Title of Invention	PROCESS FOR PREPARATION OF QUETIAPINE FUMARATE POLYMORPHS
Abstract	The present Invention relates to processes for the preparation of quetiapine fumarate polymorphic forms. Thus, for example, quetiapine free base is dissolved in acetone, fumaric acid is added, the contents are heated for complete dissolution and then collected the resulting solid at 20 -2SoC to give quetiapine fumarate polymorphic form I.

Full Text

I he present invention relates to novel polymorphic forms of quetiapine fumarate, processes for their preparation and pharmaceutical compositions containing them. BACKGROUND OF THE INVENTION 2-[2-(4-Dibenzo[b,f]-[1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]ethanol (quetiapine) and its salts were disclosed in Eur. Pat. No. 0240228 and they are useful for their antidopaminergic activity, for example, as an antipsychotic or neuroleptic. Various processes for preparation of quetiapine and 2-[2-(4-Dibenzo[b,f]-[1,4]thiazepin-11 -yl-1 -piperazinyl)ethoxy]ethanol hemifumarate (quetiapine fumarate) were described in EP 0240 228, EP 0282236, WO 01/55125 and WO 99/06381. According to the teachings of literature, quetiapine fumarate was crystallized from ethanolic solution containing quetiapine free base and fumaric acid. Quetiapine fumarate prepared according this method fails to produce well defined reproducible crystalline form. It has now been discovered stable, reproducible two crystalline forms of quetiapine fumarate. It has also been discovered that the crystalline forms of quetiapine fumarate can be obtained in very pure state. Thus, they can be used as active ingredients in pharmaceutical preparations. Thus, the object of the present invention is to provide quetiapine fumarate in stable and reproducible crystalline forms, processes for their preparation and pharmaceutical composition containing them. The present invention also provides amorphous form of quetiapine with adequate stability and good dissolution properties. Thus another object of the present invention is to provide amorphous form of quetiapine fumarate, a process for preparing it and a pharmaceutical composition containing it. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel crystalline form of quetiapine fumarate, which is designated as form I. Quetiapine fumarate crystalline Form I is characterized by x-ray powder diffraction pattern having significant reflections expressed as 29 values at about 7.3, 9.2, 11.6, 13.3, 14.4, 14.8, 15.3, 15.9, 16.2, 16.7, 17.6, 19.1, 19.7, 20.1, 20.8, 21.1, 21.8, 22.3, 23.4, 24.3, 24.7, 25.1, 25.6, 27.1, 28.5, 29.5, 33.2, 40.4 deg. x-Ray powder diffractogram of quetiapine fumarate crystalline Form I is shown in Figure 1 . The major peaks and their intensities of x-ray powder diffractogram are shown in Table 1. The intensities of the reflections are expressed as percent of most intense reflection. A further aspect of the present invention provides a process for the preparation of quetiapine fumarate crystalline Form I. Quetiapine fumarate crystalline Form I is prepared by dissolving quetiapine free base and fumaric acid in a suitable solvent and crystallizing fumarate salt. This crystallization from the suitable solvent is an effective method of removing impurities. A further aspect of the present invention thus provides quetiapine fumarate crystalline Form I which is substantially pure, for example at least 98 % preferably at least 99 %, more preferably at least 99.5 % pure. Preferably molar ratio of quetiapine free base to fumaric acid is between about 1:0.4 to about 1:1. The suitable solvents are ketones like acetone, methyl iso butyl ketone; esters like ethyl acetate, ethyl formate, methyl acetate; and mixture thereof. The preparation of quetiapine free base is described, for example in EP 0240228. Crystallization of quetiapine fumarate from solution may be initiated by conventional means such as addition of a non-solvent, evaporation of solvent, cooling or seeding the solution. The present invention also provides another novel crystalline form of quetiapine fumarate, which is designated as Form II. Quetiapine fumarate crystalline Form II is characterized by x-ray powder diffraction pattern having significant reflections expressed as 29 