WO2013136141A1 - An improved process for the preparation of alpha form of imatinib mesylate - Google Patents

An improved process for the preparation of alpha form of imatinib mesylate Download PDF

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Publication number
WO2013136141A1
WO2013136141A1 PCT/IB2012/054240 IB2012054240W WO2013136141A1 WO 2013136141 A1 WO2013136141 A1 WO 2013136141A1 IB 2012054240 W IB2012054240 W IB 2012054240W WO 2013136141 A1 WO2013136141 A1 WO 2013136141A1
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solution
form
imatinib
imatinib mesylate
process
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PCT/IB2012/054240
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French (fr)
Inventor
Aswini Kumar SHARMA
Abhishek GIRI
Tapanjyoti BISWAL
Govind Singh
Saswata Lahiri
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Fresenius Kabi Oncology Ltd.
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    • 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

An improved process, which is simple, convenient, economical and industrially viable, for the preparation of stable, free flowing, non-hygroscopic crystalline alpha form of Imatinib mesylate, free from the beta form. The process comprises a) providing a clear solution of imatinib base in organic solvent; b) optionally, filtering the solution to remove any insoluble impurity; c) adding another organic solvent to the solution of step (b) and heating to obtain a clear solution; d) adding solution of methane sulfonic acid in second organic solvent slowly to the solution of step (c) on heating; e) cooling of the reaction mixture obtained in step (d) followed by seeding of the clear solution with pure alpha crystalline form of Imatinib mesylate on heating; f) slowly cooling of the reaction mixture; g) isolating the imatinib mesylate alpha form; wherein the organic solvent is selected from the group comprising of N, N-dimethyl sulphoxide, Isopropanol and mixtures thereof.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF ALPHA FORM

OF IMATINIB MESYLATE

FIELD OF THE INVENTION

The present invention relates to an improved process, which is simple, convenient, economical and industrially viable, for the preparation of stable, free flowing, non- hygroscopic crystalline alpha form of Imatinib mesylate, free from the beta form.

BACKGROUND OF THE INVENTION

Imatinib is the international non-proprietary name of 4-(4- methylpiperazin- 1 -yl methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidin-2-ylamino) phenyl]-benzamide. Imatinib was disclosed in Eurpean Patent Application EP 0 564 409. 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 single agent for patients with relapsed or refractory Ph+ALL. The structural formula of imatinib mesylate is given below:

Figure imgf000002_0001

FORMULA I

Imatinib is 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. It is well known that imatinib mesylate may crystallize in some polymorphic forms. U.S. Patent No. 6,894,051 ("the Ό51 patent"), disclosed two polymorphic forms of mesylate salt of imatinib viz: alpha-crystal form and beta-crystal form and the processes for their preparation. The Ό51 patent also discloses that the crystalline alpha-form is characterized by needle-shaped crystals having a hygroscopic nature, which make them "not particularly well suited to pharmaceutical formulation as solid dosage forms, because their physical properties, for example their flow characteristics, are unfavorable". The process disclosed in the Ό51 patent for the preparation of the alpha-crystalline form comprises suspending imatinib base in ethanol, adding methane sulfonic acid dropwise to the said solution, heating the solution to reflux and filtering; evaporating the filtrate to 50%, filtering off the residue; evaporating the mother liquor to dryness; suspending the residue and filtered material in ethanol; dissolving under reflux conditions by simultaneously adding water; cooling overnight, filtering and drying to obtain alpha-crystalline form.

This process disclosed for preparing alpha crystalline form not only involves several steps, such as isolation of crude methanesulfonate crystals from the reaction mixture, evaporating ethanol from the reaction mixture and re-suspending the methanesulfonate salt in the same solvent, but also is cumbersome and does not give reproducible results.

U.S. Patent Publication No. 2007/0265288 ("the '288 publication") described a method of preparing crystalline imatinib mesylate alpha form by suspending imatinib base in an alcoholic or ketone solvent, adding methane sulfonic acid, heating the solution to reflux, cooling the reaction mixture to room temperature and isolating the alpha-crystalline form; however, the '288 publication teaches additional step, micronizing the product in order to change the undesirable crystalline needle form and obtain desirable physical properties of the solid.

U.S. Patent Application No. 2006/0223816 Al ("the 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, nitriles and cycloalkanes (more particularly methyl ethyl ketone, methyl isobutyl ketone, 4-methylcyclohexanone, cyclohexane, acetonitrile and mixtures thereof); b. heating to dissolve at least a portion of the imatinib base in the organic solvent; c. seeding with crystals of imatinib mesylate alpha form; d. adding methanesulfonic acidsolution in an organic solvent gradually; e. allowing the crystals to precipitate; e. isolating the precipitated crystal of imatinib mesylate alpha-form, with seeding. The process described in the '816 publication involves the use of solvents like 4-methylcyclohexanone, which are not only expensive for industrial use but also not suitable for handling in industrial scale production.

