DESC:CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to the filing dates of Indian provisional Application No.
IN202041000312, filed on Jan 03, 2020 & Indian provisional Application No.
IN202041003104, filed on Jan 23, 2020; each of the preceding are hereby incorporated by
reference in their entirety.
FIELD OF THE DISCLOUSRE
The present disclosure relates to novel crystalline and amorphous forms of Glecaprevir and
their preparation process thereof.
DESCRIPTION OF THE RELATED ART
Glecaprevir is a medication used to treat anti-hepatitis C. Glecaprevir is chemically known as
(3aR,7S,10S,12R,21E,24aR)-7-tert-butyl-N-{(1R,2R)-2(difluoromethyl)-1-[(1-
methylcyclopropane-1 sulfonyl)carbamoyl] cyclopropyl}-20,20-difluoro5,8-dioxo-
2,3,3a,5,6,7,8,11,12,20,23,24a-dodecahydro-1H,10H-9,12methanocyclopenta [18,19]
[1,10,17,3,6] trioxadiazacyclononadecino [11,12-b]quinoxaline-10carboxamide hydrate of
formula I.
Formula I
Glecaprevir and its preparation is described in U.S. Patent No. 8,648,037.
Crystalline Glecaprevir form I, methanol, dimethanol and trimethanol solvates are disclosed
in U.S. Patent No. 9,321,807.
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The inventors of the present disclosure have developed novel crystalline forms and their
preparation thereof.
SUMMARY OF THE DISCLOSURE
A first aspect of the present invention relates to novel crystalline Glecaprevir form M1.
Another aspect of the present invention relates to crystalline Glecaprevir form M1,
characterized by powder x-ray diffraction pattern having significant peaks at 2? angle
positions 6.78, 8.58, 8.83, 10.75, 13.58, 15.02, 16.04, 17.35, 18.98, 19.19, 22.56 ± 0.2°.
Yet in another aspect of the present invention relates to a process for the preparation of
crystalline Glecaprevir form M1, which comprises:
a) dissolving Glecaprevir in an alcoholic solvent at 50 °C - 60 °C,
b) adding an anti-solvent at same temperature,
c) cooling the mixture to 25±5 °C,
d) filtering to get wet solid; and
e) drying the wet solid in an oven with nitrogen blowing at 55 °C - 75 °C to get
crystalline form M1.
Yet in another aspect of the present invention relates to novel crystalline Glecaprevir form
M2.
Yet in another aspect of the present invention relates to crystalline Glecaprevir form M2,
characterized by powder x-ray diffraction pattern having significant peaks at 2? angle
positions 7.29, 9.0, 13.95, 14.66, 15.82, 16.49, 17.97, 18.77, 21.39 ± 0.2°.
Yet in another aspect of the present invention relates to a process for the preparation of
crystalline Glecaprevir form M2, which comprises:
a) dissolving Glecaprevir in an alcoholic solvent at 50 °C - 60 °C,
b) adding an anti-solvent at same temperature,
c) cooling the mixture to 25±5 °C,
d) filtering to get wet solid; and
4
e) drying under vacuum oven at 25 °C - 65 °C to get crystalline form M2.
Yet in another aspect of the present invention relates to a process for the preparation of
amorphous Glecaprevir, which comprises:
a) dissolving Glecaprevir in a solvent at 25±5 °C;
b) adding anti-solvent at 25±5 °C;
c) removing the solvent and isolating the amorphous Glecaprevir.
Yet in another aspect of the present invention relates to a process for the preparation of
amorphous Glecaprevir, which comprises:
a) dissolving Glecaprevir in a solvent at 25±5 °C;
b) heating the solution of step a) to 55-60 °C;
c) adding anti-solvent at 55-60 °C;
d) removing the solvent and isolating the amorphous Glecaprevir.
Yet in another aspect of the present invention relates to a process for the preparation of
amorphous Glecaprevir, which comprises:
a) dissolving Glecaprevir in a solvent;
b) removing the solvent and isolating the amorphous Glecaprevir.
BRIEF DESCRIPTION OF THE FIGURES
Further aspects of the present disclosure together with additional features contributing thereto
and advantages accruing there from will be apparent from the following description of
embodiments of the disclosure which are shown in the accompanying drawing figures
wherein:
Figure. 1 is an X-ray powder diffractogram of crystalline Glecaprevir form M1.
Figure. 2 is an X-ray powder diffractogram of crystalline Glecaprevir form M2.
