DESC:SOLID FORMS OF ASCIMINIB HYDROCHLORIDE
INTRODUCTION
The present invention provides crystalline forms of Asciminib
hydrochloride and its process for the preparation and pharmaceutical
composition thereof.
The drug compound having the adopted name “Asciminib
hydrochloride” has chemical name: N-[4(Chloro(difluoro)methoxy) phenyl]-6-
[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-3-yl)pyridine-3-carboxamide
hydrogen chloride of formula (I) as below.
Formula (I)
Asciminib HCl is a allosteric BCR-ABL inhibitor developed and
marketed by Novartis as SCEMBLIX oral tablet for the treatment for the
treatment of adult patients with Philadelphia chromosome-positive chronic
myeloid leukemia (Ph+ CML) in chronic phase (CP), previously treated with
two or more tyrosine kinase inhibitors (TKIs).
The US 8829195 B2 patent first disclosed Asciminib or the
pharmaceutically acceptable salt generically and specifically and its use
thereof for the treatment of chronic myeloid leukemia (CML) and acute
lymphoblastic leukemia (ALL).
Subsequently, the WO2020230099A1 patent application described
crystalline forms of Asciminib hydrochloride (Form A, Form B and Form HA).
Also described the crystalline forms of Asciminib free base (Form A, Form SA,
Form SB, Form SC and Form SD).
The WO2021154980A1 patent application discloses crystalline forms
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of Asciminib hydrochloride and its process. Also discloses crystalline forms of
Asciminib mesylate and Asciminib bromide and their process.
However, there remains a need for alternate solid forms of Asciminib
hydrochloride and preparative processes thereof, exhibiting desired properties
such as bioavailability and stability. Hence, it is desirable to provide a viable solid
form of Asciminib hydrochloride.
Different forms of Active pharmaceutical ingredients (API) in
pharmaceutical compositions can be prepared. In the synthesis of a chemical
compound intended for pharmaceutical use, it is necessary to isolate and purify
the compound at the completion of the synthetic process and prior to further
processing to provide the compound in a pharmaceutical formulation. The
isolation and the purification steps, which can be combined or separate
consecutive steps, provide the compound as a purified solid with minimal loss of
yield during isolation from other components of the reaction mixture and/or
during purification to remove impurities from the isolated compound sample. It is
desirable to prepare physically and chemically stable crystalline form using
regulatory acceptable solvents.
SUMMARY
In the first aspect, the present invention provides a crystalline form AH1 of
Asciminib hydrochloride, characterized by a PXRD comprising the peaks at about
4.8, 15.2 ± 0.2° 2?. In an embodiment, the application provides a crystalline form
AH1 of Asciminib hydrochloride, characterized by a PXRD having additional
peaks at about 9.7, 16.9 and 27.3 ± 0.2° 2?.
In the second aspect, the present invention provides a process for
preparation of crystalline form AH1 of Asciminib hydrochloride, comprising;
a) grinding or contacting Asciminib free base in Sulfolane solvent;
b) adding aqueous hydrochloride to the mixture of step a);
c) isolating crystalline form AH1 of Asciminib hydrochloride.
In the third aspect, the present invention provides a crystalline form AH2
of Asciminib hydrochloride, characterized by a PXRD comprising the peaks at
about 4.9, 21.4 ± 0.2° 2?. In an embodiment, the application provides a crystalline
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form AH2 of Asciminib hydrochloride, characterized by a PXRD having
additional peak at about 10.8, 13.4, 15.2, 18.3 ± 0.2° 2?.
In the fourth aspect, the present invention provides a process for
preparation of crystalline form AH2 of Asciminib hydrochloride, comprising;
a) providing a mixture of Asciminib hydrochloride in alcohol solvent;
b) isolating crystalline form AH2 of Asciminib hydrochloride.
In the fifth aspect, the present invention provides a crystalline form AH3
of Asciminib hydrochloride, characterized by a PXRD comprising the peaks at
about 8.2, 18.3 ± 0.2° 2?. In an embodiment, the application provides a crystalline
form AH3 of Asciminib hydrochloride, characterized by a PXRD having
additional peak at about 6.8, 10.8 and 13.3 ± 0.2° 2?.
In the sixth aspect, the present invention provides a process for preparation
of crystalline form AH3 of Asciminib hydrochloride, comprising;
a) providing a mixture of Asciminib in alcoholic hydrochloride;
b) isolating crystalline form AH3 of Asciminib hydrochloride.
In the seventh aspect, the present application provides a pharmaceutical
composition comprising crystalline Form of Asciminib hydrochloride selected
from the group comprising Form AH1, Form AH2 and Form AH3 or mixtures
thereof together with at least one pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction of crystalline Form
AH1 of Asciminib hydrochloride prepared by the method of Example-1.
Figure 2 is an illustrative X-ray powder diffraction of crystalline Form
AH2 of Asciminib hydrochloride prepared by the method of Example-2.
Figure 3 is an illustrative X-ray powder diffraction of crystalline Form
AH3 of Asciminib hydrochloride prepared by the method of Example-3.
DETAILED DESCRIPTION
In the first aspect, the present invention provides a crystalline form AH1 of
Asciminib hydrochloride, characterized by a PXRD comprising the peaks at about
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4.8, 15.2 ± 0.2° 2?. In an embodiment, the application provides a crystalline form
AH1 of Asciminib hydrochloride, characterized by a PXRD having additional
peaks at about 9.7, 16.9 and 27.3 ± 0.2° 2?.
In an embodiment, the present application provides crystalline form AH1
of Asciminib hydrochloride, characterized by a PXRD substantially as shown in
Figure 1.
In the second aspect, the present invention provides a process for
preparation of crystalline form AH1 of Asciminib hydrochloride, comprising;
a) grinding or contacting Asciminib free base in Sulfolane solvent;
b) adding aqueous hydrochloride to the mixture of step a);
c) isolating crystalline form AH1 of Asciminib hydrochloride.
The grinding process comprises grinding of Asciminib with aqueous
hydrochloric acid in sulfolane solvent. In grinding process, Asciminib and
aqueous hydrochloric acid in sulfolane solvent grind in a mortar, a grinder or a
mill to obtain a crystalline form AH1 of Asciminib hydrochloride. Grinding in a
mortar involves physical grinding of Asciminib and aqueous hydrochloric acid in
sulfolane solvent.
In the third aspect, the present invention provides a crystalline form AH2
of Asciminib hydrochloride, characterized by a PXRD comprising the peaks at
about 4.9, 21.4 ± 0.2° 2?. In an embodiment, the application provides a crystalline
form AH2 of Asciminib hydrochloride, characterized by a PXRD having
additional peak at about 10.8, 13.4, 15.2, 18.3 ± 0.2° 2?.
In an embodiment, the present application provides crystalline form AH2
of Asciminib hydrochloride, characterized by a PXRD substantially as shown in
Figure 2.
In the fourth aspect, the present invention provides a process for
preparation of crystalline form AH2 of Asciminib hydrochloride, comprising;
a) providing a mixture of Asciminib hydrochloride in alcohol solvent;
b) isolating crystalline form AH2 of Asciminib hydrochloride.
In embodiments of step a) involves the solution may optionally be treated
with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable
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material to remove color and/or to clarify the solution.
Suitable alcohol solvent used in step a) include, but are not limited to
methanol, ethanol, isopropyl alcohol, n-butanol, tertiary butanol, 1-propanol or the
like.
The temperature at which the above steps may be carried out in between
about 10 °C and about 100 °C, based on the solvent or mixture of solvent used in
particular step.
The isolation of step b) can be effected, if desired, by any suitable
separation methods such as precipitation, filtration, centrifugation, extraction,
acid-base treatment, conventional isolation and refining means such as
concentration, concentration under reduced pressure or by a combination of these
procedures.
In the fifth aspect, the present invention provides a crystalline form AH3
of Asciminib hydrochloride, characterized by a PXRD comprising the peaks at
about 8.2, 18.3 ± 0.2° 2?. In an embodiment, the application provides a crystalline
form AH3 of Asciminib hydrochloride, characterized by a PXRD having
additional peak at about 6.8, 10.8 and 13.3 ± 0.2° 2?.
In an embodiment, the present application provides crystalline form AH3
of Asciminib hydrochloride, characterized by a PXRD substantially as shown in
Figure 3.
In the sixth aspect, the present invention provides a process for preparation
of crystalline form AH3 of Asciminib hydrochloride, comprising;
a) providing a mixture of Asciminib in alcoholic hydrochloride;
b) isolating crystalline form AH3 of Asciminib hydrochloride.
In embodiments of step a) involves the solution may optionally be treated
with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable
material to remove color and/or to clarify the solution.
Suitable alcoholic hydrochloride used in step a) include, but are not
limited to methanolic hydrochloride, ethanolic hydrochloride, isopropyl alcohol
hydrochloride, n-butanol hydrochloride, 1-propanol hydrochloride or the like.
The temperature at which the above steps may be carried out in between
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about 10 °C and about 100 °C, based on the solvent or mixture of solvent used in
particular step.
The isolation of step b) can be effected, if desired, by any suitable
separation methods such as precipitation, filtration, centrifugation, extraction,
acid-base treatment, conventional isolation and refining means such as
concentration, concentration under reduced pressure or by a combination of these
procedures.
In the seventh aspect, the present application provides a pharmaceutical
composition comprising crystalline Form of Asciminib hydrochloride selected
from the group comprising Form AH1, Form AH2 and Form AH3 or mixtures
thereof together with at least one pharmaceutically acceptable excipient.
Drying in the embodiments of the present invention may be suitably
carried out by using any of an air tray dryer, vacuum tray dryer, fluidized bed
dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out
at atmospheric pressure or above, or under reduced pressures, specifically at
temperatures less than about 80 °C and more specifically less than about 60
°C. The drying may be carried out for any time period required for obtaining a
desired product quality, such as from about 30 minutes to about 24 hours, or
longer.
All PXRD data reported herein are obtained using a PANalytical X-ray
Diffractometer and Bruker D8 advance X-ray Diffractometer with copper Ka
radiation.
Starting material may be either in a crystalline or amorphous state or an
alternate crystalline form of Asciminib or Asciminib hydrochloride known in
the literature.
Certain specific aspects and embodiments of the present application will
be explained in greater detail with reference to the following examples, which are
provided only for purposes of illustration and should not be construed as limiting
the scope of the application in any manner. Variations of the described
procedures, as will be apparent to those skilled in the art, are intended to be within
the scope of the present application.
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Definitions
The term "about" when used in the present application preceding a number
and referring to it, is meant to designate any value which lies within the range of
±10%, preferably within a range of ±5%, more preferably within a range of ±2%,
still more preferably within a range of ±1 % of its value. For example "about 10"
should be construed as meaning within the range of 9 to 11, preferably within the
range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still
more preferably within the range of 9.9 to 10.1.
EXAMPLES
Example-1: Preparation of crystalline form AH1 of Asciminib
hydrochloride.
Asciminib (100 mg), Sulfolane (0.1 mL) and aqueous HCl (45 µL) were taken
in a mortar and ground the mixture using pestle for 15 minutes. Methyl tertiary
butyl ether (3 mL) was added to the resultant mass and further ground for 5
minutes using pestle to obtain the title compound.
PXRD: Crystalline Form AH1 of Asciminib hydrochloride (Figure 1).
Example-2: Preparation of crystalline form AH2 of Asciminib
hydrochloride.
Amorphous Asciminib hydrochloride (400 mg) was added to the tert-butanol
(2 mL) at 30 °C and stirred for 60 minutes. The obtained reaction mass was
filtered and washed with n-hexane (5 mL) and kept under drying in vacuum tray
drier at 45 °C for 3-4 hours to obtain the title compound.
PXRD: Crystalline Form AH2 of Asciminib hydrochloride (Figure 2).
Example-3: Preparation of crystalline form AH3 of Asciminib
hydrochloride.
Asciminib (500 mg) was added to the isopropyl alcohol hydrochloride (3 mL)
at 30 °C and stirred for 3-4 hours. The obtained reaction mass was filtered and
washed with n-hexane (5 mL) and kept under suction for 10 minutes to obtain
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the title compound.
PXRD: Crystalline Form AH3 of Asciminib hydrochloride (Figure 3). ,CLAIMS:1) A crystalline form AH1 of Asciminib hydrochloride, characterized by a PXRD
comprising the peaks at about 4.8, 9.7, 15.2, 16.9 and 27.3 ± 0.2° 2?.
2) A process for the preparation of a process for preparation of crystalline form AH1
of Asciminib hydrochloride, comprising;
a) grinding or contacting Asciminib free base in Sulfolane solvent;
b) adding aqueous hydrochloride to the mixture of step a);
c) isolating crystalline form AH1 of Asciminib hydrochloride.
3) A crystalline form AH2 of Asciminib hydrochloride, characterized by a PXRD
comprising the peaks at about 4.9, 10.8, 13.2, 15.2, 18.3 and 21.4 ± 0.2° 2?.
4) A process for preparation of crystalline form AH2 of Asciminib hydrochloride,
comprising;
a) providing a mixture of Asciminib hydrochloride in alcohol solvent;
b) isolating crystalline form AH2 of Asciminib hydrochloride.
5) The process of claim 4, wherein alcohol solvent is selected from the group
comprising of methanol, ethanol, isopropyl alcohol, n-butanol, tertiary butanol, 1-
propanol.
6) A crystalline form AH3 of Asciminib hydrochloride, characterized by a PXRD
comprising the peaks at about 6.8, 8,2, 10.8, 13.3 and 18.3 ± 0.2° 2?.
7) A process for preparation of crystalline form AH3 of Asciminib hydrochloride,
comprising;
a) providing a mixture of Asciminib in alcoholic hydrochloride;
b) isolating crystalline form AH3 of Asciminib hydrochloride.
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8) The process of claim 7, wherein alcoholic hydrochloride is selected from the
group comprising of methanolic hydrochloride, ethanolic hydrochloride, isopropyl
alcohol hydrochloride, n-butanol hydrochloride, 1-propanol hydrochloride.