'l'lie present invention provides a cryslalline fol.ni of baricitinib, a process for its
preparation, a plianiiaceutical co~nposition comprising it, and its use for the treatment of JAKassociated
diseases.
13ackground ofthe Invention
13aricitinib is a Ja~ius Kinase (JAK) inhibitor. It is chemically designated as {l-
(etliylsulfonyl)-3-[4-(7H-pyuolo~,3-d]pyri1nidin-4-y11)1-3 -pyrazol-1- yl]azetidin-3-
yl)acetonitrile, having the structure as depicted in Fortnula I.
Formula I
Processes for the preparation ofbaricitinib are disclosed in U.S. Patent No. 8,158,616.
Polymorphism, the occurrence of different crystal forms, is a property of some
molecules. When poly~norphis~onc curs, the n~oleculesa rrange thenlselves in two or more
different ways in the crystal, giving rise to differences in crystal structures and physical
properties like melting point, thermal behaviors, X-ray Powder Diffraction (XRPD) pattern,
Infrared (1R) absorption fingerprint, solid state NMR spectrum, and solubility. Thus, the
discovery of new polymorpliic forms of a lnolecule is itiiportant in the developnient of
pliarmace~~ticalass, they may provide niaterials having desirable processing properties, such as
ease of handling, case of processing, storage stability, ease of purification, improved dissolution
profile, andlor improved shelf-life.
There are 110 reported polymorplis of baricitinib.
2
S~lmniaryo f thc Invention
. . Ihe prcscnt invention providcs a crystalline for111 of baricitinib, a process fbr its
preparation, a pharmaceutical composition comp~.ising it, and its use for the treatment of JAKassociated
discascs. The crystalline fi)rlii of baricitinib is a highly pure, easy to tiltel-, h e -
flowing solid with good ther~nodynaniic stability, good solubility, residual solvent content in
conipliance with the iCI-I guidelines, prolonged shelflife, and good bioavailability.
A first aspect of the present invention provides a crystalline form of baricitinib
characterized by an X-ray Powder DifSraction (XRPD) pattern liaving peaks at d-spacings of
5.31,4.65,3.52,and3.48A.
A second aspect of the present invention provides a process for the preparation of a
crystalline form of baricitinib charactcrized by an XRPD pattern having peaks at d-spacings of
5.31,4.65, 3.52, and 3.48 A, comprising the steps of:
i) reacting (4-(1-(3-(cya~o1nelh~l)-l-(ethylsulfonyl)azetidin-3-yl)-1H-~~razol-4-~l)-
7H-pyrrolo [2,3-d]pyriniidin-7-yl)methyl pivalate with a base in the presence of
one or Inore solvents;
ii) partially recovering the solvent(s) fi0111 the reaction mixture;
iii) stirring the reaction mixture;
iv) filtering the solid obtained fro111 the reaction mixture;
v) washing the solid with a nlixture of acetonitrile and water; and
vi) drying the solid.
A third aspect of the present invention provides a pharmaceutical colnposition
comprising a crystalline form ofbaricitinib characterized by an XlZPD pattern having peaks at dspacings
of 5.31, 4.65, 3.52, and 3.48 A, and one or more pharmaceutically acceptable carriers,
dilucnts, or excipients.
A fourth aspect of the present invention provides a niethod of treating JAK-associated
diseases comprising adlninistration to a patient a therapeutically effective amount of a
coniposition comprising a crystalline form of baricitinib characterized by an XRPD pattern
having peaks at d-spacings of 5.31,4.65, 3.52, and 3.48 A.
Figure 1 : X-ray I'owder Diffraction (XI2PD) pattern of thc crystalline fbrm of
baricitinib.
Figure 2: Ilill'erentlal Scanning Calornnetry (DSC) tlicrmograrii of the crystalline ibrm
ofbal.icitinib.
Figure 3: l'her~nogravimetric Analysis (TGA) of the crystalline form ofbaricitinib.
1:igure 4: Iiifra-red (112) spectrum of thc crystalline form ofbaricitinib.
Detailed Description ofthe Invention
Various embodiments and variants of the present invention are described hereinalter.
The tern1 "'JAK-associated diseases," as used herein, includes inflarnniatory diseases,
autoimmune disorders, diabetic nephropathy, and cancer.
The tern1 "about," as used herein, refers to any value which lies within the range defined
by a number up to i10% of the value.
The crystalline forni of baricitinib is characterized by an XIZPD pattern having peaks at
d-spacings of 5.31, 4.65, 3.52, and 3.48 A. The crystalline form of baricitinib is further
characterized by an XliPD pattern having peaks at d-spacings of 7.06, 5.91, 5.75, 5.43, and 2.98
A. Table 1 sunnnarizcs the d-spacing values in A, and the corresponding 20 values of the
crystalline for111 of baricitinib.
'I'able 1 : XIZl'I) I'ealts of the Crystalline Form of ikicitinib
The crystalline for111 ofbaricitinib is f'ul.Lhcr characterized by a DSC having elldotherlns
at about 180.63"C and about 207.98OC.
5
7'he crystalline Sorm of baricitinib has a watcr contcnt of about 3'%1, as dctcrmincd by
'l'GA.
'I'hc crystalline form of baricitinib is also chal-acterized by an XRPI) patteni as depicted
in Figure 1, a DSC themiogram as depicted in Figure 2, a I'GA as depicted in Figure 3, and an
111 spectrum as depicted in Figure 4.
'fie preparation of the crystalline for111 of baricitinib is carried O L I ~ by reacting (4-(1-(3-
(cyano1nethyl)-l-(ethyls~1lfonyl)a~idin-3-yl)-1.H-pyrazol-4-yl)-7H-pyrr[2o,l3o- d]pyrimidin-7-
yl)tnethyl pivalate with a base in the presence of one or more solvents at a temperature of about
15°C to 50°C, stirring the reaction mixture for about 30 ~ninutes to about 10 hours, partially
recovering the solvent(s) fiorn the reaction mixture at a temperature of about 35°C to about 60°C
under reduced pressure, stirring the contents at about 15°C to 3S°C for about 5 hours to about 24
hours, filtering the solid, washing the solid with a mixture ofaceto~litrilea nd watcr, and drying.
The (4-(1-(3-(cyanomethyl)-I -(ethylsulfonyl)azdidi1l-3-yl)-lH-pyrazol-4-yl)-7N-pyrrolo
[2,3-d]pyri11iidi11-7-yl)methyl pivalate may be obtained by fbllowing the process disclosed in
U.S. Patent No. 8,158,616.
The base may be selected from the group consisting of inorganic and organic bases.
Exari~ples of illorgaliic bases include hydroxides, carbonates, and bicarbonates of alkali and
alkaline earth metals. Examples of alkali and alkaline earth metal hydroxides include lithiuiii
hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide,
and barium hydroxide. Exaliiples of alkali and alkaline earth metal carbonates include sodium
carbonate, potassium carbonate, calciutn carbonate, and magnesium carbonate. Examples of
alkali ineta1 bicarbonates include sodiuill bicarbonate and potassium bicarbonate. Exalliples of
organic bases include N,N-diisopropylcthylaminc, tricthylamine, triisopropylainine, N,N-2-
trimethyl-2-propanamine, N-methylmorpholine, 4-dimethylaini~iopyridine, 2,6-di-tert-butyl-4-
dimcthylaminopyridine, 1,4-diazabicyclo[2.2.2]ocVdne, and 1,8-diazabicyclo[5.4.O]undec-7-ene.
In an embodiinelit of the present invention, the base used is sodium hydroxide.
The solvents may be selected from the group consisting of hydrocarbons, alcohols,
ethers, chlorinated hydrocarbons, carboxylic acids, ketones, atiiides, sulphoxides, water, and
mixtures thereoi: Examples of liydrocarbons include benzcne, toluenc, and xylenc. Examples
of alcohols include methanol, ethanol, I-propanol, I -butanol, and 2-butanol. Examplcs of ethers
include diethyl ether, ethyl liietbyl ether, di-isopropyl ether, tetrahydrofuran, and 1,4-dioxane.
Examples of chlorinated hydrocarbons include dichlorometliane and chloroforni. Examples of
carboxylic acids include hrmic acid, acetic acid, anci propionic acid. Examples of ketones
include acctone, dimethyl ketone, ethyl mctliyl Icetone, and mctliyl iso-butyi kctonc. lixamplcs
of amidcs include N,N-di~iictliylfo~xia~i~aidned N,N-di~i~ctliylaceta~iiicic. Examples of
sulplioxidcs include dilnethyl sulplioxide and diethyl snlphoxide. In an embodiment of tlie
present invention, a mixture of methanol and teh-aIiydrof~rl.ai~si used.
In an embodiment of tlie present invention, tlie partial recovery of ilic solvent(s) fiom the
reaction mixture is carried out at a temperature of about 40°C to about 50°C under reduced
pressure.
In another embodiment of'tlie present invention, a ~iiixtureo f acetonitrile and water in a
1 :2 ratio is used for washing.
Isolation of the crystalline form of baricitinib may be carried out by concentration,
precipitation, cooling, filtration, centrifugation, or combinations thereof, followed by drying.
Drying may be carried out using any suitable method such as drying under reduced pressure, air
drying, or vacuunl 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.
In an embodiment of the present invention, the isolation of the crystalline form of
baricitinib is carried out by filtration followed by drying at a temperature of about 35OC to about
50°C for about 24 hours.
