WO2020128646A1 - Process for the preparation of sartans or salts thereof - Google Patents

Process for the preparation of sartans or salts thereof Download PDF

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Publication number
WO2020128646A1
WO2020128646A1 PCT/IB2019/051401 IB2019051401W WO2020128646A1 WO 2020128646 A1 WO2020128646 A1 WO 2020128646A1 IB 2019051401 W IB2019051401 W IB 2019051401W WO 2020128646 A1 WO2020128646 A1 WO 2020128646A1
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salt
ppm
nitrosoalkylamine
containing less
impurities
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PCT/IB2019/051401
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French (fr)
Inventor
Rakeshwar Bandichhor
Rajeev Rehani BUDHDEV
Veeranjaneyulu BANDREDDI
Vijaya Kumar Karri
Laxmi B
Vijaya Kumar Adla
Srinivasa Rao P
Kasi Reddy D
Soni FENIL
Kiran kumar CHETLUR
Venkatesh KODIGANTI
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Dr. Reddy's Laboratories Limited
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Publication of WO2020128646A1 publication Critical patent/WO2020128646A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • step c) optionally, maintaining the mixture of step c) at about 15°C to reflux temperature; e) recovering the Valsartan or salt thereof.
  • the present application provides a process for preparation of Irbesartan or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities, comprising the steps of:
  • the present application provides Losartan or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine impurities, prepared according to the process of previous aspect.
  • step b) removing the alcohol solvent from the solution of step a);
  • the present application provides Valsartan or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine, as detected through GC/MS technique. In embodiments, the present application provides Valsartan or salt thereof, containing less than 0.008 ppm of N-nitrosodiethylamine, as detected through GC/MS technique. In embodiments, the present application provides Valsartan or salt thereof, containing less than 0.04 ppm of N-nitrosodimethylamine, as detected through GC/MS technique.
  • the present application provides Candesartan cilexetil or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine impurities, prepared according to the process of previous aspect. In embodiments, the present application provides Candesartan cilexetil or salt thereof, containing less than 0.008 ppm of N- nitrosodiethylamine, prepared according to the process of previous aspect. In embodiments, the present application provides Candesartan cilexetil or salt thereof, containing less than 0.04 ppm of N-nitrosodimethylamine, prepared according to the process of previous aspect.
  • Irbesartan or salt thereof that can be used in this aspect may be prepared according to any process reported in the literature. Irbesartan or salt thereof contains N-nitrosoalkylamine impurities more than 0.05 ppm or above the limit of detection. Irbesartan or salt thereof that can be used in this aspect may be either amorphous or any crystalline form known in the art.
  • the present application provides Irbesartan or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine impurities, prepared according to the process of previous aspect. In embodiments, the present application provides Irbesartan or salt thereof, containing less than 0.008 ppm of N-nitrosodiethylamine, prepared according to the process of previous aspect. In embodiments, the present application provides Irbesartan or salt thereof, containing less than 0.04 ppm of N-nitrosodimethylamine, prepared according to the process of previous aspect.
  • steps a) to e) of the present aspect may be carried out according to the procedures described in previous aspect or exemplified in the present application.
  • Valsartan (10 g) containing 1 ppm of NDEA impurity was dissolved in methanol (30 mL) at 50°C and stirred for 24 minutes at the same temperature. The clear solution was evaporated at 50°C under reduced pressure to remove the methanol completely. Acetone (27 mL) was added to the above solid at 40°C and stirred for 30 minutes at the same temperature. The solution was cooled to 25°C and stirred for 1 hour at the same temperature. n-Heptane (150 mL) was added at 25°C and stirred for 2 hours at the same temperature. The solid was filtered and washed with n-Heptane (2x10 mL). The solid was dried under vacuum at 60°C for 4 hours to obtain the title compound. Yield: 5.5 g and NDEA content: Not detected (Below LOD).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Aspects of the present application relate to process for the preparation of Sartan or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities. Process of present application is useful to obtain Sartan or salt thereof selected from Valsartan, Candesartan cilexetil, Losartan potassium and Irbesartan, containing less than 0.05 ppm of N-nitrosoalkylamine impurities.

Description

PROCESS FOR THE PREPARATION OF SARTANS OR SALTS THEREOF
INTRODUCTION
Aspects of the present application relate to process for the preparation of Sartan or salt thereof containing N-nitrosoalkylamine impurities below the limit of detection. Specific aspects relate to process for the preparation of Sartan or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities.
