WO2007015870A2 - Crystalline forms of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide - Google Patents
Crystalline forms of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide Download PDFInfo
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- WO2007015870A2 WO2007015870A2 PCT/US2006/027875 US2006027875W WO2007015870A2 WO 2007015870 A2 WO2007015870 A2 WO 2007015870A2 US 2006027875 W US2006027875 W US 2006027875W WO 2007015870 A2 WO2007015870 A2 WO 2007015870A2
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- crystalline form
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- imidazol
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- HHZIURLSWUIHRB-UHFFFAOYSA-N Cc(nc1)c[n]1-c1cc(NC(c2cc(Nc3nc(-c4cnccc4)ccn3)c(C)cc2)=O)cc(C(F)(F)F)c1 Chemical compound Cc(nc1)c[n]1-c1cc(NC(c2cc(Nc3nc(-c4cnccc4)ccn3)c(C)cc2)=O)cc(C(F)(F)F)c1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention relates to crystalline forms or polymorphs of 4-methyl-N-[3-(4-methyl- imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide, as well as to methods of making the same, pharmaceutical compositions comprising the same and methods of treatment using the same.
- Polymorphism denotes the existence of more than one crystal structure of a substance. This ability of a chemical substance to crystallize in more than one crystal modification can have a profound effect on the shelf life, solubility, formulation properties, and processing properties of a drug. In addition, the action of a drug can be affected by the polymorphism of the drug molecule. Different polymorphs can have different rates of uptake in the body, leading to lower or higher biological activity than desired. In extreme cases, an undesired polymorph can even show toxicity. The occurrence of an unknown polymorphic form during manufacture can have an enormous impact.
- polymorpli during manufacture can mean weeks or even months of production downtime while scientists find and correct the cause of the new crystal form or go through another round of testing to obtain approval for the new form.
- WO 2004/005281 Al provides no information at all about possible crystal modifications of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4- pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.
- the compound is recrystallized from a mixture of tetrahydrofuran and ethyl acetate, but WO 2004/005281 Al gives no indication that the particular recrystallization used therein is to be applied or that particular conditions might be adopted to modify the crystalline form achieved.
- the present invention is directed to substantially pure crystalline forms of 4-methyl- N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2- ylamino)-benzamide free base.
- the present invention is also directed to substantially pure crystalline forms of the hydrochloride and sulfate salts of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl- phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.
- compositions comprising:
- the present invention is also directed to a method of treating a disease which responds to an inhibition of protein kinase activity comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of a substantially pure crystalline form of 4-methyl-N-[3-(4-methyl-imidazol-l -yl)-5-trifluoromethyl-phenyl]-3-(4- pyridin-3-yl-pyrimidin-2-ylamino)-benzamide free base or salt thereof of the present invention.
- Figure 1 shows the x-ray powder diffraction patterns (XRPDs) for forms A and B of 4-methyl-N-[3 -(4-methyl-imidazol- 1 -yl)-5 -trifluoromethyl-phenyl]-3 -(4-pyridin-3 -yl- pyrimidin-2-ylamino)-benzamide free base according to the present invention.
- XRPDs x-ray powder diffraction patterns
- Figure 2 shows the x-ray powder diffraction pattern (XRPD) for form A of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4- pyridin-3-yl-pyrimidin-2-ylamino)-benzamide according to the present invention.
- XRPD x-ray powder diffraction pattern
- Figure 3 shows the fourier transform infrared (FT-IR) spectrum for form A of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4- pyridin-3-yl-pyrimidin-2-ylamino)-benzamide as recorded inNujol mull between two KBr plates using a Bruker IFS-55 instrument.
- FT-IR Fourier transform infrared
- Figure 4 shows the fourier transform Raman (FT-RAMAN) spectrum for form A of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]- 3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide as recorded using a Bruker RFS-100 instrument.
- FT-RAMAN Fourier transform Raman
- Figure 5 shows the thermogravimetry and differential thermal analysis curve for form A of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl- phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide according to the present invention.
- Figure 6 shows the x-ray powder diffraction pattern for form A' of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl- pyrimidin-2-ylamino)-benzamide according to the present invention.
- Figure 7 shows the x-ray powder diffraction pattern for form A" of the hydrochloride salt of4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl- pyrimidin-2-ylamino)-benzamide according to the present invention.
- Figure 8 shows the x-ray powder diffraction pattern for form B of the hydrochloride salt of4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl- pyrimidin-2-ylammo)-benzarnide according to the present invention.
- Figure 9 shows the FT-IR spectrum for form B of the hydrochloride salt of 4-methyl- N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2- ylamino)-benzamide as recorded in Nujol mull between two KBr plates using a Bruker IFS-55 instrument.
- Figure 10 shows the FT-RAMAN spectrum for form B of the hydrochloride salt of 4- methyl-N- [3 -(4-methyl-imidazol- 1 -yl)-5-trifluoromethyl-phenyl] -3 -(4-pyridin-3 -yl- pyrimidin-2-ylamino)-benzamide as recorded using a Bruker RFS-100 instrument.
- Figure 11 shows the thermogravimetry and differential thermal analysis curve for form B of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide according to the present invention.
- Figure 12 shows the x-ray powder diffraction pattern for form B' of the hydrochloride salt of4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl- pyrimidin-2-ylamino)-benzamide according to the present invention.
- Figure 13 shows the x-ray powder diffraction pattern for form S B of the hydrochloride salt of 4-methyl-N- [3 -(4-methyl-imidazol- 1 -yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl- pyrimidin-2-ylamino)-benzamide according to the present invention.
