By in embodiment 12, " 37.1mg 1,5- naphthalenedisulfonic acid tetrahydrate " replace with " 74.2mgl, 5- naphthalenedisulfonic acids tetrahydrate ", and other operation be the same as Examples 12 obtain N1 crystal formations Afatinib 1,5- napadisilates.
The preparation of the N2 crystal formation Afatinib 1,5- naphthalenedisulfonic acid salt hydrates of embodiment 20
The N1 crystal formations Afatinib 1 for taking 50mg embodiments 12 to prepare, 5- napadisilates are positioned in the hygroscope of relative humidity 75% 24 hours at room temperature, obtain N2 crystal formations Afatinib 1,5- naphthalenedisulfonic acid salt hydrates.
XRPD analyses are as shown in figure 20.
PLM collection of illustrative plates is as shown in figure 21.Display：The salt is granular crystals, more regular, and more preferable mobility and machinability have been compared with the acicular crystal of Afatinib 2-maleate prior art crystal formation.
TGA collection of illustrative plates is as shown in figure 22.Display：There is 5.97% weightlessness before 100 ° of 〇 of the sample, be trihydrate, decomposition temperature is 275.4 °C, and more preferable heat endurance has been compared with 164.1 °C of decomposition temperatures of Afatinib 2-maleate prior art crystal formation.
DVS adsorption isothermal curves are as shown in figure 16.Display：N1 crystal formations Afatinib 1,5- napadisilates initially form N2 crystal formations Afatinib 1 more than 50% relative humidity, 5- naphthalenedisulfonic acid salt hydrates, form N2 crystal formations Afatinib 1, to 80% relative humidity after 5- naphthalenedisulfonic acid salt hydrates, the weight change of water suction is 1.8%, N2 crystal formations Afatinib 1,5- naphthalenedisulfonic acids salt hydrate is stable more than 30% relative humidity, starts to slough the crystallization water below 30% relative humidity.With Afatinib 2-maleate prior art crystal formation under the same conditions（Under 30%-80% relative humidity）Water suction weight change is compared for 2.2%, and N2 crystal formations Afatinib 1,5- naphthalenedisulfonic acid salt hydrates have lower hygroscopicity.
Infrared spectrum analysis is as shown in figure 23.
Raman spectrum analysis is as shown in figure 24.
The preparation of the N2 crystal formation Afatinib 1,5- naphthalenedisulfonic acid salt hydrates of embodiment 21
" hygroscope of relative humidity 75% " in embodiment 20 is replaced with " hygroscope of relative humidity 85% ", other operation be the same as Examples 20 obtain N2 crystal formations Afatinib 1,5- naphthalenedisulfonic acid salt hydrates.
The preparation of the N2 crystal formation Afatinib 1,5- naphthalenedisulfonic acid salt hydrates of embodiment 22
" 24 hours " in embodiment 20 are replaced with " 3 days ", other operation be the same as Examples 20 obtain N2 crystal formations Afatinib 1,5- naphthalenedisulfonic acid salt hydrates.
The preparation of the malonate of 23 Afatinib of embodiment one
50mg Afatinibs free alkali is taken to add 4mL ethanol stirring and dissolvings, 15.9mg malonic acid is taken to add 4mL ethanol stirring and dissolvings, the ethanol Slow of malonic acid is added dropwise in the ethanol solution of Afatinib free alkali slowly and forms slurries and stirs, solid precipitation has been stirred overnight at room temperature, 40 °C of vacuum are spin-dried for, obtain the mg of one malonate of Afatinib 59.1, yield 97.3%.
The preparation of the malonate of 24 Ml crystal formations Afatinib of embodiment one
50mg Afatinibs free alkali is taken to add 4mL methyl tertiary butyl ether(MTBE) stirring and dissolvings, 15.9mg malonic acid is taken to add 4mL methyl tertiary butyl ether(MTBE) stirring and dissolvings, the t-butyl methyl ether solution Slow of malonic acid is added dropwise in the t-butyl methyl ether solution of Afatinib free alkali slowly and forms slurries and stirs, solid precipitation has been stirred overnight at room temperature, filtering, 40 °C are dried in vacuum overnight, and obtain the malonate 55mg of Ml crystal formations Afatinib one, yield 90.6%.
XRPD analyses are as shown in figure 25.
PLM collection of illustrative plates is as shown in figure 26.Display：The salt is granular crystals, more regular, and more preferable mobility and machinability have been compared with the acicular crystal of Afatinib 2-maleate prior art crystal formation.
TGA collection of illustrative plates is as shown in figure 27.Display：The decomposition temperature of the salt is 108.3 °C.
Infrared spectrum analysis is as shown in figure 28.
Raman spectrum analysis is as shown in figure 29.
MR collection of illustrative plates is as shown in figure 30.Display：Afatinib and malonic acid are into salt.
HPLC detections show that Afatinib content is 83.0% in the salt, with Afatinib and malonic acid with 1:1 mol ratio is approached into the theoretical content 82.4% of salt, illustrates Afatinib and malonic acid with 1:1 mol ratio is into salt.
The preparation of the malonate of 25 Ml crystal formations Afatinib of embodiment one
The malonate 30mg of Afatinib one prepared by Example 19, is placed in 50ml flasks, adds 2 ml methanol and is formed Slurries, are stirred 72 hours at room temperature, filtering, and 40 °C are dried in vacuo to obtain the malonate of Ml crystal formations Afatinib one.
The preparation of the malonate of 26 Ml crystal formations Afatinib of embodiment one
" methanol " in embodiment 25 is replaced with into " ethyl acetate ", other operation be the same as Examples 25 obtain the malonate of Ml crystal formations Afatinib one.
The preparation of the malonate of 27 Ml crystal formations Afatinib of embodiment one
" methanol " in embodiment 25 is replaced with into " acetone ", other operation be the same as Examples 25 obtain the malonate of Ml crystal formations Afatinib one.
The preparation of the malonate of 28 Ml crystal formations Afatinib of embodiment one
" methanol " in embodiment 25 is replaced with into " normal heptane ", other operation be the same as Examples 25 obtain the malonate of Ml crystal formations Afatinib one.
The preparation of the malonate of 29 Afatinib of embodiment two
50mg Afatinibs free alkali is taken to add stirring and dissolving in 1.5mL acetonitriles, 21.4mg malonic acid is taken to add 4mL acetonitrile stirring and dissolvings, the acetonitrile solution Slow of Afatinib free alkali is added dropwise in the acetonitrile solution of malonic acid slowly and forms slurries, stirring, solid is stirred overnight after separating out at room temperature, 40 °C of vacuum are spin-dried for, and obtain the malonate 69mg of Afatinib two, yield 96.6%.
The preparation of the malonate of 30 M2 crystal formations Afatinib of embodiment two
The malonate of 50mg Afatinibs one prepared by Example 23, which is added, to be made into suspension in lmL ethyl acetate and stirs, 8.81mg malonic acid is taken to add 2mL ethyl acetate stirring and dissolvings, the ethyl acetate solution Slow of malonic acid is added dropwise in the ethyl acetate suspension of the malonate of Afatinib one slowly and forms slurries, it is stirred overnight at room temperature, filtering, 40 °C are dried in vacuum overnight to obtain the malonate 52.5mg of M2 crystal formations Afatinib two, yield 89.3%.
The preparation of the malonate of 31 M2 crystal formations Afatinib of embodiment two
50mg Afatinibs free alkali is taken to add stirring and dissolving in 1.5mL ethyl acetate, 21.4mg malonic acid is taken to add 4mL ethyl acetate stirring and dissolvings, the ethyl acetate solution Slow of Afatinib free alkali is added dropwise in the ethyl acetate solution of malonic acid slowly and forms slurries and stirs, solid is stirred overnight after separating out at room temperature, filtering, 40 °C are dried in vacuum overnight, and obtain the malonate 66mg of M2 crystal formations Afatinib two, yield 92.4%.
XRPD analyses are as shown in figure 31.
TGA collection of illustrative plates is as shown in figure 32.Display：The decomposition temperature of the salt is 105.7 °C.
DVS adsorption isothermal curves are as shown in Figure 33.Display：Salt weight change in 10%-80% RH ranges is 1.1%, and being compared with the weight change of Afatinib 2-maleate prior art crystal formation 2.6% has lower hygroscopicity.
Infrared spectrum analysis is as shown in figure 34.
Raman spectrum analysis is as shown in figure 35.
MR collection of illustrative plates is as shown in figure 36.Display：Afatinib and malonic acid are into salt.
HPLC detections show that Afatinib content is 70.2% in the salt, with Afatinib and malonic acid with 1:2 mol ratios are approached into the theoretical content 70.0% of salt, illustrate Afatinib and malonic acid with 1:2 mol ratios are into salt.
The preparation of the malonate of 32 M2 crystal formations Afatinib of embodiment two
The malonate 30mg of Afatinib two prepared by Example 29, is placed in 50ml flasks, adds 2 ml methanol formation slurries, stirs 72 hours at room temperature, filtering, 40 °C are dried in vacuo to obtain the malonate of M2 crystal formations Afatinib two.
The preparation of the malonate of 33 M2 crystal formations Afatinib of embodiment two
" methanol " in embodiment 32 is replaced with into " ethyl acetate ", other operation be the same as Examples 32 obtain the malonate of M2 crystal formations Afatinib two.
The preparation of the malonate of 34 M2 crystal formations Afatinib of embodiment two
" methanol " in embodiment 32 is replaced with into " acetone ", other operation be the same as Examples 32 obtain the malonate of M2 crystal formations Afatinib two.
The preparation of the malonate of 35 M2 crystal formations Afatinib of embodiment two
" methanol " in embodiment 32 is replaced with into " normal heptane ", other operation be the same as Examples 32 obtain the malonate of M2 crystal formations Afatinib two.
The preparation of the malonate of 36 M2 crystal formations Afatinib of embodiment two " 21.4mg malonic acid " in embodiment 31 is replaced with into " 42.8mg malonic acid ", other operation be the same as Examples 31 obtain the malonate of M2 crystal formations Afatinib two.
The preparation of the 2- naphthalene sulfonates of 37 Afatinib of embodiment two
50mg Afatinibs free alkali is taken to add 1.5mL acetone stirring and dissolvings, 42.8mg 2- Nai Shuo acid is taken to add 3mL acetone stirring and dissolvings, the acetone soln Slow of 2- naphthalene sulfonic acids is added dropwise in the acetone soln of Afatinib free alkali slowly and forms slurries, stirring, it is stirred overnight after having solid precipitation at room temperature, 40 °C of vacuum are spin-dried for, and obtain the 2- naphthalene sulfonate 90mg of Afatinib two, yield 97.0%.
The preparation of the 2- naphthalene sulfonates of 38 Nsl crystal formations Afatinib of embodiment two
50mg Afatinibs free alkali is taken to add 1.5mL ethyl acetate, 42.8mg 2- Nai Shuo acid is taken to add 3mL ethyl acetate stirring and dissolvings, the ethyl acetate solution Slow of 2- naphthalene sulfonic acids is added dropwise in the ethyl acetate solution of Afatinib free alkali slowly and forms slurries, stirring, it is stirred overnight after having solid precipitation at room temperature, 40 °C of filtering is dried in vacuum overnight, and obtains the 2- Nai Shuo hydrochlorate 85mg of Nsl crystal formations Afatinib two, yield 91.7%.
