WO2014060959A1 - Procédé de préparation de dipotassium de pemetrexed cristallin - Google Patents

Procédé de préparation de dipotassium de pemetrexed cristallin Download PDF

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Publication number
WO2014060959A1
WO2014060959A1 PCT/IB2013/059384 IB2013059384W WO2014060959A1 WO 2014060959 A1 WO2014060959 A1 WO 2014060959A1 IB 2013059384 W IB2013059384 W IB 2013059384W WO 2014060959 A1 WO2014060959 A1 WO 2014060959A1
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WIPO (PCT)
Prior art keywords
hemiheptahydrate
peak
crystalline
dipotassium
pemetrexed dipotassium
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PCT/IB2013/059384
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English (en)
Inventor
Vimal Kumar Shrawat
Rafiuddin .
Vinod Kumar Singh
Bhagat Raj PIPAL
Akshay Kant CHATURVEDI
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Shilpa Medicare Limited
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.)
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Publication of WO2014060959A1 publication Critical patent/WO2014060959A1/fr

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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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • 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

Definitions

  • Pemetrexed's chemical name is (S)-2-(4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3- d]pyrimidin-5-yl)ethyl)benzamido)pentanedioic acid and has the following chemical structure:
  • Pemetrexed disodium is the most common salt of pemetrexed di acid. It has the chemical name L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-lH-pyrrolo[2,3-d]pyrimidin-5-yl)- ethyl]benzoyl]-, disodium salt.
  • Pemetrexed disodium heptahydrate is the active ingredient of Eli Lilly and Company's ALIMTA® injectable composition.
  • Pemetrexed disodium heptahydrate has the following chemical structure:
  • Pemetrexed disodium is a multi-targeted antifolate that strongly inhibits various folate-dependent enzymes, including thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT).
  • TS thymidylate synthase
  • DHFR dihydrofolate reductase
  • GARFT glycinamide ribonucleotide formyltransferase
  • Pemetrexed disodium has been proved effective on a wide variety of solid tumors in clinical trials.
  • pemetrexed disodium is commercial available in USA, European Union, Canada, Japan and China etc. for treatment of malignant pleural stromal tumor as a first-line drug, and local advanced and metastatic non-small cell lung cancer as a second-line drug.
  • pemetrexed disodium is a unique chemotherapeutic agent in the market currently.
  • pemetrexed disodium has a comparative efficacy and reduced toxicities compared with the standard drug Docetaxel.
  • the clinical studies of pemetrexed disodium in the treatment of breast, bowel, pancreatic, head and neck, gastric and bladder cancers are still ongoing.
  • each of Mi and M2 is independently H , Li , Na or K + , provided that both of them are not H + ; if M 3 + is Li + , Na + or K + , then each of Mi + and M2 + is independently Li + , Na + or K + .
  • example 16 and 17 it provides mention of purification of potassium pemetrexed, however, it appears that it does not refer to other than mono potassium salt of pemetrexed with no characterization details of the said salt. Further, in our attempt to reproduce the said example disclosure, no material could be recovered.
  • Pemetrexed being an important anticancer therapeutic agent
  • additional and improved ways of preparing pemetrexed pharmaceutically acceptable salt may be of immense value to pharmaceutical science and the healthcare of cancer patients.
  • Pemetrexed dipotassium hemiheptahydrate II
  • Form-SPl Pemetrexed dipotassium hemiheptahydrate
  • Pemetrexed dipotassium hemiheptahydrate (I) process for preparation of Pemetrexed dipotassium hemiheptahydrate (I) and its stable crystalline polymorphic form designated as Form-SPl, which is substantially free from process related impurities.
  • the crystalline polymorphic form of Pemetrexed dipotassium hemiheptahydrate (I) obtained by the processes according to the present invention is useful as active pharmaceutical ingredient in pharmaceutical compositions for treating hyper-proliferative disorders, such as cancer, by administering the compound in a composition.
  • Different aspects of the present application are summarized herein below individually.
  • Crystalline Form-SPl of Pemetrexed dipotassium hemiheptahydrate is characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 29° peaks selected from the XRPD peak set of 5.00, 13.70, 16.90, 20.00, 21.40, 23.6, 24.2 and 28.30 ⁇ 0.20 2 ⁇ °.
  • XRPD diffraction angle peaks include 14.90, 15.20, 20.50, 25.10 and 27.5 ⁇ 0.20 2 ⁇ °.
  • Form- SP 1 is further characterized by DSC isotherm comprising at least three endothermic peaks ranging between- a. Peak - 1 - Between 65 to 85°C
  • Form- SP 1 of the present invention is further characterized by X-ray powder diffraction pattern substantially according to Fig-1, DSC isothermal pattern substantially according to Fig-2 and IR absorption spectrum substantially according to Fig-3.
  • the Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl obtained by the process/es of the present application may be formulated as solid compositions for oral administration in the form of lyophilized powder, capsules, tablets, pills, powders or granules useful in the treatment of hyper-pro liferative disorders, such as cancer.