TIie crystalline form of baricitinib is a highly pure, easy to filter, free-flowing solid. The
crystalline for111 of baricitinib has good thermodynamic stability, good solubility, residual
solvent content in compliance with the ICI-I guidelines, prolonged shelf life, and good
bioavailability.
l'hc crystalline form of baricitinib may be administered as pait of a pharlnaceutical
composition for the treatment of JAIC-associated diseases, including inflammatory diseases,
autoimmune disorders, diabetic nepliropathy, and cancer. Accordingly, in a further aspect of the
present invention, there is provided a pharmaceutical co~i~positiocno mprising tlie crystalline
form of baricitinib and one or more pharmaceutically acceptable carriers, diluents, or excipients,
and optionally other therapeutic ingredients.
In tlie 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 li~iiittl ie scope
of the present invention. Several variants oftlie example would be evident to persons ordinarily
skilled in the art which are within the scope of the present inventiort.
Methods
'l'he X-ray po\vder diffi.action patterns wcrc recorded using a I'ANalyticalW Cxpcrt I'RO
with X'celerator'" as ~ hdce tector, 0.02 as step size, and 3-40' 20 as range using CuKn radiation.
The IISC thcrniogram was rccorded us~nga Mettlcr Tolcdo" DSC 821e instrument.
The TGA was recorded using a TA instruments" 0500.
The iR spectrum was recordcd using a Perkin Elmer'~pectrum One FT-112
spcctroineter.
Exam1)lc: I'reparation of crystalline form of bariciti&
(4-(1-(3-(Cyanomethyl)- I -(etliylsulfoiiyl)azetidin-3-yl)- 1I -l-pyrazoI-4-yl)-714-pyrrolo[2 ,3..
dlpyritnidiii-7-yI)~iiethyl pivalate (8 g), methanol (40 mL), tetrahydrofuran (160 niL), and IM
sodium hydroxide (18.4 mL) were added into a reaction vessel at 20°C to 2SoC. 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 with water (80 mL). 'The
pH was adjusted to 7.0 to 7.5 by adding IN hydrochloric acid. Half of the solvent was
recovered at a temperature of 40°C to 50°C. The reaction niixture was stirred at 20"C to 25°C
for 18 hours, and then cooled to 5OC to IO0C. The solids were filtered, washed with a mixture of
acetonitrile (50 mL) and water (100 1111,), and then dried at 40°C to 50°C under reduced pressure
for 24 hours to obtain the crystalline form of baricitinib.
Yield: 70%

WE CLAIM:
I. A crystalline form of barlcitintb characterixd by an X-~xy Powder 1IifEI.actio1.r (XliPI))
pattern having pealts at d-spacings of5.3 I , 4.65, 3.52, and 3.48 A.
2. The crystalline form of baricitinib according to claim I , characterized by one or more of
the following:
i) XRPD pattcrn substantially as depicted in I'igure I;
ii) DSC thermograin substantially as depicted in Figure 2;
iii) TGA substantially as depicted in Figure 3;
iv) Infra-red (IR) spectrum substantially as depicted in Figure 4.
3. The crystalline for111 of baricitinib according to claim 1, characterized by a Differential
Scanning Calorimetry (DSC) thennogram having endother~ns at about 180.63"C and
about 207.98OC.
4. The crystalline for111 of baricitinib according to claiin 1, having a water content of about
3%, as determined by Thermograviinetric Analysis (TGA).
5. A process for the preparation of the crystalline forin of baricitinib according to claiin 1
cotnprising the steps of:
i) reacting (4-(1-(3-(cyanometl1yl)-l-(ethylsulfonyl)azctidin-3-yl)-lN-pyrazol-4-yl)-
7H-pyrrolo [2,3-dlpyrimidin-7-y1)methyl pivalate with a base in the presencc of
one or more solvents;
ii) partially recovering the solvent(s) from the reaction mixturc;
iii) stirring the reaction mixture;
iv) filtering a solid obtained from the reaction mixture;
v) washing the solid witti a mixture of acetonitrile and water; and
vi) drying the solid.
6. The process according to claim 5, wherein the base is selected from the group consisting
of inorganic and organic bases.
7. The process according to claim 5, wherein the one or more solvents used in step i) is
selected from the group consisting of hydrocarbons, alcohols, ethers, chlorinated
hydrocarbons, carboxylic acids, ketones, amides, sulphoxides, water, and mixtures
thereof.
8. The process according to claim 5, wherein the washing is carried out with a mixture of
acetonitrile and water in a 1:2 ratio.
9. The process according to claim 5, wherein the drying is carried out at a temperature of
35OC to 50°C.
10. A pharmaceutical composition comprising the crystalline form of baricitinib according to
claim 1, and one or more pharmaceutically acceptable carriers, diluents, or excipients.