EP2491027A1 - Salts of imatinib with tartaric acids - Google Patents

Salts of imatinib with tartaric acids

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Publication number
EP2491027A1
EP2491027A1 EP20100784881 EP10784881A EP2491027A1 EP 2491027 A1 EP2491027 A1 EP 2491027A1 EP 20100784881 EP20100784881 EP 20100784881 EP 10784881 A EP10784881 A EP 10784881A EP 2491027 A1 EP2491027 A1 EP 2491027A1
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EP
European Patent Office
Prior art keywords
imatinib
tartaric
represents
salts
di
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
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EP20100784881
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German (de)
French (fr)
Inventor
Robert Wozniak
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Kozluk Tomasz
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Kozluk Tomasz
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Filing date
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Priority to PL389357A priority Critical patent/PL389357A1/en
Application filed by Kozluk Tomasz filed Critical Kozluk Tomasz
Priority to PCT/PL2010/000105 priority patent/WO2011049474A1/en
Publication of EP2491027A1 publication Critical patent/EP2491027A1/en
Application status is Withdrawn legal-status Critical

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/04Heterocyclic 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

Abstract

New imatinib acid addition salts are represented by general formula (I), wherein R represents O-acyl group of L- or D-tartaric acid, n represents any number in the range from 1 to 2, and their solvates and hydrates. Salts are preferably selected from a group comprising imatinib salts of dibenzoyl-L-tartaric, dibenzoyl-D- tartaric, di-p-anizoyl-L-tartaric, di-p-anizoyl-D-tartaric, di-p-tolyl-L- tartaric, dipivaloyl-L-tartaric or diacetyl-L-tartaric acids, which may be used in the treatment and/ or prevention of diseases mediated by tyrosine kinases.

Description

Salts of imatinib with tartaric acids

Field of invention The present invention relates to the new salts of imatinib with tartaric acids, their preparation and the pharmaceutical compositions thereof.

Imatinib is indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) and with Kit- positive gastrointestinal stromal tumours (GIST) including unresectable and/ or metastatic malignant disease and resected disease post-surgery, for use in adult patients with newly diagnosed Ph+ acute lymphoblastic leukemia (ALL) in combination with chemotherapy, and as a single agent for patients with relapsed or refractory Ph+ALL.

The new salts, exhibiting the same pharmaceutical activity as imabinib, may be used as anticancer active substances.

Background of the invention

Imatinib, 4-[(4-methyl-l-piperazinel)methyl]-N-[4-methyl-3-[[4-(3- pyridinyl)-2-pyrimidynyl]amino]-phenyl]benzamide, as a selective inhibitor of tyrosine kinases was disclosed in the European patent application EP 0564409 Al. It is represented by the structural formula:

The active ingredient of imatinib tablets marketed as Gleevec® or Glivec® is imatinib acid addition salt with methanesulfonic acid, imatinib mesylate.

Therapeutic daily dose of imatinib in leukemia treatment in humans varies from 100 mg to 800 mg of imatinib active ingredient. On account of high daily dose, the administration of tablets comprising from 100 mg to 400 mg of imatinib (119,5 and 478 mg of imatinib mesylate, respectively) is required. For these reasons formation of tablets with high active substance content is necessary. In the European Patent EP 1501485 Bl the 'compact' tablet with the content of imatinib mesylate varying from 30 to 80 % by weight calculated on the total tablet weight, was disclosed. Tablets were manufactured in wet granulation process using active substance and excipients forming the inner phase, followed by mixing the obtained granulate with the excipients forming the outer phase, then compressing the mixture and coating the cores.

It is known that imatinib mesylate may crystallize in at least two polymorphic forms, a and β, disclosed in the publication of international patent application WO 99/03854. β-Crystal form is thermodynamically stable and it has relatively good processing parameters, while a-crystal form, crystallizing as elongated, fragile needle-like crystals, is highly hygroscopic. When used in tablets compression many difficulties are encountered due to its disadvantageous flowing properties. For these reasons, wet granulation process is not useful in case of hygroscopic a- crystal form of imatinib mesylate.