  • Fig. 1 is Illustration of X-ray powder diffraction (XRPD) pattern of Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl, prepared according to Example-2
  • Fig. 2 is an Illustration of a differential scanning calorimetric ("DSC") curve of Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl, prepared according to Example-2
  • Fig. 3 is an Illustration of a IR spectrum of Pemetrexed dipotassium hemiheptahydrate (I) Form- SPl, prepared according to Example-2
  • Fig. 4 is an Illustration of a TGA thermogram of Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl, prepared according to Example-2
  • Fig. 5 is Illustration of X-ray powder diffraction (XRPD) pattern of Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SP2
  • embodiments of the present invention provide crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl and processes for preparation thereof. Individual embodiments of the present invention are detailed herein below separately.
  • Crystalline Form-SPl of Pemetrexed dipotassium hemiheptahydrate is characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 29° peaks selected from the XRPD peak set of 5.00, 13.70, 16.90, 20.00, 21.40, 23.6, 24.2 and 28.30 ⁇ 0.20 2 ⁇ °. A few further characterizing XRPD diffraction angle peaks include 14.90, 15.20, 20.50, 25.10 and 27.5 ⁇ 0.20 2 ⁇ °.
  • Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form- SP 1 is further characterized by DSC isotherm comprising at least three endothermic peaks ranging between- a. Peak -1- Between 65 to 85°C
  • Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form- SP1 which has an IR absorption spectrum having characteristic peaks expressed in cm “1 at approximately 2936 cm “1 , 2857 cm “1 , 1396 cm “1 , 1 184 cm “1 , 1 158 cm “1 , 1092 cm “1 , 1076 cm “1 , 819 cm “1 and 788 cm “1 .
  • Form- SP 1 of the present invention is characterized by X-ray powder diffraction pattern substantially according to Fig-1, DSC isothermal pattern substantially according to Fig-2 and IR absorption spectrum substantially according to Fig-3.
  • D-spacing values are calculated with observed 2 theta angles and copper K a wavelength using the Bragg equation well known to those of having skill in the art of XRPD diffractometry science.
  • the preferred method of comparing X-ray powder diffraction patterns in order to identify a particular crystalline form is to overlay the X-ray powder diffraction pattern of the unknown form over the X-ray powder diffraction pattern of a known form.
  • one skilled in the art can overlay an X-ray powder diffraction pattern of an unidentified crystalline form of Pemetrexed dipotassium hemiheptahydrate over FIG.
  • the X-ray diffraction pattern of the unidentified form is substantially the same as the X-ray powder diffraction pattern of the crystalline form of this invention. If the X-ray powder diffraction pattern is substantially the same as FIG. 1, the previously unknown crystalline form of Pemetrexed dipotassium hemiheptahydrate can be readily and accurately identified as the crystalline Form SP1 of this invention.
  • the crystalline Form-SPl of Pemetrexed dipotassium is a hemiheptahydrate, which is evident from the Fig-3 i.e. the DSC thermogram.
  • a sample of the crystalline Form SP1 prepared by the inventors of this application showed moisture content up to about 1 1.2% w/w by KF method, which also confirms the hemiheptahydrate (theoretical water content as calculated 1 1.12% w/w) nature of the compound. While the invention is not limited to any specific theory, it should be understood however that the crystalline form SP1 of Pemetrexed dipotassium may contain additional residual or unbound moisture without losing its hemiheptahydrate character and/or its hemiheptahydrate crystalline form-SPl characteristics.
  • Water miscible organic solvents are selected from but not limited to ketone, alcohol solvent, DMF or DMSO.
  • alcohol solvent is selected from C 1 to C5 alcohol and ketone solvent may be selected from C3 to CIO ketone.
  • ratio of Pemetrexed dipotassium w.r.t. water or aqueous organic solvent mixture is important in order to obtain the specifics of the crystalline polymorph to meet, which comprise a range between 1 : 3-8 (w/v). More preferably, this range may be 1 : 4 (w/v).
  • any form of Crude or Pure Pemetrexed dipotassium salt obtained by any process may be used for preparing Form-SPl .
  • the solution may be optionally filtered through hyflow bed or any similar silica based material. As per requirement, other known techniques of filtration for e.g. filtering through micron filter paper may also be used.
  • step of adding aliphatic alcohol solvent comprises slow addition of alcohol solvent, wherein addition is preferably completed within 30-120 minutes time.
  • the solution may optionally be maintained under stirring for a time ranging between 10- 60 minutes in order to retain the desired hemiheptahydrate level with unreacted Pemetrexed dipotassium present if any.
  • the temperature of the reaction mass may be optionally raised to about 20-35°C as per need to attain the crystalline material precipitated out with no or minimal possible degradation if any. Simultaneously, it is also essentially required to cool the solution in the successive lower rate of cooling in order to retain the characteristics of Form-SPl, while achieving the pure crystal formation.
  • the process related impurities including unreacted intermediates, side products, degradation products and other medium dependent impurities, that appears in the impurity profile of the Pemetrexed dipotassium hemiheptahydrate can substantially be removed by the process of the present invention resulting in the formation pure crystalline form-SPl.
  • a substantially pure product having purities more than 99.2% (by HPLC) can be obtained by the process of the present invention.
  • the process requires quality checks, while raising the temperature, wherever required up to 20-35°C.
  • Inventors of the present application also observed during the ongoing experimentation that initially the crystalline product obtained shows XRPD pattern slightly different from the XRPD pattern of Form-SPl . This was, in fact confirmed as another polymorphic form, which is designated hereinafter as Form-SP2. It was further confirmed by inventors during experimentation, that said form is a metastable and transitory form, which on storage for about a week at temperature below 20 °C, eventually gets converted to the more stable polymorphic form i.e. Form-SPl .
  • Polymorphic Form-SP2 of Pemetrexed dipotassium hemiheptahydrate is characterized by presence of one or more additional characteristic 29° diffraction angle XRPD peaks at 5.5, 8.2, 9.4, 12.6, 13.4, 14.7, 15.0, 17.3, 24.9 and 28.0 ⁇ 0.20 2 ⁇ °, besides the presence of characteristic peaks of Form-SPl (Fig. 5). More particularly peaks present at 5.5, 8.2, 24.8 and 28.0 ⁇ 0.20 29° appear to provide distinction of metastable Form-SP2 with respect to Stable Form-SPl .
  • Pemetrexed dipotassium hemiheptahydrate exists as a stable polymorphic Form- SP1 at temperature below 10 °C or any temperatures below 20°C. When exposed to moisture and higher temperatures like 25 °C or above Form- SP1 gets converted to Form-SP2. Due to phenomenon of hydration, dehydration and rehydration, Form SP1 and Form SP2 of Pemetrexed dipotassium hemiheptahydrate may get reversibly converted into each other, depending upon the storage temperature and relative humidity parameters. In one embodiment of the present invention, any reference to Form-SPl of Pemetrexed dipotassium hemiheptahydrate shall be construed to cover Form-SP2 as well.
  • the product may be isolated from the reaction mass by conventional processes including filtering and optional drying, which may be carried out at room temperature for the suitable durations to retain the crystalline polymorphic form characteristics.
  • Crystalline Form-SPl can be recovered by conventional processes, which are not limited to scrapping, breaking, triturating and if required conventional drying.
  • Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl obtained according to present invention may be dried under vacuum to attain water content in the range between 9.5 to 12.0 % w/w.
  • Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl of the present invention may have one or more advantageous and desirable properties compared to the known Crystalline Pemetrexed disodium salt, which are not limited to better stability, solubility and quality parameter leading to improved storage and distribution.
  • Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl described herein is characterized by X-ray powder diffraction pattern (XRPD) and IR absorption spectra and Thermal techniques such as differential scanning calorimetric (DSC) Analysis and TGA.
  • XRPD X-ray powder diffraction pattern
  • DSC differential scanning calorimetric
  • the Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl obtained by the processes of the present application may be formulated as lyophilized powder composition as injectable or solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules useful in the treatment of hyper-proliferative disorders, such as cancer.
  • the active product is mixed with one or more pharmaceutically acceptable excipients.
  • the drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.
  • compositions for parenteral administration can be lyophilized powder, suspensions, emulsions or aqueous or non-aqueous sterile solutions.
  • a process for preparing lyophilized pharmaceutical composition of Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl comprising the steps of-
  • compositions as a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents.
  • the sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
  • compositions comprising Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl of the present application include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and
  • compositions derived from Crystalline Pemetrexed dipotassium hemiheptahydrate (I) Form-SPl of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
  • the process for preparing pemetrexed dipotassium salt comprise of two steps-
  • Step- 1 Pemetrexed dimethyl ester
  • Step-2 Pemetrexed dipotassium hemiheptahydrate
  • N-[4-[2-(2-amino-4,7-dihydro-4-oxo-lH-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl] benzoyl]-L- glutamic dipotassium (20.0 g) was dissolved in DM water (80 ml) under stirring at rt and filtered through hyflow bed. Cool the filtrate to 0- 10°C under continuous stirring. Add slowly the filtered ethanol (320 ml) within 60-80 minutes at 0-10°C under stirring. Temperature is raised to 20- 25°C slowly under stirring and maintained for 3-4 hours at 20-25°C. Solid material obtained was then filtered, washed with ethyl alcohol (40 ml) and dried to obtain the title compound.
  • the compound obtained was filtered and suck dried for 10 minutes, followed by washing with 80 ml of chilled ethanol.
  • the obtained wet solid material was then suck dried for 30 minutes, followed by vacuum drying at 40-45°C for 12-14 hours, to obtain the title compound.
  • wt % refers to percent by weight. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g. "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

