Classifications

• • 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
  • C07D401/02—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 two hetero rings
  • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the present application relates to a crystalline polymorphic form of imatinib mesylate.
• Imatinib mesylate has a chemical name 4-[(4-Methyl-1-piperazinyl)methyl]- N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate and can be represented by structural Formula I.
• Imatinib is a protein-tyrosine kinase inhibitor and is available in products sold by Novartis using the trademark GLEEVEC, in the form of tablets containing imatinib mesylate equivalent to 100 mg or 400 mg of imatinib free base.
• Zimmermann et al. in U.S. Patent No. 6,894,051 , describe two crystalline forms of imatinib mesylate, the alpha-form and the beta-form.
• the patent also discloses that the crystalline alpha-form is characterized by needle-shaped crystals having a hygroscopic nature and "the crystals are not particularly well- suited to pharmaceutical formulation as solid dosage forms, because their physical properties, for example their flow characteristics, are unfavorable and the alpha-crystal form is metastable at room temperature.
• Example 1 of the patent discloses a process for preparing the crystalline alpha-form, which comprises: a. Suspending imatinib base in ethanol solvent; b. Adding methanesulfonic acid drop-wise into the suspension; c. Heating the solution to reflux and filtering at 65°C; d. Evaporating the filtrate to 50% of the volume; e. Cooling to 25°C and filtering; f. Collecting the solid (material A); g. Evaporating the mother liquor (filtrate) to dryness; h.
• This process disclosed for preparing alpha crystalline form not only involves several steps, but also is cumbersome and does not give reproducible results.
• Process 1 comprises:
• Process 2 comprises:
• Adin et al. in U.S. Patent Application Publication No. 2006/0223816 A1 ('"816" publication), describe a stable, free-flowing imatinib mesylate alpha-form, which is substantially free of the beta-form.
• This publication describes a process, which comprises: a. Mixing imatinib base with an organic solvent selected from ketones, nithles and cycloalkanes (more particularly methyl ethyl ketone, methyl isobutyl ketone, 4-methylcyclohexanone, cyclohexane, acetonithle and mixtures thereof); b. Heating to dissolve; c. Adding methanesulfonic acid; d. Allowing the crystals to precipitate; e. Isolating the precipitated crystal of imatinib mesylate alpha-form, with seeding.
• an organic solvent selected from ketones, nithles and cycloalkanes (more particularly
• WO 2006/048890 A1 describes a non-needle shaped alpha-crystalline form of imatinib mesylate and a process for its preparation, which includes subjecting a solution of imatinib mesylate in a suitable solvent (which may be a polar protic or aprotic solvent, a non-polar solvent, water or mixture thereof) to agitated thin film drying under atmospheric pressure and/or under vacuum.
• a suitable solvent which may be a polar protic or aprotic solvent, a non-polar solvent, water or mixture thereof
• the present invention provides processes for preparing a non-hygroscopic, stable crystalline alpha-form of imatinib mesylate, comprising: a. Providing a solution or suspension of imatinib base in an ether solvent; b. Optionally, seeding with imatinib mesylate in alpha-form; c. Adding methanesulfonic acid; d. Allowing the reaction mass to cool; and e. Obtaining the alpha-form imatinib mesylate.
• the present invention provides process for preparing a stable crystalline alpha-form of imatinib mesylate wherein the process comprises providing a solution or suspension of imatinib mesylate in an ether solvent, followed by the steps c, d, and e described above.
• the present invention provides pharmaceutical compositions comprising stable crystalline alpha-form imatinib mesylate and at least one pharmaceutically acceptable excipient.
• Fig. 1 is an X-Ray powder diffraction ("XRPD") pattern of the alpha-form of imatinib mesylate prepared according to Example 1.
• Fig. 2 is an infrared (“IR”) absorption spectrum of the alpha-form of imatinib mesylate prepared according to Example 1.
• Fig. 3 is a differential scanning calorimetry ("DSC") curve of the alpha-form of imatinib mesylate prepared according to Example 1.
• Fig. 4 is a thermogravimetric analysis (“TGA”) curve of the alpha-form of imatinib mesylate prepared according to Example 1.
• Fig. 5 is an XRPD pattern of the alpha-form of imatinib mesylate prepared according to Example 2.