Recently, FDA and EMA reported a major issue regarding the detection of a genotoxic impurity, NDMA (N-nitrosodimethylamine), and subsequently NDEA (N- nitrosodiethylamine), in the lots of Valsartan used in manufacture generic angiotensin receptor blockers (ARBs). Valsartan is a non-peptide orally active angiotensin-II-receptor antagonist marketed for use either as a single agent or in combination with other active substances in the treatment of hypertension, heart attack and heart failure. Both NDMA and NDEA are considered genotoxic compounds as they contain a nitroso group, which is a gene mutating group. This concern has spread across the EU, Canada, and the U.S., and is expanding to other regions as well. FDA is currently aware of NDMA and NDEA in certain valsartan, Irbesartan and losartan-containing products and some active pharmaceutical ingredients (API) used to manufacture them have been recalled from the U.S. market.
When a new impurity or higher level of impurities are detected, the drug manufacturers are responsible to fully evaluate the impurities and ensure the product is safe for patients. Drug products that contain N-nitrosoalkylamine impurities such as NDMA or NDEA above the limits may pose an unacceptable risk to patients. Therefore, though the formation of any such nitroso impurities in a Sartan is dictated by the synthetic route adopted, reagents and conditions employed in manufacturing, there remains a need for the process to purify such Sartans to obtain the product devoid of these nitroso impurities. The inventors of the instant application have developed a robust, scalable and industrially viable process for the preparation of Sartans.
SUMMARY
In an aspect, the present application provides a process for preparation of a Sartan or salt thereof containing less than 0.05 ppm of nitrosoalkylamine impurities, comprising the steps of: a) providing a solution of the Sartan or salt thereof in an alcohol solvent; b) removing the alcohol solvent from the solution of step a);
c) treating the product of step b) with atleast one second solvent selected from the group consisting of ketone solvent, hydrocarbon solvent, water and mixtures thereof;
d) optionally, maintaining the mixture of step c) at about 0°C to reflux temperature; e) recovering the Sartan or salt thereof.
In another aspect, the present application provides a Sartan or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine impurities, prepared according to the process of previous aspect.
In another aspect, the present application provides a Sartan or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine, as detected through GC/MS technique.
In another aspect, the present application provides a Sartan or salt thereof, containing less than 0.008 ppm of N-nitrosodiethylamine, as detected through GC/MS technique.
In another aspect, the present application provides a Sartan or salt thereof, containing less than 0.04 ppm of N-nitrosodimethylamine, as detected through GC/MS technique.
In another aspect, the present application provides a process for preparation of Valsartan or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities, comprising the steps of:
a) providing a solution of Valsartan or salt thereof in an alcohol solvent;
b) removing the alcohol solvent from the solution of step a);
c) treating the product of step b) with atleast one second solvent selected from the group consisting of ketone solvent, hydrocarbon solvent and mixtures thereof;
d) optionally, maintaining the mixture of step c) at about 15°C to reflux temperature; e) recovering the Valsartan or salt thereof.
In another aspect, the present application provides Valsartan or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine impurities, prepared according to the process of previous aspect. In another aspect, the present application provides a process for preparation of Candesartan cilexetil or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities, comprising the steps of:
a) providing a solution of Candesartan cilexetil or salt thereof in an alcohol solvent; b) removing the alcohol solvent from the solution of step a);
c) treating the product of step b) with atleast one second solvent selected from the group consisting of ketone solvent, water and mixtures thereof;
d) optionally, maintaining the mixture of step c) at about 15°C to reflux temperature; e) recovering the Candesartan cilexetil or salt thereof.
In another aspect, the present application provides Candesartan cilexetil or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine impurities, prepared according to the process of previous aspect.
In another aspect, the present application provides a process for preparation of Irbesartan or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities, comprising the steps of:
a) providing a solution of Irbesartan or salt thereof in an alcohol solvent;
b) removing the alcohol solvent from the solution of step a);
c) treating the product of step b) with a ketone solvent;
d) optionally, maintaining the mixture of step c) at about 15°C to reflux temperature; e) recovering the Irbesartan or salt thereof.
In another aspect, the present application provides Irbesartan or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine impurities, prepared according to the process of previous aspect.
In another aspect, the present application provides a process for preparation of Losartan or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities, comprising the steps of:
a) providing a solution of Losartan or salt thereof in an alcohol solvent;
b) removing the alcohol solvent from the solution of step a);
c) treating the product of step b) with a ketone solvent;
d) optionally, maintaining the mixture of step c) at about 15°C to reflux temperature; e) recovering the Losartan or salt thereof.