- Figure 14 shows the x-ray powder diffraction pattern for form S B ' of the hydrochloride salt of 4-methyl-N- [3 -(4-methyl-imidazol- 1 -yl)-5-trifluoromethyl-phenyl] -3 -(4- pyridin-3-yl-pyrimidin-2-ylamino)-benzamide according to the present invention.
- Figure 15 shows the x-ray powder diffraction pattern for form C of the hydrochloride salt of4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl- pyrimidin-2-ylamino)-benzamide according to the present invention.
- Figure 16 shows the FT-IR spectrum for form C of the hydrochloride salt of 4-methyl- N- [3 -(4-methyl-imidazol- 1 -yl)-5-trifluoromethyl-phenyl]-3 -(4-pyridin-3 -yl-pyrimidin-2- ylamino)-benzamide as recorded in Nujol mull between two KBr plates using a Bruker IFS-55 instrument.
- Figure 17 shows the FT-RAMAN spectrum for form C of the hydrochloride salt of 4- methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl- pyrimidin-2-ylamino)-benzamide as recorded using a Bruker RFS-100 instrument.
- Figure 18 shows the x-ray powder diffraction pattern for form C of the hydrochloride salt of4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifiuoromethyl-phenyl]-3-(4-pyridin-3-yl- pyrimidin-2-ylamino)-benzamide according to the present invention.
- Figure 19 shows the x-ray powder diffraction pattern for form Sc of the hydrochloride salt of4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl- pyrimidin-2-ylamino)-benzamide according to the present invention.
- Figure 20 shows the x-ray powder diffraction pattern for a mixture of form D and form B of the hydrochloride salt of 4-methyl-N-[3 -(4-methyl-imidazol- 1 -yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide according to the present invention.
- Figure 21 shows the x-ray powder diffraction pattern for form SE of the hydrochloride salt of 4-methyl-N- [3 -(4-methyl-imidazol- 1 -yl)-5-trifluorometliyl-phenyl]-3-(4-pyridin-3-yl- pyrimidin-2-ylamino)-benzamide according to the present invention.
- Figure 22 shows the x-ray powder diffraction pattern (XRPD) for the amorphous form of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl- phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide according to the present invention.
- XRPD x-ray powder diffraction pattern
- Figure 23 shows the FT-IR spectrum for the amorphous form of the hydrochloride salt of4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl- pyrimidin-2-ylamino)-benzamide as recorded in Nujol mull between two KBr plates using a Bruker IFS-55 instrument.
- Figure 24 shows the FT-RAMAN spectrum for the amorphous form of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4- pyridin-3-yl-pyrimidin-2-ylamino)-benzamide as recorded using a Bruker RFS-100 instrument.
- Figure 25 shows the x-ray powder diffraction patterns for forms A and B of the sulfate salt of 4-methyl-N- [3 -(4-methyl-imidazol- 1 -yl)-5 -trifluoromethyl-phenyl] -3 -(4-pyridin-3 -y 1- pyrimidin-2-ylamino)-benzamide according to the present invention.
- crystalline form(s) differ with respect to thermodynamic stability, physical parameters, x-ray structure and preparation processes. While polymorphism classically refers to the ability of a compound to crystallize into more than one distinct crystal species (having identical chemical structure but quite different physicochemical properties), the term pseudopolymorphism is typically applied to solvate and hydrate crystalline forms. For purposes of this invention, however, both true polymorphs as well as pseudopolymorphs, i.e., hydrate and solvate forms, are included in the scope of "crystalline forms”.
- amorphous refers to a disordered solid state. It should be noted that different samples of a particular crystalline form will share the same major XRPD peaks, but that there can be variation in powder patterns with regard to minor peaks.
- the term "about” with regard to XRPD maxima values (in °) generally means within 0.3°, more preferably within 0.2°, and most preferably within 0.1° of the given value; alternatively, the term “about” means (in this and all contexts) within an accepted standard of error of the mean, when considered by one of ordinary skill in the art.
- the terms “isolated” and/or “substantially pure” mean more than 50% of the crystalline 4-methyl- N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2- ylamino)-benzamide or salt thereof is present in one of the forms described herein and preferably at least 70%, more preferably at least 80%, and most preferably at least 90% of one of the crystalline forms described herein is present.
- the first embodiment of the present invention is directed to a substantially pure crystalline form A of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3- (4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide free base.
- Form A of the free base is slightly hygroscopic (maximum water uptake of less than 2% at 25 0 C up to 80% r.h.) and has rather low solubility in an aqueous buffer solution, i.e., 2 mg/L at pH 6.8 and >200 mg/L at pH 1.0; hygroscopic behavior is reversible.
- Form A's basic thermal properties were studied by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and are as follows:
- the x-ray powder diffraction pattern of free base form A shows at least one, more preferably at least two, still more preferably at least four, and most preferably all, maxima selected from about 9.2°, 13.1°, 13.9°, 16.7°, 17.9°, 18.4°, 19.8°, 24.1° and 25.8° (2 ⁇ degrees).
- maxima selected from about 9.2°, 13.1°, 13.9°, 16.7°, 17.9°, 18.4°, 19.8°, 24.1° and 25.8° (2 ⁇ degrees).
- the term "about” applies to each listed maxima for this and all other forms addressed in this invention.
- a particularly preferred embodiment of the present invention is directed to a substantially pure crystalline form A of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)- 5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide free base as characterized by the XRPD of Figure 1.
