WO2012061469A2 - Formes cristallines de pralatrexate - Google Patents
Formes cristallines de pralatrexate Download PDFInfo
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- WO2012061469A2 WO2012061469A2 PCT/US2011/058913 US2011058913W WO2012061469A2 WO 2012061469 A2 WO2012061469 A2 WO 2012061469A2 US 2011058913 W US2011058913 W US 2011058913W WO 2012061469 A2 WO2012061469 A2 WO 2012061469A2
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- pralatrexate
- ray powder
- powder diffraction
- diffraction pattern
- crystalline form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
- C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
-
- 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 encompasses solid state forms of Pralatrexate, processes for preparation thereof, and pharmaceutical compositions thereof.
- Pralatrexate (25 -2-[[4-[(li?5)-l-[(2,4-diaminopteridin-6-yl)methyl]but-3- ynyl]benzoyl]amino]pentandioic acid is an anti-cancer drug having the following formula:
- Pralatrexate is approved for a treatment for patients with relapsed or refractory peripheral T-cell lymphoma. It is an antifolate and acts as an inhibitor of
- Pralatrexate is disclosed in several documents such as DeGraw et al. (J Med. Chem, 1993, 36, 2228, US 5,354,751, US 6,028,071 B2 and EP 0944389 Bl.
- Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
- a single molecule like Pralatrexate, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA”, or differential scanning calorimetry - “DSC”), X-ray powder diffraction (XRPD) pattern, infrared absorption fingerprint, and solid state nuclear magnetic resonance (NMR) spectrum.
- TGA thermogravimetric analysis -
- DSC differential scanning calorimetry -
- XRPD X-ray powder diffraction
- NMR solid state nuclear magnetic resonance
- Discovering polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
- New polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a
- the present invention provides solid state forms of Pralatrexate and pharmaceutical compositions comprising said solid state forms and at least one pharmaceutically acceptable excipient.
- the present invention also encompasses the use of any of the above solid- state forms for the preparation of a pharmaceutical composition.
- the present invention further encompasses the use of any of the above solid-state forms and pharmaceutical compositions, as a medicament, particularly for the treatment for patients with relapsed or refractory peripheral T-cell lymphoma.
- the present invention also provides a method of anti-cancer therapy, comprising administering a therapeutically effective amount of at least one of the Pralatrexate solid-state forms of the present invention, or at least one of the above pharmaceutical compositions to a person with relapsed or refractory peripheral T-cell lymphoma.
- Figure 1 shows an X-ray powder diffractogram of Pralatrexate form A.
- Figure 2 shows an X-ray powder diffractogram of Pralatrexate form B.
- Figure 3 shows an X-ray powder diffractogram of Pralatrexate form C.
- Figure 4 shows an X-ray powder diffractogram of Amorphous Pralatrexate.
- Figure 5 shows a 13 C NMR spectrum of Pralatrexate form A between 0-200 ppm.
- Figure 6 shows a 13 C NMR spectrum of Pralatrexate form B between 0-200 ppm.
- Figure 7 shows a 13 C NMR spectrum of Pralatrexate form C between 0-200 ppm.
- the present invention addresses a need in the art by providing Pralatrexate in a crystalline form, which is believed to provide significant advantages for making pharmaceutical compositions, as compared to the amorphous form disclosed in the prior art.
- important factors include chemical stability, solid state stability and "shelf life" of the drug substance.
- the drug substance, and compositions containing it should be capable of being stored over appreciable periods of time, under conditions such as high humidity without exhibiting a significant change in the active component's physico-chemical characteristics (e.g. its chemical composition, density, hygroscopicity, solubility and rate of dissolution).
- Crystalline forms of Pralatrexate such as the crystalline forms of the present invention (namely, Forms A, B and C) are believed to provide advantages over the prior art amorphous Pralatrexate in this regard.
- solid state forms of Pralatrexate of the invention are substantially free of any other polymorphic forms of Pralatrexate, or of specified polymorphic forms of Pralatrexate, respectively.
- substantially free is meant that the forms of the present invention contain 20% (w/w) or less, 10% (w/w) or less, 5% (w/w) or less, 2% (w/w) or less, particularly 1% (w/w) or less, more particularly 0.5% (w/w) or less, and most particularly 0.2% (w/w) or less of any other polymorphs of Pralatrexate, or of a specified polymorph of Pralatrexate.
