[go: up one dir, main page]

US20100136116A1 - Novel hydrated form of erlotinib free base and a process for preparation of erlotinib hydrochloride polymorph form a substantially free of polymorph form b - Google Patents

Novel hydrated form of erlotinib free base and a process for preparation of erlotinib hydrochloride polymorph form a substantially free of polymorph form b Download PDF

Info

Publication number
US20100136116A1
US20100136116A1 US11/994,599 US99459907A US2010136116A1 US 20100136116 A1 US20100136116 A1 US 20100136116A1 US 99459907 A US99459907 A US 99459907A US 2010136116 A1 US2010136116 A1 US 2010136116A1
Authority
US
United States
Prior art keywords
erlotinib
crystalline
solution
temperature
free base
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.)
Abandoned
Application number
US11/994,599
Other languages
English (en)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Rapolu Raji Reddy
Dasari Muralidhara Reddy
Thungathurthy Srinivasa Rao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hetero Drugs Ltd
Original Assignee
Hetero Drugs 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 Hetero Drugs Ltd filed Critical Hetero Drugs Ltd
Assigned to HETERO DRUGS LIMITED reassignment HETERO DRUGS LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MURALIDHARA REDDY, DASARI, PARTHASARADHI REDDY, BANDI, RAJI REDDY, RAPOLU, RATHNAKAR REDDY, KURA, SRINIVASA RAO, THUNGATHURTHY
Publication of US20100136116A1 publication Critical patent/US20100136116A1/en
Priority to US13/221,986 priority Critical patent/US8471012B2/en
Priority to US13/900,647 priority patent/US8669265B2/en
Abandoned legal-status Critical Current

Links

Images

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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]

