WO2001014379A2 - Nouvelle forme cristalline de disodium n-[4-[2-(2-amino-4,7-dihydro-4-oxo-3h-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-l- sel d'acide glutamique et procedes de preparation - Google Patents

Nouvelle forme cristalline de disodium n-[4-[2-(2-amino-4,7-dihydro-4-oxo-3h-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-l- sel d'acide glutamique et procedes de preparation Download PDF

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WO2001014379A2
WO2001014379A2 PCT/US2000/020777 US0020777W WO0114379A2 WO 2001014379 A2 WO2001014379 A2 WO 2001014379A2 US 0020777 W US0020777 W US 0020777W WO 0114379 A2 WO0114379 A2 WO 0114379A2
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disodium
ethyl
benzoyl
oxo
acid salt
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PCT/US2000/020777
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WO2001014379A3 (fr
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Erik Christopher Chelius
Linda Marie Osborne
Sharon Van Den Berghe Snorek
Gregory Alan Stephenson
Anne Marie Warner
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Eli Lilly And Company
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Priority to EP00957261A priority patent/EP1212325A2/fr
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Publication of WO2001014379A3 publication Critical patent/WO2001014379A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • 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 present invention relates to the field of pharmaceutical and organic chemistry and provides for a novel crystal form of the multi-targeted antifolate disodium N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L- glutamic acid salt (hereinafter MTA) and processes therefor.
  • MTA multi-targeted antifolate disodium N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L- glutamic acid salt
  • Pyrrolo[2,3-d]pyrimidine based antifolates have been used for a number of years as chemotherapeutic agents in the treatment of cancer.
  • a number of such pyrrolo[2,3-d]pyrimidine based antifolates are known (see: for example, U.S. Patents 4,997,838; 5,106,974; 5,939,420; and 5,877,178, incorporated by reference herein), as are processes for preparing the same (see for example, U.S. Patents 5,416,211, 5,344,932 and 5,539,113, incorporated by reference herein and hereinafter referred to as '211 Patent, '932 Patent, and '113 Patent).
  • the pyrrolo[2,3-d]pyrimidine disodium salt as represented by formula I:
  • MTA is a potent inhibitor of several folate -requiring enzymes, including thymidine synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase. MTA is currently in clinical trials for use as an anticancer treatment in patients exhibiting a wide variety of solid tumors.
  • MTA mass transfer spectrometry
  • the process by which MTA is produced needs to be one that is amenable to large scale production. Additionally, it is desirable that the product should be in a form that is readily filterable and easily dried. Finally, it is economically desirable that the product be stable for extended periods of time without the need for specialized storage conditions.
  • MTA can be prepared in crystalline form.
  • the present invention provides MTA in the new crystalline form designated disodium MTA Hydrate Form I.
  • the present invention provides a process for preparing disodium N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]-pyrimidin-5- yl)ethyl]benzoyl]-L-glutamic acid salt .
  • the process described in the '211 Patent teaches preparing the disodium salt of formula I by treating the acid of formula II with a base (Scheme I).
  • Scheme I There are several disadvantages with this process.
  • the acid of formula ⁇ is highly toxic requiring special handling measures and equipment.
  • isolation of the acid of formula U requires a difficult pH operation and a filtration, which is time-consuming and costly.
  • the disodium salt form of MTA may be prepared by a process which avoids the toxicity problem, a difficult pH operation, and a costly, time-consuming filtration process.
  • the present improved process for making MTA provides a number of advantages, e.g. it avoids the isolation and subsequent dispensing of the acid of formula ⁇ , thus avoiding the problems previously discussed. Also, the amount of solvent used in the present process is reduced by about 30 percent over the process described in Patent '211.
  • the improved process of the present invention for preparing MTA comprises reacting the 5-substituted pyrrolo[2,3-d]pyrimidine intermediate of the formula in with sodium hydroxide and an appropriate solvent according to Scheme ⁇ , where R is a carboxy protecting group.
  • Scheme ⁇ where R is a carboxy protecting group.
  • the present invention provides a novel hydrate crystal form of disodium N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L- glutamic acid salt ("disodium MTA Hydrate Form I”), having a characteristic X-ray diffraction pattern, which comprises the following intensities corresponding to d spacings: 18.66 ⁇ 0.04 and/or 9.33 ⁇ 0.04 when obtained at 22 ⁇ 2°C at ambient % relative humidity from a copper radiation source.
  • the present invention further contemplates a process for preparing a compound of formula I:
  • the invention further provides a method of use of the compound of disodium MTA Hydrate Form I for the manufacture of a medicament for the treatment of cancer.
