Title of Invention	PROCESS FOR THE PREPARATION OF POLYMORPHS OF SELECTIVE SEROTONIN REUPTAKE INHIBITOR
Abstract	A process for the preparation of polymorph forms of selective serotonin reuptake inhibitor, particularly, Sertraline hydrochloride comprises; a. Suspending or dissolving sertraline base or acetate in suitable solvents such as herein described; b. Adjusting the pH of the mixture with hydrogen chloride either in anhydrous form or aqueous form at elevated temperatures ranging between 25°C to 65°C; c. Cooling and / or stirring the reaction mixture such as herein described; and d. Isolating and drying such as herein described to obtain desired polymorph of sertraline hydrochloride.

Title of Invention

PROCESS FOR THE PREPARATION OF POLYMORPHS OF SELECTIVE SEROTONIN REUPTAKE INHIBITOR

Abstract

A process for the preparation of polymorph forms of selective serotonin reuptake inhibitor, particularly, Sertraline hydrochloride comprises; a. Suspending or dissolving sertraline base or acetate in suitable solvents such as herein described; b. Adjusting the pH of the mixture with hydrogen chloride either in anhydrous form or aqueous form at elevated temperatures ranging between 25°C to 65°C; c. Cooling and / or stirring the reaction mixture such as herein described; and d. Isolating and drying such as herein described to obtain desired polymorph of sertraline hydrochloride.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; rule 13] "A PROCESS FOR THE PREPARATION OF POLYMORPHS OF SELECTIVE SEROTONIN REUPTAKE INHIBITOR" (a) CIPLA LTD. (b) 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India (c) Indian Company incorporated under the Companies Act 1956 The following specification describes the nature of the invention and the manner in which it is to be performed: Original 1158/mum/2003 27.1.05 FIELD OF THE INVENTION The present invention relates to a process to manufacture various crystalline ploymorphic forms of selective serotonin reuptake inhibitor, particularly, Sertraline hydrochloride from either Sertraline base or Sertraline acetate. The process is rugged and suitable for large scale manufacture of various forms of Sertraline hydrochloride namely, form II, form III, form IV and form V. BACKGROUND OF THE INVENTION Sertraline hydrochloride, (1 S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1 - naphthalenamine hydrochloride, having the formula 1 is approved, under the trademark Zoloft.RTM., by the U.S. Food and Drug Administration, for the treatment of depression, obsessive-compulsive disorder and panic disorder. NHCH3 .HCI CI CI Formula 1 U.S. Patent No. 4,536,518 ("the '518 patent") describes the preparation of Sertraline hydrochloride with a melting point of 243-245° C by treating an ethyl acetate/ether solution of the free base with gaseous hydrogen chloride. The solid state properties of the Sertraline hydrochloride so produced are not otherwise disclosed. U.S. Patent No. 5,734,083 describes the preparation of a form of Sertraline hydrochloride denominated polymorph "Tl." 2 According to U.S. Patent No. 5,248,699 ("the '699 patent"), the Sertraline hydrochloride produced by the method of the '518 patent has a crystalline form denominated "Form II." The '699 patent discloses four other polymorphs of Sertraline hydrochloride designated Forms I, III, IV, and V, and characterizes them by single crystal x-ray analysis, powder x-ray diffraction, infra-red spectroscopy, and differential scanning calorimetry. The '699 patent reports that Form II is produced by rapid crystallization of Sertraline hydrochloride from an organic solvent, including isopropyl alcohol, ethyl acetate or hexane, and generally describes methods for making Sertraline hydrochloride Forms I-V. According to this patent, the preferential formation of Forms I, II or IV in an acidic solution consisting of isopropyl alcohol, hexane, acetone, methyl isobutyl ketone, glacial acetic acid or, preferably, ethyl acetate, depends on the rapidity of crystallization. The only method described in this patent for making Forms II and IV is by the rapid crystallization of sertraline hydrochloride from an organic solvent such as those listed above. US patent no 6,452,054 describes novel polymorphic Forms XI, XII, XIII, XIV, XV and XVI of Sertraline hydrochloride, processes for preparing them, methods of using them to treat disease, methods of using them to make other Sertraline hydrochloride forms, and to pharmaceutical dosages containing the novel forms. US patent no 6,495,721 discloses novel methods to make Form II of Sertraline hydrochloride. Sertraline hydrochloride Form II may be produced directly form Sertraline base or Sertraline mandelate. It may also be produced from Sertraline hydrochloride. United States Patent 6,500,987 is directed to forms II, III, V, VI, VII, VIII, IX and X of Sertraline hydrochloride and novel methods for their preparation. United States Patent 6,600,073 describes novel methods for the preparation of Sertraline hydrochloride Forms III, V, VI, VII, VII, IX and X. United States Patent Application 0020183555 relates to a process for making Sertraline hydrochloride Form II comprising the steps of dissolving Sertraline base or Sertraline mandelate in an organic solvent to form a solution; adding hydrogen chloride to the solution; heating the solution 3 to a temperature between about room temperature and about reflux for a time sufficient to induce the formation of Sertraline hydrochloride Form II; and isolating Sertraline hydrochloride Form II. US patent application 20030023117 describes new and novel polymorphic Forms XI, XII, XIII, XIV, XV and XVI of Sertraline hydrochloride, processes