Description:IELD OF THE INVENTION
The present invention relates to a process for the preparation of a-form of Imatinib
mesylate of formula (I) having acceptable levels of genotoxic impurities and having residual
solvents content less than 1/10th of ICH guidelines.
Formula (I)
BACKGROUND OF THE INVENTION
Imatinib is a small molecule kinase inhibitor. Imatinib is administered orally in the form
of a suitable salt e.g., mesylate and is marketed by Novartis under the trade name Gleevec.
Imatinib mesylate of formula (I) is designated chemically as 4-[(4-Methyl-1-piperazinyl)
methyl]-N-[4methyl-
3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-phenyl] benzamide
methanesulfonate.
Several processes have been reported for the preparation of a-form of Imatinib mesylate
for example, in U.S. Patent No. 5,521,184; Indian Patent Nos. 367768; 320033; 299984; Indian
Patent No 246334 (a2 crystalline form); Indian Patent Application Nos. 4428/CHE/2012;
7813/CHENP/2010; 1676/CHE/2010; 398/MUM/2010; 216/KOL/2009; 951/MUM/2004;
2908/MUM/2011; 341/CHE/2011; 1445/DEL/2010; 1036/CHE/2009, the contents of which are
hereby incorporated as reference in their entirety.
The use of organic solvents in the formation or crystallization of solid state Active
Pharmaceutical Ingredient (API) salts is quite common in the pharmaceutical practice, which may
involve environmental problems, such as the risk of danger of fire and explosion, in addition to
the problems which may arise from contamination of the finished medicament by residual solvents.
3
As a matter of fact, when organic solvents are employed for the preparation and/or crystallization
of API salts, such as Imatinib mesylate, these salts are contaminated by a residual amount of
organic solvents.
In view of the recommendations issued by the Regulatory Authorities, it is of main interest
to provide a new process for the production of a-form of Imatinib mesylate which allows further
improvements of both the toxicological profile and the economical aspects of the production,
whereby the Imatinib mesylate is obtained in a solid form which is substantially free from
impurities having genotoxic effects and residual solvents, such as lower alkanols, lower ketones,
halogenated hydrocarbons, aromatic hydrocarbon, and lower alkyl acetates.
The genotoxic impurities associated to Imatinib mesylate can be derived from the starting
materials themselves (i.e., Formula (2) and Formula (3)) and are the following:
Formula (2) Formula (3)
Impurities in Imatinib mesylate, or any active pharmaceutical ingredient (“API”), are
undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage
form containing the API. Further, the purity and polymorphic stability of an API produced in a
manufacturing process is critical for commercialization.
The product of a chemical reaction is rarely a single compound with sufficient purity to
comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct
reagents used in the reaction will, in most cases, also be present in the final product. At certain
stages during processing of an API, it must be analyzed for purity, typically, by high performance
liquid chromatography (“HPLC”) or thin-layer chromatography (“TLC”), to determine if it is
suitable for continued processing and, ultimately, for use in a pharmaceutical product.
4
As known by those skilled in the art, the management of process impurities is greatly
enhanced by understanding their chemical structures and synthetic pathways and by identifying
the parameters that influence the amount of impurities having genotoxic effects and residual
solvents in the final API. Extensive experimentation has been carried out by the present inventors.
As a result, the present inventors found an improved and a commercial method for the preparation
of a-form of Imatinib mesylate which is substantially free of genotoxic impurities of formula (2)
and formula (3) and which has a residual solvent content of less than 1/10th of ICH guidelines, by
controlling critical process parameters.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of a-form of
Imatinib mesylate of formula (I)
Formula (1)
having residual solvents content about less than 1/10th of limits given by the International
Conference on Harmonization on Technical Requirements for Registration of Pharmaceuticals for
Human Use (“ICH”) guidelines.
The process comprises the steps of:
a) subjecting a-form of Imatinib mesylate having residual solvents to humidification;
b) drying the humidified a-form of Imatinib mesylate in a vacuum try drier under vacuum
at 25 oC to 30 oC;
c) re-subjecting the a-form of Imatinib mesylate obtained in step b) to humidification; and
d) drying the humidified a-form of Imatinib mesylate in a vacuum try drier under vacuum
at 85 oC to 90 oC to obtain a-form of Imatinib mesylate having residual solvents content
less than 1/10th of ICH guidelines.
BRIEF DESCRIPTION OF THE DRAWINGS
A skilled person will understand that the drawings, described below, are for illustration
purposes only. The drawings are not intended to limit the scope of the present invention in any
5
way.
FIG. 1 shows an X-Ray powder diffraction pattern (XRPD) of a-form of Imatinib mesylate
as obtained by the process according to the present invention, as disclosed herein in Example 1.
DETAILED DESCRIPTION OF THE INVENTION
The term “about”, as used herein, when used along with values assigned to certain
measurements and parameters means a variation of up to 10% from such values, or in case of a
range of values, means up to a 10% variation from both the lower and upper limits of such ranges.
