FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of pure α
form of imatinib mesylate, an inhibitor of tyrosine kinases.
BACKGROUND OF THE INVENTION
Imatinib of formula I, an inhibitor of tyrosine kinases is chemically known as N-{5-[4-(4-methyl-piperazinomethyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine amine.
(Formula Removed)
It is indicated for the treatment of chronic myeloid leukemia (CML), Philadelphia chromosome positive leukemia, for patients in chronic phase and in blast crisis, accelerated phase and also for malignant gastrointestinal stromal tumors. It selectively inhibits activation of target proteins involved in cellular proliferation. Imatinib also has potential for the treatment of other cancers that express these kinases, including acute lymphocytic leukemia and certain solid tumors. Imatinib is sold in the US by Novartis as Gleevec™ capsules containing imatinib mesylate equivalent to 100 or 400 mg of imatinib free base.
Imatinib and other related compounds were first disclosed in US patent 5,521,184. US patent 5,521,184 discloses preparation of imatinib and use thereof especially as an anti-tumour agent. However, it does not specify preparation of an imatinib salt or any crystal modifications.
US patent 6,894,051 ('051) discloses preparation of imatinib mesylate in two crystalline forms such as α-crystal form and ß-crystal form. US '051 patent describes α-crystal form of imatinib mesylate characterized by needle shaped crystals and
hygroscopic nature, which make it unsuitable for pharmaceutical formulation as solid dosage forms. Patent discloses a process for preparing the α-crystal form wherein imatinib base was suspended in ethanol; methane sulfonic acid was added and heated under reflux for 20 minutes and than filtered at 65 °C. The filtrate was evaporated down to 50% and the residue filtered off at 25°C. The mother liquor was evaporated to dryness. Both residues were suspended in ethanol and dissolved under reflux with addition of water, cooling overnight to 25 °C, filtration and drying yielded imatinib mesylate α form. The above mentioned process does not give reproducible results due to its cumbersome nature and always results in mixture of forms α and ß form.
US patent application 2006/0223816 discloses process for preparation of imatinib mesylate crystal in substantially pure α- form. The process comprises step of dissolving imatinib base in an organic solvent selected from methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, 4-methylcyclohexanone, acetonitrile or mixture thereof; followed by addition of methanesulfonic acid and seeding with α-crystal form. The said process needs large volumes of expensive solvents (20-96 times volumes) to dissolve imatinib as solubility of imatinib is very less in most of the solvents, hence process adds to more cost.
US patent application 2007/0197545 discloses a process for preparing α-crystal form using a reduced molar ratio of methanesulfonic acid, ranging from 0.95-0.99 moles of methanesulfonic acid per mole of imatinib in the reaction mixture. The process includes adding methanesulfonic acid to a solution of imatinib in a solvent selected from alcohol or a mixture of alcohol and ester, cooling, and followed by seeding and further cooling and filtering. The above process is not suitable, as final product may be contaminated with unreacted imatinib base and is difficult to remove and yield is also low.
US patent application 2007/0265288 discloses a method for preparing α-crystal form of imatinib mesylate by dissolving or suspending imatinib base in a solvent selected from C2-C4 alcohols and ketone such as methyl isobutyl ketone. This application
further teaches micronizing the product in order to change the undesirable crystalline needle form and obtain desirable physical properties of solid such as particle size.
US patent application 2008/0090833 discloses the processes for preparing α-crystal form of imatinib mesylate by providing a solution of imatinib mesylate in ethylene glycol, dimethyl ether, followed by admixing the solution with t-butyl methyl ether to form the suspension comprising α-crystalline form. Other process includes slurring other crystalline of imatinib mesylate in solvents selected from ethyl acetate, acetone and mixture thereof. In another way, α-crystalline form of imatinib mesylate can be prepared by crystallization of imatinib mesylate from propylene carbonate, mixture of n-propanol, water and acetic acid; and mixture thereof.
US patent application 2008/0255138 discloses two processes for the preparation of α2-crystal form of imatinib mesylate. Although this application designate polymorphic form as novel α2-crystal form of imatinib mesylate, but XRD and DSC of this form matches with α form of imatinib mesylate. One of the processes involves suspending imatinib base in isopropyl alcohol followed by adding methanesulfonic acid, refluxing the mixture, cooling and filtering to give the α2-crystal form. Another process involves suspending ß-crystal form in water and organic solvents such as methanol, isopropyl alcohol, cyclohexane, toluene and isopropyl ether followed by azeotropic distillation of water, cooling and filtering to give α2-crystal form. Application is silent about limits of residual solvent. By repeating first process, we have found that product is always having content of isopropyl alcohol in unacceptable limits i.e. more than 5000 ppm or more than 8000ppm. Other process is through ß-crystal form, which in itself adds extra step to the process.
PCT publication WO 2006/048890 discloses process for preparation of non-needle shaped α-crystalline form of imatinib mesylate by subjecting imatinib mesylate solution in a suitable solvents such as polar protic or aprotic, a non-polar solvent, water, to agitated thin film drying under atmospheric pressure and /or under vacuum. The process involves special condition of drying i.e. agitated thin film drying for the
synthesis of α- form of imatinib mesylate which makes the process unsuitable for commercial synthesis.
PCT publication WO 2009/151899 discloses two processes for the preparation of α-crystal form of imatinib mesylate. One of the processes involves preparation of α-crystal form by providing a solution or suspension of imatinib base in an ether solvent including cyclic ether such as tetrahydrofuran, pentahydrofuran and the like , acyclic ether such as dimethyl ether, diethyl ether, t-butyl methyl ether and the like or mixture thereof followed by optionally seeding with α-crystal form, then adding methanesulfonic acid and cooled to give α-crystal form of imatinib mesylate. Another process involves preparing slurry of imatinib mesylate in a C5-C10 hydrocarbon solvent, followed by isolating the solid and drying.
Impurities may be formed or added during the manufacture of the API. Any component other than the API is considered an impurity. The impurities present in the API could be process-related impurities such as starting materials, intermediates, by-products, reagents, ligands, catalysts, filter aids, carbon adsorbents, or salts as well as degradation products, enantiomeric impurities and residual solvents used in the manufacturing process.
The International Conference on Harmonization (ICH) guidelines on impurities in New Drug Substances Q3A(R) for impurities in API indicates that the impurity profile method should be able to detect impurities (limit of quantitation) at levels greater than the reporting threshold of 0.05% for drugs with maximum daily dose of <2 g/day and 0.03% for maximum daily dose >2 g/day [1].
Therefore, in the manufacture of a drug substance, the purity of the products, such as imatinib mesylate is required before commercialization, as is the purity of the active agent in the manufacture of formulated pharmaceuticals. Therefore, pharmaceutical
active compounds must be either free from these impurities or contain the impurities in acceptable limits.
Residual solvents have had official limits in the United States as set in USP 30<467> and by the FDA in 1997 and have been monitored by most pharmaceutical manufacturers extensively for more than two decades in both bulk and finished products.
Residual process solvents in pharmaceutical samples are monitored using gas chromatography (GC) with either flame ionization detection (FID) or mass spectrometry. Based on good manufacturing practices, measuring residual solvents is mandatory for the release testing of all active pharmaceutical ingredients and is routinely performed.
In ICH guidelines there is chapter on Classification of Residual Solvents by Risk Assessment. Solvents are evaluated for their possible risk to human health and placed into one of three classes as follows:
Class 1 solvents: Solvents to be avoided-
Known human carcinogens, strongly suspected human carcinogens, and environmental hazards.
Class 2 solvents'. Solvents to be limited-
Nongenotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity. Solvents suspected of other significant but reversible toxicities.
Class 3 solvents: Solvents with low toxic potential-Solvents with low toxic potential to man; no health-based exposure limit is needed. Class 3 solvents have PDE's of 50 milligrams or more per day.
It has been noticed that polymorphic α form of imatinib mesylate when prepared as per the process reported in the prior art is not isolated in pure form it is contaminated
with other forms such as ß form or found to have residual solvent in unacceptable amounts. It is known that different polymorphs of the same active pharmaceutical ingredient (API) display distinct physical properties, such as melting point, solubility, dissolution rate, hygroscopicity, or stability. Therefore it is desirable that same polymorph of an API should result consistently to have better effect. The ability to successfully produce and reproduce specific stable polymorphs is intricately correlated with the efficiency and speed of drug development, the robustness of manufacturing process, and - ultimately - the stability and quality of APIs. It is also observed that α form of imatinib mesylate is having residual solvents in higher amounts and is difficult to remove even drying at higher temperature for longer durations. In view of this, there is an urgent need to develop an improved process wherein α form of imatinib mesylate is isolated consistently in pure form without contamination of other forms and have residual solvents in specified limits. Therefore, the present invention aimed to solve the problems associated with the prior art and to provide an efficient, process for the preparation of α form of imatinib mesylate. The process of present invention is convenient to operate on a commercial scale and gives the desired product in good yield and quality.
OBJECT OF THE INVENTION
The principal and foremost object of the present invention is to provide an improved process for the preparation of pure α form of imatinib mesylate in good yield and quality consistently.
Another object of the present invention is to provide an improved process for the preparation of α form of imatinib mesylate, wherein residual solvents are within limits as per ICH guidelines.
Another object of the present invention is to provide an improved process for the preparation of α form of imatinib mesylate having no or little tendency to convert to any other polymorphic form of imatinib mesylate
Another object of the present invention is to provide an improved process for the preparation of pure α form of imatinib mesylate, wherein other polymorphs are 2 % or less.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of α form of imatinib mesylate wherein residual solvents are present in specified limits as per ICH guidelines.
Accordingly, in one general aspect there is provided pure α form of imatinib mesylate. Embodiments of pure α form of imatinib mesylate may include one or more of the following features. For example, α form of imatinib mesylate may have no detectable quantity of other polymorphic forms of imatinib mesylate, α form of imatinib mesylate may have 2% or less of other polymorphic forms of imatinib mesylate.
According to another embodiment, present invention provides process for the preparation of pure α form of imatinib mesylate. The process includes the steps of:
a) combining imatinib base with isopropanol to form a suspension;
b) optionally, seeding with crystals of α form,
c) adding methanesulphonic acid to the above suspension,
d) refluxing the reaction mixture for sufficient time to form crystals of α form,
e) filtering crystals of α form,
f) slurring crystals of α form in suitable solvent at temperature of 10-80°C, and
g) isolating pure crystals of α form.
BRIEF DESCRIPTION OF THE DRAWINGS
Figurel. Shows a powdered X-ray diffraction pattern (PXRD) of α form of imatinib mesylate.
Figure 2. Shows a DSC of α form of imatinib mesylate
Figure 3. Shows a IR spectrum of α form of imatinib mesylate
DETAILED DESCRIPTION OF THE INVENTION
first aspect of the present invention provides pure α-form of imatinib mesylate having no tendency to convert to any other polymorphic form. Pure α form of imatinib mesylate of the present invention has 2 % or less of other polymorphic forms of imatinib mesylate and residual solvents in the specified limits as per ICH guidelines. More preferably α-form of imatinib mesylate has no detectable quantity of any other known polymorphic form of imatinib mesylate. The X-Ray powdered diffraction (PXRD) pattern and associated two-theta values of α-form of imatinib mesylate is provided in Figure 1 of the accompanied drawing. Differential scanning calorimetry (DSC) thermogram and infra-red (IR) spectrum of α-form of imatinib mesylate are provided in Figures 2 and 3 of the accompanied drawing. Accordingly, the present invention provides an efficient, industrially advantageous process for the preparation of α-form of imatinib mesylate formula I.
Imatinib to be used as the starting material can be prepared by any process known in the literature. The so obtained imatinib then is suspended in isopropanol at ambient temperature and treated with methanesulphonic acid. Optionally while preparing suspension of imatinib in isopropanol seeding with crystals of α form can be done. After complete addition of methanesulphonic acid, the reaction mixture is heated to reflux temperature and is maintained at same temperature for sufficient time to form crystals of α form and preferably for 2-4 hours and cooled to ambient temperature thereafter. The solvent is removed by the suitable technique such as filtration. So, the separated crystals are then optionally washed with a suitable solvent as described above.
The isolated product is optionally dried to get α form of imatinib mesylate or used as wet material for further process. The resulting compound wet or dried is slurry
washed in a suitable solvent at a temperature of 10-80°C. Suitable solvent can be selected from ketones, alcohols other than isopropanol, mixture of other alcohols with isopropanol, esters, ethers, nitrile, and the like. Preferably solvent is selected from acetone, methyl isobutyl ketone, methyl ethyl ketone, methanol, ethanol, butanol, mixture of isopropanol with methanol, ethanol, butanol; ethylacetate, methyl acetate, tetrahydrofuran, methyl tertiary butyl ether, isopropyl ether, diethyl ether, acetonitrile etc. It is advantageous to stir resulting a crystals of imatinib mesylate in a suitable solvent to remove excess of isopropanol remain intact with crystals. Isopropanol (IPA) found to remain intact with the desired compound and could not be removed even after drying at 80°C for more than 72 hours. The imatinib mesylate is found to have isopropanol content more than 5000 ppm.
Specifically wet or dried a crystals of imatinib mesylate having isopropanol content more than 5000 ppm is stirred in a suitable solvent at 10-80°C and preferably at 25-60°C for about 10 minutes to few hours. The resulting product is filtered and dried to get pure α form of imatinib mesylate.
The purity of α form of imatinib mesylate so obtained is greater than 99.9% when determined by known High Performance Liquid Chromatography (HPLC) methods and residual solvents are within limits i.e. IPA content less than 5000 ppm by GC.
Major advantages realize in the present invention are high purity of α form of imatinib mesylate as well as having acceptable limits of residual solvent, α-form of imatinib mesylate of the present invention has 2% or less of other polymorphic forms of imatinib mesylate. More preferably α form of imatinib mesylate has no detectable quantity of any other known polymorphic form of imatinib mesylate.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Examples
Example-l: Preparation of α form of imatinib mesylate
To a suspension of imatinib base (5g) in isopropanol (90ml), methanesulfonic acid (1.0g) was added slowly at 25-30°C. The reaction mass was stirred for 20 minutes and then refluxed for 2 hrs. The reaction mass was cooled to 25-30 °C, stirred for 30 minutes, filtered and washed with isopropanol (10ml). The wet cake was stirred in acetone (60ml) for 30 minutes at 40-45 °C, filtered, washed with acetone (10ml) and dried to get imatinib mesylate α-form (4.5g). IPA content - 2593 ppm; acetone content -202 ppm by GC.
Example-2: Preparation of α form of imatinib mesylate
To a suspension of imatinib base (5g) in isopropanol (90ml) methanesulfonic acid (1.0g) was added slowly at 25-30 °C. The reaction mass was stirred for 20 minutes and then refluxed for 2 hours. The reaction mass was cooled to 25-30 °C, stirred for 30 minutes, filtered and washed with isopropanol (10ml). The wet cake was stirred in a mixture of isopropanol and methanol (55ml, 10:1 ratio) for 30mts. at 40-45°C, filtered, washed with isopropanol (10ml) and dried to get 4.8 g of imatinib mesylate α-form. DSC: 226.7 °C, XRD matches with α-form. IPA content = 4519 ppm, methanol content =18 ppm.
Example-3: Preparation of α form of imatinib mesylate
To a suspension of imatinib base (5g) in isopropanol (90ml), methanesulfonic acid (1.0g) was added slowly at 25-30 °C. The reaction mass was stirred for 20 minutes and then refluxed for 2 hours. The reaction mass was cooled to 25-30 °C, stirred for 30 minutes, filtered and washed with isopropanol (10ml). The wet cake was stirred in n-propanol (60ml) for 30 minutes at 40-45 °C, filtered, washed with n-propanol (10ml) and dried to get imatinib mesylate alphα form (4.5g) and showing endothermic peak in DSC at 226 °C.
Example-4: Preparation of α form of imatinib mesylate
To a suspension of imatinib base (5g) in isopropanol (90ml), methanesulfonic acid (1.0g) was added slowly at 25-30 °C. The reaction mass was stirred for 20 minutes and then refluxed for 2 hours. The reaction mass was cooled to 25-30 °C, stirred for 30 minutes, filtered and washed with isopropanol (10ml). The wet cake was stirred in acetonitrile (50ml) for 30 minutes at 40-45 °C, filtered, washed with acetonitrile (10ml) and dried to get imatinib mesylate α- form (4.5g); having endothermic peak in DSC at 226.4 °C.
Example-5: Preparation of α form of imatinib mesylate
To a suspension of imatinib base (5g) and crystals of α form of imatinib mesylate in isopropanol (90ml), methanesulfonic acid (1.0g) was added slowly at 25-30 °C. The reaction mass was stirred for 20 minutes and then refluxed for 2 hours. The reaction mass was cooled to 25-30 °C, stirred for 30 minutes, filtered and washed with isopropanol (10ml). The wet cake was stirred in acetone (60ml) for 30 minutes at 40-45 °C, filtered, washed with acetone (10ml) and dried to get imatinib mesylate α form (4.5g). IPA content - 2834 ppm; acetone content -200 ppm by GC.
Comparative example
Reference example 1: Preparation of α form of imatinib mesylate
To a suspension of imatinib base (5g) in isopropanol (90ml), methanesulfonic acid (1.0g) was added slowly at 25-30°C. The reaction mass was stirred for 20 minutes and then refluxed for 2 hours. The reaction mass was cooled to 25-30 °C, stirred for 30 minutes, filtered, washed with isopropanol (10ml) and dried at 60-70°C under vacuum for 48 hours to get imatinib mesylate α form. IPA content - 8224 ppm by GC.
Reference example 2: preparation of α form of imatinib mesylate
To a suspension of imatinib base (5g) in isopropanol (90ml), methanesulfonic acid (1.0g) was added slowly at 25-30 °C. The reaction mass was stirred for 20 minutes and then refluxed for 2 hours. The reaction mass was cooled to 25-30°C , stirred for 30 minutes, filtered, washed with isopropanol (10ml) and dried at 75-80°C under vacuum for 72 hours to get imatinib mesylate α form having IP A content - 8591 ppm by GC.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. For example, the compounds described herein can be formulated into dosage forms that are suitable for administering to patients in need of the compound for treating a medical condition for which the compound is indicated, approved, or otherwise beneficial. Specifically, α form of imatinib mesylate can be formulated with one or more pharmaceutically acceptable excipients into a dosage form and administered to treat chronic myeloid leukemia.

We Claim:
1). A process for the preparation of pure α form of imatinib mesylate comprising the steps of:
a). combining imatinib base with isopropanol to form a suspension;
b). optionally, seeding with crystals of α form,
c). adding methanesulphonic acid to the above suspension,
d). refluxing the reaction mixture for sufficient time to form crystals of α form,
e). filtering crystals of α form,
f). slurring crystals of α form in a suitable solvent at a temperature of 10-80°C, and
g). isolating pure crystals of α form.
2). The process according to claim 1, wherein in step b) reaction mixture is seeded with crystals of α form of imatinib mesylate.
3). The process according to claim 1, wherein in step b) reaction mixture is not seeded with crystals of α form of imatinib mesylate.
4). The process according to claim 1, wherein in step c) methanesulphonic acid is added to imatinib at ambient temperature or lower.
5). The process according to claim 1, wherein in step d) reaction mixture is refluxed for 2-4 hours.
6). The process according to claim 1, wherein in step f) a suitable solvent is selected from ketones, alcohols other than isopropanol, mixture of other alcohols with isopropanol, esters, ethers, nitrile, and the like.
7). The process according to claim 1, wherein in step f) a suitable solvent is preferably selected from acetone, methyl isobutyl ketone, methyl ethyl ketone,
methanol, ethanol, butanol, mixture of isopropanol with methanol, ethanol, butanol; ethylacetate, methyl acetate, tetrahydrofuran, methyl tertiary butyl ether, isopropyl ether, diethyl ether, acetonitrile or mixture thereof
8). The process according to claim 1, wherein in step f) α form of imatinib mesylate is preferably slurried at 25-60°C.
9). The process according to claim 1, wherein resulting pure α form of imatinib mesylate has isopropanol content less than 5000 ppm.
10).α- Form of imatinib mesylate prepared according to claim 1, has isopropanol content less than 5000 ppm and 2% or less of other polymorphic forms of imatinib mesylate.