WO2015170345A1 - Cocristaux pharmaceutiques de gefitinib - Google Patents

Cocristaux pharmaceutiques de gefitinib Download PDF

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WO2015170345A1
WO2015170345A1 PCT/IN2015/000203 IN2015000203W WO2015170345A1 WO 2015170345 A1 WO2015170345 A1 WO 2015170345A1 IN 2015000203 W IN2015000203 W IN 2015000203W WO 2015170345 A1 WO2015170345 A1 WO 2015170345A1
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gefitinib
acid
crystal
crystals
pharmaceutical
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PCT/IN2015/000203
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English (en)
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Rajesh Ghanshyam Gonnade
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Council Of Scientific & Industrial Research
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • 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

Definitions

  • the present invention relates to pharmaceutical co-crystals of gefitinib with co-crystal former selected from aliphatic dicarboxylic acid and aromatic di and tricarboxylic acids which exhibit better solubility, dissolution rate hence enhanced bioavailability as compared to the pure drug.
  • co-crystal former selected from aliphatic dicarboxylic acid and aromatic di and tricarboxylic acids which exhibit better solubility, dissolution rate hence enhanced bioavailability as compared to the pure drug.
  • present invention relates to a process for the preparation of pharmaceutical co-crystals of gefitinib. More particularly, the present invention relates to pharmaceutical composition of gefitinib and at least one pharmaceutically acceptable carrier.
  • Gefitinib is an anilinoquinazoline (N-(3-chloro-4-fluoro-phenyl)-7-methoxy- 6-(3-morpho!in-4-ylpropoxy) quinazolin-4-amine) with the chemical name 4- Quinazolinamine, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-4-mo holin) propoxy]. It has the molecular formula C 22 H24C1FN403, a relative molecular mass of 446.9 and is a white-colored powder. Gefitinib is a free base.
  • Gefitinib can be defined as sparingly soluble at pH 1, but is practically insoluble above pH 7, with the solubility dropping sharply between pH 4 and pH 6.
  • Gefitinib is freely soluble in glacial acetic acid and dimethylsulphoxide, soluble in pyridine, sparingly soluble in tetrahydrofuran, and slightly soluble in methanol, ethanol (99.5%), ethyl acetate, propan-2-ol and Acetonitrile.
  • Gefitinib is an anticancer drug commonly used for the treatment of non- small-cell lung and breast cancer.
  • Gefitinib acts as an inhibitor of mutated or overactive epidermal growth factor receptor (EGFR) by binding to the ATP binding site. Because epidermal growth factors are responsible for controlling cell growth and proliferation, a mutated form would likely facilitate cancer growth and development.
  • EGFR inhibitor gefitinib was approved by Food and Drug Administration as third-line therapy for non-small-cell lung cancer.
  • Gefitinib was active against non-small-cell lung cancer across a broad range of doses, and in randomized phase II trials, response rate of 9% to 19% were reported with the use of doses of 250 or 500 mg per day.
  • Gefitinib is sparingly soluble in aqueous solution (0.027 mg/mL).
  • Gefitinib is a selective epidermal growth factor receptor (EGFR)-tyrosin kinase inhibitor.
  • EGFR epidermal growth factor receptor
  • Many titles in the literature refer to Gefitinib as a "specific" or "selective" inhibitor of EGFR.
  • Gefitinib binds at the ATP site of the T (tyrosine Kinase) region, a region that is highly conserved across the various transmembrane TKs.
  • Co-crystals have attracted phenomenal interest in recent years for their potential for improving the physicochemical properties of drug substances. Apart from offering potential improvements in solubility, dissolution rate, bioavailability and physical stability, pharmaceutical co-crystals can enhance other essential properties of the APIs such as flowability, chemical stability, compressability and hygroscopicity.