XRPD analyses are as shown in figure 37.
TGA collection of illustrative plates is as shown in figure 38.Display：The decomposition temperature of the salt is 249.1 °C, and more preferable heat endurance has been compared with 164.1 °C of decomposition temperatures of Afatinib 2-maleate prior art crystal formation.
Infrared spectrum analysis is as shown in figure 39.
Raman spectrum analysis is as shown in figure 40.
MR collection of illustrative plates is as shown in figure 41.Display：Afatinib and 2- naphthalene sulfonic acids are into salt.
HPLC detections show that Afatinib content is 55.0% in the salt, with Afatinib and 2- naphthalene sulfonic acids with 1:2 mol ratios are approached into the theoretical content 53.9% of salt, illustrate Afatinib and 2- naphthalene sulfonic acids with 1:2 mol ratios are into salt.
The preparation of the 2- naphthalene sulfonates of 39 Afatinib of embodiment one
10mg Afatinibs free alkali is taken to add 0.5mL ethyl acetate stirring and dissolvings, 4.3mg 2- naphthalene sulfonic acids is taken to add 0.5mL ethyl acetate stirring and dissolvings, the ethyl acetate solution Slow of 2- naphthalene sulfonic acids is added dropwise in the ethyl acetate solution of Afatinib free alkali slowly, stirring, it is stirred overnight after having solid precipitation at room temperature, 40 °C of filtering is dried in vacuum overnight, and obtains the 2- Nai Shuo hydrochlorates of white solid Afatinib one.
The preparation of the 2- naphthalene sulfonates of 40 Nsl crystal formations Afatinib of embodiment two
The 2- naphthalene sulfonate 30mg of Afatinib two prepared by Example 37, are placed in 50ml flasks, add 0.2ml methanol formation slurries, stir 72 hours at room temperature, filtering, 40 °C are dried in vacuo to obtain the 2- naphthalene sulfonates of Nsl crystal formations Afatinib two.
The preparation of the 2- naphthalene sulfonates of 41 Nsl crystal formations Afatinib of embodiment two
" methanol " in embodiment 40 is replaced with into " methyl tertiary butyl ether(MTBE) ", other operation be the same as Examples 40 obtain the 2- naphthalene sulfonates of Nsl crystal formations Afatinib two.
The preparation of the 2- naphthalene sulfonates of 42 Nsl crystal formations Afatinib of embodiment two
" methanol " in embodiment 40 is replaced with into " acetone ", other operation be the same as Examples 40 obtain the 2- naphthalene sulfonates of Nsl crystal formations Afatinib two.
The preparation of the 2- naphthalene sulfonates of 43 Nsl crystal formations Afatinib of embodiment two
" methanol " in embodiment 40 is replaced with into " normal heptane ", other operation be the same as Examples 40 obtain the 2- naphthalene sulfonates of Nsl crystal formations Afatinib two.
The preparation of the 2- naphthalene sulfonates of 44 Nsl crystal formations Afatinib of embodiment two
" 42.8mg 2- naphthalene sulfonic acids " in embodiment 38 is replaced with into " 64.2mg 2- naphthalene sulfonic acids ", other operation be the same as Examples 38 obtain the 2- naphthalene sulfonates of Nsl crystal formations Afatinib two.
The preparation of the Afatinib diamino sulfonic acid salt of embodiment 45
50mg Afatinibs free alkali is taken to add the dissolving of 1.5mL ethyl acetate, take 20mg sulfamic acids to add 2mL ethyl acetate to be made into suspension and stir, the ethyl acetate solution Slow of Afatinib free alkali is added dropwise in the ethyl acetate suspension of sulfamic acid slowly and forms slurries, stir 4 hours at room temperature, 40 °C of vacuum are spin-dried for, obtain Afatinib diamino sulfonic acid salt 67.5mg, yield 96.4%.
The preparation of the S1 crystal formation Afatinib diamino sulfonic acid salt of embodiment 46
Take 50mg Afatinibs free alkali to add the dissolving of lmL acetonitriles, take 20mg An Ji Shuo acid addition 2mL acetonitriles to be made into mixed Suspension is simultaneously stirred, the acetonitrile solution Slow of Afatinib free alkali is added dropwise in the suspension of the acetonitrile of sulfamic acid slowly and forms slurries, is stirred 4 hours at room temperature, filtering, 40 °C are dried in vacuum overnight to obtain S1 crystal formation Afatinib diamino sulfonic acid salt 62mg, yield 88.6%.
XRPD analyses are as shown in figure 42.
TGA collection of illustrative plates is as shown in figure 43.Display：The decomposition temperature of the salt is 246.3 °C, and more preferable heat endurance has been compared with 164.1 °C of decomposition temperatures of Afatinib 2-maleate prior art crystal formation.
Infrared spectrum analysis is as shown in figure 44.
Raman spectrum analysis is as shown in figure 45.
MR collection of illustrative plates is as shown in figure 46.Display：Afatinib and sulfamic acid are into salt.
HPLC detections show that Afatinib content is 70.9% in the salt, with Afatinib and sulfamic acid with 1:2 mol ratios are approached into the theoretical content 71.5% of salt, illustrate Afatinib and sulfamic acid with 1:2 mol ratios are into salt.
The preparation of the sulfamate of 47 Afatinib of embodiment one
10mg Afatinibs free alkali is taken to add the dissolving of 0.5mL ethyl acetate, take 2mg An Ji Shuo acid to add 0.5mL ethyl acetate to be made into suspension and stir, the ethyl acetate solution Slow of Afatinib free alkali is added dropwise in the ethyl acetate suspension of sulfamic acid slowly, stir 4 hours at room temperature, 40 °C of filtering is dried in vacuum overnight to obtain the sulfamate of white solid Afatinib one.
The preparation of the S1 crystal formation Afatinib diamino sulfonic acid salt of embodiment 48
The mg of Afatinib diamino sulfonic acid salt 30 prepared by Example 45, is placed in 50ml flasks, adds 2ml methanol formation slurries, stirs 72 hours at room temperature, filtering, 40 °C are dried in vacuo to obtain S1 crystal formation Afatinib diamino sulfonic acid salt.
The preparation of the S1 crystal formation Afatinib diamino sulfonic acid salt of embodiment 49
" methanol " in embodiment 48 is replaced with into " methyl tertiary butyl ether(MTBE) ", other operation be the same as Examples 48 obtain S1 crystal formation Afatinib diamino sulfonic acid salt.
The preparation of the S1 crystal formation Afatinib diamino sulfonic acid salt of embodiment 50
" methanol " in embodiment 48 is replaced with into " acetone ", other operation be the same as Examples 48 obtain S1 crystal formation Afatinib diamino sulfonic acid salt.
The preparation of the S1 crystal formation Afatinib diamino sulfonic acid salt of embodiment 51
" methanol " in embodiment 48 is replaced with into " normal heptane ", other operation be the same as Examples 48 obtain S1 crystal formation Afatinib diamino sulfonic acid salt.
The preparation of the S1 crystal formation Afatinib diamino sulfonic acid salt of embodiment 52
" 20mg An Ji Shuo acid " in embodiment 46 is replaced with into " 40mg An Ji Shuo acid ", other operation be the same as Examples 46 obtain S1 crystal formation Afatinib diamino sulfonic acid salt.
The preparation of the D-Glucose hydrochlorate of 53 Afatinib of embodiment two
50mg Afatinibs free alkali is taken to add the dissolving of 1.5mL nitromethanes, 50% D-Glucose aqueous acid 88mg is taken directly to be added dropwise in the nitromethane solution of Afatinib free alkali and stir, supernatant liquor is taken out after having grease precipitation, lmL acetonitriles are added to grease, it is stirred overnight at room temperature, obtains the D-Glucose hydrochlorate solid of Afatinib two, 40 °C of vacuum is spin-dried for, obtain 88 mg, yield 97.4%.
The preparation of the D-Glucose hydrochlorate of 54 G1 crystal formations Afatinib of embodiment two
50mg Afatinibs free alkali is taken to add the dissolving of 1.5mL ethyl acetate, 50% D-Glucose aqueous acid 88mg is taken directly to be added dropwise in the ethyl acetate solution of Afatinib free alkali and stir, supernatant liquor is taken out after having grease precipitation, lmL acetonitriles are added to grease, it is stirred overnight, filters, 40 °C are dried in vacuum overnight at room temperature, obtain the D-Glucose hydrochlorate 59mg of G1 crystal formations Afatinib two, yield 65.3%.
XRPD analyses are as shown in figure 47.
TGA collection of illustrative plates is as shown in figure 48.Display：The decomposition temperature of the salt is 129.4 °C.
DSC collection of illustrative plates is as shown in figure 49.Display：The fusing point of the salt is 101.3 °C.
Infrared spectrum analysis is as shown in figure 50.
Raman spectrum analysis is as shown in figure 50.
MR collection of illustrative plates is as shown in figure 50.Display：Afatinib and maltonic acid are into salt. HPLC detections show that Afatinib content is 54.4% in the salt, with Afatinib and maltonic acid with 1:2 mol ratios are approached into the theoretical content 55.3% of salt, illustrate Afatinib and maltonic acid with 1:2 mol ratios are into salt.
The preparation of the D-Glucose hydrochlorate of 55 Afatinib of embodiment one
10mg Afatinibs free alkali is taken to add the dissolving of 0.5mL nitromethanes, 50% D-Glucose aqueous acid 8.1mg is taken directly to be added dropwise in the nitromethane solution of Afatinib free alkali and stir, supernatant liquor is taken out after having grease precipitation, lmL acetonitriles are added to grease, it is stirred overnight, obtains the D-Glucose hydrochlorate of white solid Afatinib one.
The preparation of the D-Glucose hydrochlorate of 56 G1 crystal formations Afatinib of embodiment two
The D-Glucose hydrochlorate 30mg of Afatinib two prepared by Example 53, is placed in 50ml flasks, adds 2ml methanol formation slurries, stirs 72 hours at room temperature, filtering, 40 °C are dried in vacuo to obtain the D-Glucose hydrochlorate of G1 crystal formations Afatinib two.
The preparation of the D-Glucose hydrochlorate of 57 G1 crystal formations Afatinib of embodiment two
" methanol " in embodiment 56 is replaced with into " methyl tertiary butyl ether(MTBE) ", other operation be the same as Examples 56 obtain the D-Glucose hydrochlorate of G1 crystal formations Afatinib two.
The preparation of the D-Glucose hydrochlorate of 58 G1 crystal formations Afatinib of embodiment two
" methanol " in embodiment 56 is replaced with into " ethyl acetate ", other operation be the same as Examples 56 obtain the D-Glucose hydrochlorate of G1 crystal formations Afatinib two.
The preparation of the D-Glucose hydrochlorate of 59 G1 crystal formations Afatinib of embodiment two
" methanol " in embodiment 56 is replaced with into " acetone ", other operation be the same as Examples 56 obtain the D-Glucose hydrochlorate of G1 crystal formations Afatinib two.
The preparation of the D-Glucose hydrochlorate of 60 G1 crystal formations Afatinib of embodiment two
" methanol " in embodiment 56 is replaced with into " normal heptane ", other operation be the same as Examples 56 obtain the D-Glucose hydrochlorate of G1 crystal formations Afatinib two.
The preparation of the D-Glucose hydrochlorate of 61 G1 crystal formations Afatinib of embodiment two