The solution to the problem of preparation of the tablets comprising imatinib mesylate in the hygroscopic a-crystal form, having the acceptable physical parameters, was described in the European patent application EP 1762230 Al. According to the description, the coated tablets having the desired technological properties, ie. characterized by appropriate hardness and abrasion resistance, may be obtained when dry granulation step is performed prior to compression of granulate. The active substance content in a tablet core or a granule varies from 25% to 80% of the total tablet weight, and the particle size of at least 80 % by weight of the active substance ranges from 0,01 to 1,0 nm.

To avoid the difficulties connected with compressing imatinib mesylate into tablets, some research groups focused on discovering new crystalline forms of better physical parameters, which resulted in identification of, among others, form HI and hydrate of imatinib mesylate (WO 2004/ 106326), a2 form (WO 20059077933), non-needle form a (WO 2006/048890), form I and II (WO 2006/054314), form δ and ε (WO 2007/023182), form F, G, H, I and K (WO 2007/059963), as well as imatinib dimesylate, which may be formed in the reaction of equimolar amounts of imatinib base and methanesulfonic acid (WO 2005/095379). This diversity of crystalline forms of imatinib mesylate may be disadvantageous to keep uniformity of different manufacturing batches and, as a consequence, to preserve uniformity of tablets content. On the other hand, imatinib salt with methanesulfonic acid when used in therapy seriously threatens patients health. Preclinical studies showed the activity towards DNA alkylation of methanesulfonic acid alkyl esters, therefore their presence even as trace impurities (< 5 ppm) may cause mutagenic, cancerogenic and teratogenic changes in a living organism. Potential genotoxic effects of these esters were the topics of considerations by European Medicines Agency, which advised the pharmaceutical manufacturers to take particular precautions to produce pharmaceuticals free of alkyl sulfonates impurities.

From this point of view, it would be recommended to develop imatinib salt composed of the acid other than methanesulfonic acid, that would not generate the risk of formation of DNA alkylating agent.

In the publication of the International patent application WO 2005/075454A plethora of imatinib salts, such as tartrates, hydrochloride, citrate, malates, fumarate, succinate, benzoate, malonate, salicilate, lactates, mandelates, hemiglutarate, vanilate, ascorbate and sulfate salts, were revealed. However, many of these salts due to their physico-chemical properties are not useful in solid pharmaceutical dosage form production. Water content above 0,5%, detected in a majority of the crystalline salts, is the evidence of hygroscopic properties of these compounds. The described salts are also hardly soluble in water, it is proved over 10 fold lower in comparison with mesylate solubility, therefore the described salts cannot be used as the direct mesylate equivalents. In addition, a number of new salts obtained are characterized by low melting points, for example melting point measured for imatinib maleates is below 50°C.

These results led the authors to the conclusion, that it is difficult to predict which salt forms may possess advantageous properties for a particular purpose, as solid pharmaceutical dosage form production, unless they are prepared and characterized.

It was discovered by the present Inventors, that there is a possibility to develop new imatinib salts having tyrosine kinases inhibiting activity, deprived of disadvantageous associated with the known salts, specially mesylate. Crystalline homogeneity, advantageous crystal morphology and low hygroscopicity make these new salts useful in the manufacture of solid pharmaceutical dosage forms, in particular tablets and capsules, by any method known in the art, such as either wet and dry granulation or direct compression.

Description of the invention

The present invention relates to imatinib acid addition salts,

represented by general formula (1), wherein R represents O-acyl group of L- or D-tartaric acid, n represents any number in the range from 1 to 2. The present invention encompasses also all solvates and hydrates of imatinib acid addition salts represented by general formula (1).

The preferred salts according to the present invention are the salts selected from the group consisting, of imatinib salts with dibenzoyl-L- tartaric, dibenzoyl-D-tartaric, di-p-anizoyl-L-tartaric, di-p-anizoyl-D- tartaric, di-p-tolyl-L-tartaric, di-pivaloyl-L-tartaric and diacetyl-L-tartaric acids.

New salts of the present invention, depending on the molar ratio of imatinib free base and dicarboxylic acid used for the reaction of salt formation, may consist of 0.5 to 1 mole of dicarboxylic acid per 1 mole of imatinib.