• Fig. 6 is an XRPD pattern of the alpha-form of imatinib mesylate of the present invention after one year of storage under ambient conditions.
• Fig. 7 is an infrared (“IR”) absorption spectrum of imatinib mesylate of the present invention after one year of storage under ambient conditions.
• Fig. 8 is a TGA curve of the alpha-form of imatinib mesylate of the present invention after one year of storage under ambient conditions.
• Fig. 9 is a DSC curve of the alpha-form of imatinib mesylate of the present invention after one year of storage under ambient conditions.
• Fig.10 is a TGA curve of the alpha-form of imatinib mesylate prepared according to Example 3.
• the present application provides processes for preparing a stable crystalline alpha-form imatinib mesylate, using solvents comprising cyclic ethers and acyclic ethers.
• the invention further provides a stable crystalline alpha-form imatinib mesylate, which is non-hygroscopic, convenient to handle, and suitable for preparation of solid pharmaceutical dosage forms.
• a stable crystalline form of imatinib mesylate can be characterized by its X- ray powder diffraction pattern, as well as by other analytical techniques. All of the XRPD data reported herein were obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer with a copper K-alpha radiation source.
• crystalline alpha-form imatinib mesylate may be prepared from solvents comprising cyclic ethers and acyclic ethers, giving a product that is not only stable, but also non-hygroscopic, convenient to handle, and suitable for use in preparing solid pharmaceutical formulations.
• the processes of the present invention include crystallizing imatinib mesylate from a solution having solvents comprising cyclic ethers and acyclic ethers, with imatinib and methanesulfonic acid dissolved therein, and optionally seeding with crystals of imatinib mesylate in alpha-form.
• processes for preparing a non-hygroscopic and stable crystalline alpha-form imatinib mesylate comprising: a. providing a solution or suspension of imatinib base in an ether solvent; b. optionally, seeding with imatinib mesylate in alpha-form; c. adding methanesulfonic acid; and d. allowing the reaction mass to cool.
• Step a includes providing a solution or suspension of imatinib base in an ether solvent.
• Imatinib base used in the processes of the present invention can be obtained from processes disclosed in the art, for example U.S. Patent No. 5,521 ,184 or International Application No. PCT/US08/56588, filed on March 12, 2008, or any other processes. Any polymorphic form of the compound, such as crystalline or amorphous forms, including solvates and hydrates, may also be utilized.
• the process of suspending the imatinib base in an ether solvent comprises combining imatinib base with the solvent.
• the suspension of imatinib base may also be obtained directly from a reaction in which imatinib base is synthesized.
• Solvents which may be used for suspending imatinib base include but are not limited to cyclic ethers and acyclic ethers. Specific examples of solvents that may be utilized for the present invention include cyclic ethers such as tetrahydrofuran ("THF"), pentahydropyran, and the like, and acyclic ether solvents such as dimethyl ether, diethyl ether, methyl t-butyl ether, and the like.
• THF tetrahydrofuran
• pentahydropyran and the like
• acyclic ether solvents such as dimethyl ether, diethyl ether, methyl t-butyl ether, and the like.
• the temperatures to which the suspension of imatinib base in a solvent can be heated may range from about 25°C to about 100 0 C, depending on the solvent used.
• the suspension of imatinib mesylate in a solvent may also result in a solution, depending on the temperature to which it is heated.
• the process of the present invention is carried out at temperatures in the range of about 40-70 0 C.
• the quantities of solvent used for providing the suspension or solution depend on the solvent and the temperature adopted.
• the concentration of imatinib base in the suspension may generally range from about 0.03 to about 0.1 g/mL.
• Step b includes optionally seeding with imatinib mesylate in alpha-form.
• seeding with imatinib mesylate is optional.
• the alpha crystalline form obtained from a process disclosed in the art or from the process of the present invention may be used as a seed material.
• Seeding with crystalline alpha form imatinib mesylate is carried out before or after the addition of methanesulfonic acid and after providing a solution or suspension of imatinib base in the ether solvent. In an embodiment, seeding with crystalline alpha-form of imatinib mesylate is carried out before the addition of methanesulfonic acid.