- the second embodiment of the present invention is directed to a substantially pure crystalline form B of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3- (4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide free base.
- Form B of the free base is not hygroscopic (maximum water uptake of less than 0.2% at 25 0 C up to 80% r.h.) and has rather low solubility in an aqueous buffer solution, i.e., 0.2 mg/L at pH 6.8, 2.8 mg/L at pH 2.8 and 839 mg/L at pH 1.0; hygroscopic behavior is reversible.
- Form B's basic thermal properties were studied by thermogravimetric analysis and differential scanning calorimetry and are as follows:
- the x-ray powder diffraction pattern of free base form B shows at least one, more preferably at least two, still more preferably at least four, and most preferably all, maxima selected from about 4.3°, 6.8°, 7.2°, 13.5°, 14.5°, 17.4°, 19.6° and 26.7° (29 degrees).
- a particularly preferred embodiment of the present invention is directed to a substantially pure crystalline form B of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3- (4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide free base as characterized by the XRPD of Figure 1.
- salt refers to a compound prepared by the reaction of an organic acid or base drug with a pharmaceutically acceptable mineral or organic acid or base; suitable pharmaceutically acceptable minerals or organic acids or bases are as listed in Tables 1-8 in Handbook of Pharmaceutical Salts, P.H. Stahl and CG. Wermuth (eds.), VHCA, Zurich, pp. 334-345 (2002).
- Co-pending U.S. Patent Application No. 60/701,406 (Attorney Docket No.
- Forms A and B for the sulfate salt can be characterized by the XRPD patterns shown in Figure 25. Accordingly, additional embodiments of the present invention are directed to each of these substantially pure crystalline forms of the noted salts of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.
- Form A of the hydrochloride salt is a dihydrate which has relatively poor crystallinity. In the presence of methanol vapor, form A converts to form B (described below).
- a DSC scan of form A indicates that the dehydration of form A (typically above 77°C) is complex; a final endothermic event at about 21O 0 C corresponds to melting as shown by DSC, TGA and XRPD.
- XRPD at various temperatures shows an intermediate form between about 105-135 0 C (Form A' described further below), which is the corresponding monohydrate form, and an anhydrous form (Form A" described further below) was obtained from about 135 0 C up; after heating up to about 205 0 C, form A" retains its form upon holding at about 4O 0 C for about 30 minutes.
- the x-ray powder diffraction pattern for form A of the hydrochloride salt shows at least one, more preferably at least two, still more preferably at least four, and most preferably all, maxima selected from about 8.5°, 11.0°, 11.5°, 17.2°, 18.8°, 19.2°, 20.8°, 22.1° and 26.0° (2 ⁇ degrees).
- a particularly preferred embodiment of the present invention is directed to a substantially pure crystalline form A of the hydrochloride salt of 4-methyl-N- [3 -(4-methyl- imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide as characterized by the XRPD of Figure 2.
- the FT-IR spectrum of form A of the hydrochloride salt of 4-methyl-N- [3 -(4-methyl-imidazol- 1 -yl)-5-trifluoromethyl-phenyl]-3-(4- pyridin-3-yl-pyrimidm-2-ylamino)-benzamide is as shown in Figure 3.
- the main IR bands are about: 3342, 2925, 2854, 1682, 1619, 1541, 1448, 1421, 1399, 1378, 1316, 1299, 1255, 1226, 1159, 1147, 1099, 1089, 930, 868, 798, 749, 708, and 693 cm “1 .
- a substantially pure crystalline form A of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4- pyridin-3-yl-pyrimidin-2 ⁇ ylamino)-benzamide is characterized by an FT-IR spectrum having at least one, more preferably at least two, still more preferably at least four, and most preferably all, of the IR bands noted above.
- the FT-RAMAN spectrum of form A of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4- pyridin-3-yl-pyrimidin-2-ylamino)-benzamide is as shown in Figure 4.
- the main RAMAN bands are about: 3059, 2933, 1684, 1617, 1594, 1562, 1493, 1452, 1423, 1401, 1384, 1300, 1260, 1115, 1039, 1023, 997, 970, 807, 684, 627, 407, 318, 258, 227, 117, and 86 crn 1 .
- a substantially pure crystalline form A of the hydrochloride salt of 4-methyl-N-[3 -(4-methyl-imidazol- 1 -yl)-5 -trifluoromethyl-phenyl] -3 -(4- pyridin-3-yl ⁇ pyrimidin-2-ylamino)-benzamide is characterized by an FT-RAMAN spectrum having at least one, more preferably at least two, still more preferably at least four, and most preferably all, of the RAMAN bands noted above.
- the thermogravimetry and differential thermal analysis (TG-DTA) curve for form A of the hydrochloride salt is shown in Figure 5.
- Additional crystalline forms related to form A of the hydrochloride salt include form A' and form A", which represent a monohydrate of form A and an anhydrous form of form A, respectively.
- Form A' converts within a few minutes under room conditions to form A.
- the x-ray powder diffraction pattern for form A' (monohydrate) of the hydrochloride salt shows at least one, more preferably at least two, still more preferably at least four, and most preferably all, maxima selected from about 4.3°, 8.6°, 11.6°, 12.1°, 17.1°, 20.6°, 24.5°, 25.3°, 25.8°, 27.3° and 31.6° (2 ⁇ degrees).