In the preferred embodiment of the present invention the salts consist of dicarboxylic acid and imatinib at the molar ratio 1 : 2 or 1 : 1.

One of the preferred salt is imatinib diacetyl-L-tartrate (1 :2), which consists of one molecule of diacetyl-L-tartaric acid and two molecules of imatinib.

Imatinib diacetyl-L-tartrate (1:2) is characterized by X-ray powder diffraction (XRPD) pattern recorded with CuKa, λ = 1,5405δΑ, having the following Bragg reflections represented by inter-planar distances d [A], reflection angles 2Θ [°] and relative intensities I/Io [%]:

15.88 5.58 14.83 25.97 3.43 9.84

16.23 5.46 8.06 27.25 3.27 12.83

17.03 5.21 7.31 28.36 3.15 23.86

18.19 4.88 15.80 29.17 3.06 6.49

18.95 4.68 52.76 30.17 2.96 4.69

19.30 4.60 35.64 32.43 2.76 3.25

19.75 4.50 58.65 34.58 2.59 2.00

XRPD pattern of imatinib diacetyl-L-tartrate (1:2) is depicted on Fig. 1, and the IR spectrum on Fig. 2.

Another preferred salt according to the present invention is imatinib di-p-anizoyl-D -tartrate (1: 1), which consists of one molecule of di-p-anizoyl- D-tartaric acid and one molecule of imatinib base.

Imatinib di-p-anizoyl-D-tartrate (1: 1) is characterized by X-ray powder diffraction (XRPD) pattern recorded with CuKa, λ = 1,54056A, having the following Bragg reflections represented by inter-planar distances d [A], reflection angles 2Θ [°] and relative intensities I/Io [%]:

17.42 5.09 36.99 29.37 3.04 13.46

18.04 4.92 34.10 34.68 2.59 2.91

XRPD of imatmib di-p-anizoyl-D-tartrate (1: 1) is depicted on Fig. 3, and the IR spectrum on Fig. 4.

The other preferred salt according to the present invention is imatinib di-benzoyl-L- tartrate (1: 1), which consists of one molecule of di-benzoyl-L- tartaric acid and one molecule of imatinib base.

Imatinib di-benzoyl-L-tartrate (1: 1) is characterized by X-ray powder diffraction (XRPD) pattern recorded with CuKct, λ = 1,54056A, having the following Bragg reflections represented by inter-planar distances d [A], reflection angles 2Θ [°] and relative intensities I/Io [%]:

XRPD of imatinib di-benzoy-L- tartrate (1: 1) is depicted on Fig. 5, and the IR spectrum on Fig. 6.

The process for preparation of imatinib salts of formula (1), wherein R represents O-acyl group of L- or D-tartaric acid, n represents any number in the range from 1 to 2, comprises the following steps:

(a) combining imatinib base, its salt or solvate in organic solvent with L- or D-tartaric acid derivative or its anhydride;

(b) stirring the reaction mixture at temperature from 10°C to reflux;

(c) filtering the reaction mixture and cooling down to crystallization temperature (-20°C to 20°C);

(d) leaving the filtrate until the entire product crystallizes;

(e) isolation of the crystalline salt from the crystallization mixture; (f) drying the product.

In step (a), from 0,5 to 1 equivalents of dicarboxylic acid is reacted with 1 mol of imatinib, its salt or solvate, in respect to free base.

Organic solvent in step (a) is selected from a group comprising aliphatic alcohols, such as methanol or ethanol; aliphatic ketones, such as acetone; esters of carboxylic acids, such as ethyl acetate; ethers, such as tetrahydrofuran; nitriles, such as acetonitrile, or their mixtures.

Preferably, the solvent of choice is methyl alcohol or ethyl alcohol.

Crystalline imatinib salt is isolated from the crystallizing mixture in the manner known per se, and depending on the used solvent. It comprises filtration or decantation of the formed crystalline product or its precipitation out of the post-reaction mixture due to co-solvent addition. Imatinib salt may be isolated from the post-reaction mixture either free of solvent or in the form of solvate. The isolated salt may be purified by crystallization, maceration and/ or recrystallization, and subsequently dried. Imatinib salts obtained according to the present invention are isolated as the homogenous crystals, characterized by regular crystalline shape, which is suitable for pharmaceutical applications. Unlike imatinib mesylate, in particular its a-crystal form, new tartrate salts absorb trace amounts of water and have ' comparatively good solubility (above 5000 mg/ml of water).