Definitions

  • the present invention provides a novel and stable hydrated form of erlotinib free base, and a process for its preparation thereof.
  • the present invention also provides a process for preparation of erlotinib hydrochloride crystalline polymorph A substantially free of polymorph B.
  • the present invention further relates to erlotinib hydrochloride crystalline particles having mean particle size (D 50 ) ranging from about 4 ⁇ m to 15 ⁇ m and 90 volume-% of the particles (D 90 ) ranging from about 14 ⁇ m to 30 ⁇ m, to the methods for the manufacture of said crystalline particles, and to pharmaceutical compositions comprising said crystalline particles.
  • U.S. Pat. No. 5,747,498 disclosed 4-(substituted phenylamino) quinazoline derivatives, processes for their preparation, pharmaceutical compositions in which they are present and method of use thereof. These compounds are Tyrosine Kinase Inhibitors and are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals.
  • erlotinib hydrochloride chemically N-(3-ethynylphenyl)-6,7-bis(2-methoxy ethoxy)-4-quinazolinamine hydrochloride is a selective inhibitor of the erbB family of oncogenic and protooncogenic protein tyrosine kinases, such as epidermal growth factor receptor (EGFR), and is useful for the treatment of proliferative disorders, such as cancers, particularly non small cell lung cancer, pancreatic cancer, ovarian cancer, breast cancer, glioma, head cancer or neck cancer.
  • Erlotinib is represented by the following structure:
  • Polymorphism is defined as “the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules”. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
  • XRD X-ray diffraction
  • DSC Differential Scanning Calorimetry
  • IR Infrared spectrometry
  • Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other.
  • Erlotinib hydrochloride can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
  • PCT Patent Publication No. WO 99/55683 disclosed erlotinib mesylate anhydrate and, hydrate polymorphic forms, their method of preparation and pharmaceutical compositions containing thereof.
  • PCT Patent Publication No. WO 01/34574 A1 (herein after referred to as the '574 patent publication) described two crystalline forms of erlotinib hydrochloride (polymorph A and polymorph B), characterized by powder X-ray diffraction (p-XRD) pattern.
  • the publication further taught that the synthetic procedure described and exemplified in the '498 patent produces the erlotinib hydrochloride as a mixture of the polymorphs A and B.
  • erlotinib hydrochloride polymorph A is characterized by an X-ray powder diffraction pattern having peaks expressed as 28 at approximately 5.58, 9.84, 11.25, 18.86, 22.70, 23.50, 24.18, 24.59, 25.40 and 29.24 degrees.
  • erlotinib hydrochloride can be obtained in polymorph A form or in a mixture of polymorph A and B, by heating the filtrate containing 3-ethynylaniline in toluene, 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline and acetonitrile to reflux temperature, cooling the reaction mass to between 19 to 25° C. over three to four hours, agitating the reaction mass at a temperature between 20 and 25° C. and isolating erlotinib hydrochloride in polymorph A form or in a mixture of polymorph A and B.
  • the '574 patent publication further taught that the production of the polymorph A is favored by the reduction of the amount of acetonitrile relative to toluene, and particularly favored if isopropanol is used in place of acetonitrile.
  • erlotinib hydrochloride polymorph B is characterized by an X-ray powder diffraction pattern having peaks expressed as 2 ⁇ at approximately 6.26, 12.48, 13.39, 16.96, 20.20, 21.10, 22.98, 24.46, 25.14 and 26.91 degrees.
  • the erlotinib hydrochloride polymorph B can be prepared by heating to reflux alcohol, water and the erlotinib hydrochloride so as to form a solution; cooling the solution to between about 65 and 70° C.; clarifying the solution; and precipitating polymorph B by further cooling the clarified solution.
  • erlotinib hydrochloride polymorph E (characterized by, an X-ray powder diffraction pattern having peaks expressed as 28 at approximately 5.7, 9.7, 10.1, 11.3, 17.0, 17.4, 18.9, 19.6, 21.3, 22.8, 23.6, 24.2, 24.7, 25.4, 26.2, 26.7 and 29.3 degrees, and an IR absorption spectrum having characteristic peaks expressed in cm ⁇ 1 at approximately 3277, 3057, 16.27, 1070, 1022, 892, 873, 850, 780, 745, 725, and 652 cm ⁇ 1 ) can be prepared by reacting 3-ethynylaniline with 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline in ( ⁇ , ⁇ , ⁇ )-trifluorotoluene, and precipitating erlotinib hydrochloride polymorph E from the solution of ( ⁇ , ⁇ , ⁇ )-trifluorotoluene.
  • U.S. Patent Application No. 2006/0154941 A1 described an amorphous form of erlotinib hydrochloride prepared by dissolving crystalline erlotinib hydrochloride in an alcoholic solvent to form a solution and removing the solvent from the solution by distillation or spray drying.
  • novel and stable hydrated crystalline form of erlotinib free base which differ from the anhydrous form in its stability, in its physical properties, in its spectral characteristics and in its method of preparation.
  • the novel hydrated form is non-hygroscopic, storage stable over the time, obtainable in pure form and can be used to obtain pharmaceutically acceptable salts of erlotinib in high purity.