U.S. Patent No. US 7,732,601 describe a process for the preparation of alpha-crystal form of imatinib mesylate which involves the use of not more than 0.99 equivalents of methanesulfonic acid, per equivalent of imatinib, in a solvent selected from the group consisting of C2-e aliphatic alcohols and mixtures thereof, optionally with the addition of a solvent selected from the group consisting of esters formed from a d- C4 aliphatic alcohols and lower carboxylic acids and inoculating the reaction mixture with the alpha crystal form.

International Patent Publication WO 2006/048890 ("the '890 publication") 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. This process is quite difficult to scale up and expensive also.

International Patent Publication WO 2007/136510 ("the '510 publication") describes processes for preparing crystalline imatinib mesylate of form alpha comprising; providing a solution of imatinib mesylate in ethylene glycol dimethyl ether, and admixing the solution with t-butyl methyl ether to form a suspension comprising the crystalline form or crystallizing imatinib mesylate from a solution imatinib mesylate in a solvent selected from the group of 1 ,2-propylene carbonate, a mixture of n- propanol and acetic acid and mixture thereof.

International Patent publication WO 2009/151899 ("the '899 publication") describes a method of preparing a non-hygroscopic, stable crystalline imatinib mesylate alpha- form which involves the use of ether solvent, such as cyclic ethers (tetrahydrofuran, pentahydropyran, and the like) and acyclic ethers (dimethyl ether, diethyl ether, methyl tertiary butyl ether, and the like). The use of ethereal solvents is not quite dangerous on the commercial scale and not practically commercially feasible.

U.S. Patent No. US 8,048,883 describea non-needle alpha 2 form and a process for its preparation comprising Imatinib base in a solvent, the solvent comprising acetone, acetonitrile, a mixture of methanol and isopropanol, or a mixture of isoproponal and water; adding methanesulfonic acid to the resulting suspension at room temperature, refluxing the solution and cooling to room temperature to obtain the alpha 2 form.

International Patent publication WO 2010/133976 (A2) describes a process for preparing the alpha form of Imatinib mesylate by precipitating crystalline form of Imatinib mesylate by combining the solution of imatinib mesylatein a solvent selected from the group consisting of N.N-dimethylformamide, N.N-dimethylacetamide and mixtures thereof with an anti-solvent selected from the group consisting of isopropyl alcohol, acetone and mixtures thereof; and optionally, seeding the solution with crystalline alpha form prior to or after the addition of anti-solvent.

International Patent publication WO 201 1/099039 (A1 ) describes a process for the preparation of alpha crystalline form of imatinib mesylate with (long needle) and alpha crystal form (small needle) by mixing of imatinib base of purity at least of 99% in anhydrous solvent and adding methane sulphonic acid at a temperature between 30-60 °C followed by refluxing and cooling of the reaction mixture to isolate the solid. The base required by this process should be of very high purity, at least 99.0% pure, otherwise alpha form obtained will not be of required purity.

International Patent publication WO 201 1/108953 (A1 ) describes a process for the preparation of alpha crystalline form of imatinib mesylate by suspending imatinib base in a mixture of isopropyl alcohol and diisopropyl ether or in methylene dichloride and stirring the solution at temperature from -10 °C to reflux, followed by addition of methanesulfonic acid, stirring the reaction mixture at temperature from - 1 0 °C to reflux, (d) cooling down the reaction mixture to temperature 0 - 25 °C and isolating the crystalline product from the reaction mixture. The use of ethereal solvents is not quite dangerous on the commercial scale and not practically commercially feasible.

International Patent publication WO 201 1 /157450 (A1 ) describes a process for the preparation of alpha crystalline form of imatinib mesylate by combining imatinib base with water and/or mixture of water with alcohols 01 -04 and 0.9 to 1 .2 equivalent of organic or inorganic acid, preferably methanesulfonic acid, (ii) stirring the reaction mixture at low temperatures of 5 °C to 70 °C, crystallizing imatinib salt by addition of or combining with organic solvent inoculated with seeding crystals and stirring the reaction mixture until crystallization of imatinib salt.