The new salts exhibit good stability under accelerated and long-term storage conditions; the increase of by-products resulting from degradation is not observed. Unexpectedly, due to advantageous physico-chemical properties and processability, the new salts are suitable for direct use in solid pharmaceutical dosage forms manufacture.

One may assume on the basis of similar solubilities, the salts obtained according to the present invention will have the same pharmacological activity as imatinib mesylate.

As a result, the new imatinib salts can be used in a treatment and prevention of myeloid leukemia, acute lymphoblastic leukemia, gastrointestinal stromal tumor and other diseases mediated by tyrosine kinases. Imatinnib salts according to the invention may be administered to the patient per se or they may be formulated as the pharmaceutical compositions including therapeutic amount of active substance together with at least one pharmaceutically accepted carrier and/ or excipient.

Pharmaceutical composition of the invention may be administered in suitable pharmaceutical dosage form, by any convenient route, eg. orally or parenterally, depending on the pharmaceutical dosage form used.

The selection of the therapeutic dose of imatinib salt as well as the dosage scheme is connected with the nature and severity of condition being treated, age and body mass of the patient, and may be defined by the skilled person according to the standard treatment procedures and prophylactics in that kind of diseases. Therapeutic daily dose of the derivative of the present invention, may vary from 100 mg to 800 mg, calculated on imatinib free base. Daily dose can be administered on once-a-day basis or it can be divided into small portion doses, in monotherapy or in a combined treatment with other active substance. The combined active substances may be administered as a fixed unit dosage form, concomitantly as two different drugs or within a certain period of time, in accordance with the prescription.

Pharmaceutical composition according to the present invention, may be formulated into any suitable pharmaceutical form, by any method known in the art, such as the one described, eg., in Remington's Pharmaceutical Sciences, ed. XVI, Mack Publ. Co., 1980.

Pharmaceutical composition according to the invention may be formulated in any convenient pharmaceutical form, by any method known in the art, such as the one described, eg., in Remington's Pharmaceutical Sciences, ed. XVI, Mack Publ. Co., 1980.

Pharmaceutical dosage forms for oral administration include solid pharmaceutical dosage forms, such as tablets, dragees, powders, granules, pellets and capsules. The liquid dosage form embrace, for example, suspensions and syrups. Except for active substance, pharmaceutically accepted diluents and/ or excipients are also present. Pharmaceutically accepted diluents and excipients are any pharmacologically inert substances or their mixtures known in pharmaceutical practice. Suitable diluents for conventional release solid dosage forms include corn starch, lactose, macrocrystalline cellulose, saccharose, sorbitol, talc, mannitol, mono- or dibasic calcium phosphate, pregelatinized starch, glycine and other.

Solid pharmaceutical compositions, which are compacted into solid dosage form, such as tablet, may include other excipients to facilitate manufacturing process and to obtain drug of desired physico-chemical properties. Disintegrants, increasing dissolution rate of a compacted solid pharmaceutical composition in patient's gastrointestinal tract, comprise for example, starch and its derivatives, croscarmellose sodium, microcrystalline cellulose, crosslinked polyvinylpyrolidon, sodium starch glycolate or other ingredients based on crosslinked polymers. Binders for solid form compositions include polyvinylpyrolidon, gelatin, guar gum, cellulose derivatives, hydroxypropylmethylcellulose (HPMC), hydroxycellulose, hydroxypropylcellulose, for instance. Lubricants contain, for example, sodium lauryl sulfate, magnesium stearate, talc, fumaric acid and others. The tablets may be protected with a coating as it is described, for example, in Pharmaceutical Dosage Forms and Drug Delivery Systems, H.C.Ansel, L.V.Allen, N.G.Popovich, ed. VII (1999), Lippincott Williams & Wilkins. For the preparation of tablet coating, different substances of high molecular weight and film-forming properties are used, to enable dissolution of solid composition in appropriate part of gastro -intestinal tract. These substances are carefully selected and used together with excipients, such as plasticizers, diluents, colorants, dispersing and opacifying agents.