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Abstract

La présente invention concerne du hemiheptahydrate de dipotassium de pemetrexed cristallin (I) caractérisé par un diagramme de diffraction des rayons X sur poudres comprenant au moins 5 pics de 29° caractéristiques choisis dans l'ensemble des pics XRPD de 5,00, 13,70, 14,90, 15,20, 16,90, 20,00, 20,50, 21,40, 23,6, 24,2, 25,10, 27,5 et 28,30 ± 0,20° 29°, un isotherme DSC comprenant les pics endothermiques s'étalant de 65 et 85 °C (pic -1), de 86 °C à 105 °C (pic -2), de 120 à 132 °C (pic -3),de 250 à 265 °C (pic -4), et des pics caractéristiques d'absorption des infrarouges approximativement à 2936 cm-1, 2857 cm-1, 1396 cm-1, 1184 cm-1, 1158 cm-1, 1092 cm-1, 1076 cm-1, 819 cm-1 et 788 cm-1 utile en tant ingrédient pharmaceutique actif dans des compositions pharmaceutiques pour le traitement du cancer. L'invention concerne également un procédé de préparation de hemiheptahydrate de dipotassium de pemetrexed (I) et la composition pharmaceutique de de celui-ci.
PCT/IB2013/059384 2012-10-17 2013-10-16 Procédé de préparation de dipotassium de pemetrexed cristallin WO2014060959A1 (fr)

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IN4422CH2012 2012-10-25

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016001792A1 (fr) * 2014-06-30 2016-01-07 Shilpa Medicare Limited Formulations à base de dipotassium de pémétrexed

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001062760A2 (fr) * 2000-02-25 2001-08-30 Eli Lilly And Company Nouvelle forme cristalline de n-[4-[2-(2-amino-4,7-dihydro-4-oxo-3h-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-acide glutamique et procede correspondant
CN101417998A (zh) * 2007-10-24 2009-04-29 重庆医药工业研究院有限责任公司 一种培美曲塞盐的纯化方法
WO2010031357A1 (fr) * 2008-09-22 2010-03-25 重庆医药工业研究院有限责任公司 Trois nouvelles formes de cristaux de diacide de pemetrexed et leur procédé de préparation
CN102838602A (zh) * 2011-06-21 2012-12-26 重庆医药工业研究院有限责任公司 培美曲塞氧化物及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001062760A2 (fr) * 2000-02-25 2001-08-30 Eli Lilly And Company Nouvelle forme cristalline de n-[4-[2-(2-amino-4,7-dihydro-4-oxo-3h-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-acide glutamique et procede correspondant
CN101417998A (zh) * 2007-10-24 2009-04-29 重庆医药工业研究院有限责任公司 一种培美曲塞盐的纯化方法
WO2010031357A1 (fr) * 2008-09-22 2010-03-25 重庆医药工业研究院有限责任公司 Trois nouvelles formes de cristaux de diacide de pemetrexed et leur procédé de préparation
CN102838602A (zh) * 2011-06-21 2012-12-26 重庆医药工业研究院有限责任公司 培美曲塞氧化物及其制备方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016001792A1 (fr) * 2014-06-30 2016-01-07 Shilpa Medicare Limited Formulations à base de dipotassium de pémétrexed
US9789113B2 (en) 2014-06-30 2017-10-17 Shilpa Medicare Limited Pemetrexed dipotassium formulations

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