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, amorphous form and amorphous solid dispersion of 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
3
pharmaceutically useful compound may provide an opportunity to improve the
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.
Amorphous solid dispersions of drugs are generally known to improve the
stability and solubility of drug products. However, such dispersions are generally
unstable over time. Amorphous solid dispersions of drugs tend to convert to
crystalline forms over time, which can lead to improper dosing due to differences of
the solubility of crystalline drug material compared to amorphous drug material. The
present invention, however provides stable amorphous solid dispersions of
abrocitinib. Moreover, the present invention provides solid dispersions of abrocitinib
which may be reproduced easily and is amenable for processing into a dosage form.
SUMMARY
In an aspect, the present application provides a crystalline form RT-1 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about 13.7,
16.9, 21.0 and 23.5 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form RT-1
of abrocitinib, further characterized by a PXRD pattern comprising the peaks at
about 9.9, 11.4, 22.3 and 27.7 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form RT-2 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about 7.4,
13.8, 20.1 and 27.9 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form RT-2
4
of abrocitinib, further characterized by a PXRD pattern comprising the peaks at
about 10.3, 17.1, 22.7 and 23.9 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form RT-3 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about 9.4,
10.4, 31.0 and 38.3 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form RT-3
of abrocitinib, further characterized by a PXRD pattern comprising the peaks at
about 17.0, and 23.7 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form RT-4 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about 6.0,
8.0, 9.2 and 12.1 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form RT-4
of abrocitinib, further characterized by a PXRD pattern comprising the peaks at
about 24.6, and 26.3 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form RT-5 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about 5.0,
8.1 and 19.8 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form RT-5
of abrocitinib, further characterized by a PXRD pattern comprising the peaks at
about 27.9, and 31.3 ± 0.2° 2?.
In an aspect, the present application provides a pharmaceutical composition
comprising amorphous form of abrocitinib and one or more pharmaceutically
acceptable excipients.
In an aspect, the present application provides a solid dispersion comprising
amorphous form of abrocitinib and one or more pharmaceutically acceptable carriers.
In another aspect, the present application provides a process for the
preparation of crystalline Form RT-1 of abrocitinib, comprising
a) suspending abrocitinib in ethyl acetoacetate;
b) optionally heating the slurry obtained in step (a); and
c) isolating the crystalline form RT-1 of abrocitinib.
In another aspect, the present application provides pharmaceutical
5
compositions comprising crystalline form RT-1 of abrocitinib and at least one
pharmaceutically acceptable excipient.
In another aspect, the present application provides a process for the
preparation of crystalline Form RT-2 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib in acetone;
b) Adding acid followed by base to the slurry obtained in step (a); and
c) isolating the crystalline form RT-2 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form RT-2 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib in acetone;
b) optionally adding acid followed by base to the slurry obtained in
step (a); and
c) isolating the crystalline form RT-2 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form RT-3 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib in formic acid;
b) adding solution or suspension obtained in step (a) to methyl tertbutyl
ether or adding methyl tert-butyl ether to solution or
suspension obtained in step (a); and
c) isolating the crystalline form RT-3 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form RT-4 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib in hexanoic acid;
b) adding solution or suspension obtained in step (a) to methyl tertbutyl
ether or adding methyl tert-butyl ether to solution or
suspension obtained in step (a); and
c) isolating the crystalline form RT-4 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form RT-5 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib in propionic acid;
b) adding solution or suspension obtained in step (a) to methyl tert6
butyl ether or adding methyl tert-butyl ether to solution or
suspension obtained in step (a); and
c) isolating the crystalline form RT-5 of abrocitinib.
In an aspect, the present application provides a method for preparing a solid
dispersion comprising amorphous abrocitinib and one or more pharmaceutically
acceptable carriers comprising the steps of:
a) providing a mixture of abrocitinib and one or more pharmaceutically
acceptable carriers in a solvent; and
b) isolating solid dispersion comprising amorphous abrocitinib and one or
more pharmaceutically acceptable carriers.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline
form RT-1 of abrocitinib, prepared by the method of Example-1.
Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline
form RT-2 of abrocitinib, prepared by the method of Example-2 and 3
Figure 3 is an illustrative X-ray powder diffraction pattern of crystalline
form RT-3 of abrocitinib, prepared by the method of Example-4
Figure 4 is an illustrative X-ray powder diffraction pattern of crystalline
form RT-4 of abrocitinib, prepared by the method of Example-5
Figure 5 is an illustrative X-ray powder diffraction pattern of crystalline
form RT-5 of abrocitinib, prepared by the method of Example-6
Figure 6 is an illustrative X-ray powder diffraction pattern of Abrocitinib
present in amorphous solid dispersion according to example 7.
Figure 7 is an illustrative X-ray powder diffraction pattern of Abrocitinib
present in amorphous solid dispersion according to example 8.
Figure 8 is an illustrative X-ray powder diffraction pattern of Abrocitinib
present in amorphous solid dispersion according to example 9.
Figure 9 is an illustrative X-ray powder diffraction pattern of Abrocitinib
present in amorphous solid dispersion according to example 10
Figure 10 is an illustrative X-ray powder diffraction pattern of Abrocitinib
present in amorphous solid dispersion according to example 11
7
Figure 11 is an illustrative X-ray powder diffraction pattern of Abrocitinib
present in amorphous solid dispersion according to example 12
DETAILED DESCRIPTION
In an aspect, the present application provides a crystalline form RT-1 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about 13.7,
16.9, 21.0 and 23.5 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form RT-1
of abrocitinib, further characterized by a PXRD pattern comprising the peaks at
about 9.9, 11.4, 22.3 and 27.7 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form RT-2 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about 7.4,
13.8, 20.1 and 27.9 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form RT-2
of abrocitinib, further characterized by a PXRD pattern comprising the peaks at
about 10.3, 17.1, 22.7 and 23.9 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form RT-3 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about 9.4,
10.4, 31.0 and 38.3 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form RT-3
of abrocitinib, further characterized by a PXRD pattern comprising the peaks at
about 17.0, and 23.7 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form RT-4 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about 6.0,
8.0, 9.2 and 12.1 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form RT-4
of abrocitinib, further characterized by a PXRD pattern comprising the peaks at
about 24.6, and 26.3 ± 0.2° 2?.
In an aspect, the present application provides a crystalline form RT-5 of
abrocitinib, characterized by a PXRD pattern comprising the peaks at about 5.0,
8.1 and 19.8 ± 0.2° 2?.
In another aspect, the present application provides a crystalline form RT-5
8
of abrocitinib, further characterized by a PXRD pattern comprising the peaks at
about 27.9, and 31.3 ± 0.2° 2?.
In an aspect, the present application provides a pharmaceutical composition
comprising amorphous form of abrocitinib and one or more pharmaceutically
acceptable excipients.
In an aspect, the present application provides a solid dispersion comprising
amorphous form of abrocitinib and one or more pharmaceutically acceptable carriers.
Solid dispersion as used herein refers to the dispersion of one or more active
ingredients in an inert excipient or polymer or carrier, where the active ingredients
could exist in finely crystalline, solubilized or amorphous state (Sareen et al., 2012
and Kapoor et al., 2012). Solid dispersion consists of two or more components,
generally a polymer or carrier and drug optionally along with stabilizing agent
(and/or surfactant or other additives). The most important role of the added polymer
or carrier or excipient in solid dispersion is to reduce the molecular mobility of the
drug to avoid the phase separation and re-crystallization of drug during storage. The
resulting solid dispersions may have increased solubility. The increase in solubility
of the drug in solid dispersion is mainly because drug remains in amorphous form
which is associated with a higher energy state as compared to crystalline counterpart
and due to that it requires very less external energy to dissolve.
A solid dispersion is a molecular dispersion of a compound, particularly a
drug substance within a polymer or carrier. Formation of a molecular dispersion
provides a means of reducing the particle size to nearly molecular levels (i.e. there
are no particles). As the carrier dissolves, the drug is exposed to the dissolution
media as fine particles that are amorphous, which can dissolve and be absorbed more
rapidly than larger particles.
In general, the term "solid dispersion" refers to a system in a solid state
comprising at least two components, wherein one component is dispersed throughout
the other component or components. The term "solid dispersion" as used herein,
refers to stable solid dispersions comprising amorphous drug substance and one or
more polymers or carriers. Further the term "solid dispersion" as used herein also
refers to stable solid dispersions comprising amorphous drug substance and one or
9
more polymers or carriers with or without adsorbent/absorbent. By "amorphous drug
substance," it is meant that the amorphous solid contains drug substance in a
substantially amorphous solid state form i.e. at least about 80% of the drug substance
in the dispersion is in an amorphous form. More preferably at least about 90% and
most preferably at least about 95% of the drug substance in the dispersion is in
amorphous form.