  • the invention further provides for a process for preparing a medicament comprising combining crystalline disodium N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H- pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid salt in an aqueous solution.
  • the invention further provides for a formulation comprising crystalline disodium N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L- glutamic acid salt in association with a pharmaceutically acceptable carrier.
  • the invention further provides for a process for the preparation of crystalline disodium N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]-pyrimidin-5- yl)ethyl]benzoyl]-L-glutamic acid salt comprising crystallizing disodium N-[4-[2-(2- amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid salt from an appropriate solvent.
  • the invention further provides for the preparation of disodium MTA Hydrate
  • Form I which comprises adjusting the pH of an aqueous solution of disodium N-[4-[2-(2- amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid salt from about 6.5 to about 9.5 and precipitating disodium MTA Hydrate Form I from the pH adjusted aqueous solution.
  • the invention further provides an article of manufacture comprising packaging material and a composition comprising crystalline disodium N-[4-[2-(2-amino-4,7- dihydro-4-oxo-3H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid salt contained within said packaging material, wherein said crystalline salt is effective in the treatment of cancer and a label which indicates that said crystalline salt can be used in the treatment of cancer.
  • Figure 1 depicts a representative XRD pattern of disodium MTA Hydrate Form I.
  • Figure 2 is a representative solid state NMR spectrum of disodium MTA Hydrate Form I.
  • Figures 3 depicts a representative FT-IR spectra for disodium MTA Hydrate Form I.
  • hydrate as used herein describes the crystalline lattice of disodium N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]-pyrimidin-5- yl)ethyl]benzoyl]-L-glutamic acid salt, which can contain variable amounts of water, from about 0.01 to about 3 equivalents of water, depending upon the relative humidity in the storage conditions.
  • disodium MTA Hydrate Form I contains from about 2 to about 3 equivalents of water, most preferred is 2.4-2.6 equivalents of water.
  • cancer as used herein describes a disease state well known in the art wherein the tumor responds to treatment with an antifolate drug.
  • disease states include, but are not limited to, colorectal, breast, cervical, acute myeloid leukemia (ALM), acute lymphoblastic leukemia (ALL), nonsmall-cell lung cancer, bladder, head and neck, non-Hodgkin's lymphoma, sarcoma, prostate, melanoma, mesothelioma, gastrointestinal tract, stomach, rectal, colorectal, ovarian, pancreatic, lung, hepatoma, malignant fibrous histiocytoma, and oropharyngeal.
  • ALM acute myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • nonsmall-cell lung cancer bladder, head and neck
  • non-Hodgkin's lymphoma sarcoma
  • prostate melanoma
  • mesothelioma mesothelioma
  • an effective amount refers to an amount of a compound or drug, which is capable of performing the intended result.
  • an effective amount of disodium MTA Hydrate Form I that is administered in an effort to reduce tumor growth is that amount which is required to reduce tumor growth.
  • ambient % relative humidity as used herein describes a range of humidity of about 20% to about 50% relative humidity.
  • carboxy protecting group refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound.
  • the species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is labile accessible and is stable to conditions up to its removal and can be removed by the action on sodium hydroxide. See E. Haslam, Protective Groups in Organic Chemistry, J.G.W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T.W. Greene, Protective Groups in Organic Synthesis. John Wiley and Sons, New York, N.Y., 1981, Chapter 5.
  • a related term is "protected carboxy,” which refers to a carboxy-protecting groups.
  • Preferred esters include, straight or branched Ci-C ⁇ alkyl esters, preferably methyl ester or ethyl ester.
  • the compounds of formula HI exist as acid addition salts formed with a wide variety of inorganic and organic acids.
  • the acid salts of the formula HJ can be prepared by methods known in the art, for example, according to the '211 Patent, incorporated by reference herein.
  • Typical acids which can be used include sulfuric, hydrochloric, hydrobromic, phosphoric, hypophosphoric, hydroiodic, sulfamic, citric, acetic, maleic, malic, succinic, tartaric, cinnamic, benzoic, ascorbic, mandelic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, trifluoroacetic, hippuric and the like.
  • the preferred salts are those formed with p-toluenesulfonic acid, hydrochloric acid or acetic acid.
  • the process of Scheme II may be performed by reacting a 5-substituted pyrrolo[2,3-d]pyrimidine acid and formula HI, wherein R is carboxy protecting groups or a salt thereof with sodium hydroxide.
  • At least 2 w/v (g mL) equivalents of sodium hydroxide are needed when using Form II and the salt of Form LLT.