The term “substantially free” as used herein, has residual solvents content less than 1/10th
of limits given by the International Conference on Harmonization on Technical Requirements for
Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
Use of exemplary language, such as “for example”, “such as”, and the like, is merely
intended to better illustrate the invention and does not indicate a limitation on the scope of the
invention unless so claimed.
In one aspect, the present invention provides a process for the preparation of a-form of
Imatinib mesylate of formula (I)
Formula (1)
having residual solvents content about less than 1/10th of limits given by the International
Conference on Harmonization on Technical Requirements for Registration of Pharmaceuticals for
Human Use (“ICH”) guidelines, comprising the steps of:
a) subjecting a-form of Imatinib mesylate having residual solvents to humidification;
b) drying the humidified a-form of Imatinib mesylate in a vacuum try drier under vacuum
at 25 oC to 30 oC;
c) re-subjecting the a-form of Imatinib mesylate obtained in step b) to humidification; and
6
d) drying the humidified a-form of Imatinib mesylate in a vacuum try drier under vacuum
at 85 oC to 90 oC to obtain a-form of Imatinib mesylate having residual solvents content
less than 1/10th of ICH guidelines.
In one embodiment of this aspect, step a) of subjecting a-form of Imatinib mesylate to
humidification, and step c) of re-subjecting a-form of Imatinib mesylate to humidification
comprises spraying water on a-form of Imatinib mesylate. The water can be purified water without
any additives or other components.
In another embodiment of this aspect, step a) of subjecting a-form of Imatinib mesylate to
humidification and step c) of re-subjecting Imatinib mesylate to humidification comprises the
deposition of water on the surface of Imatinib mesylate in an amount of at least 1 mg/cm2. The
water can be purified water without any additives or other components.
In one embodiment of this aspect, step a) of subjecting a-form of Imatinib mesylate to
humidification comprises subjecting a-form of Imatinib mesylate having undesired amounts of
residual solvents. Particularly, subjecting a-form of Imatinib mesylate having more than 1/5th of
limits given by the International Conference on Harmonization on Technical Requirements for
Registration of Pharmaceuticals for Human Use (“ICH”) guidelines of residual solvents. More
particularly, step a) of subjecting a-form of Imatinib mesylate to humidification comprises
subjecting a-form of Imatinib mesylate having at least one or more of: more than 7000 parts per
million (ppm) of isopropyl alcohol and 6500 ppm of ethyl acetate as residual solvents to
humidification.
In another embodiment of this aspect, step b) of drying the humidified a-form of Imatinib
mesylate in a vacuum try drier comprises drying for about 4 hours to about 5 hours.
In another embodiment of this aspect, step d) of drying the humidified a-form of Imatinib
mesylate in a vacuum try drier comprises drying for about 8 hours to about 12 hours.
7
In another embodiment of this aspect, the humidification and the drying step can be
performed either sequentially or simultaneously.
In another embodiment of this aspect, the a-form of Imatinib mesylate of formula (I)
Formula (1)
obtained by the process has less than 1.3 ppm of each genotoxic impurity of formula (2) and
formula (3),
Formula (2) Formula (3)
and has residual solvents content about less than 1/10th of limits given by the International
Conference on Harmonization on Technical Requirements for Registration of Pharmaceuticals for
Human Use (“ICH”) guidelines.
In another embodiment of this aspect, the residual solvents can be lower alkanols, lower
ketones, halogenated hydrocarbons, aromatic hydrocarbon, and lower alkyl acetates. In
particular, the residual solvents (1/10th of the ICH guidelines) can be ethanol (not more than 500
ppm), isopropyl alcohol (not more than 500 ppm), acetone (not more than 500 ppm),
dichloromethane (not more than 60 ppm), toluene (not more than 89 ppm), ethyl acetate (not
more than 500 ppm).
In another embodiment, the a-form of Imatinib mesylate of formula (I) obtained may have
X-Ray powder diffraction (XRPD) pattern as shown in FIG. 1 and the 2 theta values (main values)
provided in Table 1.
8
2? values
4.9963
9.8068
10.5564
11.3465
11.9949
12.2857
13.0066
13.9739
14.9988
15.4677
16.5997
17.5987
17.8236
18.1918
18.7266
19.1908
19.5483
20.0124
20.6304
21.1592
21.3904
21.5994
21.7640
22.0903
22.7514
23.2731
23.8418
24.1614
24.9613
25.1216
26.4277
26.8863
27.2756
27.5159
28.1154
28.6378
28.9730
29.6394
30.1753
30.5472
31.0120
32.0898
32.7301
34.0535
35.4603
36.0822
36.8480
Table 1
As should be apparent from the foregoing, the present invention provides several
advantages over prior art methods of preparing a-form of Imatinib mesylate. These advantages
include:
1. Improved overall purity (>99.9 % by HPLC) in the preparation of a-form of Imatinib
mesylate.