  • Co-crystals are homogeneous solid phases containing two or more neutral molecular components in a crystal lattice with defined stoichiometry, which are solids at room temperature and are held together by weak interactions, mainly hydrogen bonding. In co-crystals at least one component is molecular and a solid at room temperature i.e.
  • API in pharmaceutical compositions can exist in variety of distinct solid forms and each form exhibit unique physiochemical properties such as morphology, hygroscopicity and more significantly the solubility.
  • the desirable molecular pharmacological properties of some of the potentially useful drug compound could not be utilized to its maximum potential because the physical properties of the bulk compound show unfavorable bioavailability, unwanted processing characteristics, and unacceptable shelf life. Therefore, the active pharmaceutical ingredients (API) in pharmaceutical compositions can be prepared in a variety of different chemical forms to address these issues.
  • the current methods of altering the solid state properties of API include exploitation of polymorphs, salts, hydrates, and solvates.
  • the crystalline polymorphs typically have different solubility from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph.
  • Pharmaceutical co-crystals can also differ in properties such as shelf-life, bioavailability, morphology, vapor pressure, density, color, and compressibility. Accordingly, variation of the crystalline state of an API is one of many ways in which to modulate the physical properties thereof.
  • New forms of APIs having improved properties such as increased aqueous solubility and stability in oral formulations is always preferred. It is also advantageous to improve the processability and crystallization of formulation so as to avoid obtaining the needle shaped crystals which causes aggregation and thus affects the compression properties and poses difficulties in tablet making. It is also desirable to increase the dissolution rate of API- in aqueous solution which eventually increases its bioavailability and thus provide a more rapid onset to therapeutic effect.
  • the new co- crystalline forms of APIs can be obtained as free acid, free base, zwitterions, salts, etc. which improve the properties of APIs as compared to such APIs in a non-co-crystalline state.
  • PCT Publication no. 2003072108 discloses certain crystalline solvates and hydrates of gefitinib.
  • the invention discloses a first solvate that occurs in the presence of methanol which is designated as Form 2 ZD 1839 MeOH solvate, a second solvate that occurs in the presence of dimethyl sulphoxide which is designated as Form 3 ZD1839 DMSO solvate and a trihydrate that occurs in the presence of water which is designated Form 5 ZD 1839 trihydrate.
  • US patent application no. 20050209229 concerns a first solvate that occurs in the presence of methanol which is designated as Form 2 ZD 1839 MeOH solvate, a second solvate that occurs in the presence of dimethyl sulphoxide which is designated as Form 3 ZD 1839 DMSO solvate and a trihydrate that occurs in the presence of water which is designated Form 5 ZD 1839 trihydrate.
  • PCT Publication no. 2006090413 discloses a stable novel crystalline form of Gefitinib designated as Form-6, and a process for the preparation of the same.
  • the invention further discloses a pharmaceutical composition useful for anti-cancer activity comprising the novel stable crystalline Form-6 of Gefitinib and a pharmaceutically acceptable carrier.
  • US patent application no. 2010031 1701 discloses a co-crystal of an API and a co-crystal former; wherein the API has at least one functional group selected from ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, imine, thiocyanate, cyanamide, oxime, nitrile diazo, organohalide, nitro, S-heterocyclic ring, thiophene, N-heterocyclic ring, pyrrole, O-heterocyclic ring, furan, epoxide, peroxide, hydroxamic acid
  • PCT Publication no. 2014016848 discloses solid forms of tyrosine kinase inhibitors, in particular combinations of tyrosine kinase inhibitors with anti-oxidative acids, wherein the kinase inhibitor is imatinib, gefitinib, erlotinib, sorafenib, nilotinib, dasatinib, lapatinib, or sunitinib and the antioxidative acid is a benzoic acid derivative selected from p-hydroxy benzoic acid, vanillic acid, syringic acid, or 3,4-dihydroxy benzoic acid and cinnamic acid derivative is selected from p-coumaric acid, ferulic acid, sinapic acid, or caffeic acid.