There is also a possibility of preparing liquid pharmaceutical composition of the new imatinib salts. They may comprise compositions for intravenous, subcutaneous or intramuscular injections, for instance. These liquid pharmaceutical compositions comprise sterile aqueous, hydro- organic and anhydrous solutions, suspensions, dry substances as well as tablets for making solutions. For the preparation of suspensions, some excipients are used to disperse active substance uniformly through the composition in the liquid carrier. Such emulsifying agents include, for example, polysorbates, lecitin, polyoxyethylene and polyoxypropylene copolymers, peptizers, such as phosphates, polyphosphates and citrates, water soluble polymers, such as carboxymethylcellulose, methylcellulose, polyvinylpyrolidon, gums and gelatin. Injection compositions contain, for example, pharmaceutically accepted excipients, such as pH-regulators, buffers, preservatives. Dry substances are designed for the preparation of solutions or suspensions ex tempore, due to dilution of the substance with suitable solvent. The present invention provides new imatinib salts, characterized by advantageous physico-chemical properties, such as low hygroscopicity and uniform crystalline form. These properties make new imatinib salts suitable for solid dosage forms preparation of homogenous composition. The invention is illustrated by the following examples, which should not be constructed to limit its scope in any way.

Examples Analytical methods

Nuclear magnetic resonance spectra were recorded on Bruker Avance spectrometer type DRX 500 MHz. IR spectra were recorded on Perkin Elmer Spectrum BC spectrometer.

X-Ray powder diffraction data were recorded on X'Pert Pro by PANalytica powder diffractometer with copper radiation CuKa, λ = 1,54056A, with the following measurement parameters:

• 2Θ scanning range: 3° - 40°

• Scanning rate Δω: 0.5°/ min.

• Step size Δ2Θ: 0.03°

The composition of obtained salts was determined by nuclear magnetic resonance method (Ή-NMR). The molar ratio of acid and imatinib base was determined on the basis of signals integrations of the corresponding protons assigned to base and acid moieties, respectively.

Example 1. Imatinib diacetyl-L-tartrate (1:2)

Imatinib base 5,0 g (0,010 mol) and diacetyl-L-tartrate anhydride 1,1 g (0,0051 mol) were dissolved in 50 ml of 96% ethanol. After 18 h, to the dense solution 50 ml portion of 96% ethanol was added and stirring was continued for 2 h. The solid was filtered off, washed with small amount of ethanol and dried under vacuum at 60°C for 24. Imatinib diacetyl-L-tartrate (1:2) of > 99,9% purity was obtained in 5,6 yield. M.p. 150-151 °C (uncorrected). The identity of the product was confirmed by spectroscopic data analysis. iH-NMR: DMSO-d6 δ 10.16 [1H, s, NH]; 9.28 [lH,d, Ar]; 8.96 [1H, s, NH]; 8.69 [1H, dd, Ar]; 8.51 [1H, d, Ar]; 8.47 [1H, dt, Ar]; 8.09 [1H, d, Ar]; 7.92 [2H, d, Ar]; 7.51 [2H, m, Ar]; 7.46 [2H, d, Ar]; 7.43 [1H, d, Ar]; 7.22 [1H, d, Ar]; 5.34 [lH,s, tartaric]; 3.58 [2H, s, CH2]; 2.72 [4H, bb, piperaz.]; 2.50 [4H, bb, piperaz.]; 2.42 [3H, s, CH3]; 2.23 [3H, s, CH3]; 2.05 [3H, s, CH3 acetyl.].

IR: KBr cm-i 3264, 2829, 1735, 1650, 1577, 1538, 1480, 1453, 1421, 1373, 1324, 1291, 1247, 1225, 1182, 1130, 1054, 1026, 984, 915, 879, 851, 800, 710, 647, 585, 549, 454.