  • the salt of Form HI an additional equivalence of sodium hydroxide is required.
  • Preferably from about 3 to 5 equivalents of the sodium hydroxide is required.
  • about 3 to 10 equivalents are employed, preferably from about 4 to about 6 equivalents. More preferred is from about 3 to about 10 equivalents, most preferably from about 4 to about 7 equivalents are employed.
  • a typical reaction is carried out in the presence of an appropriate solvent.
  • an aqueous solvent is suitable.
  • the process of Scheme II could be carried out under anhydrous conditions, however, water or an aqueous solution is preferable.
  • Such aqueous solutions contain water and a water miscible solvent such as acetone, acetonitrile, dimethyl formamide, ethanol, methanol, isopropanol, and tetrahydrofuran.
  • the process can be can be carried out at ambient or elevated temperatures, preferably maintaining the solution from about 40 to 70°C.
  • a crystalline form can be collected by lypho zation, evaporation and recrystallization
  • the present invention provides a process for the preparation of crystalline disodium N-[4-[2-(2-am ⁇ no-4,7-d ⁇ hydro-4-oxo-3H-pyrrolo[2,3-d]-pynm ⁇ dm-5- yl)ethyl]benzoyl]-L-glutam ⁇ c acid salt which comp ⁇ ses crystallizing MTA from a solution under conditions which yield crystalline disodium N-[4-[2-(2-am ⁇ no-4,7-d ⁇ hydro- 4-oxo-3H-pyrrolo[2,3-d]-py ⁇ m ⁇ d ⁇ n-5-yl)ethyl]benzoyl]-L-glutam ⁇ c acid salt
  • Crystalline disodium N-[4-[2-(2-am ⁇ no-4,7-d ⁇ hydro-4-oxo-3H-pyrrolo[2,3-d]- py ⁇ m ⁇ dm-5-yl)ethyl]benzoyl]-L-glutam ⁇ c acid salt may be prepared by adjusting the pH of an aqueous solution of disodium N-[4-[2-(2-am ⁇ no-4,7-d ⁇ hydro-4-oxo-3H-pyrrolo[2,3- d]-py ⁇ m ⁇ d ⁇ n-5-yl)ethyl]benzoyl]-L-glutam ⁇ c acid salt from about 5 to about 12 and precipitating crystalline disodium N-[4-[2-(2-am ⁇ no-4,7-d ⁇ hydro-4-oxo-3H-pyrrolo[2,3- d]-py ⁇ m ⁇ d ⁇ n-5-yl)ethyl]benzoyl]-L-glutam ⁇ c
  • an aqueous solution is defined as about 1 to about 20, preferably, 3 to about 10 volumes, more preferably from about 4 to about 7 volumes, of water and an approp ⁇ ate solvent
  • solvents include, but are not limited to alcohols, dimethylsulfoxide, acetonitrile, dimethyl formamide, tetrahydrofuran and acetone
  • the temperature of the solution should be maintained at about room temperature to about the boiling point of the solution, preferably from about 60°C to about 70°C.
  • the pH of the solution may be adjusted to the desired pH through the use of acid and base buffers
  • Acid and base buffers are well known to the skilled artisan and are commercially available
  • the methods in which crystals are precipitated from the solution are well known to the skilled artisan and are not c ⁇ tical to the process of the present invention
  • an anti-solvent may be added, the solution may be cooled, or the solution may be seeded.
  • the precise conditions under which crystalline disodium MTA Hydrate Form I is formed may be empirically determined and it is only possible to give a number of methods that have been found to be suitable in practice.
  • the crystalline disodium MTA Hydrate Form I can be prepared by adjusting the pH of an aqueous solution of the disodium MTA salt from about 6.5 to about 9.5, preferably about 7.5 to about 8.5, most preferably about 8.0 and precipitating crystalline disodium MTA Hydrate Form I from the pH adjusted aqueous solution.
  • an aqueous solution is defined as about 1 to about 20, preferably, 3 to about 10 volumes, more preferably from about 4 to about 7 volumes, of water and an approp ⁇ ate solvent.
  • an approp ⁇ ate solvent The skilled artisan will appreciate that numerous solvents may be employed so long as the solvent in conjunction with the water dissolves the disodium MTA salt.
  • the temperature of the solution should be maintained at about room temperature to about the boiling point of the solution, preferably from about 60°C to about 70°C .
  • crystals are precipitated from the solution are well known to the skilled artisan and are not c ⁇ tical to the process of the present invention.