  • the kinase inhibitor is imatinib, gefitinib, erlotinib, sorafenib, nilotinib, dasatinib, lapatini
  • the invention also particularly describes a solid form comprising gefitinib and caffeic acid, or gefitinib and p-coumaric acid, or gefitinib and ferulic acid, wherein the solid form is a salt, a co-crystal, or a polymorph of a salt or of a co-crystal.
  • the main objective of the present invention is to provide pharmaceutical co- crystals of gefitinib which exhibit better solubility, dissolution rate hence enhanced bioavailability and processes for their preparation.
  • Another objective of present invention is to provide co-crystals of gefitinib with co-crystals coformers selected from aliphatic dicarboxylic acid and aromatic di and tri carboxylic acid to enhance the aqueous solubility of the API so as to increase the dissolution and hence affecting its bioavailability so that it is easily absorbed as a medication in the systemic circulation.
  • Yet another objective of present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising pharmaceutical co-crystals of gefitinib and at least one pharmaceutically acceptable carrier.
  • present invention provides a pharmaceutical co- crystals of gefitinib comprising gefitinib and co-crystal formers selected from aliphatic dicarboxylic acid and aromatic di and tricarboxylic acids in stoichiometric ratio in the ratio ranging between 1 :0.5 to 1 :3, characterized in that solubility and dissolution of co- crystals is enhanced.
  • aliphatic dicarboxylic acid and aromatic di and tricarboxylic acids are selected from oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, citric acid, terephthalic acid, benzoic acid and its derivatives such as /?-amino benzoic acid and 7-chloro benzoic acid and the like.
  • said cocrystals are useful in the treatment of cancer.
  • the pharmaceutical co-crystal of gefitinib as claimed in claim 1, wherein the co-crystal of gefitinib may prepared by various co-crystallization techniques like solution crystallization, dry grinding, and liquid-assisted grinding.
  • the solution crystallization and liquid-assisted grinding are done by the solvent selected from polar organic solvent either alone or in aqueous mixture thereof, preferably the polar protic or aprotic solvents include lower alcohols, nitromethane, acetone, acetonitrile, ethyl acetate, dichloromethane, dimethylformamide and the like.
  • present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising pharmaceutical co-crystals of gefitinib as claimed in claim 1 with one or more pharmaceutically acceptable carriers.
  • said composition is useful in the treatment of cancer.
  • said co-crystal is composed of gefitinib and oxalic acid having characteristic peaks in X-ray powder diffraction pattern at 5.2, 8.0, 9.9, 18.25 and 26.4.
  • said co-crystal is composed of gefitinib and malonic acid having characteristic peaks in X-ray powder diffraction pattern at 8.6, 16.4, 20.2, 25.5, 37.0 and 42.2.
  • said co-crystal is composed of gefitinib and succinic acid having characteristic peaks in X-ray powder diffraction pattern for G-SAl at 6.4, 9.4, 20.0, 22.2, 26.0, 27.4, 28.5 and for G-SA2 at 5.7, 8.8, 12.3, 15.0, 17.7, 21.3, 22.6, 26.3, 28.4.
  • said co-crystal is composed of gefitinib and glutaric acid having characteristic peaks in X-ray powder diffraction pattern at 5.3, 1 1.6, 21.8, 26.6.
  • said co-crystal is composed of gefitinib and adipic acid having characteristic peaks in X-ray powder diffraction pattern for G-AA1 at 5.7, 10.3, 12.2, 20.0, 23.5, 26.3, for G-AA2 at 5.7, 10.4, 17.8, 20.2, 23.4, 26.1 and for G-AA3 at 4.8, 5.9, 1 1.1, 15.7, 17.8, 20.6, 23.8, 25.6, 26.3.
  • said co-crystal is composed of gefitinib and fumaric acid having characteristic peaks in X-ray powder diffraction pattern at 4.0, 7.2, 16.1, 19.5, 23.0, 24.4, 26.8 and 29.0.
