Polymorphic form of imatinib mesylate and a process for its preparation

FIELD OF INVENTION

The invention provides a novel, polymorphic form of Imatinib mesylate and a process for its preparation. The novel, polymorphic form of Imatinib mesylate, which is designated by us as α₂, is stable at room temperature and even at higher temperatures up to 120° C. and accelerated stress conditions and freely soluble in water.

The present invention also relates to a process for the preparation of the novel polymorphic form and pharmaceutical compositions containing the novel stable α₂form of Imatinib mesylate and usually employed excepients useful in the treatment of Chronic Myelogenous Leukemia (CML). The Imatinib mesylate has the formula given below

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BACKGROUND OF THE INVENTION

Imatinib mesylate which is N-{5-[4-(4-methylpiperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl) 2-pyrimidine-amine, having the formula given above is approved under the trademark “Gleevec®” by the US Food and Drug Administration for the treatment of Chronic Myelogenous Leukemia before and after the failure of interferon alpha. It has also been approved for the treatment of patients with kit (CD117) positive unresectable and/or metastatic malignant Gastro Intestinal Stromal Tumors (GISTs). Recently it has been approved for the treatment of pediatric patients with Philadelphia chromosome positive (Ph+) Chronic Myeloid Leukemia (CML) in chronic phase. It is known that Imatinib mesylate exists in two polymorphic forms α and β (WO 99/03854).

In the said WO application it has been sated that the α form prepared is needle shaped and is hygroscopic. It has also been stated that in this form the crystals are not well suited for pharmaceutical formulations as solid dosage from because their physical properties for example, their flow characteristics are unfavorable. The applicants have also mentioned that under certain conditions however, it is possible to obtain a crystal form which is not needle shaped. This form, in the above patent is named as βform.

From the above given description regarding the α form it is very clear that the α form of Imatinib mesylate is not suitable for preparing formulations due to its: unsuitable physical characteristics and the form which is used is only the β form.

The said WO application also describes processes for the preparation of both the forms of Imatinib Mesylate. In the Examples 1 to 3 of the said patent the process for the preparation of Imatinib mesylate β-form has described using a maximum of 50 gms Imatinib base in solution.

In the Example-2 of the said patent a process has been described for the preparation of the β-form which involves suspending Imatinib base in methanol, adding methane sulfonic acid in methanol, heating to 50° C., followed by carbon treatment and distilling off methanol. Then dissolving the residue in minimum methanol and inoculation by some seeding crystals of Imatinib mesylate β-form.

The said WO application also describes processes for the preparation of both the forms of Imatinib Mesylate In the Example-1 of the said WTO application, the α-crystal form is prepared as follows:

Imatinib base was suspended in ethanol, methane sulfonic acid was added and heated under reflux for 20 minutes and than filtered at 65° C. The filtrate was evaporated down to 50% and the residue filtered off at 25° C. (filter material A). The mother liquor was evaporated to dryness. The residue and filter material A were suspended in ethanol dissolved under reflux with addition of water. Cooling overnight to 25° C., filtration and drying yielded Imatinib mesylate α-crystal form.

The above process for preparing α-crystal form suffers from the following disadvantages

a) In Examples 2 and 3 seed crystals of β-form are required to crystallize out the product
b) The process for preparing α-crystal form given under Example-1 is not reproducible. Repetition of the experiment exactly under identical conditions as reported in the above patent (WO 99/03854) resulted only in the α-form
c) Thus, there is currently no available process to prepare the α-crystal modification.

Important solid state properties of a pharmaceutical substance are its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patients stomach fluid may have therapeutic consequences because it imposes an upper limit on the rate at which an orally-administered active ingredient may reach the blood stream. The solid state form of a compound may also affect its behavior on compaction and its storage stability.

These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorph form of a substance. The polymorphic form may give rise to thermal behavior different form that of the amorphous material (or) another polymorphic form.

Thermal behaviour is measured in the laboratory by such techniques as capillary melting point, Thermo Gravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC), and may be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct properties that may be detectable by X-Ray Powder Diffraction (XRPD) solid state ¹³CNMR spectrometry and infrared spectrometry.

The various characteristics and properties of the polymorphic forms of a substance. e.g. shape, colour, density and the like, will make one polymorphic form preferable over the others for production and/or pharmaceutical compounding. As a result, a very first step in the processes of product development of a new pharmaceutical agent is the determination of whether it exists in polymorphic forms and if so which of such form possesses advantages for the eventual commercial pharmaceutical application. In the case of Imatinib mesylate, β form is offered commercially under the trade name Gleevec®/Glivec®.