  • an anti-solvent may be added, the solution may be cooled, or the solution may be seeded.
  • additional methods of precipitating crystals see, for example, A.E. Nielsen, Treatise on Analytical Chemistry, 2 nd ed., Part I, vol. 3, Chapter 27, 1983.
  • an anti-solvent such as ethanol, isopropanol, acetonitrile, or acetone, is added to the pH adjusted aqueous solution.
  • the solvents employed in the process of converting the 5-substituted pyrrolo[2,3- d]py ⁇ m ⁇ d ⁇ ne intermediate of the formula HI to MTA include water, which may be combined with a miscible organic solvent such as ethanol, acetonit ⁇ le, acetone, isopropyl alcohol or the like
  • Suitable bases for this same conversion include any inorganic base, such as potassium hydroxide and preferably sodium hydroxide.
  • the salt form of the 5-substituted pyrrolo[2,3-d]py ⁇ m ⁇ d ⁇ ne depends on the base used For example sodium hydroxide with convert the compound of formula HI to the disodium salt, whereas potassium hydroxide will form the dipotassium salt form of the compound of formula EQ.
  • a number of methods are available to characterize crystalline forms of organic compounds. Among these methods are differential scanning calorimetry, solid state NMR spectrometry, infra-red spectroscopy, and x-ray powder diffraction. The x-ray powder diffraction pattern is very useful for distinguishing between different crystalline forms of a compound.
  • the relative intensities of the diffraction peaks may vary due to a number of factors, including the effects of preferred orientation which result from a particular crystal morphology, and particle size. Where the effects of prefe ⁇ ed orientation and/or particle size are present, peak intensities (that is, the I/Io value) are altered, but the characteristic peak positions of the polymorph are unchanged. See, e.g., The United States Pharmacopoeia #23, National Formulary #18, pages 1843-1844, 1995. X-ray powder diffraction analysis can be readily performed as follows.
  • the sample After lightly g ⁇ ndmg the sample with an agate mortar and pestle, the sample is loaded into a sample holder for the x-ray powder diffraction measurement.
  • Disodium MTA Hydrate Form I has a typical XRD pattern with interplanar spacings (d) in Angstroms and typical relative intensities (I/I 0 ) as shown in Table I. The error of measurement is +/- 0.04 A. X-ray peaks with I/Ij of 10% or greater were reported m
  • Disodium MTA Hydrate Form I is characte ⁇ zed by X-ray diffraction pattern which comp ⁇ ses intensities corresponding to the following d spacings: 18.66 and/or 9.33 +/-0.04 A when obtained at 22 ⁇ 2°C and at ambient % relative humidity using a copper radiation source.
  • a properly prepared sample of disodium MTA Hydrate Form I may be characte ⁇ zed as having an X-ray diffraction pattern which comp ⁇ ses peaks co ⁇ esponding to the following d spacings: 18.66, 9.33 and/or 4.92 +/- 0.04 A when obtained at 22 ⁇ 2°C and 31 ⁇ 10% relative humidity from a copper radiation source.
  • disodium MTA Hydrate Form I may also be characterized by solid state NMR spectroscopy.
  • Solid state NMR (l ⁇ C) analysis can be carried out using a Varian Unity 400 MHz spectrometer operating at a carbon frequency of 100.580 MHz, equipped with a complete solids accessory and Varian 7 mm VT CP/MAS probe. Acquisition parameters were as follows: 90° proton r.f. pulse width 4.0 ⁇ s, contact time 1.0 ms, pulse repetition time 5 s, MAS frequency 7.0 kHz, spectral width 50 kHz, and acquisition time 50 ms.
  • Solid state ⁇ C chemical shifts reflect not only the molecular structure of disodium MTA Hydrate Form I, but also the electronic environment of the molecule in the crystal.
  • the diagnostic ⁇ C resonances for disodium MTA Hydrate Form I were processed in D2O and are reported in Table 2.
  • Table 2 Solid State 13 C NMR Data for disodium MTA Hydrate Form I
  • the IR bands are found at 3496 cm “1 , 3434 cm “1 , 3391 cm “1 , 3229 cm “1 , 3071 cm “1 , 3009 cm “1 1623 cm “1 , 1591 cm “1 and 1569 cm “1 and the Raman bands at 3108 cm '1 , 3070 cm “1 , 1612 cm “1 , 675 cm “1 , 677 cm “1 and 1569 cm “1 .
  • the present invention also includes methods employing pharmaceutical formulations which contain, as the active ingredient, disodium MTA Hydrate Form I or a crystalline form of disodium N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]- pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid salt, in association with pharmaceutical carriers.