" D-Glucose aqueous acid 88mg " in embodiment 54 is replaced with into " D-Glucose aqueous acid 160mg ", other operation be the same as Examples 54 obtain the D-Glucose hydrochlorate of G1 crystal formations Afatinib two.
The preparation of the Afatinib bicyclohexane sulfamate of embodiment 62
50mg Afatinibs free alkali is taken to add the dissolving of lmL ethyl acetate, take 40.6mg cyclohexane sulfamic acids to add 3mL ethyl acetate to be made into suspension and stir, the ethyl acetate solution Slow of Afatinib free alkali is added dropwise in the suspension of the ethyl acetate of cyclohexane sulfamic acid slowly, it is stirred overnight at room temperature, 40 °C of vacuum are spin-dried for, obtain Afatinib bicyclohexane sulfamate 80mg, yield 92.2%.
The preparation of the C1 crystal formation Afatinib bicyclohexane sulfamates of embodiment 63
50mg Afatinibs free alkali is taken to add the dissolving of lmL acetonitriles, take 40.6mg cyclohexane sulfamic acids to add 3mL acetonitriles to be made into suspension and stir, the acetonitrile solution Slow of Afatinib free alkali is added dropwise in the suspension of the acetonitrile of cyclohexane sulfamic acid slowly, it is stirred overnight at room temperature, 40 °C of filtering is dried in vacuum overnight, obtain C1 crystal formation Afatinib bicyclohexane sulfamate 74.6mg, yield 85.9%.
XRPD analyses are as shown in figure 50.
TGA collection of illustrative plates is as shown in figure 50.Display：The decomposition temperature of the salt is 246.1 °C, and more preferable heat endurance has been compared with 164.1 °C of decomposition temperatures of Afatinib 2-maleate prior art crystal formation.
Infrared spectrum analysis is as shown in figure 50.
Raman spectrum analysis is as shown in figure 50.
MR collection of illustrative plates is as shown in figure 50.Display：Afatinib and cyclohexane sulfamic acid are into salt.
HPLC detections show that Afatinib content is 58.3% in the salt, with Afatinib and cyclohexane sulfamic acid with 1:2 mol ratios are approached into the theoretical content 57.6% of salt, illustrate Afatinib and cyclohexane sulfamic acid with 1:2 mol ratios are into salt.
The preparation of the cyclamate of 64 Afatinib of embodiment one
10mg Afatinibs free alkali is taken to add the dissolving of 0.5mL acetonitriles, take the own alkylamino Shuo acid of 4.1mg rings to add lmL acetonitriles to be made into suspension and stir, the acetonitrile solution Slow of Afatinib free alkali is added dropwise in the suspension of the acetonitrile of cyclohexane sulfamic acid slowly, it is stirred overnight at room temperature, filtering, 40 °C are dried in vacuum overnight to obtain the cyclohexane sulfamic acid of white solid Afatinib one Salt.
The preparation of the CI crystal formation Afatinib bicyclohexane sulfamates of embodiment 65
The mg of Afatinib bicyclohexane sulfamate 30 prepared by Example 62, it is placed in 50 ml flasks, adds 2 ml methanol formation slurries, stir 72 hours at room temperature, filtering, 40 °C are dried in vacuo to obtain C1 crystal formation Afatinib bicyclohexane sulfamates.
The preparation of the C1 crystal formation Afatinib bicyclohexane sulfamates of embodiment 66
" methanol " in embodiment 65 is replaced with into " ethyl acetate ", other operation be the same as Examples 65 obtain C1 crystal formation Afatinib bicyclohexane sulfamates.
The preparation of the C1 crystal formation Afatinib bicyclohexane sulfamates of embodiment 67
" methanol " in embodiment 65 is replaced with into " methyl tertiary butyl ether(MTBE) ", other operation be the same as Examples 65 obtain C1 crystal formation Afatinib bicyclohexane sulfamates.
The preparation of the C1 crystal formation Afatinib bicyclohexane sulfamates of embodiment 68
" methanol " in embodiment 65 is replaced with into " acetone ", other operation be the same as Examples 65 obtain C1 crystal formation Afatinib bicyclohexane sulfamates.
The preparation of the C1 crystal formation Afatinib bicyclohexane sulfamates of embodiment 69
" methanol " in embodiment 65 is replaced with into " normal heptane ", other operation be the same as Examples 65 obtain C1 crystal formation Afatinib bicyclohexane sulfamates.
The preparation of the C1 crystal formation Afatinib bicyclohexane sulfamates of embodiment 70
" 40.6mg cyclohexane sulfamic acids " in embodiment 63 is replaced with into " 73mg cyclohexane sulfamic acids ", other operation be the same as Examples 63 obtain C1 crystal formation Afatinib bicyclohexane sulfamates.
The preparation of the 4- amino phenyl sulfonyl hydrochlorates of 71 Afatinib of embodiment two
50mg Afatinibs free alkali is taken to add lmL acetone solutions, take 39.2mg4- aminobenzenesulfonic acids to add 3mL acetone to be made into suspension and stir, the acetone soln Slow of Afatinib free alkali is added dropwise in the acetone suspension of 4- aminobenzenesulfonic acids slowly, it is stirred overnight at room temperature, 40 °C of vacuum are spin-dried for, obtain the 4- amino phenyl sulfonyl hydrochlorate 78mg of Afatinib two, yield 91.1%.
The preparation of the 4- amino phenyl sulfonyl hydrochlorates of 72 A1 crystal formations Afatinib of embodiment two
50mg Afatinibs free alkali is taken to add the dissolving of lmL acetonitriles, take 39.2mg4- aminobenzenesulfonic acids to add 3mL acetonitriles to be made into suspension and stir, the acetonitrile solution Slow of Afatinib free alkali is added dropwise in the acetonitrile suspension of 4- aminobenzenesulfonic acids slowly, it is stirred overnight at room temperature, filter and 40 °C are dried overnight, obtain the 4- amino phenyl sulfonyl hydrochlorate 65mg of A1 crystal formations Afatinib two, yield 75.9%.
XRPD analyses are as shown in figure 50.
TGA collection of illustrative plates is as shown in figure 50.Display：The decomposition temperature of the salt is 261.7 °C, and more preferable heat endurance has been compared with 164.1 °C of decomposition temperatures of Afatinib 2-maleate prior art crystal formation.
Infrared spectrum analysis is as shown in figure 50.
Raman spectrum analysis is as shown in Figure 61.
MR collection of illustrative plates is as shown in Figure 62.Display：Afatinib and 4- aminobenzenesulfonic acids are into salt.
HPLC detections show that Afatinib content is 59.1% in the salt, with Afatinib and 4- aminobenzenesulfonic acids with 1:2 mol ratios are approached into the theoretical content 58.4% of salt, illustrate Afatinib and 4- aminobenzenesulfonic acids with 1:2 mol ratios are into salt.
The preparation of the 4- amino phenyl sulfonyl hydrochlorates of 73 Afatinib of embodiment one
10mg Afatinibs free alkali is taken to add the dissolving of 0.5mL acetonitriles, take 3.9mg 4- An Ji Ben Shuo acid to add lmL acetonitriles to be made into suspension and stir, the acetonitrile solution Slow of Afatinib free alkali is added dropwise in the acetonitrile suspension of 4- aminobenzenesulfonic acids slowly, it is stirred overnight at room temperature, filters and 40 °C are dried overnight to obtain the 4- amino phenyl sulfonyl hydrochlorates of white solid Afatinib one.
The preparation of the 4- amino phenyl sulfonyl hydrochlorates of 74 A1 crystal formations Afatinib of embodiment two
The mg of two 4- amino phenyl sulfonyls hydrochlorate of Afatinib 30 prepared by Example 71, it is placed in 50ml flasks, adds 2ml methanol formation slurries, stir 72 hours at room temperature, filtering, 40 °C are dried in vacuo to obtain the 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations Afatinib two.
The preparation of the 4- amino phenyl sulfonyl hydrochlorates of 75 A1 crystal formations Afatinib of embodiment two " methanol " in embodiment 74 is replaced with into " ethyl acetate ", other operation be the same as Examples 74 obtain the 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations Afatinib two.
The preparation of the 4- amino phenyl sulfonyl hydrochlorates of 76 A1 crystal formations Afatinib of embodiment two
" methanol " in embodiment 74 is replaced with into " methyl tertiary butyl ether(MTBE) ", other operation be the same as Examples 74 obtain the 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations Afatinib two.
The preparation of the 4- amino phenyl sulfonyl hydrochlorates of 77 A1 crystal formations Afatinib of embodiment two
" methanol " in embodiment 74 is replaced with into " acetone ", other operation be the same as Examples 74 obtain the 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations Afatinib two.
The preparation of the 4- amino phenyl sulfonyl hydrochlorates of 78 A1 crystal formations Afatinib of embodiment two
" methanol " in embodiment 74 is replaced with into " normal heptane ", other operation be the same as Examples 74 obtain the 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations Afatinib two.
The preparation of the 4- amino phenyl sulfonyl hydrochlorates of 79 A1 crystal formations Afatinib of embodiment two
" 39.2mg 4- aminobenzenesulfonic acids " in embodiment 72 is replaced with into " 70mg 4- aminobenzenesulfonic acids ", other operation be the same as Examples 72 obtain the 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations Afatinib two.
The preparation of the Afatinib glycol hydrochlorate of embodiment 80
50mg Afatinibs free alkali is taken to add 1.5mL ethyl acetate stirring and dissolvings, 8.6mg Glycolic acids are taken to add 1.5mL ethyl acetate stirring and dissolvings, the ethyl acetate solution Slow of Glycolic acid is added dropwise in the ethyl acetate solution of Afatinib free alkali slowly and forms slurries and stirs, there is solid precipitation during dropwise addition, it is stirred overnight at room temperature, 40 °C of vacuum are spin-dried for, and obtain Afatinib glycol hydrochlorate 54.4mg, yield 94.1%.
The preparation of the G1-1 crystal formation Afatinib glycol hydrochlorates of embodiment 81
50mg Afatinibs free alkali is taken to add 1.5mL nitromethane stirring and dissolvings, 8.6mg Glycolic acids are taken to add 3mL nitromethane stirring and dissolvings, the nitromethane solution Slow of Glycolic acid is added dropwise in the nitromethane solution of Afatinib free alkali slowly and forms slurries and stirs, there is solid precipitation after being stirred overnight at room temperature, filter and 40 °C are dried in vacuum overnight to obtain G1-1 crystal formation Afatinib glycol hydrochlorate 50mg, yield 86.5%.
XRPD analyses are as shown in Figure 63.
TGA collection of illustrative plates is as shown in Figure 64.Display：The decomposition temperature of the salt is 1 12.4 °C.
DSC collection of illustrative plates is as shown in Figure 65.Display：The fusing point of the salt is 83.5 °C.
Infrared spectrum analysis is as shown in Figure 66.
Raman spectrum analysis is as shown in Figure 66.
MR collection of illustrative plates is as shown in Figure 66.Display：Afatinib and Glycolic acid are into salt.
HPLC detections show that Afatinib content is 85.4% in the salt, with Afatinib and Glycolic acid with 1:1 mol ratio is close into salt theoretical content 86.5%, illustrates Afatinib and Glycolic acid with 1:1 mol ratio is into salt.
The preparation of the Afatinib diethylene glycol (DEG) hydrochlorate of embodiment 82