• the quantity of the seed crystals used herein may be in the range of about 1 -8% by weight of alpha-form seeding material, based on the weight of suspended imatinib free base.
• Step c includes adding methanesulfonic acid.
• the molar quantities of methanesulfonic acid that may be used are in the range of about 0.9 to about 1.1 moles, per mole of imatinib base. In embodiments, the molar quantity of methane sulfonic acid used is about 1 mole, per mole of imatinib base.
• Methane sulfonic acid can be added in the form of solution or optionally dissolved in an ether solvent.
• the quantity of ether solvent used to prepare a solution of methanesulfonic acid may range between about 10 and about 25 ml_, per gram of imatinib base. In an embodiment, a volume of ether solvent may be about 15 ml_, per gram of imatinib base.
• the temperatures at which methanesulfonic acid can be added to the mass of step b) may range from about 25°C to about 100 0 C. Any other temperatures may also be acceptable, as long as a solution or suspension of imatinib base is provided. In an embodiment, the process of the present invention is carried out at temperatures in the range of about 40 0 C to about 70°C.
• Step d includes allowing the mass to cool.
• the mass obtained in step c is cooled to obtain the alpha-form of imatinib mesylate.
• the temperature to which the reaction mass is cooled may range from about 0 0 C to about 35°C, depending on the solvent used. Any temperature is acceptable as long as the alpha-form of imatinib mesylate is obtained selectively and completely.
• the cooling may be carried out to temperatures in the range of about 10 0 C to about 30 0 C.
• the product may be obtained from step d by isolation, followed by drying the product.
• Isolation of the crystalline alpha-form obtained in step d can be accomplished by techniques known in art, which include but are not limited to decantation, filtration by gravity or by suction, distillation, centhfuging, slow solvent evaporation, and the like.
• the obtained alpha-form of the present invention is isolated by filtration.
• the isolated solid may optionally be further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperatures about 35°C to about 90 0 C, with or without vacuum. Drying may be carried out for any desired time until the desired product purity is achieved, such as time periods from about 1 to 20 hours, or longer.
• the solid obtained is dried at temperatures ranging from about 30°C to about 60°C, or at temperatures about 40 0 C to about 45°C, under vacuum for a period of 2-3 hours.
• Embodiments of the process provide imatinib mesylate alpha-form having a purity, as determined using high performance liquid chromatograpgy, at least about 98%, at least about 99%, at least about 99.5%, or at least about 99.8%, by weight.
• the present invention provides processes for preparing substantially anhydrous crystalline alpha-form imatinib mesylate, comprising slurrying imatinib mesylate in a hydrocarbon solvent, followed by isolating the solid and drying.
• Hydrocarbon solvents that can be utilized include aliphatic hydrocarbons having 5-10 carbon atoms, and aromatic hydrocarbons having 6-10 carbon atoms. Mixtures of hydrocarbon solvents are useful. Specific examples of some useful hydrocarbons are n-hexane and n-heptane.
• the substantially anhydrous crystalline alpha-form imatinib mesylate obtained by the process has a TGA weight loss (from ambient temperature to about 150 0 C, or to about 200 0 C) less than about 0.5%, which may include water content and other volatile substances that are present.
• a substantially anhydrous crystalline alpha-form imatinib mesylate has a TGA weight loss less than about 0.2%, or less than about 0.1 %.
• the substantially anhydrous product obtained is a stable crystalline alpha- form of imatinib mesylate, which is non-hygroscopic, convenient to handle, and suitable for preparation of solid pharmaceutical dosage forms.
• Imatinib mesylate used as a starting material in the processes can be obtained using a process disclosed in the art, e.g., U.S. Patent No. 6,894,051 , or any other process. Any polymorphic form of imatinib mesylate may be used in the preparation of alpha-form of the present invention.
• a crystalline alpha-form of imatinib mesylate obtained according to the processes of the present invention when packaged in a polyethylene bag that is sealed and placed inside another sealed polyethylene bag, is stable during storage at ambient temperature for at least about one year.
• Stored crystalline alpha-form of imatinib mesylate of the present invention can be characterized by any one or more of: an XRPD diffraction pattern substantially in accordance with Fig. 6; a TGA curve substantially in accordance with Fig. 8; and a DSC curve substantially in accordance with Fig. 9.
