The present invention provides salts of quetiapine and processes for their preparation. The present invention further relates to polymorphic forms of salts of quetiapine, processes for their preparation and pharmaceutical compositions thereof.
2-[2-(4-dibenzo[6,f][1,4]thiazepin-11-ylpiperazin-1-yl)ethoxy]ethanol; commonly known as quetiapine of Formula I is a psychotropic agent belonging to a chemical class of dibenzothiazepine derivatives and is indicated for the treatment of schizophrenia, acute manic episodes associated with bipolar I disorder.
(Formula Removed)
US Patent No. 4,879,288 (the '288 patent) provides a process for preparation of quetiapine or pharmaceutically acceptable salts thereof which includes hydrochloride, maleate, fumarate, citrate, phosphonate, methane sulphonate, in particular the hemifumarate salt. However, no physical characteristics such as X-Ray Powder Diffraction Pattern (XRPD) or Infrared spectrum of the crystalline form have been reported in this patent.
EP Patent No 282,236, PCT Application No WO 05/012274; WO 05/028457; WO 05/028458; WO 05/028459 provides processes for the preparation of quetiapine or pharmaceutically acceptable salts thereof.
PCT Application No WO 01/55125; WO 04/076431 provides processes for the preparation of quetiapine hemifumarate.
PCT Application No WO 05/014590 provides processes for the preparation of Quetiapine freebase and quetiapine hemifumarate.
US Patent No 6,372,734 provides a process for purification of crystalline quetiapine or pharmaceutically acceptable salts thereof which includes hydrochloride, maleate, fumarate, citrate, phosphonate, methane sulphonate, in particular the hemifumarate salt, which involves crystallising quetiapine freebase.
PCT Application No WO 03/80065 provides processes for the preparation of crystalline forms of quetiapine hemifumarate referred to as Form II and Form III, which are solvated polymorphic forms with dichloromethane and chloroform. This PCT application further discloses that following the processes disclosed in the '288 patent provides crystalline Form I of quetiapine hemifumarate.
PCT Patent Application WO 04/78735 provides a process for the preparation of crystalline forms of quetiapine fumarate referred to as Form I and Form II. It further provides processes for the preparation of amorphous quetiapine fumarate.
Salt formation of pharmaceutically active substance provides a means of altering the physicochemical and resultant biological characteristics of that substance without modifying its chemical structure. A salt form can have a dramatic influence on the properties of the drug, which includes yield, quantity of the crystalline structure, hygroscopicity, stability, solubility and the ease of formulation.
The present inventors have prepared oxalate salt of quetiapine, which is found to be stable and having improved solubility in water than the known hemifumarate salt.
The present inventors have also prepared hereto unknown, three crystalline polymorphic forms of quetiapine hydrochloride (hereinafter referred to as Forms A, B, C respectively) and an amorphous form. Further, the present inventors have also prepared hereto unknown, a crystalline polymorphic form of quetiapine maleate. These
crystalline forms have characteristically different XRPD pattern as compared to known crystalline forms and offer distinct advantage over the known forms of hydrochloride or maleate in terms of stability and solubility.
A first aspect of the invention provides quetiapine oxalate. The oxalate salt exists in crystalline form having X-Ray Powder Diffraction (XRPD) pattern and Fourier Transform Infra-red (FTIR) spectrum as provided in Figure 1 and 2 respectively. The oxalate salt of quetiapine has improved solubility in water when compared with quetiapine hemifumarate salt. The oxalate salt in addition is stable and can be processed with ease.
A second aspect of the invention provides a process for the preparation of acid addition salt of quetiapine, wherein the said process comprises of:
a) treating quetiapine fumarate with a base to get quetiapine free base,
b) treating the quetiapine free base obtained in step a) with desired acid,
c) isolating acid addition salt of quetiapine from the reaction mass thereof.
Quetiapine fumarate used is prepared through various methods, which are known to a person of ordinary skills in the art. Quetiapine fumarate is mixed one or more solvents, selected from the group comprising of water, esters, lower alkanols, ethers, ketones, halogenated hydrocarbons or mixtures thereof. The reaction mixture is basified with a base selected from inorganic or organic bases such as alkali and alkaline earth metal hydroxide or alkoxide, ammonia, triethylamine, dicyclohexylamine amine or diisopropylamine and the like. The organic layer is concentrated to an oily mass and is dissolved in an organic solvent selected from the group comprising of esters, lower alkanols, ethers, ketones, halogenated hydrocarbons or mixtures thereof. The resultant mixture is acidified with a suitable acid and stirred. The precipitated solids are filtered, washed and dried to yield Quetipine acid addition salt.