10mg Afatinibs free alkali is taken to add the dissolving of 0.5mL ethyl acetate, 3.4mg Glycolic acids are taken to add lmL ethyl acetate stirring and dissolvings, the ethyl acetate solution Slow of Glycolic acid is added dropwise in the ethyl acetate solution of Afatinib free alkali and stirred slowly, there is solid precipitation during dropwise addition, filtered after being stirred overnight at room temperature, 40 °C are dried in vacuum overnight to obtain white solid Afatinib diethylene glycol (DEG) hydrochlorate.
The preparation of the G1-1 crystal formation Afatinib glycol hydrochlorates of embodiment 83
Afatinib glycol hydrochlorate 30mg prepared by Example 80, is placed in 50ml flasks, adds 2ml methanol formation slurries, stirs 72 hours at room temperature, filtering, 40 °C are dried in vacuo to obtain the crystal formation Afatinib glycol hydrochlorates of G1- 1.
The preparation of the G1-1 crystal formation Afatinib glycol hydrochlorates of embodiment 84
" methanol " in embodiment 83 is replaced with into " methyl tertiary butyl ether(MTBE) ", other operation be the same as Examples 83 obtain G1-1 crystal formation Afatinib glycol hydrochlorates.
The preparation of the G1-1 crystal formation Afatinib glycol hydrochlorates of embodiment 85
" methanol " in embodiment 83 is replaced with into " acetone ", other operation be the same as Examples 83 obtain G1-1 crystal formation Afatinib glycol hydrochlorates. The preparation of the Gl-1 crystal formation Afatinib glycol hydrochlorates of embodiment 86
" methanol " in embodiment 83 is replaced with into " normal heptane ", other operation be the same as Examples 83 obtain G1-1 crystal formation Afatinib glycol hydrochlorates.
The preparation of the G1-1 crystal formation Afatinib glycol hydrochlorates of embodiment 87
" 8.6mg Glycolic acids " in embodiment 81 is replaced with into " 15.5mg Glycolic acids ", other operation be the same as Examples 81 obtain G1-1 crystal formation Afatinib glycol hydrochlorates.
The Afatinib 2-maleate crystal formation N of embodiment 88 preparation
50mg Afatinibs free alkali is taken to add 2mL nitromethane stirring and dissolvings, 26.5mg maleic acids are taken to add lmL nitromethane stirring and dissolvings, the nitromethane solution Slow of maleic acid is added dropwise in the nitromethane solution of Afatinib free alkali slowly and forms slurries and stirs, there is solid precipitation during dropwise addition, filtered after being stirred overnight at room temperature, 40 °C are dried in vacuum overnight to obtain 63mg Afatinib 2-maleate crystal formation N, yield 85.3%.
XRPD analyses are as shown in Figure 66.
TGA collection of illustrative plates is as shown in Figure 74.Display：The decomposition temperature of the salt is 133.7 °C.
Infrared spectrum analysis is as shown in Figure 74.
Raman spectrum analysis is as shown in Figure 74.
HPLC detections show that Afatinib content is 68.1% in the salt, with Afatinib and maleic acid with 1:2 mol ratios are approached into the theoretical content 67.7% of salt, illustrate Afatinib and maleic acid with 1:2 mol ratios are into salt.
The Afatinib 2-maleate crystal formation N of embodiment 89 preparation
" 26.5mg maleic acids " in embodiment 88 is replaced with " 39.8mg maleic acids ", other operation be the same as Examples 88 obtain Afatinib 2-maleate crystal formation N.
Embodiment 90
Prepared according to the prescription of table 2 and include the Afatinib 2-maleate crystal formation N C embodiments 88 of the present invention of various dose) five kinds of tablets of A, B, C, D and E.
Table five kinds of tablet formulations of 2 A, B, C, D, E
The preparation method of tablet is：Afatinib 2-maleate crystal formation N made from the embodiment 88 for make Wei Jing Xian Victoria elements, Jiao Ju Victoria ketone, not grinding passes through #30 mesh sieves（About 430 μ to about 655 μ).Jiao Ju Victoria ketone after sieving is fitted into 3 cubic foot twin shells rolling mixer, Wei Jing Xian Victoria elements and the lactose monohydrate added after sieving is mixed about 5 minutes；The Afatinib 2-maleate crystal formation Ν added after sieving, is remixed 25 minutes.The pre-composition is moved back in rolling mixer by having the roller compactor of beater grinder at discharge.Magnesium stearate and colloidal silica anhydrous are added in rolling mixer, are mixed about 3 minutes.Final mixture is suppressed on rotary tablet machine, production batch 200,000.
Embodiment 91-101
According to the prescription of table 2 and the preparation method of embodiment 90, the Afatinib 2-maleate crystal formation Ν (embodiment 88) in embodiment 90 is replaced with to the E1 crystal formation ethanedisulphonates of Afatinib respectively（Embodiment 3), N1 crystal formation 1,5- napadisilates (embodiment 12), N2 crystal formation 1,5- naphthalenedisulfonic acid salt hydrates（Embodiment 20), the malonate of Ml crystal formations one（Embodiment 24), the malonate of M2 crystal formations two（Embodiment 31), the 2- naphthalene sulfonates of Nsl crystal formations two（Embodiment 38), S1 crystal formation diamino sulfonic acid salt（Embodiment 46), the D-Glucose hydrochlorate of G1 crystal formations two（Embodiment 54), C1 crystal formation bicyclohexane sulfamates（Embodiment 63), the 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations two（Embodiment 72) and G1-1 crystal formation glycol hydrochlorates（Embodiment 81), respectively obtain embodiment 91-101 tablet.
Embodiment 102
The capsule for including Afatinib 2-maleate crystal formation N (embodiment 88) of the present invention is prepared, table 3 lists its single dose formula and batch recipe.
Table 3 includes Afatinib 2-maleate crystal formation N capsule formula
The preparation method of capsule is：Lactose monohydrate, Wei Jing Xian Victoria elements and Afatinib 2-maleate crystal formation N made from embodiment 88 is sieved by 710 μ ι η, be then charged into the diffusion mixer inserted with baffle plate, mix 15 minutes.Magnesium stearate is sieved by 210 μ ι η, be added in diffusion mixer.Then filled this blend into using Dosator type capsule fillers in 0# capsules, 500 mg/ capsules, production 84000 capsules of batch.
Embodiment 103-113
Be formulated according to table 3 and embodiment 102 preparation method, the Afatinib 2-maleate crystal formation N (embodiment 88) in embodiment 102 is replaced with to the E1 crystal formation Afatinib ethanedisulphonates of Afatinib respectively（Embodiment 3), N1 crystal formation 1,5- napadisilates（Embodiment 12), the naphthalenedisulfonic acid salt hydrate of N2 crystal formations 1,5（Embodiment 20), the malonate of Ml crystal formations one（Embodiment 24), the malonate of M2 crystal formations two（Embodiment 31), the 2- naphthalene sulfonates of Nsl crystal formations two（Embodiment 38), S1 crystal formation diamino sulfonic acid salt（Embodiment 46), the D-Glucose hydrochlorate of G1 crystal formations two（Embodiment 54), C1 crystal formation bicyclohexane sulfamates（Embodiment 63), the 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations two（Embodiment 72) and G1-1 crystal formation glycol hydrochlorates（Embodiment 81), respectively obtain embodiment 103-113 capsule.
In ratio 1
The acid-addition salts of preparation example 1, the Afatinib of embodiment 3,12,20,24,31,38,46,54,63,72,81 and 88 are respectively taken into 5mg, pure water progressively is added until the whole dissolved clarifications of sample, the solubility of sample is calculated according to the amount of the actual weight of sample and water into every part of sample under 25 °C.4 are the results are shown in Table, parallel test shows that sample does not occur to turn crystalline substance in the detection process.
The solubility test result of the Afatinib acid-addition salts of table 4
The salt solubility of Afatinib（Mg/ml) 2-maleate crystal formation（Prior art）（Preparation example 1) 7.5
E1 crystal formation ethanedisulphonates（Embodiment 3) 55.7
N1 crystal formation 1,5- napadisilates（Embodiment 12) 1.4
N2 crystal formation 1,5- naphthalenedisulfonic acid salt hydrates（Embodiment 20) 1.4
The malonate of Ml crystal formations one（Embodiment 24) 40.8
The malonate of M2 crystal formations two（Embodiment 31) 26.2
The 2- naphthalene sulfonates of Nsl crystal formations two（Embodiment 38) 2.0
S1 crystal formation diamino sulfonic acid salt（Embodiment 46) 138.3
The D-Glucose hydrochlorate of G1 crystal formations two（Embodiment 54) 5.4
C1 crystal formation bicyclohexane sulfamates（Embodiment 63) 63.1
The 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations two（Embodiment 72) 123.8 Gl-1 crystal formation glycol hydrochlorates（Embodiment 81) it is less than 0.1 2 maleic acid crystal formation N (embodiment 88) 12.7 comparative examples 2
According to the tablet formulation and preparation method in embodiment 90, embodiment 91-101, prepare the tablet of Afatinib 2-maleate prior art crystal formation and E1 crystal formation Afatinibs ethanedisulphonate, the N1 crystal formations Afatinib 1 of the present invention, 5- napadisilates, N2 crystal formations 1, each 100 of the tablet of 5- naphthalenedisulfonic acids salt hydrate, the malonate of Ml crystal formations Afatinib one, observation tableting processes and piece type.As a result show：The tablet 23% of prior art Afatinib 2-maleate crystal formation has sticking phenomenon, and remaining tablet does not have then.Explanation：In terms of the machinability of tablet, the granular crystals of the invention described above Afatinib acid-addition salts crystal formation are superior to the acicular crystal of prior art Afatinib 2-maleate crystal formation.
Comparative example 3
Take the intact tablet and E1 crystal formation Afatinibs ethanedisulphonate, N1 crystal formations Afatinib 1 of the Afatinib 2-maleate prior art crystal formation of the preparation of comparative example 2,5- napadisilates, N2 crystal formations 1, each 20 of the intact tablet of 5- naphthalenedisulfonic acids salt hydrate, the malonate of Ml crystal formations Afatinib one, carries out hardness test.As a result show：The hardness average value of E1 crystal formation Afatinib ethionic acid salt tablets（9.54Kg), the hardness average value (9.01Kg) of N1 crystal formations Afatinib 1,5- naphthalenedisulfonic acid salt tablets, the hardness average value of N2 crystal formation Afatinib 1,5- naphthalenedisulfonic acid salt hydrate tablets（8.55Kg), the hardness average value of the malonate tablet of Ml crystal formations Afatinib one（8.71Kg) it is above the hardness average value of prior art Afatinib 2-maleate crystal formation tablet（7.10Kg) .Explanation：In terms of the compressibility of tablet, the granular crystals of the invention described above Afatinib acid-addition salts crystal formation are superior to the acicular crystal of prior art Afatinib 2-maleate crystal formation.
It is described above; only embodiment of the invention; but protection scope of the present invention is not limited thereto; any those skilled in the art disclosed herein technical scope in; the change or replacement that can be expected without creative work, should all be included within the scope of the present invention.

