WO2013054147A2 - Erlotinib salts - Google Patents

Erlotinib salts Download PDF

Info

Publication number
WO2013054147A2
WO2013054147A2 PCT/HU2012/000102 HU2012000102W WO2013054147A2 WO 2013054147 A2 WO2013054147 A2 WO 2013054147A2 HU 2012000102 W HU2012000102 W HU 2012000102W WO 2013054147 A2 WO2013054147 A2 WO 2013054147A2
Authority
WO
WIPO (PCT)
Prior art keywords
erlotinib
acid salt
ray powder
powder diffraction
diffraction peaks
Prior art date
Application number
PCT/HU2012/000102
Other languages
English (en)
French (fr)
Other versions
WO2013054147A3 (en
Inventor
Ede MÁRVÁNYOS
Gábor NÉMETH
Balázs VOLK
László Pongó
József Barkóczy
András DANCSÓ
Mónika MEZŐVÁRI
Zoltán VARGA
Original Assignee
Egis Gyógyszergyár Nyilvánosan Műkődő
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 Egis Gyógyszergyár Nyilvánosan Műkődő filed Critical Egis Gyógyszergyár Nyilvánosan Műkődő
Priority to BR112014008733A priority Critical patent/BR112014008733A2/pt
Priority to EP12826647.5A priority patent/EP2776406A2/en
Priority to CN201280058335.8A priority patent/CN103958483A/zh
Priority to EA201490773A priority patent/EA201490773A1/ru
Publication of WO2013054147A2 publication Critical patent/WO2013054147A2/en
Publication of WO2013054147A3 publication Critical patent/WO2013054147A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to new erlotinib salts, anhydrous forms, hydrates and solvates thereof, a process for the preparation thereof, pharmaceutical compositions containing the same and use of said pharmaceutical compositions in therapy.
  • [6,7-bis-(2-methoxyethoxy)-4-chinazolinyl](3-ethynyl-phenyl) amine of the Formula 1 is a pharmaceutical active ingredient acting by the tyrosine kinase inhibitor mechanism having the INN erlotinib and which can be preferably used for the treatment of non-small cell lung carcinoma and pancreas cancer.
  • the erlotinib of the Formula 1 was first described in EP 817,775. In this patent the synthesis of the erlotinib hydrochloric acid salt is disclosed and the product is characterized by the melting point.
  • EP 1,076,652 relates to the mesylate hydrate of erlotinib and the anhydrous forms (A, B and C) thereof. According to the patent the solubility of the mesylate salt is low.
  • a process is set forth for the preparation of erlotinib salts and the conversion of the erlotinib salts into the base.
  • the acidic conditions cover the following disclosed acids: HC1, HBr, H 2 S0 4 , p-toluenesulfonic acid, benzoic acid, citric acid, succinic acid, oxalic acid, benzenesulfonic acid, tartaric acid, methanesulfonic acid, phosphoric acid and mixtures thereof.
  • Particularly the preparation of the hydrochloric acid salt from the base by using aqueous hydrochloric acid or a solvent containing hydrochloric acid is described.
  • the object of the present invention is to provide a process for the preparation of morphologically pure new erlotinib salts of high purity which possess more favourable physical-chemical properties than the known salts and have at least as high chemical stability as the known salts and can be prepared in a reproducible manner suitable fore industrial scale manufacture.
  • Erlotinib hydrochloride is poorly soluble in aqueous medium which restricts the bioavailability thereof.
  • the low solubility also limits the route of administration thereof and the finishing of the active ingredient into solid pharmaceutical compositions.
  • the above object is solved according to the present invention by the preparation of the new salts of erlotinib, namely by salts formed with maleic acid, salicylic acid, L-mandelic acid, adipinic acid, 1,5-naphthalene-disulfonic acid, L-pyroglutamic acid, 1 -hydroxys- naphthoic acid and DL-mandelic acid.
  • the common inventive idea of the present invention resides in the preparation of new erlotinib salts which are more soluble in aqueous medium than the erlotinib hydrochloride salt.
  • the invention relates to normal or acidic salts of erlotinib and the hydrate and solvate forms thereof.