In the patent mentioned above (WO 99/03854), β-form was selected over α-form based on the following observations and conclusions.

(i) β-form is thermodynamically stable at room temperature and at temperatures below 140° C. Greater stability of the β form is thus expected.
(ii) (β-crystal form is less hygroscopic than the α-crystal form.
(iii) α-crystal form is meta stable at room temperature
(iv) β-crystal has the advantage that its flow properties are substantially more favourable than those of that the α-crystal form.

Based on the above information, we undertook a detailed study of the solid state physical properties of the polymorphic forms of Imatinib mesylate. The presumption was that these properties may be influenced by controlling the conditions under which Imatinib mesylate is obtained in solid form.

Our detailed studies by carrying out research and development work on polymorphic forms of Imatinib Mesylate, and their processes for preparation surprisingly revealed the existence of another novel, stable polymorphic form of imatinib mesylate which we have designated as α₂form, having the below mentioned characteristics.

The novel α₂form of the present invention, can be prepared under certain specific conditions with improved physical properties such as greater stability and less hygroscopicity etc thereby making it suitable just like the β-form for commercial pharmaceutical applications.

Accordingly, we focussed our R&D efforts in taking up an elaborate study on the polymorphism of Imatinib Mesylate with particular reference to stable forms. Our detailed studies of the novel α₂form revealed that:

i. The novel α₂-form is not meta stable and is stable at room temperature and even at higher temperatures like 120° C.
ii. The novel α₂-form is stable at normal and accelerated stress conditions both in bulk and formulated capsule form.
iii. The novel α₂-form is as freely soluble in water as is the β-form. The rate of dissolution of the α₂-form in the formulation is comparable and even better than that of the β-form.
iv. The flow properties of the formulations prepared with the α₂form and β-forms are comparable as the same excipient composition is employed in both cases.

The above mentioned stable α₂form of imatinib Mesylate is not hither to known and is a novel polymorphic form. In addition, the form prepared by us now is also suitable for developing a pharmaceutical composition. Such a pharmaceutical composition containing α₂form is also not known and is novel.

Therefore, the main objective of the present invention is to provide a novel α₂crystalline form of Imatinib Mesylate which is stable at room temperature and even at higher temperatures like 120° C. and accelerated stress conditions, freely soluble in water and having the characteristics given in Table 1 given below

Another objective of the present invention is to provide a process for the preparation of novel α₂form of Imatinib Mesylate which is stable and less hygroscopic and water soluble having the characteristics given in Table 1

Yet another objective of the present invention is to provide a pharmaceutical composition useful for the treatment of Chronic Myeloid Leukemia containing the novel α₂form of Imatinib Mesylate which is stable and less hygroscopic and water soluble having the characteristics given in table 1.

Still another objective of the present invention is to provide an improved process for the preparation of β-polymorphic Imatinib mesylate.

Accordingly, the present invention provides a novel α₂crystalline form of Imatinib Mesylate which is stable at room temperature and even at higher temperatures up to 120° C. and accelerated stress conditions, freely soluble in water having the XRD characteristics given in the Table-I below.

TABLE I

Angle

[2-
d-value

Theta]
Angstrom
Intensity %

4.841
18.24057
33.6

10.410
8.49070
100.0

11.194
7.89775
14.2

11.856
7.45827
19.9

12.881
6.86709
6.8

13.819
6.40328
12.9

14.860
5.95663
67.7

16.439
5.38788
32.4

17.049
5.19665
5.6

17.623
5.02870
58.6

18.052
4.91000
61.6

18.567
4.77491
98.8

19.032
4.65925
70.2

19.772
4.48657
15.3

21.236
4.18055
60.8

21.582
4.11431
59.4

22.594
3.93217
19.7

23.137
3.84112
21.8

23.696
3.75172
25.0

24.851
3.57993
58.6

26.250
3.39226
9.1

27.341
3.25932
18.7

28.475
3.13204
42.4

31.896
2.80347
9.0

32.533
2.75005
6.6

43.447
2.08117
6.4

According to another embodiment of the present invention there is provided a process for the preparation novel α₂crystalline form of Imatinib Mesylate which is stable at room temperature and even at higher temperatures like 120° C. and accelerated stress conditions, freely soluble in water and having the characteristics given in Table 1 which comprises suspending Imatinib base in isopropanol and adding methane sulfonic acid at room temperature and maintaining the reaction mixture at a temperature in the range of 40-80° C., for a period in the range of 20-30 minutes, cooling and filtering to obtain the α₂crystal form.

According to yet another embodiment of the invention there is provided another process for the preparation of novel α₂crystalline form of Imatinib Mesylate which comprises converting Imatinib mesylate β-polymorphic modification which comprises suspending β-polymorphic it in water and organic solvents like methanol, Isopropyl ether, toluene, cyclohexane and Isopropyl alcohol, distilling off water azeotropically and, cooling filtering to obtain the α₂crystal form.

According to stiff another embodiment of the present invention, there is provided a pharmaceutical composition useful for the treatment of Chronic Myeloid Leukemia which comprises novel α₂form of Imatinib Mesylate which is stable and less hygroscopic and water soluble having the characteristics given in table 1 and a commonly employed pharmaceutically acceptable excipients.

According to another embodiment of the present invention there is provided an improved process for the preparation of β-polymorphic form of Imatinib mesylate which comprises suspending Imatinib base in a solvent selected from acetone, acetonitrile, mixture of methanol and isopropanol and mixture of isopropanol and water and adding methane sulfonic acid to the resulting solution at room temperature and maintaining the solution at the reflux temperature of the solvent (or) at room temperature and filtering the β-crystal form.

It is to be noted that the α₂form of Imatinib mesylate prepared by the process of the present invention does not substantially convert over time to form β, either as such in bulk form or after formulation in the dosage form, upon storage at about 40° and about 75% relative humidity for at least about 6 months.

Determination of presence of imatinib mesylate form-β in Imatinib mesylate α₂-form prepared by the process of the present invention may be made by analysis for the presence of various peaks associated with form-β particularly at 9.7, 13.9, 18.2, 20.0, 20.6, 21.1, 22.1, 22.7, 23.8, 29.8, 30.8±0.2 degree 2θ. (WO99/03854).

FIG. 1 of the drawings accompanying these specifications shows the X-Ray Powder Diffraction (XRPD) pattern which substantially depicts a typically pure sample of Imatinib Mesylate of α₂-form prepared by the process disclosed in the Example-1 given below. The 2θ values and intensities are tabulated in Table-1.

The other figures correspond to the data as detailed below:—

FIG. - 1
XRD spectrum of the novel α₂form

FIG. - 2
IR spectrum of the novel α₂form

FIG. - 3
DSC thermogram of the novel α₂form

FIG. - 4
XRD spectrum of the novel α₂form capsules stored for

6 months at 40° ± 2°/75 ± 5% (Table-5)

FIG. - 5
XRD spectrum of β form prepared by he process of the

invention

FIG. - 6
XRD spectrum of β form form prepared by he process of

the invention

FIG. - 7
XRD spectrum of β form form prepared by he process of

the invention

FIG. - 8
XRD spectrum of β form form prepared by he process of

the invention

The dosage form of the formulation containing the novel, stable α₂form prepared by the process of the present invention, preferably oral dosage form, may be a capsule containing the composition preferably a powdered on granulated solid composition, within either a hard (or) soft shell. The shell may be made from gelatine and optionally contains a plasticizer such as glycerin and sorbitol and an opacifying agent (or) colorant.

Methods known in the art, may be used to prepare the pharmaceutical composition containing Imatinib mesylate α₂form in the form of capsules. The excipients which may be employed include micro crystalline cellulose, lactose, crospovidone XL, colloidal silicondioxide magnesium stearate and talc

Table-2 shows suitable ranges of active ingredients and excipients (weight %) and the preferred amounts for the present pharmaceutical formulations.

TABLE 2

Pharmaceutical compositions containing Imatinib Mesylate α₂-form

Range of %

composition
Preferred %

S. No.
Material
(w/w)
composition
Function

1.
Imatinib mesylate
45-60%
53
Active

α₂-form

ingredient

2.
Micro crystalline
15-25%
21
Filler and

cellulose

disintegrant

3.
Lactose
10-20%
13
Diluent

4.
Crospovidone XL
5-10%
8.7
Disintegrant

5.
Magnesium stearate
1-2%
1.3
Lubricant

6.
Talc
0.5-1.0%
0.80
Glidant

7.
Colloidal Silicon
1.5-2.5%
2.20
Glidant

dioxide

Table-3 shows two typical examples of the capsule formulation containing Imatinib Mesylate α₂-form and their dissolution and stability characteristics.

