WO2012014000A1 - STABLE α-CRYSTAL FORM OF IMATINIB MESYLATE AND PREPARING PROCESS THEREOF - Google Patents
STABLE α-CRYSTAL FORM OF IMATINIB MESYLATE AND PREPARING PROCESS THEREOF Download PDFInfo
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- WO2012014000A1 WO2012014000A1 PCT/IB2010/001888 IB2010001888W WO2012014000A1 WO 2012014000 A1 WO2012014000 A1 WO 2012014000A1 IB 2010001888 W IB2010001888 W IB 2010001888W WO 2012014000 A1 WO2012014000 A1 WO 2012014000A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Definitions
- Tne!i art i given herein pertains to stable, free flowing and non-hygroscopic a- crjfsi ll olYni rph of methane sulfonic acid addition salt of 4-(4-methyl piperazin-
- Imiitiiij sAld by the Novartis as GleevecTM is used for the treatment of chronic my ioii lei bid mia (CML), malignant gasiro intestinal tumors and other solid tumdrs!
- CML chronic my ioii lei bid mia
- 10dl 1 thej process for the crystal involves a number of unit operations maJdng it
- 095379 teaches preparation of a-polymoiph of imatinib mesylate using equivalents (0.95 - 0.99) of methane sulfonic acid in an alkanol or a alkanol and alkanoic acid ester.
- the process requires seeding with a- Thii process is a little lengthy and inconsistent for repeatability.
- Use of bh eiits of alkanol and alkanoic ester is not favourable as it leads to small il l bf npesired form.
- 6/ 0 ⁇ 4863 describes a process which produces non-inform a-crystals rr icionization. It is likely to result in non-uniform crystals. it 2 ⁇
- I describes formation of ⁇ -polymorph of imatinibS ate as well as forms I and II of imatinib di methane sulfonate salts.
- ⁇ y of the mole ratio of base to acid in the formation of mono and di salt detail.
- the formation of a-polymorph is carried out in a mixture of !col!iol and an alkanol selected from Q-C 4 alkanol. Mixture of solvents is ira )l for an individual process. It was observed in our hand that any jwt ici has solubility in water or tends to be hygroscopic gave inconsistent Jbrmation of pure a-crystal polymorph. .
- the invention application describes a simple, facile and industrially operational mi . dfiogjy in order to achieve consistent results in terms of yield and quality of the oryssttaallllrine polymorph.
- This invention yields a stable, free flowing and! h ⁇ jjtW ⁇ gfcoscopic a-crystal polymorph substantially free of ⁇ -crystal h.
- liment of the invention a free flowing, stable and non-hygroscopic ⁇ - obtained by conducting salt formation in a water immiscible or miscible organic solvent or a mixture there of. ler (embodiment of the invention a jfree flowing, stable and non-hygroscopic is formed by performing the reaction in a alkanoic acid ester or a
- tsj achieved by mixing a suspension or a partially soluble solution of imatihilibi [with a solution of methane sulfonic acid under stirring.
- the THaiioh of a-crystal polymorph is carried out, preferably, in an alkanoic acid ester an] kanone or a mixture there of under stirring at a temperature of 20-
- the salt formation is preferably carried out in an alkaf id ester R'-COOR 2 where R l is methyl, ethyl & propyl and R 2 is methyl k jl [propyl and butyl or mixtures there of, an alkanone R 1 CO R 2 where
- R 1 is ; ilnl ithyl and isobutyl and R 2 is methyl or mixture there of and a mixture of an all ox cid ester and an alkanone. It e to use to an alkanoic acid ester, a mixture of alkanoic acid ester, an alii mixture of alkanone and a mixture of an alkanoic acid ester and an alkanc preferable to use an alkanoic acid ester or an alkanone. It is most ;o use an alkanoic acid ester.
- solvents are methyl acetate, ethyl acetate, propyl acetate, isopropyl jbu yli acetate or a mixture there of, or acetone, methyl ethyl ketone, methyl t etbne or mixtures there or mixture of an alkanoic acid ester and an
- the salt formation is carried at a oin0-80°C.
- the mole ratio methane to that of imatinib base is preferably 0.95 to 1.0.
- the preferable solvents are ethyl acetate and but a ⁇ 3 ⁇ 4at3.
