FIELD OF THE INVENTION
The present invention relates to a process for the preparation of solid-state forms of
N-(4-{1[(2,6-difluorophenyl) methyl]-5-[(dimethylamino)methyl]-3-(6-methoxy
pyridazin-3-yl)-2,4-dioxo-1,2,3,4 tetrahydro thieno [2,3-d] pyrimidin-6-yl}
5 phenyl)-N’-methoxy urea.
BACKGROUND OF THE INVENTION
N-(4-{1[(2,6-difluorophenyl) methyl]-5-[(dimethylamino)methyl]-3-(6-
methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4 tetrahydro thieno [2,3-d] pyrimidin-6-
10 yl} phenyl)-N’-methoxy urea is known as Relugolix (1). The structure is given
below:
Relugolix (1) is a gonadotropin-releasing hormone (GnRH) receptor antagonist,
15 indicated for the treatment of adult patients with advanced prostate cancer. It is
approved by United States Federal Drug Administration (USFDA) on Dec 18, 2020,
to Myovant Sciences GmBH under the brand name Orgovyx ™. It is available in
120MG oral Tablet.
20 Relugolix (1) is reported in US 7300935 by Takeda Pharmaceutical Co Ltd. The
synthetic process for Relugolix is explained and not disclosed about polymorphism
in US’935.
US 9758528 B2 of Takeda discloses two crystalline forms of Relugolix,
25 characterized by FIGS. 1 and 2. The crystalline form of FIG. 1 has been
characterized as tetrahydrofuran solvate, however no characterization is given for
FIG. 2.
3
US 11306104 B2 of Teva pharmaceuticals discloses Crystalline Form F, Form G,
Form H, Form J, Amorphous form of Relugolix and its process for the preparation
thereof.
5
US 202200220123 A1 of Dr. Reddy’s discloses crystalline Form R1 to R10,
Amorphous form & Amorphous solid dispersion of Relugolix and its process for
the preparation thereof.
10 Relugolix exists in a crystalline form and the crystalline form has distinct crystal
structures and physical properties. Consequently, there is an ongoing search for a
new polymorphic form of drug, which may provide improved performance thereof.
In view of the foregoing, the present inventors have provided a process of preparing
15 solid forms of Relugolix (1) with commercially suitable reaction conditions with
high yield and purity. The process is simple, efficient, more economical, and ecofriendlier.
OBJECTIVE OF THE INVENTION
20 Accordingly, in the first objective, the present invention provides a process for the
preparation of solid-state forms of Relugolix (1).
In the second objective, the present invention provides a process for the preparation
of crystalline form of Relugolix (1).
25
In the third objective, the present invention provides a process for the preparation of
amorphous form of Relugolix (1).
In the fourth objective, the present invention provides a process for the preparation
30 of solid dispersion comprising Relugolix (1) and at least one pharmaceutically
acceptable excipient.
4
In the fifth objective, the present invention provides solid-state forms of Relugolix
(1) so obtained is having purity greater than 99% by HPLC, preferably greater than
99.5% by HPLC, more preferably greater than 99.9% by HPLC.
5
SUMMARY OF THE INVENTION
Accordingly, in the first aspect, the present invention provides a process for the
preparation of solid-state forms of Relugolix (1),
10 In the second aspect, the present invention provides a process for the preparation of
crystalline form of Relugolix (1), comprising the steps of:
a) dissolving Relugolix (1) in a solvent or mixture of solvents,
b) optionally, adding non-polar solvent at 0-5°C to the solution obtained in step
a), and
15 c) isolating crystalline form of Relugolix (1).
In the third aspect, the present invention provides a process for the preparation of
solid dispersion comprising Relugolix (1) and at least one pharmaceutically
acceptable excipient, comprising the steps of:
20 a) dissolving Relugolix (1) in a solvent or mixture of solvents.
b) adding at least one pharmaceutically acceptable excipient to the solution
obtained in step a); and
c) isolating the solid dispersion of Relugolix (1)
25 In the fourth aspect, the present invention provides a process for the preparation of
solid dispersion comprising Relugolix (1) and at least one pharmaceutically
acceptable excipient, comprising the steps of:
a) dissolving Relugolix (1) and at least one pharmaceutically acceptable excipient
in a solvent or mixture of solvents, and
30 b) isolating the solid dispersion of Relugolix (1).