  • pharmaceutical formulations which contain, as the active ingredient, disodium MTA Hydrate Form I or a crystalline form of disodium N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]- pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid salt, in association with pharmaceutical carriers.
  • a skilled artisan would know of such formulations and their manufacture, see, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES
  • the formulations are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the crystals are effective over a wide dosage range.
  • dosages per day normally fall within the range of about 0.5 to about 30 mg/kg of body weight.
  • the amount of the crystal actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual crystal administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
  • the crystals of the present invention can be administered alone or in the form of a pharmaceutical composition in combination with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the solubility and chemical properties of the compound selected, the chosen route of administration, and standard pharmaceutical practice.
  • the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of the crystal in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art.
  • the carrier or excipient may be a solid, semi-solid, or liquid material, which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art.
  • the pharmaceutical composition may be adapted for oral, inhalation, parenteral, or topical use and may be administered to the patient in the form of tablets, capsules, aerosols, inhalants, suppositories, solution, suspensions, or the like.
  • the crystals of the present invention may be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • the crystals may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
  • These preparations should contain at least 4% of the compound of the present invention, the active ingredient, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit.
  • the amount of the crystal present in compositions is such that a suitable dosage will be obtained.
  • Preferred compositions and preparations according to the present invention may be determined by someone skilled in the art.
  • the tablets, pills, capsules, troches and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, com starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate or orange flavoring.
  • a liquid carrier such as polyethylene glycol or a fatty oil.
  • dosage unit forms may contain other various materials, which modify the physical form of the dosage unit, for example, as coatings.
  • tablets or pills may be coated with sugar, shellac, or other enteric coating agents.
  • a syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
  • the crystals of the present invention may be inco ⁇ orated into a solution or suspension. These preparations should contain at least 0.1% of a crystal of the invention, but may be varied to be between 0.1 and about 50% of the weight thereof.
  • compositions and preparations are able to be determined by one skilled in the art.
  • the crystals of the present invention may also be administered by inhalation, such as by aerosol or dry powder. Delivery may be by a liquefied or compressed gas or by a suitable pump system, which dispenses the compounds of the present invention or a formulation thereof. Formulations for administration by inhalation of compounds of formula (1) may be delivered in single phase, bi-phasic, or tri-phasic systems. A variety of systems are available for the administration by aerosol of the compounds of formula (1). Dry powder formulations are prepared by either pelletizing or milling the compound of formula (1) to a suitable particle size or by admixing the pelletized or milled compound of formula (1) with a suitable carrier material, such as lactose and the like. Delivery by inhalation includes the necessary container, activators, valves, subcontainers, and the like. Preferred aerosol and dry powder formulations for administration by inhalation can be determined by one skilled in the art.
  • the crystals of the present invention may also be administered topically, and when done so the carrier may suitably comprise a solution, ointment or gel base.
  • the base for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.
  • Topical formulations may contain a concentration of the formula (1) or its pharmaceutical salt from about 0.1 to about 10% w/v (weight per unit volume).
  • the solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, such as sodium chloride and mannitol, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials mane of glass or plastic.
  • Active ingredient means either disodium MTA Hydrate Form I or a crystalline form of disodium N-[4-[2-(2-amino-4,7-dihydro-4- oxo-3H-py ⁇ olo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid salt.
  • Quantity Ingredient (mg/capsule)
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • Formulation Example 3 A dry powder inhaler formulation is prepared containing the following components:
  • the active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
  • Formulation Example 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows: Quantity
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpy ⁇ olidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50-60°C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • Capsules each containing 40 mg of medicament are made as follows:
  • Quantity Ingredient (mg/capsule)
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Formulation Example 6 Suppositories, each containing 25 mg of active ingredient are made as follows: Ingredient Amount Active ingredient 25 mg
  • the active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
  • An intravenous formulation may be prepared as follows:
  • a topical formulation may be prepared as follows: Ingredient Quantity Active ingredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20 g
  • Subl gual or buccal tablets each containing 10 mg of active ingredient, may be prepared as follows: Quantity
  • the glycerol, water, sodium citrate, polyvmyl alcohol, and polyvinylpyrro done are admixed together by continuous stir ⁇ ng and maintaining the temperature at about 90°C.
  • the solution is cooled to about 50-55°C and the active ingredient is slowly admixed.