  • the experimental data disclosed in the '574 patent publication shows that the polymorph A has a peak in PX-RD at about 6.26 ⁇ 0.2 which is the characteristic peak of polymorph B.
  • the erlotinib hydrochloride product prepared by the methods as described in the prior art has a very small particle size i.e., erlotinib hydrochloride crystalline particles with a mean particle size (D 50 ) ranging from about 2 ⁇ m to 3.5 ⁇ m and 90 volume-% of the particles (D 90 ) ranging from about 4 ⁇ m to 8.5 ⁇ m resulting in similarly poor flow properties.
  • D 50 mean particle size
  • One object of the present invention is to provide a novel and stable hydrated, crystalline form of erlotinib free base and a process for preparing it.
  • According to another object of the present invention is to provide a novel process for preparing erlotinib hydrochloride crystalline polymorph form A substantially free of polymorph B.
  • According to another object of the present invention is to provide erlotinib hydrochloride crystalline polymorph form A characterized by peaks in the powder X-ray diffraction pattern having 29 angle positions at about 5.75, 9.88, 11.40, 18.97, 22.84, 23.65, 24.29, 24.75, 25.56 and 29.37 ⁇ 0.2 degrees and by the absence of a peak at about 6.26 ⁇ 0.2 degrees.
  • According to another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising erlotinib hydrochloride crystalline polymorph form A characterized by peaks in the powder X-ray diffraction pattern having 29 angle positions at about 5.75, 9.88, 11.40, 18.97, 22.84, 23.65, 24.29, 24.75, 25.56 and 29.37 ⁇ 0.2 degrees by the absence of a peak at about 6.26 ⁇ 0.2 degrees.
  • According to another object of the present invention is to provide erlotinib hydrochloride and formulations containing erlotinib hydrochloride particles having mean particle size (D 50 ) ranging from about 4 ⁇ m to 15 ⁇ m and 90 volume-% of the particles (D 90 ) ranging from about 14 ⁇ m to 30 ⁇ m, and methods for manufacturing such particles.
  • D 50 mean particle size
  • D 90 volume-% of the particles
  • a novel hydrated crystalline form of erlotinib free base having water content in the range of about 1-10% by weight, characterized by peaks in the powder X-ray diffraction pattern having 20 angle positions at about 6.4, 7.4, 11.2, 12.8, 14.5, 16.3, 18.2, 20.0, 20.5, 21.9, 22.3, 23.3, 23.5, 24.6, 27.6 and 30.0 ⁇ 0.2 degrees.
  • the typical X-ray powder diffraction pattern is shown in FIG. 1 .
  • the crystalline erlotinib hydrate is further characterized by a Differential Scanning Calorimetry (DSC) thermogram having a small endotherm in the range between 100-112° C. followed by a sharp endotherm in the range between 156-159° C.
  • DSC Differential Scanning Calorimetry
  • a process for preparation of crystalline erlotinib hydrate having water content in the range of about 1-10% by weight which comprises:
  • the temperature at which slurrying is done in step (a) is not critical and the slurrying is preferably carried out at a temperature below 60° C., more preferably carried out at a temperature between 0° C. and 45° C. and still more preferably carried out at 20-40° C.
  • the slurry obtained in step (a) is preferably stirred at least for about 30 minutes, more preferably stirred at least for about 1 hour and still more preferably stirred for about 1 hour to 4 hours.
  • the crystalline erlotinib hydrate in step (b) is collected from the slurry by conventional methods such as filtration or centrifugation.
  • Another process for preparation of crystalline erlotinib hydrate having water content in the range of about 1-10% by weight which comprises:
  • the organic solvent used in step (a) is selected from the group consisting of acetone, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, acetonitrile, and an alcoholic solvent such as methanol, ethanol, propanol, isopropyl alcohol, butanol, isoamyl alcohol.
  • alcoholic solvent such as methanol, ethanol, propanol, isopropyl alcohol, butanol, isoamyl alcohol.
  • Preferable organic solvent is selected from methanol, ethanol, isopropyl alcohol and acetone.
  • the erlotinib free base in step (a) may be dissolved in the organic solvent at a temperature above about 30° C., more preferably at a temperature between 40° C. and reflux temperature of the solvent used and still more preferably at a temperature between 45° C. and 80° C.
  • Erlotinib free base used as starting material may be obtained by processes described in the art, for example by the process described in the U.S. Pat. No. 5,747,498.
  • the erlotinib hydrochloride crystalline polymorph form A substantially free of polymorph form B obtained by the process described above is characterized by peaks in the powder X-ray diffraction pattern having 29 angle positions at about 5.75, 9.88, 11.40, 18.97, 22.84, 23.65, 24.29, 24.75, 25.56 and 29.37 ⁇ 0.2 degrees.
  • the typical X-ray powder diffraction pattern is shown in FIG. 5 .
  • B refers to the erlotinib hydrochloride polymorph form A containing less than about 10% crystalline polymorph form B of erlotinib hydrochloride, preferably less than 5% crystalline polymorph form B of erlotinib hydrochloride, more preferably less than 1% crystalline polymorph form B of erlotinib hydrochloride, and still more preferably essentially free of crystalline polymorph form B of erlotinib hydrochloride.
  • “Essentially free of crystalline polymorph form B of erlotinib hydrochloride” means that no crystalline polymorph form B of erlotinib hydrochloride can be detected within the limits of a powder X-ray diffractometer.