5
In the fifth aspect, the present invention provides a process for the preparation of
amorphous form of Relugolix (1), comprising the steps of:
a) dissolving Relugolix (1) in a solvent or mixture of solvents,
b) optionally, adding water at 0-5°C to the solution obtained in step a), and
5 c) isolating amorphous form of Relugolix (1).
In the sixth aspect, the present invention provides solid forms of Relugolix (1) is
having purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC,
more preferably greater than 99.9% by HPLC with total impurities less than 1.0%,
10 more preferably less than 0.5%.
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1: Illustrates PXRD pattern of crystalline form of Relugolix (1).
Figure 2: Illustrates PXRD pattern of amorphous solid dispersion of Relugolix (1)
15 with hydroxypropyl beta cyclodextrin (HPβCD).
Figure 3: Illustrates PXRD pattern of amorphous solid dispersion of Relugolix (1)
with Soluplus.
Figure 4: Illustrates PXRD pattern of amorphous form of Relugolix (1).
20 DETAILED DESCRIPTION OF THE INVENTION
Accordingly, in the first embodiment, the present invention provides a process for
the preparation of solid-state forms of Relugolix (1).
In the second embodiment, the present invention provides a process for the
25 preparation of crystalline form of Relugolix (1), comprising the steps of:
a) dissolving Relugolix (1) in a solvent or mixture of solvents,
b) optionally, adding non-polar solvent at 0-5°C to the solution obtained in step
a), and
c) isolating crystalline form of Relugolix (1).
30
6
In the process of the second embodiment, the suitable solvent used in step-a) is
selected from alcohol solvents such as methanol, ethanol, 1 -propanol, 2-propanol,
1-butanol, 2-butanol, and the like; chloro solvents such as dichloromethane, 1, 2-
dichloroethane, trichloroethylene, chloroform, carbon tetrachloride and/or mixture
5 thereof; the suitable non-polar solvent is diethyl ether.
In the process of the second embodiment, wherein in step-c), the term "isolating"
refers to the removal of solvent by filtration or distillation or decantation from the
mixture.
10
In the third embodiment, the present invention provides a process for the preparation
of solid dispersion comprising Relugolix (1) and at least one pharmaceutically
acceptable excipient, comprising the steps of:
a) dissolving Relugolix (1) in a solvent or mixture of solvents.
15 b) adding at least one pharmaceutically acceptable excipient to the solution
obtained in step a)
c) isolating the solid dispersion of Relugolix (1)
In the process of the third embodiment, the suitable solvent used in step-a) is selected
20 from alcohol solvents such as methanol, ethanol, 1 -propanol, 2-propanol, 1-butanol,
2-butanol, and the like; chloro solvents such as dichloromethane, 1, 2-
dichloroethane, trichloroethylene, chloroform, carbon tetrachloride and/or mixture
thereof.
25 In the process of the third embodiment, the suitable pharmaceutically acceptable
excipient used in step-b) 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), copovidone, Eudragit, Soluplus, polyethylene glycol
30 (macrogol or PEG), polyethylene glycol-6000 (PEG-6000), polyvinyl alcohol,
polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate
7
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,
5 hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl
methylcellulose acetate succinate (HPMC-AS), hydroxyethyl methyl cellulose
succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPCAS),
hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl
methylcellulose acetate phthalate, microcrystalline cellulose (MCC), sulfo butyl
10 ether-β-cyclodextrin (SBECD), hydroxypropyl beta cyclodextrin (HPβCD), 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,
15 maltitol, maltose, Isomaltose. 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
20 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, Salcaprozate sodium,
sodium caprylate, meglumine, arginine, polyethylene oxide, polyvinyl acetate
phthalates and the like.
25
In the fourth embodiment, the present invention provides a process for the
preparation of solid dispersion comprising Relugolix (1) and at least one
pharmaceutically acceptable excipient, comprising the steps of:
a) dissolving Relugolix (1) and at least one pharmaceutically acceptable excipient
30 in a solvent or mixture of solvents, and
b) isolating the solid dispersion of Relugolix (1).
8
In the process of the fourth embodiment, the suitable solvent used in step-a) is same
as defined in the third embodiment.
5 In the process of the fourth embodiment, the suitable pharmaceutically acceptable
excipient used in step-a) is same as defined in the third embodiment.
In the fifth embodiment, the present invention provides a process for the preparation
of amorphous form of Relugolix (1), comprising the steps of:
10 a) dissolving Relugolix (1) in a solvent or mixture of solvents,
b) optionally, adding the obtained solution of step a) to water at 0-5°C, and
c) isolating amorphous form of Relugolix (1).
In the process of fifth embodiment, wherein the solvent is selected from polar15 aprotic solvents such as dimethyl acetamide (DMA), dimethylformamide (DMF),
dimethylsulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like.
In the process of the foregoing embodiments, isolating involves removal of solvent
is carrying out by suitable techniques which includes but not limited to decantation,
20 evaporation under reduced pressure, flash evaporation, vacuum drying,
concentrating the reaction mixture, atmospheric distillation, distillation under
reduced pressure, distillation by using a rotational distillation device such as Buchi
rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze
drying (lyophilization), spray-freeze drying, cooling the clear solution to lower
25 temperatures to precipitate the solid followed by filtration by gravity or suction, thin
film drying, centrifugation or any other suitable techniques known in the art.
In the process of the foregoing embodiments, drying solid dispersion of Relugolix
(1) by a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone
30 dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The
drying can be carried out at atmospheric pressure or under reduced pressures at
9
temperatures of less than about 100°C, less than about 60°C, less than about 40°C,
or any other suitable temperatures. The drying can be carried out for any time period
required for obtaining a desired quality, such as from about 15 minutes to 10 hours
or longer.
5
Solid dispersion/amorphous form of Relugolix (1) prepared according to the present
invention can be further micronized or milled in conventional techniques to get the
desired particle size to achieve desired solubility profile based on different forms of
pharmaceutical composition requirements. Techniques that may be used for particle
10 size reduction include, but are not limited to ball milling, roll milling and hammer
milling, and jet milling. Milling or Micronisation may be performed before drying,
or after the completion of drying of the product.
In the sixth embodiment, the present invention provides a process for the preparation
15 of amorphous form of Relugolix (1), comprising the steps of:
a) dissolving Relugolix (1) in a solvent or mixture of solvents,
b) spray drying the solution obtained in step a) to get amorphous form of Relugolix
(1).
20 In the process of sixth embodiment, the suitable solvent used in step-a) is same as
defined in the fifth embodiment.
In the seventh embodiment, the present invention provides a process for the
preparation of amorphous form of Relugolix (1), comprising the steps of:
25 a) dissolving Relugolix (1) in a solvent or mixture of solvents,
b) lyophilizing the solution obtained in step a) to get amorphous form of Relugolix
(1).
In the process of seventh embodiment, the suitable solvent used in step-a) is same
30 as defined in the fifth embodiment.
10
In the present invention, pharmaceutically acceptable excipient used for the
preparation of solid dispersion can be amorphous, crystalline or any other physical
form.
5 The amorphous solid dispersion or amorphous form of Relugolix (1) of the present
invention can be further micronized or milled to achieve desired particle size
distribution to make suitable formulation.
In the eighth embodiment, the present invention provides solid-state forms of
10 Relugolix (1) so obtained is having purity greater than 99% by HPLC, preferably
greater than 99.5% by HPLC, more preferably greater than 99.9% by HPLC with
total impurities less than 1.0%, more preferably less than 0.5%.
In the nineth embodiment, the present invention provides solid-state forms of
15 Relugolix (1) has water content not more than 5.0% (w/w), preferably not more than
2.0% (w/w), more preferably not more than 1.0% (w/w).
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
20 should not be construed as limitation to the scope of the invention.
Examples
Example 1: Preparation of crystalline form of Relugolix (1).
10 g of Relugolix (1) was dissolved in 250 ml of methylene dichloride at room
25 temperature and stirred to get a clear solution. 600 mL of diethyl ether were taken
in another flask at room temperature and cooled to 0-5°C. To this the obtained clear
solution was added slowly at 0-5°C and stirred. Filtered the reaction mass, washed
with chilled water, and dried at below 45°C for 12-15 hours to get crystalline form
of Relugolix (1). Yield: 9.0-9.5g. The PXRD pattern of the obtained compound is
30 illustrated in figure 1.
Example 2: Preparation of crystalline form of Relugolix (1).
11
100 g of Relugolix (1) was dissolved in 25 volumes of methylene dichloride at room
temperature and stirred to get a clear solution. To this reaction mass, 60 volumes of
diethyl ether were added at room temperature and stirred. Filtered the reaction mass
and suck dried. The solid so obtained was unloaded and dried at below 45°C for 12-
5 15 hours to get crystalline form of Relugolix (1). Yield: 90-95g.
Example 3: Preparation of crystalline form of Relugolix (1).
10 g of Relugolix (1) was dissolved in 100 ml of methanol at room temperature and
stirred for 1-3 hours at 50-55°C. The reaction mass was cooled to room temperature
and stirred for 30-45 minutes. Filtered the reaction mass and suck dried. The solid
10 so obtained was unloaded and dried at below 55°C for 12-15 hours to get crystalline
form of Relugolix (1). Yield: 90-95g.
Example 4: Preparation of amorphous form of Relugolix (1).
50 g of Relugolix (1) was dissolved in 100 ml of Dimethyl sulfoxide at room
temperature and stirred to get a clear solution. 30 volumes of water were taken in
15 another flask at room temperature and cooled to 0-5°C. To this the obtained clear
solution was added slowly at 0-5°C and stirred. Filtered the reaction mass, washed
with chilled water, and dried at below 45°C to get amorphous form of Relugolix
(1). Yield: 45-47.5 gm.
Example 5: Preparation of amorphous form of Relugolix (1).
20 20 g of Relugolix (1) was dissolved in 400 ml of methylene dichloride at room
temperature and stirred to get a clear solution. The total reaction mixture was then
transferred to a beaker and spray dried with the below parameters:
Inlet Temperature : 45°C
Outlet Temperature : 30°C
Aspirator : 1400
Feeding : 15 mL
N2 Pressure : 2.0 kg/cm2
The solid so obtained was unloaded and dried at below 50°C for 12-15 hours to get
amorphous form of Relugolix (1). Yield: 11-12 gm. The PXRD pattern of the
25 obtained compound is illustrated in figure 4.
Example 6: Preparation of amorphous form of Relugolix (1).
12
10 g of Relugolix was dissolved in 400 ml of methylene dichloride and stirred. The
solvent was distilled completely at below 45°C under vacuum in a Buchi Rotavapor.
The solid so obtained was unloaded and dried at below 45°C for 12-15 hours to get
amorphous form of Relugolix (1). Yield: 9-9.5g.
5 Example 7: Preparation of amorphous form of Relugolix (1).
10 g of Relugolix (1) was dissolved in 50 ml of Dimethyl formamide at room
temperature and stirred to get a clear solution. 500 ml of water were taken in another
flask at room temperature and cooled to 0-5°C. To this the obtained clear solution
was added slowly at 0-5°C and stirred. Filtered the reaction mass, washed with
10 chilled water, and dried at below 45°C for 12-15 hours to get amorphous form of
Relugolix (1). Yield: 9.0-9.5g.
Example 8: Preparation of amorphous solid dispersion of Relugolix (1) with
hydroxypropyl beta cyclodextrin (HPβCD).
10 g of Relugolix was dissolved in 100 ml of methylene dichloride was added and
15 stirred to get clear solution. To this reaction mass, 10 g of hydroxypropyl beta
cyclodextrin (HPβCD) was dissolved in 100 ml of methanol was added at room
temperature. The solvent was distilled completely at below 45°C under vacuum in
a Buchi Rotavapor. The solid so obtained was unloaded and dried at below 45°C
for 12-15 hours to get amorphous solid dispersion of Relugolix (1) with
20 hydroxypropyl beta cyclodextrin (HPβCD). Yield: 8.0-8.5 g. The PXRD pattern of
the obtained compound is illustrated in figure 2.
Example 9: Preparation of amorphous solid dispersion of Relugolix (1) with
Soluplus
10 g of Relugolix and 20 g of Soluplus was dissolved in 500 ml of methylene
25 dichloride was added and stirred to get clear solution. The solvent was distilled
completely at below 45°C under vacuum in a Buchi Rotavapor. The solid so
obtained was unloaded and dried at below 45°C for 12-15 hours to get amorphous
solid dispersion of Relugolix (1) with Soluplus. Yield: 9.0-9.5 g. The PXRD pattern
of the obtained compound is illustrated in figure 3
30
13
We Claim:
1. A process for the preparation of crystalline form of Relugolix (1), comprising
the steps of:
a) dissolving Relugolix (1) in a solvent or mixture of solvents,
b) optionally, adding non-polar solvent at 0-5°C to the solution obtained in step
5 a), and
c) isolating crystalline form of Relugolix (1).
2. A process for the preparation of amorphous form of Relugolix (1), comprising
the steps of:
a) dissolving Relugolix (1) in a solvent or mixture of solvents,
10 b) optionally, adding water at 0-5°C to the solution obtained in step a), and
c) isolating amorphous form of Relugolix (1).
3. A process for the preparation of solid dispersion comprising Relugolix (1) with
at least one pharmaceutically acceptable excipient, comprising the steps of:
a) dissolving Relugolix (1) in a solvent or mixture of solvents.
15 b) adding at least one pharmaceutically acceptable excipient to the solution
obtained in step a); and
c) isolating the solid dispersion of Relugolix (1)
4. The process as claimed in claim 3 wherein, the pharmaceutically acceptable
excipient used in step-b) is selected form polyvinylpyrrolidone (povidone or
20 PVP), polyvinylpolypyrrolidone, PVP-K30, polysorbate, cross linked polyvinyl
pyrrolidone (crospovidone), 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), carboxymethylethyl cellulose (CMEC),
25 ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose,
hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl
cellulose acetate succinate (HPCAS), hydroxypropyl methyl cellulose
(hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate
(HPMC-AS), hydroxypropyl methylcellulose-E5 (HPMC-E5), hydroxyethyl
30 methyl cellulose succinate (HEMCS), hydroxypropyl beta cyclodextrin
14
(HPβCD), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl
methylcellulose acetate phthalate, microcrystalline cellulose (MCC), syloid,
eudragit, and copovidone.
5. The process as claimed in any of the proceeding claims, wherein the solvent or
mixture of solvents is selected from alcohol solvents such as methanol, ethanol,
1 -propanol, 2-propanol, 1-butanol, 2-butanol, and the like; chloro solvents
such as dichloromethane, 1, 2-dichloroethane, trichloroethylene, chloroform,
carbon tetrachloride and/or mixture thereof.
6. The process as claimed in claim 1, wherein the suitable non-polar solvent is
diethyl ether.
7. The process as claimed in claims 2 and 3 wherein, isolating Relugolix (1)
involves removal of solvent by decantation, evaporation under reduced
pressure, flash evaporation, vacuum drying, concentrating the reaction mixture,
atmospheric distillation, distillation under reduced pressure, distillation by
using a rotational distillation device such as Buchi rotavapor, agitated thin film
drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization),
spray-freeze drying, cooling the clear solution to lower temperatures to
precipitate the solid followed by filtration by gravity or suction, thin film
drying, centrifugation.