The solid dispersion of abrocitinib of the present invention can be made by
any of the numerous methods that result in a solid dispersion comprising amorphous
abrocitinib. Several approaches can be used for the preparation of solid dispersion
which includes spray drying, lyophilization, fusion method, solvent evaporation, hotmelt
extrusion, ball milling, particle size reduction, supercritical fluid (SCF)
processes, kneading, inclusion complexes, electrostatic spinning method, melt
crystallization and surface-active carriers.
Abrocitinib can be incorporated in the dispersion in amorphous state.
The dispersing agent is typically composed of a pharmaceutically acceptable
substance that does not substantially interfere with the pharmaceutical action of
Abrocitinib. The phrase "pharmaceutically acceptable" is employed herein to refer to
those substances which are, within the scope of sound medical judgment, suitable for
use in contact with the tissues of human beings and animals without excessive
toxicity, irritation, allergic response, or other problem or complication,
commensurate with a reasonable benefit/risk ratio. In some embodiments, the carrier
is a solid at room temperature.
Non-limiting examples of suitable polymers or excipients or
pharmaceutically acceptable carriers are celluloses (e.g., carboxymethylcelluloses,
methylcelluloses, hydroxypropylcelluloses, hydroxypropylmethylcelluloses);
polysaccharides, heteropolysaccharides (pectins); poloxamers; poloxamines;
ethylene vinyl acetates; polyethylene glycols; dextrans; polyvinylpyrrolidones;
chitosans; polyvinylalcohols; propylene glycols; polyvinylacetates;
phosphatidylcholines (lecithins); miglyols; polylactic acid; polyhydroxybutyric acid;
mixtures of two or more thereof, copolymers thereof, derivatives thereof, and the
like. Further examples of carriers include copolymer systems such as polyethylene
10
glycol-polylactic acid (PEG-PLA), polyethylene glycol-polyhydroxybutyric acid
(PEG-PHB), polyvinylpyrrolidone-polyvinylalcohol (PVP-PVA), and derivatized
copolymers such as copolymers of N-vinyl purine (or pyrimidine) derivatives and Nvinylpyrrolidone.
An enteric coating polymer can also be used according to the present
invention. Specific examples of the enteric coating polymers include cellulose
acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate,
hydroxymethylcellulose ethyl phthalate, hydroxypropylmethylcellulose phthalate,
eudragit, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethyl
acetate maleate, hydroxypropylmethyl trimellitate, carboxymethylethylcellulose,
polyvinyl butyrate phthalate, polyvinyl alcohol acetate phthalate, methacrylic
acid/ethyl acrylate copolymer, and methacrylic acid/methyl methacrylate copolymer,
hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate
succinate (HPMCAS), hydroxypropylmethyl acetate maleate and
hydroxypropylmethyl trimellitate.
In another aspect, the present application provides a process for the
preparation of crystalline Form RT-1 of abrocitinib, comprising
a) suspending abrocitinib in ethyl acetoacetate;
b) optionally heating the slurry obtained in step (a); and
c) isolating the crystalline form RT-1 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form RT-2 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib in acetone;
b) Adding acid followed by base to the slurry obtained in step (a); and
c) isolating the crystalline form RT-2 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form RT-2 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib in acetone;
b) optionally adding acid followed by base to the slurry obtained in
step (a); and
c) isolating the crystalline form RT-2 of abrocitinib.
11
In another aspect, the present application provides a process for the
preparation of crystalline Form RT-3 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib in formic acid;
b) adding solution or suspension obtained in step (a) to methyl tertbutyl
ether or adding methyl tert-butyl ether to solution or
suspension obtained in step (a); and
c) isolating the crystalline form RT-3 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form RT-4 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib in hexanoic acid;
b) adding solution or suspension obtained in step (a) to methyl tertbutyl
ether or adding methyl tert-butyl ether to solution or
suspension obtained in step (a); and
c) isolating the crystalline form RT-4 of abrocitinib.
