DESC:FIELD OF INVENTION
The present invention relates to process for reducing content of nitrosamine impurity represented by formula (II) in drug substance of formula (I) or its intermediate of formula (I) or its salt thereof, which comprises; subjecting drug substance of formula (I) or its intermediate of formula (I) or its salt thereof containing nitrosamine impurity (II) to hydrogenation reaction in presence of hydrogen source, metal catalyst and suitable solvent(s).

BACKGROUND OF INVENTION
Recently, FDA and EMA reported a major issue regarding the presence of nitrosamine impurities classified as genotoxic as they contain a nitroso group, which is a gene mutating group and is believed to have been introduced into the finished products and active pharmaceutical ingredients (API) as a result of the manufacturing process. Health agencies like USFDA and EMEA have stringent regulatory requirements for acceptable limit of undesired impurities in drug products. Drug products that contain nitrosamine impurities above the acceptable limits as defined by regulatory authorities may pose an unacceptable risk to patients. Recently EMEA published regulatory guidance [Document no: EMA/72902/2024 /Rev. 3; Published on 04-feb-2024] on intake limits for nitrosamines in various medications Therefore, there remains a need for the process to obtain the drug products including API or its intermediates that are devoid of nitroso impurities. The inventors of the instant application have developed a robust, scalable and industrially viable process for reducing content of nitrosamine impurity represented by formula (II) in drug substance or its salt or its intermediate of formula (I).
SUMMARY OF INVENTION
In one aspect, the present invention relates to process for reducing content of nitrosamine impurity represented by formula (II) in drug substance of formula (I) or its intermediate of formula (I) or its salt thereof, which comprises; subjecting drug substance of formula (I) or its intermediate of formula (I) or its salt thereof containing nitrosamine impurity of formula (II) to hydrogenation reaction in presence of hydrogen source, metal catalyst and suitable solvent(s).
In second aspect, the present invention particularly relates to a process for reducing content of nitrosamine impurity represented by formula (II) drug substance of formula (I) or its intermediate of formula (I) or its salt thereof

which comprises;
(a) subjecting drug substance of formula (I) or its intermediate of formula (I) or its salt thereof containing nitrosamine impurity (II) to hydrogenation reaction in presence of hydrogen source, metal catalyst and suitable solvent(s),
wherein
- R1 is a residue of drug substance or its intermediate or its salt thereof;
- X1, X2, X3, X4 is independently selected from C, N or O;
- m and n are independently selected from 0, 1 and 2; and
(b) isolating drug substance of formula (I) or its intermediate of formula (I) or its salt thereof which is substantially free of nitrosamine impurity represented by compound of formula (II).

In another aspect of the present invention comprises; subjecting drug substance of formula (I) or its intermediate of formula (I) or its salt thereof containing nitrosamine impurity of formula (II) to hydrogenation reaction in presence of hydrogen source, metal catalyst and suitable solvent(s), wherein the drug substance or its intermediate or its salt thereof is stable under hydrogenation conditions and does not undergo any undesired degradation or side-reaction.
DETAILED DESCRIPTION
In one embodiment, the present invention relates to process for reducing content of nitrosamine impurity represented by formula (II) in drug substance of formula (I) or its intermediate of formula (I) or its salt thereof which comprises; subjecting drug substance of formula (I) or its intermediate of formula (I) or its salt thereof containing nitrosamine impurity of formula (II) to hydrogenation reaction in presence of hydrogen source, metal catalyst and suitable solvent(s).
In second embodiment, the present invention particularly relates to a process for reducing content of nitrosamine impurity represented by formula (II) in drug substance of formula (I) or its intermediate of formula (I) or its salt thereof

which comprises;
(a) subjecting drug substance of formula (I) or its intermediate of formula (I) or its salt thereof containing nitrosamine impurity (II) to hydrogenation reaction in presence of hydrogen source, metal catalyst and suitable solvent(s),
wherein
- R1 is a residue of drug substance or its intermediate or its salt thereof;
- X1, X2, X3, X4 is independently selected from C, N or O;
- m and n are independently selected from 0, 1 and 2; and
(b) isolating drug substance of formula (I) or its intermediate of formula (I) or its salt thereof which is substantially free of nitrosamine impurity represented by compound of formula (II).