• crystalline alpha-form of imatinib mesylate obtained from a process of present invention has a particle size distribution with Di 0 less than about 10 ⁇ m, D 50 less than about 50 ⁇ m, and D 90 less than about 100 ⁇ m.
• D 90 refers to a particle size value for which at least 90 volume percent of the particles have a size smaller than the value given.
• D 50 and Di 0 refer to the values for the particle size for which 50 volume percent, and 10 volume percent, respectively, of the particles have a size smaller than the value given.
• the present invention provides pharmaceutical formulations comprising a stable crystalline alpha-form of imatinib mesylate and one or more pharmaceutically acceptable excipients.
• Suitable pharmaceutically acceptable excipients which can be used in combination with imatinib mesylate include, but are not limited to, hydrophilic substances like polymers of N-vinylpyrrolidone, commonly known as polyvinyl pyrrolidines (“PVP” or “povidone”), gums, cellulose derivatives, cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, polyethylene glycols, polyethylene oxides, polyoxyalkylene derivatives, methacrylic acid copolymers, polyvinylalcohols, propylene glycol derivatives and the like.
• Other pharmaceutically acceptable excipients that are of use include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
• EXAMPLE 1 PREPARATION OF CRYSTALLINE ALPHA-FORM IMATINIB MESYLATE.
• lmatinib base (70.0 g) is added to THF (1750 mL), heated to about 55-60 0 C under a nitrogen atmosphere to form a solution having some turbidity, and seeded with crystalline alpha-form imatinib mesylate (1.0 g, 1.42% w/w).
• a solution of methanesulfonic acid (9.2 mL, 13.628 g) in THF (1050 mL) is added slowly over 3 hours under a nitrogen atmosphere. The mass is stirred for another 30 minutes at 55-60 0 C and cooled to 27°C.
• the formed crystals are filtered and dried under vacuum for about 14 hours at 40-45 0 C, to obtain 68.415 g of crystalline alpha- form imatinib mesylate having a purity of about 99.91 % by weight, as determined using high performance liquid chromatography.
• the product obtained has the X- ray powder diffraction pattern shown in Fig. 1.
• the product is also analyzed by IR spectrophotometry, DSC, and TGA, and the information obtained is shown in Figs. 2, 3, and 4, respectively.
• EXAMPLE 2 PREPARATION OF CRYSTALLINE ALPHA-FORM IMATINIB MESYLATE.
• Imatinib base (1.0 g) is added to THF (25 mL) and heated to about 55-60°C under a nitrogen atmosphere.
• a solution of methanesulfonic acid (0.13 mL, 0.192 g) in THF (15 mL) is added slowly over 3 hours under a nitrogen atmosphere.
• the mass is stirred for another 30 minutes at 55-60 0 C and cooled to 25°C.
• the formed crystals are filtered and dried under vacuum for 1 hour at 40-45 0 C, to obtain 0.950 g of crystalline alpha-form imatinib mesylate.
• the product obtained has the X-ray powder diffraction pattern shown in Fig. 5.
• the crystalline alpha-form of imatinib mesylate obtained in the above example is stable during storage for at least one year, when packaged in a sealed polyethylene bag, and the X-ray powder diffraction pattern for material stored for one year is substantially as shown in Fig. 6.
• the stored material provides an infrared absorption spectrum substantially as shown in Fig. 7, a thermogravimetric analysis curve substantially as shown in Fig. 8 (weight loss about 1 %) and a differential scanning calorimetry curve substantially as shown in Fig. 9 (major peak at about 220 0 C).
• EXAMPLE 3 PREPARATION OFANHYDROUS CRYSTALLINE ALPHA-FORM IMATINIB MESYLATE.
• Alpha-form imatinib mesylate (5.0 g) is suspended in n-heptane (62.5 mL) and slurried for 45 minutes at room temperature under a nitrogen atmosphere. The suspension is filtered and the solid washed with n-heptane (12 mL). The solid is dried under vacuum for 3 hours at 40-45°C, to obtain 4.9 g of light yellow solid crystalline alpha-form imatinib mesylate that is substantially anhydrous. Analyses are reported in the following table. The TGA curve for the product is substantially as shown in Fig. 10.

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• 2009
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