In another aspect, the present application provides a process for the
preparation of crystalline Form RT-5 of abrocitinib, comprising
a) providing a solution or suspension of abrocitinib in propionic acid;
b) adding solution or suspension obtained in step (a) to methyl tertbutyl
ether or adding methyl tert-butyl ether to solution or
suspension obtained in step (a); and
c) isolating the crystalline form RT-5 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 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 90°C, less than about
70°C, less than about 40°C, less than about 30°C, less than about 20°C, less than
12
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.
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 an aspect, the present application provides a method for preparing a solid
dispersion comprising amorphous abrocitinib and one or more pharmaceutically
acceptable carriers comprising the steps of:
a) providing a mixture of abrocitinib and one or more pharmaceutically
acceptable carriers in a solvent; and
b) isolating solid dispersion comprising amorphous abrocitinib and one or
more pharmaceutically acceptable carriers.
Step (a) involves providing a mixture of abrocitinib and one or more
13
pharmaceutically acceptable carriers in a solvent;
Any physical form of abrocitinib may be utilized for providing the
mixture of Abrocitinib in step (a).
Suitable solvent which can be used for preparing the solid dispersion of
abrocitinib are the same as described in step (a) include water, alcohols or ketone
solvents or mixture thereof.
Any undissolved particles in the solution obtained in step (a) may be removed
by suitable method as described herein above or any other technique known in the
art.
Step (b) involves isolation of solid dispersion comprising amorphous
Abrocitinib and one or more pharmaceutically acceptable carriers.
Isolation of solid dispersion in step (b) may be carried out by removing
solvent from a solution or suspension or mixture obtained in step (a). Suitable
techniques which can be used for the removal of solvent are the same as described in
step (b) of third embodiment or any other technique known in the art.
The solid dispersions of the present invention are prepared using
conventional spray drying techniques, vacuum drying, fluid-bed drying, freezedrying,
rotary evaporation, rotary vacuum paddle dryer, drum drying, or other
solvent removal process known in the art.
Another aspect of the invention involves preparation of solid dispersions of
abrocitinib by melt processing, wherein the compound and a carrier are heated to a
temperature above the melting point of both the carrier and compound, which results
in the formation of a fine colloidal (as opposed to molecular) dispersion of
compound particles, with some solubilization of the compound in the carrier matrix.
Processing of such a molten mixture often includes rapid cooling, which results in
the formation of a congealed mass which must be subsequently milled to produce a
powder which can be filled into capsules or made into tablets.
The resulting solid dispersion comprising an amorphous form of abrocitinib
and one or more pharmaceutically acceptable polymers or carriers may be optionally
further dried. Drying can be carried out by methods as described in step (b) of third
embodiment herein above or any other technique known in the art.
14
The amount of Abrocitinib in the solid dispersions of the present invention
ranges from about 0.1% to about 90% by weight of the solid dispersion; or from
about 10% to about 70% by weight of the solid dispersion; or from about 20% to
about 60% by weight of the solid dispersion; or from about 20% to about 40% by
weight of the solid dispersion; or about 30% by weight of the solid dispersion. In
some aspects, the weight ratio of abrocitinib to polymer or carrier is about 1:99 to
about 99:1. In some aspects, the weight ratio of abrocitinib to polymer or carrier is
about 1:99 to about 75:25 or about 1:99 to about 60: 40. In further aspects, the
weight ratio of abrocitinib to polymer or carrier is about 1:99 to about 15:85; about
1:99 to about 10:90; or about 1:99 to about 5:95. In further aspects, the weight ratio
of abrocitinib to polymer or carrier is about 25:75 to about 75:25, about 40:60 to
about 60:40 or about 1:1 or about 2:1.
Amorphous form or the solid dispersions of abrocitinib of the present
application can be optionally subjected to particle size reduction procedures before or
after the completion of drying of the product to produce desired particle sizes and
distributions. Milling or micronization can be performed to achieve the desired
particle sizes or distributions. Equipment that may be used for particle size reduction
include, without limitation thereto, ball mills, roller mills, hammer mills, and jet
mills.
In an aspect, the present application provides pharmaceutical formulations
comprising an amorphous form of abrocitinib or solid dispersion comprising
amorphous form of Abrocitinib, together with one or more pharmaceutically
acceptable carriers.
Abrocitinib which may be used as the input in the process for preparation of
the solid states of the present application can be prepared by any process known in
the art.
In another aspect, the present application provides crystalline form of
abrocitinib or amorphous form or amorphous solid dispersion 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.