- the polymorphs of Pralatrexate of the invention contain from 1% to 20% (w/w), from 5% to 20% (w/w), or from 5% to 10% (w/w)) of any other polymorphs or of a specified polymorph of Pralatrexate or of an amorphous form of Pralatrexate.
- the present invention addresses a need in the art by providing new crystalline forms of Pralatrexate that have advantageous properties selected from at least one of: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability- such as thermal and mechanical stability to polymorphic conversion, stability to dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility, and bulk density.
- a crystal form may be referred to herein as being characterized by graphical data "as shown in,” or “as depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra.
- a crystal form of Pralatrexate referred to herein as being characterized by graphical data "as shown in,” or “as depicted in” a Figure will thus be understood to include any crystal forms of the Pralatrexate characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.
- the term "isolated" in reference to any of the Pralatrexate crystalline forms of the present invention corresponds to Pralatrexate crystalline form that is physically separated from the reaction mixture, wherein it was formed.
- the XRPD measurements are taken using copper Ka radiation wavelength 1.54184 A.
- a thing e.g., a reaction mixture
- room temperature (often abbreviated "RT"). This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located.
- room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.
- a process or step may be referred to herein as being carried out
- overnight This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, typically about 16 hours.
- reduced pressure refers to a pressure of about 10 mbar to about 50 mbar.
- anhydrous in relation to crystalline Pralatrexate relates to a crystalline Pralatrexate which contains not more than 1.5% (w/w), or not more than 1% (w/w) of either water or organic solvents (bound and unbound) as measured by TGA or by Karl Fisher titration, for example, Pralatrexate which contains between about 0% to about 1.5% (w/w) or between about 0% to about 1% (w/w) of either water or organic solvents as measured by TGA or by Karl Fisher titration.
- volume can be used to refer to ml per gram of the corresponding Pralatrexate.
- a statement that 0.5 g of Pralatrexate is dissolved in ten volumes of a Solvent X would be understood to mean that the 0.5 g of Pralatrexate was dissolved in 5 ml of Solvent X.
- the present invention comprises a crystalline form of Pralatrexate, designated as Form A.
- Form A can be characterized by data selected from: an X-ray powder diffraction (XRPD) pattern having peaks at 8.7, 12.3, 15.2, 19.2 and 21.9° 2 ⁇ ⁇ 0.2° 20; an X-ray powder diffraction (XRPD) pattern having peaks at 8.7, 12.3, 14.3, 16.0 and 21.9° 20 ⁇ 0.2° 20; an XRPD pattern substantially as depicted in figure 1; a solid state 13 C NMR spectrum having signals at 25.1, 35.9, 53.2, 122.0 and 146.8 ⁇ 0.2 ppm; a solid state C NMR spectrum as depicted in Figure 5; and combinations thereof.
- XRPD X-ray powder diffraction
- XRPD X-ray powder diffraction
- Crystalline Form A of Pralatrexate can be further characterized by data selected from: an XRPD pattern having any one, two, three, four or five additional peaks selected from: 10.9, 14.3, 16.0, 23.3 and 24.3° 2 ⁇ ⁇ 0.2° 2 ⁇ ; and an XRPD pattern having any one, two, three, four or five additional peaks selected from: 10.9, 15.2, 19.2, 23.3 and 24.3° 2 ⁇ ⁇ 0.2° 2 ⁇ .
- the present invention comprises a crystalline form of Pralatrexate, designated as Form B.
- Form B can be characterized by data selected from: an XRPD pattern having peaks at 8.9, 11.0, 13.8 and 15.4° 2 ⁇ + 0.2° 2 ⁇ ; an XRPD pattern substantially as depicted in figure 2; a solid state 13 C NMR spectrum having signals at 27.8, 35.4, 68.6, 128.8 and 157.4 ⁇ 0.2 ppm; a solid state 13 C NMR spectrum as depicted in Figure 6; and combinations thereof.
- Crystalline Form B of Pralatrexate can be further characterized by an X-ray powder diffraction (XRPD) pattern having any one, two, three or four additional peaks selected from: 12.3, 19.2, 21.9 and 24.7° 2 ⁇ ⁇ 0.2° 2 ⁇ .
- XRPD X-ray powder diffraction
- the present invention comprises a crystalline form of Pralatrexate, designated as Form C.