- a particularly preferred embodiment of the present invention is directed to a substantially pure crystalline form A' of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l -yl)-5-trifluoromethyl-phenyl]-3-(4- pyridin-3-yl-pyrimidin-2-ylamino)-benzamide as characterized by the XRPD of Figure 6.
- the x-ray powder diffraction pattern for form A" (anhydrous) of the hydrochloride salt shows at least one, more preferably at least two, still more preferably at least four, and most preferably all, maxima selected from about 4.5°, 8.8°, 11.5°, 11.9°, 13.0°, 14.4°, 14.8°, 15.3°, 16.9°, 17.6°, 19.2°, 19.5°, 19.9°, 21.3°, 24.6°, 25.4°, 26.4°, 27.9° and 31.5° (2 ⁇ degrees).
- a particularly preferred embodiment of the present invention is directed to a substantially pure crystalline form A" of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluorometliyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide as characterized by the XRPD of Figure 7.
- Crystalline form B of the hydrochloride salt is a monohydrate which has a theoretical moisture content of 3.1% and shows superior crystallinity and physical stability with respect to form A of the hydrochloride salt. In the presence of ethanol, form B converts to form A.
- a DSC scan of form B shows a first endotherm at about 100 0 C- 12O 0 C which corresponds to dehydration, i.e., transition to an anhydrous crystalline form B'; DSC also shows a second endotherm at about 19O 0 C which corresponds to melting.
- XRPD at various temperatures shows anhydrous form B' between about 145°C-195°C; after melting at about 195 0 C, form B' becomes amorphous upon holding at about 4O 0 C for about 30 minutes.
- Form B' converts within a few minutes under room conditions to form B.
- the x-ray powder diffraction pattern for form B of the hydrochloride salt shows at least one, more preferably at least two, still more preferably at least four, and most preferably all, maxima selected from about 7.2°, 9.2°, 11.4°, 12.0°, 12.3°, 14.6°, 14.8°, 15.7°, 17.6°, 19.2°, 19.5,° 20.5°, 22.0°, 23.4°, 23.9°, 25.0°, 25.5°, 25.9°, 27.0° (2 ⁇ degrees).
- a particularly preferred embodiment of the present invention is directed to a substantially pure crystalline form B of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide as characterized by the XRPD of Figure 8.
- the FT-IR spectrum of form B of the hydrochloride salt of 4-methyl-N- [3 -(4-methyl-imidazol- 1 -yl)-5 -trifluoromethyl-phenyl]-3 -(4-pyridin-3 -yl- pyrimidm-2-ylamino)-benzamide is as shown in Figure 9.
- the main IR bands are about: 3211, 3058, 2925, 2854, 1676, 1614, 1587, 1454, 1411, 1378, 1343, 1304, 1279, 1263, 1230, 1197, 1181, 1120, 1089, 1046, 1033, 1005, 905, 892, 874, 801, 755, 706, and 695 cm '1 .
- a substantially pure crystalline form B of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4- pyridin-3-yl-pyrimidin-2-ylamino)-benzamide is characterized by an FT-IR spectrum having at least one, more preferably at least two, still more preferably at least four, and most preferably all, of the IR bands noted above.
- the main RAMAN bands are about: 3078, 3026, 2975, 2930, 1672, 1610, 1602, 1593, 1541, 1476, 1451, 1400, 1385, 1332, 1303, 1263, 1251, 1210, 1089, 1046, 1033, 851, 802, 755, 660, 483, 456, 395, 355, 317, 217, 243, 198, .160, 148, and 114 cm "1 .
- a substantially pure crystalline form B of the hydrochloride salt of 4-methyl-N-[3- (4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)- benzamide is characterized by an FT-RAMAN spectrum having at least one, more preferably at least two, still more preferably at least four, and most preferably all, of the RAMAN bands noted above.
- the thermogravimetry and differential thermal analysis (TG-DTA) curve for form B of the hydrochloride salt is shown in Figure 11.
- the x-ray powder diffraction pattern for form B' (anhydrous) of the hydrochloride salt shows at least one, more preferably at least two, still more preferably at least four, and most preferably all, maxima selected from about 7.2°, 9.2°, 11.5°, 12.0°, 13.9°, 14.3°, 15.4°, 17.6°, 18.6°, 20.3°, 21.7°, 22.5°, 23.2°, 24.7°, 24.9°, 25.2°, 26.0°, 26.6°, 27.5°, 28.2°, 29.2° and 30.0° (2 ⁇ degrees).
- a particularly preferred embodiment of the present invention is directed to a substantially pure crystalline form B' of the hydrochloride salt of 4-methyl-N-[3- (4-methyl-imidazol-l-yl)-5-tri:fluoromethyl-pheny ⁇ benzamide as characterized by the XRPD of Figure 12.
- the anhydrous form B' converts back to the monohydrate.
- Form B is favored in solvents with low moisture content ( ⁇ 5%), and form A is favored in solvents with a high moisture content.
- Form B of the hydrochloride salt can be produced from methanol; however, it appears that it crystallizes first as a methanol solvate (form S B described further below) which then converts quickly to the monohydrate form B when exposed to air.
- the methanol solvate does not, however, convert to form B if vacuum dried; air drying suffices for conversion to form B.
- An additional embodiment of the present invention is directed to form S B of the hydrochloride salt, which is a dimethanol solvate corresponding to form B of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l -yl)-5-trifluoiOmethyl-phenyl]-3-(4- pyridin-3-yl-pyrimidin-2-ylamino)-benzamide; this form can be isolated only if protected from ambient conditions, i.e., ambient moisture, which causes conversion to the form B monohydrate hydrochloride salt.