  • X-ray powder diffraction provides a convenient and practical means for quantitative determination of the relative amounts of crystalline polymorph A and/or crystalline polymorph B forms in a solid mixture.
  • X-ray powder diffraction is adaptable to quantitative applications because the intensities of the diffraction peaks of a given compound in a mixture are proportional to the fraction of the corresponding powder in the mixture. Therefore, the percent composition of crystalline polymorph A or crystalline polymorph B form of erlotinib hydrochloride in an unknown composition can be determined by using standard calibration curve, which can be constructed by spiking known amount of pure crystalline polymorph B into crystalline polymorph A of erlotinib hydrochloride to determine the percent ratio of crystalline polymorph B.
  • the process of the invention may be carried out by dissolving erlotinib free base in a solvent or a mixture of solvents selected from isopropyl acetate and methyl isobutyl ketone to form a clear solution; adding hydrochloric acid to the solution; and isolating erlotinib hydrochloride crystalline polymorph form A substantially free of polymorph B from the solution.
  • the erlotinib free base may be dissolved in the solvent or a mixture of solvents selected from isopropyl acetate and methyl isobutyl ketone at a temperature above about 30° C., more preferably at a temperature between 40° C. and reflux temperature of the solvent used and still more preferably at a temperature between 50° C. and 80° C.
  • Hydrochloric acid used may be in the form of aqueous hydrochloric acid or in the form of hydrogen chloride gas or hydrogen chloride dissolved in an organic solvent.
  • the organic solvent used for dissolving hydrogen chloride is preferably selected from the group consisting of ethanol, methanol, isopropyl alcohol, ethyl acetate, diethyl ether, dimethyl ether and acetone.
  • hydrogen chloride gas or hydrogen chloride dissolved in ethyl acetate may be used.
  • Isolation of erlotinib hydrochloride crystalline particles having mean particle size (D 50 ) ranging from about 4 ⁇ m to 15 ⁇ m and 90 volume-% of the particles (D 90 ) ranging from about 14 ⁇ m to 30 ⁇ m from the solution may be carried out by methods usually known in the art such as cooling, partial removal of the solvent from the solution, addition of precipitating solvent or a combination thereof.
  • Erlotinib free base in anhydrous form or in hydrated form may be used to prepare erlotinib hydrochloride crystalline particles having mean particle size (D 50 ) ranging from about 4 ⁇ m to 15 ⁇ m and 90 volume-% of the particles (D 90 ) ranging from about 14 ⁇ m to 30 ⁇ m.
  • D 50 mean particle size
  • D 90 volume-% of the particles
  • Hydrated form of erlotinib free base used as starting material can be obtained by the process described in the present invention.
  • crystalline particles means any combination of single crystals, aggregates and agglomerates.
  • P.S.D. particle Size Distribution
  • a pharmaceutical composition comprising erlotinib hydrochloride crystalline polymorph form A characterized by peaks in the powder X-ray diffraction pattern having 20 angle positions at about 5.75, 9.88, 11.40, 18.97, 22.84, 23.65, 24.29, 24.75, 25.56 and 29.37 ⁇ 0.2 degrees by the absence of a peak at about 6.26 ⁇ 0.2 degrees, and one or more pharmaceutically inert excipients.
  • a pharmaceutical composition comprising erlotinib hydrochloride crystalline particles having mean particle size (D 50 ) ranging from about 4 ⁇ m to 15 ⁇ m and 90 volume-% of the particles (D 90 ) ranging from about 14 ⁇ m to 30 ⁇ m, and one or more pharmaceutically inert excipients.
  • Preferable pharmaceutical composition of erlotinib hydrochloride crystalline particles having mean particle size (D 50 ) ranging from about 4 ⁇ m to 15 ⁇ m and 90 volume-% of the particles (D 90 ) ranging from about 14 ⁇ m to 30 ⁇ m is selected from a solid dosage form and a oral suspension.
  • solid dosage form includes conventional solid dosage forms such as tablet, capsule, granules, sachet, and the like.
  • Pharmaceutically inert excipients include all physiologically inert excipients used in the pharmaceutical art of dispensing. Examples include binders, diluents, surfactants, disintegrants, lubricants/glidants, coloring agents, and the like.
  • binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
  • diluents include calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like and mixtures thereof.
  • Surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms. These include polyethoxylated fatty acids and its derivatives, for example, polyethylene glycol 400 distearate, polyethylene glycol-20 dioleate, polyethylene glycol 4-150 mono dilaurate, and polyethylene glycol—20 glyceryl stearate; alcohol—oil transesterification products, for example, polyethylene glycol—6 corn oil; polyglycerized fatty acids, for example, polyglyceryl—6 pentaoleate; propylene glycol fatty acid esters, for example, propylene glycol monocaprylate; mono and diglycerides, for example, glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example, polyethylene glycol—20 sorbitan monooleate and sorbitan monolaurate; polyethylene glyco