Claims (49)

  1. Claim
    1st, Ah method replaces
    2nd, the preparation method of the Afatinib ethanedisulphonate described in claim 1, is comprised the following steps：The mol ratio for forming the molten Afatinib and ethionic acid of Afatinib and ethionic acid in soluble solvent respectively is 1: 1-1 :2, two System forming slurries are mixed, and then remove soluble solvent；It is preferred that the soluble solvent is nitrile, alcohols, ketone, esters, protective embankment hydro carbons, ethers or its mixture, more preferably described soluble solvent is acetonitrile, methanol, acetone, ethyl acetate, positive protective embankment in heptan or methyl tertiary butyl ether(MTBE)；It is preferred to use the method that is spin-dried for and removes soluble solvent.
    3rd, the Afatinib ethanedisulphonate according to claim 1, it is characterized in that, the Afatinib Yi bis- Shuo hydrochlorates are E1 crystal formation Afatinib ethanedisulphonates, are radiated using Cu- Κ α, and its X-ray powder diffraction figure is 6.3 ± 0.2 in the Θ of the angle of diffraction 2.、 7.0±0.2.、 17.6±0.2.、 17.8±0.2.、 21.7±0.2.、 22.8±0.2.With 24.6 ± 0.2.Place has feature
    4th, E1 crystal formations Afatinib ethanedisulphonate according to claim 3, it is characterised in that：Its X-ray powder diffraction figure is 6.3 ± 0.2 in the Θ of the angle of diffraction 2.、 7.0±0.2.、 12.6±0.2.、 14.5±0.2.、 17.6±0.2.、 17.8±0.2.、 18.3±0.2、 19.0±0.2.、 21.7±0.2.、 22.8±0.2.、 24.6.±0.2、 26.3±0.2.With 28.6 ± 0.2 ° at have feature
    5th, E1 crystal formations Afatinib ethanedisulphonate according to claim 4, it is characterised in that the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure are as follows：
    The Θ relative intensities % of the angle of diffraction 2
    6.3±0.2° 26.9
    7.0±0.2° 47.3
    12.6±0.2C 16.8
    14.1±0.2C 10.2
    14.5±0.2C 15.2
    16.4±0.2C 10.8
    17.6±0.2C 62.8
    17.8±0.2C 100.0
    18.3±0.2C 21.8
    19.0±0.2C 23.9
    21.3±0.2C 12.7
    21.7±0.2C 49.9
    22.5±0.2C 17.8
    22.8±0.2C 65.3
    23.0±0.2C 40.5
    24.1±0.2C 18.0
    24.6±0.2C 91.5
    25.4±0.2C 13.6
    26.3±0.2C 16.9
    27.6±0.2C 15.8
    28.6±0.2C 39.8
    29.0±0.2C 17.5
    29.4±0.2° 10.9
    36.7±0.2° 13.0
    6th, the preparation method of the El crystal formation Afatinib ethanedisulphonates any one of claim 3-5, is comprised the following steps：Form solution system in soluble solvent of Afatinib and ethionic acid respectively, the mol ratio of Afatinib and ethionic acid is 1: 1-1 :2, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, then remove solvent, wherein the soluble solvent is selected from C2-C4Nitrile, d-C4Alcohol, C3-C5Ketone, C4-C5Ester, C6-C9Alkane, C4-C6Ether or its mixture；It is preferred that the soluble solvent is acetonitrile, methanol, acetone, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；It is preferred that the operation temperature of the preparation method is room temperature.
    7th, the preparation method of the E1 crystal formation Afatinib ethanedisulphonates any one of claim 3-5, comprises the following steps：The Afatinib ethanedisulphonate obtained according to preparation method described in claim 2 is formed into slurries in organic solvent and stirred, slurries are kept 1 72 hours under -10-50 °C, and then solvent is removed, wherein the organic solvent is selected from acetonitrile, methanol, acetone, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；It is preferred that the operation temperature of the preparation method is room temperature.
    8th, Afatinib
    9th, the Afatinib 1 described in claim 8, the preparation method of 5- napadisilates, it is characterised in that comprise the steps of：Form solution system in soluble solvent of Afatinib and 1,5- naphthalenedisulfonic acid respectively, the mol ratio of Afatinib and 1,5- naphthalenedisulfonic acid is 1: 1-1 :2, two System forming slurries are mixed, and then remove soluble solvent；It is preferred that the soluble solvent is nitrile, alcohols, ketone, esters, alkanes, ethers or its mixture, more preferably described soluble solvent is acetonitrile, methanol, acetone, ethyl acetate, normal heptane or methyl tertiary butyl ether(MTBE)；It is preferred to use the method that is spin-dried for and removes soluble solvent.
    10th, Afatinib 1 according to claim 8,5- napadisilates, it is characterised in that：The Afatinib 1,5- Nai bis- Shuo hydrochlorates be N1 crystal formations Afatinib 1,5- napadisilates, using Cu- Κ α radiate, its X-ray powder diffraction figure the Θ of the angle of diffraction 2 be 6.6 ± 0.2 °, 13.4 ± 0.2.、 16.6±0.2.、 17.5±0.2., there is characteristic peak at 20.8 ± 0.2 ° and 24.2 ± 0.2 °.
    11st, N1 crystal formations Afatinib 1 according to claim 10,5- napadisilates, it is characterised in that：Its X ray powder diffraction pattern is 6.6 in the Θ of the angle of diffraction 2.±0.2、 8.1±0.2.、 13.4±0.2.、 14.8±0.2.、 16.3±0.2.、 16.6±0.2.、 17.5±0.2.、 18.3±0.2.、 20.8±0.2.、 22.0±0.2.、 22.7±0.2.With 24.2 ± 0.2.Place has feature
    12nd, N1 crystal formations Afatinib 1 according to claim 11,5- napadisilates, it is characterised in that the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X ray powder diffraction pattern are as follows：
    The Θ relative intensities % of the angle of diffraction 2
    6.6±0.2° 100.0
    8.1±0.2° 16.1
    11.2±0.2° 12.2
    13.4±0.2° 75.6
    14.8±0.2° 21.2
    16.3±0.2° 13.4
    16.6±0.2° 53.5
    17.5±0.2° 27.1
    17.9±0.2° 13.0
    18.3±0.2° 23.1
    19.2±0.2° 20.7
    19.5±0.2° 22.5
    20.5±0.2° 29.9
    20.8±0.2° 38.0
    21.8±0.2° 24.5
    22.0±0.2° 24.8
    22.4±0.2° 26.4
    22.7±0.2° 28.9
    23.2±0.2° 14.3
    23.5±0.2° 15.4
    24.2±0.2° 62.3
    24.7±0.2° 15.6
    26.5±0.2° 15.3
    30.2±0.2° 19.5
    13rd, the N1 crystal formations Afatinib 1 any one of claim 10-12, the preparation method of 5- napadisilates is comprised the steps of：Form solution system in soluble solvent of Afatinib and 1,5- naphthalenedisulfonic acid respectively, the mol ratio of Afatinib and 1,5- naphthalenedisulfonic acid is 1: 1-1 :2, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, and then solvent is removed, wherein the soluble solvent is selected from C2-C4Nitrile, d-C4Alcohol, C3-C5Ketone, C4-C5Ester, C6-C9Alkane, C4-C6Ether or its mixture；It is preferred that the soluble solvent is acetonitrile, methanol, ethanol, acetone, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；It is preferred that the operation temperature of the preparation method is room temperature.
    14th, the N1 crystal formations Afatinib 1 any one of claim 10-12, the preparation method of 5- napadisilates comprises the following steps：The Afatinib 1 that will be obtained according to preparation method described in claim 9,5- napadisilates form slurries and stirred in organic solvent, slurries are kept 1 72 hours under -10-50 °C, and then solvent is removed, wherein the organic solvent is selected from methanol, ethanol, acetonitrile, acetone, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；It is preferred that the operation temperature of the preparation method is room temperature.
    15th, Afatinib 1 according to claim 8,5- napadisilates, it is characterized in that, the Afatinib 1,5- napadisilates are N2 crystal formations Afatinib 1,5- naphthalenedisulfonic acid salt hydrates, are radiated using Cu- Κ α, and its X-ray powder diffraction figure is 6.7 ± 0.2 in the Θ of the angle of diffraction 2.、 8.1±0.2.、 9.3±0.2.、 14.9±0.2.、 20.9±0.2.With 23.0 ± 0.2.Place has characteristic peak.
    16th, N2 crystal formations Afatinib 1 according to claim 15,5- naphthalenedisulfonic acid salt hydrates, it is characterised in that its X-ray powder diffraction figure the Θ of the angle of diffraction 2 be 6.7 ± 0.2 °, 8.1 ± 0.2.、 9.3±0.2.、 13.9±0.2.、 14.9±0.2.、 15.8±0.2.、 16.7±0.2.、 17.5±0.2.、 20.5±0.2.、 20.9±0.2.、 21.7±0.2.、 23.0±0.2.、 24.1±0.2.With 24.3 ± 0.2 ° at have characteristic peak.
    17th, N2 crystal formations Afatinib 1 according to claim 16,5- naphthalenedisulfonic acid salt hydrates, it is characterised in that the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure are as follows：
    The Θ relative intensities % of the angle of diffraction 2
    5.9±0.2° 12.1
    6.7±0.2° 25.2
    8.1±0.2° 36.7
    9.3±0.2° 27.4
    12.0±0.2° 13.9
    13.5±0.2° 12.6
    13.9±0.2° 26.8
    14.9±0.2° 93.0
    15.8±0.2° 39.0
    16.3±0.2° 14.7
    16.7±0.2° 28.6
    17.5±0.2° 26.8
    18.1±0.2° 19.8
    19.4±0.2° 12.1
    20.0±0.2° 30.1
    20.5±0.2° 47.9
    20.9±0.2° 53.1
    21.7±0.2° 45.9
    22.2±0.2° 15.3
    23.0±0.2° 100.0
    24.1±0.2° 43.3
    24.3±0.2。 47.5
    24.8±0.2° 18.9
    25.7±0.2° 15.9
    26.1±0.2° 28.0
    27.6±0.2° 26.6
    18th, the N2 crystal formations Afatinib 1 any one of claim 15-17, the preparation method of 5- naphthalenedisulfonic acid salt hydrates, comprise the following steps：By the N1 crystal formations Afatinib 1 any one of claim 10-12,5- napadisilates are placed in the room temperature environment of 75%-100% relative humidity, 17 days standing times;In the room temperature environment for being preferably positioned at 75%-85% relative humidity, 13 days standing times.
    19th, A Fa
    20th, the preparation method of the malonate of Afatinib one described in claim 19, comprises the following steps：The mol ratio 1 of the solution system of Afatinib and malonic acid in soluble solvent, Afatinib and malonic acid is formed respectively: 1-1 :1.5, two System forming slurries are mixed, solvent is then removed；It is preferred that the soluble solvent is ether solvent, more preferably described soluble solvent is C4-C5Ether；It is preferred to use the method that is spin-dried for and removes solvent.
    21st, the malonate of Afatinib one according to claim 19, it is characterized in that, the malonate of Afatinib one is the malonate of Ml crystal formations Afatinib one, is radiated using Cu- Κ α, and its X-ray powder diffraction figure is 6.6 ± 0.2 in the Θ of the angle of diffraction 2.、 7.2±0.2.、 13.2±0.2.、 13.4±0.2.、 17.3±0.2.、 20.8±0.2.With 25.1 ± 0.2.Place has characteristic peak.
    22nd, the malonate of Ml crystal formations Afatinib one according to claim 21, it is characterised in that：Its X-ray powder diffraction figure is 6.6 ± 0.2 in the Θ of the angle of diffraction 2.、 7.2±0.2.、 8.7±0.2.、 13.2±0.2.、 13.4±0.2.、 14.3±0.2.、 17.3±0.2.、 18.0±0.2.、 19.7±0.2.、 20.8±0.2.、 21.4±0.2.、 25.1±0.2.With 26.1 ± 0.2.Place has feature
    23rd, the malonate of Ml crystal formations Afatinib one according to claim 22, it is characterised in that the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure are as follows：
    The Θ relative intensities % of the angle of diffraction 2
    6.6±0.2° 92.8
    7.2±0.2° 31.1
    8.7±0.2° 12.4
    13.2±0.2° 29.7
    13.4±0.2° 32.2
    14.3±0.2。 15.0
    17.3±0.2° 30.8
    18.0±0.2° 25.5
    19.3±0.2° 15.7
    19.7±0.2° 22.2
    20.8±0.2° 42.1
    21.4±0.2° 18.7
    22.3±0.2。 10.7
    22.7±0.2° 16.6
    23.6±0.2° 18.5
    25.1±0.2° 100.0
    26.0±0.2° 32.2
    24th, the preparation method of the malonate of Ml crystal formations Afatinib one any one of claim 21-23, comprises the following steps：Afatinib and malonic acid are formed respectively in C4-C5The mol ratio of solution system in ether, Afatinib and malonic acid is 1: 1-1 :2, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, and then remove solvent；It is preferred that the C4-C5Ether is methyl tertiary butyl ether(MTBE)；It is preferred that the operation temperature of the preparation method is room temperature.
    25th, the preparation method of the malonate of Ml crystal formations Afatinib one any one of claim 21-23, comprises the following steps：The malonate of Afatinib one obtained according to the preparation method described in claim 20 is formed into slurries in organic solvent and stirred, slurries are kept 1 72 hours under -10-50 °C, and then solvent is removed, wherein the organic solvent is selected from methanol, acetone, acetonitrile, methyl tertiary butyl ether(MTBE), ethyl acetate, normal heptane or its mixture；It is preferred that the operation temperature of the preparation method is room temperature.
    26th, A Fa
    27th, the preparation method of the malonate of Afatinib two described in claim 26, comprises the following steps：The mol ratio 1 of the solution system of Afatinib and malonic acid in soluble solvent, Afatinib and malonic acid is formed respectively:2-1 :4, two System forming slurries are mixed, solvent is then removed；It is preferred that the soluble solvent is esters solvent, more preferably C4-C5Ester；It is preferred to use the method that is spin-dried for and removes solvent.
    28th, the malonate of Afatinib two according to claim 26, it is characterized in that, the malonate of Afatinib two is the malonate of M2 crystal formations Afatinib two, is radiated using Cu- Κ α, and its X-ray powder diffraction figure is 6.5 ± 0.2 in the Θ of the angle of diffraction 2.、 8.1±0.2.、 13.1±0.2.、 16.1±0.2., there is characteristic peak at 20.8 ± 0.2 ° and 25.8 ± 0.2 °.
    29th, the malonate of M2 crystal formations Afatinib two according to claim 28, it is characterised in that its X-ray powder diffraction figure is 6.5 ± 0.2 in the Θ of the angle of diffraction 2.、 8.1±0.2.、 9.7±0.2.、 10.9±0.2.、 13.1±0.2.、 14.0±0.2.、 16.1±0.2.、 18.3±0.2.、 19.0±0.2.、 20.8±0.2., there is characteristic peak at 25.8 ± 0.2 ° and 27.0 ± 0.2 °.