for preparing and methods of using them to treat disease, methods of using them to make other Sertraline hydrochloride forms, and to pharmaceutical dosages containing the novel forms. US patent application 20030055112 describes forms II, III, V, VI, VII, VIII, IX and X of Sertraline hydrochloride and novel methods for their preparation. According to the present invention, Sertraline hydrochloride polymorph II may be produced by slurrying sertraline hydrochloride polymorph VI in aprotic organic solvent. Sertraline hydrochloride polymorphic form III may be produced by heating Sertraline hydrochloride polymorphs V and VI. Sertraline hydrochloride forms V and VI may be produced from either Sertraline hydrochloride or Sertraline base by crystallization. Sertraline hydrochloride Form VII may be produced by suspending Sertraline chloride polymorph V in water, followed by filtration. Sertraline hydrochloride Forms VIII and IX may be produced by suspending Sertraline base in water followed by acidification and filtration. Sertraline hydrochloride Form X may be produced by suspending Sertraline hydrochloride in benzyl alcohol with heating, followed by filtration. US patent no 6,517,866 deals with various salts of Sertraline such as Sertraline aspartate, Sertraline acetate, Sertraline lactate and sustained release dosage forms thereof. SUMMARY OF THE INVENTION The present invention relates to a process for making polymorphs Form II, Form III, Form IV and Form V of selective serotonin reuptake inhibitor, particularly, Sertraline hydrochloride. The present invention further relates to novel and cost effective processes for making Sertraline hydrochloride Form II form III, form IV and form V, comprising the steps of treating Sertraline 4 acetate in suitable solvents with hydrogen chloride gas to give either form II, form III or form IV depending on the solvent and temperature. The present invention still further relates to a process for making a Sertraline hydrochloride Form V comprising the steps of dissolving Sertraline base in acetic acid and treating with hydrochloric acid and isolating Sertraline hydrochloride Form V. DETAILED DESCRIPTION OF THE INVENTION This invention relates to a process for preparation of various polymorphic forms II, III, IV and V of selective serotonin reuptake inhibitor, particularly, Sertraline hydrochloride from Sertraline acetate as a starting material. Sertraline acetate is prepared as per the process described in US patent No. 6,517,866 from Sertraline base. A process for preparation of polymorph form V from Sertraline base directly is also described. Sertraline base is dissolved in a suitable solvent. Suitable solvents include ethyl acetate, toluene, acetone, t-methyl-butyl ether, hexane and cyclohexane, and mixtures thereof. The pH of the Sertraline base solution is lowered by the addition of glacial acetic acid to precipitate Sertraline acetate. The most preferred solvents are n-hexane and toluene. In a preferred embodiment of the present invention, Sertraline acetate is suspended / dissolved in suitable solvents and hydrogen chloride is added to convert the Sertraline acetate into Sertraline hydrochloride. Hydrogen chloride used may be added as a gas or a solution with an organic solvent, such as a solution of isopropyl alcohol and hydrogen chloride, n-butanol and hydrogen chloride, acetone and hydrogen chloride, or the like. In another preferred embodiment of this invention to make form II of Sertraline hydrochloride, Sertraline acetate is suspended / dissolved in suitable solvents such as isopropanol, toluene, methanol, ethanol, ethyl acetate or mixtures thereof at ambient to elevated temperatures ranging 5 from 30°C to 80°C, hydrogen chloride is added to adjust the pH of the reaction mixture to between 1 to 2. The addition of hydrogen chloride to Sertraline acetate in suitable solvents is exothermic and the temperature rises from ambient to 60°C - 65°C. The mixture is then cooled gradually to 25°C within 3 hours, with no external cooling provided. The product so obtained is isolated and dried at about 80°C under vacuum to give Sertraline hydrochloride form II. The most preferred solvent for making Sertraline hydrochloride form II is a mixture of isopropanol and toluene. The solvents are preferably taken in ratios ranging from 1% to 95% toluene. The more preferred ratio being in the range of 2 - 8% toluene. The most preferred ratio being 3% - 5% of toluene in isopropanol. In another preferred embodiment of this invention to make Sertaline hydrochloride form III, Sertraline acetate is suspended/ dissolved in suitable solvents such as isopropanol, toluene, methanol, ethanol, ethyl acetate or mixtures thereof at ambient to elevated temperatures ranging from 30°C to 80°C, hydrogen chloride is added to adjust the pH of the reaction mixture to between 1 to 2. The addition of hydrogen chloride to Sertraline acetate in suitable solvents is exothermic and the temperature rises from ambient to 60°C - 65°C. The mixture is then cooled rapidly with aid of an ice bath and the temperature is brought down to 15°C to 18°C with in 20 minutes. The product so obtained is isolated by filtration and dried at about 80°C under vacuum to give Sertraline hydrochloride form III. The most preferred solvent for making Sertraline hydrochloride form III is a mixture of isopropanol and toluene. The solvents are preferably taken in ratios ranging from 1% to 95% toluene. The more preferred ratio being in the range of 2 - 8% toluene. The most preferred ratio being 3% - 5% of toluene in isopropanol. In another preferred embodiment of this invention to make Sertaline hydrochloride