  • the homogenous mixture is poured into forms made of an inert mate ⁇ al to produce a drug-containing diffusion mat ⁇ x having a thickness of about 2-4 mm This diffusion mat ⁇ x is then cut to form individual tablets having the approp ⁇ ate size.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent 5,023,252, issued June 11, 1991, herein inco ⁇ orated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents

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Abstract

L'invention relève du domaine de la chimie pharmaceutique et organique, et concerne un meilleur procédé de préparation de l'antifolique multicible N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]-pyrimidin-5-yl)éthyl]benzoyl]-L-acide glutamique et des cristaux de ce dernier.
PCT/US2000/020777 1999-08-23 2000-08-15 Nouvelle forme cristalline de disodium n-[4-[2-(2-amino-4,7-dihydro-4-oxo-3h-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-l- sel d'acide glutamique et procedes de preparation WO2001014379A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU68908/00A AU6890800A (en) 1999-08-23 2000-08-15 A novel crystalline form of disodium n-[4-[2-(2-amino-4,7-dihydro-4-oxo-3h-pyrrolo[2,3-D]- pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid salt and processes therefor
EP00957261A EP1212325A2 (fr) 1999-08-23 2000-08-15 Nouvelle forme cristalline de disodium n-[4-[2-(2-amino-4,7-dihydro-4-oxo-3h-pyrrolo 2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-l- sel d'acide glutamique et procedes de preparation

Applications Claiming Priority (4)

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US15025499P 1999-08-23 1999-08-23
US60/150,254 1999-08-23
US18496400P 2000-02-25 2000-02-25
US60/184,964 2000-02-25

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WO2008021405A1 (fr) * 2006-08-14 2008-02-21 Sicor Inc. Formes cristallines de diacide de pemetrexed et leurs procédés de préparation
WO2009056029A1 (fr) 2007-10-24 2009-05-07 Chongqing Pharmaceutical Research Institute Co., Ltd. Procédé de purification de sels, sels sodiques et sels dissodiques de pemetrexed
EP2072518A1 (fr) * 2007-12-23 2009-06-24 Sun Pharma Advanced Research Company Limited Forme amorphe stable de Pemextred disodium
EP2129674A2 (fr) * 2007-04-03 2009-12-09 Dr. Reddy's Laboratories Ltd. Formes solides de pemetrexed
WO2010030598A2 (fr) * 2008-09-11 2010-03-18 Dr. Reddy's Laboratories Limited Formulations pharmaceutiques comprenant du pemetrexed
EP2269599A1 (fr) 2004-03-22 2011-01-05 Laboratoires Besins International Compositions stables à base de 4-hydroxy tamoxifène
CN102050825A (zh) * 2009-11-05 2011-05-11 上海希迪制药有限公司 制备培美曲塞二钠2.5水结晶的方法
WO2011064256A1 (fr) 2009-11-24 2011-06-03 Azad Pharmaceutical Ingredients Ag Nouvelle forme cristalline du pemetrexed disodique
EP2334685A2 (fr) * 2008-09-08 2011-06-22 Dr. Reddy's Laboratories, Ltd. Disodium de pemetrexed amorphe
WO2011019986A3 (fr) * 2009-08-13 2011-06-30 Dr. Reddy's Laboratories Ltd. Procédés de préparation du pemetrexed
US7994180B2 (en) 2006-08-14 2011-08-09 Sicor Inc. Processes for preparing intermediates of pemetrexed
WO2012017443A1 (fr) * 2010-08-02 2012-02-09 Neon Laboratories Ltd. Procédé pour la préparation de pemetrexed dialkylé de haute pureté
WO2012134392A1 (fr) 2011-03-25 2012-10-04 Scinopharm Taiwan Ltd Procédé pour la production d'un sel de pémétrexed
WO2012111027A3 (fr) * 2011-02-15 2012-10-11 Hetero Research Foundation Procédé d'obtention de pemetrexed disodique
US8324382B2 (en) 2008-09-22 2012-12-04 Chongqing Pharmaceutical Research Institute Co., Ltd. Crystalline forms of Pemetrexed diacid, and preparations thereof