  • said co-crystal is composed of gefitinib and citric acid having characteristic peaks in X-ray powder diffraction pattern at 5.4, 9.4, 10.7, 13.8, 20.2, 23.9, 27.2
  • said co-crystal is composed of gefitinib and terephthalic acid having characteristic peaks in X-ray powder diffraction pattern for TA1 at 5.7, 17.4, 20.6, 23.1, 26.3, 29.0, 30.6.
  • said co-crystal is composed of gefitinib and benzoic acid which exhibits characteristic DSC endothermic peak at l54.13°C.
  • said co-crystal is composed of gefitinib and p-amino benzoic acid having characteristic peaks in X-ray powder diffraction pattern at 4.8, 21.6, 22.5, 23.5, 26.4 and 30.8.
  • said co-crystal is composed of gefitinib and p-chloro benzoic acid having characteristic peaks in X-ray powder diffraction pattern at 4.66, 15.58, 16.72, 20.5, 25.94.
  • Figure 1 The ORTEPs of cocrystals (a) pure gefitinib anhydrous Form I crystals, (b) gefitinib- oxalic acid cocrystals (1 : 1), with two molecules of water (solvent system: isopropanol-water mixture, 1 :1 , v/v), (c) gefitinib-malonic acid cocrystals (1 : 1) (solvent system: n-Butanol), (d) gefitinib-succinic acid cocrystals (1 : 1) with two molecules of water (solvent system: acetonitrile), (e) gefitinib- succinic acid cocrystals (1 :2) (solvent system: nitromethane), (f) gefitinib-glutaric acid cocrystals (1 :1) with two molecules of water (solvent system: ethanol-water (1 :1, v/v), (g) gefitinib-adipic
  • Figure 2 The collected DSC thermogram of (a) pure gefitinib anhydrous Form I crystals, (b) gefitinib-oxalic acid cocrystals (1 :1), with two molecules of water (solvent system: isopropanol-water mixture, 1 :1 , v/v), (c) gefitinib-malonic acid cocrystals (1 :1) (solvent system: n-Butanol), (d) gefitinib-succinic acid cocrystals (1 :1) with two molecules of water (solvent system: acetonitrile), (e) gefitinib-succinic acid cocrystals (1 :2) (solvent system: nitromethane), (f) gefitinib-glutaric acid cocrystals (1 :1) with two molecules of water (solvent system: ethanol-water (1 :1, v/v), (g) gefitinib-adipic acid cocrystals (1
  • Figure 3 The collected thermogravemetric analysis of (a) pure gefitinib anhydrous Form I crystals, (b) gefitinib-oxalic acid cocrystals(l: l), with two molecules of water (solvent system: isopropanol-water mixture, 1 :1, v/v), (c) gefitinib-malonic acid cocrystals (1:1) (solvent system: n-Butanol), (d) gefitinib-succinic acid cocrystals (1 : 1) with two molecules of water (solvent system: acetonitrile), (e) gefitinib-succinic acid cocrystals (1 :2) (solvent system: nitromethane), (f) gefitinib-glutaric acid cocrystals (1 : 1) with two molecules of water (solvent system: ethanol-water, 1 :1, v/v), (g) gefitinib-adipic acid cocrystals (1
  • Figure 4 The collected PXRD patterns of gefitinib and cocrystals of gefitinib, (a) pure gefitinib anhydrous Form I crystals (b) gefitinib- oxalic acid cocrystals (1:1), with two molecules of water (solvent system: isopropanol-water mixture, 1:1, v/v), (c) gefitinib-malonic acid cocrystals (1:1) (solvent system: n- Butanol), (d) gefitinib-succinic acid cocrystals (1:1) with two molecules of water (solvent system: acetonitrile), (e) gefitinib- succinic acid cocrystals (1:2) (solvent system: nitromethane), (f) gefitinib-glutaric acid cocrystals (1:1) with two molecules of water (solvent system: ethanol-water, 1:1, v/v), (g) gefitinib-
  • Figure 5 The dissolution study of gefitinib (black) and cocrystals of gefitinib with various cocrystals former such as G-OA, G-MA G-SA], G-SA 2j G-FA, G-GA, GAALGAAZ.GAAJ.G-CA, G-TAI, G-J3ABA.
  • Present invention provides pharmaceutical co-crystals of gefitinib which exhibit better solubility, dissolution rate hence enhanced bioavailability as compared to parent drug.
  • the present invention provides pharmaceutical co-crystals of gefitinib with co-crystals coformers selected from aliphatic dicarboxylic acid and aromatic di and tri carboxylic acid in various compositions.
  • the pharmaceutical co-crystal of gefitinib may be prepared by various co- crystallization techniques like solution crystallization, dry grinding, and liquid-assisted grinding and solvent for solution crystallization and liquid assisted grinding is selected from polar organic solvent either alone or in aqueous mixture thereof, preferably the polar protic or aprotic solvents include lower alcohols, nitromethane, acetone, acetonitrile, ethyl acetate, DCM, DMF and the like.
  • the ratio of gefitinib to coformers may be stoichiometric or non- stoichiometric according to the present invention.
  • the ratio of gefitinib to co-crystal formers is in the range of 1 :0.5 to 1 :3.
  • the ratio is in the range of 1 :0.5 to 1 :2, Most preferably the ratio is 1 : 1.
  • the present invention provides a controlled process for the synthesis of gefitinib cocrystals with various coformers selected from aliphatic and aromatic dicarboxylic and tricarboxylic acid in various compositions.
  • the processes for preparation include various co-crystallization techniques like solution crystallization, dry grinding, and liquid-assisted grinding.
  • the process for preparation comprises: i. providing a grinded mixture of amorphous gefitinib and a coformer in stoichiometric ratio in suitable solvent until complete dissolution and;
  • the solvent for solution crystallization and liquid assisted grinding is selected from polar organic solvent either alone or in aqueous mixture thereof.
  • the polar protic or aprotic solvents include lower alcohols, nitromethane, acetone, acetonitrile, ethyl acetate, DCM, DMF and the like.
  • novel co-crystals of gefitinib prepared by the process of instant invention are characterized by single crystal X-ray crystallography which is summarized below in Table 1 ; melting point, DSC analysis and TGA .
  • the pharmaceutical co-crystal of gefitinib and succinic acid showing characteristic peaks in X-ray powder diffraction pattern for G-SA1 at 6.4, 9.4, 20.0, 22.2, 26.0, 27.4, 28.5 and for G-SA2 at 5.7, 8.8, 12.3, 15.0, 17.7, 21.3, 22.6, 26.3, 28.4.
  • the pharmaceutical co-crystal of gefitinib glutaric acid showing characteristic peaks in X-ray powder diffraction pattern at 5.3, 1 1.6, 21.8, 26.6.
  • the pharmaceutical co-crystal of gefitinib and adipic acid showing characteristic peaks in X-ray powder diffraction pattern for G-AAl at 5.7, 10.3, 12.2, 20.0, 23.5, 26.3, for G-AA2 at 5.7, 10.4, 17.8, 20.2, 23.4, 26.1 and for G-AA3 at 4.8, 5.9, 1 1.1 , 15.7, 17.8, 20.6, 23.8, 25.6, 26.3.
  • the pharmaceutical co-crystal of gefitinib and fumaric acid showing characteristic peaks in X-ray powder diffraction pattern at 4.0, 7.2, 16.1 , 19.5, 23.0, 24.4, 26.8 and 29.0.
  • the pharmaceutical co-crystal of gefitinib and citric acid showing characteristic peaks in X- ray powder diffraction pattern at 5.4, 9.4, 10.7, 13.8, 20.2, 23.9, 27.2.
  • the pharmaceutical co-crystal of gefitinib and terephthalic acid showing characteristic peaks in X-ray powder diffraction pattern for TA1 at 5.7, 17.4, 20.6, 23.1 , 26.3, 29.0, 30.6.
  • the pharmaceutical co-crystal of gefitinib and p-amino benzoic acid showing characteristic peaks in X-ray powder diffraction pattern at 4.8, 21.6, 22.5, 23.5, 26.4 and 30.8.
  • the pharmaceutical co-crystal of gefitinib and p-chloro benzoic acid having characteristic peaks in X-ray powder diffraction pattern at 4.66, 15.58, 16.72, 20.5, 25.94
  • the present invention provides a pharmaceutical composition comprising therapeutically effective amount of co crystals of gefitinib prepared by the processes of the present invention.
  • the pharmaceutical composition comprising a therapeutically effective amount of gefitinib with any one of the co-crystal former as mentioned above along with one or more suitable pharmaceutically acceptable carriers/excipients.
  • the pharmaceutical composition of the invention may be any pharmaceutical form which contains the co-crystals of the invention.
  • the pharmaceutical composition may be solid form such as tablets, powders, capsule, liquid suspension or an injectable composition along with any suitable carrier well known in the prior art.
  • the dosage forms can also be prepared as sustained, controlled, modified and immediate release dosage forms. Suitable excipients and the amounts to use may be radially determined by the standard procedures and reference works in the field, e.g. the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents, disintegrants, etc.
  • the present invention provides comparative solubility and dissolution studies of gefitinib (Form I) and pharmaceutical co-crystals of gefitinib.
  • gefitinib co-crystals with oxalic acid G-OA
  • malonic acid G-MA
  • succinic acid G-SA-1, G-SA-2
  • glutaric acid G- GA
  • adipic acid G-AA-1, G-AA-2, G-AA-3
  • fumaric acid(G-FA) citric acid
  • G-CA terephthalic acid
  • G-TA-1, G-TA-2 benzoic acid
  • G-BA p-amino benzoic acid
  • G-pCBA p-chloro benzoic acid
  • the DSC curve for form I crystals (known anhydrous form) of gefitinib showed onl a single sharp endothermic peak centered at 1.94.2°C corresponding to its melting point (Fig. 2a).
  • the DSC thermo gram of all the co-crystals of gefitinib with oxalic acid, malonie acid, succinic acid, glutaric acid, adipic acid, fumarle acid, citric acid, .terepH ' thalic acid, benzoic acid and its derivatives revealed small phase transition endothermic peak followed by sharp endothemiic peak attributed to its melting.
  • the DSC thermo gram of gefitinib oxalic acid co-crystal (G- QA, Fig.
  • gefitinib-adipic acid co-crystal 130.87°C followed fey endotherm at 185.88°C corresponding to the melting point of the gefitinib- adipic acid co-crystal.
  • the DS.C thermogram of gefitinib-adipic acid co-crystal (G-AA-. 2, Fig. 2h) reveals the phase transition peak centred at 1.37. °C followed endotherm at I 57.32°C, corresponding to the melting point of the gefitinib-adipic acid co-crystal.
  • the DSC thermogram of gefitinib-adipic acid co-crystal (G-AA-3, Fig, 2i) reveals the phase transition peaks centred at 104.75, 123.25°C respectively followed a endotherm at 207.61°C corresponding to the it's melting.
  • the DSC thermogram of gefitinib-fumaric acid co-crystal (G-FA, Fig. 2j) reveals the phase transition peaks centred at 126.17,195.73°C respectively followed a endotherm at 237.95°C corresponding to the melting point of the gefitinib-fumaric acid co-crystal.
  • the DSC thermogram of gefitinib citric acid co-crystal (G-CA, Fig. 2k) reveals the phase transition peaks centered at 144.34°C followed a small endotherm at 193.84°C corresponding to the melting point of the gefitinib citric acid co-crystal.
  • the DSC thermogram of gefitinib-terephthalic acid co-crystal (G-TA-l,Fig. 21) reveals the phase transition peaks centered at 136.18°C and 170.43°C respectively followed by a endotherm at 230.13°C corresponding to its melting point.
  • the DSC thermogram of gefitinib-benzoic acid co-crystals (G-BA, Fig.
  • the melting point of gefitinib and all the co-crystals of gefitinib was determined on a Buchi melting point apparatus.
  • the melting point of gefitinib form I (Known anhydrous form) was found to be 193-195°C and co-crystals of gefitinib with oxalic acid (G-OA) was found to be 247-250°C, while the melting point of co-crystal of gefitinib-malonic acid (G-MA), was found to be 173-176°C.
  • the co- crystal of gefitinib-adipic acid co-crystal crystallized from Ethanol water mixture (G- AA-1), n-ButanoI (G-SA-2) and Nitrobenzene (G-SA-3) were found to be 184-186°C, 156-158°C and 206-208°C respectively, and the co-crystal of gefitinib-Fumaric acid (G- FA) were found to be 237-238°C.
  • the melting point of gefitinib citric acid co-crystals (G-CA) was found to be 190-194°C.
  • thermogravimetric analysis of gefitinib and all the cocrystals of gefitinib with malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid were carried out at TA Q10 apparatus.
  • novel crystalline co-crystals of gefitinib are obtained with various cocrystal former such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, citric acid, terephthalic acid, benzoic acid and its derivatives by various co-crystallization techniques like solution crystallization, dry grinding, and liquid-assisted grinding (solvent drop grinding using few drops of ethanol). Both polar organic solvents as well as mixture of solvent comprising aqueous solution with organic solvents were used for the cocrystal synthesis.
  • cocrystal former such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, citric acid, terephthalic acid, benzoic acid and its derivatives by various co-crystallization techniques like solution crystallization, dry grinding, and liquid-assisted grinding (solvent drop grinding using few drops of ethanol).
  • EXAMPLE 1 CO-CRYSTALS WITH OXALIC ACID (G-OA)
  • amorphous gefitinib and oxalic acid 28.20 mg was taken in 1 : 1 stoichiometric molar ratio, and both components were grinded with the help of mortar and pestle. Both dry grinding and liquid-assisted grinding (with few drops of absolute ethanol, also known as solvent drop grinding, SDG) was employed for the cocrystal synthesis. The grinded material was then transferred to round bottom flask and dissolved in 10-15 mL of isopropanol and water mixture (1 : 1, v/v). The resulting mixture was stirred at 50-60°C for 30 min to dissolve the solute.
  • SDG solvent drop grinding
  • amorphous gefitinib and succinic acid (26.42 mg) was taken in 1 :1 stoichiometric molar ratio and both components grinded with the help of mortar and pestle. The grinded material was then transferred to round bottom flask and dissolved in 20 mL of acetonitrile. The resulting mixture was stirred at 60-70°C for 30 min to dissolve the compound. The resulting mixture was filtered to remove the traces of undissolved compound and filtrate was kept for crystallization for 24h. Needle type crystals were obtained which were characterized by single crystal X-ray diffraction, powder X-ray diffraction, DSC and TGA techniques. These cocrystals were also produced from acetone as well as from n-propanol.
  • Block type crystals were observed in the crystallization flask which was characterized by single crystal X-ray diffraction, melting point, powder X-ray diffraction, DSC and TGA techniques. These cocrystals were also produced from n-butanol, water, ethyl acetate and nitromethane solvents.
  • Cocrystal lization of gefitinib with adipic acid produced four different cocrystals having different pharmaceutical compositions depending on the solvent of crystallization.
  • Ethanol-water mixture (1 :1 v/v) gave needle (1 :1, gefitinib: adipic acid with two molecules of water), and block (l :l ,gefitinib:adipic acid with ten water molecules and one molecule of ethanol) shaped cocrystals.
  • crystallization from n- butanol produced block types crystals (1 :1, gefitinib: adipic acid with one water molecule).
  • Cocrystallization of gefitinib and terephthalic acid yielded two different cocrystal compositions depending on the solvent of crystallization.
  • Cocrystallization form ethanol-water mixture (1 :1, v/v) gave plate type crystals with 1 :1 ratio of gefitinib and terephthalic acid along with two molecules of water molecule, while crystallization from ethyl acetate produced again plate type crystals however with l :0.5ratio of gefitinib and terephthalic acid which also includes two water molecules.
  • EXAMPLE 10 CO-CRYSTALS WITH P-AMINO BENZOIC ACID (G-PABA)
  • Novel co-crystals of gefitinib have improved bioavailability compared to the other known forms.

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Abstract

L'invention concerne des cocristaux pharmaceutiques de gefitinib, l'agent de formation du cocristal étant choisi parmi un acide dicarboxylique aliphatique et des acides dicarboxyliques et tricarboxyliques aromatiques présentant une meilleure vitesse de solubilité et de dissolution, et donc une meilleure biodisponibilité par rapport au médicament mère.
PCT/IN2015/000203 2014-05-09 2015-05-08 Cocristaux pharmaceutiques de gefitinib WO2015170345A1 (fr)

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US10259805B2 (en) * 2015-12-30 2019-04-16 Synthon B.V. Process for making crystalline form a of gefitinib
CN110128356A (zh) * 2019-06-05 2019-08-16 鲁南制药集团股份有限公司 一种吉非替尼与3-羟基苯甲酸共晶体
CN110156700A (zh) * 2019-06-05 2019-08-23 鲁南制药集团股份有限公司 吉非替尼与水杨酸共晶体
CN111454221A (zh) * 2020-04-21 2020-07-28 华南理工大学 一种吉非替尼和布美他尼药物共晶体及其制备方法
CN113801068A (zh) * 2020-06-15 2021-12-17 鲁南制药集团股份有限公司 一种吉非替尼的有机酸盐
CN113929630A (zh) * 2020-07-13 2022-01-14 鲁南制药集团股份有限公司 一种吉非替尼药物共晶体

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Publication number Priority date Publication date Assignee Title
US10259805B2 (en) * 2015-12-30 2019-04-16 Synthon B.V. Process for making crystalline form a of gefitinib
CN110128356A (zh) * 2019-06-05 2019-08-16 鲁南制药集团股份有限公司 一种吉非替尼与3-羟基苯甲酸共晶体
CN110156700A (zh) * 2019-06-05 2019-08-23 鲁南制药集团股份有限公司 吉非替尼与水杨酸共晶体
CN112047893A (zh) * 2019-06-05 2020-12-08 鲁南制药集团股份有限公司 吉非替尼与水杨酸共晶体
CN112047892A (zh) * 2019-06-05 2020-12-08 鲁南制药集团股份有限公司 一种吉非替尼与3-羟基苯甲酸共晶体
CN112047893B (zh) * 2019-06-05 2023-10-24 鲁南制药集团股份有限公司 吉非替尼与水杨酸共晶体
CN112047892B (zh) * 2019-06-05 2023-10-24 鲁南制药集团股份有限公司 一种吉非替尼与3-羟基苯甲酸共晶体
CN111454221A (zh) * 2020-04-21 2020-07-28 华南理工大学 一种吉非替尼和布美他尼药物共晶体及其制备方法
CN113801068A (zh) * 2020-06-15 2021-12-17 鲁南制药集团股份有限公司 一种吉非替尼的有机酸盐
CN113929630A (zh) * 2020-07-13 2022-01-14 鲁南制药集团股份有限公司 一种吉非替尼药物共晶体
CN113929630B (zh) * 2020-07-13 2024-04-19 山东新时代药业有限公司 一种吉非替尼药物共晶体

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