FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
“NOVEL POLYMORPHS OF BRUTON'S TYROSINE KINASE INHIBITOR”
2. APPLICANT
(a) NAME: CIPLA LIMITED
(b) NATIONALITY: Indian Company incorporated under the Companies
Act, 1956
(c) ADDRESS: Cipla House, Peninsula Business Park, Ganpatrao Kadam
Marg, Lower Parel, Mumbai 400013, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which
it has to be performed.
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Technical field of the Invention
The present invention relates to new polymorphs of Bruton's tyrosine kinase
inhibitor, processes for the preparation of the new polymorphs, pharmaceutical
compositions containing these new polymorphs and use of such composition in
treatment of cancer.
Background of the Invention
Acalabrutinib is a second generation Bruton's tyrosine kinase inhibitor developed
by Acerta Pharma. Chemically Acalabrutinib is known as 4-{8-amino-3-[(2S)-1-
(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl)}-N-(pyridine-2-
yl)benzamide. The structure of Acalabrutinib is represented as follows:
Acalabrutinib is indicated for the treatment of adult patients with mantle cell
lymphoma (MCL).
Acalabrutinib and its preparation was first disclosed in WO2013010868 along with
other compounds. WO2017002095 describes various polymorphs of Acalabrutinib
such Form I, II, III, IV, V, VI, VII, VIII, amorphous form, Form A of citrate salt,
Form A of gentisate salt, Form A of oxalate salt, Form A of sulphate salt, Form A
of maleate salt, Form A of fumarate salt, phosphate salt, L-tartrate, Cocrystals –
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with L-arabitol, L-proline, D-sorbitol, succinic acid and amorphous dispersions
with various polymers.
WO2018064797 which is in Chinese language describes form 1, form 2 and form
3 as appeared from Google translation. While WO2018148961 which is also in
Chinese language, describes Form 1 & amorphous form of malate salt, Form 1 of
hemi-fumarate salt, Form 1 of maleate salt, Form 1 of phosphate salt, Form 1 of
sulphate salt.
WO 2019159097 patent application publication describes form S and form S2 of
Acalabrutinib which are characterised by XRD, DSC, IR and TGA.
It is a well known fact that different polymorphic forms of the same drug may have
substantial differences in certain pharmaceutically important properties such as
dissolution characteristics, bioavailability patterns, handling properties, solubility,
flow characteristics and stability.
Further, different physical forms may have different particle size, hardness and
glass transition temperatures.
The discovery of new polymorphic forms of a pharmaceutically useful compound
provides a new opportunity to improve the performance characteristics of a
pharmaceutical product.
These polymorphic forms exhibit distinct X-ray diffractogram, solid state 13C NMR
spectrometry, infrared spectrometry. Further, these polymorphic forms may give
rise to peculiar thermal behaviour which can be measured by melting point,
thermogravimetric analysis (TGA), differential scanning calorimetry (DSC). All
these properties can be used to distinguish a particular polymorph from the other
form.
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Objectives of the invention
The object of the invention is to provide new polymorphic forms of Acalabrutinib
and processes for the preparation of these new polymorphic forms of Acalabrutinib.
Another object of the present invention is to provide pharmaceutical compositions
comprising new polymorphic forms of Acalabrutinib.
Yet another aspect of the present invention is to provide pharmaceutical
compositions comprising new polymorphic forms of Acalabrutinib for use in
medical treatment of cancer.
Summary of the invention
In one aspect, the invention provides new polymorphic forms which hereinafter are
referred to as crystalline form (also known as “polymorph”) Form-C2, Form-C3,
Form-C4 and Form- C5 of Acalabrutinib.
In another aspect, the invention provides processes for the preparation of new
polymorphic forms of Acalabrutinib.
In yet another aspect, the invention provides pharmaceutical compositions
comprising new polymorphic forms of Acalabrutinib along with a pharmaceutically
acceptable carrier.
In further aspect, the invention provides use of the pharmaceutical compositions
comprising new polymorphic forms of Acalabrutinib along with a pharmaceutically
acceptable carrier in treatment of cancer.