    30th, the malonate of M2 crystal formations Afatinib two according to claim 29, it is characterised in that the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure are as follows：
    The Θ relative intensities % of the angle of diffraction 2
    5.8±0.2° 12.3
    6.5±0.2° 58.7
    8.1±0.2° 24.1
    9.7±0.2° 14.2
    10.9±0.2° 14.9
    13.1±0.2° 42.9
    13.6±0.2° 16.0
    14.0±0.2° 31.9
    15.1±0.2° 14.7
    16.1±0.2° 35.0
    16.4±0.2° 18.8
    18.3±0.2° 15.9
    19.0±0.2° 19.9
    19.8±0.2° 18.0
    20.4±0.2° 14.7
    20.8±0.2° 41.7
    21.5±0.2° 10.5
    22.2±0.2° 19.9
    23.6±0.2° 11.3
    25.8±0.2° 100.0
    26.5±0.2° 13.3
    27.0±0.2° 39.3
    27.7±0.2° 11.8
    29.3±0.2° 12.0
    31st, the preparation method of the malonate of M2 crystal formations Afatinib two any one of claim 28-30, comprises the following steps：Afatinib and malonic acid are formed respectively in C4-C5The mol ratio of solution system in ester, Afatinib and malonic acid is 1:2-1 :4, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, and then solvent is removed, obtain the malonate of M2 crystal formations Afatinib two；Or, the malonate of Afatinib one is formed respectively in C4-C5Suspension liquid system and malonic acid in ester is in C4-C5The mol ratio of solution system in ester, the malonate of Afatinib one and malonic acid is 1: 1-1 :2, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, and then solvent is removed, obtain the malonate of M2 crystal formations Afatinib two；It is preferred that the C4-C5Ester is ethyl acetate；It is preferred that the operation temperature of the preparation method is room temperature.
    32nd, the preparation method of the malonate of M2 crystal formations Afatinib two any one of claim 28-30, comprises the following steps：The malonate of Afatinib two obtained according to preparation method described in claim 27 is formed into slurries in organic solvent and stirred, slurries are kept 1 72 hours under -10-50 °C, and then solvent is removed, wherein the organic solvent is selected from methanol, acetone, acetonitrile, methyl tertiary butyl ether(MTBE), ethyl acetate, normal heptane or its mixture；It is preferred that the operation temperature of the preparation method is room temperature.
    33rd, A Fa
    34th, the preparation method of the 2- naphthalene sulfonates of Afatinib two described in claim 33, comprises the following steps：Form solution system in soluble solvent of Afatinib and 2- naphthalene sulfonic acids respectively, the mol ratio of Afatinib and 2- naphthalene sulfonic acids is 1:2-1 :4, two System forming slurries are mixed, and then remove solvent；It is preferred that the soluble solvent is alcohols, ketone, esters, alkanes, ethers or its mixture, more preferably described soluble solvent is methanol, acetone, ethyl acetate, normal heptane or methyl tertiary butyl ether(MTBE)；It is preferred to use the method that is spin-dried for and removes solvent.
    35th, the 2- naphthalene sulfonates of Afatinib two according to claim 33, it is characterized in that, the described 2- naphthalene sulfonates of Afatinib two are the 2- naphthalene sulfonates of Nsl crystal formations Afatinib two, radiated using Cu- Κ α, its X-ray powder diffraction figure is to have characteristic peak at 5.6 ± 0.2 °, 24.0 ± 0.2 ° and 26.8 ± 0.2 ° in the Θ of the angle of diffraction 2.
    36th, the 2- naphthalene sulfonates of Nsl crystal formations Afatinib two according to claim 35, it is characterised in that the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X ray powder diffraction pattern are as follows：
    The Θ relative intensities % of the angle of diffraction 2
    5.6±0.2° 26.0
    24.0±0.2° 100.0
    26.8±0.2° 54.3
    37th, the preparation method of the 2- Nai Shuo hydrochlorates of Nsl crystal formations Afatinib two any one of claim 35-36, comprises the following steps：Form solution system in soluble solvent of Afatinib and 2- naphthalene sulfonic acids respectively, the mol ratio of Afatinib and 2- naphthalene sulfonic acids is 1:2-1 :4, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, and then solvent is removed, wherein the soluble solvent is selected from d-C4Alcohol, C3-C5Ketone, C4-C5Ester, C6-C9Alkane, C4-C6Ether or its mixture;It is preferred that the soluble solvent is methanol, acetone, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture, more preferably ethyl acetate；It is preferred that the operation temperature of the preparation method is room temperature.
    38th, the preparation method of the 2- naphthalene sulfonates of Nsl crystal formations Afatinib two any one of claim 35-36, comprises the following steps：The 2- naphthalene sulfonates of Afatinib two obtained according to preparation method described in claim 34 are formed into slurries in organic solvent and stirred, slurries are kept 1 72 hours under -10-50 °C, and then solvent is removed, wherein the organic solvent is selected from methanol, acetone, acetonitrile, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；It is preferred that the operation temperature of the preparation method is room temperature.
    39th, Ah
    40th, the preparation method of the Afatinib diamino sulfonic acid salt described in claim 39, comprises the following steps：The mol ratio of the suspension liquid system of the solution system and sulfamic acid formed respectively in Afatinib soluble solvent in organic solvent, Afatinib and sulfamic acid is 1:2-1 :4, two System forming slurries are mixed, solvent is then removed；It is preferred that the soluble solvent or organic solvent are nitrile, alcohols, ketone, esters, alkanes, ethers or its mixture, more preferably acetonitrile, methanol, acetone, ethyl acetate, normal heptane or methyl tertiary butyl ether(MTBE)；It is preferred to use the method that is spin-dried for and removes solvent.
    41st, the Afatinib diamino sulfonic acid salt according to claim 39, it is characterized in that, the Afatinib diamino sulfonic acid salt is the crystal formation Afatinib diamino sulfonic acid salt of S 1, is radiated using Cu- Κ α, and its X-ray powder diffraction figure is 5.3 ± 0.2 in the Θ of the angle of diffraction 2.、 10.7±0.2.、 13.2±0.2.、 21.5±0.2.、 22.3±0.2.、 25.5±0.2.With 26.1 ± 0.2.Place has characteristic peak.
    42nd, the crystal formation Afatinib diamino sulfonic acid salt of S 1 according to claim 41, it is characterised in that：Its X ray powder diffraction pattern is 5.3 ± 0.2 in the Θ of the angle of diffraction 2.、 10.7±0.2.、 1 1.0±0.2.、 12.3±0.2.、 13.2±0.2.、 13.6±0.2.、 17.1±0.2.、 20.2±0.2.、 21.5±0.2.、 22.3±0.2.、 25.5±0.2.With 26.1 ± 0.2.Place has feature
    43rd, S1 crystal formations Afatinib Afatinib diamino sulfonic acid salt according to claim 42, it is characterised in that the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure are as follows：
    The Θ relative intensities % of the angle of diffraction 2
    5.3±0.2° 65.4
    10.7±0.2° 42.4
    1 1.0±0.2° 15.7
    12.3±0.2。 13.5
    12.9±0.2° 10.1
    13.2±0.2° 26.1
    13.6±0.2° 12.0
    17.1±0.2° 17.0
    19.0±0.2° 10.1
    20.2±0.2° 19.3
    21.5±0.2° 22.4
    22.3±0.2。 22.2
    23.0±0.2° 11.2
    25.5±0.2° 100.0
    26.1±0.2° 53.2
    44th, the preparation method of the SI crystal formation Afatinib diamino sulfonic acid salt any one of claim 41-43, comprises the following steps：Form solution system and sulfamic acid suspension liquid system in organic solvent of the Afatinib in soluble solvent respectively, the mol ratio of Afatinib and sulfamic acid is 1:2-1 :4, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, and then solvent is removed, S1 type Afatinib diamino sulfonic acid salt is obtained, wherein the soluble solvent or organic solvent are selected from C2-C4Nitrile, d-C4Alcohol, C3-C5Ketone, C4-C5Ester, C6-C9Alkane, C4-C6Ether or its mixture；It is preferred that the soluble solvent or organic solvent are acetonitrile, methanol, acetone, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；It is preferred that the operation temperature of the preparation method is room temperature.
    45th, the preparation method of the S1 crystal formation Afatinib Er An Ji Shuo hydrochlorates any one of claim 41-43, comprises the following steps：The Afatinib Er An Ji Shuo hydrochlorates obtained according to preparation method described in claim 40 are formed into slurries in organic solvent and stirred, slurries are kept 1 72 hours under -10-50 °C, and then solvent is removed, wherein the organic solvent is selected from methanol, acetone, acetonitrile, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；It is preferred that the operation temperature of the preparation method is room temperature.
    46th, A Fa
    47th, the preparation method of the D-Glucose hydrochlorate of Afatinib two described in claim 46, comprises the following steps：The mol ratio of solution of the formation Afatinib in soluble solvent, Afatinib and maltonic acid is 1:2-1 :4, solution of the Afatinib in soluble solvent and D-Glucose aqueous acid are mixed to form slurries, and then remove solvent；It is preferred that the soluble solvent is nitrile, alcohols, ketone, esters, alkanes, ethers or its mixture, more preferably described soluble solvent is acetonitrile, methanol, acetone, ethyl acetate, normal heptane or methyl tertiary butyl ether(MTBE)；It is preferred to use the method that is spin-dried for and removes solvent；It is preferred that the concentration of D-Glucose aqueous acid is 50%.
    48th, the D-Glucose hydrochlorate of Afatinib two according to claim 46, it is characterized in that, the D-Glucose hydrochlorate of Afatinib two is the D-Glucose hydrochlorate of G1 crystal formations Afatinib two, radiated using Cu- Κ α, its X-ray powder diffraction figure is to have characteristic peak at 4.9 ± 0.2 °, 5.5 ± 0.2 °, 10.0 ± 0.2 °, 13.0 ± 0.2 °, 25.3 ± 0.2 ° and 25.9 ± 0.2 ° in the Θ of the angle of diffraction 2.
    49th, the D-Glucose hydrochlorate of G1 crystal formations Afatinib two according to claim 48, characterized in that, its X-ray powder diffraction figure the Θ of the angle of diffraction 2 be 4.9 ± 0.2 °, 5.5 ± 0.2 °, 6.1 ± 0.2 °, 9.6 ± 0.2 °, 10.0 ± 0.2 °, 13.0 ± 0.2 °, 17.1 ± 0.2.、 19.6±0.2.、 20.0±0.2.、 20.3±0.2.、 25.3±0.2.With 25.9 ± 0.2.Place has characteristic peak.
    50th, the D-Glucose hydrochlorate of G1 crystal formations Afatinib two according to claim 49, it is characterised in that the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure are as follows：
    The Θ relative intensities % of the angle of diffraction 2
    4.9±0.2° 60.6
    5.5±0.2° 23.8
    6.1±0.2° 17.4
    8.5±0.2° 14.1
    9.6±0.2° 18.5 10 0±0.2。 44.4
    12 1±0.2° 14.7
    13 0±0.2。 26.8
    15 2±0.2。 10.3
    17 1±0.2° 29.4
    18 8±0.2。 15.6
    19 6±0.2。 21.8
    20 0±0.2。 33.5
    20 3±0.2。 33.8
    22 3±0.2。 11.2
    25 3±0.2。 100.0
    25 9±0.2。 53.2
    26 6±0.2。 11.8
    27 3±0.2。 13.8
    27 7±0.2。 11.8
    51st, the preparation method of the D-Glucose hydrochlorate of Gl crystal formations Afatinib two any one of claim 48-50, comprises the following steps：The mol ratio of solution of the formation Afatinib in soluble solvent, Afatinib and maltonic acid is 1:2-1 :4, solution of the Afatinib in soluble solvent and D-Glucose aqueous acid are mixed to form slurries and stirred, is kept for 1-48 hour under -10-50 °C, and then solvent is removed, wherein the soluble solvent is selected from C2-C4Nitrile, d-C4Alcohol, C3-C5Ketone, C4-C5Ester, C6-C9Alkane, the C C of nitro substitution3Alkane, C4-C6Ether or its mixture；It is preferred that the soluble solvent is ethyl acetate, acetonitrile, nitromethane, methanol, acetone, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；It is preferred that the concentration of D-Glucose aqueous acid is 50%;It is preferred that the operation temperature of the preparation method is room temperature.
    52nd, the preparation method of the D-Glucose hydrochlorate of G1 crystal formations Afatinib two any one of claim 48-50, comprises the following steps：The D-Glucose hydrochlorate of Afatinib two obtained according to preparation method described in claim 47 is formed into slurries in organic solvent and stirred, slurries are kept 1 72 hours under -10-50 °C, and then solvent is removed, wherein the organic solvent is selected from methanol, acetonitrile, ethyl acetate, nitromethane, acetone, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；It is preferred that the operation temperature of the preparation method is room temperature.
    53rd, Afatinib
    54th, the preparation method of the Afatinib bicyclohexane sulfamate described in claim 53, comprises the following steps：Form solution system and cyclohexane sulfamic acid suspension system in organic solvent of the Afatinib in soluble solvent respectively, the mol ratio of Afatinib and cyclohexane sulfamic acid is 1:2-1 :4, two System forming slurries are mixed, and then remove solvent；It is preferred that the soluble solvent or organic solvent are nitrile, alcohols, ketone, esters, alkanes, ethers or its mixture, more preferably acetonitrile, methanol, acetone, ethyl acetate, normal heptane or methyl tertiary butyl ether(MTBE)；It is preferred to use the method that is spin-dried for and removes solvent.
    55th, Afatinib bicyclohexane sulfamate according to claim 53, it is characterized in that, the Afatinib bicyclohexane sulfamate is C1 crystal formation Afatinib bicyclohexane sulfamates, using Cu- Κ α radiate, its X-ray powder diffraction figure the Θ of the angle of diffraction 2 be 5.0 ± 0.2 °, 6.0 ± 0.2.、 16.5±0.2.、 17.9±0.2., 18.6 ± 0.2 ° and 20.2 ± 0.2.Place has characteristic peak.