form IV, Sertraline acetate is suspended/ dissolved in suitable solvents such as isopropanol, toluene, methanol, ethanol, ethyl acetate or mixtures thereof at ambient to elevated temperatures ranging from 30°C to 80°C, hydrogen chloride is added to adjust the pH of the reaction mixture to between 1 to 2. The addition of hydrogen chloride to Sertraline acetate in suitable solvents is exothermic and 6 the temperature rises from ambient to 60°C - 65°C. The mixture is then cooled rapidly with aid of an ice bath and the temperature is brought down to 15°C to 18°C within 30 minutes. The product so obtained is isolated and dried at 60°C in a fluid bed drier to give Sertraline hydrochloride form IV. The most preferred solvent for making Sertraline hydrochloride form IV is isopropanol In another preferred embodiment of this invention to make Sertaline hydrochloride form V, Sertraline acetate is suspended / dissolved in water at room temperature, filtered to get clear solution and hydrochloric acid is added to adjust the pH of the reaction mixture to between 1 to 2. The mixture is stirred at about 25°C for 2 hours. The product so obtained is isolated and dried at 60° C under vacuum to give Sertraline hydrochloride form V. In another preferred embodiment of this invention to make Sertaline hydrochloride form V, Sertraline base is dissolved in acetic acid at room temperature and stirred to obtain clear solution, to which water is added as a diluent under stirring for 20 minutes at room temperature, 25°C. The said clear solution is cooled to 5-10°C and stirred for 1 hour, followed by addition of concentrated hydrogen chloride to adjust the pH of the reaction mixture to between 1 to 2 and maintained the reaction mixture at same temperature. The reaction mixture is stirred for 15 minutes to precipitate the product; the reaction is further diluted with water before isolation of the product. The product so obtained is isolated and dried at 65 °C in a fluid bed drier to give Sertraline hydrochloride form V. The following examples describe the process of the invention and are in no way limiting the scope of the invention. Reference Examples Preparation of sertraline acetate 30 gms of Sertraline base is dissolved in 200 ml of toluene under stirring at room temperature. 5 ml acetic acid is added to the clear toluene solution and stirred for 1 hour at 25 °C to obtain a thick 7 white precipitate. The solids are filtered and re-slurried in 100 ml toluene for 30 minutes and filtered. The product is dried under vacuum at 60°C for 5 - 6 hours to give Sertraline acetate. Preparation of sertraline acetate 71 gms of Sertraline base is dissolved in 350 ml of n-Hexane under stirring at room temperature. 14 ml acetic acid is added to the clear solution and stirred for 10 minutes at 25°C and refluxed at 60°C for 30 minutes to obtain a thick white precipitate. The precipitated solid is filtered. The product is dried in a fluid bed dryer at 60°C for 3 - 4 hours to give Sertraline acetate. Example 1 Preparation of sertraline hydrochloride form II 20 grams of Sertraline acetate is suspended in a mixture of 100 ml of isopropyl alcohol and 4 ml toluene. The mixture is heated to 50°C to get a clear solution and dry hydrogen chloride gas is bubbled to adjust the pH between1 to 2. The reaction is exothermic and the temperature rises to 60°C. The reaction mixture was cooled gradually to room temperature i.e. 25°C in about 3 hour. The precipitated solids are filtered and washed with isopropyl alcohol and dried under vacuum at 80°C to give Sertraline hydrochloride form II. Example 2 Preparation of sertraline hydrochloride form III 20 grams of Sertraline acetate is suspended in a mixture of 100 ml of isopropyl alcohol and 4 ml toluene. The mixture is heated to 50°C to get a clear solution and dry hydrogen chloride gas is bubbled to adjust the pH between 1 to 2. The reaction is exothermic and the temperature rises to 60°C. The reaction mixture was cooled rapidly to 15°C within 20 minutes with an ice bath. The precipitated solid is filtered and washed with isopropyl alcohol and dried under vacuum at 80°C to give Sertraline hydrochloride form III. 8 Example 3 Preparation of Sertraline hydrochloride form IV 50 grams of Sertraline acetate is suspended in 250 ml of isopropyl alcohol at room temperature. The mixture is heated to 50°C to get a clear solution and bubbled dry hydrogen chloride gas to reduce the pH between 1-2. The reaction mixture is cooled to 20° C within 30 minutes under stirring. The precipitated solid is filtered and washed with isopropyl alcohol and dried in a fluid bed drier at 60°C to give Sertraline hydrochloride form IV Example 4 Preparation of Sertraline hydrochloride form V 10 gms of Sertraline acetate is dissolved in 100 ml of water at room temperature under stirring. The solution is filtered to obtain a clear solution. To the clear filtrate 5 ml concentrated hydrochloric acid is added drop wise under stirring to adjust pH between 1 to 2. The precipitated solids are stirred for 1 hour at 25 °C and filtered. The solids are dried under vacuum at 60°C to give Sertraline hydrochloride form V. Example 5. Preparation of Sertraline hydrochloride form V from sertraline base 300 gms of Sertraline base is dissolved in 600 ml Acetic acid at room temperature and stirred to obtain a clear solution. To the above clear solution, 3000 ml water is added under stirring in 20 min at 25° C. The reaction mixture is cooled to 10° C and stirred for 1 hour. Concentrated hydrochloric acid is added to the above clear solution and the pH adjusted between 1 to 2 at 10° C. The reaction mixture is stirred for 15 minutes and the Sertraline hydrochloride precipitates during this period. 