  • disintegrants include low-substituted hydroxypropylcellulose (L-HPC), sodium starch glycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium A-type (Ac-di-sol), starch, crystalline cellulose, hydroxypropyl starch, pregelatinized starch, and the like and mixtures thereof.
  • lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like and mixtures thereof.
  • Coloring agents include any FDA approved colors for oral use.
  • FIG. 1 shows a typical x-ray powder diffraction spectrum of hydrate form of erlotinib free base.
  • FIG. 2 shows a Differential Scanning Calorimetry (DSC) thermogram of hydrate form of erlotinib free base.
  • FIG. 3 shows a typical x-ray powder diffraction spectrum of anhydrous erlotinib free base.
  • FIG. 4 shows a Differential Scanning Calorimetry (DSC) thermogram of anhydrous erlotinib free base.
  • FIG. 5 shows a typical x-ray powder diffraction spectrum of erlotinib hydrochloride polymorph form A substantially free of polymorph form B.
  • X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X-ray powder diffractometer having a copper-k ⁇ radiation. Approximately 1 gm of sample was gently flattened on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.03 degrees two-theta per step and a step time of 0.5 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and 35 mA.
  • Erlotinib free base (5 gm, obtained in reference example 3) is dissolved in chloroform (200 ml) at 25-30° C. to form a clear solution and then added diethyl ether (50 ml). To the resulting solution slowly added 15% diethyl ether HCl (5 ml) at 25-30° C. and stirred for 30 minutes at 25-30° C. Filtered the material, washed with a mixture of diethyl ether (10 ml) and chloroform (10 ml), and then dried at 60-65° C.
  • Anhydrous erlotinib free base (33 gm, moisture content: 0.1%) is suspended in water (200 ml) at 25-30° C. (clear solution is not observed) and then stirred for 2 hours at 25-30° C. Filtered the material, washed with water (150 ml) and then dried the material at 50-55° C. to give 32 gm of crystalline erlotinib hydrate (HPLC Purity: 99.3%, Moisture Content: 4.23%).
  • Anhydrous erlotinib free base (100 gm, moisture content: 0.2%) is added to methanol at 25-30° C., the contents are heated to 50-55° C. to form a clear solution and then stirred for 30 minutes at 50-55° C.
  • To the solution slowly added 1200 ml of water during 1 hour at 50-55° C., the resulting mass is slowly cooled to 25-30° C. and then stirred for 1 hour at 25-30° C. Filtered the material, washed with the mixture (1:1) of methanol and water (100 ml) and then dried the material at 60° C. to give 90 gm of crystalline erlotinib hydrate (HPLC Purity: 99.2%, Moisture Content: 4.39%).
  • Crystalline erlotinib hydrate (10 gm, Moisture Content: 4.23%) is added to isoamyl alcohol (300 ml) under stirring at 25-30° C., heated to 80° C. to form a clear solution and stirred for 30 minutes at 78-80° C. The solution is slowly cooled to 25-30° C. and then stirred for 30 minutes. Filtered the material, washed with isoamyl alcohol (20 ml) and then dried to give 9 gm of erlotinib hydrate (HPLC Purity: 99.4%, Moisture Content: 4.03%).
  • Crystalline erlotinib hydrate (50 gm, Moisture Content: 4.23%) is added to methanol (250 ml) under stirring at 25-30° C. and heated to reflux to form a 0.20 clear solution.
  • activated carbon (4.5 gm) and stirred for 20 minutes at reflux. Filtered the mass through hyflo bed, washed the bed with hot methanol (80 ml), the filtrate is slowly cooled to 25-30° C. and then stirred for 0.1 hour at 25-30° C. Filtered the material, washed with chilled methanol (50 ml) and then dried to give 43 gm of erlotinib hydrate (HPLC Purity: 99.3%, Moisture Content: 3.98%).
  • Erlotinib free base (10 gm) is added to methyl isobutyl ketone (300 ml) under stirring at 25-30° C., the contents are heated to 60° C. and then stirred at 60-65° C. to form a clear solution.
  • To the solution slowly added 7% ethyl acetate HCl (40 ml) at 60-65° C., the resulting mass is slowly cooled to 25-30° C. and then stirred for 1 hour. Filtered the mass, washed with methyl isobutyl ketone (20 ml) and then dried at 50-55° C. to give 9.8 gm of erlotinib hydrochloride crystalline polymorph form A having polymorph form B undetected (HPLC Purity: 99.87%, Moisture Content: 0.2%).
  • Erlotinib free base (10 gm) is added to isopropyl acetate (400 ml) under stirring at 25-30° C., the contents are heated to 60° C. and then stirred at 60-65° C. to form a clear solution.
  • To the solution slowly added 7% ethyl acetate HCl (40 ml) at 60-65° C. and stirred for 2 hours at 60-65° C.
  • the resulting mass is slowly cooled to 25-30° C. and then stirred for 1 hour. Filtered the mass, washed with the mixture of isopropyl acetate (40 ml) and ethyl acetate (4 ml) and then dried at 50-55° C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US11/994,599 2007-08-17 2007-08-17 Novel hydrated form of erlotinib free base and a process for preparation of erlotinib hydrochloride polymorph form a substantially free of polymorph form b Abandoned US20100136116A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US13/221,986 US8471012B2 (en) 2007-08-17 2011-08-31 Hydrated form of erlotinib free base and a process for preparation of erlotinib hydrochloride polymorph form a substantially free of polymorph form B
US13/900,647 US8669265B2 (en) 2007-08-17 2013-05-23 Hydrated form of erlotinib free base and a process for preparation of erlotinib hydrochloride polymorph form a substantially free of polymorph form B

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2007/000351 WO2009024989A2 (fr) 2007-08-17 2007-08-17 Nouvelle forme hydratée de base libre d'erlotinib et procédé de préparation de la forme polymorphe a de chlorhydrate d'erlotinib sensiblement exempte de la forme polymorphe b

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2007/000351 A-371-Of-International WO2009024989A2 (fr) 2007-08-17 2007-08-17 Nouvelle forme hydratée de base libre d'erlotinib et procédé de préparation de la forme polymorphe a de chlorhydrate d'erlotinib sensiblement exempte de la forme polymorphe b

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/221,986 Division US8471012B2 (en) 2007-08-17 2011-08-31 Hydrated form of erlotinib free base and a process for preparation of erlotinib hydrochloride polymorph form a substantially free of polymorph form B

Publications (1)

Publication Number Publication Date
US20100136116A1 true US20100136116A1 (en) 2010-06-03

Family

ID=40378797

Family Applications (3)

Application Number Title Priority Date Filing Date
US11/994,599 Abandoned US20100136116A1 (en) 2007-08-17 2007-08-17 Novel hydrated form of erlotinib free base and a process for preparation of erlotinib hydrochloride polymorph form a substantially free of polymorph form b
US13/221,986 Expired - Fee Related US8471012B2 (en) 2007-08-17 2011-08-31 Hydrated form of erlotinib free base and a process for preparation of erlotinib hydrochloride polymorph form a substantially free of polymorph form B
US13/900,647 Expired - Fee Related US8669265B2 (en) 2007-08-17 2013-05-23 Hydrated form of erlotinib free base and a process for preparation of erlotinib hydrochloride polymorph form a substantially free of polymorph form B

Family Applications After (2)

Application Number Title Priority Date Filing Date
US13/221,986 Expired - Fee Related US8471012B2 (en) 2007-08-17 2011-08-31 Hydrated form of erlotinib free base and a process for preparation of erlotinib hydrochloride polymorph form a substantially free of polymorph form B
US13/900,647 Expired - Fee Related US8669265B2 (en) 2007-08-17 2013-05-23 Hydrated form of erlotinib free base and a process for preparation of erlotinib hydrochloride polymorph form a substantially free of polymorph form B

Country Status (3)

Country Link
US (3) US20100136116A1 (fr)
EP (3) EP2218713A1 (fr)
WO (1) WO2009024989A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120302749A1 (en) * 2009-11-12 2012-11-29 Ranbaxy Laboratories Limited Processes for the preparation of erlotinib hydrochloride form a and erlotinib hydrochloride form b