    56th, the C1 crystal formations Afatinib bicyclohexane sulfamate according to claim 55, it is characterised in that its X-ray powder diffraction figure the Θ of the angle of diffraction 2 be 5.0 ± 0.2 °, 6.0 ± 0.2.、 12.5±0.2.、 14.9±0.2.、 16.5±0.2.、
    17.9±0.2.、 18.4±0.2.、 18.6±0.2.、 20.2±0.2.、 21.3±0.2.、 21.6±0.2.With 24.2 ± 0.2.Place has feature
    57th, C1 crystal formations Afatinib bicyclohexane sulfamate according to claim 56, it is characterised in that the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure are as follows：
    The Θ relative intensities % of the angle of diffraction 2
    5.0±0.2° 100.0
    6.0±0.2° 27.1
    12.5±0.2。 9.6
    14.9±0.2° 9.9
    16.5±0.2° 13.6
    17.9±0.2° 15.3
    18.4±0.2° 17.6
    18.6±0.2° 31.3
    19.5±0.2° 9.6
    20.2±0.2° 27.9
    21.3±0.2° 12.2
    21.6±0.2° 13.1
    24.2±0.2° 12.9
    27.8±0.2° 10.2
    58th, the preparation method of the C1 crystal formation Afatinib bicyclohexane sulfamates any one of claim 55-57, comprises the following steps：Form solution system and cyclohexane sulfamic acid suspension system in organic solvent of the Afatinib in soluble solvent respectively, the mol ratio of Afatinib and cyclohexane sulfamic acid is 1:2-1 :4, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, and then solvent is removed, wherein the soluble solvent or organic solvent are selected from C2-C4Nitrile, d-C4Alcohol, C3-C5Ketone, C4-C5Ester, C6-C9Alkane, C4-C6Ether or its mixture;It is preferred that the soluble solvent or organic solvent are acetonitrile, methanol, acetone, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；It is preferred that the operation temperature of the preparation method is room temperature.
    59th, the preparation method of the C1 crystal formation Afatinib bicyclohexane An Ji Shuo hydrochlorates any one of claim 55-57, comprises the following steps：The Afatinib bicyclohexane sulfamate obtained according to preparation method described in claim 54 is formed into slurries in organic solvent and stirred, slurries are kept 1 72 hours under -10-50 °C, and then solvent is removed, wherein the organic solvent is selected from methanol, acetone, acetonitrile, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；It is preferred that the operation temperature of the preparation method is room temperature.
    60th, Ah method replaces 4- amino phenyl sulfonyl hydrochlorates, and its structural formula is as follows：
    61st, the preparation method of the 4- amino phenyl sulfonyl hydrochlorates of Afatinib two described in claim 60, comprises the following steps：Form solution system and 4- aminobenzenesulfonic acid suspension system in organic solvent of the Afatinib in soluble solvent respectively, the mol ratio of Afatinib and 4- aminobenzenesulfonic acids is 1:2-1 :4, two System forming slurries are mixed, and then remove solvent；It is preferred that the soluble solvent or organic solvent are nitrile, alcohols, ketone, alkanes, ethers or its mixture, more preferably acetonitrile, methanol, acetone, ethyl acetate, normal heptane or methyl tertiary butyl ether(MTBE)；It is preferred to use the method that is spin-dried for and removes solvent.
    62nd, the 4- amino phenyl sulfonyl hydrochlorates of Afatinib two according to claim 60, it is characterized in that, the 4- amino phenyl sulfonyls hydrochlorate of Afatinib two is the 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations Afatinib two, radiated using Cu- Κ α, its X-ray powder diffraction figure is 12.9 ± 0.2 in the Θ of the angle of diffraction 2.、 17.1±0.2.、 18.2±0.2.、 23.8±0.2.、 24.5±0.2.With
    There is characteristic peak at 25.7 ± 0.2 °.
    63rd, the 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations Afatinib two according to claim 62, characterized in that, its X ray powder diffraction pattern the Θ of the angle of diffraction 2 be 5.6 ± 0.2 °, 12.9 ± 0.2 °, 17.1 ± 0.2 °, 18.2 ± 0.2 °, 21.3 ± 0.2 °, 23.8 ± 0.2 °, 24.5 ± 0.2.、 25.7±0.2.、 27.6±0.2.With 34.3 ± 0.2.Place has characteristic peak.
    64th, the 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations Afatinib two according to claim 63, it is characterised in that the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure are as follows：
    The Θ relative intensities % of the angle of diffraction 2
    5.6±0.2° 10.5
    12.9±0.2° 23.9
    17.1±0.2° 1 1.9
    18.2±0.2° 100.0
    21.3±0.2° 12.9
    23.8±0.2° 19.1
    24.5±0.2° 29.6
    25.7±0.2° 23.1
    27.6±0.2° 18.3
    34.3±0.2。 16.1
    65th, the preparation method of the 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations Afatinib two any one of claim 62-64, comprises the following steps：Form solution system and 4- aminobenzenesulfonic acid suspension system in organic solvent of the Afatinib in soluble solvent respectively, the mol ratio of Afatinib and 4- aminobenzenesulfonic acids is 1:2-1 :4, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, and then solvent is removed, wherein the soluble solvent or organic solvent are selected from C2-C4Nitrile, d-C4Alcohol, C3-C5Ketone, C6-C9Alkane, C4-C6Ether or its mixture；It is preferred that the soluble solvent or organic solvent are acetonitrile, methanol, acetone, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；It is preferred that the operation temperature of the preparation method is room temperature.
    66th, the preparation method of the 4- amino phenyl sulfonyl hydrochlorates of A1 crystal formations Afatinib two any one of claim 62-64, comprises the following steps：The 4- amino phenyl sulfonyls hydrochlorate of Afatinib two obtained according to preparation method described in claim 61 is formed into slurries in organic solvent and stirred, slurries are kept 1 72 hours under -10-50 °C, and then solvent is removed, wherein the organic solvent is selected from methanol, acetone, acetonitrile, ethyl acetate, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；It is preferred that the operation temperature of the preparation method is room temperature.
    67th, A Fa
    HOCH COOH
    68th, the preparation method of Afatinib glycol hydrochlorate described in claim 67, comprises the following steps：Form solution system in soluble solvent of Afatinib and Glycolic acid respectively, the mol ratio of Afatinib and Glycolic acid is 1: 1-1 :2, two System forming slurries are mixed, solvent is then removed；It is preferred that the soluble solvent is alcohols, ketone, esters, alkanes, ethers or its mixture, more preferably described soluble solvent is methanol, acetone, ethyl acetate, normal heptane or methyl tertiary butyl ether(MTBE)；It is preferred to use the method that is spin-dried for and removes solvent.
    69th, Afatinib glycol hydrochlorate according to claim 67, it is characterized in that, the Afatinib glycol hydrochlorate is G1-1 crystal formation Afatinib glycol hydrochlorates, is radiated using Cu- Κ α, and its X-ray powder diffraction figure is 5.1 ± 0.2 in the Θ of the angle of diffraction 2.、 6.4±0.2.、 13.0±0.2.、 13.3±0.2.、 20.8±0.2.With 25.0 ± 0.2.Place has characteristic peak.
    70th, G1-1 crystal formations Afatinib glycol hydrochlorate according to claim 69, it is characterised in that its X-ray powder diffraction figure the Θ of the angle of diffraction 2 be 5.1 ± 0.2 °, 6.4 ± 0.2.、 7.0±0.2.、 13.0±0.2.、 13.3±0.2.、 17.2±0.2.、
    17.9±0.2.、 19.7±0.2.、 20.8±0.2.、 22.4±0.2., there is characteristic peak at 25.0 ± 0.2 ° and 25.9 ± 0.2 °.
    71st, G1-1 crystal formations Afatinib glycol hydrochlorate according to claim 70, it is characterised in that the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure are as follows：
    The Θ relative intensities % of the angle of diffraction 2
    5.1±0.2° 28.9
    6.4±0.2° 100.0
    7.0±0.2° 11.5
    13.0±0.2° 21.7
    13.3±0.2° 19.0
    17.2±0.2° 14.7
    17.9±0.2° 13.9
    19.0±0.2° 11.2
    19.7±0.2° 11.5
    20.8±0.2° 24.7
    21.2±0.2° 12.0
    22.4±0.2° 14.8
    23.5±0.2° 12.6
    25.0±0.2° 67.5
    25.9±0.2° 20.1
    72nd, the preparation method of G1-1 crystal formations Afatinib glycol hydrochlorate any one of claim 69-71, comprises the following steps：Form solution system in solvable of Afatinib and Glycolic acid respectively, the mol ratio of Afatinib and Glycolic acid is 1: 1-1 :2, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, and then solvent is removed, wherein the soluble solvent is selected from d-C4Alcohol, C3-C5Ketone, C4-C5Ester, C6-C9Alkane, the d-C of nitro substitution3Alkane, C4-C6Ether or its mixture；It is preferred that the soluble solvent is ethyl acetate or nitromethane；It is preferred that the operation temperature of the preparation method is room temperature.
    73rd, the preparation method of G1-1 crystal formations Afatinib glycol hydrochlorate any one of claim 69-71, comprises the following steps：The Afatinib glycol hydrochlorate obtained according to preparation method described in claim 68 is formed into slurries in organic solvent and stirred, slurries are kept 1 72 hours under -10-50 °C, and then solvent is removed, wherein the organic solvent is selected from methanol, acetone, acetonitrile, ethyl acetate, nitromethane, normal heptane, methyl tertiary butyl ether(MTBE) or its mixture；It is preferred that the operation temperature of the preparation method is room temperature.
    74th, a kind of crystal formation N of Afatinib 2-maleate, it is characterised in that using Cu- Κ α radiation, its X-ray powder diffraction figure the Θ of the angle of diffraction 2 be 4.8 ± 0.2 °, 9.7 ± 0.2.、 14.5±0.2.、 17.0±0.2.、 19.5±0.2., 20.1 ± 0.2, there is characteristic peak at 25.6 ± 0.2 °.
    75th, according to claim 74 Afatinib 2-maleate crystal formation N, it is characterised in that the Θ characteristic peaks of the angle of diffraction 2 and its relative intensity of its X-ray powder diffraction figure are as follows：
    The Θ relative intensities % of the angle of diffraction 2
    4.8±0.2° 100.0
    9.7±0.2°
    14.5±0.2° 3.6
    17.0±0.2° 2.2
    19.5±0.2°
    20.1±0.2° 2.3
    25.5±0.2° 5.0 。
    76th, Afatinib any one of claim 74 75-- maleate crystal formation N preparation method, comprises the following steps：Form solution system in nitromethane of Afatinib and maleic acid respectively, the mol ratio of Afatinib and maleic acid is 1:2-1 :4, mix two System forming slurries and stir, kept for 1-48 hours under -10-50 °C, and then remove solvent.
    77th, a kind of Yao Wu Group compounds, are selected from according to right comprising treatment and/or the one or more kinds of of prevention effective dose It is required that Afatinib acid-addition salts or its crystal formation and at least one pharmaceutically acceptable excipient described in 1,3,4,5,8,10,11,12,15,16,17,19,21,22,23,26,28,29,30,33,35,36,39,41,42,43,46,48,49,50,53,55,56,57,60,62,63,64,67,69,70,71,74 or 75.
    78, Yao Wu Group compounds according to claim 77, it is characterized in that, the Yao Wu Group compounds can be solid-state or liquid, including selected from tablet, granule, powder, pill, the solid oral dosage form of powder or capsule, or selected from solution, syrup, supensoid agent, the liquid oral dosage form of dispersant or emulsion, or selected from solution, dispersant or freeze-dried injectable formulation, or selected from the rapid releasing agent suitable for active component, sustained release agent or regulation releasing agent, or selected from routine, it is dispersible, it is masticable, Orally dissolving or rapid melting formulation, or its method of administration is selected from orally, vein is subcutaneously injected, Zhu She Ru Group knit administration, cutaneous penetration, rectally or intranasal administration.
    79, claim 1, 3, 4, 5, 8, 10, 11, 12, 15, 16, 17, 19, 21, 22, 23, 26, 28, 29, 30, 33, 35, 36, 39, 41, 42, 43, 46, 48, 49, 50, 53, 55, 56, 57, 60, 62, 63, 64, 67, 69, 70, 71, Afatinib acid-addition salts or its crystal formation any one of 74 or 75 are preparing the purposes in being used to treat the medicine of the advanced breast cancer disease of advanced Non-small cell lung and the HER2 positives.
    80, it is a kind of to treat and/or prevent advanced Non-small cell lung and the method for the positive advanced breast cancers of HER2, methods described includes giving patient's treatment of needs and/or the claim 1 of prevention effective dose, 3, 4, 5, 8, 10, 11, 12, 15, 16, 17, 19, 21, 22, 23, 26, 28, 29, 30, 33, 35, 36, 39, 41, 42, 43, 46, 48, 49, 50, 53, 55, 56, 57, 60, 62, 63, 64, 67, 69, 70, 71, Afatinib acid-addition salts or its crystal formation or claim 77 described in 74 or 75, Yao Wu Group compounds described in 78.
CN201480002096.3A 2013-07-16 2014-07-15 Afatinib acid-addition salts and crystal formation, its preparation method and pharmaceutical composition Active CN104540820B (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN201610664357.9A CN106279127B (en) 2013-07-16 2014-07-15 Afatinib acid-addition salts and its crystal form, preparation method and pharmaceutical composition
CN201480002096.3A CN104540820B (en) 2013-07-16 2014-07-15 Afatinib acid-addition salts and crystal formation, its preparation method and pharmaceutical composition
CN201610659418.2A CN106279126B (en) 2013-07-16 2014-07-15 Afatinib acid-addition salts and its crystal form, preparation method and pharmaceutical composition