CZ303772B6 (cs) * 2000-02-25 2013-05-02 Eli Lilly And Company Heptahydrátová krystalická forma disodné soli N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]-benzoyl]L-glutamové kyseliny a zpusob její prípravy
KR101308767B1 (ko) 2011-01-20 2013-12-31 에스티팜 주식회사 고 순도 페메트렉세드 디에틸 에스테르의 제조방법 및 이 방법을 포함하는 페메트렉세드 이나트륨염의 제조방법
US8629152B2 (en) 2006-08-14 2014-01-14 Sicor, Inc. Processes for the preparation of lyophilized pharmaceutically acceptable salts of pemetrexed diacid
CN103784454A (zh) * 2014-01-22 2014-05-14 海南锦瑞制药股份有限公司 一种含有培美曲塞二钠化合物的药物组合物
WO2014122460A2 (fr) 2013-02-06 2014-08-14 Cipla House Complexes de pémétrexed et compositions pharmaceutiques contenant des complexes de pémétrexed
WO2015008221A1 (fr) 2013-07-16 2015-01-22 Dr. Reddy’S Laboratories Limited Nouvelles formes cristallines de sels de trométhamine de pemetrexed
WO2015075601A1 (fr) * 2013-11-25 2015-05-28 Shilpa Medicare Limited Procédé de préparation de sel dipotassique de pémétrexed cristallin
US9051322B2 (en) 2011-03-23 2015-06-09 Scinopharm Taiwan, Ltd. Process for the production of a pemetrexed salt
EP2909208A4 (fr) * 2012-10-17 2016-07-13 Shilpa Medicare Ltd Procédé pour préparer du dipotassium de pémetrexed et ses hydrates
US9562050B2 (en) 2006-08-14 2017-02-07 Sicor, Inc. Crystalline forms of pemetrexed diacid and processes for the preparation thereof
EP2985025B1 (fr) * 2008-06-06 2018-01-17 Boehringer Ingelheim International Gmbh Association pharmacologique

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CZ303772B6 (cs) * 2000-02-25 2013-05-02 Eli Lilly And Company Heptahydrátová krystalická forma disodné soli N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]-benzoyl]L-glutamové kyseliny a zpusob její prípravy
EP2269599A1 (fr) 2004-03-22 2011-01-05 Laboratoires Besins International Compositions stables à base de 4-hydroxy tamoxifène
EP2322526A1 (fr) * 2006-08-14 2011-05-18 Sicor, Inc. Forme cristalline de diacide de pemetrexed et son procédé de préparation
EP2270012A1 (fr) * 2006-08-14 2011-01-05 Sicor, Inc. Forme cristalline de diacide de pemetrexed et son procédé de préparation
US8362245B2 (en) 2006-08-14 2013-01-29 Sicor Inc. Processes for preparing intermediates of pemetrexed
US9156841B2 (en) 2006-08-14 2015-10-13 Sicor Inc. Crystalline forms of pemetrexed diacid and processes for the preparation thereof
US9562050B2 (en) 2006-08-14 2017-02-07 Sicor, Inc. Crystalline forms of pemetrexed diacid and processes for the preparation thereof
EP2270013A1 (fr) * 2006-08-14 2011-01-05 Sicor, Inc. Forme cristalline de diacide de pemetrexed et son procédé de préparation
US9718829B2 (en) 2006-08-14 2017-08-01 Sicor Inc. Crystalline forms of pemetrexed diacid and processes for the preparation thereof
US7994180B2 (en) 2006-08-14 2011-08-09 Sicor Inc. Processes for preparing intermediates of pemetrexed
EP2311838A1 (fr) * 2006-08-14 2011-04-20 Sicor, Inc. Forme cristalline de diacide de pemetrexed et son procédé de préparation
WO2008021405A1 (fr) * 2006-08-14 2008-02-21 Sicor Inc. Formes cristallines de diacide de pemetrexed et leurs procédés de préparation
US8629152B2 (en) 2006-08-14 2014-01-14 Sicor, Inc. Processes for the preparation of lyophilized pharmaceutically acceptable salts of pemetrexed diacid
US8088919B2 (en) 2006-08-14 2012-01-03 Sicor Inc. Crystalline forms of pemetrexed diacid and processes for the preparation thereof
EP2305681A1 (fr) 2006-08-14 2011-04-06 Sicor, Inc. Forme cristalline de diacide de pemetrexed et son procédé de préparation
EP2129674A2 (fr) * 2007-04-03 2009-12-09 Dr. Reddy's Laboratories Ltd. Formes solides de pemetrexed
US8507508B2 (en) 2007-04-03 2013-08-13 Dr. Reddy's Laboratories Limited Solid forms of pemetrexed
