DESC:A PROCESS FOR THE PURIFICATION OF NORTRIPTYLINE
FIELD OF THE INVENTION
The present application relates to a process for the purification of Nortriptyline.
BACKGROUND OF THE INVENTION
Nortriptyline hydrochloride, the hydrochloride salt of Nortriptyline, is chemically named 10,11-Dihydro-N-methyl-5H-dibenzo[a,d]cycloheptene-?,?-propylamine hydrochloride and is structurally represented by Formula I:

Formula I
Nortriptyline, the N-demethylated active metabolite of amitriptyline, is a dibenzocycloheptene derivative tricyclic antidepressant. It exerts its antidepressant effects by inhibiting reuptake of norepinephrine and serotonin in CNS nerve terminals. It is characterised by a well-established safety and efficacy profile and is being broadly prescribed for the amelioration of depressive symptoms. It may also be used in children for the treatment of some cases of nocturnal enuresis.
U.S. Pat. No. 3,922,305 discloses and claims Nortriptyline, its derivatives and pharmaceutically acceptable salts, as well as a method of treatment using Nortriptyline and / or pharmaceutically acceptable salts thereof.
The known processes suffer from problems of purity of Nortriptyline or its pharmaceutically acceptable salts thereof regarding presence of undesirable carcinogenic NDSRIs (Nitrosamine drug substance-related impurities). The processes disclosed in the prior art fail to provide the control of carcinogenic/genotoxic NDSRIs.
NDSRIs such as N-Nitroso nortriptyline, which are highly mutagenic/genotoxic/carcinogenic and are point of concern. The processes for the preparation of Nortriptyline disclosed in the prior arts fail to provide the control of said carcinogenic/genotoxic Nitroso impurity.
N-Nitroso nortriptyline is represented by the following formula II

Formula II
Consequently, there is a need for an improved process for the preparation of Nortriptyline or its pharmaceutically acceptable salts thereof, which not only overcomes the problems in the prior art processes, but also is simple, economically viable, industrially feasible and environment friendly for the preparation of Nortriptyline or its pharmaceutically acceptable salts thereof having a good control over carcinogenic/genotoxic NDSRIs and their carcinogenic precursor impurities.
The problem has been solved by providing an improved process, wherein Nortriptyline or its pharmaceutically acceptable salts thereof is heated / treated in the presence of reducing agent and isolating pure Nortriptyline or its pharmaceutically acceptable salts thereof, which is free from carcinogenic / genotoxic NDSRIs and their carcinogenic precursor impurities.

SUMMARY OF THE INVENTION
It is a principal object of the present invention to improve upon limitations of the prior arts by providing an efficient process for the purification of Nortriptyline and / or pharmaceutically acceptable salts thereof.
In the first embodiment the present application provides a process for the purification of Nortriptyline or its pharmaceutically acceptable salts thereof, comprising:
heating Nortriptyline or its pharmaceutically acceptable salts thereof with a reducing agent.
In the second embodiment the present application provides a process for the purification of Nortriptyline hydrochloride, comprising:
heating Nortriptyline hydrochloride with sodium borohydride.

DETAILED DESCRIPTION OF THE INVENTION
In the aspects of the first embodiment, the present application provides a process for the purification of Nortriptyline or its pharmaceutically acceptable salts thereof, comprising:
heating Nortriptyline or its pharmaceutically acceptable salts thereof with a reducing agent.
The heating may be carried out in presence of a base. The base includes but not limited to organic base such as triethylamine, diisopropyl ethylamine and the like; inorganic base such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and the like. Specifically, the base may be an inorganic base. More specifically, the base may be sodium hydroxide.
The heating may be carried out for about 30 minutes to about 15 hours at about 0 °C to about boiling point of the solvent. Specifically, the reaction may be carried out for about 4 hours to about 10 hours at about 90 °C to about 95 °C. The resulting compound of formula I, Nortriptyline may be isolated from the reaction mass by any method known in the art.
The isolated Nortriptyline may be optionally be converted to its pharmaceutically acceptable salts thereof.
In the aspects, the reducing agent includes but not limited to sodium borohydride, sodium triacetoxy borohydride, lithium aluminium hydride, Pd/C, Fe/Acetic acid, Raney Ni and ascorbic acid. Specifically, the reducing agent may be sodium borohydride.
In the aspects of the second embodiment, the present application provides a process for the purification of Nortriptyline hydrochloride, comprising:
heating Nortriptyline hydrochloride with sodium borohydride.
The heating may be carried out in presence of a base. The base includes but not limited to organic base such as triethylamine, diisopropyl ethylamine and the like; inorganic base such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and the like. Specifically, the base may be an inorganic base. More specifically, the base may be sodium hydroxide.
The heating may be carried out for about 30 minutes to about 15 hours at about 0 °C to about boiling point of the solvent. Specifically, the reaction may be carried out for about 4 hours to about 10 hours at about 25 °C to about 35 °C. The resulting compound of formula I, Nortriptyline may be isolated from the reaction mass by any method known in the art.
The isolated Nortriptyline may be optionally be converted to its pharmaceutically acceptable salts thereof.
In another general aspect, there is provided pharmaceutical composition comprising therapeutically effective amount of Nortriptyline or its salts and one or more pharmaceutically acceptable carriers, excipients or diluents.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms "about," "general, "generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25 °C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms "comprising" and "comprises" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
The term "optional" or "optionally" is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
Room temperature as used herein refers to ‘the temperatures of the thing close to or same as that of the space, e.g., the room or fume hood, in which the thing is located’. Typically, room temperature can be from about 20 °C to about 30 °C, or about 22 °C to about 27 °C, or about 25 °C.
The reaction time should be sufficient to complete the reaction which depends on scale and mixing procedures, as is commonly known to one skilled in the art. Typically, the reaction time can vary from about few minutes to several hours.
The reactions of the processes described herein can be carried out in air or under an inert atmosphere. Typically, reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the person skilled in art.
The isolation may be affected by methods such as, removal of solvent, crash cooling, flash evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying, freeze drying, or any other suitable fast evaporation technique.
Suitable temperatures for isolation may be less than about 120 °C, less than about 80 °C, less than about 60 °C, less than about 40 °C, less than about 30 °C, less than about 20 °C, less than about 10 °C, less than about 0 °C, less than about -10 °C, less than about -40 °C or any other suitable temperatures.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present application in any manner.

EXAMPLES

Example 1: Purification of Nortriptyline

In a round bottom flask charged toluene (90 ml) and Nortriptyline (30 g) at room temperature and stirred for 15 minutes. Activated carbon (3.7 g) was charged into the round bottom flask and stirred for 30 minutes. The reaction mass was filtered and washed with toluene (30 ml). The filtrate was charged into a fresh round bottom flask and sodium borohydride (1.25 g) was charged. This reaction mass was maintained for 6 hours at 30 oC and water (50 ml) was added and stirred for 25 minutes. Layers were separated and organic layer was washed with water (50 ml) twice and layers separated. Organic layers were combined and distilled under vacuum at 80 oC. The material was washed twice with acetone (246 ml) and IPA.HCl (18 ml) was added to the reaction mass and stirred for 50 minutes. The material was filtered and dried under vacuum at room temperature for 7 hours to get pure Nortriptyline.
N-Nitroso nortriptyline – 0.0206 ppm.

Example 2: Purification of Nortriptyline hydrochloride

In a round bottom flask charged, water (90ml), toluene (90 ml) and Nortriptyline hydrochloride (30 g) at room temperature and stirred for 15 minutes. pH was adjusted to 12-13 by adding Sodium hydroxide (10 ml) and stirred for 30 minutes. The reaction mass was filtered and extracted with toluene (30 ml). The filtrate was charged into a fresh round bottom flask and sodium borohydride (0.6 g) was charged. This reaction mass was maintained for 6 hours at 30 oC and water (50 ml) was added and stirred for 25 minutes. Layers were separated and organic layer was washed with water (50 ml) twice and layers separated. Organic layers were combined and distilled under vacuum at 80 oC. The material was washed twice with acetone (246 ml) and IPA.HCl (18 ml) was added to the reaction mass and stirred for 50 minutes. The material was filtered and dried under vacuum at room temperature for 7 hours to get pure Nortriptyline hydrochloride.
N-Nitroso nortriptyline – 0.0099 ppm.

Dated this on 22nd day of July, 2024

Signature: ___________________
Name: Dr. Phani Kumar Balusu
Vasudha Pharma Chem Limited
,CLAIMS:We Claim:
1) A process for the purification of Nortriptyline or its pharmaceutically acceptable salts thereof, comprising:
heating Nortriptyline or its pharmaceutically acceptable salts thereof with a reducing agent.

2) The process according to claim 1, wherein the reducing agent is selected from the group comprising sodium borohydride, sodium triacetoxy borohydride, lithium aluminium hydride, Pd/C, Fe/Acetic acid, Raney Ni and ascorbic acid.

3) The process according to claim 1, wherein the heating is performed in the presence of a base.

4) The process according to claim 3, where in the base is selected from the group comprising organic base such as triethylamine, diisopropyl ethylamine and the like; inorganic base such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and the like.

5) A process for the purification of Nortriptyline hydrochloride, comprising:
heating Nortriptyline hydrochloride with sodium borohydride.

Dated this on 22nd day of July, 2024
Signature: ___________________
Name: Dr. Phani Kumar Balusu
Vasudha Pharma Chem Limited