Example 2. Imatinib di-p-anizoyl-D-tartrate (1:1)

Imatinib base 5,0 g (0,010 mol) and di-p-anizoyl-D-tartaric acid 4,24 g (0,0101 mol) were dissolved in 100 ml of methanol. After 18 h the solid was filtered off, washed with small amount of methanol and dried under vacuum at 60°C for 24 h. Imatinib di-p-anizoyl-D-tartrate (1: 1) of > 99,9% purity was obtained in 6,9 g yield. M.p. 150-152°C (uncorrected). The identity of the product was confirmed by spectroscopic data analysis. iH-NMR: MeOH-d6 δ 9.22 [lH,d, Ar]; 8.60 [1H, d, Ar]; 8.55 [1H, d, Ar]; 8.44 [1H, d, Ar]; 8.20 [1H, d, Ar]; 8.07 [4H, dd, Ar anizoyl.]; 7.88 [2H, d, Ar]; 7.50 [1H, dd, Ar]; 7.40 [3H, m, Ar]; 7.31 [1H, d, Ar]; 7.22 [1H, d, Ar]; 6.98 [4H, dd, Ar anizoyl.]; 5.87 [2H, s, tartaric]; 3.83 [6H, s, 2(-OCH3) anizoyl.]; 3.54 [2H, d, CH2]; 3.15 [4H, bb, piperaz.]; 2.74 [3H, s, CH3]; 2.64 [4H, bb, piperaz.]; 2.29 [3H, s, CH3]. IR: KBr cm-i 3268, 2839, 1715, 1654, 1605, 1577, 1533, 1511, 1479, 1450, 1418, 1255, 1169, 1102, 1025, 986, 850, 798, 770, 704, 646, 612.

Example 3. Imatinib di-benzoyl-L- tartrate (1:1)

Imatinib base 5,0 g (0,010 mol) and di-benzoyl-L-tartaric acid 3,80 g (0,0101 mol) were dissolved in 100 ml of methanol. After 18 h the solid was filtered off, washed with small amount of methanol and dried under vacuum at 60°C for 24 h. Imatinib di-benzoyl-L-tartrate (1: 1) of > 99,9% purity was obtained in 6,3 g yield. M.p. 187-191°C (uncorrected) . The identity of the product was confirmed by spectroscopic data analysis. iH-NMR: MeOH-d6 δ 9.28 [lH,d, Ar]; 8.62 [1H, d, Ar]; 8.55 [1H, d, Ar]; 8.20 [1H, d, Ar]; 8.13 [4H, dd, Ar benzoyl.]; 7.91 [2H, d, Ar]; 7.59 [2H, d, Ar]; 7.53 [1H, dd, AT]; 7.47 [6H, m, Ar benzoyl.]; 7.39 [1H, dd, Ar]; 7.34 [1H, d, Ar]; 7.23 [1H, dd, Ar]; 5.91 [2H,s, tartaric]; 3.65 [2H, s, CH2]; 3.18 [4H, bb, piperaz.]; 2.79 [3H, s, CH3]; 2.68 [4H, bb, piperaz.]; 2.31 [3H, s, CH3].

IR: KBr cm-i 3251, 2837, 1714, 1643, 1599, 1579, 1544, 1507, 1482, 1454, 1424, 1334, 1308, 1293, 1265, 1209, 1172, 1106, 1068, 1038, 1023, 1005, 988, 909, 846, 796, 748, 723, 691, 671, 647, 623, 587, 546, 450.

Example 4

Two batch series of tablets were produced, containing imatinib di-acetyl- L-tartrate (1:2) and imatinib mesylate a-crystal form as the reference. Each tablet contained 100 mg of imatinib free base, the composition was prepared according to the procedure according to EP 1501485 Bl: a) Components of the inner phase of granulate:

Imatinib mesylate di-acetyl-L-tartrate

83 83

HPMC (Methocel LV E5) 4 3

Microcrystalline cellulose (Vivapur) 4 5 b) Components of the outer phase of granulate:

Microcrystalline cellulose (Vivapur) 5 4

Crospovidon 2 3

Aerosil 1 1

Magnesium stearate 1 1

Tablet weight: 145 mg

Punch: 7 mm, concave

Water for granulation c.a. 6 g c.a. 6,5 g The active substance and excipients were weighted and sieved through the mash screen of appropriate diameter. Granulate was obtained by wet granulation of the active substance, microcrystalline cellulose and hydroxypropyl methylcellulose. The obtained imatinib diacetyl-L-tartrate granulate was dried in a shelf-type drier for 0.5 h, and then sieved through # 1,0 mm, then 0,8 mm mash screen.

