DESC:The following specification describes particularly the invention and in the
manner in which it is to be performed:
2
INTRODUCTION
Aspects of the present application relate to solid forms of abrocitinib
and pharmaceutical compositions thereof. Specific aspects relate to the
crystalline form abrocitinib and processes for their preparation.
The drug compound having the adopted name “Abrocitinib” is a Janus
kinase (JAK) inhibitor having a chemical name N-((1s,3s)-3-(methyl(7Hpyrrolo[
2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide and the
structure as below.
Abrocitinib” is a Janus kinase (JAK) inhibitor indicated for the
treatment of adults with refractory, moderate-to-severe atopic dermatitis whose
disease is not adequately controlled with other systemic drug products,
including biologics, or when use of those therapies is inadvisable.
US 9035074 B2 discloses abrocitinib, its pharmaceutically acceptable
salts and pharmaceutical formulations.
Further, WO2020008391A1discloses crystalline form of abrocitinib and
process for its preparation.
WO2020261041 A1 discloses crystalline form of abrocitinib and process
for its preparation. Also covers amorphous solid dispersion of abrocitinib.
WO 2021218948 A1 discloses crystalline forms of abrocitinib and
processes for their preparation.
The existence and possible numbers of polymorphic forms for a given
compound cannot be predicted, and there are no “standard” procedures that can be
used to prepare polymorphic forms of a substance. However, new forms of a
pharmaceutically useful compound may provide an opportunity to improve the
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performance characteristics of pharmaceutical products. Further, discovery of
additional polymorphic forms, including solvate polymorphs, may help in the
identification of the polymorphic content of a batch of an active pharmaceutical
ingredient. For example, in some cases, different forms of the same drug can
exhibit very different solubility and different dissolution rates. The discovery of
new polymorphic forms enlarges selection of materials with which formulation
scientists can design a pharmaceutically acceptable dosage form of a drug with a
targeted release profile or other desired characteristics. Therefore, there remains a
need for preparing new and stable polymorphic forms of abrocitinib which can
overcome the disadvantages of the prior art and their preparation in a more cost
effective and industrially viable manner.
SUMMARY
In an aspect, the present application provides a crystalline form CC-1 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about
10.3 and 20.9 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form
CC-1 of abrocitinib, further characterized by a PXRD pattern comprising the
peaks at about 27.4, and 27.9 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form CC-2 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about
11.4, 12.2, 16.6, 18.2 and 19.5 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form
CC-2 of abrocitinib, further characterized by a PXRD pattern comprising the
peaks at about 23.6 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form CC-3 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about
4.2, 6.2, 10.9, 12.0 and 13.8 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form
CC-3 of abrocitinib, further characterized by a PXRD pattern comprising the
peaks at about 29.4 ± 0.2° 2?.
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In an aspect, the present application provides a crystalline form CC-4 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about
13.1, 15.0, 18.2 and 19.6 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form
CC-4 of abrocitinib, further characterized by a PXRD pattern comprising the
peaks at about 23.5, 24.4, 26.1 and 32.1 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form CC-5 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about
5.5, 6.6, 8.3, 18.2 and 18.9 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form
CC-5 of abrocitinib, further characterized by a PXRD pattern comprising the
peaks at about 21.1, 21.9, 22.4 and 29.1 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form CC-6 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about
8.1, 11.0, 12.1, 13.1, 13.8 and 14.1 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form
CC-6 of abrocitinib, further characterized by a PXRD pattern comprising the
peaks at about 21.9, 22.4 and 24.3 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form CC-7 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about
6.6, 8.0, 8.5, 10.0, 14.2, 19.0 and 19.8 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form
CC-7 of abrocitinib, further characterized by a PXRD pattern comprising the
peaks at about 14.3, 22.6 and 26.0 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form CC-8 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about
9.3, 11.0, 11.9, 15.2, 18.1 and 19.9 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form
CC-8 of abrocitinib, further characterized by a PXRD pattern comprising the
peaks at about 22.4, 23.4, 26.2, 27.7 and 28.3 ± 0.2° 2?.
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In another aspect, the present application provides a process for the
preparation of crystalline Form CC-1 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib and
Parahydroxybenzoic Acid in a solvent selected from methanol,
isopropyl alcohol, water or mixture thereof;
b) isolating the crystalline form CC-1 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form CC-2 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib and Fumaric
acid in a solvent selected from methanol, isopropyl alcohol,
water or mixture thereof;
b) isolating the crystalline form CC-2 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form CC-3 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib and gentisic
acid in a solvent selected from methanol, isopropyl alcohol,
water or mixture thereof;
b) isolating the crystalline form CC-3 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form CC-4 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib and
Acesulfame K in a solvent selected from methanol, isopropyl
alcohol, water or mixture thereof;
b) isolating the crystalline form CC-4 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form CC-5 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib and Aspartame
in a solvent selected from methanol, isopropyl alcohol, water or
mixture thereof;
b) isolating the crystalline form CC-5 of abrocitinib.