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2376495A4 (fr) 2008-12-08 2012-10-31 Vm Pharma Llc Compositions d'inhibiteurs de tyrosine kinase de récepteur protéique
CN102438995B (zh) 2009-03-26 2014-12-17 兰贝克赛实验室有限公司 厄洛替尼或其药学上可接受的盐的制备工艺
WO2012028861A1 (fr) * 2010-07-23 2012-03-08 Generics [Uk] Limited Erlotinib pur
CN101914068A (zh) * 2010-08-14 2010-12-15 浙江华海药业股份有限公司 一种厄洛替尼碱的新晶型及其制备方法
CN103420924B (zh) * 2012-05-25 2016-08-31 浙江九洲药业股份有限公司 一种盐酸埃罗替尼晶型a的制备方法
NZ630289A (en) 2012-09-04 2016-08-26 Shilpa Medicare Ltd Crystalline erlotinib hydrochloride process
WO2014118112A1 (fr) * 2013-01-29 2014-08-07 Synthon B.V. Composition pharmaceutique comprenant du chlorhydrate d'erlotinib
WO2014118737A1 (fr) 2013-01-31 2014-08-07 Ranbaxy Laboratories Limited Sels d'erlotinib
WO2014136126A2 (fr) * 2013-03-08 2014-09-12 Laurus Labs Private Limited Procédé pour la préparation de forme a du chlorhydrate d'erlotinib
US8999992B2 (en) 2013-03-15 2015-04-07 Vm Pharma Llc Crystalline forms of tryosine kinase inhibitors and their salts
CN104138380B (zh) * 2013-05-09 2018-07-13 江苏豪森药业集团有限公司 厄洛替尼或其可药用盐的组合物及其制备方法和用途
WO2015169932A1 (fr) 2014-05-07 2015-11-12 Pharos Generics Ltd Pureté polymorphe, surveillance et compositions associées
KR101592258B1 (ko) 2014-06-20 2016-02-05 보령제약 주식회사 제제 및 이의 제조방법
CN104230825B (zh) * 2014-09-03 2016-07-06 山东金城医药股份有限公司 厄洛替尼碱一水合物晶型FormⅠ的制备方法
US10301271B2 (en) 2014-09-17 2019-05-28 Purdue Pharma L.P. Crystalline forms of tyrosine kinase inhibitors and their salts

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5747498A (en) * 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
US20040162300A1 (en) * 2003-02-17 2004-08-19 Bubendorf Andre Gerard Novel [6,7-Bis(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)amine hydrochloride polymorph
US20060154941A1 (en) * 2005-01-12 2006-07-13 Mai De Ltd. Novel amorphous form of erlotinib hydrochloride and its solid amorphous dispersion

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ298230B6 (cs) 1998-04-29 2007-08-01 Osi Pharmaceuticals, Inc. Anhydrát a monohydrát N-(3-ethinylfenyl)-6,7-bis(2-methoxyethoxy)-4-chinazolinamin mesylátu
UA74803C2 (uk) 1999-11-11 2006-02-15 Осі Фармасьютікалз, Інк. Стійкий поліморф гідрохлориду n-(3-етинілфеніл)-6,7-біс(2-метоксіетокси)-4-хіназолінаміну, спосіб його одержання (варіанти) та фармацевтичне застосування
WO2006110811A1 (fr) * 2005-04-12 2006-10-19 Elan Pharma International Limited Formules de nanoparticules de derives de quinazoline
WO2007056244A2 (fr) * 2005-11-04 2007-05-18 Merck & Co., Inc. Procedes d'utilisation de saha et d'erlotinibe aux fins de traitement du cancer
WO2007060691A2 (fr) * 2005-11-23 2007-05-31 Natco Pharma Limited Nouveau procede pour la preparation d'erlotinib
EP2436381A1 (fr) * 2006-06-27 2012-04-04 Sandoz AG Cristallisation d'hydrohalogénures de composés pharmaceutiques
EP2054393A1 (fr) 2006-07-28 2009-05-06 Synthon B.V. Forme cristalline d'erlobtinib
US8372856B2 (en) * 2006-10-27 2013-02-12 Synthon Bv Hydrates of erlotinib hydrochloride

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5747498A (en) * 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
US20040162300A1 (en) * 2003-02-17 2004-08-19 Bubendorf Andre Gerard Novel [6,7-Bis(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)amine hydrochloride polymorph
US20060154941A1 (en) * 2005-01-12 2006-07-13 Mai De Ltd. Novel amorphous form of erlotinib hydrochloride and its solid amorphous dispersion

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120302749A1 (en) * 2009-11-12 2012-11-29 Ranbaxy Laboratories Limited Processes for the preparation of erlotinib hydrochloride form a and erlotinib hydrochloride form b

Also Published As

Publication number Publication date
EP2218713A1 (fr) 2010-08-18
US20130252978A1 (en) 2013-09-26
US8669265B2 (en) 2014-03-11
EP2176241A2 (fr) 2010-04-21
EP2213665A1 (fr) 2010-08-04
WO2009024989A3 (fr) 2010-02-18
US20120022256A1 (en) 2012-01-26
WO2009024989A2 (fr) 2009-02-26
US8471012B2 (en) 2013-06-25
EP2176241A4 (fr) 2010-08-04
EP2176241B1 (fr) 2015-12-23

Similar Documents

Publication Publication Date Title
US8471012B2 (en) Hydrated form of erlotinib free base and a process for preparation of erlotinib hydrochloride polymorph form a substantially free of polymorph form B
CN106083714B (zh) N-(4-{[6,7-双(甲基氧基)喹啉-4-基]氧基}苯基)-n′-(4-氟苯基)环丙烷-1,1-二甲酰胺苹果酸盐及其结晶型
US9895377B2 (en) Solid forms of tyrosine kinase inhibitors, process for the preparation and their pharmaceutical composition thereof
US8673912B2 (en) Crystalline Forms on N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]-quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
CN107531678B (zh) Egfr抑制剂及其药学上可接受的盐和多晶型物及其应用
KR20200029633A (ko) C-met 조절제 약제학적 조성물
JP6717947B2 (ja) キナゾリン誘導体の結晶及びその調製方法
US8507010B2 (en) Compositions comprising quinazoline derivatives
EP3919485B1 (fr) Cristaux de dérivés de quinoléine
US20250026773A1 (en) Mono-p-toluenesulfonate of axl kinase inhibitor and crystal form thereof
EP3023421A1 (fr) Formes cristallines de dimaléate d'afatinib
CN110234639A (zh) 替吡法尼的晶型及其制备方法及药物组合物
CN108602774B (zh) 阿立哌唑的新晶型
CN114716410A (zh) 喹啉衍生物的结晶
US20040186112A1 (en) Polymorphic forms of dihydrochloride salts of cetirizine and processes for preparation thereof
CN105732596B (zh) N-[3-氯-4-(3-氟苄氧基)苯基]-6-[5-[[2-(甲亚磺酰基)乙基]氨基]甲基]-2-呋喃基]-4-喹唑啉胺多晶型物及其制备方法
CN111848580B (zh) 含1,2,4-三嗪-3,5-二酮的喹啉类化合物的晶型及其制备方法和应用
JP2022527931A (ja) フロピリミジン化合物の酸付加塩の結晶形
TW201833112A (zh) 化合物的晶型
HK40024130A (en) Malate salt and crystal form thereof
HK1231054A (en) Malate salt of n-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-n'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof
HK1231054A1 (en) Malate salt of n-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-n'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof
HK1231054B (zh) N-(4-{[6,7-雙(甲基氧基)喹啉-4-基]氧基}苯基)-n'-(4-氟苯基)環丙烷-1,1-二甲酰胺蘋果酸鹽及其結晶型
HK1233961A1 (en) C-met modulator pharmaceutical compositions
HK1233961A (en) C-met modulator pharmaceutical compositions

Legal Events

Date Code Title Description
AS Assignment

Owner name: HETERO DRUGS LIMITED,INDIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PARTHASARADHI REDDY, BANDI;RATHNAKAR REDDY, KURA;RAJI REDDY, RAPOLU;AND OTHERS;REEL/FRAME:020367/0286

Effective date: 20080110

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION