AMORPHOUS FORM OF BARICITINIB
Field of the Invention
The present invention provides an amorphous form of baricitinib, processes for its
preparation, a pharmaceutical composition comprising it, and its use for the treatment of JAKassociated
diseases.
Background of the Invention
Baricitinib is a Janus Kinase (JAK) inhibitor. It is chemically designated as {1-
(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]azetidin-3-yl}acetonitrile,
having the structure as depicted in Formula I.
Processes for the preparation of baricitinib are disclosed in U.S. Patent No. 8,158,616.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules.
When polymorphism occurs, the molecules arrange themselves in two or more different ways in the
crystal giving rise to differences in crystal structures and physical properties such as melting point,
thermal behaviors, X-ray powder diffraction (XRPD) pattern, infrared absorption fingerprint, solid
state NMR spectrum, and solubility. Thus, the discovery of new polymorphic forms of a molecule
is important in the development of pharmaceuticals as they may provide materials having desirable
processing properties, such as ease of handling, ease of processing, storage stability, ease of
purification, improved dissolution profile, and/or improved shelf-life.
There are no reported polymorphs of baricitinib.
Summary of the Invention
The present invention provides an amorphous form of baricitinib, processes for its
preparation, a pharmaceutical composition comprising it, and its use for the treatment of JAKassociated
diseases. The amorphous form of baricitinib is a highly pure, easy to filter, free-flowing
solid. The amorphous form of baricitinib has a small average particle size and a content of residual
solvents in compliance with ICH guidelines. The amorphous form of baricitinib is stable towards
polymorphic conversion and exhibits good bioavailability.
A first aspect of the present invention provides an amorphous form of baricitinib.
A second aspect of the present invention provides a process for the preparation of an
amorphous form of baricitinib comprising:
i) reacting 4-( 1 -(3 -(cyanomethy 1)-1 -(ethy lsulfony l)azetidin-3 -y 1)-1 H-pyrazol-4-yl)-7Hpyrrolo[
2,3-d]pyrimidin-7-yl)methyl pivalate with a base in the presence of one or
more solvents to form a reaction mixture;
ii) completely recovering the one or more solvents from the reaction mixture;
iii) adding water; and
iv) isolating the amorphous form of baricitinib.
A third aspect of the present invention provides a process for the preparation of an
amorphous form of baricitinib comprising subjecting a solution of baricitinib in a solvent to spray
drying.
A fourth aspect of the present invention provides a process for the preparation of an
amorphous form of baricitinib comprising subjecting a solution of baricitinib in a solvent to
agitated thin film drying.
A fifth aspect of the present invention provides a process for the preparation of an
amorphous form of baricitinib comprising subjecting a solution of baricitinib in a solvent to
lyophilization.
A sixth aspect of the present invention provides a process for the preparation of an
amorphous form of baricitinib comprising concentrating a reaction mixture containing baricitinib in
a solvent under reduced pressure.
A seventh aspect of the present invention provides a pharmaceutical composition
comprising an amorphous form of baricitinib and one or more pharmaceutically acceptable carriers,
diluents, or excipients.
An eighth aspect of the present invention provides the use of an amorphous form of
baricitinib for the treatment of JAK-associated diseases.
Brief Description of the Drawings
Figure 1: X-ray powder diffraction (XRPD) pattern of an amorphous form of baricitinib.
Figure 2: Differential Scanning Calorimetry (DSC) of an amorphous form of baricitinib.
Figure 3: Thermogravimetric Analysis (TGA) of an amorphous form of baricitinib.
Figure 4: Infra-Red (IR) spectrum of an amorphous form of baricitinib.
Detailed Description of the Invention
Various embodiments and variants of the present invention are described hereinafter.
The term "JAK-associated diseases," as used herein, includes inflammatory diseases,
autoimmune disorders, diabetic nephropathy, and cancer.
The term "about," as used herein, refers to any value which lies within the range defined by
a number up to ±10% of the value.
The term "ambient temperature," as used herein, refers to a temperature in the range of
about 20°C to about 35°C.
4-( 1 -(3 -(Cyanomethyl)-1 -(ethylsulfony l)azetidin-3 -yl)-1 H-pyrazol-4-yl)-7H-pyrrolo[2,3 -
d]pyrimidin-7-yl)methyl pivalate can be obtained by following the process disclosed in U.S. Patent
No. 8,158,616.
The base is selected from the group consisting of inorganic and organic bases. Examples of
inorganic bases include hydroxides, carbonates, and bicarbonates of alkali and alkaline earth
metals. Examples of alkali and alkaline earth metal hydroxides include lithium hydroxide, sodium
hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, and barium hydroxide.
Examples of alkali and alkaline earth metal carbonates include sodium carbonate, potassium
carbonate, calcium carbonate, and magnesium carbonate. Examples of alkali metal bicarbonates
include sodium bicarbonate and potassium bicarbonate. Examples of organic bases include N,Ndiisopropylethylamine,
triethylamine, triisopropylamine, N,N-2-trimethyl-2-propanamine, Nmethylmorpholine,
4-dimethylaminopyridine, 2,6-di-tert-butyl-4-dimethylaminopyridine, 1,4-
diazabicyclo[2.2.2]octane, and l,8-diazabicyclo[574.0Jundec-7-ene. in one embodiment of the
present invention, the base used is sodium hydroxide.
The solvents are selected from the group comprising hydrocarbons, alcohols, ethers,
chlorinated hydrocarbons, carboxylic acids, ketones, amides, sulphoxides, water, and mixtures
thereof. Examples of hydrocarbons include benzene, toluene, and xylenes. Examples of alcohols
include methanol, ethanol, 1-propanol, 1-butanol, and 2-butanol. Examples of ethers include
diethyl ether, ethyl methyl ether, di-isopropyl ether, tetrahydrofuran, and 1,4-dioxane. Examples of
chlorinated hydrocarbons include dichloromethane and chloroform. Examples of carboxylic acids
include formic acid, acetic acid, and propionic acid. Examples of ketones include acetone,
dimethyl ketone, ethyl methyl ketone, and methyl iso-butyl ketone. Examples of amides include
N,N-dimethylformamide and N,N-dimethylacetamide. Examples of sulphoxides include dimethyl
sulphoxide and diethyl sulphoxide. In one embodiment of the present invention, a mixture of
methanol arid tetrahydrofuran is used.
The preparation of the amorphous form of baricitinib may be carried out by spray drying,
agitated thin film drying, lyophilization, or by concentrating a reaction mixture containing
baricitinib in a solvent under reduced pressure.
In an embodiment of the present invention, the preparation of the amorphous form of
baricitinib is carried out by reacting 4-(l-(3-(cyanomethyl)-l-(ethylsulfonyl)azetidin-3-yl)-lHpyrazol-
4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate with a base in the presence of one
or more solvents at ambient temperature for about 30 minutes to about 5 hours, completely
recovering the solvent(s) from the reaction mixture, adding water, and isolating the amorphous
form of baricitinib.
Isolation of the amorphous form of baricitinib may be carried out by concentration,
precipitation, cooling, filtration, centrifiigation, or a combination thereof, followed by drying.
Drying may be carried out using any suitable method such as drying under reduced pressure, air
drying, or vacuum tray drying. Drying may be carried out at a temperature of about 35°C to about
£ 50°C for about 10 hours to about 2 days.
H, In an embodiment of the present invention, the isolation of the amorphous form of
CM
£ baricitinib is carried out by filtration followed by drying at a temperature of about 40°C to about
o
^ 45°C for about 24 hours.
o
co The amorphous form of baricitinib of the present invention exhibits an XRPD pattern as
5 depicted in Figure 1.
o
CN'
5> The amorphous form of baricitinib of the present invention is further characterized by a
CO
5 DSC thermogram having endotherms at about 125.28°C and about 202.52°C. Figure 2 depicts the
CO
o
CM
CD
G)
DSC thermogram of the amorphous form of baricitinib of the present invention.
^ 5
CD
G)
CD
E
o
The amorphous form of baricitinib of the present invention shows a weight loss of about
1.6% as determined by TGA. Figure 3 depicts the TGA of the amorphous form of baricitinib of the
present invention.
The amorphous form of baricitinib of the present invention is also characterized by an IR
spectrum as depicted in Figure 4.
The amorphous form of baricitinib is a highly pure, easy to filter, free-flowing solid, having
small average particle size, and a content of residual solvents in compliance with the ICH
guidelines. The amorphous form of baricitinib is stable towards polymorphic conversion and has a
good bioavailability.
The amorphous form of baricitinib of the present invention may be administered as part of a
pharmaceutical composition for the treatment of JAK-associated diseases, including inflammatory
diseases, autoimmune disorders, diabetic nephropathy, and cancer. Accordingly, in a further aspect
of the present invention, there is provided a pharmaceutical composition comprising the amorphous
form of baricitinib and one or more pharmaceutically acceptable carriers, diluents, or excipients,
and optionally other therapeutic ingredients.
In the foregoing section, embodiments are described by way of an example to illustrate the
process of the present invention. However, this is not intended in any way to limit the scope of the
present invention. Several variants of the example would be evident to persons ordinarily skilled in
the art which are within the scope of the present invention.
Method
XRPD pattern was recorded using a PANalytical® Expert PRO with X'celerator® as the
detector, 0.02 as step size, and 3-40° 20 as range using CuKa radiation.
The DSC thermogram was recorded using a Mettler Toledo® DSC 82 le instrument.
The TGA was recorded using a TA Instruments® Q500.
The IR spectrum was recorded using a PerkinElmer® Spectrum One FT-IR spectrometer.
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EXAMPLES
Comparative Examples
Example 1: Repetition of the process according to Example 78, Method B of U.S. Patent No.
8.158.616-
4-(l-(3-(Cyanomethyl)-l-(ethylsulfonyl)azetidin-3-yl)-lH-pyrazol-4-yl)-7H-pyrrolo[2,3-
d]pyrimidin-7-yl)methyl pivalate (1 g), methanol (5 mL), tetrahydrofuran (20 mL), and IM sodium
hydroxide (2.3 mL) were added into a reaction vessel at 20°C to 25°C. The reaction mixture was
stirred for 3 hours. Progress of the reaction was monitored by thin layer chromatography. On
completion, the reaction mixture was quenched by adding water (20 mL). The pH was adjusted to
7.0 to 7.5 by adding IN hydrochloric acid, and the contents were stirred for 1.5 hours. No solid
material was obtained.
Example 2: Repetition of the process according to Example 78, Method C of U.S. Patent No.
8,158,616
4-(l-(3-(Cyanomethyl)-l-(ethylsulfonyl)azetidin-3-yl)-lH-pyrazol-4-yl)-7H-pyrrolo[2,3-
d]pyrimidin-7-yl)methyl pivalate (2 g), lithium hydroxide monohydrate (0.51 g), acetonitrile (8
mL), and 2-propanol (2 mL) were added into a reaction vessel at 20°C to 25°C. The reaction
mixture was stirred at 45°C to 50°C for 6 hours. Progress of the reaction was monitored by thin
layer chromatography. On completion, the reaction mixture was cooled to 20°C to 25°C. The pH
was adjusted to 6.0 to 7.0 by adding IN hydrochloric acid, and the contents were stirred overnight.
No solid material was obtained.
Working Example:
Preparation of an amorphous form of baricitinib
4-( 1-(3-(Cyanomethyl)-1-(ethylsulfonyO
d]pyrimidin-7-yl)methyl pivalate (1 g), methanol (5 mL), tetrahydrofuran (20 mL), and IM sodium
hydroxide (2.3 mL) were added into a reaction vessel at 20°C to 25°C. The reaction mixture was
stirred for 3 hours. Progress of the reaction was monitored by thin layer chromatography. On
completion, the reaction mixture was quenched by adding water (20 mL). The pH was adjusted to
7.0 to 7.5 by adding IN hydrochloric acid, followed by completely recovering the solvent under
reduced pressure at 40°C to 50°C. A sticky material was obtained. Water (10 mL) was added to
the sticky material at 20°C to 25°C. The contents were stirred for 10 minutes. A solid material was
precipitated out. The solid material was filtered, washed with water (20 mL), and then dried under
reduced pressure at 40°C to 45°C for 24 hours to obtain the amorphous form of baricitinib.
Yield: 81%.
The amorphous form of baricitinib may be used in a pharmaceutical composition with one
or more pharmaceutical ly acceptable carriers, diluents, or excipients, and optionally other
therapeutic ingredients. The pharmaceutical composition may be used for the treatment of JAKassociated
diseases.

WE CLAIM:
1. An amorphous form of baricitinib.
2. The amorphous form of baricitinib according to claim 1, characterized by XRPD
pattern, DSC thermogram, TGA, and IR spectrum substantially as depicted in
Figures 1, 2, 3, and 4, respectively.
3. The amorphous form of baricitinib according to claim 1, characterized by a DSC
thermogram having endotherms at about 125.28°C and about 202.52°C.
4. A process for the preparation of an amorphous form of baricitinib comprising:
i) reacting 4-( 1 -(3-(cyanomethyl)-1 -(ethylsulfonyl)azetidin-3-yl)- lH-pyrazol-4-
yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate with a base in the
presence of one or more solvents to form a reaction mixture;
ii) completely recovering the one or more solvents from the reaction mixture;
iii) adding water; and
iv) isolating the amorphous form of baricitinib.
5. The process according to claim 4, wherein the solvent is a mixture of methanol and
tetrahydrofiiran.
6. The process according to claim 4, wherein the base is selected from the group
consisting of inorganic and organic bases.
7. A process for the preparation of an amorphous form of baricitinib comprising
subjecting a solution of baricitinib in a solvent to spray drying, or agitated thin film
drying, or lyophilization, or concentrating a reaction mixture containing baricitinib
in a solvent under reduced pressure, followed by completely recovering the solvent
from the reaction mixture, and isolating the amorphous form of baricitinib.
The process according to any one of claim 7, wherein the solvent is selected from
the group comprising of hydrocarbons, alcohols, ethers, chlorinated hydrocarbons,
carboxylic acids, ketones, amides, sulphoxides, water, and mixtures thereof
A pharmaceutical composition comprising an amorphous form of baricitinib
according to claim 1 and one or more pharmaceutical^ acceptable carriers,
diluents, or excipients.
Use of an amorphous form of baricitinib according to claim 1 for the treatment of
JAK-associated diseases selected from inflammatory, diseases, autoimmune
disorders, diabetic nephropathy, and cancer.