- Form C can be characterized by data selected from: an XRPD pattern having peaks at 8.5, 12.5, 13.1, 22.2, and 24.0° 2 ⁇ ⁇ 0.2° 20; an XRPD pattern having peaks at 8.5, 12.5, 13.1, 22.2, and 29.3° 2 ⁇ ⁇ 0.2° 20; an XRPD pattern substantially as depicted in figure 3; a solid state 13 C NMR spectrum having signals at 42.0, 44.6, 132.5, 153.1 and 180.1 ⁇ 0.2 ppm; a solid state 13 C NMR spectrum as depicted in Figure 7; and combinations thereof.
- Crystalline Form C of Pralatrexate can be further characterized by data selected from: an XRPD pattern having any one, two, three, four or five additional peaks selected from: 10.8, 15.1, 19.1, 28.5 and 29.3° 2 ⁇ + 0.2° 2 ⁇ ; and an XRPD pattern having any one, two, three, four or five additional peaks selected from: 10.8, 15.1, 19.1, 24.0 and 28.5 ° 20 ⁇ 0.2° 20.
- the crystalline forms of the present invention are anhydrous forms.
- the present invention also describes an amorphous form of Pralatrexate.
- the amorphous form of Pralatrexate can be characterized by an XRPD pattern as depicted in figure 4.
- the above described forms of Pralatrexate can be used to prepare pharmaceutical compositions by any method known in the art.
- the present invention further encompasses 1) a pharmaceutical composition comprising at least one of the solid state forms of Pralatrexate as described above, and at least one pharmaceutically acceptable excipient; 2) the use of any one or combination of the above-described solid state forms of Pralatrexate in the manufacture of a pharmaceutical composition, and 3) a method of treating relapsed or refractory peripheral T-cell lymphoma, said method comprising administering a pharmaceutically effective amount of at least one of the solid state forms of
- Pralatrexate as described above to a subject, e.g., a patient, in need of the treatment.
- the pharmaceutical composition can be useful for preparing a medicament.
- the present invention also provides at least one of the solid state forms of Pralatrexate as described above for use as a medicament.
- the pharmaceutical composition may be in a form of a solution.
- the scanning parameters were: range: 3-40 degrees two-theta; scan mode: continuous scan; step size: 0.0167°; and time per step: 37 sec.
- NMR spectra of solid samples were recorded on a Varian NMR System 600 MHz NMR spectrometer equipped with a 3.2 mm NB Double Resonance HX MAS Solids Probe. Larmor frequency of carbon nuclei was 150.79 MHz. The C CP- MAS NMR spectra were externally referenced to the methyl groups of
- the pulse sequence used for acquiring spectra was a standard cross-polarization MAS pulse sequence with high-power proton decoupling during acquisition. Repetition delay was 5 s and the number of scans was between 3200 and 9000.
- Example 1 Preparation of Pralatrexate according to U.S. Patent No. 6,028,071, example 1
- FIG. 4 of U.S. Patent No. 6,028,071 shows a synthetic scheme useful in preparing pralatrexate.
- Example 1A Compound 2 of Figure 4 of US 6,028,071
- a mixture of 60% NaH in oil dispersion (1.06 g, 26.5 mmol) in 18 mL of sieve-dried THF was cooled to 0°C.
- the cold mixture was treated with a solution of homoterephthalic acid dimethyl ester (5.0 g, 24 mmol.; compound 1 in FIG. 4 of US 6,0280,71) in dry THF (7 mL), and the mixture was stirred for 1 hour at 0°C.
- Propargyl bromide (26.4 mmol) was added, and the mixture was stirred at 0°C for an additional 1 hour, and then at room temperature for 16 hours.
- the resulting mixture was treated with 2.4 mL of 50% acetic acid and then poured into 240 mL of water.
- the mixture was extracted with ether (2 times; 150 mL). The ether extracts were combined, dried over Na 2 S04, and concentrated to an orange-yellow oil.
- Example IB 10-Propargyl-10-carbomemoxy-4-deoxy-4-arnino-10-deazapteroic acid methyl ester (compound 3 in Figure 4 of US 6,028,071)
- a mixture was formed by combining 0.36 g of NaH (9 mmol, 60% dispersion in oil) with 10 mL of dry DMF, and cooling the mixture to 0-5°C.
- the cold mixture was treated dropwise with a solution of the product of the first reaction (compound 2 from Example 1 A) (2.94 g, 12 mmol) in 10 mL dry DMF, and then stirring this mixture at 0°C for 30 minutes.