TABLE 3

PHARMACEUTICAL COMPOSITIONS CONTAINING

IMATINIB MESYLATE α₂-FORM

Dissolution and stability characteristics

Composition (%)
Composition (%)

Material
B. No. 001
B. No. 002

Imatinib mesylate α₂-form
50
53

Microcrystalline cellulose
25
21

Lactose
12
13

Crosporidone XL
6
8.7

Magnesium stearate
1.5
1.3

Tale
0.5
0.80

Colloidal silicon dioxide
2.0
2.2

Dissolution rate
85% (10 min)
85% (10 min)

90% (20 min)
90% (20 min)

100% (45 min)
100% (45 min)

Stability
1. stable at
1. stable at

40° ± 2° C. and
40° ± 2° C. and

75 ± 5% RH
75 ± 5% RH

2. stable at
2. stable at

25° ± 2° C. and
25° ± 2° C. and

60 ± 5% RH
60 ± 5% RH

Inference: Two typical batch formulations of Imatinib α₂-form are prepared. The dissolution and stability characteristics indicate that α₂-form has excellent formulation characteristics.

Table-4 shows the heat stability of α₂form over the temperature range 110-120° C. The α₂form is shown to be non-metastable and stable when heated at 120° C. for 6 hours.

Stability of α₂-Crystal Form

Pure α₂-crystal polymorph 1 gm prepared by the process described in Example 1 was taken in a boiling test tube and heated gradually in oil bath the substance was examined by XRPD. The results are tabulated below

TABLE 4

Polymorph

Time of
Polymorph

content*

heating
form detected*

before hating
Temperature
(hours)
after heating

α₂form
110° C.
2
α₂form

α₂form
110° C.
4
α₂form

α₂form
120° C.
2
α₂form

α₂form
120° C.
4
α₂form

α₂form
120° C.
6
α₂form

*The presence of form-β was below the detection level in these examples.

Inference: The α₂form of Imatinib mesylate is not metastable.

- It is fairly stable to heat even at 120° C./6 hours.

Table-5 shows the stability of α₂form under accelerated stress conditions (45±2° C., 75±5% RH, 6 months) in the bulk and capsule formulation

TABLE 5

Stability of α₂form of Imatinib mesylate in bulk and

formulated capsule

Polymorph content* of
Polymorph content*

imatinib mesylate in
of bulk

formulated capsule
imatinib mesylate
Duration of storage

Polymorph form
Polymorph form
(months) at

detected
detected
40 ± 2° C./75 ± 5% RH

α₂form
α₂form
0 Month

α₂form
α₂form
1 Month

α₂form
α₂form
2 Months

α₂form
α₂form
3 Months

α₂form
α₂form
6 Months

(XRPD FIG. - 4)

*The presence of form-β was below the detection level in these examples showing that α₂form is not converted to β-form over a time period. The stability of α₂form in bulk and in the formulated capsule is thus established.

Table-6 shows comparative dissolution data of Imatinib capsule formulation containing α₂form and β-form. The formulation with α₂form is found to have better dissolution characteristics.

TABLE 6

Comparative dissolution data for Imatinib mesylate capsules 100 mg*

(α₂and β-forms)

Test parameters

1.
Dissolution medium
0.1 N HCl

2.
Dissolution volume
900 ml

3.
RPM (Revolutions Per Minute)
50

4.
Wave length
240 nm

(for assay determination)

Imatinib mesylate
Imatinib mesylate

(β-crystal form)
(α₂crystal form)

Release profile
capsules 100 mg
capsules 100 mg

5 minutes
32.6%
61.3%

10 minutes
54.4%
85.5%

15 minutes
69.4%
90.5%

20 minutes
78.2%
92.6%

30 minutes
95.8%
98.0%

45 minutes
100.0%
100.0%

- The capsules contain Imatinib Mesylate equivalent of 100 mg of Imatinib base. The excipients are as per the Example-7

Inference: The release profile and dissolution data show that the capsule formulation with α₂-form is better than the formulation with β-form.