6
In another aspect, the present application provides a process for the
preparation of crystalline Form CC-6 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib and Saccharin
in a solvent selected from methanol, isopropyl alcohol, water or
mixture thereof;
b) isolating the crystalline form CC-6 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form CC-7 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib and
Naphthalenedisulfonic acid in a solvent selected from methanol,
isopropyl alcohol, water or mixture thereof;
b) isolating the crystalline form CC-7 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form CC-8 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib and 1-
Pentanesulfonic Acid in a solvent selected from methanol,
isopropyl alcohol, water or mixture thereof;
b) isolating the crystalline form CC-8 of abrocitinib.
In another aspect, the present application provides pharmaceutical
compositions comprising crystalline form CC-1, CC-2, CC-3, CC-4, CC-5,
CC-6, CC-7 or CC-8 of abrocitinib and at least one pharmaceutically
acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline
form CC-1 of abrocitinib, prepared by the method of Example-1
Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline
form CC-2 of abrocitinib, prepared by the method of Example-2
Figure 3 is an illustrative X-ray powder diffraction pattern of crystalline
form CC-3 of abrocitinib, prepared by the method of Example-3
Figure 4 is an illustrative X-ray powder diffraction pattern of crystalline
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form CC-4 of abrocitinib, prepared by the method of Example-4
Figure 5 is an illustrative X-ray powder diffraction pattern of crystalline
form CC-5 of abrocitinib, prepared by the method of Example-5
Figure 6 is an illustrative X-ray powder diffraction pattern of crystalline
form CC-6 of abrocitinib, prepared by the method of Example-6
Figure 7 is an illustrative X-ray powder diffraction pattern of crystalline
form CC-7 of abrocitinib, prepared by the method of Example-7
Figure 8 is an illustrative X-ray powder diffraction pattern of crystalline
form CC-8 of abrocitinib, prepared by the method of Example-8
DETAILED DESCRIPTION
In an aspect, the present application provides a crystalline form CC-1 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about
10.3 and 20.9 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form
CC-1 of abrocitinib, further characterized by a PXRD pattern comprising the
peaks at about 27.4, and 27.9 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form CC-2 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about
11.4, 12.2, 16.6, 18.2 and 19.5 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form
CC-2 of abrocitinib, further characterized by a PXRD pattern comprising the
peaks at about 23.6 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form CC-3 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about
4.2, 6.2, 10.9, 12.0 and 13.8 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form
CC-3 of abrocitinib, further characterized by a PXRD pattern comprising the
peaks at about 29.4 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form CC-4 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about
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13.1, 15.0, 18.2 and 19.6 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form
CC-4 of abrocitinib, further characterized by a PXRD pattern comprising the
peaks at about 23.5, 24.4, 26.1 and 32.1 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form CC-5 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about
5.5, 6.6, 8.3, 18.2 and 18.9 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form
CC-5 of abrocitinib, further characterized by a PXRD pattern comprising the
peaks at about 21.1, 21.9, 22.4 and 29.1 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form CC-6 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about
8.1, 11.0, 12.1, 13.1, 13.8 and 14.1 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form
CC-6 of abrocitinib, further characterized by a PXRD pattern comprising the
peaks at about 21.9, 22.4 and 24.3 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form CC-7 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about
6.6, 8.0, 8.5, 10.0, 14.2, 19.0 and 19.8 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form
CC-7 of abrocitinib, further characterized by a PXRD pattern comprising the
peaks at about 14.3, 22.6 and 26.0 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form CC-8 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about
9.3, 11.0, 11.9, 15.2, 18.1 and 19.9 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form
CC-8 of abrocitinib, further characterized by a PXRD pattern comprising the
peaks at about 22.4, 23.4, 26.2, 27.7 and 28.3 ± 0.2° 2?.