- a solution of 2,4,diamino-6-(bromomethyl)pteridine hydrobromide-0.2 2-propanol (1.00 g, 2.9 mmol) in 10 mL dry DMF was added dropwise while the temperature was maintained near -25°C.
- Example 1C Compound 4 of Figure 4 of US 6,028,071
- Example ID 10-Propargyl-4-deoxy-4-amino-10-deazapteroic acid (compound 5 of Figure 4 of US 6,028,071)
- Example IE 10-Propargyl-lO-deazaaminopterin dimethyl ester (compound 6 of Figure 4 of US 6,028,071
- the crude product (350 mg) was purified by silica gel chromatography eluting with CHCl 3 ⁇ MeOH (10:1) containing triethylamine (0.25% by volume) to recover 165 mg of 10-propargyl-lO-deazaaminopterin dimethyl ester (compound 6 of Figure 4 of US 6,028,071, 50% yield), which was homogeneous by TLC (CHCb-MeOH 5:1).
- Amorphous pralatrexate 400 mg, purity 96%) was dissolved in formamide at room temperature (1 mL, 2.5 Vol.). The solution was poured into water at room temperature (10 mL, 25 Vol.), resulting in the formation of a precipitate. The precipitate was filtered off and dried in a vacuum drying oven at 35°C under vacuum for 18 h, furmshing pralatrexate Form A (200 mg, 50% yield, 96% purity).
- Amorphous pralatrexate (200 mg, purity 96% %) was suspended in MeOH (2 mL, 10 Vol.), and the slurry was stirred at room temperature. After 24 h of stirring, the solid was filtered off and dried in a vacuum drying oven at 35°C under vacuum for 18 h, furrmhing pralatrexate Form B (118 mg, 59% yield, 96% purity).
- Amorphous pralatrexate (200 mg, purity 96%) was suspended in MeOH (2 mL, 10 Vol.) and the slurry was heated up to 50 °C. After 24 h the solid was filtered off and dried in a vacuum drying oven at 35°C under vacuum, furnishing pralatrexate Form B (96 mg, 48% yield, 96% purity).
- pralatrexate A solution of pralatrexate in water was prepared as described in example IF above (according to U.S. Patent No. 6,028,071, example 1). Pralatrexate was precipitated by addition of aq. HC1 10 % to adjust to pH 4.5. The solid was filtered off and dried in a vacuum drying oven at 35°C under vacuum, furnishing pralatrexate as a pale yellow solid.
- Example 6 Preparation of crystalline Pralatrexate Form A:
- Amorphous pralatrexate 400 mg, purity 98.5%) was suspended in water (4 mL, 10 Vol.) pre-heated at 50 °C, and the slurry was stirred for 4 h at 50°C. The solid was then filtered off and dried in a vacuum drying oven at 45 °C under vacuum for 18h, furnishing pralatrexate form A (305 mg, 76% yield, 98.5% purity).
- Amorphous pralatrexate 400 mg, purity 98.5%) was suspended in MeOH (4 mL, 10 Vol.) pre-heated at 50 °C, and the slurry was stirred for 16 h at 50 °C. The solid was then filtered off and dried in a vacuum drying oven at 45 °C under vacuum for 18 h, furnishing pralatrexate form B (250 mg, 63% yield, 97% purity).
- Amorphous pralatrexate 400 mg, purity 98.5%) was suspended in a mixture of water (2 mL, 5 Vol.) and MeOH (2 mL, 5 Vol.) pre-heated at 50 °C, and the slurry was stirred for 2 h at 50 °C. The solid was filtered off and dried in a vacuum drying oven at 45 °C under vacuum for 18 h, furnishing pralatrexate form C (320 mg, 80% yield, 98.5% purity).
- Amorphous pralatrexate (200 mg, purity 96%) was suspended in MeOH (2 mL, 10 Vol.) Upon heating at 50 °C, water was added (2 mL, 10 Vol.) and the resulting slurry was kept at 50 °C for 24 h. The solid was then filtered off and dried in a vacuum drying oven at 35°C under vacuum, furnishing pralatrexate Form C (96 mg, 48% yield, 96% purity).
Abstract
La présente invention concerne des formes cristallines de pralatrexate, en particulier la forme A, la forme B et la forme C, des compositions pharmaceutiques comprenant une forme cristalline de pralatrexate et au moins un excipient pharmaceutiquement acceptable, et des procédés d'utilisation d'une des compositions pour le traitement du lymphome à lymphocytes T périphériques récurrent ou réfractaire.
