DESC:AMORPHOUS SOLID DISPERSIONS OF ASCIMINIB
HYDROCHLORIDE AND PROCESESS THEREOF
INTRODUCTION
Aspects of the present application relates to amorphous solid
dispersions of Asciminib hydrochloride with polymer matrix and processes
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
Aspects of the present application relates to amorphous solid
dispersions of Asciminib hydrochloride with polymer matrix and procesess
thereof.
In an aspect, the present application provides a process for the preparation
of amorphous solid dispersion of Asciminib hydrochloride, comprising the steps
of providing a solution of Asciminib hydrochloride and polymer matrix in a
solvent and removing the solvent.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of amorphous
solid dispersion of Asciminib hydrochloride with Copovidone (1:2 w/w)
prepared by the method of Example-1.
Figure 2 is an illustrative X-ray powder diffraction of amorphous solid
dispersion of Asciminib hydrochloride with PVP K30 (1:2 w/w) prepared by the
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method of Example-2.
Figure 3 is an illustrative X-ray powder diffraction of amorphous solid
dispersion of Asciminib hydrochloride with HPMC (1:2 w/w) prepared by the
method of Example-3.
Figure 4 is an illustrative X-ray powder diffraction of amorphous solid
dispersion of Asciminib hydrochloride with HPMC (1:1 w/w) prepared by the
method of Example-4.
Figure 5 is an illustrative X-ray powder diffraction of amorphous solid
dispersion of Asciminib hydrochloride with HPC (1:2 w/w) prepared by the
method of Example-5.
DETAILED DESCRIPTION
Aspects of the present application relates to amorphous solid
dispersions of Asciminib hydrochloride with polymer matrix and processes
thereof.
In embodiments, polymer matrix may be selected from the group
consisting of hydroxypropyl methylcellulose (HPMC; also referred to as
hypromellose) such as HPMC E3; hydroxypropyl methylcellulose acetate
succinate (HPMC AS; also referred to as hypromellose acetate succinate) such as
L, M, and H grades of HPMC AS; eudragit L-100; hydroxypropyl cellulose
(HPC); methylcellulose (MC); hypromellose phthalate (HPMC-P); cellulose
acetate phthalate; vinylpyrrolidone-vinyl acetate copolymer (copovidone);
polyvinyl pyrrolidone (PVP); polymethacrylate-based copolymers;
polyvinylcaprolactam-based copolymers, cyclodextrins, chitosan, polyvinyl
alcohol, alginic acid or mixture thereof. Preferably, the polymer chosen to form
the polymer matrix is HPMC E3, HPMCAS, Eudragit L-100 (or) mixture thereof.
In an aspect, the present application provides a process for the preparation
of amorphous solid dispersion of Asciminib hydrochloride, comprising the steps
of providing a solution of Asciminib hydrochloride and polymer matrix in a
solvent and removing the solvent.
In embodiments, solvent may be selected from the group consisting of
methanol, dichloromethane, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol,
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2-pentanol, 3-pentanol, tetrahydrofuran, 1,4-dioxane, acetone, methyl ethyl
ketone, methyl isobutyl ketone; methyl acetate, ethyl acetate, isopropyl acetate,
acetonitrile, dimethylformamide, dimethylsulfoxide, dimethylacetamide, Nmethylpyrrolidone,
water or mixtures thereof. Preferably, the solvent is mixture of
methanol and dichloromethane.
In embodiments, a solution of Asciminib hydrochloride and polymer
matrix may be prepared at any suitable temperatures, such as about 0°C to about
the reflux temperature of the solvent used. Stirring and heating may be used to
reduce the time required for the dissolution process.
In embodiments, a solution of Asciminib hydrochloride and polymer
matrix may be filtered to make it clear and free of unwanted particles. In
embodiments, the obtained solution may be optionally treated with an adsorbent
material, such as carbon and/or hydrose, to remove colored components, etc.,
before filtration.
In an embodiment, removal of solvent may be carried out by methods
known in the art or any procedure disclosed in the present application. In
preferred embodiments, removal of solvent may include, but not limited to:
solvent evaporation under atmospheric pressure or reduced pressure / vacuum
such as a rotational distillation using Buchi Rotavapor, spray drying, freeze
drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer
(RVPD) and the like.
In embodiments, amorphous solid dispersion of Asciminib hydrochloride
with polymer, wherein the ratio of Asciminib hydrochloride and polymer is 1:0.1
to 1:5 w/w.
In other embodiments, amorphous solid dispersion of Asciminib
hydrochloride with polymer, wherein the ratio of Asciminib hydrochloride and
polymer is 1:1 to 1:2.
In specific aspect, the present application relates to amorphous solid
dispersion of Asciminib hydrochloride with Copovidone.
In specific aspect, the present application provides a process for the
preparation of amorphous solid dispersion of Asciminib hydrochloride with
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Copovidone, comprising the steps of providing a solution of Asciminib
hydrochloride and Copovidone in presence of methanol and removing the
methanol solvent.
In embodiments, a solution of Asciminib hydrochloride with Copovidone
may be prepared at any suitable temperatures, such as about 0°C to about the
reflux temperature of the solvent used. Stirring and heating may be used to reduce
the time required for the dissolution process.
In embodiments, a solution of Asciminib hydrochloride with Copovidone
may be filtered to make it clear and free of unwanted particles. In embodiments,
the obtained solution may be optionally treated with an adsorbent material, such
as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent may be carried out by solvent
evaporation under atmospheric pressure or reduced pressure / vacuum such as a
rotational distillation using Buchi Rotavapor or spray drying.
Figure 1 is an illustrative X-ray powder diffraction pattern of amorphous
solid dispersion of Asciminib hydrochloride with Copovidone (1:2 w/w)
prepared by the method of Example-1.
In specific aspect, the present application relates to amorphous solid
dispersion of Asciminib hydrochloride with PVP K30.
In specific aspect, the present application provides a process for the
preparation of amorphous solid dispersion of Asciminib hydrochloride with PVP
K30, comprising the steps of providing a solution of Asciminib hydrochloride and
PVP K30 in presence of methanol and removing the methanol solvent.
In embodiments, a solution of Asciminib hydrochloride with PVP K30
may be prepared at any suitable temperatures, such as about 0°C to about the
reflux temperature of the solvent used. Stirring and heating may be used to reduce
the time required for the dissolution process.
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In embodiments, a solution of Asciminib hydrochloride with PVP K30
may be filtered to make it clear and free of unwanted particles. In embodiments,
the obtained solution may be optionally treated with an adsorbent material, such
as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent may be carried out by solvent
evaporation under atmospheric pressure or reduced pressure / vacuum such as a
rotational distillation using Buchi Rotavapor or spray drying.
Figure 2 is an illustrative X-ray powder diffraction pattern of amorphous
solid dispersion of Asciminib hydrochloride with PVP K30 (1:2 w/w) prepared
by the method of Example-2.
In specific aspect, the present application relates to amorphous solid
dispersion of Asciminib hydrochloride with HPMC.
In specific aspect, the present application provides a process for the
preparation of amorphous solid dispersion of Asciminib hydrochloride with
HPMC, comprising the steps of providing a solution of Asciminib hydrochloride
and HPMC in presence of methanol and removing the methanol solvent.
In embodiments, a solution of Asciminib hydrochloride with HPMC may
be prepared at any suitable temperatures, such as about 0°C to about the reflux
temperature of the solvent used. Stirring and heating may be used to reduce the
time required for the dissolution process.
In embodiments, a solution of Asciminib hydrochloride with HPMC may
be filtered to make it clear and free of unwanted particles. In embodiments, the
obtained solution may be optionally treated with an adsorbent material, such as
carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent may be carried out by solvent
evaporation under atmospheric pressure or reduced pressure / vacuum such as a
rotational distillation using Buchi Rotavapor or spray drying.
Figure 3 is an illustrative X-ray powder diffraction pattern of amorphous
solid dispersion of Asciminib hydrochloride with HPMC (1:2 w/w) prepared by
the method of Example-3.
Figure 4 is an illustrative X-ray powder diffraction pattern of amorphous
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solid dispersion of Asciminib hydrochloride with HPMC (1:1 w/w) prepared by
the method of Example-4.
In specific aspect, the present application relates to amorphous solid
dispersion of Asciminib hydrochloride with HPC.
In specific aspect, the present application provides a process for the
preparation of amorphous solid dispersion of Asciminib hydrochloride with
HPC, comprising the steps of providing a solution of Asciminib hydrochloride
and HPC in presence of methanol and removing the methanol solvent.
In embodiments, a solution of Asciminib hydrochloride with HPC may
be prepared at any suitable temperatures, such as about 0°C to about the reflux
temperature of the solvent used. Stirring and heating may be used to reduce the
time required for the dissolution process.
In embodiments, a solution of Asciminib hydrochloride with HPC may
be filtered to make it clear and free of unwanted particles. In embodiments, the
obtained solution may be optionally treated with an adsorbent material, such as
carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent may be carried out by solvent
evaporation under atmospheric pressure or reduced pressure / vacuum such as a
rotational distillation using Buchi Rotavapor or spray drying.
Figure 5 is an illustrative X-ray powder diffraction pattern of amorphous
solid dispersion of Asciminib hydrochloride with HPC (1:2 w/w) prepared by
the method of Example-5.
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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EXAMPLES
Example-1: Process for the preparation of amorphous solid dispersion of
Asciminib hydrochloride with Copovidone.
Asciminib hydrochloride (500 mg) and Copovidone (1 g) were dissolved in
methanol (30 mL) at 50°C. The solution was filtered to make it particle free. The
obtained clear solution was evaporated under reduced pressure at 50°C to obtain
amorphous solid dispersion of Asciminib hydrochloride with Copovidone.
Example-2: Process for the preparation of amorphous solid dispersion of
Asciminib hydrochloride with PVP K30.
Asciminib hydrochloride (500 mg) and PVP K30 (1 g) were dissolved in
methanol (30 mL) at 50°C. The solution was filtered to make it particle free. The
obtained clear solution was evaporated under reduced pressure at 50°C to obtain
amorphous solid dispersion of Asciminib hydrochloride with PVP K30.
Example-3: Process for the preparation of amorphous solid dispersion of
Asciminib hydrochloride with HPMC.
Asciminib hydrochloride (500 mg) and HPMC (1 g) were dissolved in methanol
(30 mL) at 50°C. The solution was filtered to make it particle free. The obtained
clear solution was evaporated under reduced pressure at 50°C to obtain
amorphous solid dispersion of Asciminib hydrochloride with HPMC.
Example-4: Process for the preparation of amorphous solid dispersion of
Asciminib hydrochloride with HPMC.
Asciminib hydrochloride (1 g) and HPMC (1 g) were dissolved in methanol (30
mL) at 50°C. The solution was filtered to make it particle free. The obtained clear
solution was evaporated under reduced pressure at 50°C to obtain amorphous
solid dispersion of Asciminib hydrochloride with HPMC.
Example-5: Process for the preparation of amorphous solid dispersion of
Asciminib hydrochloride with HPC.
,CLAIMS:1) Amorphous solid dispersion of Asciminib hydrochloride with polymer matrix.
2) The solid dispersion according to claim 1, polymer matrix is selected from the
group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl
methylcellulose acetate succinate (HPMC AS), Eudragit L-100, hydroxypropyl
cellulose (HPC), methylcellulose (MC), hypromellose phthalate (HPMC-P),
cellulose acetate phthalate, vinylpyrrolidone-vinyl acetate copolymer
(copovidone), polyvinyl pyrrolidone (PVP), polymethacrylate-based
copolymers, polyvinylcaprolactam-based copolymers, cyclodextrins, chitosan,
polyvinyl alcohol and alginic acid.
3) Amorphous solid dispersion of Asciminib hydrochloride with Copovidone.
4) A process for the preparation of amorphous solid dispersion of Asciminib
hydrochloride with Copovidone, comprising the steps of providing a solution
of Asciminib hydrochloride and Copovidone in presence of methanol and
removing the methanol solvent.
5) Amorphous solid dispersion of Asciminib hydrochloride with PVP K30.
6) A process for the preparation of amorphous solid dispersion of Asciminib
hydrochloride with PVP K30, comprising the steps of providing a solution of
Asciminib hydrochloride and PVP K30 in presence of methanol and removing
the methanol solvent.
7) Amorphous solid dispersion of Asciminib hydrochloride with HPMC.
8) A process for the preparation of amorphous solid dispersion of Asciminib
hydrochloride with HPMC, comprising the steps of providing a solution of
Asciminib hydrochloride and HPMC in presence of methanol and removing
the methanol solvent.
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9) Amorphous solid dispersion of Asciminib hydrochloride with HPC.
10) A process for the preparation of amorphous solid dispersion of Asciminib hydrochloride with HPC, comprising the steps of providing a solution of Asciminib hydrochloride and HPC in presence of methanol and removing the methanol solvent.