WO2009056029A1 (fr) 2007-10-24 2009-05-07 Chongqing Pharmaceutical Research Institute Co., Ltd. Procédé de purification de sels, sels sodiques et sels dissodiques de pemetrexed
US8686140B2 (en) 2007-10-24 2014-04-01 Chongqing Pharmaceutical Research Institute Co., Ltd. Method of purifying a salt, sodium salt and disodium salt of pemetrexed
EP2072518A1 (fr) * 2007-12-23 2009-06-24 Sun Pharma Advanced Research Company Limited Forme amorphe stable de Pemextred disodium
EP2985025B1 (fr) * 2008-06-06 2018-01-17 Boehringer Ingelheim International Gmbh Association pharmacologique
EP2334685A4 (fr) * 2008-09-08 2011-10-26 Reddys Lab Ltd Dr Disodium de pemetrexed amorphe
EP2334685A2 (fr) * 2008-09-08 2011-06-22 Dr. Reddy's Laboratories, Ltd. Disodium de pemetrexed amorphe
WO2010030598A2 (fr) * 2008-09-11 2010-03-18 Dr. Reddy's Laboratories Limited Formulations pharmaceutiques comprenant du pemetrexed
WO2010030598A3 (fr) * 2008-09-11 2010-06-03 Dr. Reddy's Laboratories Limited Formulations pharmaceutiques comprenant du pemetrexed
US8324382B2 (en) 2008-09-22 2012-12-04 Chongqing Pharmaceutical Research Institute Co., Ltd. Crystalline forms of Pemetrexed diacid, and preparations thereof
WO2011019986A3 (fr) * 2009-08-13 2011-06-30 Dr. Reddy's Laboratories Ltd. Procédés de préparation du pemetrexed
CN102050825A (zh) * 2009-11-05 2011-05-11 上海希迪制药有限公司 制备培美曲塞二钠2.5水结晶的方法
CN102050825B (zh) * 2009-11-05 2014-12-17 上海创诺制药有限公司 制备培美曲塞二钠2.5水结晶的方法
WO2011064256A1 (fr) 2009-11-24 2011-06-03 Azad Pharmaceutical Ingredients Ag Nouvelle forme cristalline du pemetrexed disodique
US9174991B2 (en) 2009-11-24 2015-11-03 Azad Pharmaceutical Ingredients Ag Crystalline form of pemetrexed disodium
WO2012017443A1 (fr) * 2010-08-02 2012-02-09 Neon Laboratories Ltd. Procédé pour la préparation de pemetrexed dialkylé de haute pureté
KR101308767B1 (ko) 2011-01-20 2013-12-31 에스티팜 주식회사 고 순도 페메트렉세드 디에틸 에스테르의 제조방법 및 이 방법을 포함하는 페메트렉세드 이나트륨염의 제조방법
WO2012111027A3 (fr) * 2011-02-15 2012-10-11 Hetero Research Foundation Procédé d'obtention de pemetrexed disodique
US9051322B2 (en) 2011-03-23 2015-06-09 Scinopharm Taiwan, Ltd. Process for the production of a pemetrexed salt
JP2014508805A (ja) * 2011-03-25 2014-04-10 サイノファーム タイワン リミテッド ペメトレキセド塩の製造方法
EP2688888A1 (fr) * 2011-03-25 2014-01-29 Scinopharm Taiwan, Ltd. Procédé pour la production d'un sel de pémétrexed
EP2688888A4 (fr) * 2011-03-25 2014-08-20 Scinopharm Taiwan Ltd Procédé pour la production d'un sel de pémétrexed
WO2012134392A1 (fr) 2011-03-25 2012-10-04 Scinopharm Taiwan Ltd Procédé pour la production d'un sel de pémétrexed
EP2909208A4 (fr) * 2012-10-17 2016-07-13 Shilpa Medicare Ltd Procédé pour préparer du dipotassium de pémetrexed et ses hydrates
WO2014122460A2 (fr) 2013-02-06 2014-08-14 Cipla House Complexes de pémétrexed et compositions pharmaceutiques contenant des complexes de pémétrexed
US9688682B2 (en) 2013-07-16 2017-06-27 Dr. Reddy's Laboratories Limited Crystalline forms of pemetrexed tromethamine salts
WO2015008221A1 (fr) 2013-07-16 2015-01-22 Dr. Reddy’S Laboratories Limited Nouvelles formes cristallines de sels de trométhamine de pemetrexed
WO2015075601A1 (fr) * 2013-11-25 2015-05-28 Shilpa Medicare Limited Procédé de préparation de sel dipotassique de pémétrexed cristallin
US10072012B2 (en) 2013-11-25 2018-09-11 Shilpa Mecicare Limited Process for crystalline pemetrexed dipotassium salt
CN103784454A (zh) * 2014-01-22 2014-05-14 海南锦瑞制药股份有限公司 一种含有培美曲塞二钠化合物的药物组合物

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WO2001014379A3 (fr) 2001-09-07

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