values at about 4.9, 7.4, 9.2, 11.7, 13.4, 14.4, 14.9, 15.4, 15.9, 16.3, 16.7, 17.7, 18.6, 19.8, 20.2, 20.8, 21.2, 21.9, 22.4, 22.9, 23.4, 24.3, 24.7, 25.2, 25.7, 26.9, 27.8, 28.8, 29.4, 33.2, 35.9, 38.0, 38.7, 39.9, 42.8 deg. x-Ray powder diffractogram of quetiapine fumarate Form II is shown in Fig. 2. The major peaks and their intensities of x-ray powder diffractogram are shown in table 2. The intensities of the peaks are expressed as percent of most intense reflection. A further aspect of the present invention provides a process for the preparation of quetiapine fumarte Form II. Quetiapine fumarate crystalline Form II is prepared by dissolving quetiapine free base in methyl tert. butyl ether, heating to reflux, adding fumaric acid at reflux, maintaining at reflux for about 30 minutes to about 1 hour, cooling to 20-30°C, maintaining for about 30 minutes with or without stirring, optionally seeding with quetiapine fumarate crystalline Form II, filtering and washing the crystals formed with methyl tert. butyl ether. Preferably molar ratio of quetiapine free base to fumaric acid is between about 1:0.4 to about 1:1. The present invention also provides a novel amorphous form of quetiapine fumarate, which is designated as amorphous quetiapine fumarate. The amorphous quetiapine fumarate is characterized by having broad x-ray diffraction maximum expressed as 20 between about 10 and about 30 deg. A further aspect of the present invention provides a process for the preparation of amorphous quetiapine fumarate. Amorphous quetiapine fumarate may be prepared by dissolving quetiapine fumarate in a solvent mixture, removing the solvent from the solution. Quetiapine fumarate crystalline Form I or Form II, which are obtained as described herein above, or quetiapine fumarate obtained by previously known methods may be used for the preparation of amorphous quetiapine fumarate. The solvent mixture comprises chloroform and methanol in a ratio between about 1:0.5 and 1:2 volume/volume, preferably in the ratio of 1:1 volume/volume. The solvent can be removed form the solution by techniques such as vacuum drying or spray drying. A further aspect of the present invention provides a pharmaceutical composition comprising an effective amount of quetiapine fumarate polymorphic form and a pharmaceutical^ acceptable carrier. The quetiapine fumarate polymorphic forms include quetiapine fumarate crystalline Form I, quetiapine fumarate crystalline Form II and amorphous quetiapine fumarate. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is x-ray powder diffraction pattern of quetiapine fumarate crystalline Form I. Figure 2 is x-ray powder diffraction pattern of quetiapine fumarate crystalline Form II. Figure 3 is x-ray powder diffractogram of amorphous quetiapine fumarate. The x-ray powder diffraction spectra was measured on a Siemens D-5000 diffractometer. The following examples are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. Example 1 Quetiapine free base (5 gm) obtained by the process described in EP 0240228 (example 1) is dissolved in acetone (60 ml). To this solution, fumaric acid (0.9 gm) is added and then heated for complete dissolution. The solution is cooled to 20 to 25°C and maintained for 1 hour. The product obtained is filtered washed with acetone and dried to give 4.9 gm of quetiapine fumarate Form I. (HPLC purity: 99.8 %). Example 2 Example 1 is repeated using 60 ml ethyl acetate instead of acetone. Yield of quetiapine fumarate Form I is 5.2 gm (HPLC purity: 99.6 %). Example 3 Example 1 is repeated by seeding the solution with quetiapine fumarate Form 1 during maintenance at 20 to 25°C. Yield of quetiapine fumarate Form I is 5.2 gm (HPLC purity: 99.8 %). Example 4 Quetiapine free base (10 gm), obtained by the process described in example 1 Of EP 024099ft is rliQQnlv/*arl in mothwl tort hi itwl other Mnn ™i\ Th** solution is heated to reflux and fumaric acid (1.5 gm) is added at reflux. The refluxing is continued for 45 minutes, cooled to 20-25°C and stirred for 30 minutes. The resulting crystals are filtered washed with methyl tert. butyl ether and dried to give 19.2 gm of quetiapine fumarate Form It. Example 5 Example 4 is repeated by seeding the contents during maintenance at 20 to 25°C