2. Preparation of a-form of Imatinib mesylate with safe and easy handling of chemicals
at industrial scale with:
a. Genotoxic impurities of formula (2) and formula (3), each between 1.0 and 1.3
ppm
b. No residual solvent > 1/10th of ICH Guidelines
c. Other known and unknown impurities < 0.05 % (by HPLC)
d. Total impurities < 0.1 %
e. Water content < 0.5%
9
The Imatinib mesylate prepared according to the procedure of the present invention can
therefore be conveniently formulated with one or more acceptable pharmaceutical excipients. The
formulated product can therefore be used in medicine.
In the following section, the aspect is described by way of examples to illustrate the
processes of the invention. However, these do not limit the scope of the present invention. Several
variants of these examples would be evident to persons ordinarily skilled in the art.
EXAMPLES
EXAMPLE 1: PROCESS FOR THE PREPARATION OF a-FORM OF IMATINIB
MESYLATE
Isopropanol (2.3 l) and Imatinib base (0.7 kg) were charged at 25 to 30 oC Ethyl acetate
(2.3 l) was charged at 25-30 oC. The mixture was heated to 64 to 66 oC and stirred for 5 minutes
at 64 to 66 oC. Isopropanol (1.1 l) was charged into reaction mass at 64 to 66 oC and stirred for 5
minutes at 64 to 66 oC. Purified water (0.14 l) at charged at 64 to 66 oC and stirred for 5 minutes
at 64 to 66 oC. Methane sulphonic acid solution (Methanesulphonic acid (0.13 kg) in ethyl
acetate (1.1 l)) was added slowly into the reaction mass over 30 to 60 minutes at 64 to 66 oC The
reaction mass was heated to 75 to 80 oC and stirred for 30 minutes at 75 to 80 oC The mixture
was seeded with a-form of Imatinib mesylate at 75-80 oC and the mass was cooled to 45 to 50
oC. The solid was filtered through Buchner funnel and suck dried under vacuum. The solid was
washed with hot isopropanol and ethyl acetate mixture (0.35 l +0.35 l) and suck dried. The solid
was washed twice with hot ethyl acetate (2*0.35 l) and suck dried. The wet cake was unloaded
and placed in tray drier at 25 to 30 oC. Purified water (35 ml) was sprayed on the wet cake to
increase the humidity of the cake. The wet cake was dried at 25 to 30 oC for 4 hours to 5 hours.
Purified water (35 ml) was again sprayed on the cake to increase the humidity of the cake. The
wet cake was dried at 85 to 90 oC for 8 hours to 12 hours to provide the tilted compound.
Yield (%): 87.3 % , Claims:A process for the preparation of a-form of Imatinib mesylate of formula (I)
Formula (1)
having residual solvents content less than 1/10th of limits given by the International Conference on
Harmonization on Technical Requirements for Registration of Pharmaceuticals for Human Use
(“ICH”) guidelines, comprising the steps of:
a) subjecting a-form of Imatinib mesylate having residual solvents to humidification;
b) drying the humidified a-form of Imatinib mesylate in a vacuum try drier under vacuum
at 25 oC to 30 oC;
c) re-subjecting the a-form of Imatinib mesylate obtained in step b) to humidification; and
d) drying the humidified a-form of Imatinib mesylate in a vacuum try drier under vacuum
at 85 oC to 90 oC to obtain a-form of Imatinib mesylate having residual solvents content
less than 1/10th of ICH guidelines.
2. The process as claimed in claim 1, wherein step a) of subjecting a-form of Imatinib mesylate
to humidification, and step c) of re-subjecting a-form of Imatinib mesylate to humidification
comprises spraying water.
3. The process as claimed in claim 2, wherein the water is purified water without any additives
or other components.
4. The process as claimed in claim 1, wherein step a) of subjecting a-form of Imatinib mesylate
to humidification and step c) of subjecting Imatinib mesylate to humidification comprises the
deposition of water on the surface of Imatinib mesylate in an amount of at least 1 mg/cm2.
5. The process as claimed in claim 4, wherein the water is purified water without any additives
or other components.
11
6. The process as claimed in claim 1, wherein step a) of subjecting a-form of Imatinib mesylate
to humidification comprises subjecting a-form of Imatinib mesylate having more than 7000
parts per million (ppm) of isopropyl alcohol and 6500 ppm of ethyl acetate as residual solvents
to humidification.
7. The process as claimed in claim 1, wherein step b) of drying the humidified a-form of Imatinib
mesylate in a vacuum try drier comprises drying for about 4 hours to about 5 hours.
8. The process as claimed in claim 1, wherein step d) of drying the humidified a-form of Imatinib
mesylate in a vacuum try drier comprises drying for about 8 hours to about 12 hours.
9. The process as claimed in claim 1, wherein the a-form of Imatinib mesylate of formula (I)
Formula (1)
obtained has less than 1.3 ppm of each genotoxic impurity of formula (2) and formula (3).
Formula (2) Formula (3)
10. The process as claimed in claim 1, wherein the residual solvents (1/10th of the ICH
guidelines) are ethanol (not more than 500 ppm), isopropyl alcohol (not more than 500 ppm),
acetone (not more than 500 ppm), dichloromethane (not more than 60 ppm), toluene (not
more than 89 ppm), ethyl acetate (not more than 500 ppm).