- Fork at In f a-polymorph is achieved by adding a solution of methane sulfonic acid in ii cjfganic solvent to a partially soluble suspension of imatinib base in the sortie ante solvent under stirring at a temperature of 30 to 75 °C, preferably at 50-601 li rkel addition of the methane sulfonic acid may be preferably done in i more preferably 1 - 2 hrs.
- the maintenance, after completion of ⁇ erably, is 1-2 hrs and more preferably 1 - X .5 hrs.
- the iveiits used in this invention include methyl acetate, ethyl acetate, propyl acetalti p
- I sported herein is quite rugged since it can be performed at wide range teii
- ie mole ratio of acid to base is 1 : 1, wherein, one can achieve ie 1 fcfemiation of ⁇ -polymorph, which is easily filtered and dried. gives, a free flowing, non-hygroscopic and stable a-polymorph free of p-polymorph in at least 88.5% yield and at least 95% yield, fer hj?ice of conditions, su h as solvent and temperature, HPLC purity of ati ! abM can be obtained. k ation of a-crystal polymorph has been confirmed by studying their J , ⁇ tW).
- Fi ure gives IR spectra, figiitefij gi el? the DSC and figure iii gives the XRD.
- T uk ife applicants have developed a rugged method for the formation of a-crystal pol n: jph vhich has excellent physical properties such as easy filterability, drying >jjcijtics, stability and non-hygroscopic nature.
- the i[i il if) % and HPLC purity is 99.4%.
Abstract
A stable, free flowing and non -hygroscopic α-crystalline form of 4-(4-methyl piperazin-1-yl methyl)-N-[4-methyl-3- (4-pyridin-3-yl)pyrimidin-2-yl amino)phenyl]-benzamide monomethanesulfonate (imatinib mesylate) is disclosed. A process for preparing the a-crystal polymorph of the said imatinib mesylate is also described.
Description
STABLE -CRYSTAL FORM OF IMATMtB MESYLATE AND PREPARING PROCESS THEREOF
FiM ithb invention;
Tne!i art i given herein pertains to stable, free flowing and non-hygroscopic a- crjfsi ll olYni rph of methane sulfonic acid addition salt of 4-(4-methyl piperazin-
1 L letliy !)-N-[4-mctliyl(3-(4-pyridm-3'-yl) pyrimidin-2-yl amino)phenyl]- beJ piifomiula-I and process for the preparation thereof.
d I f the invention:
Imiitiiij sAld: by the Novartis as Gleevec™ is used for the treatment of chronic my ioii lei bid mia (CML), malignant gasiro intestinal tumors and other solid tumdrs! uslpklit Ao 6894051 describes a and β crystalline forms of imatinib mesylate. a Jr stkline described in that patent is described as hygroscopic and unstable an 10dl 1 thej process for the crystal involves a number of unit operations maJdng it
!
curabbrS6m
ι0 632 ? relating to HI crystal of imatinib mesylate, makes use of solvents, which are undesirable on account of its hazaradous
5/|095379 teaches preparation of a-polymoiph of imatinib mesylate using equivalents (0.95 - 0.99) of methane sulfonic acid in an alkanol or a alkanol and alkanoic acid ester. The process requires seeding with a- Thii process is a little lengthy and inconsistent for repeatability. Use of bh eiits of alkanol and alkanoic ester is not favourable as it leads to small il l bf npesired form.
6/ 0^4863 describes a process which produces non-inform a-crystals rr icionization. It is likely to result in non-uniform crystals. it 2<|)06/0223816 A1 describes formation of a-polymorph of imatinib
US class ΠΙ as well as class TT solvents. Repeating this process it was at temperatures close to 70-80°CT impurities formation were more
15 p(f Alteration of addition salt took several hours. Additionally the crystals formation needed seeding by a-crystals.
!nt |2C(07/0197545 A I describes formation of α-polymorph of imatinibS ate as well as forms I and II of imatinib di methane sulfonate salts.
ίοψίΐ y of the mole ratio of base to acid in the formation of mono and di salt detail. The formation of a-polymorph is carried out in a mixture of !!col!iol and an alkanol selected from Q-C4 alkanol. Mixture of solvents is ira )l for an individual process. It was observed in our hand that any jwt ici has solubility in water or tends to be hygroscopic gave inconsistent Jbrmation of pure a-crystal polymorph. .