Brief description of the drawings
FIG. 1 represents a powder X-ray diffraction pattern of Form- C2 of Acalabrutinib.
FIG. 2 represents a powder X-ray diffraction pattern of Form- C3 of Acalabrutinib.
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FIG. 3 represents a Differential Scanning Calorimetry (DSC) of Form–C3 of
Acalabrutinib
FIG. 4 represents a thermogravimetric analysis (TGA) of Form–C3 of
Acalabrutinib
FIG. 5 represents a powder X-ray diffraction pattern of Form- C4 of Acalabrutinib.
FIG. 6 represents a Differential Scanning Calorimetry (DSC) of Form–C4 of
Acalabrutinib
FIG. 7 represents a thermogravimetric analysis (TGA) of Form–C4 of
Acalabrutinib
FIG. 8 represents an Infra-Red (IR) absorption spectrum of Form–C4 of
Acalabrutinib
FIG. 9 represents a powder X-ray diffraction pattern of Form- C5 of Acalabrutinib.
FIG. 10 represents a Differential Scanning Calorimetry (DSC) of Form–C5 of
Acalabrutinib
FIG. 11 represents a thermogravimetric analysis (TGA) of Form–C5 of
Acalabrutinib
Detailed description of the invention
The invention will now be described in its various preferred as well as optional
embodiments, so that the various aspects therein will be more clearly understood
and appreciated.
The present invention relates to crystalline Acalabrutinib polymorphs, the process
for preparation thereof and pharmaceutical compositions containing said
polymorphs as active ingredient.
As used herein, the term "PXRD" refers to powder X-ray diffraction, the term "IR"
refers to infrared, the term "NMR" refers to nuclear magnetic resonance, the term
"TGA" refers to thermogravimetric analysis, the term "DSC" refers to differential
scanning calorimetry and the term "DVS" refers to dynamic vapour sorption
isotherm.
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As used herein, the term "substantially the same X-ray powder diffraction pattern"
is understood to mean that those X-ray powder diffraction patterns having
diffraction peaks with 2θ values within ± 0.2° of the diffraction patterns referred to
herein are within the scope of the referred to diffraction pattern.
As used herein, the term “solvate" refers to an association or complex of one or
more solvent molecules and a compound of the invention. Such solvents for the
invention may not interfere with the biological activity of the solute. Typically, the
solvent used is a pharmaceutically acceptable solvent.
The solvate can be isolated either as an amorphous form or in a crystalline form,
preferably in crystalline form.
The solvate can be further isolated either in anhydrous form or hydrated form.
As used herein, the term "hydrate" refers to the complex where the solvent
molecule is water. The skilled person will appreciate that the water molecules are
absorbed, adsorbed or contained within a crystal lattice of the solid compounds,
usually in defined stoichiometric ratio. The notation for a hydrated compound may
be. nH2O, where n is the number of water molecules per formula unit of the
compound. For example, in a hemihydrate, n is 0.5; in a monohydrate n is one; in a
sesquihydrate, n is 1.5; in a dihydrate, n is 2; and so on.
The novel polymorphs of the present invention may be isolated in pseudo
polymorphic form as a solvate optionally in hydrated form, or as a non-hydrated
solvate.
As polymorphic forms are reliably characterized by peak positions in the X-ray
diffractogram, the polymorphs of the present invention have been characterized by
powder X-ray diffraction spectroscopy which produces a fingerprint of the
crystalline form and is able to distinguish it from all other crystalline and
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amorphous forms of Acalabrutinib. Measurements of 2θ values are accurate to
within ± 0.2 degrees. All the powder diffraction patterns were measured on a
PANalytical X’Pert3 X-ray powder diffractometer with a copper-K-α radiation
source.
The invention will now be described in detail in connection with certain preferred
and optional embodiments, so that various aspects thereof may be more fully
understood and appreciated.
Thus, in one aspect, the present invention provides the crystalline Acalabrutinib
which is herein and in the claims designated as “Form-C2”.
In one embodiment, the crystalline Form-C2 is characterized by an X-ray powder
diffraction pattern comprising the following 2θ values measured using CuKα,
radiation.
In an embodiment, the crystalline Form-C2 has an XRD pattern with characteristics
peaks at 7.4, 10.9, 12.5, 13.9, 14.8, 20.8, 21.6 and 22.6 ± 0.2°2θ.
Crystalline Form-C2 of Acalabrutinib may be characterized by powder X-ray
diffraction pattern, as shown in Figure 1.
Crystalline Form-C2 may further also contain water in it. The water content may be
in the range of 1 to 2%.
Those skilled in the art would recognize that Form-C2 may be further characterized
by other methods including, but not limited to IR, solid state NMR, DSC, TGA,
intrinsic dissolution and Raman spectroscopy.
In another embodiment, the invention provides process for preparation of
crystalline Form-C2 of Acalabrutinib which process involves mixing Acalabrutinib
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with toluene solvent. This process of mixing is carried out at 20°C to 30°C. The
reaction mixture was then stirred at higher temperature at about 60°C to 100°C for
1 to 2 hours. The so obtained reaction mass was then cooled to 20°C to 30°C and
filtered under vacuum. The resultant solid material was dried to get crystalline
Form-C2.
According to second aspect, the present invention provides the crystalline
Acalabrutinib which is herein and in the claims designated as “Form-C3”.
In one embodiment, the crystalline Form-C3 is characterized by an X-ray powder
diffraction pattern comprising the following 2θ values measured using CuKα,
radiation.
In an embodiment, the crystalline Form-C3 has an XRD pattern with characteristics
peaks at 8.5, 10.0, 11.7, 12.9, 15.3, 17.9, 18.3, 20.1 and 21.6 ± 0.2° 2θ
Crystalline Form-C3 of Acalabrutinib may be characterized by powder X-ray
diffraction pattern, as shown in Figure 2.
Crystalline Form-C3 of Acalabrutinib may also be characterized as having a DSC
spectrum. The DSC plot for the sample shows one endotherm with an onset at
95.65°C, a peak maximum at 113.70°C; and a second endotherm with an onset at
141.49°C and a peak maximum at 152.86°C.
In an embodiment, crystalline Form-C3 of Acalabrutinib is characterized by having
a DSC spectrum as shown in Figure 3.
In another embodiment, crystalline Form-C3 of Acalabrutinib is characterized by
having a thermogravimetric analysis (TGA) profile as shown in Figure 4.
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In another embodiment, the invention provides process for preparation of
crystalline Form-C3 of Acalabrutinib which process involves following steps:
i) dissolving Acalabrutinib in the suitable solvent at suitable temperature,
ii) cooling the solution obtained in above step,
iii) stirring the solution
iv) filtering the obtained mass.
The suitable solvent used in step i) can be selected from but not limited to acids
(such as but not limited to acetic acid, formic acid), esters (such as but not limited
to ethyl acetate, isopropyl acetate), ethers (such as but not limited to
tetrahydrofuran, 2-methyl tetrahydrofuran, t-butyl methyl ether), alcohols (such as
but not limited to methanol, ethanol, isopropanol, t-butanol), ketones (such as but
not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone), alkyl nitriles
(such as but not limited to acetonitrile, propionitrile), hydrocarbons including
halogenated hydrocarbons (such as but not limited to toluene, xylene,
dichloromethane), aprotic polar solvents (such as but not limited to sulfolane,
dimethyl sulfoxide, N-methyl pyrrolidone), water or mixture thereof.
The suitable temperature used in step i) is preferably higher temperature ranging in
between 50°C to 100°C.
The suitable temperature used in step ii) for cooling may be in the range of -10°C
to 10°C.
The stirring in step iii) is done till precipitation is obtained.
According to third aspect, the present invention provides the crystalline
Acalabrutinib which is herein and in the claims designated as “Form-C4”, which
may be non-hygroscopic (or non-hydroscopic).
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In one embodiment, the crystalline Form-C4 is characterized by an X-ray powder
diffraction pattern comprising the following 2θ values measured using CuKα,
radiation.
In an embodiment, the crystalline Form-C4 has an XRD pattern with characteristics
peaks at 8.3, 9.9, 12.1, 15.4, 15.9, 16.7, 19.9, 21.5 and 24.4 ± 0.2° 2θ.
Crystalline polymorph C4 of Acalabrutinib may be characterized by powder X-ray
diffraction pattern, as shown in Figure - 5.
Crystalline Form-C4 of Acalabrutinib may also be characterized as having a DSC
spectrum. The DSC plot for the sample shows one endotherm with an onset at
62.97°C, a peak maximum at 91.72°C; and a second endotherm with an onset at
146.35°C and a peak maximum at 157.71°C.
In an embodiment, crystalline Form-C4 of Acalabrutinib is characterized by having
a DSC spectrum as shown in Figure 6.
Crystalline Form-C4 of Acalabrutinib may be a hydrate. In the hydrate of crystalline
Form-C4 of Acalabrutinib, water is present in the non-stoichiometric ratio ranging
from about 3.0 wt% to about 9.0 wt% per molecule of Acalabrutinib.
In another embodiment, crystalline Form-C4 of Acalabrutinib is characterized by
having a thermogravimetric analysis (TGA) profile as shown in Figure 7.
In yet another embodiment, crystalline Form-C4 of Acalabrutinib is characterized
by having an IR spectrum as shown in Figure 8.
In another embodiment, the invention provides process for preparation of
crystalline Form-C4 of Acalabrutinib which process involves drying the crystalline
Form-C3 of Acalabrutinib at a suitable temperature.
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The suitable temperature used for drying of Form-C3 may be in the range of 30° to
90°C, preferably 30° to 70°C, more preferably 40° to 60°C for a period of about 2
hour to about 20 hours, preferably 4 hours to about 15 hours, more preferably for
about 6 hours to 12 hours.
According to fourth aspect, the present invention provides the crystalline
Acalabrutinib which is herein and in the claims designated as “Form-C5”.
In one embodiment, the crystalline Form-C5 is characterized by an X-ray powder
diffraction pattern comprising the following 2θ values measured using CuKα,
radiation.
In an embodiment, the crystalline Form-C5 has an XRD pattern with characteristics
peaks at 7.7, 9.4, 10.8, 13.3, 15.4, 17.3, 22.0 and 23.1 ± 0.2° 2θ.
Crystalline Form-C5 of Acalabrutinib may be characterized by powder X-ray
diffraction pattern, as shown in Figure 9.
Crystalline Form-C5 of Acalabrutinib may also be characterized as having a DSC
spectrum. The DSC plot for the sample shows an endotherm with an onset at
147.70°C, a peak maximum at 158.13 °C.
In an embodiment, crystalline Form-C5 of Acalabrutinib is characterized by having
a DSC spectrum as shown in Figure 10.
In another embodiment, crystalline Form-C5 of Acalabrutinib is characterized by
having a thermogravimetric analysis (TGA) profile as shown in Figure 11.
In another embodiment, the invention provides process for preparation of
crystalline Form-C5 of Acalabrutinib which process involves drying the crystalline
polymorph C4 of Acalabrutinib at a suitable temperature.
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The suitable temperature used for drying of form C4 may be in the range of 80° to
150°C, preferably 100° to 140°C, more preferably 120° to 130°C for a period of
about 1 hour to about 10 hours, preferably 2 hours to about 8 hours, more preferably
for about 3 hours to 5 hours.
Those skilled in the art will recognize that these polymorphic forms may be further
characterized by other methods including, but not limited to Infra-red (IR),
differential scanning calorimetry (DSC), thermo-gravimetric analysis (TGA),
dynamic vapour sorption (DVS), intrinsic dissolution, solid state NMR and Raman
spectroscopy. Further bulk and tapped density of the polymorphic forms may also
be evaluated.
In one embodiment, the Form-C2, Form-C3, Form-C4 or Form-C5 of Acalabrutinib
contain less than 5% by weight total impurities.
In one embodiment, the Form-C2, Form-C3, Form-C4 or Form-C5 of Acalabrutinib
is at least 50% pure, or at least 75% pure, or at least 80% pure, or at least 90% pure,
or at least 95% pure, or at least 98% pure.
The crystalline Form-C2, Form-C3, Form-C4 or Form-C5 of Acalabrutinib,
obtained according to the present invention is substantially free from other forms
of Acalabrutinib, "Substantially free" from other forms of Acalabrutinib, shall be
understood to mean that the polymorphs of Acalabrutinib, contain less than 10%,
preferably less than 5%, of any other forms of Acalabrutinib and less than 1% of
other impurities.
The process of the present invention may be used as a method for purifying any
form of Acalabrutinib, as well as for the preparation of the new polymorphic forms
and salts thereof.
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Acalabrutinib, used as a starting material in the present invention for the preparation
of crystalline forms C2, C3, C4 and C5 may be prepared by methods known in the
art such as those described in WO2013010868.
The present invention comprises 1) a pharmaceutical composition comprising any
one, or combination of Acalabrutinib crystalline forms C2, C3, C4 or C5
described above and at least one pharmaceutically acceptable excipient; and 2) the
use of any one, or combination, of the above-described Acalabrutinib crystalline
forms C2, C3, C4 or C5, in the manufacture of a pharmaceutical composition,
wherein the pharmaceutical composition can be useful for the treatment or
prevention of mantle cell lymphoma (MCL).
The pharmaceutical composition can be prepared by a process comprising
combining any one, or combination of the above-described Acalabrutinib
crystalline forms C2, C3, C4 or C5; with at least one pharmaceutically acceptable
excipient.
Any one, or combination, of the above-mentioned Acalabrutinib crystalline forms
C2, C3,C4 or C5 particularly in a pharmaceutical composition and dosage form,
can be used to treat or prevent mantle cell lymphoma (MCL) in a mammal such as
a human, comprising administering a treatment effective amount of the one, or
combination, of the Acalabrutinib crystalline forms C2, C3,C4 or C5 in the
mammal.
Having described the invention with reference to certain preferred embodiments,
other embodiments will become apparent to one skilled in the art from
consideration of the specification. The invention is further defined by reference to
the following examples. It will be apparent to those skilled in the art that many
modifications, both to materials and methods, may be practiced without departing
from the scope of the invention.
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EXAMPLES
Example 1:
Preparation of Form-C2:
3.0 g of Acalabrutinib was charged in to the 100.0 ml round bottom flask, then 30.0
ml toluene was charged in to the above flask at 20 °C to 25 °C. The reaction mass
was stirred at high temperature at about 70 °C to 80 °C for 1 to 2 hours. The reaction
mass was cooled to 20 °C to 25 °C and the material obtained was filtered using
Buchner funnel. The resultant powder was dried at about 70 °C for 2 hours to obtain
the desired form.
Example 2:
Preparation of Form-C3:
3.0 g Acalabrutinib was dissolved in 10 volumes of Methanol-Water (95:5) solvent
mixture at high temperature at about 70 °C to 80 °C. The so obtained solution was
cooled to -5° C and stirred for 20 to 30 min. The material obtained was filtered
under vacuum to obtain the title compound.
Example 3:
Process to prepare Form-C4:
The crystalline Form-C3 was dried in a vacuum try drier at 50 °C for 3 to 4 hours
to obtain the desired compound.
Purity: 99.68%
Total impurities : < 1%
Example 4:
Process to prepare Form-C5:
The crystalline Form-C4 was dried in vacuum try drier at 120 °C for 3 to 4 hours to
obtain the desired compound.
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We claim:
1. Crystalline Form-C3, Form-C4 or Form-C5 of Acalabrutinib.
2. The crystalline Form-C3 of Acalabrutinib of claim 1, wherein the crystalline
form has an X-ray powder diffraction (XRPD) pattern comprising 2-theta
peaks at 8.5, 10.0, 11.7, 12.9, 15.3, 17.9, 18.3, 20.1 and 21.6 ± 0.2° 2θ.
3. The crystalline form of claim 2, wherein the crystalline form has an X-ray
powder diffraction (XRPD) pattern as the one set forth in Fig.2.
4. The crystalline form of claim 2, wherein the crystalline form characterized
by a DSC thermogram having first endothermic peak at about 113.70°C and
second endothermic peak at about 152.86°C.
5. The crystalline form of claim 4, wherein the crystalline form, characterized
by a DSC, substantially as depicted in Fig. 3
6. The crystalline form of claim 2, characterized by a TGA substantially as
depicted in Figure 4.
7. A process for the preparation of crystalline Form-C3 comprising following
steps:
i. dissolving Acalabrutinib in the suitable solvent at suitable temperature,
ii. cooling the solution obtained in above step,
iii. stirring the solution
iv. filtering the obtained mass.
8. The process according to the claim 7, wherein suitable solvent is selected
from but not limited to acids (such as but not limited to acetic acid, formic
acid), esters (such as but not limited to ethyl acetate, isopropyl acetate),
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ethers (such as but not limited to tetrahydrofuran, 2-methyl tetrahydrofuran,
t-butyl methyl ether), alcohols (such as but not limited to methanol, ethanol,
isopropanol, t-butanol), ketones (such as but not limited to acetone, methyl
isobutyl ketone, methyl ethyl ketone), alkyl nitriles (such as but not limited
to acetonitrile, propionitrile), hydrocarbons including halogenated
hydrocarbons (such as but not limited to toluene, xylene, dichloromethane),
aprotic polar solvents (such as but not limited to sulfolane, dimethyl
sulfoxide, N-methyl pyrrolidone), water or mixture thereof.
9. The process according to the claim 7, further comprising cooling the
solution prior to crystallization.
10. The crystalline Form-C4 of Acalabrutinib of claim 1, wherein the crystalline
form characterized by a DSC thermogram having first endothermic peak at
about 91.72°C and second endothermic peak at about 157.71°C.
11. The crystalline form of claim 10, wherein the crystalline form, characterized
by a DSC, substantially as depicted in Fig. 6.
12. A process for the preparation of crystalline Form-C4 comprising, drying the
crystalline polymorph C3 of Acalabrutinib at a suitable temperature ranging
from 30° to 90°C, preferably 30° to 70°C, more preferably 40° to 60°C for
a period of about 2 hour to about 20 hours, preferably 4 hours to about 15
hours, more preferably for about 6 hours to 12 hours .
13. The crystalline Form-C5 of Acalabrutinib of claim 1, wherein the crystalline
form has an X-ray powder diffraction (XRPD) pattern comprising 2-theta
peaks at 7.7, 9.4, 10.8, 13.3, 15.4, 17.3, 22.0 and 23.1 ± 0.2° 2θ.
14. The crystalline form of claim 13, wherein the crystalline form has an X-ray
powder diffraction (XRPD) pattern as the one set forth in Fig.9.
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15. The crystalline form of claim 13, wherein the crystalline form characterized
by a DSC thermogram having endothermic peak at about 158.13°C.
16. The crystalline form of claim 15, wherein the crystalline form,
characterized by a DSC, substantially as depicted in Fig.10.
17. The crystalline form of claim 13, characterized by a TGA substantially as
depicted in Figure 11.
18. A process for the preparation of crystalline Form-C5 comprising drying the
crystalline polymorph C4 of Acalabrutinib at a suitable temperature ranging
from 80° to 150°C, preferably 100° to 140°C, more preferably 120° to
130°C for a period of about 1 hour to about 10 hours, preferably 2 hours to
about 8 hours, more preferably for about 3 hours to 5 hours.
19. The Form-C3, Form-C4 or Form-C5 of Acalabrutinib of claim 1, wherein
the polymorph contains less than 5% by weight total impurities.
20. The Form-C3, Form-C4 or Form-C5 of Acalabrutinib of claim 1, wherein
the form is at least 50% pure, or at least 75% pure, or at least 80% pure, or
at least 90% pure, or at least 95% pure, or at least 98% pure.
21. A pharmaceutical composition comprising one or more of a Form-C3,
Form-C4 or Form-C5 of Acalabrutinib and a pharmaceutically acceptable
carrier.
22. The pharmaceutical composition of claim 21, further comprising one or
more pharmaceutically acceptable excipients.
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23. A method of treating, preventing or alleviating a mantle cell lymphoma
(MCL) comprising administering to a subject in need thereof an effective
amount of one or more Form-C3, Form-C4 or Form-C5 of Acalabrutinib.