In an embodiment, the ring in compound of formula (I) and (II) is a saturated heterocyclic ring selected from but not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl.
In another embodiment the present invention comprises subjecting drug substance or its intermediate or its salt thereof which contain nitrosamine impurity of formula (II) to hydrogenation reaction, wherein the drug substance or its intermediate or its salt thereof are stable under hydrogenation conditions and does not undergo any undesired degradation or side-reaction.
In another embodiment the present invention comprises subjecting salt form of drug substance or its intermediate represented by compound of formula (I) which contain nitrosamine impurity of formula (II) to hydrogenation reaction, wherein the drug substance or its intermediate or it salt thereof are stable under hydrogenation conditions and does not undergo any undesired degradation or side-reaction.
In yet another embodiment the present invention provides a process for reducing nitrosamine in a given drug substance comprising reducing said drug substance containing the nitrosamine under hydrogenation reaction as described herein. The drug substance is selected from those drugs that are described in the recently published regulatory guidance on intake limits for nitrosamines by EMEA [Document no: EMA/72902/2024 /Rev. 3; Published on 04-feb-2024]. The process as described herein wherein “reducing nitrosamine” means that content of nitrosamine reduced to level that is within the acceptable limits as prescribed by various regulatory bodies such as ICH, USFDA, PMDA, EMEA, TGA and like.
In one embodiment of the invention, compound of formula (I) is selected from Palbociclib, Ribociclib, Vortioxetine, Avapritinib, Letermovir, Trilaciclib, Infgratinib, Entrectinib, Avatrombopag, Netupitant, Venetoclax, Brexpiprazole, Vilazodone, Flibanserin, Aripiprazole, Cariprazine, Bosutinib, Ponatinib, Nintedanib, Abemaciclib, Gilteritinib, Brigatinib, Maralixibat, Mitapivat, Zavegepant, Olaparib, Fostemsavir, Reboxetine, Aprepitant, Finafloxacin, meropenem, ertapenem, doripenem or its corresponding intermediate or its salt form thereof.
In another embodiment of the invention, R1 is residue of drug selected from Ribociclib, Palbociclib, Olaparib, Vortioxetine, Avapritinib, Letermovir, Trilaciclib, Infgratinib, Entrectinib, Avatrombopag, Netupitant, Venetoclax, Brexpiprazole, Vilazodone, Flibanserin, Aripiprazole, Cariprazine, Bosutinib, Ponatinib, Nintedanib, Abemaciclib, Gilteritinib, Brigatinib, Maralixibat, Mitapivat, Zavegepant, Fostemsavir, Reboxetine, Aprepitant, Finafloxacin, Meropenem, Ertapenem, Doripenem or its corresponding intermediate or its salt thereof which is prone to formation of nitrosamine impurity.
In one embodiment, metal catalyst used in hydrogenation reaction is selected from, but not limited to, palladium on carbon, platinum oxide, platinum black, palladium acetate, rhodium on carbon (rhodium on carbon) and the like. Palladium on carbon catalysts are commercially available with palladium adsorbed on carbon in the concentration range of 1-10%. The source of hydrogen may be hydrogen gas or a compound capable of producing hydrogen gas when used in a hydrogenation reaction. The hydrogen source is selected from ammonium formate, formic acid, alkali metal formates (e.g., sodium formate and potassium formate). When these compounds are used as a hydrogen source, the reaction can be carried out under atmospheric pressure and low temperature conditions.
In one embodiment, hydrogenation reaction is typically carried out in suitable solvent(s) or suitable organic solvent(s) that does not affect the course of the reaction selected from, but not limited to, methanol, ethanol, propanol, isopropanol, cyclopropanol, butanol, isobutanol, tertiary butanol, formamide, dimethylacetamide, dimethylformamide, N-Methyl-2-pyrrolidone, Piperidine, Pyridine, diethylenetriamine, ethylenediamine, tributylamine, ethyl acetate, methyl acetate, ethyl acetoacetate, propyl acetate, butyl acetate, isobutyl acetate, diisopropyl ether, di-tert-butyl ether, diethyl ether, tetrahydrofuran, 1,4-dioxane, dichloromethane (DCM), dichloroethane, chloroform, chlorobenzene, heptane, hexane, toluene, cycloheptane, cyclohexane, cyclohexene, cyclooctane, cyclopentane; acetone, butanone, ethyl isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, acetonitrile, proprionitrile, or benzonitrile.
The hydrogenation reaction may be performed by applying hydrogen pressure of 1-5 kg, preferably 2-4 kg more preferably 2-3 kg. The temperature range for the hydrogenation reaction may be 10°C to reflux temperature, preferably 10°C to 90°C.
The hydrogenation reaction is allowed to proceed for a period sufficient time until the content of nitrosamine impurity of formula (II) is reduced below limits as required by regulatory authorities.
After reaction complies, product is isolated from reaction mixture by conventional techniques well known in the art. Typically the product is separated from the reaction mass by filtration of the catalyst, and the solvent is then concentrated to obtain residue followed by its isolation using any method known in art such as crystallization/recrystallization involving single solvent, mixture of solvents or solvent-anti solvent technique; re-precipitation; slurring in a solvent or mixture of solvents; conversion into salt form and reconversion into corresponding unsalted form or vice-versa. The isolated compound according to the present invention may be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried.
In an embodiment, the content of nitrosamine impurity represented by formula (II) in drug substance of formula (I) or its intermediate of formula (I) or its salt thereof is in the range of about 0.5 ppm to about 50 ppm.
The term “substantially free of nitrosamine impurity” wherein content of nitrosamine impurity is less than about 0.5 ppm.
One embodiment of the present invention is to provide Ribociclib containing less than about 0.4 ppm nitrosamine impurity of Ribociclib as depicted below:

The present invention is also directed to a process for preparing Ribociclib, which comprises of:
(a) providing a reaction mixture comprising Ribociclib and nitrosamine impurity represented by following formula;

(b) hydrogenating the reaction mixture in presence of hydrogen source, metal catalyst and suitable solvent(s); and
(c) isolating Ribociclib which is substantially free of nitrosamine impurity.
In an embodiment, hydrogenation reaction is carried out in presence of hydrogen source, metal catalyst and suitable solvent(s) as described herein.
In one embodiment, hydrogenation step is particularly carried out in suitable organic solvent(s) that does not affect the course of the reaction selected from, as described herein.
One embodiment of the present invention is to provide Olaparib containing less than about 0.4 ppm nitrosamine impurity of Olaparib as depicted below:

The present invention is also directed to a process for preparing Olaparib, which comprises of:
(a) providing a reaction mixture comprising Olaparib and nitrosamine impurity represented by following formula;

(b) hydrogenating the reaction mixture in presence of hydrogen source, metal catalyst and suitable solvent(s); and
(c) isolating Olaparib which is substantially free of nitrosamine impurity.
In an embodiment, hydrogenation reaction is carried out in presence of hydrogen source, metal catalyst and suitable solvent(s) as described herein.
In an embodiment, hydrogenation step is particularly carried out in suitable organic solvent(s) that does not affect the course of the reaction selected from, as described herein.
One embodiment of the present invention is to provide Palbociclib substantially free of nitrosamine impurity of Palbociclib as depicted below:

The present invention is also directed to a process for preparing Palbociclib, which comprises of:
(a) providing a reaction mixture comprising Palbociclib and nitrosamine impurity represented by following formula;

(b) hydrogenating the reaction mixture in presence of hydrogen source, metal catalyst and suitable solvent(s); and
(c) isolating Palbociclib which is substantially free of nitrosamine impurity.
In one embodiment, hydrogenation reaction is carried out in presence of hydrogen source, metal catalyst and suitable solvent(s) as described herein.
In one embodiment, hydrogenation step is particularly carried out in suitable organic solvent(s) that does not affect the course of the reaction selected from, as described herein.
One embodiment of the present invention is to provide Vortioxetine substantially free of nitrosamine impurity of Vortioxetine as depicted below:

The present invention is also directed to a process for preparing Vortioxetine, which comprises of:
(a) providing a reaction mixture comprising Vortioxetine and nitrosamine impurity represented by formula;

(b) hydrogenating the reaction mixture in presence of hydrogen source, metal catalyst and suitable solvent(s); and
(c) isolating Vortioxetine which is substantially free of nitrosamine impurity.
In one embodiment, hydrogenation reaction is carried out in presence of hydrogen source, metal catalyst and suitable solvent(s) as described herein.
In one embodiment, hydrogenation step is particularly carried out in suitable organic solvent(s) that does not affect the course of the reaction selected from, as described herein
In an embodiment, the hydrogenation step as described herein can be carried out in presence of an antioxidant and/or reducing agent like but not limited to triphenyl phosphine (TPP), Butylated hydroxy toluene (BHT), Sodium metabisulfite (Na2S2O5), Ascorbic acid, Uric acid, Glutathione, preferably BHT.
In an embodiment, the present invention provides a process which comprises treating drug substance containing nitrosamine impurity with an antioxidant and/or reducing agent like but not limited to triphenyl phosphine (TPP), Butylated hydroxy toluene (BHT), Sodium metabisulfite (Na2S2O5), Ascorbic acid, Uric acid, Glutathione, preferably BHT.
In an embodiment, the present invention provides a process for conversion of drug substance into its salt form such as but not limited to succinate, fumarate, hydrochloride, hydrobromide; wherein process comprises treating reaction mixture during salt formation with an antioxidant and/or reducing agent like but not limited to triphenyl phosphine (TPP), Butylated hydroxy toluene (BHT), Sodium metabisulfite (Na2S2O5), Ascorbic acid, Uric acid, Glutathione, preferably BHT.
The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.
GENERAL PROCEDURE
To a solution of compound of Formula (I) containing nitrosamine impurity (II) in alcohol solvent; was added 5% palladium on carbon at 70-80°C in an autoclave, and subjected the reaction mixture to hydrogen pressure of 2 to 3 kg for 10-20 hrs. After the reaction complies the reaction mixture was filtered through hyflo and washed with alcohol solvent. The solvent is evaporated under reduced pressure to obtain compound of formula (I).
EXAMPLES:
Example 1: Preparation of Ribociclib

To a solution of Ribociclib base (5 gm) containing N-nitrosamine Ribociclib impurity (5 ppm) in isopropyl alcohol (500 ml); was added 5% palladium on carbon (1 g) at 70-80°C in an autoclave, and subjected the reaction mixture to hydrogen pressure of 2 to 3 kg for 10-20 hrs. After the reaction complies the reaction mixture was filtered through hyflo and washed with isopropyl alcohol. The solvent was evaporated under reduced pressure to obtain Ribociclib base (4.9 gm).
To reaction mass containing Ribociclib base (200 g) in DM water (2000 ml) was added hydrochloric acid at 10-20oC till pH of reaction mass is about 3 and stirred for about 60 minutes. DCM (1000 ml) was added to the reaction mass at same temperature and stirred for about 15 minutes. The aqueous layer was separated and added to the solution of potassium hydroxide (50.4 g) in water (1400 ml) at 15-25oC and stirred for about 60 minutes. The reaction mass was filtered, washed with DM water (3x500 ml) and dried to obtain Ribociclib base containing N-nitrosamine Ribociclib impurity (0.03 ppm) by LCMS.
Example 2: Preparation of Ribociclib Succinate

To a solution of Ribociclib base (50 gm) containing N-nitrosamine Ribociclib impurity (5 ppm) in isopropyl alcohol (500 ml); was added 5% palladium on carbon (10 g) at 60-70°C in an autoclave, and subjected the reaction mixture to hydrogen pressure of 1.5 to 2 kg for 20-24 hrs. After the reaction complies the reaction mixture was filtered through hyflo and washed with isopropyl alcohol. The solvent was evaporated under reduced pressure to obtain Ribociclib base (48.5 gm).
To reaction mass containing Ribociclib base (100 g) in DM water (1000 ml) was added acetic acid (20 ml) at 10-20oC and stirred for about 60 minutes. DCM (500 ml) was added to the reaction mass at same temperature and stirred for about 15 minutes. The aqueous layer was separated and added to the solution of sodium hydroxide (25.2 g) in water (700 ml) at 15-25oC and stirred for about 60 minutes. The reaction mass was filtered, washed with DM water (3x200 ml) and dried to obtain Ribociclib base.
The above obtained Ribociclib free base was added to a solution of isopropanol alcohol (4000 ml) and triphenyl phosphine (1.0 g) at 25-30oC under nitrogen atmosphere and temperature of reaction mass was raised to 60-65oC along with stirring. The reaction mass was filtered and seed (0.2 g) was added to the filtrate followed by addition of solution of succinic acid (28.6 g) and triphenyl phosphine (1.0 g) in isopropanol (800 ml) at 60-65oC along with stirring under nitrogen atmosphere. The reaction mass was again seeded (0.2 g) at 60-65oC followed by cooling at 20-25oC with stirring. The reaction mass was filtered, washed with isopropanol and dried to obtain Ribociclib succinate containing N-nitrosamine Ribociclib impurity (0.05 ppm).
Example 3: Preparation of Ribociclib Succinate

To a solution of Ribociclib succinate (5 gm) containing N-nitrosamine Ribociclib impurity in isopropyl alcohol (650 ml); was added 10% palladium on carbon (1 g) at 70-80°C in an autoclave, and subjected the reaction mixture to hydrogen pressure of 2 to 3 kg for 10-20 hrs. After the reaction complies the reaction mixture was filtered through hyflo and washed with isopropyl alcohol. The solvent was evaporated under reduced pressure to obtain Ribociclib succinate (4.8 gm) which complies as per regulatory requirements.
Example 4: Preparation of Palbociclib

To a solution of Palbociclib base (5 gm) containing N-nitrosamine Palbociclib impurity in methanol; was added 5% palladium on carbon (1 g) at 55-60°C in an autoclave, and subjected the reaction mixture to hydrogen pressure of 2 to 3 kg for 10-20 hrs. After the reaction complies the reaction mixture was filtered through hyflo and washed with methanol. The solvent was evaporated under reduced pressure to obtain Palbociclib base (4.9 gm) which complies as per EMEA guidelines.
Example 5: Preparation of Olaparib

To a solution of Olaparib base (5 gm) containing N-nitrosamine impurity (0.271 ppm) in methanol; was added 5% palladium on carbon (1 g) at 55-60°C in an autoclave, and subjected the reaction mixture to hydrogen pressure of 2 to 3 kg for 10-20 hrs. After the reaction complies the reaction mixture was filtered through hyflo and washed with methanol. The solvent was evaporated under reduced pressure to obtain Olaparib base (4.7 gm) containing N-nitrosamine impurity (0.025 ppm) by LCMS.
Example 6: Preparation of Vortioxetine

To a solution of Vortioxetine base (5 gm) containing N-nitrosamine Vortioxetine impurity (2-5 ppm) in isopropyl alcohol (500 ml); was added 5% palladium on carbon (1 g) at 70-80°C in an autoclave, and subjected the reaction mixture to hydrogen pressure of 2 to 3 kg for 10-20 hrs. After the reaction complies the reaction mixture was filtered through hyflo and washed with isopropyl alcohol. The solvent was evaporated under reduced pressure to obtain Vortioxetine base (4.7 gm) substantially free of nitrosamine impurity.

Dated this: 20th of March 2025 Dr. S. Ganesan
,CLAIMS:WE CLAIM:
1. A process for reducing the content of nitrosamine impurity in the drug substance of formula (I) or its intermediate of formula (I) or its salt thereof

which comprises of:
(a) subjecting drug substance of formula (I) or its intermediate of formula (I) or its salt thereof containing nitrosamine impurity of Formula (II) to hydrogenation reaction in presence of hydrogen source, metal catalyst and suitable solvent(s),
wherein
- R1 is a residue of drug substance or its salt or its intermediate;
- X1, X2, X3, X4 is independently selected from C, N or O;
- m and n are independently selected from 0, 1 and 2; and
(b) isolating drug substance of formula (I) or its intermediate of formula (I) or its salt thereof which is substantially free of nitrosamine impurity represented by compound of formula (II).

2. The process as claimed in claim 1 wherein compound of formula (I) is selected from Palbociclib, Ribociclib, Vortioxetine, Avapritinib, Letermovir, Trilaciclib, Infgratinib, Entrectinib, Avatrombopag, Netupitant, Venetoclax, Brexpiprazole, Vilazodone, Flibanserin, Aripiprazole, Cariprazine, Bosutinib, Ponatinib, Nintedanib, Abemaciclib, Gilteritinib, Brigatinib, Maralixibat, Mitapivat, Zavegepant, Olaparib, Fostemsavir, Reboxetine, Aprepitant, Finafloxacin, meropenem, ertapenem, doripenem or its salt or its intermediate.

3. The process as claimed in claim 1 wherein hydrogen source is selected from hydrogen gas, ammonium formate, formic acid and alkali metal formates and metal catalyst selected from palladium on carbon, platinum oxide, platinum black, palladium acetate and rhodium on carbon (rhodium on carbon).

4. The process as claimed in claim 1, wherein solvent(s) selected from methanol, ethanol, propanol, isopropanol, cyclopropanol, butanol,, isobutanol, tertiary butanol, formamide, dimethylacetamide, dimethylformamide, N-Methyl-2-pyrrolidone, piperidine, pyridine, diethylenetriamine, ethylenediamine, tributylamine, ethyl acetate, methyl acetate, ethyl acetoacetate, propyl acetate, butyl acetate, isobutyl acetate, diisopropyl ether, di-tert-butyl ether, diethyl ether, tetrahydrofuran, 1,4-dioxane, dichloromethane, dichloroethane, chloroform, chlorobenzene, heptane, hexane, toluene, cycloheptane, cyclohexane, cyclohexene, cyclooctane, cyclopentane; acetone, butanone, ethyl isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, acetonitrile, propionitrile, or benzonitrile.
5. A process for preparing Ribociclib containing less than about 0.4 ppm nitrosamine impurity, which comprises of:
(a) providing a reaction mixture comprising Ribociclib and nitrosamine impurity represented by following formula;

(b) hydrogenating the reaction mixture in presence of hydrogen source, metal catalyst and solvent(s); and
(c) isolating Ribociclib which is substantially free of nitrosamine impurity.
6. A process for preparing Olaparib containing less than about 0.4 ppm nitrosamine impurity, which comprises of:
(a) providing a reaction mixture comprising Olaparib and nitrosamine impurity represented by formula;

(b) hydrogenating the reaction mixture in presence of hydrogen source, metal catalyst and solvent(s); and
(c) isolating Olaparib which is substantially free of nitrosamine impurity.
7. A process for preparing Palbociclib free of nitrosamine impurity, which comprises of:
(a) providing a reaction mixture comprising Palbociclib and nitrosamine impurity represented by formula;

(b) hydrogenating the reaction mixture in presence of hydrogen source, metal catalyst and solvent(s); and
(c) isolating Palbociclib which is substantially free of nitrosamine impurity.
8. A process for preparing Vortioxetine free of nitrosamine impurity, which comprises of:
(a) providing a reaction mixture comprising Vortioxetine and nitrosamine impurity represented by formula;

(b) hydrogenating the reaction mixture in presence of hydrogen source, metal catalyst and solvent(s); and
(c) isolating Vortioxetine which is substantially free of nitrosamine impurity.

Dated this: 20th of March 2025 Dr. S. Ganesan