  • the invention relates to the Ml polymorph /Form 1/ of the crystalline erlotinib maleate monohydrate salt of the Formula 2 which has the following characteristic X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 6.870; 8.190; 8.880; 12.760; 13.740; 16.080; 19.430; 20.850; 21.710; 25.030; 25.740; 26.920; 28.450.
  • this product can be characterized by the following characteristic X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 6.870; 8.190; 8.880; 10.690; 12.760; 13.740; 16.080; 17.700; 18.490; 19.110; 19.430; 20.850; 21.170. 21.710; 24.750; 25.030; 25.740; 26.920; 27.720; 28.450; 32.230.
  • the characteristic X-ray powder diffractogram of the product is shown on Figure 1 and the signals having an intensity larger than 6 % are summarized in Table 1
  • the present invention is also concerned with the M2 polymorph /Form 21 of the crystalline erlotinib maleate monohydrate of the Formula 2 which has the following characteristic X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 6.710; 8.018; 8.702; 12.552; 12.951 ; 13.533; 18.224; 18.859; 19.142; 21.385; 24.395; 25.960.
  • this product can be characterized by the following characteristic X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 6.710; 8.018; 8.702; 10.494; 10.891 ; 12.552; 12.951 ; 13.533; 17.510; 18.224; 18.859; 19.142; 20.454; 20.843; 21.385; 22.806; 24.395; 25.316; 25.960; 28.979; 30.413; 31.194; 34.408.
  • the characteristic X-ray powder diffractogram of this product is shown on Figure 2 and the signals having an intensity larger than 1 % are summarized in Table 2:
  • the crystalline erlotinib salicylic acid /1 : 1/ salt of the Formula 3 which has the following characteristic X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 5.830; 6.990; 16.060; 23.490; 26.000. More particularly this product can be characterized by the following X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 5.830; 6.990; 16.060; 20.220; 22.740; 23.490; 24.930; 26.000.
  • the characteristic X-ray powder diffractogram of this product is shown on Figure 3 and the signals having an intensity larger than 10 % are summarized in Table 3:
  • the invention also relates to the crystalline erlotinib L-mandelic acid salt / 1 :1/ of the Formula 4 which has the following characteristic X-ray powder diffraction peaks 2 ⁇ ( ⁇ 0.2°. 2 ⁇ ): 6.040; 12.190; 16.200; 17.090; 18.270; 19.230; 20.030; 23.250; 24.870. 26.170. More particularly this product can be characterized by the following X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 6.040; 8.010; 12.190; 16.200; 18.270; 19.230; 20.030; 21.170; 21.780; 22.630; 23.250; 24.870; 26.170.
  • the characteristic X-ray powder diffractogram of this product is shown on Figure 4 and the signals having an intensity larger than 6 % are summarized in Table 4:
  • the invention also relates to the crystalline erlotinib adipinic acid salt /1 : 1/ of the Formula 5 which has the following characteristic X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 6.400; 7.050; 8.990; 12.920; 18.740; 21.820; 22.660; 28.830. More particularly this product can be characterized by the following X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 6.400; 7.050; 8.990; 12.920; 16.860; 17.350; 18.740; 20.430; 21.240; 21.820; 22.660; 23.370; 28.830.
  • the characteristic X-ray powder diffractogram of this product is shown on Figure 5 and the signals having an intensity larger than 7 % are summarized in Table 5:
  • the crystalline erlotinib L- pyroglutamic acid /1 : 1/ salt of the Formula 7 which has the following characteristic X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2°. 2 ⁇ ): 7.180; 13.310; 14.920. 19.590; 20.850; 22.160; 23.100; 24.170; 26.500.
  • this product can be characterized by the following X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 5.180; 7.180; 13.310; 14.920; 16.260; 16.610; 18.460; 19.060; 19.590; 20.080; 20.850; 22.160; 23.100; 24.170; 24.580; 25.070; 26.500; 27.360; 28.290; 28.670.
  • the X-ray powder diffractogram of this product is shown on Figure 7 and the signals having an intensity larger than 5% are summarized in table 7:
  • the invention also relates to the crystalline erlotinib l-hydroxy-2-naphthoic acid /1 : 1/ salt of the Formula 8 which has the following characteristic X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 4.300; 1 1.630; 14.340; 17.470; 19.140; 19.850; 22.800; 26.200. More particularly this product can be characterized by the following X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 4.300; 6.760; 1 1.630; 13.120; 13.750; 14.340; 16.860; 17.470; 18.540; 19.140; 19.850; 21.030; 22.800; 23.660; 24.540; 26.200; 28.580.
  • the characteristic X-ray powder diffractogram of this product is shown on Figure 8 and the signals having an intensity larger than 6 % are summarized in Table 8:
  • the invention also relates to the crystalline erlotinib DL-mandelic acid salt of the Formula 9 , which has the following characteristic X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 5.400; 9.160; 14.530; 18.140; 21.700; 23.010. More particularly this product can be characterized by the following X-ray powder diffraction peaks. 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 5.400; 9.160; 14.530; 15.490; 17.040; 17.360; 18.140; 18.370; 20.190; 21.180; 21.700; 23.010; 23.800; 24.700; 25.230; 25.960; 27.030.
  • the characteristic X-ray powder diffractogram of this product is shown on Figure 9 and the signals having an intensity larger than 3 % are summarized in Table 9:
  • a process for the preparation of erlotinib salts which comprises reacting an amorphous or crystalline form of erlotinib of the Formula 1 or an anhydrous form, hydrate or solvate thereof in a suitable organic solvent with the desired acid and separating the erlotinib salt formed.
  • the salts according to the present invention can be prepared by reacting erlotinib free base of the Formula 1 in an organic solvent with the desired acid, separating the crystallized salt and if desired washing with organic solvent.
  • the salts according to the present invention can also be prepared by reacting the free erlotinib base of the Formula 1 without isolation in an organic solvent with the desired acid, separating the crystallized salt and if desired washing it with an organic solvent.
  • the salt can be separated by known methods of pharmaceutical industry suitable for the separation of a solid phase and a liquid, such as filtration which is optionally carried out under atmospheric pressure or in vacuo or under pressure or by using a centrifuge.
  • mono-or polybasic organic or inorganic acids can be used, such as maleic acid, salicylic acid, L-mandelic acid, adipinic acid, 1,5-naphthalene-disulfonic acid, L-pyroglutamic acid ,l-hydroxy-2-naphthoic acid or DL-mandelic acid.
  • the process can be carried out in an organic solvent, e.g. C aliphatic alcohols, ethers, esters or mixtures thereof. It is preferred to use as organic solvent a C ether, ester or alcohol or a dipolar-aprotic solvent, particularly tetrahydrofurane, diethyl ether, ethyl acetate, acetonitrile, methanol, ethanol or 2-propanol or mixtures thereof.
  • organic solvent e.g. C aliphatic alcohols, ethers, esters or mixtures thereof. It is preferred to use as organic solvent a C ether, ester or alcohol or a dipolar-aprotic solvent, particularly tetrahydrofurane, diethyl ether, ethyl acetate, acetonitrile, methanol, ethanol or 2-propanol or mixtures thereof.
  • the salt forming acid is preferably applied in a 0.3-3.0 molar equivalent amount related to the amount of the erlotinib of the Formula 1.
  • One may proceed preferably by using the solution of the organic acid and carrying out the reaction at a temperature between 0°C and the boiling point of the solvent,
  • One may particularly preferably proceed by reacting the ethanolic solution of erlotinib of the Formula 1 with a solution containing a 0.3-3.0 molar equivalent of the acid at a temperature near to the boiling point of the solvent.
  • the precipitated product is separated by filtration.
  • the precipitated product is separated by filtration.