In another aspect, the present application provides Losartan or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine impurities, prepared according to the process of previous aspect.
In another aspect, the present application provides a pharmaceutical composition comprising a Sartan or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine impurities, prepared according to the process of any previous aspect and atleast one pharmaceutically acceptable excipient.
DETAILED DESCRIPTION
In an aspect, the present application provides a process for preparation of a Sartan or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities, comprising the steps of:
a) providing a solution of the Sartan or salt thereof in an alcohol solvent;
b) removing the alcohol solvent from the solution of step a);
c) treating the product of step b) with atleast one second solvent selected from the group consisting of ketone solvent, hydrocarbon solvent, water and mixtures thereof;
d) optionally, maintaining the mixture of step c) at about 0°C to reflux temperature; e) recovering the Sartan or salt thereof.
Sartan or salt thereof that can be used in this aspect may be prepared according to any process reported in the literature. Such Sartan or salt thereof contains N-nitrosoalkylamine impurities more than 0.05 ppm or above the limit of detection. Sartan or salt thereof that can be used in this aspect may be either amorphous or any crystalline form known in the art. Such Sartan may include, but not limited to Losartan, Valsartan, Candesartan cilexetil, Irbesartan, Olmesartan medoxomil and any drug containing a Sartan such as LCZ-696.
In embodiments, the solution of the Sartan or salt thereof of step a) may be obtained either by dissolving the Sartan or salt thereof in alcohol solvent, optionally by heating or taking the reaction mixture directly containing Sartan or salt thereof in alcohol solvent. In embodiments, the alcohol solvent of step a) may be selected from the group consisting of methanol, ethanol, isopropyl alcohol, 2-butanol and the like.
In embodiments, the solution of step a) may be treated with activated carbon and filtered to make it particle free solution.
In embodiments, the alcohol solvent may be removed from the solution of step a) by any of the methods known in the art. In an embodiment, the alcohol solvent may be removed completely by evaporating the solution of step a) under suitable temperature and pressure to obtain the solids. In alternate embodiment, the alcohol solvent may be partially removed through evaporation and then be cooled to precipitate out the solids.
In embodiments, the product obtained in step b) may be treated with atleast one second solvent at a temperature of about 0°C and above. In embodiments, the second solvent of step c) may be selected from the group consisting of ketone solvent, hydrocarbon solvent, water and mixtures thereof. Ketone solvent may include, but not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone and the like. Hydrocarbon solvent may include, but not limited to cyclohexane, n-hexane, n-heptane, toluene and the like.
The mixture of step c) may be either heterogeneous or homogeneous in nature. In an embodiment, the mixture of step c) is heterogeneous such as a suspension or slurry.
In embodiments, the mixture of step c) may be optionally maintained at a suitable temperature of about 0°C to reflux temperature. The mixture of step c) may be maintained for atleast 15 minutes or more. In embodiments, the mixture of step c) or d) may be cooled prior to step e).
In alternate embodiments, when the mixture of step c) or d) is a homogeneous solution, the solids may be precipitated out either by cooling or by anti-solvent addition. Anti-solvent is a solvent where in the solubility of the Sartan or salt thereof is very low or minimal.
In embodiments, step e) may be carried out either by any method known in the art or by following procedures described in the present application. In an embodiment, step e) may be carried out either by filtration or decantation. The separated solids may be optionally washed or slurred with the second solvent and dried under controlled conditions.
Solid may be dried under suitable drying conditions such as aerial drying, vacuum drying, fluidized bed drying, rotatory vacuum drying, drying under inert gas flow such as nitrogen drying or under humid conditions. Drying may be carried out at a temperature of about 40°C and above under reduced pressure for atleast one hour or more. In embodiments, the Sartan or salt thereof recovered from step e) contains less than 0.05 ppm of N-nitrosoalkylamine impurities or below the specification as per regulatory guidelines. N-nitrosoalkylamine impurities may include, but not limited to N- Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine (NDEA), N- Nitrosomethylethylamine (NMEA), N-Nitrosodiisopropylamine (NDIPA), N- Nitrosoisopropylethylamine (NIPEA) and N-Nitrosoisopropylmethylamine (NIPMA). In embodiments, the Sartan or salt thereof recovered from step e) contains less than 0.04 ppm of N-nitrosodimethylamine and / or less than 0.008 ppm of N-nitrosodiethylamine.