In another aspect, the present application provides a process for the
preparation of crystalline Form CC-1 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib and
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Parahydroxybenzoic Acid in a solvent selected from methanol,
isopropyl alcohol, water or mixture thereof;
b) isolating the crystalline form CC-1 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form CC-2 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib and Fumaric
acid in a solvent selected from methanol, isopropyl alcohol,
water or mixture thereof;
b) isolating the crystalline form CC-2 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form CC-3 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib and gentisic
acid in a solvent selected from methanol, isopropyl alcohol,
water or mixture thereof;
b) isolating the crystalline form CC-3 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form CC-4 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib and
Acesulfame K in a solvent selected from methanol, isopropyl
alcohol, water or mixture thereof;
b) isolating the crystalline form CC-4 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form CC-5 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib and Aspartame
in a solvent selected from methanol, isopropyl alcohol, water or
mixture thereof;
b) isolating the crystalline form CC-5 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form CC-6 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib and Saccharin
in a solvent selected from methanol, isopropyl alcohol, water or
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mixture thereof;
b) isolating the crystalline form CC-6 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form CC-7 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib and
Naphthalenedisulfonic acid in a solvent selected from methanol,
isopropyl alcohol, water or mixture thereof;
b) isolating the crystalline form CC-7 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form CC-8 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib and 1-
Pentanesulfonic Acid in a solvent selected from methanol,
isopropyl alcohol, water or mixture thereof;
b) isolating the crystalline form CC-8 of abrocitinib.
Providing a solution or suspension of abrocitinib includes:
i) direct use of a reaction mixture containing abrocitinib that is
obtained in the course of its synthesis; or
ii) providing a solution suspension of abrocitinib in a solvent
Any physical form of abrocitinib including solvates, hydrates,
anhydrous or amorphous may be utilized for providing solution or suspension
of abrocitinib. In embodiments, abrocitinib can be suspended in a solvent or
mixture of one or more solvents. The suspension temperatures may range from
about 0°C to about the reflux temperature of the solvent, or less than about
60°C, less than about 50°C, less than about 40°C, less than about 30°C, less
than about 20°C, less than about 10°C, or any other suitable temperatures
without affecting its quality.
Isolation of crystalline form of abrocitinib may involve methods
including cooling, concentrating the mass, adding an anti-solvent, adding seed
crystals, or filtration at higher temperature or the like. Stirring or other
alternate methods such as shaking, agitation, or the like, may also be employed
for the isolation.
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The crystalline form of abrocitinib may be recovered by methods
including decantation, centrifugation, gravity filtration, suction filtration,
agitated nutsche filter & dryer or any other technique for the recovery of solid
under pressure or under reduced pressure. The recovered solid may optionally
be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven,
cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer,
flash dryer, agitated nutsche filter & dryer or the like.
The drying may be carried out at temperatures less than about 100°C,
less than about 80°C, less than about 60°C, less than about 50°C, less than
about 30°C, or any other suitable temperatures, at atmospheric pressure or
under a reduced pressure, as long as the abrocitinib is not degraded in quality.
The drying may be carried out for any desired times until the required product
quality is achieved.
The dried product may optionally be subjected to a size reduction
procedure to produce desired particle sizes. Milling or micronization may be
performed before drying, or after the completion of drying of the product.
Techniques that may be used for particle size reduction include, without
limitation, ball, roller and hammer milling, and jet milling.
In another aspect, the present application provides crystalline form of
abrocitinib according to instant application and pharmaceutical compositions
thereof, wherein the chemical purity of abrocitinib may be more than 99% by
HPLC or more than 99.5% by HPLC or more than 99.9% by HPLC.
In another aspect, the present application provides pharmaceutical
compositions comprising crystalline form CC-1, CC-2, CC-3, CC-4, CC-5,
CC-6, CC-7 or CC-8 of abrocitinib and at least one pharmaceutically
acceptable excipient.
One or more of the crystalline forms of present application may be
Abrocitinib and corresponding acid/compound co-crystal.
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
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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.
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 CC-1 of abrocitinib
Abrocitinib (100 mg) and Parahydroxybenzoic Acid (500 mg) and
mixture of methanol, isopropyl alcohol & DM Water (8 mL; 1:1:1) charged in
to round bottom flask and the resultant reaction mass was stirred for 15 days.
Solid was filtered and dried to afford the title compound.
XRPD: Crystalline form CC-1, as depicted in Figure-1.
Example-2: Preparation of crystalline form CC-2 of abrocitinib
Abrocitinib (100 mg) and Fumaric Acid (500 mg) and mixture of
methanol, isopropyl alcohol & DM Water (8 mL; 1:1:1) charged in to round
bottom flask and the resultant reaction mass was stirred for 15 days. Solid was
filtered and dried to afford the title compound.
XRPD: Crystalline form CC-2, as depicted in Figure-2.
Example-3: Preparation of crystalline form CC-3 of abrocitinib
Abrocitinib (100 mg) and Gentisic Acid (500 mg) and mixture of
methanol, isopropyl alcohol & DM Water (8 mL; 1:1:1) charged in to round
bottom flask and the resultant reaction mass was stirred for 15 days. Solid was
filtered and dried to afford the title compound.