- the x-ray powder diffraction pattern for form S B of the hydrochloride salt shows at least one, more preferably at least two, still more preferably at least four, and most preferably all, maxima selected from about 7.5°, 9.3°, 11.5°, 14.8°, 19.4°, 21.9°, 23.0°, 23.8°, 24.9°, 25.6°, 25.9°, 26.3° and 26.7° (2 ⁇ degrees).
- a particularly preferred embodiment of the present invention is directed to a substantially pure crystalline form SB of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]- 3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide as characterized by the XRPD of Figure 13.
- Another related crystalline form is form S B ', which is believed to be a mono- methanol solvate corresponding to form B.
- the x-ray powder diffraction pattern for form S B ' of the hydrochloride salt shows at least one, more preferably at least two, still more preferably at least four, and most preferably all, maxima selected from about 7.5°, 9.3°, 11.6°, 12.4°, 13.4°, 13.8°, 14.9°, 19.7°, 20.2°, 22.0°, 23.0°, 23.9°, 24.2°, 25.1°, 26.0°, 26.8°, 29.3° and 30.7° (2 ⁇ degrees).
- a particularly preferred embodiment of the present invention is directed to a substantially pure crystalline form S B ' of the hydrochloride salt of 4-methyl-N-[3-(4- methyl-imidazol- 1 -yl)-5-trifluoromethyl-phenyl] -3 -(4-pyridin-3 -yl-pyrimidin-2-ylamino)- benzamide as characterized by the XRPD of Figure 14.
- Form C of the hydrochloride salt is another monohydrate.
- form C converts to form B.
- a DSC scan of form C shows a first endotherm at about 100°C-120°C which corresponds to dehydration, i.e., transition to an anhydrous crystalline form C; DSC also shows a second endotherm at about 18O 0 C which corresponds to melting.
- XRPD at various temperatures shows anhydrous form C between about 155-195 0 C; after melting at about 195 0 C, form C becomes amorphous upon holding at about 4O 0 C for about 30 minutes.
- the x-ray powder diffraction pattern for form C of the hydrochloride salt shows at least one, more preferably at least two, still more preferably at least four, and most preferably all, maxima selected from about 6.6°, 7.0°, 8.9°, 11.2°, 11.8°, 13.3°, 14.0°, 17.3°, 18.4°, 20.0°, 22.1° and 23.0° (2 ⁇ degrees).
- a particularly preferred embodiment of the present invention is directed to a substantially pure crystalline form C of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl- pyrimidm-2-ylamino)-benzamide as characterized by the XRPD of Figure 15.
- the FT-IR spectrum of form C of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide is as shown in Figure 16.
- the main IR bands are about: 3332, 2925, 2854, 1670, 1615, 1588, 1556, 1455, 1414, 1312, 1293, 1260, 1234, 1179, 1126, 1087, 1087, 1050, 1032, 886, 797, 758, and 696 cm “1 .
- a substantially pure crystalline form C of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide is characterized by an FT-IR spectrum having at least one, more preferably at least two, still more preferably at least four, and most preferably all, of the IR bands noted above.
- the FT-RAMAN spectrum of form C of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide is as shown in Figure 17.
- the main RAMAN bands are about: 3075, 2932, 1670, 1610, 1592, 1494, 1452, 1398, 1383, 1309, 1294, 1259, 1210, 1087, 1047, 1033, 1022, 852, 799, 639, 271, 244, 162, 100, and 85 cm "1 .
- a substantially pure crystalline form C of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylammo)-benzamide is characterized by an FT-RAMAN spectrum having at least one, more preferably at least two, still more preferably at least four, and most preferably all, of the RAMAN bands noted above.
- Form C converts within a few minutes under room conditions to a mixture of forms B and C.
- the x-ray powder diffraction pattern for form C of the hydrochloride salt shows at least one, more preferably at least two, still more preferably at least four, and most preferably all, maxima selected from about 6.7°, 6.9°, 9.1°, 11.4°, 12.0°, 13.8°, 14.2°, 24.8° and 25.8° (20 degrees).
- a particularly preferred embodiment of the present invention is directed to a substantially pure crystalline form C of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)- 5-trifluoromethyl-phenyl] -3 -(4-pyridin-3 -yl-pyrimidin-2-ylamino)-benzamide as characterized by the XRPD of Figure 18.
- An additional embodiment of the present invention is directed to form Sc of the hydrochloride salt, which is a methanol solvate corresponding to form C of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l -yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl- pyrimidin-2-ylamino)-benzamide.
- Form C appears to crystallize first as a methanol solvate (form Sc) which then converts quickly to the monohydrate form C when exposed to air.
- the methanol solvate does not, however, convert to form C if vacuum dried; air drying suffices for conversion to form C.
- the x-ray powder diffraction pattern for form Sc of the hydrochloride salt shows at least one, more preferably at least two, still more preferably at least four, and most preferably all, maxima selected from about 6.5°, 7.3°, 9.1°, 10.8°, 12.1°, 13.0°, 14.5°, 14.9°, 18.9°, 19.4°, 24.2°, 25.0°, 25.4°, 26.2°, 27.4° and 28.4° (2 ⁇ degrees).
- a particularly preferred embodiment of the present invention is directed to a substantially pure crystalline form Sc of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl] -3 -(4-pyridin-3 -yl-pyrimidin-2-ylamino)-benzamide as characterized by the XRPD of Figure 19.
- Another crystalline form of the hydrochloride salt is form D.
- Crystalline form D has thus far been obtained in mixture with form B of the hydrochloride salt.
- the x-ray powder diffraction pattern for form D of the hydrochloride salt shows at least one, more preferably at least two, and most preferably all, maxima selected from about 5.7°, 8.4° and 9.8° (2 ⁇ degrees); the XRPD also shares the maxima of form B noted above due to the presence of form B in mixture with form D.
- a preferred embodiment of the present invention is directed to a crystalline form D of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)- 5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide as shown in Figure 20.
- a more preferred embodiment comprises a substantially pure crystalline form D of the hydrochloride salt.
- Form S E is a dimethylformamide solvate of the hydrochloride salt.
- Form S E can be obtained by treating either form C or the amorphous form of the hydrochloride salt with dimethylformamide vapor at, e.g., 25 0 C.
- the x-ray powder diffraction pattern for form S E of the hydrochloride salt shows at least one, more preferably at least two, still more preferably at least four, and most preferably all, maxima selected from about 3.4°, 4.5°, 5.1°, 5.8°, 7.2°, 9.3°, 10.1°, 12.9°, 13.3°, 13.8°, 14.8°, 15.7°, 17.4°, 19.6°, 20.8°, 21.3°, 22.5°, 24.4°, 25.5°, 26.0°, 27.4° and 27.9° (2 ⁇ degrees).
- a particularly preferred embodiment of the present invention is directed to a substantially pure crystalline form S E of the hydrochloride salt of 4-methyl-N-[3-(4- methyl-imidazol- 1 -yl)-5-trifluoromethyl-phenyl] -3 -(4-pyridin-3 -yl-pyrimidin-2-ylamino)- benzamide as characterized by the XRPD of Figure 21.
- the hydrochloride salt in addition to all of the above-noted crystalline forms (i.e., polymorphs, pseudopolymorphs) of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl] -3 -(4-pyridin-3 -yl-pyrimidin-2-ylamino)-benzamide, the hydrochloride salt also exists in an amorphous form. The amorphous form spontaneously converts to the form A hydrochloride salt after storage at various relative humidities. In the presence of methanol vapor, the amorphous form converts to form B.
- the main IR bands are about: 1671, 1615, 1556, 1479, 1447, 1416, 1379, 1354, 1308, 1263, 1225, 1173, 1130, 1025, 1090, 802, 753, 707, and 695 cm “1 .
- a substantially pure amorphous form of the hydrochloride salt of 4-methyl-N-[3-(4-methyl- imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide is characterized by an FT-IR spectrum having at least one, more preferably at least two, still more preferably at least four, and most preferably all, of the IR bands noted above.
- the FT- RAMAN spectrum of the amorphous form of the hydrochloride salt of 4-methyl-N-[3-(4- methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)- benzamide is as shown in Figure 24.
- the main RAMAN bands are about: 3059, 2931, 1672, 1614, 1591, 1485, 1445, 1400, 1383, 1298, 1261, 1206, 1091, 1041, 1024, 999, 969, 807, 755, 710, 614, 315, and 109 cm "1 .
- a substantially pure amorphous form of the hydrochloride salt of 4-methyl-N-[3-(4-methyl- imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide is characterized by an FT-RAMAN spectrum having at least one, more preferably at least two, still more preferably at least four, and most preferably all, of the RAMAN bands noted above.
- Form A of the sulfate salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl] -3 -(4-pyridin-3 -yl-pyrimidin-2-ylamino)-benzamide is another embodiment of this invention.
- the x-ray powder diffraction pattern for form A of the sulfate salt of 4-methyl-N-[3-(4-methyl-imidazol-l -yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl- pyrimidin-2-ylamino)-benzamide shows at least one, more preferably at least two, still more preferably at least four, and most preferably all, maxima selected from about 6.3°, 7.7°, 9.5°, 10.7°, 17.9° and 18.9° (2 ⁇ degrees).
- a particularly preferred embodiment of the present invention is directed to a substantially pure crystalline form A of the sulfate salt of 4-methyl- N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2- ylamino)-benzamide as characterized by the XRPD of Figure 25.
- Form B of the sulfate salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide is another embodiment of this invention.
- the x-ray powder diffraction pattern for form B of the sulfate salt of4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl- pyrimidin-2-ylamino)-benzamide shows at least one, more preferably at least two, still more preferably at least four, and most preferably all, maxima selected from about 7.3°, 17.7°, 19.0°, 20.2° and 20.8° (2 ⁇ degrees).
- a particularly preferred embodiment of the present invention is directed to a substantially pure crystalline form B of the sulfate salt of 4-methyl- N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2- ylamino)-benzamide as characterized by the XRPD of Figure 25.
- the sulfate salt in addition to the above-noted crystalline forms of the sulfate salt of 4-methyl-N-[3- (4-methyl-imidazol- 1 -yl)-5 -trifluoromethyl-phenyl] -3 -(4-pyridin-3-yl-pyrimidin-2-ylamino)- benzamide, the sulfate salt also exists in an amorphous form.
- a preferred embodiment of the present invention comprises a substantially pure amorphous form of the sulfate salt of. 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl- pyrimidin-2-ylamino)-benzamide.
- Another embodiment of the present invention is directed to a pharmaceutical composition
- a pharmaceutical composition comprising:
- the substantially pure crystalline form is form B of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4- pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.
- more than 50%, more preferably at least 70%, still, more preferably at least 80%, and most preferably at least 90%, of the crystalline form present in the composition is of one of the selected forms.