Though the formation of any such N-nitrosoalkylamine impurities in a Sartan is majorly dictated by the synthetic route adopted, reagents and other conditions employed in manufacturing, the present process for Sartans is useful to obtain Sartan products devoid of such N-nitrosoalkylamine impurities. The present process is consistent and easily scalable. The experiments were conducted by adding known content of NDEA and / or NDMA to a Sartan and subjected to the process of present invention to reduce these impurities below the limit of detection and well below the specification as per regulatory guidance.
In another aspect, the present application provides a Sartan or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine impurities, prepared according to the process of previous aspect.
In embodiments, the present application provides the Sartan or salt thereof, containing less than 0.008 ppm of N-nitrosodiethylamine, prepared according to the process of previous aspect. In embodiments, the present application provides the Sartan or salt thereof, containing less than 0.04 ppm of N-nitrosodimethylamine, prepared according to the process of previous aspect.
In another aspect, the present application provides a Sartan or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine, as detected through GC/MS technique. In embodiments, the present application provides a Sartan or salt thereof, containing less than 0.008 ppm of N-nitrosodiethylamine, as detected through GC/MS technique. In embodiments, the present application provides a Sartan or salt thereof, containing less than 0.04 ppm of N-nitrosodimethylamine, as detected through GC/MS technique. Sartan or salt thereof may include, but not limited to Losartan potassium, Valsartan, Candesartan cilexetil, Irbesartan, Olmesartan medoxomil and any drug containing a Sartan such as LCZ-696.
N-nitrosoalkylamine impurities may include, but not limited to N- Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine (NDEA), N- Nitrosomethylethylamine (NMEA), N-Nitrosodiisopropylamine (NDIPA), N- Nitrosoisopropylethylamine (NIPEA) and N-Nitrosoisopropylmethylamine (NIPMA).
In another aspect, the present application provides a process for preparation of Valsartan or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities, comprising the steps of:
a) providing a solution of Valsartan or salt thereof in an alcohol solvent;
b) removing the alcohol solvent from the solution of step a);
c) treating the product of step b) with atleast one second solvent selected from the group consisting of ketone solvent, hydrocarbon solvent and mixtures thereof;
d) optionally, maintaining the mixture of step c) at about 15°C to reflux temperature; e) recovering the Valsartan or salt thereof.
Valsartan or salt thereof that can be used in this aspect may be prepared according to any process reported in the literature. Valsartan or salt thereof contains N- nitrosoalkylamine impurities more than 0.05 ppm or above the limit of detection. Valsartan or salt thereof that can be used in this aspect may be either amorphous or any crystalline form known in the art.
In embodiments, steps a) to e) of the present aspect may be carried out according to the procedures described in previous aspect or exemplified in the present application.
In embodiments, the alcohol solvent of step a) may be selected from the group consisting of methanol, ethanol, isopropyl alcohol, 2-butanol or the like. In embodiments, the second solvent of step c) may be selected from the group consisting of ketone solvent, hydrocarbon, water and mixtures thereof. Ketone solvent may include, but not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone and the like. Hydrocarbon solvent may include, but not limited to cyclohexane, n-hexane, n-heptane, toluene and the like.
In embodiments, the Valsartan or salt thereof recovered from step e) contains less than 0.05 ppm of N-nitrosoalkylamine impurities. In embodiments, the Valsartan or salt thereof recovered from step e) contains less than 0.04 ppm of N-nitrosodimethylamine and / or less than 0.008 ppm of N-nitrosodiethylamine.
In another aspect, the present application provides Valsartan or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine impurities, prepared according to the process of previous aspect. In embodiments, the present application provides Valsartan or salt thereof, containing less than 0.008 ppm of N-nitrosodiethylamine, prepared according to the process of previous aspect. In embodiments, the present application provides Valsartan or salt thereof, containing less than 0.04 ppm of N-nitrosodimethylamine, prepared according to the process of previous aspect.
In another aspect, the present application provides Valsartan or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine, as detected through GC/MS technique. In embodiments, the present application provides Valsartan or salt thereof, containing less than 0.008 ppm of N-nitrosodiethylamine, as detected through GC/MS technique. In embodiments, the present application provides Valsartan or salt thereof, containing less than 0.04 ppm of N-nitrosodimethylamine, as detected through GC/MS technique.
In another aspect, the present application provides a process for preparation of Candesartan cilexetil or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities, comprising the steps of:
a) providing a solution of Candesartan cilexetil or salt thereof in an alcohol solvent; b) removing the alcohol solvent from the solution of step a);
c) treating the product of step b) with atleast one second solvent selected from the group consisting of ketone solvent, water and mixtures thereof;
d) optionally, maintaining the mixture of step c) at about 15°C to reflux temperature; e) recovering the Candesartan cilexetil or salt thereof.
Candesartan cilexetil or salt thereof that can be used in this aspect may be prepared according to any process reported in the literature. Candesartan cilexetil or salt thereof contains N-nitrosoalkylamine impurities more than 0.05 ppm or above the limit of detection. Candesartan cilexetil or salt thereof that can be used in this aspect may be either amorphous or any crystalline form known in the art. In embodiments, steps a) to e) of the present aspect may be carried out according to the procedures described in previous aspect or exemplified in the present application.
In embodiments, the alcohol solvent of step a) may be selected from the group consisting of methanol, ethanol, isopropyl alcohol, 2-butanol and the like. In embodiments, the second solvent of step c) may be selected from the group consisting of ketone solvent, water and mixtures thereof. Ketone solvent may include, but not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone and the like.
In embodiments, the Candesartan cilexetil or salt thereof recovered from step e) contains less than 0.05 ppm of N-nitrosoalkylamine impurities. In embodiments, the Candesartan cilexetil or salt thereof recovered from step e) contains less than 0.04 ppm of N- nitrosodimethylamine and / or less than 0.008 ppm of N-nitrosodiethylamine.
In another aspect, the present application provides Candesartan cilexetil or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine impurities, prepared according to the process of previous aspect. In embodiments, the present application provides Candesartan cilexetil or salt thereof, containing less than 0.008 ppm of N- nitrosodiethylamine, prepared according to the process of previous aspect. In embodiments, the present application provides Candesartan cilexetil or salt thereof, containing less than 0.04 ppm of N-nitrosodimethylamine, prepared according to the process of previous aspect.
In another aspect, the present application provides Candesartan cilexetil or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine, as detected through GC/MS technique. In embodiments, the present application provides Candesartan cilexetil or salt thereof, containing less than 0.008 ppm of N-nitrosodiethylamine, as detected through GC/MS technique. In embodiments, the present application provides Candesartan cilexetil or salt thereof, containing less than 0.04 ppm of N-nitrosodimethylamine, as detected through GC/MS technique.
In another aspect, the present application provides a process for preparation of Irbesartan or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities, comprising the steps of:
a) providing a solution of Irbesartan or salt thereof in an alcohol solvent;
b) removing the alcohol solvent from the solution of step a);
c) treating the product of step b) with a ketone solvent; d) optionally, maintaining the mixture of step c) at about 15°C to reflux temperature; e) recovering the Irbesartan or salt thereof.
Irbesartan or salt thereof that can be used in this aspect may be prepared according to any process reported in the literature. Irbesartan or salt thereof contains N-nitrosoalkylamine impurities more than 0.05 ppm or above the limit of detection. Irbesartan or salt thereof that can be used in this aspect may be either amorphous or any crystalline form known in the art.
In embodiments, steps a) to e) of the present aspect may be carried out according to the procedures described in previous aspect or exemplified in the present application.
In embodiments, the alcohol solvent of step a) may be selected from the group consisting of methanol, ethanol, isopropyl alcohol, 2-butanol and the like. In embodiments, the Ketone solvent of step c) may be selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like.
In embodiments, the Irbesartan or salt thereof recovered from step e) contains less than 0.05 ppm of N-nitrosoalkylamine impurities. In embodiments, the Irbesartan or salt thereof recovered from step e) contains less than 0.04 ppm of N-nitrosodimethylamine and / or less than 0.008 ppm of N-nitrosodiethylamine.
In another aspect, the present application provides Irbesartan or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine impurities, prepared according to the process of previous aspect. In embodiments, the present application provides Irbesartan or salt thereof, containing less than 0.008 ppm of N-nitrosodiethylamine, prepared according to the process of previous aspect. In embodiments, the present application provides Irbesartan or salt thereof, containing less than 0.04 ppm of N-nitrosodimethylamine, prepared according to the process of previous aspect.
In another aspect, the present application provides Irbesartan or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine, as detected through GC/MS technique. In embodiments, the present application provides Irbesartan or salt thereof, containing less than 0.008 ppm of N-nitrosodiethylamine, as detected through GC/MS technique. In embodiments, the present application provides Irbesartan or salt thereof, containing less than 0.04 ppm of N-nitrosodimethylamine, as detected through GC/MS technique. In another aspect, the present application provides a process for preparation of Losartan or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities, comprising the steps of:
a) providing a solution of Losartan or salt thereof in an alcohol solvent;
b) removing the alcohol solvent from the solution of step a);
c) treating the product of step b) with a ketone solvent;
d) optionally, maintaining the mixture of step c) at about 15°C to reflux temperature; e) recovering the Losartan or salt thereof.
Losartan or salt thereof that can be used in this aspect may be prepared according to any process reported in the literature. Losartan or salt thereof contains N-nitrosoalkylamine impurities more than 0.05 ppm or above the limit of detection. Losartan or salt thereof that can be used in this aspect may be either amorphous or any crystalline form known in the art.
In embodiments, steps a) to e) of the present aspect may be carried out according to the procedures described in previous aspect or exemplified in the present application.
In embodiments, the alcohol solvent of step a) may be selected from the group consisting of methanol, ethanol, isopropyl alcohol, 2-butanol and the like. In embodiments, the Ketone solvent of step c) may be selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like.
In embodiments, the Losartan or salt thereof recovered from step e) contains less than 0.05 ppm of N-nitrosoalkylamine impurities. In embodiments, the Losartan or salt thereof recovered from step e) contains less than 0.04 ppm of N-nitrosodimethylamine and / or less than 0.008 ppm of N-nitrosodiethylamine.
In another aspect, the present application provides Losartan or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine impurities, prepared according to the process of previous aspect. In embodiments, the present application provides Losartan or salt thereof, containing less than 0.008 ppm of N-nitrosodiethylamine, prepared according to the process of previous aspect. In embodiments, the present application provides Losartan or salt thereof, containing less than 0.04 ppm of N-nitrosodimethylamine, prepared according to the process of previous aspect.
In another aspect, the present application provides Losartan or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine, as detected through GC/MS technique. In embodiments, the present application provides Losartan or salt thereof, containing less than 0.008 ppm of N-nitrosodiethylamine, as detected through GC/MS technique. In embodiments, the present application provides Losartan or salt thereof, containing less than 0.04 ppm of N-nitrosodimethylamine, as detected through GC/MS technique.
In another aspect, the present application provides a pharmaceutical composition comprising a Sartan or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine impurities, prepared according to the process of any previous aspect and atleast one pharmaceutically acceptable excipient. In embodiments, Sartan may include, but not limited to Losartan potassium, Irbesartan, Valsartan, Olmesartan medoxomil, Candesartan Cilexetil and any drug containing a Sartan such as LCZ-696. In embodiments, pharmaceutical composition comprising Sartan or salt thereof, containing less than 0.04 ppm of N- nitrosodimethylamine and / or less than 0.008 ppm of N-nitrosodiethylamine, prepared according to the process of any previous aspect.
In another aspect, the present application provides a method for analyzing a Sartan or salt thereof, with a limit of detection below 0.05 ppm of N-nitrosoalkylamine comprising the following analytical parameters in a suitable GC/MS instrument.
Oven Program:
Figure imgf000013_0001
Figure imgf000013_0002
Figure imgf000014_0001
Limit of detection (LOD) was determined by preparing standards of known concentrations and calculating the signal to noise ratio. The lowest standard concentration with S/N of > 3 was designated as the method LOD. The limit of detection for N- nitrosoalkylamine selected from the group consisting of N-nitrosodiethylamine and N- nitrosodimethylamine is 0.008 ppm and 0.04 ppm, respectively. Limit of Quantitation (LOQ) was determined by spiking known amounts of standards at different levels into replicate samples (n is 3) of Sartan drug substance. Spiked sample level with recoveries of 70 - 130% and a % RSD of < 15 was designated as the method LOQ. The limit of quantification for N-nitrosoalkylamine selected from the group consisting of N- nitrosodiethylamine and N-nitrosodimethylamine is 0.024 ppm and 0.125 ppm, respectively.
In embodiments, method of analysis was performed using suitable GC/MS instrument such as Shimadzu GC/MS 2010 Ultra (GC AA488). Sartan may include, but not limited to Valsartan, Candesartan cilexetil, Losartan potassium and Irbesartan.
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.
EXAMPLE
EXAMPLE 1: Preparation of Valsartan
Valsartan (10 g) containing 1 ppm of NDEA impurity was dissolved in methanol (30 mL) at 50°C and stirred for 24 minutes at the same temperature. The clear solution was evaporated at 50°C under reduced pressure to remove the methanol completely. Acetone (27 mL) was added to the above solid at 40°C and stirred for 30 minutes at the same temperature. The solution was cooled to 25°C and stirred for 1 hour at the same temperature. n-Heptane (150 mL) was added at 25°C and stirred for 2 hours at the same temperature. The solid was filtered and washed with n-Heptane (2x10 mL). The solid was dried under vacuum at 60°C for 4 hours to obtain the title compound. Yield: 5.5 g and NDEA content: Not detected (Below LOD).
EXAMPLE 2: Preparation of Candesartan Cilexetil
Candesartan Cilexetil (10 g) containing 1 ppm of NDEA impurity was dissolved in methanol (100 mL) at 60°C and stirred at the same temperature for 20 minutes. The clear solution was evaporated at 60°C under reduced pressure to remove the methanol completely. Acetone (72 mL) was added at 45°C and cooled to 25°C. Stirred the mass at 25°C for 30 minutes and added DM Water (72 mL). Stirred the mass at 25°C for 2 hours at the same temperature. The solid was filtered and washed with 1:1 mixture of acetone & water (2x10 mL). The wet solid was dried under vacuum at 60°C for 4 hours to obtain the title compound. Yield: 5.4 g and NDEA content: Not detected (Below LOD).
EXAMPLE 3: Preparation of Irbesartan
Irbesartan (10 g) containing 1 ppm of NDEA impurity was dissolved in methanol (100 mL) at 60 °C. The clear solution was evaporated at 60 °C under reduced pressure to remove the methanol completely. Acetone (30 mL) was added 45°C and cooled to 25°C. The mass was stirred for 3 hours at 25°C and the solid was filtered. The solid was washed with acetone (2x10 mL) and dried under vacuum at 60 °C for 4 hours to obtain the title compound. Yield: 5.6 g and NDEA content: Not detected (Below LOD).
EXAMPLE 4: Preparation of Losartan Potassium
Losartan potassium (10 g) containing 0.3 ppm of NDEA impurity was dissolved in methanol (30 mL) at 24.5°C and the clear solution was evaporated at 45°C under reduced pressure to remove the methanol completely. Acetone (10 mL) was added to the above solid at 45°C and stirred for 10 minutes at the same temperature. The mixture was cooled to 26°C and stirred for 3 hours at the same temperature. The solid was filtered and washed with acetone (2x10 mL). The wet solid was dried under vacuum at 58°C for 6 hours to obtain the title compound. Yield: 7.9 g and NDEA content: Not detected (Below 0.008 ppm).
EXAMPLE 5: Preparation of Losartan Potassium
Losartan potassium (50 g) containing 0.3 ppm of NDEA impurity was dissolved in methanol (150 mL) at 27°C and the clear solution was evaporated at 48°C under reduced pressure to remove the methanol completely. Acetone (150 mL) was added to the above solid at 27°C and stirred for 20 minutes at the same temperature. The mixture was heated to 45°C and stirred for 30 minutes at the same temperature. The mixture was cooled to 27°C and stirred for 1.5 hours at the same temperature. The solid was filtered and washed with acetone (2x50 mL). The wet solid was dried under vacuum at 58°C for 6 hours to obtain the title compound. Yield: 45.5 g and NDEA content: Not detected (Below 0.008 ppm).
EXAMPLE 6: Preparation of Losartan Potassium
Losartan potassium (100 g) containing 0.3 ppm of NDEA impurity was dissolved in methanol (300 mL) at 27°C and the clear solution was evaporated at 48°C under reduced pressure to remove the methanol completely. Acetone (300 mL) was added to the above solid at 27°C and stirred for 15 minutes at the same temperature. The mixture was heated to 45°C and stirred for 30 minutes at the same temperature. The mixture was cooled to 27°C and stirred for 2 hours at the same temperature. The solid was filtered and washed with acetone (2x100 mL). The wet solid was dried under vacuum at 55°C for 6 hours to obtain the title compound. Yield: 88.5 g and NDEA content: 0.008 ppm.
EXAMPLE 7: Preparation of Losartan Potassium
Losartan potassium (100 g) containing 0.3 ppm of NDEA impurity was dissolved in methanol (300 mL) at 27°C and the clear solution was evaporated at 50°C under reduced pressure to remove the methanol completely. Acetone (300 mL) was added to the above solid at 27°C and stirred for 20 minutes at the same temperature. The mixture was heated to 47°C and stirred for 30 minutes at the same temperature. The mixture was cooled to 27°C and stirred for 2 hours at the same temperature. The solid was filtered and washed with acetone (2x100 mL). The wet solid was dried under vacuum at 55°C for 6 hours to obtain the title compound. Yield: 89.5 g and NDEA content: 0.008 ppm.

Claims

Claims
1. A Sartan or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine, as detected through GC/MS technique.
2. A process for preparation of a Sartan or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities, comprising the steps of:
a) providing a solution of the Sartan or salt thereof in an alcohol solvent;
b) removing the alcohol solvent from the solution of step a);
c) treating the product of step b) with atleast one second solvent selected from the group consisting of ketone solvent, hydrocarbon solvent, water and mixtures thereof;
d) optionally, maintaining the mixture of step c) at about 0°C to reflux temperature;
e) recovering the Sartan or salt thereof.
3. The Sartan of claims 1 and 2 containing less than 0.008 ppm of N- nitrosodiethylamine, as detected through GC/MS technique.
4. The Sartan of claims 1 and 2 containing less than 0.04 ppm of N- nitrosodimethylamine, as detected through GC/MS technique.
5. The Sartan of claims 1 to 4 is selected from the group consisting of Losartan, Valsartan, Candesartan cilexetil, Irbesartan, Olmesartan medoxomil and LCZ-696.
6. The N-nitrosoalkylamine of claims 1 and 2 is selected from the group consisting of N-
Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine (NDEA), N-
Nitrosomethylethylamine (NMEA), N-Nitrosodiisopropylamine (NDIPA), N- Nitrosoisopropylethylamine (NIPEA) and N-Nitrosoisopropylmethylamine (NIPMA).
7. A process for preparation of Valsartan or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities, comprising the steps of:
a) providing a solution of Valsartan or salt thereof in an alcohol solvent;
b) removing the alcohol solvent from the solution of step a);
c) treating the product of step b) with atleast one second solvent selected from the group consisting of ketone solvent, hydrocarbon solvent and mixtures thereof;
d) optionally, maintaining the mixture of step c) at about 15°C to reflux temperature; e) recovering Valsartan or salt thereof.
8. Valsartan or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities, prepared according to the process of claim 7.
9. A process for preparation of Candesartan cilexetil or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities, comprising the steps of:
a) providing a solution of Candesartan cilexetil or salt thereof in an alcohol solvent; b) removing the alcohol solvent from the solution of step a);
c) treating the product of step b) with atleast one second solvent selected from the group consisting of ketone solvent, water and mixtures thereof;
d) optionally, maintaining the mixture of step c) at about 15°C to reflux temperature; e) recovering Candesartan cilexetil or salt thereof.
10. Candesartan cilexetil or salt thereof containing less than 0.05 ppm of N- nitrosoalkylamine impurities, prepared according to the process of claim 9.
11. A process for preparation of Irbesartan or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities, comprising the steps of:
a) providing a solution of Irbesartan or salt thereof in an alcohol solvent;
b) removing the alcohol solvent from the solution of step a);
c) treating the product of step b) with a ketone solvent;
d) optionally, maintaining the mixture of step c) at about 15°C to reflux temperature; e) recovering Irbesartan or salt thereof.
12. Irbesartan or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities, prepared according to the process of claim 11.
13. A process for preparation of Losartan or salt thereof containing less than 0.05 ppm of N-nitrosoalkylamine impurities, comprising the steps of:
a) providing a solution of Losartan or salt thereof in an alcohol solvent;
b) removing the alcohol solvent from the solution of step a);
c) treating the product of step b) with a ketone solvent;
d) optionally, maintaining the mixture of step c) at about 15°C to reflux temperature; e) recovering Losartan or salt thereof.
14. Losartan or salt thereof, containing less than 0.05 ppm of N-nitrosoalkylamine impurities, prepared according to the process of claim 13.
PCT/IB2019/051401 2018-12-21 2019-02-21 Process for the preparation of sartans or salts thereof WO2020128646A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108896693A (en) * 2018-07-07 2018-11-27 浙江华海药业股份有限公司 A kind of detection method of N-Nitrosodimethylamine impurity

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108896693A (en) * 2018-07-07 2018-11-27 浙江华海药业股份有限公司 A kind of detection method of N-Nitrosodimethylamine impurity

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