Storage of capsule containing pure Imatinib mesylate α₂form prepared by the process of the present invention at about 40° C. and about 75% relative humidity for 6 months, does not show any significant conversion to β-polymorphic form of Imatinib mesylate preferably less than about 5%. The detection of Imatinib mesylate form-β in a pharmaceutical formulation to the extent about 1% w/w or more may be accomplished by use of x-ray powder diffraction.

The pharmaceutical formulations containing the novel, stable α₂form prepared by the process of the present invention are useful in the treatment of Chronic Myelogenous Leukemia. The oral pharmaceutical dosage forms preferably contain about 100 mg of the base equivalent.

The preparative aspects, physical and functional properties of novel Imatinib mesylate α₂form prepared by the process of the present invention are compared with the properties of α form described in the prior art (WO 99/03854) and tabulated in Table-7. The tabulated data clearly demonstrates the stability and functional superiority of the novel α₂polymorph of the present invention over the α polymorph described in WO 99/03854.

TABLE 7

A COMPARATIVE ACCOUNT OF IMATINIB MESYLATE α-FORM

KNOWN IN PRIOR ART AND THE NOVEL α₂FORM OF CURRENT

INVENTION

Literature α form
Present invention

S. No.
Property
WO 99/03854
α₂form

1.
Method of
Preparation reported in
The method results in novel and

preparation
ethanol solvent. However
stable α₂form consistently in

method not reproducible
high purity and yield.

yielding β-form only

2.
Melting point
226° C.
223-227° C.

3.
Differential scanning
226° C. (start of melting)
225-227° C. Peak 227°

thermogram

4.
XRD
Spectrum scan given 2θ
Spectra given in FIGS. 1& 4

values not listed
Principal 2θ values 4.9, 10.4,

14.9, 16.4, 17.6, 18.6, 19.1,

21.2, 24.6, 24.9, 28.5

5.
Crystal shape
Needle shape (Not free
Non-needle shaped free-flowing

flowing)
crystals

6.
Hygroscopicity
Hygroscopic
Non-hygroscopic

7.
Dissolution
Not mentioned
Dissolves freely in water

characteristic

Dissolution of more than 95%

during 30 min in capsule

formulation

8.
Flow properties
Not well-suited to
Found to be well suited for

pharmaceutical solid
pharmaceutical formulations as

dosage forms
solid dosage forms.

9.
Stability
Metastable at room
Stable at room temperature and

temperature
even at 120° C.

The details of the invention are provided in the Examples given below which are provided to illustrate the invention only and therefore they should not be construed to limit the scope of the invention.

EXAMPLE-1
Preparation of Novel Imatinib Mesylate Form-α 2 in Lab Scale

Imatinib base (200 gms) obtained directly from the synthesis was suspended in 2.5 L of isopropanol. Methane sulfonic acid (38.9 gms) in 400 ml anhydrous Isopropanol was added slowly during 20 minutes at room temperature. Reaction mass was heated to 75-80° C. for 30 minutes and slowly cooled to 40-45° C. during 45 minutes. Filtered at 40-45° C. and washed with 250 ml Isopropanol. The wet cake was dried for 6 hours at 80° C. The yield was 170 gms (71%)

Melting range—226-227° C. (DSC)

The FIG. 1 of the drawings accompanying this specification shows the X-Ray Powder Diffraction (XRPD) pattern which substantially depicts a typically pure sample of Imatinib mesylate of form-α₂prepared as per the process disclosed in this Example The 2θ values and intensities are tabulated in Table-1.

FIG. 2 shows the IR spectrum of α₂form prepared by the process described in this Example

FIG. 3 shows the DSC thermogram of α₂form prepared by the process described in this Example

FIG. 4 shows the XRD spectrum of α₂form from capsules stored for 6 months at 40°±2°/75±5% (Table-5)

EXAMPLE-2
Preparation of Novel Imatinib Mesylate Form-α 2 on Industrial Scale

Imatinib base (10 Kg) obtained directly from the synthesis was suspended in 125 L of Isopropanol. Methane sulfonic acid (1.94 Kg) in 20 L Isopropanol was added slowly during 40-60 minutes at room temperature. Reaction mass was heated to 75-80° C. for 30 minutes and slowly cooled to 40-45° C. during 45 minutes. Filtered at 40±45° C. and washed with 12 L Isopropanol. The wet cake was dried for 6 hours at 80° C. The yield was 8.6 Kg (72%)

Melting range—225-226° C. (DSC)