Figure. 3 is an X-ray powder diffractogram of amorphous Glecaprevir.
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DETAILED DESCRIPTION OF THE DISCLOSURE
It is to be understood that the description of the present invention has been simplified to
illustrate elements that are relevant for a clear understanding of the invention, while
eliminating, for purposes of clarity, other elements that may be well known.
The X-ray diffraction patterns of the crystalline Glecaprevir form M1 and form M2 Figure-1,
2 and 3 are provided herein were measured on PAN analytical, X'Pert PRO powder
diffractometer equipped with goniometer of ?/? configuration and X'Celerator detector. The
Cu- anode X-ray tube is operated at 40kV and 30mA. The experiments were conducted over
the 2? range of 2.0º-50.0°, 0.030° step size and 50 seconds step time.
The present invention provides novel crystalline forms Glecaprevir designated as forms M1
and M2 and their preparation process thereof.
In another embodiment, the present invention provides process for the preparation of
amorphous Glecaprevir.
Yet in another embodiment, the present invention provides crystalline Glecaprevir form M1
characterized by X-ray diffraction pattern shown in Fig. 1.
Yet in another embodiment, the present invention provides crystalline Glecaprevir form M1,
characterized by powder x-ray diffraction pattern having significant peaks at 2? angle
positions 6.78, 8.58, 8.83, 10.75, 13.58, 15.02, 16.04, 17.35, 18.98, 19.19, 22.56 ± 0.2°.
Yet in another embodiment, the present invention provides a process for the preparation of
crystalline Glecaprevir form M1, which comprises:
a) dissolving Glecaprevir in alcoholic solvent at 50 - 60 °C,
b) adding an anti-solvent at same temperature,
c) cooling the mixture to 25±5°C,
d) filtering to get wet solid; and
e) drying the wet solid in an oven with nitrogen blowing at 55 - 75 °C to get crystalline
form M1.
Within the context of the present invention, Glecaprevir may be dissolved in an alcoholic
solvent at 55±5°C and added with an antisolvent such as water at same temperature for a
6
period of 90 to 120 minutes. The solid thus precipitated may be gradually cooled to 25±5 °C
for 3 hours, filtered and dried for 15-20 hours at 55 - 75 °C to obtain crystalline form M1.
Within the context of this embodiment of the present invention, the alcohols include, but are
not limited to methanol, ethanol, isopropanol, n-propanol or t-butanol. In particular
embodiment of the present invention, the solvent is methanol.
Yet in another embodiment, the present invention provides crystalline Glecaprevir form M2
characterized by X-ray diffraction pattern shown in Fig. 2.
Yet in another embodiment, the present invention provides crystalline Glecaprevir form M2,
characterized by powder x-ray diffraction pattern having significant peaks at 2? angle
positions 7.29, 9.0, 13.95, 14.66, 15.82, 16.49, 17.97, 18.77, 21.39 ± 0.2°.
Yet in another embodiment, the present invention provides a process for the preparation of
crystalline Glecaprevir form M2, which comprises:
a) dissolving Glecaprevir in alcoholic solvent at 50 - 60 °C,
b) adding an anti-solvent at same temperature,
c) cooling the mixture to 25±5 °C,
d) filtering to get wet solid; and
e) drying under vacuum oven at 25 - 65 °C to get crystalline form M2.
Within the context of the present invention, Glecaprevir may be dissolved in an alcoholic
solvent at 55±5°C and added with an antisolvent such as water at same temperature for a
period of 90 to 120 minutes. The solid thus precipitated may be cooled the reaction mixture
to 25±5 °C for 3 hours, filtered and dried under vacuum oven for 15 to 20 hours at 25 - 65 °C
to get crystalline form M2.
Within the context of this embodiment of the present invention, the alcohols include, but are
not limited to methanol, ethanol, isopropanol, n-propanol or t-butanol. In particular
embodiment of the present invention, the solvent is methanol.
Yet in another embodiment, the present invention provides a process for the preparation of
amorphous Glecaprevir, which comprises:
a) dissolving Glecaprevir in a solvent at 25±5 °C;
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b) adding anti-solvent at 25±5 °C;
c) removing the solvent and isolating the amorphous Glecaprevir.
Within the context of the present invention, Glecaprevir may be dissolved in a solvent at
25±5 °C and added with an antisolvent such as water. The solid thus precipitated may be
filtered and dried to obtain amorphous Glecaprevir.
Within the context of this embodiment of the present invention, the solvent employed may
include organic solvents such as methanol, ethanol or propanol. In particular embodiment of
the present invention, the solvent is methanol.
Yet in another embodiment, the present invention provides a process for the preparation of
amorphous Glecaprevir, which comprises:
a) dissolving Glecaprevir in a solvent at 25±5 °C;
b) heating the solution of step a) to 55-60 °C;
c) adding anti-solvent at 55-60 °C; and
d) removing the solvent and isolating the amorphous Glecaprevir.
Within the context of the present invention, Glecaprevir may be dissolved in a solvent at
room temperature and the resulting solution may be heated to 55-60 °C followed by addition
of water as an antisolvent at 55-60 °C for 15 to 20 minutes. The solid thus precipitated may
filtered and dried to obtain amorphous Glecaprevir.
Within the context of this embodiment of the present invention, the solvent employed may
include, organic solvents such as methanol, ethanol or propanol. In particular embodiment of
the present invention, the solvent is methanol.
Yet in another embodiment, the present invention provides a process for the preparation of
amorphous Glecaprevir, which comprises:
a) dissolving Glecaprevir in a solvent; and
b) removing the solvent and isolating the amorphous Glecaprevir.
Within the context of the present invention, Glecaprevir may be dissolved in a solvent at
25±5 °C followed by removal of the solvent using conventional techniques to get amorphous
Glecaprevir.
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Within the context of this embodiment of the present invention, the solvent employed may
include organic solvents such as such as methanol, ethanol, propanol dichloromethane, ethyl
acetate, acetonitrile or mixtures thereof. In particular embodiment of the present invention,
the solvent is dichloromethane.
Within the context of this embodiment of the present invention, removing of solvent may be
carried by decantation, filtration by gravity or suction, centrifugation, slow evaporation,
distillation, lyophilization, agitated thin film dryer (ATFD) and spray drying. In particular
useful embodiment of the present invention, the solvent is removed by distillation.
Within the context of the present invention, Glecaprevir is prepared by following the method
shown in scheme 1.
Scheme-1
In view of the above description and the examples below, one of ordinary skill in the art will
be able to practice the invention as claimed without undue experimentation. The foregoing
will be better understood with reference to the following examples that detail certain
procedures for the preparation of molecules, compositions and Formulations according to the
present invention. All references made to these examples are for the purposes of illustration.
The following examples should not be considered exhaustive, but merely illustrative of only
a few of the many aspects and embodiments contemplated by the present disclosure.
EXAMPLES
Example-1: Preparation of crystalline Glecaprevir form M1
Compound of formula II (20g) 2-hydroxypyridine N-oxide (5.09g,) 1-ethyl-3-(3-
dimethylaminopropyl) carbodiimide hydrochloride (EDAC;1.04g) were taken in acetonitrile
(80mL) and stirred for 30 minutes at 25±5°C to get clear solution of acid complex. In
9
another flask sulfonamide compound of formula III (11.38g) and triethylamine (7.56g) was
taken in acetonitrile (80mL) and stirred at 25±5 °C. Acid complex solution was added slowly
to the sulfonamide mixture for 15 minutes at 25±5 °C and stirred for 15 hours. After
completion of reaction, mixture quenched with water (20mL) and then heated to 45-50 °C. A
solution of acetic acid (5mL) and water (90mL) were added to the reaction mixture at 45-50
°C, seed crystals of crystalline form M1 were added and maintained for 1 hour at 45-50 °C,
water (150mL) was added slowly to the reaction mixture for 90-120 minutes at same
temperature. Reaction mixture was cooled to 25±5 °C and stirred for 5-6 hours to get a
precipitation. Filtered the obtained solid and washed the compound with water (20mL) to get
wet solid.
The wet compound was dissolved in methanol (400mL) at 55±5 °C, water (200mL) was
added to the reaction mixture at same temperature and stirred for 90-120 minutes to get
precipitation. Reaction mixture gradually cooled to 25±5 °C for 3 hours and maintained
stirring for 60-90 minutes. The obtained solid was filtered and washed with water (20mL).
Compound dried in oven with nitrogen blowing for 15 hours at 65 °C to get crystalline form
M1.
Example-2: Preparation of crystalline Glecaprevir form M2
Compound of formula II (100g) 2-hydroxypyridine N-oxide (25.48g,) 1-ethyl-3-(3-
dimethylaminopropyl) carbodiimide hydrochloride (EDAC; 42.33g) were taken in
acetonitrile (900mL) and stirred for 30-60 minutes at 25±5°C to get clear solution of acid
complex. Sulfonamide compound of formula III (56.90g) was added to the above clear
solution. Triethylamine (38.68g) was slowly added to the above reaction mixture and stirred
at 25±5 °C for 15 to 20 hours. After completion of reaction, mixture quenched with water
(100mL) and then heated to 45-50 °C. A solution of acetic acid (5mL) and water (90mL)
were added to the reaction mixture at 45-50 °C, seed crystals of crystalline form M1 were
added and maintained for 1-2 hours at 45-50 °C, water (750mL) was added slowly to the
reaction mixture for 60-90 minutes at same temperature. Reaction mixture was cooled to
25±5 °C and stirred for 10-11 hours to get a precipitation. Filtered the obtained solid and
washed the compound with water (20mL) to get wet solid.
The wet compound was dissolved in methanol (1900mL) at 55±5 °C and stirred for, 30
minutes. Reaction mixture was filtered on micron filter. To the filtrate, water (1000mL) was
added slowly at same temperature for 30-45 minutes and reaction mixture was gradually
cooled to 27±5 °C for 3 to 4 hours and maintained the stirring for 90-120 minutes. The
obtained solid was filtered and washed with water (2x1000mL) to get wet compound as
crystalline form M1. Wet compound was dried under vacuum at 60±5 °C for 7-9 hours to get
crystalline form M2.
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Example-3: Preparation of crystalline Glecaprevir form M2
The Glecaprevir wet compound dissolved in methanol (400mL) at 55±5 °C then water
(200mL) was added to the reaction mixture at same temperature and stirred for 90-120
minutes to get precipitation. Reaction mixture gradually cooled to 25±5 °C for 3 hours,
reaction maintained for 60-90 minutes then filtered the obtained solid and washed the wet
compound with water (20mL). Wet compound dried in hot air oven at 50 °C for 15 hours to
get crystalline form M2.
Example-4: Preparation of crystalline Glecaprevir form M2
The Glecaprevir wet compound dissolved in methanol (400mL) at 55±5 °C then water
(200mL) was added to the reaction mixture at same temperature and stirred for 90-120
minutes to get precipitation. Reaction mixture gradually cooled to 25±5 °C for 3 hours,
reaction maintained for 60-90 minutes then filtered the obtained solid and washed the wet
compound with water (20mL). Wet compound dried under vacuum oven for 15 hours at 25
°C to get crystalline form M2.
Example-5: Preparation of crystalline Glecaprevir form M2
The Glecaprevir wet compound dissolved in methanol (400mL) at 55±5 °C then water
(200mL) was added to the reaction mixture at same temperature and stirred for 90-120
minutes to get precipitation. Reaction mixture gradually cooled to 25±5 °C for 3 hours,
reaction maintained for 60-90 minutes then filtered the obtained solid and washed the wet
compound with water (20mL). Wet compound dried in vacuum oven for 15 hours at 45 °C to
get crystalline form M2.
Example-6: Preparation of crystalline Glecaprevir form M2
The Glecaprevir wet compound dissolved in methanol (400mL) at 55±5 °C then water
(200mL) was added to the reaction mixture at same temperature and stirred for 90-120
minutes to get precipitation. Reaction mixture gradually cooled to 25±5 °C for 3 hours,
reaction maintained for 60-90 minutes then filtered the obtained solid and washed the wet
compound with water (20mL). Wet compound dried in vacuum oven for 15 hours at 65 °C to
get crystalline form M2.
Example-7: Preparation of amorphous Glecaprevir
Compound of formula II (2.0g), 2-Hydroxypyridine N-oxide (0.5g) 1-ethyl-3-(3-
dimethylaminopropyl) carbodiimide (EDAC;1.04g) were taken in acetonitrile(8mL) and
stirred for 30 minutes at 25±5 °C to get clear solution of acid complex. In another flask
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carboxamide compound of formula III (1.2g) and triethylamine (0.85g) was taken in
acetonitrile (8mL) and stirred at 25±5 °C. Acid complex solution was added slowly to the
carboxamide mixture for 15minutes at 25±5 °C and stirred for 15 hours. After completion of
reaction, water was added slowly to the reaction mixture followed by aqueous acetic acid
solution. The reaction mixture was extracted with ethyl acetate and organic layer was
concentrated under vacuum to obtain foamy solid.
Methanol (24mL) was added to obtained foamy solid at 25±5 °C and heated to 55-60 °C then
water (24mL) was slowly added to the reaction mixture at same temperature and stirred for 2
hours. The obtained solid was filtered and washed with water. Wet compound was dried
under vacuum to get amorphous Glecaprevir of formula I.
Yield: 2.0 g
Example-8: Preparation of amorphous Glecaprevir
Glecaprevir (5.0g) was dissolved in methanol (60 mL) at 25±5 °C and water (60mL) was
added slowly over 15minutes at 20-25 °C and reaction mixture was stirred for 60minutes.
Filtered the obtained solid and washed with water, dried the wet compound under vacuum at
50°C for 5 hours to get amorphous product.
Yield: 2.0 g
Example-9: Preparation of amorphous Glecaprevir
Glecaprevir (5g) was dissolved in dichloromethane (100 mL) at 25±5 °C. The contents were
distilled out under vacuum at 40°C. The distilled product was dried in rotavapor for 60
minutes to obtain amorphous solid.
Yield: 4.8g
Example-10: Preparation of amorphous Glecaprevir
Crude Glecaprevir (5g) was purified by column chromatography with eluent of ethyl acetate
in n-hexane (1:1) and distilled of pure fraction under vacuum at 50-55°C in rotavapor to get
amorphous solid.
Yield: 4.2g
Example-11: Preparation of amorphous Glecaprevir
Glecaprevir (5g) was dissolved in methanol (100mL) at 60°C. The resulting clear solution
was filtered at 60 °C to remove undissolved particulate and then cooled to 25-30 °C, clear solution was subjected to spray drying in a laboratory spray dryer with feed rate of the solution 5mL/min and inlet temperature at 70°C. The resulting product was identified as
amorphous form of Glecaprevir.
Yield: 4.0 g ,CLAIMS:Crystalline Glecaprevir form M2.
2. The crystalline Glecaprevir form M2 as claimed in claim 1, is characterized by
powder x-ray diffraction pattern having significant peaks at 2? angle positions 7.29,
9.0, 13.95, 14.66, 15.82, 16.49, 17.97, 18.77, 21.39 ± 0.2°.
3. The crystalline Glecaprevir form M2 as claimed in claim 1, is prepared comprising
the steps of
a) dissolving Glecaprevir in an alcoholic solvent at 50 °C - 60 °C,
b) adding an anti-solvent at same temperature,
c) cooling the mixture to 25±5 °C,
d) filtering to get wet solid; and
e) drying under vacuum oven at 25 °C - 65 °C to get crystalline form M2.
4. Crystalline Glecaprevir form M1.
5. The crystalline Glecaprevir form M1 as claimed in claim 4, is characterized by
powder x-ray diffraction pattern having significant peaks at 2? angle positions 6.78,
8.58, 8.83, 10.75, 13.58, 15.02, 16.04, 17.35, 18.98, 19.19, 22.56 ± 0.2°.
6. The crystalline Glecaprevir form M1 as claimed in claim 4, is prepared comprising
the steps of
a) dissolving Glecaprevir in an alcoholic solvent at 50 °C - 60 °C,
b) adding an anti-solvent at same temperature,
c) cooling the mixture to 25±5 °C,
d) filtering to get wet solid; and
e) drying the wet solid in an oven with nitrogen blowing at 55 °C - 75 °C to get
crystalline form M1.
7. A process for the preparation of amorphous Glecaprevir comprising the steps of:
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a) dissolving Glecaprevir in a solvent at 25±5 °C;
b) adding anti-solvent at 25±5 °C;
c) removing the solvent and isolating the amorphous Glecaprevir.
8. A process for the preparation of amorphous Glecaprevir comprising the steps of:
a) dissolving Glecaprevir in a solvent at 25±5 °C;
b) heating the solution of step a) to 55-60 °C;
c) adding anti-solvent at 55-60 °C;
d) removing the solvent and isolating the amorphous Glecaprevir.
9. A process for the preparation of amorphous Glecaprevir comprising the steps of:
a) dissolving Glecaprevir in a solvent;
b) removing the solvent and isolating the amorphous Glecaprevir.
10. The process according to any of the preceding claims, wherein the alcoholic solvent is
selected from methanol, ethanol, IPA and solvent is dichloromethane, methanol or
mixtures thereof.