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201310304272 2013-07-16
CN2013103042726 2013-07-16
CN201480002096.3A CN104540820B (en) 2013-07-16 2014-07-15 Afatinib acid-addition salts and crystal formation, its preparation method and pharmaceutical composition
PCT/CN2014/082252 WO2015007206A1 (en) 2013-07-16 2014-07-15 Afatinib acid addition salts and crystal forms thereof, preparation method and pharmaceutical composition thereof

Related Child Applications (2)

Application Number Title Priority Date Filing Date
CN201610659418.2A Division CN106279126B (en) 2013-07-16 2014-07-15 Afatinib acid-addition salts and its crystal form, preparation method and pharmaceutical composition
CN201610664357.9A Division CN106279127B (en) 2013-07-16 2014-07-15 Afatinib acid-addition salts and its crystal form, preparation method and pharmaceutical composition

Publications (2)

Publication Number Publication Date
CN104540820A true CN104540820A (en) 2015-04-22
CN104540820B CN104540820B (en) 2016-12-21

Family

ID=52345755

Family Applications (3)

Application Number Title Priority Date Filing Date
CN201610659418.2A Active CN106279126B (en) 2013-07-16 2014-07-15 Afatinib acid-addition salts and its crystal form, preparation method and pharmaceutical composition
CN201610664357.9A Active CN106279127B (en) 2013-07-16 2014-07-15 Afatinib acid-addition salts and its crystal form, preparation method and pharmaceutical composition
CN201480002096.3A Active CN104540820B (en) 2013-07-16 2014-07-15 Afatinib acid-addition salts and crystal formation, its preparation method and pharmaceutical composition

Family Applications Before (2)

Application Number Title Priority Date Filing Date
CN201610659418.2A Active CN106279126B (en) 2013-07-16 2014-07-15 Afatinib acid-addition salts and its crystal form, preparation method and pharmaceutical composition
CN201610664357.9A Active CN106279127B (en) 2013-07-16 2014-07-15 Afatinib acid-addition salts and its crystal form, preparation method and pharmaceutical composition

Country Status (2)

Country Link
CN (3) CN106279126B (en)
WO (1) WO2015007206A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016185485A3 (en) * 2015-05-18 2017-01-19 Msn Laboratories Private Limited Process for the preparation of n-[4-[(3-chloro-4-fluoro phenyl) amino]-7-[[(3s)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4- (dimethyl amino)-(2e)-2-butenamide (2z)-2-butenedioate (1 :2) and its polymorphs thereof

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10349113A1 (en) 2003-10-17 2005-05-12 Boehringer Ingelheim Pharma Process for the preparation of aminocrotonyl compounds
CA2982423C (en) * 2015-04-17 2024-01-16 Hetero Labs Ltd Polymorphs and process for the preparation of quinazolinyl derivatives
CN107980041A (en) * 2015-06-12 2018-05-01 费森尤斯卡比肿瘤学有限公司 The polymorphic forms of Afatinib free alkali and its dimaleate
CN108250138A (en) * 2016-12-28 2018-07-06 上海宣创生物科技有限公司 A Pa is for Buddhist nun's A crystal forms and its preparation method and application

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1867564A (en) * 2003-10-17 2006-11-22 贝林格尔·英格海姆国际有限公司 Process for preparing amino crotonyl compounds
WO2007054550A1 (en) * 2005-11-11 2007-05-18 Boehringer Ingelheim International Gmbh Quinazoline derivatives for the treatment of cancer diseases
WO2011003853A2 (en) * 2009-07-06 2011-01-13 Boehringer Ingelheim International Gmbh Process for drying of bibw2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient
CN102056589A (en) * 2008-06-06 2011-05-11 贝林格尔.英格海姆国际有限公司 Solid pharmaceutical formulations comprising BIBW 2992
WO2012121764A1 (en) * 2010-11-25 2012-09-13 Ratiopharm Gmbh Novel salts and polymorphic forms of afatinib

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2673472A1 (en) * 2006-12-21 2008-07-03 Vertex Pharmaceuticals Incorporated 5-cyan0-4- (pyrrolo) [2, 3b] pyridine-3-yl) -pyrimidine derivatives useful as protein kinase inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1867564A (en) * 2003-10-17 2006-11-22 贝林格尔·英格海姆国际有限公司 Process for preparing amino crotonyl compounds
WO2007054550A1 (en) * 2005-11-11 2007-05-18 Boehringer Ingelheim International Gmbh Quinazoline derivatives for the treatment of cancer diseases
CN102056589A (en) * 2008-06-06 2011-05-11 贝林格尔.英格海姆国际有限公司 Solid pharmaceutical formulations comprising BIBW 2992
WO2011003853A2 (en) * 2009-07-06 2011-01-13 Boehringer Ingelheim International Gmbh Process for drying of bibw2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient
WO2012121764A1 (en) * 2010-11-25 2012-09-13 Ratiopharm Gmbh Novel salts and polymorphic forms of afatinib

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016185485A3 (en) * 2015-05-18 2017-01-19 Msn Laboratories Private Limited Process for the preparation of n-[4-[(3-chloro-4-fluoro phenyl) amino]-7-[[(3s)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4- (dimethyl amino)-(2e)-2-butenamide (2z)-2-butenedioate (1 :2) and its polymorphs thereof
US10550107B2 (en) 2015-05-18 2020-02-04 Msn Laboratories Private Limited Process for the preparation of N-[4-[(3-chloro-4-fluoro phenyl) amino]-7-[[(3s-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethyl amino)-(2E)-2-butenamide (2Z)-2-butenedioate (1:2) and its polymorphs thereof

Also Published As

Publication number Publication date
CN106279126B (en) 2019-05-24
CN106279126A (en) 2017-01-04
CN104540820B (en) 2016-12-21
CN106279127B (en) 2019-05-24
CN106279127A (en) 2017-01-04
WO2015007206A1 (en) 2015-01-22

Similar Documents

Publication Publication Date Title
KR101470715B1 (en) Polymorphs of Dasatinib, preparation methods and pharmaceutical compositions thereof
CN104540820A (en) Afatinib acid addition salts and crystal forms thereof, preparation method and pharmaceutical composition thereof
JP6727419B2 (en) Novel crystalline form of sodium-glucose cotransporter inhibitor, its production method and use
EP1819688A2 (en) Crystalline forms of docetaxel and processes for their preparation
EP3672968B1 (en) Solid state form of ribociclib succinate
CN112142679B (en) Gefitinib and vanilloid eutectic methanol solvate and preparation method thereof
CN106458857A (en) Crystalline free acid, hemicalcium salt and alfa-phenylethylamine salt of ahu-377 as well as preparation method therefor and application thereof
CN104918937A (en) Crystalline forms of trametinib and solvate thereof, preparation method therefor, pharmaceutical composition comprising same and use thereof
CN105859691A (en) Novel crystal form of thymidine phosphorylase inhibitor and preparation method thereof
CN103059013B (en) Crystal formation of Dasatinib monohydrate and preparation method thereof
EP4341260A1 (en) Process for preparation of sotorasib and solid state form thereof
CN104755481A (en) Solid salt form of alpha-6-mPEG6-O-hydroxycodone as opioid agonists and uses thereof
TWI535724B (en) New polymorphic forms of icotinib phosphate and uses thereof
CN113045554A (en) Fexotinib crystal form and preparation method thereof
CN106916157A (en) The crystal formation of substituted amino pyran derivate
CN105367492B (en) His quinoline not crystal form of moral and preparation method thereof, its pharmaceutical composition and purposes
CN107868059B (en) Salt of quinazoline derivative, preparation method and application thereof
WO2024017365A1 (en) Pharmaceutically acceptable salt and polymorph of substituted pyrazolo[1,5-a]pyrimidin-7-amine derivative and use thereof
CN105085421A (en) Orbit azine-fumarate, hydrates, crystal forms and preparation methods therefor
EP4229057A1 (en) Solid state forms of lorecivivint
CN116120341A (en) Crystal form of GDC-0077 and preparation method and application thereof
CN117425651A (en) Hydrate crystal form of Lazertinib mesylate as well as preparation method and application thereof
CN104812752B (en) Crystal formation of Azilsartan and preparation method thereof
TW201506029A (en) Polymorphic forms of icotinib and uses thereof
CN116262746A (en) Novel maleate crystal form of atorvastatin and preparation method thereof

Legal Events

Date Code Title Description
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20191014

Address after: 318000 room 3-1-202, Tengda new village, Jiaojiang District, Taizhou City, Zhejiang Province

Patentee after: Ni Yun

Address before: 310018 room 2B12, building 452, No. 6, Hangzhou Economic & Technological Development Zone, Hangzhou, Zhejiang, China

Patentee before: HANGZHOU PUSHA PHARMACEUTICAL TECHNOLOGY CO., LTD.