- a “therapeutically effective amount” is intended to mean the amount of the inventive crystalline form that, when administered to a subject in need thereof, is sufficient to effect treatment for disease conditions alleviated by the inhibition of protein kinase activity.
- the amount of a given compound of the invention that will be therapeutically effective will vary depending upon factors such as the disease condition and the severity thereof, the identity of the subject in need thereof, etc., which amount may be routinely determined by artisans of ordinary skill in the art.
- the at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient can readily be selected by one of ordinary skill in the art and will be determined by the desired mode of administration.
- suitable modes of administration include oral, nasal, parenteral, topical, transdermal, and rectal.
- the pharmaceutical compositions of this invention may take any pharmaceutical form recognizable to the skilled artisan as being suitable. Suitable pharmaceutical forms include solid, semisolid, liquid, or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions, liposomes, and aerosols.
- Yet another embodiment of the present invention is directed to a method of treating a disease which responds to an inhibition of protein kinase activity comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of a substantially pure crystalline form of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide according to one of the earlier embodiments of the present invention.
- the substantially pure crystalline form is form B of the hydrochloride salt of 4-methyl-N-[3-(4- methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)- benzamide.
- more than 50%, more preferably at least 70%, still more preferably at least 80%, and most preferably at least 90%, of the crystalline form administered is of one of the inventive forms.
- illustrative modes of administration include oral, nasal, parenteral, topical, transdermal, and rectal.
- Administration of the crystalline form may be accomplished by administration of a pharmaceutical composition of this invention or via any other effective means.
- Form B of the hydrochloride salt of 4- methyl-N- [3 -(4-methyl-imidazol- 1 -yl)-5-trifluoromethyl-phenyl]-3 -(4-pyridin-3 -yl- pyrimidin-2-ylamino)-benzamide is dissolved in a medium where the solubility is high, and a solvent in which the salt is highly insoluble is added. The precipitates are collected on a filter, dried and investigated by XRPD.
- Granulating solvent is added dropwise to form B of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl- pyrimidin-2-ylamino)-benzamide until the solid is wetted sufficiently.
- the material is vortexed between each addition. Then the material is dried under vacuum to ⁇ 2% or less and evaluated for form and degree of crystallinity by XRPD or DSC.
- Amorphous 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4- pyridin-3-yl-pyrimidm-2-ylamino)-benzamide hydrochloride was crystallized in acetonitrile to form a mixture of form A of the hydrochloride salt and form A of the free base.
- Amorphous 4-methyl-N- [3 -(4-methyl-imidazol- 1 -yl)-5 -trifluoromethyl-phenyl]-3 -(4-pyridin- 3-yl-pyrimidin-2-ylamino)-benzamide hydrochloride was crystallized in isopropanol to form a mixture of form A of the hydrochloride salt and a small amount of form A of the free base.
- the resulting solution was filtered through a polypropylene pad, while maintaining the batch temperature above 4O 0 C.
- the clear solution was transferred under nitrogen atmosphere to another 1 L, 4-neck, round-bottom flask equipped with a mechanical stirrer, a thermometer, and heating/cooling capacity.
- the batch was stirred and cooled to 3O 0 C over a period of 30 minutes. Seeds (20 mg) were added at this temperature, and the batch was cooled to 23 0 C over a period of 45 minutes.
- the batch was stirred for an additional 3 hours to obtain a thick white suspension.
- the suspension was cooled to -1O 0 C over a period of 1.5 hours and stirred for an additional 30 minutes.
- form A of the free base has a lower solubility at 25 0 C as compared to form B of the free base in the different solvent mixtures. Solubility was too low to perform proper comparison in water.
- the suspension is stirred at 42 0 C for 2.5 hours and afterwards cooled down to -1O 0 C according to a slow cooling profile.
- the cooling is interrupted for four hours in order to let a potentially formed methanol solvate transform to the desired monohydrate.
- the suspension is filtered and washed with two portions of methanol/water mixture (99% methanol/1% water).
- the filter cake is dried in an oven at 7O 0 C under a vacuum below 10 mbar overnight.
- the water content after filtration was found to be below the theoretical value of 3.05% for 50 g scale and above.
- a second drying stage is added where water is evaporated in a stirred vessel and transported to the dryer by a vacuum pump.
- the conditions in the dryer are changed to 6O 0 C and 30 mbar in order to assure adequate conditions for the desired water content.
- the water is added until the saturation capacity is reached.
- a water content of 3.5-3.6% was obtained with two lab scale (1 L) paddle dryer experiments.
- the suspension is kept for 79 hours before filtration under vacuum.
- the solid is. washed 2 times with a cold mixture of methanol/water 66 mL/5.26 mL (-1O 0 C) and dried under vacuum at 7O 0 C for 20 hours to obtain form C of the hydrochloride salt of4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl- pyrimidin-2-ylamino)-benzamide .
- the solution is spray dried in a Buchi Mini spray at about 65 0 C to form the amorphous hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl- phenyl] -3 -(4-pyridin-3 -yl-pyrimidin-2-ylamino)-benzamide .
- the dimethanol solvate form S B of the hydrochloride salt of 4-methyl-N- [3 -(4-methyl-imidazol- 1 -yl)-5 -trifluoromethyl-phenyl] -3 ⁇ (4-pyridin-3 -yl- pyrimidin-2-ylamino)-benzarnide is obtained.