with quetiapine fumarate Form II. The yield of quetiapine fumarate Form II is 19.5 gm. Example 6 Quetiapine fumarate (2 gm) obtained by the process described in example 4 of EP 0240228 added to a solvent mixture containing methanol (10 ml) and chloroform (10 ml). The contents are heated to 40-45°C for dissolution and the clear solution is subjected to vacuum drying at 35-40°C for 15 to 20 hours to give 1.9 gm of amorphous quetiapine fumarate. Example 7 Example 6 is repeated using quetiapine fumarate Form I instead of quetiapine fumarate. The yield of amorphous quetiapine fumarate is 1.8 gm. Example 8 Example 6 is repeated by subjecting the clear solution to spray drying instead of vacuum drying to give 1.8 gm of amorphous quetiapine fumarate. We claim: 1) A process for the preparation of quetiapine fumarate polymorphs, crystalline form I, characterized by an x-ray powder diffractogram having peaks expressed as 29 at about 7.3, 9.2, 11.6, 13.3, 14.4, 14.8, 15.3, 15.9, 16.2, 16.7, 17.6, 19.1, 19.7, 20.1, 20.8, 21.1, 21.8, 22.3, 23.4, 24.3, 24.7, 25.1, 25.6, 27.1, 28.5, 29.5, 33.2, 40.4 degrees; crystalline form II, characterized by an x-ray powder diffractogram having peaks expressed as 28 at about 4.9, 7.4, 9.2, 11.7, 13.4, 14.4, 14.9, 15.4, 15.9, 16.3, 16.7, 17.7, 18.6, 19.8, 20.2, 20.8, 21.2, 21.9, 22.4, 22.9, 23.4, 24.3, 24.7, 25.2, 25.7, 26.9, 27.8, 28.7, 29.4, 33.2, 35.9, 38.0, 38.7, 39.9, 42.8 degrees; amorphous form, characterized by having x-ray powder diffractogram as shown in figure 3; as herein described comprising the steps of; a) either i) dissolving quetiapine free base in a specific organic solvent selected from the group consisting of acetone, methyl isobutyl ketone, ethyl acetate, ethyl formate, methyl acetate and methyl tert. butyl ether, and adding fumaric acid to the solution, or ii) dissolving quetiapine fumarate in a combination of specific organic solvents chloroform and methanol; and b) collecting i) quetiapine fumarate crystalline polymorph form I from the solution obtained in step (a)(i) when acetone, methyl isobutyl ketone, ethyl acetate, ethyl formate, methyl acetate are used as the solvents; ii) quetiapine fumarate crystalline polymorph form II from the solution obtained in step (a)(i) when methyl tert. butyl ether is used as the solvent; iii) amorphous quetiapine fumarate by removing the solvents from the solution obtained in step (a)(ii) either by vacuum drying or by spray drying. 2) The process as claimed in claim 1, wherein the process comprising the steps of: a) dissolving quetiapine free base and fumaric acid in a solvent selected from the group consisting of acetone, methyl isobutyl ketone, ethyl acetate, ethyl formate and methyl acetate; b) crystallizing quetiapine fumarate crystalline polymorph form I from the solution formed in step (a) at 20 - 25°C. 3) The process as claimed in claim 2, wherein the solvent is acetone. 4) The process as claimed in claim 2, wherein the solvent is ethyl acetate. 5) The process as claimed in claim 2, wherein the crystallization is initiated by seeding with quetiapine fumarate Form I. 6) The process as claimed in claim 1, wherein the process comprising the steps of dissolving quetiapine free base in methyl tert. butyl ether, heating to reflux, adding fumaric acid at reflux, maintaining at reflux for about 30 minutes to about 1 hour, cooling to about 20 to 30°C, maintaining for about 30 minutes with or without stirring, optionally seeding, and collecting the crystals formed with quetiapine fumarate Form II. 7) The process as claimed in claim 6, wherein the solution is seeded with quetiapine fumarate Form II. 8) The process as claimed in claim 1, wherein the process comprising the steps of: a) dissolving quetiapine fumarate in a mixture of chloroform and methanol; and b) removing the solvents from the solution formed in step (a) either by vacuum drying or by spray drying to obtain amorphous quetiapine fumarate. 9) The process as claimed in claim 8, wherein the solvents are removed by vacuum drying. 10) The process as claimed in claim 8, wherein the solvents are removed by spray drying.

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746-chenp-2003-abstract.pdf

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