XRPD: Crystalline form CC-3, as depicted in Figure-3.
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Example-4: Preparation of crystalline form CC-4 of abrocitinib
Abrocitinib (100 mg) and Acesulfame K (500 mg) and mixture of
methanol, isopropyl alcohol & DM Water (8 mL; 1:1:1) charged in to round
bottom flask and the resultant reaction mass was stirred for 15 days. Solid was
filtered and dried to afford the title compound.
XRPD: Crystalline form CC-4, as depicted in Figure-4.
Example-5: Preparation of crystalline form CC-5 of abrocitinib
Abrocitinib (100 mg) and Aspartame (500 mg) and mixture of
methanol, isopropyl alcohol & DM Water (8 mL; 1:1:1) charged in to round
bottom flask and the resultant reaction mass was stirred for 15 days. Solid was
filtered and dried to afford the title compound.
XRPD: Crystalline form CC-5, as depicted in Figure-5.
Example-6: Preparation of crystalline form CC-6 of abrocitinib
Abrocitinib (100 mg) and Saccharin (500 mg) and mixture of methanol,
isopropyl alcohol & DM Water (8 mL; 1:1:1) charged in to round bottom flask
and the resultant reaction mass was stirred for 15 days. Solid was filtered and
dried to afford the title compound.
XRPD: Crystalline form CC-6, as depicted in Figure-6.
Example-7: Preparation of crystalline form CC-7 of abrocitinib
Abrocitinib (100 mg) and 1,5-Naphthalenedisulfonic Acid (500 mg)
and mixture of methanol, isopropyl alcohol & DM Water (8 mL; 1:1:1)
charged in to round bottom flask and the resultant reaction mass was stirred for
15 days. Solid was filtered and dried to afford the title compound.
XRPD: Crystalline form CC-7, as depicted in Figure-7.
Example-8: Preparation of crystalline form CC-8 of abrocitinib
Abrocitinib (100 mg) and 1-Pentanesulfonic Acid (500 mg) and mixture
of methanol, isopropyl alcohol & DM Water (8 mL; 1:1:1) charged in to round
bottom flask and the resultant reaction mass was stirred for 15 days. Solid was
filtered and dried to afford the title compound.
XRPD: Crystalline form CC-8, as depicted in Figure-8. ,CLAIMS:1. A pharmaceutical composition comprising abrocitinib co-crystal selected
from Parahydroxybenzoic Acid, Fumaric Acid, Gentisic Acid, Acesulfame
K, Aspartame, Saccharin, Naphthalenedisulfonic Acid, 1-Pentanesulfonic
Acid.
2. Co-crystal according to claim 1, wherein co-crystal is crystalline form
CC-1 of abrocitinib, characterized by a PXRD pattern comprising the
peaks at about 10.3 and 20.9 ± 0.2° 2?.
3. Co-crystal according to claim 1, wherein co-crystal is crystalline form
CC-2 of abrocitinib, characterized by a PXRD pattern comprising the
peaks at about 11.4, 12.2, 16.6, 18.2 and 19.5 ± 0.2° 2?.
4. Co-crystal according to claim 1, wherein co-crystal is crystalline form
CC-3 of abrocitinib, characterized by a PXRD pattern comprising the
peaks at about 4.2, 6.2, 10.9, 12.0 and 13.8 ± 0.2° 2?.
5. Co-crystal according to claim 1, wherein co-crystal is crystalline form
CC-4 of abrocitinib, characterized by a PXRD pattern comprising the
peaks at about 13.1, 15.0, 18.2 and 19.6 ± 0.2° 2?.
6. Co-crystal according to claim 1, wherein co-crystal is crystalline form
CC-5 of abrocitinib, characterized by a PXRD pattern comprising the
peaks at about 5.5, 6.6, 8.3, 18.2 and 18.9 ± 0.2° 2?.
7. Co-crystal according to claim 1, wherein co-crystal is crystalline form
CC-6 of abrocitinib, characterized by a PXRD pattern comprising the
peaks at about 8.1, 11.0, 12.1, 13.1, 13.8 and 14.1 ± 0.2° 2?.
8. Co-crystal according to claim 1, wherein co-crystal is crystalline form
CC-7 of abrocitinib, characterized by a PXRD pattern comprising the
peaks at about 6.6, 8.0, 8.5, 10.0, 14.2, 19.0 and 19.8 ± 0.2° 2?.
9. Co-crystal according to claim 1, wherein co-crystal is crystalline form
CC-8 of abrocitinib, characterized by a PXRD pattern comprising the
peaks at about 9.3, 11.0, 11.9, 15.2, 18.1 and 19.9 ± 0.2° 2?.