- the suspension is kept for 2.5 hours at 42 0 C, cooled down within 7 hours at 2O 0 C, and maintained at this temperature for 11 hours.
- the methanol solvate form Sc of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl] -3 -(4-pyridin-3 -yl-pyrimidin-2-ylamino)-benzamide is obtained.
- the seed solution was obtained from 3.6 mg of hydrochloride 4-methyl-N-[3-(4- methyl-imidazol- 1 -yl)-5 -trifluoromethyl-phenyl] -3-(4-pyridin-3 -yl-pyrimidin-2-ylamino)- benzamide dissolved in a methanol/water solution (360 mg/36 mg).
- a methanol/water solution 360 mg/36 mg.
- an additional 36 mg of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4- pyridin-3-yl-pyrimidin-2-ylamino)-benzamide are added.
- the suspension is maintained for 1 hour at room temperature, and the suspension is placed in an ultrasonic bath for 10 seconds.
- Form A of the free base of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl] -3 -(4-pyridin-3 -yl-pyrimidin-2-ylamino)-benzamide is made according to the following scheme:
- Form B of the free base of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl] -3 -(4-pyridin-3 -yl-pyrimidin-2-ylamino)-benzamide is made according to the following scheme:
- Form B of the free base of 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl- phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide (crystalline solid) is collected by filtration and washed with 150 mL of cold ethanol 94%. The product is then dried at 50°C in vacuo.
- IDR Intrinsic Dissolution Rate
- the intrinsic dissolution rate was also determined for each of form A, form B, form C and the amorphous form of the hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-l- yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide in various solvents.
- the measurements were carried out on a VanKel instrument using a Gary 100 photometer. The results are shown in Table 23 below. Table 23.
- each of the forms has good chemical stability for 1 month at 50°C, for 1 month at 8O 0 C and for 1 month at 8O 0 C and 75% relative humidity, though both form C and the amorphous form showed a mixture with form A under the last condition.
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Abstract
Description
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Priority Applications (35)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PL06800109T PL1912973T3 (en) | 2005-07-20 | 2006-07-18 | Crystalline forms of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
EP06800109A EP1912973B1 (en) | 2005-07-20 | 2006-07-18 | Crystalline forms of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
EP10173956.3A EP2284167B2 (en) | 2005-07-20 | 2006-07-18 | Crystalline form of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
CN200680026434.2A CN101228150B (en) | 2005-07-20 | 2006-07-18 | Crystalline forms of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
EA200800201A EA013464B1 (en) | 2005-07-20 | 2006-07-18 | Crystalline forms of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-2-ylamino)-benzamide |
US11/995,906 US8343984B2 (en) | 2005-07-20 | 2006-07-18 | Crystalline forms of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
BRPI0613615-0A BRPI0613615B1 (en) | 2005-07-20 | 2006-07-18 | CRYSTALLINE B FORM OF 4-METHYL-N-[3-(4-METHYLIMIDAZOLE-1-YL)-5-TRIFLUOROMETHYL-PHENYL]-3-(4-PYRIDIN-3-YLPYRIMIDIN-2-ILAMINO)- BENZAMIDE AND PHARMACEUTICAL COMPOSITION |
UAA200800629A UA94234C2 (en) | 2005-07-20 | 2006-07-18 | Crystalline forms of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
PL10173956T PL2284167T5 (en) | 2005-07-20 | 2006-07-18 | crystalline forms of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
MX2008000899A MX2008000899A (en) | 2005-07-20 | 2006-07-18 | Crystalline forms of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-tri fluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benz amide. |
CA2614334A CA2614334C (en) | 2005-07-20 | 2006-07-18 | Crystalline forms of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
SI200631365T SI1912973T1 (en) | 2005-07-20 | 2006-07-18 | Crystalline forms of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl] 3-(4-pyridin- 3-yl-pyrimidin-2-ylamino)-benzamide |
KR1020137016680A KR20130077915A (en) | 2005-07-20 | 2006-07-18 | Crystalline forms of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
NZ564409A NZ564409A (en) | 2005-07-20 | 2006-07-18 | Crystalline forms of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide hydrochloride |
SM200800011T SMP200800011B (en) | 2005-07-20 | 2006-07-18 | Crystalline forms of 4-methyl-n- [3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -benzamide |
DK06800109.8T DK1912973T3 (en) | 2005-07-20 | 2006-07-18 | Crystalline forms of 4-methyl-N- [3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl-phenyl] -3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -benzamide |
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AU2011202047A AU2011202047A1 (en) | 2005-07-20 | 2011-05-04 | Crystalline forms of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
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AU2012201453A AU2012201453C1 (en) | 2005-07-20 | 2012-03-09 | Crystalline forms of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
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US13/565,913 US8415363B2 (en) | 2005-07-20 | 2012-08-03 | Crystalline forms of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
CU2012000123A CU20120123A7 (en) | 2005-09-12 | 2012-08-29 | CRYSTAL FORMS OF 4-METHYL-N- [3- (4-METHYL-IMIDAZOL-1-IL) -5-TRIFLUORO-METHYL-PHENYL] -3-IL-PYRIMIDIN-2-IL-AMINO) -BENZAMIDA |
US13/774,433 US8829015B2 (en) | 2005-07-20 | 2013-02-22 | Crystalline forms of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
PH12013501590A PH12013501590A1 (en) | 2005-07-20 | 2013-07-26 | Crystalline forms of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
US14/449,446 US20140343087A1 (en) | 2005-07-20 | 2014-08-01 | Crystalline Forms of 4-Methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
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