  • the new erlotinib salts of the present invention can be prepared by dissolving erlotinib base of the Formula 1 in a suitable solvent, preferably a Ci -6 alcohol, particularly ethanol, methanol or isopropanol and adding a 0.5-3.0, preferably a 0.5-1.0 molar equivalent amount of an acid in solid form or as a solution. If the salt precipitates at the temperature of the addition or under cooling it is filtered, if desired purified by digestion or recrystallization and finally filtered, washed and dried. If the precipitation does not spontaneously take place, the solvent is removed in vacuo and the residue is crystallized by adding a suitable solvent or solvent mixture, if desired purified by digestion or recrystallization and finally filtered, washed and dried.
  • a suitable solvent preferably a Ci -6 alcohol, particularly ethanol, methanol or isopropanol
  • a 0.5-3.0 preferably a 0.5-1.0 molar equivalent amount of an acid in solid form
  • the erlotinib maleic acid salt of the Formula 2 is preferably prepared by stirring the solution of the formed erlotinib base of the Formula 1 with an alcohol type solvent, preferably ethanol and adding the ethanolic solution of maleic acid at a temperature between 0°C and the boiling point of the solvent, preferably at a temperature between 0°C and 80°C, more preferably at 70°C. If necessary the reaction mixture is cooled to 5-25°C, the precipitated crystals are filtered, optionally washed and dried. The product is recrystallized from an alcohol type solvent or a mixture thereof formed with water, preferably from methanol, if necessary. From the erlotinib maleic acid /1 : 1/ salt of the Formula 2 thus obtained the anhydrous erlotinib maleic acid salt can be prepared by known methods e.g. by drying.
  • the erlotinib salicylic acid /1 :1/ salt of the Formula 3 can be preferably prepared by stirring the erlotinib free base of the Formula 1 in an alcohol type solvent, preferably methanol, adding to the mixture solid crystalline salicylic acid at a temperature between 0°C and the boiling point of the solvent, preferably at a temperature between 0°C and 80°C. more preferably at 70°C.
  • the reaction mixture is cooled to 5-25°C, the precipitated crystals are dried, optionally washed and dried. If desired the product is crystallized from an alcohol type solvent, preferably 2-propanol.
  • the erlotinib L-mandelic acid /1 : 1/ salt of the Formula 4 is prepared in an analogous manner to the preparation of the salicylic acid salt except that salicylic acid is replaced by L- mandelic acid.
  • the erlotinib adipinic acid l ⁇ A I salt of the Formula 5 can be prepared in an analogous manner to the preparation of the salicylic acid salt except that salicylic acid is replaced by an ethanolic solution of adipinic acid.
  • the erlotinib 1 ,5-naphthalene-disulfonic acid I2: ⁇ l salt of the Formula 6 can be preferably prepared by stirring erlotinib free base 111 in an alcohol type solvent, preferably ethanol, adding to the solution solid 1 ,5-naphthalene-disulfonic acid at a temperature between 0°C and the boiling point of the solvent, preferably between room temperature and 80°C, more preferably at 70°C, then stirring the mixture, preferably at room temperature overnight.
  • the precipitated crystals are filtered, optionally washed and dried.
  • the product is recrystallized from a polar-aprotic solvent, preferably from dimethyl sulfoxide.
  • the erlotinib L-pyroglutamic acid /1 : 1/ salt of the Formula 7 can be prepared in an analogous manner to the preparation of the salicylic acid salt except that salicylic acid is replaced by crystalline L-pyroglutamic acid.
  • the erlotinib l-hydroxy-2-naphthoic acid /1 : 1/ of the Formula 8 can be prepared in an analogous manner to the preparation of the salicylic acid salt except that salicylic acid is replaced by crystalline 1 -hydroxy-2-naphthoic acid.
  • the erlotinib DL-mandelic acid /1 : 1/ salt of the Formula 9 can be prepared in an analogous manner to the preparation of the salicylic acid salt except that salicylic acid is replaced by crystalline DL-mandelic acid.