The acid used is inorganic or organic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, oxalic acid, maleic
acid, fumaric acid, succinic acid, citric acid, methane sulphonic acid, acetic acid and the like.
A third aspect of the present invention provides polymorphic Form A of quetiapine hydrochloride having XRPD pattern as depicted in Figure 3 of the accompanied drawing wherein characteristic 29 values are obtained at 6.74, 7.96, 12.88, 13.62, 14.36, 14.58, 14.98, 15.98, 18.56, 20.40, 21.74, 22.04, 24.06, 25.26, 25.52, 26.40, 27.12, 28.10, 30.38, 31.18. The FTIR spectrum of Form A of quetiapine hydrochloride in potassium bromide is depicted in Figure 4 of the accompanied drawing.
A fourth aspect of the present invention provides polymorphic Form B of quetiapine hydrochloride having XRPD pattern as depicted in Figure 5 of the accompanied drawing wherein characteristic 20 values are obtained at 5.22, 6.88, 8.00, 10.36, 11.66, 13.08, 13.68, 14.80, 15.56, 16.10, 16.58, 17.32, 17.98, 18.70, 19.42, 20.80, 22.64, 24.06, 25.20, 25.54, 31.40. The FTIR spectrum of Form B of quetiapine hydrochloride in potassium bromide is depicted in Figure 6 of the accompanied drawing.
A fifth aspect of the present invention provides polymorphic Form C of quetiapine hydrochloride having XRPD pattern as depicted in Figure 7 of the accompanied drawing wherein characteristic 29 values are obtained at 5.46, 7.98, 10.12, 10.94, 11.64, 12.94, 13.62, 14.20, 14.54, 15.90, 16.44, 16.74, 17.96, 18.84, 20.28, 22.02, 22.50, 23.64, 24.02, 25.18, 25.48, 26.10, 29.28, 30.32. The FTIR spectrum of Form C of quetiapine hydrochloride in potassium bromide is depicted in Figure 8 of the accompanied drawing.
A sixth aspect of the present invention provides amorphous quetiapine hydrochloride having XRPD pattern as depicted in Figure 9 of the accompanied drawing. The amorphous quetiapine hydrochloride is found to stable, non-hygroscopic and more soluble in water as compared to any other crystalline form.
A seventh aspect of the present invention provides polymorphic Form I of quetiapine maleate having XRPD pattern as depicted in Figure 10 of the accompanied drawing
wherein characteristic 20 values are obtained at 6.32, 11.06, 11.64, 12.76, 13.80, 14.48, 15.26, 16.30, 16.76, 18.82, 19.56, 20.06, 20.32, 20.88, 21.88, 22.26, 22.94, 23.46, 23.72, 24.58, 25.02, 26.06, 26.58, 29.48. The FTIR spectrum of polymorphic Form I of quetiapine maleate in potassium bromide is depicted in Figure 11 of the accompanied drawing.
The above polymorphic forms of the quetiapine salts are prepared by the process described in the second aspect of this present invention.
An eighth aspect of the present invention provides a pharmaceutical composition comprising Form A or Form B or Form C or amorphous form of quetiapine hydrochloride optionally containing an excipient / diluent.
A ninth aspect of the present invention provides a pharmaceutical composition comprising quetiapine oxalate optionally containing an excipient / diluent.
A tenth aspect of the present invention provides a pharmaceutical composition comprising or polymorphic Form I of quetiapine maleate optionally containing an excipient / diluent.
An eleventh aspect of the present invention provides a method of treating schizophrenia, acute manic episodes associated with bipolar I disorder comprising administering to a mammal in need thereof a therapeutically effective amount of Form A or Form B or Form C or amorphous form of quetiapine hydrochloride or quetiapine oxalate or polymorphic Form of quetiapine maleate.
A twelfth aspect of the present invention provides a method of treating schizophrenia, acute manic episodes associated with bipolar I disorder comprising administering to a mammal in need thereof a therapeutically effective amount of quetiapine oxalate.
An eleventh aspect of the present invention provides a method of treating schizophrenia, acute manic episodes associated with bipolar I disorder comprising administering to a mammal in need thereof a therapeutically effective amount of polymorphic Form I of quetiapine maleate.
Figure 1 depicts XRPD of quetiapine oxalate Figure 2 depicts FTIR of quetiapine oxalate Figure 3 depicts XRPD of Form A of quetiapine hydrochloride Figure 4 depicts FTIR of Form A of quetiapine hydrochloride Figure 5 depicts XRPD of Form B of quetiapine hydrochloride Figure 6 depicts FTIR of Form B of quetiapine hydrochloride Figure 7 depicts XRPD of Form C of quetiapine hydrochloride Figure 8 depicts FTIR of Form C of quetiapine hydrochloride Figure 9 depicts XRPD of amorphous quetiapine hydrochloride Figure 10 depicts XRPD of Form I of quetiapine maleate Figure 11 depicts FTIR of Form I of quetiapine maleate
Powder XRPD of the samples were determined by using X-Ray Difractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A
FTIR of the samples were determined by using Instrument: Perkin Elmer, 16 PC, SCAN: 16scans, 4.0 cm"1, according to the USP 25, general test methods page 1920, infrared absorption spectrum by potassium bromide pellet method.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
PREPARATION OF QUETIAPINE OXALATE
Quetiapine fumarate (50 g) was charged to water (500 ml) and ethyl acetate (500 ml) at room temperature. Ammonia solution was added with stirring till pH 10. The organic phase was separated and washed with water (500 ml X 2). Organic layer was concentrated to oily mass under reduced pressure at 45-50°C. The obtained oil was dissolved in acetone (750 ml) and heated to 45-48°C. Oxalic acid (14.9 g in acetone (375 ml) at 45°C) was added in one lot and stirred for 30 minutes at 45-48°C. The mixture was further stirred at room temperature for one hour, filtered, washed with acetone (250 ml) and dried at 45°C under reduced pressure to obtain the title compound. Yield: 46.0 g
EXAMPLE 2
PREPARATION OF MORPH A OF QUETIAPINE HYDROCHLORIDE
Quetiapine fumarate (50 g) was charged to water (500 ml) and ethyl acetate (500 ml) at room temperature. Ammonia solution was added with stirring till pH 10. The organic phase was separated and washed with water (500 ml X 2). Organic layer was concentrated to oily mass under reduced pressure at 45-50°C. The obtained oil was dissolved in isopropanol (200 ml) and water (12.5 ml). Concentrated hydrochloric acid (23.5 ml) was added at room temperature. To the obtained solid, ethyl acetate (500 ml) was added in 15 minutes and the reaction mixture was stirred and filtered. The solid was dried at 45-50°C under vacuum to obtain the title compound.
EXAMPLE 3
PREPARATION OF MORPH B OF QUETIAPINE HYDROCHLORIDE
Quetiapine fumarate (1 g) was charged to water (10 ml) and ethyl acetate (10 ml) at room temperature. Ammonia solution was added with stirring till pH 10. The organic phase was separated and washed with water (10 ml X 2). Organic layer was concentrated to oily mass under reduced pressure at 45-50°C. The obtained oil was dissolved in isopropanol (4 ml). It was acidified with isopropanol-hydrochloride. To this mixture, ethyl acetate (20 ml) was added and stirred. Again ethyl acetate (10 ml) was added and stirred for one hour. The solid obtained was filtered, washed with ethyl acetate and dried at 45-50°C under vacuum to obtain the title compound. Yield: 0.8 g
EXAMPLE 4
PREPARATION OF MORPH C OF QUETIAPINE HYDROCHLORIDE
Quetiapine fumarate (1 g) was charged to water (10 ml) and ethyl acetate (10 ml) at room temperature. Ammonia solution was added with stirring till pH 10. The organic phase was separated and washed with water (10 ml X 2). Organic layer was concentrated to oily mass under reduced pressure at 45-50°C. The obtained oily mass was dissolved in isopropanol (4 ml) and acidified with concentrated hydrochloride. To this mixture, ethyl acetate (20 ml) was added dropwise. The mixture was further stirred for one hour and left for over night. The solid obtained was filtered, dried at 45-50°C under vacuum to obtain the title compound. Yield: 0.66 g
EXAMPLE 5
PREPARATION OF AMORPHOUS QUETIAPINE HYDROCHLORIDE
Quetiapine fumarate (20 g) was charged to water (200 ml) and ethyl acetate (200 ml) at room temperature. Ammonia solution was added with stirring till pH 10. The organic phase was separated and washed with water (200 ml X 2). Organic layer was concentrated to oily mass under reduced pressure at 45-50°C. The obtained oily mass was dissolved in ethyl acetate (200 ml) and acidified with dry hydrochloride gas till pH 1.0 at 10°C. The sticky mass was stirred for one hour, filtered and dried at 45-50°C under vacuum to obtain the title compound. Yield: 17.5 g
EXAMPLE 6
PREPARATION OF FORM I OF QUETIAPINE MALEATE
Quetiapine fumarate (50 g) was charged to water (500 ml) and ethyl acetate (500 ml) at room temperature. Ammonia solution was added with stirring till pH 10. The organic phase was separated and washed with water (500 ml X 2). Organic layer was concentrated to oily mass under reduced pressure at 45-50°C. The obtained oil was dissolved in ethyl acetate (500 ml) and heated to 60-65°C. Maleic acid solution (13.05 g in 420 ml ethyl acetate at 50-60°C) was added in one lot and stirred for 10 minutes at 65°C and cooled to room temperature. The solid obtained was filtered, washed with ethyl acetate (100 ml X 2) and dried at 40°C under reduced pressure to obtain the title compound.

WE CLAIM:
1. An oxalate salt of quetiapine.
2. A process for the preparation of acid addition salt of quetiapine, wherein the said process comprises of:

a) treating quetiapine fumarate with a base to get quetiapine free base,
b) treating the quetiapine free base obtained in step a) with desired acid,
c) isolating acid addition salt of quetiapine from the reaction mass thereof.

3. A process according to claim 2, wherein the acid used in step b) is selected form the group comprising of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, citric acid, methane sulphonic acid, acetic acid.
4. Form A of quetiapine hydrochloride having X-Ray powder Diffraction (XRPD) pattern wherein characteristic 26 values are obtained at 6.74, 7.96, 12.88, 13.62, 14.58, 14.98, 15.98, 18.56, 20.40, 22.04, 24.06, 25.52, 26.40, 27.12, 28.10, 30.38..
5. Form B of quetiapine hydrochloride having X-Ray powder Diffraction (XRPD) pattern wherein characteristic 26 values are obtained at 5.22, 6.88, 8.00, 10.36, 11.66, 13.08, 13.68, 14.80, 15.56, 16.10, 16.58, 17.32, 17.98, 18.70, 19.42, 20.80, 22.64, 24.06, 25.20,25.54,31.40..
6. Form C of quetiapine hydrochloride having X-Ray powder Diffraction (XRPD) pattern wherein characteristic 26 values are obtained at 5.46, 7.98, 10.12, 10.94, 11.64, 12.94, 13.62, 14.54, 15.90, 16.44, 16.74, 18.84, 20.28, 22.02, 22.50, 23.64, 24.02, 26.10, 29.28, 30.32..
7. Amorphous quetiapine hydrochloride having X-Ray powder Diffraction (XRPD)
pattern as depicted in Figure 9..
8. A polymorphic Form I of quetiapine maleate having X-Ray powder Diffraction (XRPD) pattern wherein characteristic 26 values are obtained at 6.32, 11.06, 11.64, 12.76, 13.80, 14.48, 15.26, 16.30, 16.76, 18.82, 19.56, 20.06, 20.32, 20.88, 21.88, 22.94, 23.46, 24.58, 25.02, 26.06, 26.58, 29.48..
9. A pharmaceutical composition comprising Form A or Form B or Form C of quetiapine hydrochloride optionally containing an excipient / diluent.

10. A pharmaceutical composition comprising amorphous quetiapine hydrochloride optionally containing an excipient / diluent.
11. A pharmaceutical composition comprising quetiapine oxalate or polymorphic form, solvate, hydrate thereof optionally containing an excipient / diluent.
12. A pharmaceutical composition comprising polymorphic Form I of quetiapine maleate optionally containing an excipient / diluent.
13. A method of treating schizophrenia, acute manic episodes associated with bipolar I disorder comprising administering to a mammal in need thereof a therapeutically effective amount of Form A or Form B or Form C of quetiapine hydrochloride.
14. A method of treating schizophrenia, acute manic episodes associated with bipolar I disorder comprising administering to a mammal in need thereof a therapeutically effective amount of amorphous quetiapine hydrochloride.
15. A method of treating schizophrenia, acute manic episodes associated with bipolar I disorder comprising administering to a mammal in need thereof a therapeutically effective amount of quetiapine oxalate or polymorphic form, solvate, hydrate thereof.
16. A method of treating schizophrenia, acute manic episodes associated with bipolar I disorder comprising administering to a mammal in need thereof a therapeutically effective amount of polymorphic Form I of quetiapine maleate.