CJL he fact that the methods described in the preceding paragraph have t^n is of simplicity and consistency in the formation of the required polyih< )hjc crystals, it was decided to develop a simple methodology, which will a-j oiymorph in stable form.
Sumih rv m the invention application describes a simple, facile and industrially operational mi . dfiogjy in order to achieve consistent results in terms of yield and quality of the oryssttaallllrine polymorph. This invention yields a stable, free flowing and! h< jjtW ^gfcoscopic a-crystal polymorph substantially free of β-crystal h.
liment of the invention a free flowing, stable and non-hygroscopic α- obtained by conducting salt formation in a water immiscible or miscible organic solvent or a mixture there of. ler (embodiment of the invention a jfree flowing, stable and non-hygroscopic is formed by performing the reaction in a alkanoic acid ester or a
embodiment of the present invention, the formation of a-polymorph •y using C1.4 alkanoic acid ester, an alkanone or a mixture of CM ester and an alkanone there of.
In- ! embodiment of the present invention, the selective formation of a-
I
tsj achieved by mixing a suspension or a partially soluble solution of imatihilibi [with a solution of methane sulfonic acid under stirring.
In one ther embodiment of the present invention by conducting the salt forfeit: -0-80°C. in sjolj ents, which give consistent formation of free flowing, stable and ic a-polymorph is achieved by conducting salt formation in a se; j ic ed from the group methyl acetate, ethyl acetate, propyl acetate, E cejtate, butyl acetate, methyl propionate, ethyl propionate, methyl
te,| ethyl butanoate or a mixture there of, acetone, ethyl methyl ketone, isoibAtyl ketone or a mixture there of or a mixture of an alkanoic acid ester and alkdnine.
The THaiioh of a-crystal polymorph is carried out, preferably, in an alkanoic acid ester an] kanone or a mixture there of under stirring at a temperature of 20-
80¾
Detajl description of the invention
It has (Jbserved that a free flowing, stable and nonrhygroscopic a-crystal ith consistent particle size, is formed, by conducting the salt form^tiln hji an alkanoic acid ester, a mixture of alkanoic acid esters, an alkanone, a misiuiffe oft lkanones and a mixture of alkanoic acid ester and a alkanone under stirciiigipt ake! nperature of 0-80°C.
In orie |mb|)d iiient of the invention the salt formation is preferably carried out in an alkaf id ester R'-COOR2 where Rl is methyl, ethyl & propyl and R2 is methyl k jl [propyl and butyl or mixtures there of, an alkanone R1 CO R2 where
| i
R1 is;ilnl ithyl and isobutyl and R2 is methyl or mixture there of and a mixture of an all ox cid ester and an alkanone.
it e to use to an alkanoic acid ester, a mixture of alkanoic acid ester, an alii mixture of alkanone and a mixture of an alkanoic acid ester and an alkanc preferable to use an alkanoic acid ester or an alkanone. It is most ;o use an alkanoic acid ester. solvents are methyl acetate, ethyl acetate, propyl acetate, isopropyl jbu yli acetate or a mixture there of, or acetone, methyl ethyl ketone, methyl t etbne or mixtures there or mixture of an alkanoic acid ester and an
It is lri erable to use an alkanoic acid ester or an alkanone or a mixture of an aU ano add ester and an alkanone.
It is mtfsit pfei erable to use an industrially available alkanoic acid ester.
^nbodiment of the present invent, the salt formation is carried at a oin0-80°C.
It is p to use a temperature of 15-80°C. pj-eijerable to use a temperature of 20-70°C. ferable to use temperature between 50-60°C.
ant> er embodiment of the present invention, the mole ratio methane to that of imatinib base is preferably 0.95 to 1.0.
Ids ferable to use a mole ratio of 0.98 to 1.0.
\ t ifreiferable to use equi molar ratio of methane sulfonic acid and base. e to use a 10-40 volumes of solvent. It will be more preferable to use !01uja^s of solv nt. ijfer, ible to conduct the salt formation at 15 to 80°C. It is more preferable to 2! to 70°C. mist irjferable to form a-polymorph crystals of imatinib mesylate at 30 to
As per itie ai dings of this applicants the preferable solvents are ethyl acetate and but a< ¾at3.
Fork at In f a-polymorph is achieved by adding a solution of methane sulfonic acid in ii cjfganic solvent to a partially soluble suspension of imatinib base in the sortie ante solvent under stirring at a temperature of 30 to 75 °C, preferably at 50-601 li rkel addition of the methane sulfonic acid may be preferably done in
i more preferably 1 - 2 hrs. The maintenance, after completion of ■erably, is 1-2 hrs and more preferably 1 - X .5 hrs. is very simple, easily operational resulting in the formation of stable, wjnj;, non-hygroscopic a-polymorphic crystals of imatinib methane sulfdn! A iditionally the preferential -polymorph crystal formation takes place with©1 se|d|ng by a-crystals.
The iveiits used in this invention include methyl acetate, ethyl acetate, propyl acetalti p|:opyI acetate, butyl acetate, methyl propionate, ethyl propionate,,
>ate, ethyl butanoate and mixtures there of.
I sported herein is quite rugged since it can be performed at wide range teii|nleratui{es preferably 20-80°C, more preferably 25-75°C and mot preferably
T|ie mole ratio of acid to base is 1 : 1, wherein, one can achieve ie1 fcfemiation of α-polymorph, which is easily filtered and dried. gives, a free flowing, non-hygroscopic and stable a-polymorph free of p-polymorph in at least 88.5% yield and at least 95% yield, fer hj?ice of conditions, su h as solvent and temperature, HPLC purity of ati ! abM can be obtained.
k ation of a-crystal polymorph has been confirmed by studying their J , τΜ tW).
Fi ure gives IR spectra, figiitefij gi el? the DSC and figure iii gives the XRD.
T uk ife applicants have developed a rugged method for the formation of a-crystal pol n: jph vhich has excellent physical properties such as easy filterability, drying >jjcijtics, stability and non-hygroscopic nature.
Exam ng examples illustrate this invention. This should not be miscrued in a jplication of this invention in any way. The person skilled in the art tile jarameters within the scope this invention.
etsijon of imatinib base (99 g, 0,2 mole), stirred at 40-60°C in methyl was added a solution of methane sulfonic acid (19.22 g, 0.2 mole) in 1 Icei^e1 (100 ml) during 1.5 - 2hrs, After the addition, the reaction mixture
that temperature for 1-2 hr and filtered. The solid wa$ washed with !e sbl ent and dried under vacuum at 40-50°C. d fs 90% and HPLC purity is 99.5%. .
spfsnfcioii of imatinib base (99 g, 0.2 mole), stirred at 40-60°C in ethyl , was added a solution of methane sulfonic acid (19.22 g, 0.2 mole) in (100 ml) during 1.5 - 2hrs. After the addition, the reaction mixture was hed all that temperature for 1-2 hr and filtered.
The solid was washed with the same solvent and dried under vacuum at 40-50 C. im ii 96% and HPLC purity is 99.85%.
Example 3
To 1 Spehsion of imatinib base (99 g, 0.2 mole), stirred at 40-60°C in propyl acetatej was added a solution of methane sulfonic acid (19.22 g, 0.2 mole) in prop yl cetkte (100 ml) during 1.5 - 2hrs. After the addition, the reaction mixture was stifi tat that temperature for 1-2 hr and filtered. The solid was washed with solvent and dried under vacuum at 40-50°C.
The 89% and HPLC purity is 99.5%.
sponsion of imatimb base (99 g, 0.2 mole), stirred at 40-60°C in butyl [2 jts)} was added a solution of methane sulfonic acid (19.22 g, 0.2 mole) in etate (100 ml) during 1.5 - 2hrs. After the addition, the reaction mixture ecj at that temperature for 1-2 hr and filtered. The solid was washed with lent and dried under vacuum at 40-50°C.
1% and HPLC purity is 99,5%.
s«pehsion of imatinib base (99 g? 0.2 mole), stirred at 40-60°C in isopropyl s J was added a solution of methane sulfonic acid (19.22 g, 0.2 mole) in
1 ac 1etate (100 ml) during 1.5 - 2hrs. After the addition, the reaction was stirred at that temperature for 1-2 hr and filtered. The solid was le same solvent and dried under vacuum at 40-50°C.
The i[i il if) % and HPLC purity is 99.4%.
Exaittr 6 |
To ύ slfcpeksion of imatinib base (99 g3 0.2 mole), stirred at 40-60°C in methyl propfoJatc 2 lt$). was added a solution of methane sulfonic acid (19.22 g, 0.2
mb! fe)||f ifaejthyl propionate (100 ml) during 1.5 - 2hrs. After the addition, the rrjij-jture was stirred at that temperature for 1-2 hr and filtered. The solid was Shdd with the same solvent and dried under vacuum at 40-50°C.
1¾ej jy||id s k.5% and HPLC purity is 98.8%.
Examf
To lisplnlion of imatinib base (99 g, 0.2 mole), stirred at 40-60°C in ethyl rojiii .ate (2 Its), was added a solution of methane sulfonic acid (19.22 g, 0.2 mole) in i thyl propionate (100 ml) during 1.5— 2hrs. After the addition, the reac .©j :c m xlure was stirred at that temperature for 1-2 hr and filtered. The solid was !he 1 with the same solvent and dried under vacuum at 40-50°C.
The mm if 89% and HPLC purity is 99.3%.
Claims
ί ptfocess for the preparation of substantially pure a-polymorph of imatinib je by adding a solution of methane sulfonic acid, dissolved in an organic preferably alkanoic acid ester to a stirred suspension or sparingly tispension of imatinib base in the same organic solvent, preferably jeid ester. as claimed in claim 1, wherein the alkanoic acid ester is methyl te, elhyl acetate, propyl acetate, iropropyl acetate, butyl acetate, methyl MomtL ethyl propionate, propyl propionate, isopropyl propionate, methyl b^tlnoa ;ej ethyl butanoate or a mixture there of las claimed in claim 2, wherein the alkanoic acid ester is methyl thyl acetate, propyl acetate, isopropyl acetate, butyl acetate or mixture
4. A claimed in claims 2 and 3,, where in the alkanoic acid ester is methyl e, ethyl acetate or their mixture,
5. A cj ml as claimed in claim 1, wherein the addition of methane sulfonic acid to imalniblbase is carried out at 20-80uC, preferably at 50-60°C.
i ll Ί I
6. Ail llainl as claimed in claim 1, wherein the crystals of imatinib mesylate substantially pure a-polymorph, >99.5%. a! claimed in claims 1 and 6, wherein the crystals of imatinib mesylate atje substantially pure a-polymorph, which shows in an X-ray ,ctii>n diagram lines having a relative line intensity, as compared to the se line in the diagram, of about 20% or more at the following angles idn 2theta: 4.9°, 10.5°, 14.9° 16.5°, 17-7°, 18.2°, 18.7°, 19.2° 21,4°, °, 23.2°, 23.8°, 25.0° and 28.6°.
s claimed in claims 1 and 6, wherein the crystals of imatinib mesylate substantially pure a-polymorph, which has a melting range of 223 - ifferential scanning calorimetry (DSC) thermogram.
' is claimed in claims 1 and 6, wherein the crystals of imatinib mesylate
W- are substantially pure a-polymorph, which has the IR spectrum ab! & bands using a KBr pellets at 3033, 2924, 2824, 2707, 1660, 1575,
IS1 1317, 1220, 1163, 1036, 807 and 554 cm-1.
10Λ lainj, fa claimed in claim 1, wherein α-polymorph is formed in not less that 85 yi< ;ldj and preferably not less than 95% yield.
11. A) ,r Js claimed in claim 1, wherein the HPLC purity of α-polymorph is not le fl 3 % and preferably not less than 99.5%.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005095379A2 (en) * | 2004-04-02 | 2005-10-13 | Instytut Farmaceutyczny | Crystalline methanesulfonic acid addition salts of imatinib |
US20060223816A1 (en) * | 2006-05-08 | 2006-10-05 | Chemagis Ltd. | Imatinib mesylate alpha form and production process therefor |
WO2009151899A2 (en) * | 2008-05-26 | 2009-12-17 | Dr. Reddy's Laboratories Ltd. | Preparation of imatinib mesylate |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005095379A2 (en) * | 2004-04-02 | 2005-10-13 | Instytut Farmaceutyczny | Crystalline methanesulfonic acid addition salts of imatinib |
US20060223816A1 (en) * | 2006-05-08 | 2006-10-05 | Chemagis Ltd. | Imatinib mesylate alpha form and production process therefor |
WO2009151899A2 (en) * | 2008-05-26 | 2009-12-17 | Dr. Reddy's Laboratories Ltd. | Preparation of imatinib mesylate |
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