International Patent publication WO 201 1 /158255 (A1 ) describes a process for the preparation of alpha crystalline form of imatinib mesylate providing a suspension or solution of imatinib base in an organic solvent, wherein the organic solvent is selected from the group consisting of anisole, [gamma]- butyro lactone, Ci-4 alcohols, xylenes and mixtures thereof; addition of methane sulfonic acid and optionally, heating the mixture to about ambient temperature to about reflux temperature followed by cooling the reaction mixture to ambient temperature.

The above mentioned documents collectively disclose diverse processes for the preparation of alpha crystalline form of Imatinib mesylate using various types of solvents, but methods reported in the literature isolate the alpha form at ambient temperature which results in contamination with small amount of beta crystalline form of Imatinib mesylate. This is due to the fact that beta crystalline form of imatinib mesylate is thermodynamically more stable than that of alpha form. Moreover due to various reasons such as use of volatile solvents, lower yield they are not particularly convenient and amenable to scale-up for preparing the stable alpha form. Thus there is an unmet need in the field for the provision of simple, controlled procedures for the preparation of an alpha form of imatinib mesylate, free of beta form, which is not only stable but also amenable to scale-up.

SUMMARY OF THE INVENTION

The present invention discloses a reproducible process for preparation of a stable, free flowing, non-hygroscopic crystalline alpha form of imatinib mesylate, which is free of the beta form, and also amenable to scale-up. In accordance with one embodiment of the present invention, a process for the preparation of stable, free flowing, non-hygroscopic crystalline alpha form of imatinib mesylate, free of the beta form, comprising:

a) providing a clear solution of imatinib base in organic solvent;

b) optionally, filtering the solution to remove any insoluble impurity;

c) Adding another organic solvent to the above solution and heating to obtain a clear solution;

d) adding solution of methane sulfonic acid in second organic solvent slowly to

the above solution of step c) on heating;

e) Cooling of the reaction mixture obtained in step d) followed by seeding of the clear solution with pure alpha crystalline form of Imatinib mesylate on heating;

f) Slowly cooling of the reaction mixture;

g) isolating the imatinib mesylate alpha form.

DESCRIPTION OF THE DRAWINGS AND FIGURES

FIG. 1 illustrates a powder X-ray diffraction pattern (XRPD) of imatinib mesylate alpha form prepared according to Example- 1 .

FIG. 2 illustrates a characteristic differential scanning calorimeter (DSC)

thermogram of imatinib mesylate alpha form prepared according to Example-1 .

FIG. 3 illustrates a characteristic differential scanning calorimeter (DSC)

thermogram of imatinib mesylate alpha form of the present invention obtained at ambient temperature .

DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses a reproducible process for preparation of a stable, free flowing, non-hygroscopic crystalline alpha form of imatinib mesylate, free of the beta form and also amenable to scale-up.

A stable, free flowing, non-hygroscopic crystalline alpha form of imatinib mesylate can be characterized by its X- ray powder diffraction pattern (XRPD), and Differential Scanning Calorimeter (DSC), as well as by other analytical techniques.

The present invention provides a process for the preparation of stable crystalline alpha form of Imatinib mesylate, free of the beta crystalline form of Imatinib mesylate and amenable to scale-up, comprising:

a) providing a clear solution of imatinib base in organic solvent;

b) optionally, filtering the solution to remove any insoluble impurity; c) Adding another organic solvent to the above solution and heating to obtain a clear solution;

d) adding solution of methane sulfonic acid in second organic solvent slowly to the above solution of step c) on heating;

e) Cooling of the reaction mixture obtained in step d) followed by seeding of the clear solution with pure alpha crystalline form of Imatinib mesylate on heating; f) Slowly cooling of the reaction mixture;

g) isolating the imatinib mesylate alpha form.

The starting material, imatinib base used in the process of the present invention is known in the art and can be prepared by any known method, for example, imatinib base can be synthesized by the process mentioned in US 7,550,591 .

The present inventors have noted that methods reported in the literature for the preparation of alpha form of Imatinib mesylate isolate the alpha form at ambient temperature which results in contamination with beta crystalline form of Imatinib mesylate. This is due to the fact that beta crystalline form of imatinib mesylate is thermodynamically more stable than that of alpha form. In order to avoid the contamination with beta crystalline form, the solution of imatinib mesylate should be clear and it should be above ambient temperature.

The process of providing a clear solution of imatinib base in organic solvent comprises combining the imatinib base with the organic solvent and heating it to the temperature till imatinib base is completely dissolved in the organic solvent as the Imatinib free base is insoluble in most of the organic solvents. The solubility of imatinib free base is as follows:

Soluble: DMF, DMSO

Slightly soluble: Methanol, Dichloromethane

Insoluble: Water, IPA, Acetone, Toluene, Ethyl Acetate, Cyclohexane

The temperature suitable for dissolving imatinib base depends on the solvent used and the amount of imatinib base in the solution. Typically, the reaction is heated at a temperature of at least about 60 °C to about reflux; preferably, the reaction is heated at about 70 °C to about 90 °C, more preferably about 70 °C to about 80 °C.

As clear from the solubility of imatinib free base in various solvents as mentioned above, the imatinib free base will be soluble on heating and organic solvent chosen should have high boiling point. The organic solvent include, but are not limited to dimethyl sulphoxide (DMSO), CrC4 alcohols such as isopropanol, methanol etc. and mixtures thereof. Preferably the organic solvent is mixture of DMSO and isopropanol, Imatinib base present in an amount of about 1 to about 10 volumes of the solvent, preferably about 2 to about 8 volumes, more preferably about 2 to about 6 volumes, most preferably about 3 to about 5 volumes. The methane sulfonic acid in the abovementioned step d) may be used in the range of about 0.9 to about 1 .1 mole per mole of imatinib base, preferably about 1 mole per mole of imatinib base.

Methane sulfonic acid is added in the form of solution (dissolved in IPA) used for the reaction. The quantity of the solvent used to prepare a solution of methane sulfonic acid may range between about 1 and about 10 ml, per gram of imatinib base, preferably about 5 to about 8ml, per gram of imatinib base. The rate of addition of methane sulfonic acid solution is critical and it should be such that the reaction mixture always remain a clear solution, otherwise contamination with beta form is possible.

The temperatures at which methane sulfonic acid can be added to the mass of step c) may range from about 10°C to about reflux temperature of the solvent. Preferably the addition of methane sulfonic acid can be added at a temperature of about 85 °C to about 105°C, more preferably at about 90 °C to about 95 °C.

The temperature at which seeding with pure alpha crystalline form of Imatinib mesylate is done is critical as the solution should be clear even after seeding. The temperature of seeding may range from about 60 °C to about reflux temperature of the solvent. Preferably the seeding with alpha form can be added at a temperature of about 75 °C to about 95 °C, more preferably at about 75 °C to about 85 °C.

In step e) cooling the resultant reaction mass can be done at a temperature from about 60 °C or less, more preferably at temperature below 50° or less but in any case temperature should not go below 35 °C otherwise beta crystalline form will also precipitate with alpha crystalline form. The resultant imatinib mesylate alpha form formed from the present invention is isolated by filtration.

By performing the process of the present invention, substantially pure imatinib mesylate can be obtained with a degree of purity as determined by HPLC greater than or equal to about 99%, preferably greater than or equal to about 99.5% and more preferably greater than or equal to about 99.8%.

According to one aspect of the present invention, the formation of the beta-form crystals is not observed even after incubating the crystallization mixture, containing the alpha-form crystals, for prolonged periods in the reaction vessel overnight, as determined by using the XRPD and DSC technique.

The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the claims. Example-1 : Preparation of crystalline alpha form of Imatinib mesylate (from a mixture of DMSO +IPA)

Into a round bottom flask fitted with a mechanical stirrer and a reflux condenser was charged Imatinib free base (80. Og) and DMSO (320ml_) and heated to 70-80°C to form a clear solution. The hot solution was filtered through 5micron filter paper at 45-55 °C. IPA (720ml_) was added to the filtrate and heated to a temperature of 90-95 °C to get a clear solution. Solution of methane sulfonic acid in IPA (15.6g in 80ml_) was added slowly to the clear solution at 90-95 °C. The clear solution was cooled to 78-82 <C followed by seeding with pure alpha crystalline form of Imatinib mesylate (0.8g) at 78- 82<C.the mass was slowly cooled to 35-45 °C in 1 .5-2.0 hours. The mass was stirred at 35-45 < for 1 -1 .5hours. The solid obtained was filtered and washed with IPA under nitrogen atmosphere. The wet product was dried at 45-55 °C under reduced pressure for 10-12 hours to get crystalline alpha form of Imatinib mesylate.

Yield: 76.5gm (80.0%),

DSC: 225-228 <C,

Water Content: Not more than 0.5%

Hygroscopicity: Material is non-hygroscopic at 80% RH

Crystal structure: Needle shape

The XRD is set forth in FIG-1.

The DSC is set forth in FIG-2.

Example-2: Preparation of crystalline alpha form of Imatinib mesylate (from a mixture of DMSO +IPA)

Into a round bottom flask fitted with a mechanical stirrer and a reflux condenser was charged Imatinib free base (40. Og) and DMSO (200ml_) and heated to 70-80 °C to form a clear solution. The hot solution was filtered through 5micron filter paper at 45-55 °C. IPA (600ml_) was added to the filtrate and heated to a temperature of 90-95 °C to get a clear solution. Solution of methane sulfonic acid in IPA (7.8g in 40ml_) was added slowly to the clear solution at 90-95 °C. The clear solution was cooled to 78-82 <C followed by seeding with pure alpha crystalline form of Imatinib mesylate (0.4g) at 78- 82<C.the mass was slowly cooled to 35-45 °C in 1 .5-2.0 hours. The mass was stirred at 35-45 < for 1 -1 .5hours. The solid obtained was filtered and washed with IPA under nitrogen atmosphere. The wet product was dried at 45-55 °C under reduced pressure for 10-12 hours to get crystalline alpha form of Imatinib mesylate.

Yield: 36.0gm Example-3: Preparation of crystalline alpha form of Imatinib mesylate (from a mixture of DMSO +IPA)

Into a round bottom flask fitted with a mechanical stirrer and a reflux condenser was charged Imatinib free base (40. Og) and DMSO (200ml_) and heated to 70-80°C to form a clear solution. The hot solution was filtered through 5micron filter paper at 45-55 °C. IPA (520ml_) was added to the filtrate and heated to a temperature of 90-95 °C to get a clear solution. Solution of methane sulfonic acid in IPA (7.8g in 40ml_) was added slowly to the clear solution at 90-95 °C. The clear solution was cooled to 78-82 °C followed by seeding with pure alpha crystalline form of Imatinib mesylate (0.4g) at 78- 82qC.the mass was slowly cooled to 35-45 °C in 1 .5-2.0 hours. The mass was stirred at 35-45 <Ό for 1 -1 .5hours. The solid obtained was filtered and washed with IPA under nitrogen atmosphere. The wet product was dried at 45-55 °C under reduced pressure for 10-12 hours to get crystalline alpha form of Imatinib mesylate.

Yield: 35.0gm

Claims

1 . A process for the preparation of stable crystalline alpha form of Imatinib mesylate, free of the beta form, comprising:
a) providing a clear solution of imatinib base in organic solvent;
b) optionally, filtering the solution to remove any insoluble impurity;
c) Adding another organic solvent to the above solution and heating to obtain a clear solution;
d) adding solution of methane sulfonic acid in second organic solvent
slowly to the above solution of step c) on heating;
e) Cooling of the reaction mixture obtained in step d) followed by seeding of the clear solution with pure alpha crystalline form of Imatinib mesylate on heating;
f) Slowly cooling of the reaction mixture;
g) isolating the imatinib mesylate alpha form. wherein the organic solvent is selected from the group consisting of
N, N-dimethyl sulphoxide, Isopropanol and mixtures thereof;
2. The process of claim 1 wherein the organic solvent is a mixture of isopropanol and dimethylsulphoxide.
The process of claim 1 wherein the molar ratio of imatinib abse to methane sulfonic acid is about 1 :0.9 to 1 :1 .1 .
The process of claim 1 wherein methane sulfonic acid is added in step d) at temperature of 90-95<C.
The process of claim 1 wherein cooling of the reaction mixture in step e) id done upto 78-82 °C.
The process of claim 1 wherein seeding with pure alpha form of imatinib mesylate in step e) is done at 78-82 °C.
The process of claim 1 wherein cooling of the reaction mixture is done at 35 45 <C.
The process of claim 1 wherein the crystalline form of imatinib mesylate is characterized by XRD pattern substantially in accordance with Figure. 01 .
9. The process of claim 1 , wherein the crystalline alpha form of imatinib charaterizeed by differential scanning calorimetric (DSC) thermogram in accordance with Figure-02.
10. A process for the preparation of stable crystalline alpha form of Imatinib
mesylate, comprising:
a) providing a clear solution of imatinib base in DMSO at 90-95^;
b) Filtering the solution to remove insoluble impurity;
c) Adding IPA to the above solution and heat the solution to 90-95 °C;
d) adding solution of methane sulfonic acid in isopropanol slowly to the above solution at 90-95 <C;
e) Cooling of the reaction mixture obtained in step d) to 78-82 <C followed by seeding of the clear solution with pure alpha crystalline form of Imatinib mesylateat 78-82 <C;
f) Slowly cooling of the reaction mixture to 35-45^;
g) isolating the imatinib mesylate alpha form at 35-45 °C.
PCT/IB2012/054240 2012-03-13 2012-08-22 An improved process for the preparation of alpha form of imatinib mesylate WO2013136141A1 (en)

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