FIELD OF THE INVENTION
The present invention provides solid forms comprising solid dispersion of 1-[3-
(aminomethyl) phenyl]-N-(5-{(R)-(3-cyanophenyl) [(cyclopropyl methyl) amino]
methyl}-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide
bishydrochloride and process for its preparation thereof. The compound of formula The present invention also provides premix of compound of formula (1) and process
for its preparation.
The present invention further provides process for the preparation of amorphous
form of compound of formula (1).
BACKGROUND OF THE INVENTION
1-[3-(aminomethyl)phenyl]-N-(5-{(R)-(3-cyanophenyl) [(cyclopropyl methyl)
amino] methyl}-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide
bishydrochloride (1) is commonly known as Berotralstat bishydrochloride and it is
a plasma kallikrein inhibitor, indicated for prophylaxis to prevent attacks of
hereditary angioedema (HAE) in adults and pediatric patients 12 years of age and
older. Berotralstat bishydrochloride is approved by United States Federal Drug
Administration (USFDA) on Dec 3, 2020, to Biocryst Pharmaceuticals Inc under
the brand name ORLADEYO™. It is available in EQ 110 mg & 150 mg oral
Capsule. Maximum dosage for prophylaxis is 150 mg.
US Patent No. 10,125,102 B2 (herein after referred as US ‘102) first discloses
Berotralstat bishydrochloride (1) and process of preparation thereof. US’102 further
discloses Berotralstat bishydrochloride (1) obtained as white solid.
US Patent No.10,662,160 B2 (herein after referred as US ‘160) discloses crystalline
form of Berotralstat bishydrochloride (1) and process of preparation thereof.
International PCT publication WO 2021/025969 A1 discloses crystalline form B1,
B2, B3, B4 of Berotralstat bishydrochloride (1) and process of preparation thereof.
Further, WO’969 discloses process for the preparation of amorphous form of
Berotralstat bishydrochloride (1).
Still, there is a significant need in the art to develop novel polymorphic form of the
said compound which is stable and has advantageous physical properties such as
free flowability, greater stability and greater bioavailability.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an amorphous solid
dispersion comprising Berotralstat bishydrochloride (1) and at least one
pharmaceutically acceptable excipient.
In another objective of the present invention is to provide a process for the
preparation of amorphous solid dispersion comprising Berotralstat bishydrochloride
(1) and at least one pharmaceutically acceptable excipient.
In another objective of the present invention is to provide premix comprising
Berotralstat bishydrochloride (1) and at least one pharmaceutically acceptable
excipient.
In yet another objective of the present invention is to provide a process for the
preparation of premix comprising Berotralstat bishydrochloride (1) and at least one
pharmaceutically acceptable excipient.
In further objective of the present invention is to provide a process for the
preparation of amorphous form of Berotralstat bishydrochloride (1).
SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide amorphous solid dispersion
comprising Berotralstat bishydrochloride (1) and at least one pharmaceutically
acceptable excipient.
In another aspect of the present invention is to provide a process for the preparation
of amorphous solid dispersion comprising Berotralstat bishydrochloride (1) and at
least one excipient, which comprising of:
a) dissolving Berotralstat bishydrochloride (1) and at least one excipient in one or
more solvent at a suitable temperature; and
b) removing the solvent from the reaction mixture and drying to provide amorphous
solid dispersion comprising Berotralstat bishydrochloride (1) and excipient.
In another aspect of the present invention is to provide a process for the preparation
of amorphous solid dispersion comprising Berotralstat bishydrochloride (1) and at
least one excipient, which comprising of:
i. dissolving Berotralstat bishydrochloride (1) in one or more solvents at a suitable
temperature.
ii. adding at least one excipient to step a); and
iii. removing the solvent from the reaction mixture and drying to provide amorphous
solid dispersion comprising Berotralstat bishydrochloride (1) and excipient.
In another aspect of the present invention is to provide a process for the preparation
of amorphous solid dispersion comprising Berotralstat bishydrochloride (1) and at
least one excipient, which comprising of:
I. heating Berotralstat bishydrochloride (1) in presence of at least one
pharmaceutically acceptable excipient to get a solution;
II. cooling the solution; and
III. isolating to get solid dispersion of Berotralstat bishydrochloride (1).
In another aspect of the present invention is to provide a premix comprising
Berotralstat bishydrochloride (1) and at least one pharmaceutically acceptable
excipient.