  • the erlotinib salts of the present invention show a higher stability than the salts known from prior art in the storage tests carried out under various conditions. It has been found that from the new salts of the present invention the maleic acid monohydrate and the adipinic acid salts proved to be particularly stable. Said salts are particularly useful in the preparation of pharmaceutical compositions.
  • the solubility of the new erlotinib salts of the invention was tested in a 0.1 M hydrochloric acid solution.
  • the solubility was tested in said 0.1 M hydrochloric acid solution because the pH of this solution is 1.0 which is suitably similar to the pH value of 0.8-1.5 of the gastric fluid. It has been found in a surprising manner that the new erlotinib salts of the present invention show a better solubility than the hydrochloride salt known from prior art in the 0.1 M hydrochloric acid solution modeling the physiological conditions.
  • compositions comprising a therapeutically effective amount of an erlotinib salt of the present invention and if desired a pharmaceutically active carrier.
  • compositions of the invention can be administered preferably orally.
  • Such oral compositions may be e.g. tablets, capsules, dragees, solutions, elixirs, suspensions or emulsions.
  • the pharmaceutical compositions according to the present invention may contain conventional pharmaceutical carriers and/or auxiliary agents.
  • carrier e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, PEG, cocoa butter etc.
  • carrier often serves as the capsule wall material so that no additional carrier is required.
  • Chartula and lozenge are further oral pharmaceutical compositions. Particularly preferred oral administration forms are the powders, pirules, chartula and lozenges.
  • the tablets are prepared by admixing the active ingredient with suitable carriers in an appropriate ratio and from this mixture tablets of desired shape and size are pressed.
  • the powders are prepared by admixing the finely powdered active ingredient with the carriers.
  • the liquid compositions may be solutions, suspensions and emulsions which can also be sustained release compositions.
  • Aqueous solutions and aqueous propylene glycol solutions proved to be advantageous.
  • Compositions suitable for parenteral administration can be prepared preferably in the form of aqueous polyethylene glycol solutions.
  • compositions of the invention can be preferably prepared in the form of dosage units which contain the desired amount of the active ingredient.
  • the dosage units can be put on the market in the form of packages comprising separated amounts of the compositions e.g. packed tablets, capsules, vials or ampoules which contain the powder.
  • the term "dosage unit" relates to the capsules, chartula, lozenge and also to the package comprising a suitable amount of dosage units.
  • a process for the preparation of the above pharmaceutical compositions which comprises admixing an erlotinib salt of the Formula 2, 3, 4, 5, 6, 7, 8 or 9 or a mixture thereof with pharmaceutically acceptable solid or liquid diluents and/or auxiliary agents and bringing the mixture to a galenic composition.
  • compositions of the present invention can be prepared by conventional methods of pharmaceutical industry.
  • the pharmaceutical compositions of the present invention may contain further pharmaceutical active ingredients which are compatible with the new salts of the Formula 2, 3, 4, 5, 6, 7, 8 or 9 or mixtures thereof.
  • the advantage of the present invention is that the compounds of the Formulae 2, 3, 4, 5, 6, 7, 8 and 9 are substances of uniform morphology and have an advantageous crystal form.
  • the salts of the present invention possess preferable and reproducible properties, such as dissolving velocity, bioavailability, chemical stability and processing characteristics e.g. filtration, drying and tabletting properties.
  • the active ingredients of the Formulae 2, 3, 4, 5, 6, 7, 8 and 9 can be prepared by procedures readily suitable for industrial scale manufacture.
  • Figure 1 shows the X-ray powder diffractogram of the Ml polymorph /Form 1/ of the erlotinib maleic acid monohydrate of the Formula 2.
  • Figure 2 shows the X-ray powder diffractogram of the M2 polymorph /Form 21 of the erlotinib maleic acid monohydrate salt of the Formula 2.
  • Figure 4 shows the X-ray powder diffractogram of the erlotinib L-mandelic acid salt of the Formula 4.
  • Figure 5 shows the X-ray powder diffractogram of the erlotinib adipinic acid salt of the Formula 5.
  • Figure 6 shows the X-ray powder diffractogram of the erlotinib 1,5-naphthalene-disulfonic acid salt of the Formula 6.
  • Figure 7 shows the X-ray powder diffractogram of the erlotinib L-pyroglutamic acid salt of the Formula 7.
  • Figure 8 shows the X-ray powder diffractogram of the erlotinib l-hydroxy-2 -naphthoic acid salt of the Formula 8.
  • Figure 9 shows the X-ray powder diffractogram of the erlotinib DL-mandelic acid salt of the Formula 9.
  • the erlotinib base used in the following Examples is prepared from erlotinib hydrochloride by methods well-known for the person skilled in the art.
  • the erlotinib hydrochloride was obtained from the firm Zheijang Jiuzhou /China/.
  • the NMR spectra of the new salts according to the present invention is registered by use of the following apparatus: VARIAN INOVA 500 /500 MHz/, BRUKER AVANCE III 400/400 MHz/.
  • the X-ray powder diffraction data of all prepared products are obtained under the following measuring conditions:
  • Orifices 1,25° (divergence, scattered); 0,3 mm (receiving)
  • a) are recrystallized from 90 ml of a 80:20 mixture of methanol and water whereupon the reaction mixture is cooled to 20-25°C within an hour under stirring.
  • the precipitate is filtered and washed with a 80:20 mixture of methanol and water.
  • the wet solid is dried at room temperature in vacuo until constant weight.
  • 1,06 g of the crude product thus obtained are recrystallized from 20 ml of dimethyl sulfoxide.
  • the precipitate is filtered, washed with a small amount of cold dimethyl sulfoxide and tertiary butyl methyl ether.
  • the crude product thus obtained is recrystallized from 10 ml of isopropanol.
  • the suspension obtained is allowed to stand in a refrigerator, filtered and washed with a small amount of cold isopropanol and thereafter with tertiary butyl methyl ether.
  • Erlotinib maleate monohydrate salt 10 mg of erlotinib maleate monohydrate are weighed in a 25 ml round-bottomed flask whereupon a 0.1 M hydrochloric acid solution /exact titre/ is added under continuous stirring /Heidolph 3001 mixer, 1000 rpm/ After addition of 10 ml of the hydrochloric acid solution immediately a clear solution is obtained.
  • Erlotinib adipinate salt 10 mg of erlotinib adipinate are weighed in a 25 ml round-bottomed flask whereupon a 0.1 M hydrochloric acid solution /exact titre/ is added under continuous stirring /Heidolph 3001 mixer. 1000 rpm/. After addition of 2 ml of the hydrochloric acid solution immediately a clear solution is obtained.
  • Erlotinib hydrochloride 10 mg of erlotinib hydrochloride salt are weighed into a 50 ml round- bottomed flask whereupon a 0.1 M hydrochloric acid solution /exact titre/ is added under continuous stirring. After addition of 50 ml of the hydrochloric acid solution no clear solution is obtained even after stirring for two hours /according to visual observation the mixture still contains insoluble particles/.
  • the further advantage of the above salt formation procedures is that as a result of the aqueous washing steps the precipitated salt contains no residual inorganic contaminations /e.g. sodium chloride/ contrary e.g. to the precipitation of the base carried out from an alcoholic solution with sodium acetate.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
PCT/HU2012/000102 2011-10-10 2012-10-10 Erlotinib salts WO2013054147A2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
BR112014008733A BR112014008733A2 (pt) 2011-10-10 2012-10-10 sais de erlotinib
EP12826647.5A EP2776406A2 (en) 2011-10-10 2012-10-10 Erlotinib salts
CN201280058335.8A CN103958483A (zh) 2011-10-10 2012-10-10 厄洛替尼盐
EA201490773A EA201490773A1 (ru) 2011-10-10 2012-10-10 Соли эрлотиниба

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU1100562A HU230483B1 (hu) 2011-10-10 2011-10-10 Erlotinib sók
HUP1100562 2011-10-10

Publications (2)

Publication Number Publication Date
WO2013054147A2 true WO2013054147A2 (en) 2013-04-18
WO2013054147A3 WO2013054147A3 (en) 2013-06-13

Family

ID=89990469

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU2012/000102 WO2013054147A2 (en) 2011-10-10 2012-10-10 Erlotinib salts

Country Status (6)

Country Link
EP (1) EP2776406A2 (pt)
CN (1) CN103958483A (pt)
BR (1) BR112014008733A2 (pt)
EA (1) EA201490773A1 (pt)
HU (1) HU230483B1 (pt)
WO (1) WO2013054147A2 (pt)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014118737A1 (en) * 2013-01-31 2014-08-07 Ranbaxy Laboratories Limited Erlotinib salts

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104250230A (zh) * 2014-09-05 2014-12-31 亿腾药业（泰州）有限公司 厄洛替尼柠檬酸盐与其晶型以及它们的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0817775A1 (en) 1995-03-30 1998-01-14 Pfizer Inc. Quinazoline derivatives
EP1076652A1 (en) 1998-04-29 2001-02-21 Pfizer Products Inc. N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate anhydrate and monohydrate
WO2008122776A2 (en) 2007-04-04 2008-10-16 Cipla Limited Process for preparation of erlotinib and its pharmaceutically acceptable salts
WO2011068403A2 (en) 2009-12-02 2011-06-09 Ultimorphix Technologies B.V. Novel n-{3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamjne salts

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7960545B2 (en) * 2005-11-23 2011-06-14 Natco Pharma Limited Process for the prepartion of erlotinib
US8440823B2 (en) * 2009-03-26 2013-05-14 Ranbaxy Laboratories Limited Process for the preparation of erlotinib or its pharmaceutically acceptable salts thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0817775A1 (en) 1995-03-30 1998-01-14 Pfizer Inc. Quinazoline derivatives
EP1076652A1 (en) 1998-04-29 2001-02-21 Pfizer Products Inc. N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate anhydrate and monohydrate
WO2008122776A2 (en) 2007-04-04 2008-10-16 Cipla Limited Process for preparation of erlotinib and its pharmaceutically acceptable salts
WO2011068403A2 (en) 2009-12-02 2011-06-09 Ultimorphix Technologies B.V. Novel n-{3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamjne salts

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014118737A1 (en) * 2013-01-31 2014-08-07 Ranbaxy Laboratories Limited Erlotinib salts

Also Published As

Publication number Publication date
BR112014008733A2 (pt) 2017-04-25
EP2776406A2 (en) 2014-09-17
HUP1100562A2 (en) 2013-05-28
WO2013054147A3 (en) 2013-06-13
HU230483B1 (hu) 2016-07-28
CN103958483A (zh) 2014-07-30
EA201490773A1 (ru) 2014-10-30

Similar Documents

Publication Publication Date Title
KR101221864B1 (ko) 4-［［(7ｒ)-8-사이클로펜틸-7-에틸-5,6,7,8-테트라하이드로-5-메틸-6-옥소-2-프테리디닐］아미노］-3-메톡시-ｎ-(1-메틸-4-피페리디닐)벤즈아미드의 수화물 및 다형체, 이들의 제조방법, 및 약제로서의 이들의 용도
CN106661015B (zh) 达沙替尼盐
US11028100B2 (en) Polymorphs and solid forms of (s)-2-((2-((s)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide, and methods of production
EP3201197B1 (en) Acid addition salt of ibrutinib
WO2011110876A1 (en) Novel salts for the manufacture of pharmaceutical compositions
KR20080044841A (ko) 이마티닙 메실레이트의 다형 및 신규한 결정형과 비결정형및 α형의 제조 방법
WO2013054147A2 (en) Erlotinib salts
US11111250B2 (en) Polymorphs of Ribociclib mono succinate
RU2712226C2 (ru) Фениламинопиримидин или полиморфная форма соли фениламинопиримидина
JP2001524548A (ja) ２−〔２−〔４−〔ビス（４−フルオロフェニル）メチル〕−１−ピペラジニル〕エトキシ〕酢酸ジヒドロクロリドの偽多形
EP2547681B1 (en) Tosylate salt of cyclopropanecarboxylic acid 4-(6-chloro-3-metyhl-4,10-dihydro-3h-2,3,4,9-tetrabenzo[f]azulene-9-carbonyl)-2-fluorobenzylamide
EP2751094B1 (en) Novel crystal form
EP3368527B1 (en) Palbociclib tosylate
EP2729461B1 (en) Polymorphs of 6-(piperidin-4-yloxy)-2h-isoquinolin-1-one hydrochloride
WO2014188226A2 (en) Lapatinib salts
EP2729460B1 (en) Crystalline solvates of 6-(piperidin-4-yloxy)-2h-isoquinolin-1-one hydrochloride
JP2022544672A (ja) ピリミジノジアゼピン誘導体の結晶性形態
WO2015028828A1 (en) Sorafenib salts
CN118146216A (zh) Ceralasertib的盐的多晶型物及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12826647

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: A201404939

Country of ref document: UA

REEP Request for entry into the european phase

Ref document number: 2012826647

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2012826647

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 201490773

Country of ref document: EA

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112014008733

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112014008733

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20140410