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US40926310P | 2010-11-02 | 2010-11-02 | |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013177713A1 (fr) * | 2012-05-31 | 2013-12-05 | Alphora Research Inc. | Procédé de préparation d'un agent antifolate |
WO2014020553A1 (fr) | 2012-08-03 | 2014-02-06 | Fresenius Kabi Oncology Ltd. | Sels de pralatrexate |
CN104418859A (zh) * | 2013-09-09 | 2015-03-18 | 上海医药工业研究院 | 普拉曲沙的晶型、含其的药物组合物及其制备方法和应用 |
WO2014068599A3 (fr) * | 2012-11-02 | 2015-03-19 | Hetero Research Foundation | Procédé pour le pralatrexate |
CN104628727A (zh) * | 2013-11-07 | 2015-05-20 | 正大天晴药业集团股份有限公司 | 一种普拉曲沙的晶型及其制备方法 |
CN105272983A (zh) * | 2014-06-12 | 2016-01-27 | 连云港润众制药有限公司 | 一种高纯度普拉曲沙固体及其制备方法 |
CN108069971A (zh) * | 2016-11-18 | 2018-05-25 | 鲁南制药集团股份有限公司 | 一种普拉曲沙中间体的精制方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5354751A (en) | 1992-03-03 | 1994-10-11 | Sri International | Heteroaroyl 10-deazaamino-pterine compounds and use for rheumatoid arthritis |
US6028071A (en) | 1996-07-17 | 2000-02-22 | Sloan-Kettering Institute For Cancer Research | Purified compositions of 10-propargyl-10-deazaaminopterin and methods of using same in the treatment of tumors |
-
2011
- 2011-11-02 WO PCT/US2011/058913 patent/WO2012061469A2/fr active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5354751A (en) | 1992-03-03 | 1994-10-11 | Sri International | Heteroaroyl 10-deazaamino-pterine compounds and use for rheumatoid arthritis |
US6028071A (en) | 1996-07-17 | 2000-02-22 | Sloan-Kettering Institute For Cancer Research | Purified compositions of 10-propargyl-10-deazaaminopterin and methods of using same in the treatment of tumors |
EP0944389B1 (fr) | 1996-07-17 | 2008-09-10 | Sloan-Kettering Institute For Cancer Research | Compositions purifiees de 10-propargyl-10-deazaaminopterine et leur methodes d'utilisation pour le traitement de tumeurs |
Non-Patent Citations (1)
Title |
---|
DEGRAW ET AL., J. MED. CHEM, vol. 36, 1993, pages 2228 |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013177713A1 (fr) * | 2012-05-31 | 2013-12-05 | Alphora Research Inc. | Procédé de préparation d'un agent antifolate |
WO2014020553A1 (fr) | 2012-08-03 | 2014-02-06 | Fresenius Kabi Oncology Ltd. | Sels de pralatrexate |
WO2014068599A3 (fr) * | 2012-11-02 | 2015-03-19 | Hetero Research Foundation | Procédé pour le pralatrexate |
US9783542B2 (en) | 2012-11-02 | 2017-10-10 | Hetero Research Foundation | Process for pralatrexate |
CN104418859A (zh) * | 2013-09-09 | 2015-03-18 | 上海医药工业研究院 | 普拉曲沙的晶型、含其的药物组合物及其制备方法和应用 |
CN104418859B (zh) * | 2013-09-09 | 2016-06-22 | 上海医药工业研究院 | 普拉曲沙的晶型、含其的药物组合物及其制备方法和应用 |
CN104628727A (zh) * | 2013-11-07 | 2015-05-20 | 正大天晴药业集团股份有限公司 | 一种普拉曲沙的晶型及其制备方法 |
CN105272983A (zh) * | 2014-06-12 | 2016-01-27 | 连云港润众制药有限公司 | 一种高纯度普拉曲沙固体及其制备方法 |
CN105272983B (zh) * | 2014-06-12 | 2021-01-15 | 连云港润众制药有限公司 | 一种高纯度普拉曲沙固体及其制备方法 |
CN108069971A (zh) * | 2016-11-18 | 2018-05-25 | 鲁南制药集团股份有限公司 | 一种普拉曲沙中间体的精制方法 |
CN108069971B (zh) * | 2016-11-18 | 2021-02-12 | 鲁南制药集团股份有限公司 | 一种普拉曲沙中间体的精制方法 |
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