In another aspect the present invention is to provide a process for the preparation of
premix comprising Berotralstat bishydrochloride (1) and at least one excipient,
which comprising of:
A. adding Berotralstat bishydrochloride (1) to at least one excipient to get a solid
mass;
B. optionally adding one or more solvent to get a solution; and
C. removing the solvent from the solution and drying to provide premix comprising
Berotralstat bishydrochloride (1) and excipient.
In another aspect of the present invention is to provide a process for the preparation
of amorphous form of Berotralstat bishydrochloride (1), which comprising of:
a) dissolving Berotralstat bishydrochloride (1) in one or more solvent; and
b) isolating the amorphous form of Berotralstat bishydrochloride (1).
In another aspect of the present invention is to provide a process for the preparation
of amorphous form of Berotralstat bishydrochloride (1), which comprising of:
a) dissolving Berotralstat bishydrochloride (1) in one or more solvent;
b) lyophilizing the solution obtained in step a); and
c) isolating the amorphous form of Berotralstat bishydrochloride (1).
In another aspect of the present invention is to provide process for the preparation
of amorphous Berotralstat bishydrochloride (1), which comprising of:
a) milling/grinding Berotralstat bishydrochloride (1) under suitable milling
conditions; and
b) isolating the amorphous form of Berotralstat bishydrochloride (1).
In another, the present invention provides solid forms of Berotralstat
bishydrochloride (1) is having chemical purity greater than 99% by HPLC,
preferably greater than 99.5% by HPLC, more preferably greater than 99.9% by
HPLC.
DETAILED DESCRIPTION OF THE INVENTION
The main embodiment of the present invention is to provide amorphous solid
dispersion comprising Berotralstat bishydrochloride (1) and at least one
pharmaceutically acceptable excipient.
In general, the excipient is selected from but not limited to polyvinylpyrrolidone,
(povidone or PVP; PVP of different grades like K-IS, K-30, K-60, K-90 and K-120
may be used), polyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl
pyrrolidone (crospovidone), Eudragit, polyethylene glycol (macrogol or PEG),
polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose,
cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC,
its sodium and calcium salts), carboxymethyl ethyl cellulose (CMEC), ethyl
cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethyl
cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate
succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC),
hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxyethyl methyl
cellulose succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPCAS),
hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl
methylcellulose acetate phthalate, microcrystalline cellulose (MCC), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium
carboxymethyl cellulose, magnesium stearate, aluminum stearate, calcium stearate,
magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates,
dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol,
maltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate,
starches such as maize starch or corn starch, sodium starch glycolate, sodium
carboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate
disodium, .sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium
phosphate, polydextrose, α,β,γ-cyclodextrins, sulfo butyl ether beta-cyclodextrin,
sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene
glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl
behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl
acetate phthalates and the like.
The amorphous solid dispersion of the present invention is stable at room
temperature under normal stability conditions and does not convert to any other
solid-state form.
In another embodiment of the present invention is to provide a process for the
preparation of amorphous solid dispersion comprising Berotralstat bishydrochloride
(1) and at least one, excipient, which comprising of:
a) dissolving Berotralstat bishydrochloride (1) and at least one excipient in one or
more solvent at a suitable temperature; and
b) removing the solvent from the reaction mixture and drying to provide amorphous
solid dispersion comprising Berotralstat bishydrochloride (1) and excipient.
wherein, in step-a) the suitable excipient is same as defined above in the main
embodiment.
After dissolving Berotralstat bishydrochloride (1) and excipient in the solvent
system, the solution may optionally be treated with charcoal or any other suitable
material to remove color and/or to clarify the solution.
In step-b) suitable techniques which may be used for the removal of solvent from
the reaction mixture includes but not limited to evaporation, evaporation under
reduced pressure, flash evaporation, vacuum drying, concentrating the reaction
mixture, atmospheric distillation, vacuum distillation, distillation by using a
rotational distillation device such as a Buchi Rotavapor, agitated thin film drying,
melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying,
addition of suitable anti-solvent to the reaction mixture followed by filtration of the
precipitated solid, cooling the clear solution to lower temperatures to precipitate the
solid followed by filtration of the reaction or by any other suitable techniques known
in the art.
The solvent may be removed optionally under reduced pressures, at temperatures
less than about 130°C, less than about 60°C, less than about 40°C, less than about
20°C, less than about 0°C, less than about -20°C, less than about -40°C or less than
about -60°C.
The amorphous solid dispersion of Berotralstat bishydrochloride (1) of the present
invention can be further micronized or milled to achieve desired particle size
distribution to make suitable formulation.
In another embodiment of the present invention is to provide process for the
preparation of amorphous solid dispersion comprising Berotralstat bishydrochloride
(1) and at least one excipient, which comprising of:
i. dissolving Berotralstat bishydrochloride (1) in one or more solvent;
ii. adding at least one excipient to step a); and iii. removing the solvent from the reaction mixture and drying to provide
amorphous solid dispersion comprising Berotralstat bishydrochloride (1) and
excipient.
wherein, in step-ii) the suitable excipient is same as defined above in the main
embodiment.
wherein, in step-iii) suitable techniques for the removal of solvent is same as defined
above in the second aspect.
In another embodiment of the present invention is to provide process for the
preparation of amorphous solid dispersion comprising Berotralstat bishydrochloride
(1) and at least one excipient, which comprising of:
I. heating Berotralstat bishydrochloride (1) in presence of at least one
pharmaceutically acceptable excipient to get a solution;
II. cooling the solution to suitable temperature; and
III. isolating solid dispersion of Berotralstat bishydrochloride (1).
wherein, in step I) the suitable excipient is same as defined above in the main
embodiment.
In another embodiment of the present invention is to provide a premix comprising
Berotralstat bishydrochloride (1) and at least one pharmaceutically acceptable
excipient.
In another embodiment the present invention is to provide a process for the
preparation of premix comprising Berotralstat bishydrochloride (1) and at least one
excipient, which comprising of:
A. adding Berotralstat bishydrochloride (1) to at least one excipient to get a solid
mass;
B. optionally adding one or more solvent to get a solution; and C. removing the solvent from the solution and drying to provide premix comprising
Berotralstat bishydrochloride (1) and excipient.
wherein, in step A) the suitable excipient is same as defined above in the main
embodiment.
wherein, in step C) suitable techniques for the removal of solvent is same as defined
above in the second aspect.
In another embodiment of the present invention is to provide process for the
preparation of amorphous form of Berotralstat bishydrochloride (1), which
comprising of:
a) dissolving Berotralstat bishydrochloride (1) in one or more solvent; and
b) isolating the amorphous form of Berotralstat bishydrochloride (1).
In another embodiment, solution of Berotralstat bishydrochloride (1) may be
combined with the anti-solvent at suitable temperature and for sufficient time to
obtain amorphous product.
In another embodiment, amorphous form is isolated by removal of solvent at step b)
above, which may be carried out by methods known in the art or any procedure
disclosed in the present invention wherein said method is selected from, but not
limited to, solvent evaporation under atmospheric pressure or reduced pressure /
vacuum such as a rotational distillation using Buchi® Rotavapor®, spray drying,
freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer
(RVPD), lyophilization and the like. In preferred embodiment, the solvent may be
removed under reduced pressures and at temperatures of less than about 100°C, less
than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C,
less than about -20°C, less than about -40°C, less than about -60°C, less than about
-80°C, or any other suitable temperatures.
Moreover, 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,
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 reduced
pressure. 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 Micronisation 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 or hammer milling; or jet milling; or bead milling.
In another embodiment of the present invention is to provide a process for the
preparation of amorphous form of Berotralstat bishydrochloride (1), which
comprising of:
a) dissolving Berotralstat bishydrochloride (1) in one or more solvent;
b) lyophilizing the solution obtained in step a); and
c) isolating the amorphous form of Berotralstat bishydrochloride (1).
In another embodiment, the amorphous form of Berotralstat bishydrochloride (1)
obtained after lyophilization is isolated by a process such as drying at room
temperature, drying under vacuum, or by any known conventional method.
Moreover, 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,
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 reduced
pressure. 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 Micronisation 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 or hammer milling; or jet milling; or bead milling.
In another embodiment of the present invention is to provide process for the
preparation of amorphous Berotralstat bishydrochloride (1), which comprising of:
a) milling/grinding Berotralstat bishydrochloride (1) under suitable milling
conditions; and
b) isolating the amorphous form of Berotralstat bishydrochloride (1).
In another embodiment, the present invention provides solid forms of Berotralstat
bishydrochloride (1) is having chemical purity greater than 99% by HPLC,
preferably greater than 99.5% by HPLC, more preferably greater than 99.9% by
HPLC.
The term “suitable solvent or mixture thereof” used in the present application
include, but are not limited to; water; alcohols, such as methanol, ethanol, 1 -
propanol, 2-propanol, 1-butanol, and 2-butanol; ethers, such as diethyl ether,
diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 2-
methyltetrahydrofuran, cyclopropyl methyl ether, dioxane, and dimethoxy ethane;
esters, such as methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl
acetate, butyl acetate, and isobutyl acetate; ketones, such as acetone,
methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; nitriles, such as
acetonitrile and propionitrile; amides, such as formamide, Ν,Νdimethylformamide, and N,N-dimethylacetamide; sulfoxides, such as
dimethylsulfoxide; aliphatic and aromatic hydrocarbons such as n-pentane,
isopentane, neopentane, n-hexane, isohexane, n-heptane, cyclohexane,
methylcyclohexane, cycloheptane, petroleum ethers, benzene, toluene,
ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin,
trimethylbenzene; halogenated hydrocarbons such as dichloromethane, 1, 2-
dichloroethane, trichloroethylene, chloroform, carbon tetrachloride; or mixtures of
two or more thereof.
The best mode of carrying out the present invention is illustrated by the below
mentioned examples. These examples are provided as illustration only and hence
should not be construed as limitation to the scope of the invention.

We claim:
1. A process for the preparation of amorphous solid dispersion comprising
Berotralstat bishydrochloride (1) and at least one excipient, comprising the
steps of:
a) dissolving Berotralstat bishydrochloride (1) and at least one excipient in
one or more solvent; and
b) isolating to get amorphous solid dispersion Berotralstat bishydrochloride.
2. The process as claimed in claim 1, wherein said pharmaceutically acceptable
excipient is selected from the group comprising of polyvinylpyrrolidone,
(povidone or PVP; PVP of different grades like K-IS, K-30, K-60, K-90 and K120 may be used), polyvinylpolypyrrolidone, polysorbate, cross linked
polyvinyl pyrrolidone (crospovidone), Eudragit, polyethylene glycol (macrogol
or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene
glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose,
carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethyl
ethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl
hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose
(HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl
cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate
succinate (HPMCAS), hydroxyethyl methyl cellulose succinate (HEMCS),
hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl
methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate
phthalate, microcrystalline cellulose (MCC), cross linked sodium
carboxymethyl cellulose (croscarmellose sodium), cross linked calcium
carboxymethyl cellulose, magnesium stearate, aluminum stearate, calcium
stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid,
dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol,
mannitol, maltitol, maltose, raffinose, fructose, maltodextrin, anhydrous
lactose, lactose monohydrate, starches such as maize starch or corn starch,
sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch,
gelatin, sodium dodecyl sulfate, edetate disodium, .sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, polydextrose, α,β,γcyclodextrins, sulfo butyl ether beta-cyclodextrin, sodium stearyl fumarate,
fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric
acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl
stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates
and the like.
3. The process as claimed in claim 1, wherein said solution of Berotralstat
bishydrochloride may be obtained by dissolving Berotralstat bishydrochloride
in a suitable solvent or by directly taking the reaction mixture containing
Berotralstat bishydrochloride.
4. A process for the preparation of amorphous solid dispersion comprising
Berotralstat bishydrochloride (1) and at least one excipient, which comprising
of:
I. heating Berotralstat bishydrochloride (1) in presence of at least one
pharmaceutically acceptable excipient to get a solution;
II. cooling the solution; and
III. isolating to get solid dispersion of Berotralstat bishydrochloride (1).
5. A process for the preparation of amorphous form of Berotralstat
bishydrochloride (1), which comprising of:
a) dissolving Berotralstat bishydrochloride (1) in one or more solvent; and
b) isolating the amorphous form of Berotralstat bishydrochloride (1).
6. A process for the preparation of amorphous form of Berotralstat
bishydrochloride (1), which comprising of:
a) dissolving Berotralstat bishydrochloride (1) in one or more solvent;
b) lyophilizing the solution obtained in step a); and
c) isolating the amorphous form of Berotralstat bishydrochloride (1).
7. A process for the preparation of amorphous Berotralstat bishydrochloride (1),
which comprising of:
a) milling/grinding Berotralstat bishydrochloride (1) under suitable milling
conditions; and
b) isolating the amorphous form of Berotralstat bishydrochloride (1).
8. A process according to any of the proceeding claims, wherein the solvent is
selected from "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, 2-butanol, tert-butanol, ethane-1,2-diol,
propane-1,2-diol and the like; "chloro solvents" such as dichloromethane,
dichloroethane, chloroform, carbon tetrachloride and the like.
9. Composition comprising Berotralstat bishydrochloride, and atleast one
pharmaceutically acceptable excipient, wherein said Berotralstat
bishydrochloride is selected from solid dispersion or amorphous form.
10. A method for preparation of composition comprising Berotralstat
bishydrochloride, wherein said composition is prepared by combining either
amorphous form of Berotralstat bishydrochloride, or amorphous solid
dispersion of Berotralstat bishydrochloride, along with atleast one
pharmaceutically acceptable excipients.