600 ml of water is charged and the reaction mixture stirred at 15° C for 1 hour. The solids are filtered and dried in a Fluid Bed Dryer at 60-70° C to give form V of Sertraline hydrochloride 9 WE CLAIM: 1. A process for the preparation of polymorph forms of selective serotonin reuptake inhibitor, particularly, Sertraline hydrochloride comprises; a. Suspending or dissolving sertraline base or acetate in suitable solvents such as herein described; b. Adjusting the pH of the mixture with hydrogen chloride either in anhydrous form or aqueous form at elevated temperatures ranging between 25°C to 65°C; c. Cooling and / or stirring the reaction mixture such as herein described; and d. Isolating and drying such as herein described to obtain desired polymorph of sertraline hydrochloride. 2. The process for preparation of polymorph forms II of Sertraline hydrochloride starting from Sertraline acetate or base as claimed in claim 1, wherein said process comprises suspending or dissolving sertraline acetate in suitable solvent; adjusting the pH of the mixture between 1-2, with hydrogen chloride either in anhydrous form or aqueous form, at elevated temperature such as 40 to 65° C; cooling the reaction mixture from 65° C to 20° C in about 2 hours; isolating product, polymorph form II by filtration; and drying the said isolated polymorph form II under vacuum at 80° C. 3. The process for preparation of polymorph form III of Sertraline hydrochloride starting from Sertraline acetate or base as claimed in claim 1, wherein said process comprises suspending or dissolving sertraline acetate in suitable solvents; adjusting the pH of the mixture between 1-2 with hydrogen chloride, either in anhydrous form or aqueous form, at elevated temperature such as 40 to 65° C; cooling the mixture rapidly from 65° C to 15-18° C within 20 minutes; isolating product, polymorph form III by filtration and drying the said isolated polymorph form III under vacuum at 80° C. 4. The process for preparation of polymorph form IV of Sertraline hydrochloride starting from Sertraline acetate or base as claimed in claim 1, wherein said process comprises suspending or dissolving sertraline acetate in suitable solvents; adjusting the pH of the mixture between 1 -2 with hydrogen chloride, either in anhydrous form or aqueous form, at elevated temperature such as 40 to 65° C; cooling the mixture from 65° C to 15-18° C 10 within 30 minutes; isolating product, polymorph form IV by filtration; and drying the said isolated polymorph form IV on fluid bed drier at 60° C. 5. The process for preparation of polymorph form V of Sertraline hydrochloride starting from Sertraline acetate or base as claimed in claim 1, wherein said process comprises suspending or dissolving sertraline acetate in suitable solvent; adjusting the pH of the reaction mixture between 1-2 with hydrochloric acid; stirring the said reaction mixture at 25° C for 2 hours; isolating product, polymorph form V by filtration; and drying the said isolated polymorph form V under vacuum at 60°. 6. The process as claimed in claims 2 to 3, wherein the said solvent for the said process for preparation of Polymorph form II and III of Sertraline hydrochloride is selected from methanol, ethanol, isopropanol, ethyl acetate, toluene or mixtures thereof. 7. The process as claimed in claims 2 to 3 and 6, wherein the preferred solvent for the said process for preparation of Polymorph form II and III of Sertraline hydrochloride is mixture of isopropanol and toluene. 8. The process as claimed in claims 2 to 3 and 6 to 7, wherein the preferred solvent for the said process for preparation of Polymorph form II and III of Sertraline hydrochloride is 2 to 8 % toluene in isopropanol, more preferred 3 to 5 % toluene in isopropanol. 9. The process as claimed in claims 4, wherein said solvent for said process for preparation of Polymorph form IV of Sertraline hydrochloride is selected from methanol, ethanol, isopropanol, ethyl acetate, toluene or mixtures thereof. 10. The process as claimed in claims 9, wherein the preferred solvent for the said process for preparation of Polymorph form IV of Sertraline hydrochloride is isopropanol. 11. The process as claimed in claim 5, wherein said solvent for said process for preparation of Polymorph form V of Sertraline hydrochloride is selected from methanol, ethanol, isopropanol, ethyl acetate, toluene, water or mixtures thereof. 12. The process as claimed in claim 11, wherein the preferred solvent for said process for preparation of Polymorph form V of Sertraline hydrochloride is water. 13. The process for preparation of polymorph form V of Sertraline hydrochloride starting from Sertraline base as claimed in claim 1 wherein the said process comprises suspending or dissolving sertraline base in acetic acid at room temperature to get clear solution; adding water to the said clear solution under stirring at 25° C, cooling the 11 reaction mixture to 5 to 10° C, stirring the said reaction mixture for 1 hour; adjusting the pH of the said reaction mixture between 1-2 with concentrated hydrochloric acid at 5 to 10° C; stirring the said reaction mixture for 15 minutes for precipitating the product, polymorph form V; isolating said product, polymorph form V by filtration; and drying said isolated polymorph form V on fluid bed drier at 65° C. 14. The processe for preparation of polymorph forms of Sertraline hydrochloride starting from Sertraline acetate / base as substantially described herein with reference to foregoing examples 1 to 5. Dated this the 4th day of Nov 2003 12 Dr. Gopakumar G. Nair Agent for the Applicant