15
In another aspect, the present application provides pharmaceutical
compositions comprising crystalline form RT-1, RT-2, RT-3, RT-4 and RT-5 of
abrocitinib and at least one pharmaceutically acceptable excipient.
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.
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 RT-1 of abrocitinib
Abrocitinib (2 g) and ethyl acetoacetate (40 mL) charged in to round
bottom flask, heated to 60 ° C and the resulting slurry was stirred at 60° C for 24
hours. Solid was filtered and dried at 100 °C for 3 hours to afford the title
compound.
XRPD: Crystalline form RT-1, as depicted in Figure-1.
Example-2: Preparation of crystalline form RT-2 of abrocitinib
Abrocitinib (1 g) and acetone (20 mL) charged in to round bottom flask
and stirred for 10 minutes. Con. Sulfuric acid solution (0.1 mL in 10 mL acetone)
was slowly added to the reaction mass at 25 °C and stirred for 20 minutes.
Triethylamine solution (0.3 mL in 10 mL acetone) was slowly added to the
reaction mass and the resulting slurry was stirred at 25° C for 1 hour. Solid was
filtered and dried at 100 °C for 3 hours to afford the title compound.
16
XRPD: Crystalline form RT-2, as depicted in Figure-2.
Example-3: Preparation of crystalline form RT-2 of abrocitinib
Abrocitinib (100 mg) and acetone (2 mL) charged in to round bottom flask
and stirred for 10 minutes. Con. Sulfuric acid (32 µL) was slowly added to the
reaction mass at 25 °C and stirred for 10 minutes. Conc. ammonia (50 µL) was
slowly added to the reaction mass and the resulting slurry was stirred at 25° C for
1 hour 30 minutes. Solid was filtered and dried to afford the title compound.
XRPD: Crystalline form RT-2, as depicted in Figure-2.
Example-4: Preparation of crystalline form RT-3 of abrocitinib
Abrocitinib (1 g) and formic acid (5 mL) charged in to round bottom flask
and stirred for 10 minutes. The resultant clear solution was slowly added to precooled
methyl tert-butyl ether solution (15 mL) at -50 °C and stirred for 2 hours.
Solid was filtered and dried to afford the title compound.
XRPD: Crystalline form RT-3, as depicted in Figure-3.
Example-5: Preparation of crystalline form RT-4 of abrocitinib
Abrocitinib (1 g) and hexanoic acid (5 mL) charged in to round bottom
flask and stirred for 10 minutes. The resultant clear solution was slowly added to
pre-cooled methyl tert-butyl ether solution (15 mL) at -50 °C and stirred for 2
hours. Solid was filtered and dried to afford the title compound.
XRPD: Crystalline form RT-4, as depicted in Figure-4.
Example-6: Preparation of crystalline form RT-5 of abrocitinib
Abrocitinib (1 g) and propionic acid (4 mL) charged in to round bottom
flask and stirred for 10 minutes. The resultant clear solution was slowly added to
pre-cooled methyl tert-butyl ether solution (15 mL) at -50 °C and stirred for 2
hours. Solid was filtered and dried to afford the title compound.
XRPD: Crystalline form RT-5, as depicted in Figure-5.
Example-7: Preparation of abrocitinib solid dispersion with
hydroxypropylmethylcellulose acetate succinate (HPMCAS)
Abrocitinib (1.25 g), HPMCAS (3.75 g), mixture of methanol & acetone
(200 mL; 1:1) and water (20 mL) charged into flask. Reaction mass was heated to
50 °C and stirred at 50 °C for 25 minutes. Filtered the reaction mass and the
17
filtrate was subjected to spray drying to afford title compound. (Spray dryer was
operated at inlet temp of 70 °C, Flow rate of 8 gm/min, nozzle pressure of 2 Bar,
Inlet pressure of 0.4 Bar).
The Powder X-ray diffraction (PXRD) pattern of abrocitinib solid dispersion
obtained in above example is in accordance with Figure 6.
Example-8: Preparation of abrocitinib solid dispersion with
hydroxypropylmethylcellulose acetate succinate (HPMCAS)
Abrocitinib (1.67 g), HPMCAS (3.33 g), mixture of methanol & acetone
(200 mL; 1:1) and water (20 mL) charged into flask. Reaction mass was heated to
50 °C and stirred at 50 °C for 20 minutes. Filtered the reaction mass and the
filtrate was subjected to spray drying to afford title compound. (Spray dryer was
operated at inlet temp of 70 °C, Flow rate of 8 gm/min, nozzle pressure of 2 Bar,
Inlet pressure of 0.4 Bar).
The Powder X-ray diffraction (PXRD) pattern of abrocitinib solid dispersion
obtained in above example is in accordance with Figure 7.
Example-9: Preparation of abrocitinib solid dispersion with
hydroxypropylmethylcellulose acetate succinate (HPMCAS)
Abrocitinib (2.5 g), HPMCAS (2.5 g), mixture of methanol & acetone
(200 mL; 1:1) and water (20 mL) charged into flask. Reaction mass was heated to
50 °C and stirred at 50 °C for 20 minutes. Filtered the reaction mass and the
filtrate was subjected to spray drying to afford title compound. (Spray dryer was
operated at inlet temp of 70 °C, Flow rate of 8 gm/min, nozzle pressure of 2 Bar,
Inlet pressure of 0.4 Bar).
The Powder X-ray diffraction (PXRD) pattern of abrocitinib solid dispersion
obtained in above example is in accordance with Figure 8.
Example-10: Preparation of abrocitinib solid dispersion with Eudragit L100
Abrocitinib (1.25 g), Eudragit L100 (3.75 g), mixture of methanol &
acetone (200 mL; 1:1) and water (20 mL) charged into flask. Reaction mass was
heated to 50 °C and stirred at 50 °C for 25 minutes. Filtered the reaction mass and
the filtrate was subjected to spray drying to afford title compound. (Spray dryer
was operated at inlet temp of 70 °C, Flow rate of 8 gm/min, nozzle pressure of 2
18
Bar, Inlet pressure of 0.4 Bar).
The Powder X-ray diffraction (PXRD) pattern of abrocitinib solid dispersion
obtained in above example is in accordance with Figure 9.
Example-11: Preparation of abrocitinib solid dispersion with Eudragit L100
Abrocitinib (1.67 g), Eudragit L100 (3.33 g), mixture of methanol &
acetone (200 mL; 1:1) and water (20 mL) charged into flask. Reaction mass was
heated to 50 °C and stirred at 50 °C for 25 minutes. Filtered the reaction mass and
the filtrate was subjected to spray drying to afford title compound. (Spray dryer
was operated at inlet temp of 70 °C, Flow rate of 8 gm/min, nozzle pressure of 2
Bar, Inlet pressure of 0.4 Bar).
The Powder X-ray diffraction (PXRD) pattern of abrocitinib solid dispersion
obtained in above example is in accordance with Figure 10.
Example-12: Preparation of abrocitinib solid dispersion with Eudragit L100
Abrocitinib (2.5 g), Eudragit L100 (2.5 g), mixture of methanol & acetone
(200 mL; 1:1) and water (20 mL) charged into flask. Reaction mass was heated to
50 °C and stirred at 50 °C for 20 minutes. Filtered the reaction mass and the
filtrate was subjected to spray drying to afford title compound. (Spray dryer was
operated at inlet temp of 70 °C, Flow rate of 8 gm/min, nozzle pressure of 2 Bar,
Inlet pressure of 0.4 Bar).
The Powder X-ray diffraction (PXRD) pattern of abrocitinib solid dispersion
obtained in above example is in accordance with Figure 11.
Dated: 10th of August 2023.
Signature: _________________
Dr. B. Dinesh Kumar.
Intellectual Property Management,
Dr. Reddy’s Laboratories Limited. ,CLAIMS:1. A pharmaceutical composition comprising amorphous form of abrocitinib
and one or more pharmaceutically acceptable excipients.
2. A solid dispersion comprising amorphous form of abrocitinib and one or
more pharmaceutically acceptable carriers.
3. A solid dispersion according to claim 2, wherein the pharmaceutically
acceptable carrier is hydroxypropylmethylcellulose acetate succinate
(HPMCAS) or Eudragit L100
4. A method for preparing a solid dispersion comprising amorphous abrocitinib
and one or more pharmaceutically acceptable carriers comprising the steps of:
a) providing a mixture of abrocitinib and one or more pharmaceutically
acceptable carriers in a solvent; and
b) isolating solid dispersion comprising amorphous abrocitinib and one or
more pharmaceutically acceptable carriers.
5. A method according to claim 3, wherein solvent is selected from water,
alcohols or ketone solvents or mixture thereof