Imatinib mesylate granulate was dried for 20 min., sieved through # 1,0 mm mash screen (mesh gluing was observed), dried for 5 min., and sieved through # 0,8 mm mash screen.

Granulate was blended with the components of the outer phase, compressed into tablets in a tabletting machine, using 7 mm concave punches. Tablets were obtained of average weight 145 mg.

Active substance imatinib di-acetyl-L-tartrate was more suitable for technological process in comparison to imatinib mesylate; obtained tablets were characterized by satisfactory hardness, disintegration time and composition homogeneity.

Imatinib mesylate di-acetyl-L-tartrate

Tablet average hardness [N] 154 106,8 Disintegration time [min] 6 '30" 12'25"

Claims

1. Imatinib acid addition salts of general formula (1),
wherein R represents O-acyl group of L- or D-tartaric acid,
n represents any number in the range from 1 to 2,
and their solvates and hydrates.
2. Salts according to claim 1, selected from a group comprising imatinib salts with dibenzoyl-L-tartaric, dibenzoyl-D-tartaric, di-p-anizoyl-L- tartaric, di-p-anizoyl-D-tartaric, di-p-tolyl-L-tartaric, dipivaloyl-L-tartaric or diacetyl-L-tartaric acids.
3. Salts according to claim 1, wherein n in formula (1) represents 1.
4. Salts according to claim 1, wherein n in formula (1) represents 2.
5. Salt according to claim 1 or 4, which is imatinib diacetyl-L-tartrate of formula (1), where n = 2.
6. Salt according to claim 1, which is imatinib di-p-anizoyl-D-tartrate of formula (1), where n = 1.
7. Salt according to claim 1, which is imatinib di-benzoyl-L- tartrate of formula (1), where n = 2.
8. Process for preparation of imatinib salts of formula (1), wherein R represents O-acyl group of L- or D-tartaric acid, n represents any number in the range from 1 to 2, comprising the following steps:
(a) combining imatinib base, its salt or solvate in organic solvent with L- or D-tartaric acid derivative or its anhydride; (b) stirring the reaction mixture at temperature from IOC to reflux;
(c) filtering the reaction mixture and cooling down to crystallization temperature (-20C to 20°C);
(d) leaving the filtrate until the entire product crystallizes;
(e) isolation of the crystalline salt from the crystallization mixture;
(f) drying the product.
9. The process according to claim 8, wherein from 0.5 to 1 equivalents of L- or D-tartaric acid or its anhydride is used to 1 mol of imatinib, its salt or solvate, calculated on free base.
10. The process according to claim 8, wherein organic solvent is selected from a group comprising aliphatic alcohols, such as methanol or ethanol; aliphatic ketones, such as acetone; esters of carboxylic acids, such as ethyl acetate; ethers, such as tetrahydrofuran; nitriles, such as acetonitrile, or their mixtures.
11. The process according to claim 10, wherein organic solvent is methanol or ethanol.
12. Pharmaceutical composition comprising active substance together with known and pharmaceutically acceptable diluents and/ or excipients, wherein the active substance is imatinib acid addition salt of general formula (1), wherein R represents O-acyl group of L- or D-tartaric acid, n represents any number in the range from 1 to 2, its solvate or hydrate.
13. The use of imatinib addition salt of general formula (1), wherein R represents O-acyl group of L- or D-tartaric acid, n represents any number in the range from 1 to 2, its solvates or hydrates, for treatment and/ or prevention of diseases mediated by tyrosine kinases.
EP20100784881 2009-10-22 2010-10-21 Salts of imatinib with tartaric acids Withdrawn EP2491027A1 (en)

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PL389357A PL389357A1 (en) 2009-10-22 2009-10-22 Tartaric acids derivatives imatinib salts and process for the preparation thereof
PCT/PL2010/000105 WO2011049474A1 (en) 2009-10-22 2010-10-21 Salts of imatinib with tartaric acids

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