Full Text

FORM 2 THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
[See section 10; rule 13]
"A PROCESS FOR THE PREPARATION OF POLYMORPHS OF SELECTIVE SEROTONIN REUPTAKE INHIBITOR"
(a) CIPLA LTD.
(b) 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
(c) Indian Company incorporated under the Companies Act 1956
The following specification describes the nature of the invention and the manner in which it is to be performed:

Original
1158/mum/2003
27.1.05

FIELD OF THE INVENTION
The present invention relates to a process to manufacture various crystalline ploymorphic forms of selective serotonin reuptake inhibitor, particularly, Sertraline hydrochloride from either Sertraline base or Sertraline acetate. The process is rugged and suitable for large scale manufacture of various forms of Sertraline hydrochloride namely, form II, form III, form IV and form V.
BACKGROUND OF THE INVENTION
Sertraline hydrochloride, (1 S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1 -
naphthalenamine hydrochloride, having the formula 1 is approved, under the trademark Zoloft.RTM., by the U.S. Food and Drug Administration, for the treatment of depression, obsessive-compulsive disorder and panic disorder.

NHCH3
.HCI
CI CI

Formula 1 U.S. Patent No. 4,536,518 ("the '518 patent") describes the preparation of Sertraline hydrochloride with a melting point of 243-245° C by treating an ethyl acetate/ether solution of the free base with gaseous hydrogen chloride. The solid state properties of the Sertraline hydrochloride so produced are not otherwise disclosed.

U.S. Patent No. 5,734,083 describes the preparation of a form of Sertraline hydrochloride denominated polymorph "Tl."
2

According to U.S. Patent No. 5,248,699 ("the '699 patent"), the Sertraline hydrochloride produced by the method of the '518 patent has a crystalline form denominated "Form II." The '699 patent discloses four other polymorphs of Sertraline hydrochloride designated Forms I, III, IV, and V, and characterizes them by single crystal x-ray analysis, powder x-ray diffraction, infra-red spectroscopy, and differential scanning calorimetry. The '699 patent reports that Form II is produced by rapid crystallization of Sertraline hydrochloride from an organic solvent, including isopropyl alcohol, ethyl acetate or hexane, and generally describes methods for making Sertraline hydrochloride Forms I-V. According to this patent, the preferential formation of Forms I, II or IV in an acidic solution consisting of isopropyl alcohol, hexane, acetone, methyl isobutyl ketone, glacial acetic acid or, preferably, ethyl acetate, depends on the rapidity of crystallization. The only method described in this patent for making Forms II and IV is by the rapid crystallization of sertraline hydrochloride from an organic solvent such as those listed above.
US patent no 6,452,054 describes novel polymorphic Forms XI, XII, XIII, XIV, XV and XVI of Sertraline hydrochloride, processes for preparing them, methods of using them to treat disease, methods of using them to make other Sertraline hydrochloride forms, and to pharmaceutical dosages containing the novel forms.
US patent no 6,495,721 discloses novel methods to make Form II of Sertraline hydrochloride. Sertraline hydrochloride Form II may be produced directly form Sertraline base or Sertraline mandelate. It may also be produced from Sertraline hydrochloride.
United States Patent 6,500,987 is directed to forms II, III, V, VI, VII, VIII, IX and X of Sertraline hydrochloride and novel methods for their preparation.
United States Patent 6,600,073 describes novel methods for the preparation of Sertraline hydrochloride Forms III, V, VI, VII, VII, IX and X.
United States Patent Application 0020183555 relates to a process for making Sertraline hydrochloride Form II comprising the steps of dissolving Sertraline base or Sertraline mandelate in an organic solvent to form a solution; adding hydrogen chloride to the solution; heating the solution
3

to a temperature between about room temperature and about reflux for a time sufficient to induce the formation of Sertraline hydrochloride Form II; and isolating Sertraline hydrochloride Form II.
US patent application 20030023117 describes new and novel polymorphic Forms XI, XII, XIII, XIV, XV and XVI of Sertraline hydrochloride, processes for preparing and methods of using them to treat disease, methods of using them to make other Sertraline hydrochloride forms, and to pharmaceutical dosages containing the novel forms.
US patent application 20030055112 describes forms II, III, V, VI, VII, VIII, IX and X of Sertraline hydrochloride and novel methods for their preparation. According to the present invention, Sertraline hydrochloride polymorph II may be produced by slurrying sertraline hydrochloride polymorph VI in aprotic organic solvent. Sertraline hydrochloride polymorphic form III may be produced by heating Sertraline hydrochloride polymorphs V and VI. Sertraline hydrochloride forms V and VI may be produced from either Sertraline hydrochloride or Sertraline base by crystallization. Sertraline hydrochloride Form VII may be produced by suspending Sertraline chloride polymorph V in water, followed by filtration. Sertraline hydrochloride Forms VIII and IX may be produced by suspending Sertraline base in water followed by acidification and filtration. Sertraline hydrochloride Form X may be produced by suspending Sertraline hydrochloride in benzyl alcohol with heating, followed by filtration.
US patent no 6,517,866 deals with various salts of Sertraline such as Sertraline aspartate, Sertraline acetate, Sertraline lactate and sustained release dosage forms thereof.
SUMMARY OF THE INVENTION
The present invention relates to a process for making polymorphs Form II, Form III, Form IV and Form V of selective serotonin reuptake inhibitor, particularly, Sertraline hydrochloride.
The present invention further relates to novel and cost effective processes for making Sertraline hydrochloride Form II form III, form IV and form V, comprising the steps of treating Sertraline
4

acetate in suitable solvents with hydrogen chloride gas to give either form II, form III or form IV depending on the solvent and temperature.
The present invention still further relates to a process for making a Sertraline hydrochloride Form V comprising the steps of dissolving Sertraline base in acetic acid and treating with hydrochloric acid and isolating Sertraline hydrochloride Form V.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to a process for preparation of various polymorphic forms II, III, IV and V of selective serotonin reuptake inhibitor, particularly, Sertraline hydrochloride from Sertraline acetate as a starting material. Sertraline acetate is prepared as per the process described in US patent No. 6,517,866 from Sertraline base. A process for preparation of polymorph form V from Sertraline base directly is also described.
Sertraline base is dissolved in a suitable solvent. Suitable solvents include ethyl acetate, toluene, acetone, t-methyl-butyl ether, hexane and cyclohexane, and mixtures thereof. The pH of the Sertraline base solution is lowered by the addition of glacial acetic acid to precipitate Sertraline acetate. The most preferred solvents are n-hexane and toluene.
In a preferred embodiment of the present invention, Sertraline acetate is suspended / dissolved in suitable solvents and hydrogen chloride is added to convert the Sertraline acetate into Sertraline hydrochloride.
Hydrogen chloride used may be added as a gas or a solution with an organic solvent, such as a solution of isopropyl alcohol and hydrogen chloride, n-butanol and hydrogen chloride, acetone and hydrogen chloride, or the like.
In another preferred embodiment of this invention to make form II of Sertraline hydrochloride, Sertraline acetate is suspended / dissolved in suitable solvents such as isopropanol, toluene, methanol, ethanol, ethyl acetate or mixtures thereof at ambient to elevated temperatures ranging
5

from 30°C to 80°C, hydrogen chloride is added to adjust the pH of the reaction mixture to between 1 to 2. The addition of hydrogen chloride to Sertraline acetate in suitable solvents is exothermic and the temperature rises from ambient to 60°C - 65°C. The mixture is then cooled gradually to 25°C within 3 hours, with no external cooling provided. The product so obtained is isolated and dried at about 80°C under vacuum to give Sertraline hydrochloride form II.
The most preferred solvent for making Sertraline hydrochloride form II is a mixture of isopropanol and toluene. The solvents are preferably taken in ratios ranging from 1% to 95% toluene. The more preferred ratio being in the range of 2 - 8% toluene. The most preferred ratio being 3% - 5% of toluene in isopropanol.
In another preferred embodiment of this invention to make Sertaline hydrochloride form III, Sertraline acetate is suspended/ dissolved in suitable solvents such as isopropanol, toluene, methanol, ethanol, ethyl acetate or mixtures thereof at ambient to elevated temperatures ranging from 30°C to 80°C, hydrogen chloride is added to adjust the pH of the reaction mixture to between 1 to 2. The addition of hydrogen chloride to Sertraline acetate in suitable solvents is exothermic and the temperature rises from ambient to 60°C - 65°C. The mixture is then cooled rapidly with aid of an ice bath and the temperature is brought down to 15°C to 18°C with in 20 minutes. The product so obtained is isolated by filtration and dried at about 80°C under vacuum to give Sertraline hydrochloride form III.
The most preferred solvent for making Sertraline hydrochloride form III is a mixture of isopropanol and toluene. The solvents are preferably taken in ratios ranging from 1% to 95% toluene. The more preferred ratio being in the range of 2 - 8% toluene. The most preferred ratio being 3% - 5% of toluene in isopropanol.
In another preferred embodiment of this invention to make Sertaline hydrochloride form IV, Sertraline acetate is suspended/ dissolved in suitable solvents such as isopropanol, toluene, methanol, ethanol, ethyl acetate or mixtures thereof at ambient to elevated temperatures ranging from 30°C to 80°C, hydrogen chloride is added to adjust the pH of the reaction mixture to between 1 to 2. The addition of hydrogen chloride to Sertraline acetate in suitable solvents is exothermic and
6

the temperature rises from ambient to 60°C - 65°C. The mixture is then cooled rapidly with aid of an ice bath and the temperature is brought down to 15°C to 18°C within 30 minutes. The product so obtained is isolated and dried at 60°C in a fluid bed drier to give Sertraline hydrochloride form IV.
The most preferred solvent for making Sertraline hydrochloride form IV is isopropanol
In another preferred embodiment of this invention to make Sertaline hydrochloride form V, Sertraline acetate is suspended / dissolved in water at room temperature, filtered to get clear solution and hydrochloric acid is added to adjust the pH of the reaction mixture to between 1 to 2. The mixture is stirred at about 25°C for 2 hours. The product so obtained is isolated and dried at 60° C under vacuum to give Sertraline hydrochloride form V.
In another preferred embodiment of this invention to make Sertaline hydrochloride form V, Sertraline base is dissolved in acetic acid at room temperature and stirred to obtain clear solution, to which water is added as a diluent under stirring for 20 minutes at room temperature, 25°C. The said clear solution is cooled to 5-10°C and stirred for 1 hour, followed by addition of concentrated hydrogen chloride to adjust the pH of the reaction mixture to between 1 to 2 and maintained the reaction mixture at same temperature. The reaction mixture is stirred for 15 minutes to precipitate the product; the reaction is further diluted with water before isolation of the product. The product so obtained is isolated and dried at 65 °C in a fluid bed drier to give Sertraline hydrochloride form V.
The following examples describe the process of the invention and are in no way limiting the scope of the invention.
Reference Examples
Preparation of sertraline acetate
30 gms of Sertraline base is dissolved in 200 ml of toluene under stirring at room temperature. 5 ml acetic acid is added to the clear toluene solution and stirred for 1 hour at 25 °C to obtain a thick
7

white precipitate. The solids are filtered and re-slurried in 100 ml toluene for 30 minutes and filtered. The product is dried under vacuum at 60°C for 5 - 6 hours to give Sertraline acetate. Preparation of sertraline acetate
71 gms of Sertraline base is dissolved in 350 ml of n-Hexane under stirring at room temperature. 14 ml acetic acid is added to the clear solution and stirred for 10 minutes at 25°C and refluxed at 60°C for 30 minutes to obtain a thick white precipitate. The precipitated solid is filtered. The product is dried in a fluid bed dryer at 60°C for 3 - 4 hours to give Sertraline acetate.
Example 1
Preparation of sertraline hydrochloride form II
20 grams of Sertraline acetate is suspended in a mixture of 100 ml of isopropyl alcohol and 4 ml toluene. The mixture is heated to 50°C to get a clear solution and dry hydrogen chloride gas is bubbled to adjust the pH between1 to 2. The reaction is exothermic and the temperature rises to 60°C. The reaction mixture was cooled gradually to room temperature i.e. 25°C in about 3 hour. The precipitated solids are filtered and washed with isopropyl alcohol and dried under vacuum at 80°C to give Sertraline hydrochloride form II.
Example 2
Preparation of sertraline hydrochloride form III
20 grams of Sertraline acetate is suspended in a mixture of 100 ml of isopropyl alcohol and 4 ml toluene. The mixture is heated to 50°C to get a clear solution and dry hydrogen chloride gas is bubbled to adjust the pH between 1 to 2. The reaction is exothermic and the temperature rises to 60°C. The reaction mixture was cooled rapidly to 15°C within 20 minutes with an ice bath. The precipitated solid is filtered and washed with isopropyl alcohol and dried under vacuum at 80°C to give Sertraline hydrochloride form III.
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Example 3
Preparation of Sertraline hydrochloride form IV
50 grams of Sertraline acetate is suspended in 250 ml of isopropyl alcohol at room temperature. The mixture is heated to 50°C to get a clear solution and bubbled dry hydrogen chloride gas to reduce the pH between 1-2. The reaction mixture is cooled to 20° C within 30 minutes under stirring. The precipitated solid is filtered and washed with isopropyl alcohol and dried in a fluid bed drier at 60°C to give Sertraline hydrochloride form IV
Example 4
Preparation of Sertraline hydrochloride form V
10 gms of Sertraline acetate is dissolved in 100 ml of water at room temperature under stirring. The solution is filtered to obtain a clear solution. To the clear filtrate 5 ml concentrated hydrochloric acid is added drop wise under stirring to adjust pH between 1 to 2. The precipitated solids are stirred for 1 hour at 25 °C and filtered. The solids are dried under vacuum at 60°C to give Sertraline hydrochloride form V.
Example 5.
Preparation of Sertraline hydrochloride form V from sertraline base
300 gms of Sertraline base is dissolved in 600 ml Acetic acid at room temperature and stirred to obtain a clear solution. To the above clear solution, 3000 ml water is added under stirring in 20 min at 25° C. The reaction mixture is cooled to 10° C and stirred for 1 hour. Concentrated hydrochloric acid is added to the above clear solution and the pH adjusted between 1 to 2 at 10° C. The reaction mixture is stirred for 15 minutes and the Sertraline hydrochloride precipitates during this period. 600 ml of water is charged and the reaction mixture stirred at 15° C for 1 hour. The solids are filtered and dried in a Fluid Bed Dryer at 60-70° C to give form V of Sertraline hydrochloride
9

WE CLAIM:
1. A process for the preparation of polymorph forms of selective serotonin
reuptake inhibitor, particularly, Sertraline hydrochloride comprises;
a. Suspending or dissolving sertraline base or acetate in suitable solvents such as
herein described;
b. Adjusting the pH of the mixture with hydrogen chloride either in anhydrous form or
aqueous form at elevated temperatures ranging between 25°C to 65°C;
c. Cooling and / or stirring the reaction mixture such as herein described; and
d. Isolating and drying such as herein described to obtain desired polymorph of
sertraline hydrochloride.
2. The process for preparation of polymorph forms II of Sertraline hydrochloride starting from Sertraline acetate or base as claimed in claim 1, wherein said process comprises suspending or dissolving sertraline acetate in suitable solvent; adjusting the pH of the mixture between 1-2, with hydrogen chloride either in anhydrous form or aqueous form, at elevated temperature such as 40 to 65° C; cooling the reaction mixture from 65° C to 20° C in about 2 hours; isolating product, polymorph form II by filtration; and drying the said isolated polymorph form II under vacuum at 80° C.
3. The process for preparation of polymorph form III of Sertraline hydrochloride starting from Sertraline acetate or base as claimed in claim 1, wherein said process comprises suspending or dissolving sertraline acetate in suitable solvents; adjusting the pH of the mixture between 1-2 with hydrogen chloride, either in anhydrous form or aqueous form, at elevated temperature such as 40 to 65° C; cooling the mixture rapidly from 65° C to 15-18° C within 20 minutes; isolating product, polymorph form III by filtration and drying the said isolated polymorph form III under vacuum at 80° C.
4. The process for preparation of polymorph form IV of Sertraline hydrochloride starting from Sertraline acetate or base as claimed in claim 1, wherein said process comprises suspending or dissolving sertraline acetate in suitable solvents; adjusting the pH of the mixture between 1 -2 with hydrogen chloride, either in anhydrous form or aqueous form, at elevated temperature such as 40 to 65° C; cooling the mixture from 65° C to 15-18° C
10

within 30 minutes; isolating product, polymorph form IV by filtration; and drying the said isolated polymorph form IV on fluid bed drier at 60° C.
5. The process for preparation of polymorph form V of Sertraline hydrochloride starting from Sertraline acetate or base as claimed in claim 1, wherein said process comprises suspending or dissolving sertraline acetate in suitable solvent; adjusting the pH of the reaction mixture between 1-2 with hydrochloric acid; stirring the said reaction mixture at 25° C for 2 hours; isolating product, polymorph form V by filtration; and drying the said isolated polymorph form V under vacuum at 60°.
6. The process as claimed in claims 2 to 3, wherein the said solvent for the said process for preparation of Polymorph form II and III of Sertraline hydrochloride is selected from methanol, ethanol, isopropanol, ethyl acetate, toluene or mixtures thereof.
7. The process as claimed in claims 2 to 3 and 6, wherein the preferred solvent for the said process for preparation of Polymorph form II and III of Sertraline hydrochloride is mixture of isopropanol and toluene.
8. The process as claimed in claims 2 to 3 and 6 to 7, wherein the preferred solvent for the said process for preparation of Polymorph form II and III of Sertraline hydrochloride is 2 to 8 % toluene in isopropanol, more preferred 3 to 5 % toluene in isopropanol.
9. The process as claimed in claims 4, wherein said solvent for said process for preparation of Polymorph form IV of Sertraline hydrochloride is selected from methanol, ethanol, isopropanol, ethyl acetate, toluene or mixtures thereof.
10. The process as claimed in claims 9, wherein the preferred solvent for the said process for preparation of Polymorph form IV of Sertraline hydrochloride is isopropanol.
11. The process as claimed in claim 5, wherein said solvent for said process for preparation of Polymorph form V of Sertraline hydrochloride is selected from methanol, ethanol, isopropanol, ethyl acetate, toluene, water or mixtures thereof.
12. The process as claimed in claim 11, wherein the preferred solvent for said process for preparation of Polymorph form V of Sertraline hydrochloride is water.
13. The process for preparation of polymorph form V of Sertraline hydrochloride starting from Sertraline base as claimed in claim 1 wherein the said process comprises suspending or dissolving sertraline base in acetic acid at room temperature to get clear solution; adding water to the said clear solution under stirring at 25° C, cooling the
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reaction mixture to 5 to 10° C, stirring the said reaction mixture for 1 hour; adjusting the
pH of the said reaction mixture between 1-2 with concentrated hydrochloric acid at 5 to
10° C; stirring the said reaction mixture for 15 minutes for precipitating the product,
polymorph form V; isolating said product, polymorph form V by filtration; and drying
said isolated polymorph form V on fluid bed drier at 65° C.
14. The processe for preparation of polymorph forms of Sertraline
hydrochloride starting from Sertraline acetate / base as substantially described herein with reference to foregoing examples 1 to 5.
Dated this the 4th day of Nov 2003

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Dr. Gopakumar G. Nair Agent for the Applicant

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Patent Number

206564

Indian Patent Application Number

1158/MUM/2003

PG Journal Number

30/2007

Publication Date

27-Jul-2007

Grant Date

01-May-2007

Date of Filing

04-Nov-2003

Name of Patentee

M/S. CIPLA LIMITED

Applicant Address

289, BELLASIS ROAD, MUMBAI CENTRAL, MUMBAI

Inventors:

#	Inventor's Name	Inventor's Address
1	KANKAN, RAJENDRA NARAYANRAO	A-3/5, N.B.D. SOCIETY, N.S.S. ROAD, GHATKOPAR, MUMBAI 400 084,
2	RAO, DHARMARAJ RAMACHANDRA	.4/403, GARDEN ENCLAVE, POKHRAN ROAD 2 THANE(W) 400 601
3	NARAYAN BHANU MANJUNATH	103/SARITA Co-OP.HSG SOCIETY I. C. COLONY; BORIVILI (W) Mumbai 400 103

PCT International Classification Number

A61K 031/135

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA