WO2007102074A2

WO2007102074A2 - Salts of quetiapine

Info

Publication number: WO2007102074A2
Application number: PCT/IB2007/000537
Authority: WO
Inventors: Tejas Chandrakant Shah; Manoj Kumar Singh; Jay Shantilal Kothari; Virendra Kumar Agrawal
Original assignee: Cadila Healthcare Ltd
Current assignee: Zydus Lifesciences Ltd
Priority date: 2006-03-07
Filing date: 2007-03-07
Publication date: 2007-09-13
Anticipated expiration: 2008-09-07
Also published as: WO2007102074A3

Abstract

Novel Salts of Quetiapine are disclosed. These salts of the formula (II) wherein S represents an acid selected from the group consisting of benzoic acid, tartaric acid, oxalic acid, p-toluene sulfonic acid, naphthalene sulfonic acid, succinic acid, malic acid, hydrobromic acid; which forms a salt with Quetiapine.

Description

SALTS OF QUETIAPINE Field of the invention

The present invention relates to novel salts of Quetiapine or its solvates and process for preparing the novel salts of Quetiapine. Quetiapine, which is the generic name for the compound of formula (I), 2-[2-(4-dibenzo [b,f ] [l,4]thiazepin-l l-yl-l- piperazinyl)ethoxy]-ethanol, is an orally active dosage form is a dopamine and serotonin, specifically D₁, D₂, 5-HT_1A and 5-HT₂, inhibitor or antagonist and useful for the treatment of psychotic disorders and symptoms such as hallucinations, delusions, and hostility.

(I) Background of the invention

Compounds used as antipsychotics and neuroleptics have, however, been plagued by the problems of undesired side effects. Such side effects include acute dyskinesias, acute dystonias, motor restlessness, pseudo-Parkinsonism and tardive dyskinesias (TD). Acute syndromes usually have an early onset, for example, 1 to 5 days for acute dystonias and dyskinesias, and may include torsion spasms, muscle spasms and dystonia of the face, neck or back with protrusion of the tongue and tonic spasms of the limbs (dyskinesia). Tardive dyskinesia has a time of maximal risk after months or years of treatment. TD's comprise oral-facial dyskinesia, lingual-facial-buc- cal-cervical dystonias sometimes with involvement of the trunk and extremities. TD's also include repetitive stereotypical movements of the face, tongue and limb such as sucking and smacking of the lips, lateral jaw movements and protrusions of the tongue. When the antipsychotic drug treatment is stopped the symptoms continue, often for months or years. These involuntary movements constitute the most undesirable side effect of antipsychotic drug treatment; for example, the percentage of patients that develop TD has been variously reported to be as high as 20 percent. Schizophrenia is a serious and disabling psychiatric disorder affecting approximately 1% of the world's population, with its economic cost in the United States alone estimated to exceed that of all cancers combined. The new generation of atypical antipsychotics introduced over the past decade have comparable or greater efficacy than traditional antipsychotics in treating the psychotic symptoms of schizophrenia and a much improved neurologic side effect profile. Quetiapine, a dibenzothiazepine derivative, is an atypical antipsychotic with, theoretically, a low propensity for movement disorder adverse effects, marketed in the United States as its salt with fumaric acid, was approved by the U.S. Food and Drug Administration in September 1997 and is also currently approved in over 70 countries worldwide for the treatment of psychosis associated with schizophrenia.

Quetiapine was first time disclosed in US patent no. 4879288. It also discloses its hydrochloride salt, hemifumarate and maleate salt.

Although Quetiapine fumarate provides good pharmaceutical activity, it would be beneficial to find other forms of Quetiapine. In particular, Quetiapine forms that are easier to handle would be advantageous. Quetiapine fumarate, hydrochloride and maleate are relatively aggressive towards handling equipment (corrosive) and are irritating to the skin, etc. of human personnel that handle the pure active. A Quetiapine form that is less aggressive and less irritating would be desirable. It is further desirable to provide a Quetiapine form that can be easily formulated into various dosage forms. Objects of the Invention

The object of the present invention is to provide a novel salts of Quetiapine with organic acid or its hydrate.

Another object of the present invention is to provide a process for preparing novel salts of Quetiapine with organic acid or its hydrate.

Yet another object of the present invention is to provide a pharmaceutical composition comprising a novel salt of Quetiapine salts. Description of the invention

The present invention provides novel salts of Quetiapine of formula (II)

(H) wherein in S represent the acid selected from the group consisting of benzoic acid, tartaric acid, oxalic acid, p-toluene sulfonic acid, naphthalene sulfonic acid, succinic acid, malic acid, hydrobromic acid; which forms a salt with Quetiapine. Accordingly, a first aspect of the invention relates to new salts of Quetiapine, namely Quetiapine benzoate, Quetiapine tartrate, Quetiapine oxalate, Quetiapine tosylate, Quetiapine naphsylate, Quetiapine succinate, Quetiapine maleate, Quetiapine hydrobromide compounds or its hydrate. The compound can be isolated and/or purified or it can be part of a composition. The compound can be in solid form including crystalline forms but is not limited thereto. Preferred compounds are in the form of crystalline Quetiapine salts or its hydrate.

Another aspect of the present invention relates to the process for preparing novel salt of Quetiapine of formula (II)

(H) wherein in S represent the acid selected from the group consisting of benzoic acid, tartaric acid, oxalic acid, p-toluene sulfonic acid, naphthalene sulfonic acid, succinic acid, malic acid, hydrobromic acid, which comprises reacting Quetiapine of formula (I) with acid selected from the group consisting of benzoic acid, tartaric acid, oxalic acid, p-toluene sulfonic acid, naphthalene sulfonic acid, succinic acid, malic acid, hydrobromic acid to give the novel salts of formula (II). The reaction of acid with Quetiapine (I) is preferably carried out in organic solvent or in mixture with water.

Another aspect of the present invention relates to a pharmaceutical composition comprising an effective amount of Quetiapine salt of formula (II), a pharmaceutically acceptable excipient. The composition can be an immediate release dosage form or an extended release dosage form and embraces tablets as well as pellets/beads/spheroids or other encapsulated forms.

The compound can be in isolated and/or purified form, but such is not required. The compound includes various physical forms of the salt including dissolved forms, oil or liquid forms, and solid forms including amorphous and crystalline forms.

The novel salt of Quetiapine is typically in a crystalline form. Crystalline forms include Quetiapine salts with organic acid such as described above, anhydrates, hydrates, and solvates.

The Quetiapine salts (II) can be isolated, if desired, by precipitation, evaporation, spray drying, or other conventional techniques known in the art.

According to another aspect of the present invention relates to the crystalline form of Quetiapine malate. The crystalline form of Quetiapine malate is herein after designated as "Form I". The Form I of Quetiapine malate is characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 7.1, 9.0, 16.0, 21.0 degrees. The form I of Quetiapine malate is further characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 11.4, 14.7, 15.1, 16.5, 17.4, 21.6, 22.1, 23.1 degrees. FIG. 1 shows typical Form I x-ray powder diffraction pattern.

The present invention also provides a process for preparing crystalline form of Quetiapine malate, which comprises treating Quetiapine with malic acid. The reaction is preferably carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting malate. Advantageously, both Quetiapine and the malic acid are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of Quetiapine and a solvent may be contacted with a malic acid, or conversely, a mixture, slurry, or solution of malic acid and a solvent may be contacted with Quetiapine. In another embodiment, both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for malic acid may be identical with or different from the solvent system used for the Quetiapine. The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two phase reaction scheme may be used wherein the Quetiapine and malic acid are primarily reacted in one phase and the resulting Quetiapine malate compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include water, a lower alcohol (C₁- Cg) such as methanol, ethanol, isopropanol, n-propanol, n- butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, di isoproipyl ether, dioxane and the like.

The temperature of contact of Quetiapine and malic acid in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e., a slurry or two phase solution are also possible, though a single solution is generally preferred.

The Quetiapine malate compound can be isolated or recovered from the salt forming reaction by any convenient means. For example, the Quetiapine malate compound can be precipitated out of a solution or reaction mixture. The precipitation may be spontaneous depending upon the solvent system used and the conditions. Alternatively, the precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent or by adding a contra solvent, i.e. a liquid miscible with the solvent in which the Quetiapine malate is less soluble. Seed crystals of Quetiapine malate may also be added to help induce precipitation. The precipitated Quetiapine malate compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure.

Alternatively, Quetiapine malate can be isolated by evaporating the solvent and collecting residue. Such a method generally leads to an oil or solid amorphous form of Quetiapine malate. Similarly, an amorphous solid form of the Quetiapine malate compound can be recovered by spray drying a solution containing the Quetiapine malate compound.

In the preferred embodiment, Quetiapine base (I) is dissolved in ethyl acetate and treated with malic acid to obtain Form I of Quetiapine malate. According to another aspect of the present invention relates to the crystalline form of Quetiapine succinate. The crystalline form of Quetiapine succinate is herein after designated as "Form II". The Form II of Quetiapine succinate is characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 7.4, 9.3, 20.0, 22.5 degrees. The Form II of Quetiapine succinate is further characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 11.8, 13.5, 16.7, 17.5, 21.3, 25.2 degrees. FIG. 2 shows typical Form II x-ray powder diffraction pattern.

The Form II of Quetiapine succinate is characterized by its Differential Scanning Calorimetry (DSC), which shows peaks at about 115-118⁰C.

The present invention also provides a process for preparing crystalline form of Quetiapine succinate, which comprises treating Quetiapine with succinic acid.

The reaction is preferably carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting succinate. Advantageously, both Quetiapine and the succinic acid are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of Quetiapine and a solvent may be contacted with a succinic acid, or conversely, a mixture, slurry, or solution of succinic acid and a solvent may be contacted with Quetiapine. In another embodiment, both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for succinic acid may be identical with or different from the solvent system used for the Quetiapine. The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two phase reaction scheme may be used wherein the Quetiapine and succinic acid are primarily reacted in one phase and the resulting Quetiapine succinate compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include water, a lower alcohol (Ci- C₆) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, diisoproipyl ether, dioxane and the like.

The temperature of contact of Quetiapine and succinic acid in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e. a slurry or two phase solution are also possible, though a single solution is generally preferred.

The Quetiapine succinate compound can be isolated or recovered from the salt forming reaction by any convenient means. For example, the Quetiapine succinate can be precipitated out of a solution or reaction mixture. The precipitation may be spontaneous depending upon the solvent system used and the conditions. Alternatively, the precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent or by adding a contra solvent, i.e. a liquid miscible with the solvent in which the Quetiapine succinate is less soluble. Seed crystals of Quetiapine succinate may also be added to help induce precipitation. The precipitated Quetiapine succinate compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure.

Alternatively, Quetiapine succinate can be isolated by evaporating the solvent and collecting residue. Such a method generally leads to an oil or solid amorphous form of Quetiapine succinate. Similarly, an amorphous solid form of the Quetiapine succinate compound can be recovered by spray drying a solution containing the Quetiapine succinate compound.

In the preferred embodiment, Quetiapine base (I) is dissolved in acetone and treated with succinic acid to obtain Form II of Quetiapine succinate.

According to another aspect of the present invention relates to the crystalline form of Quetiapine tosylate. The crystalline form of Quetiapine tosylate is herein after designated as "Form III". The Form III of Quetiapine tosylate is characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 11.3, 12.2, 12.7, 13.3, 17.3 degrees. The Form III of Quetiapine tosylate is further characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 14.6, 14.9, 20.6, 21.1, 22.9, 23.1, 23.6 degrees. FIG. 3 shows typical Form III x-ray powder diffraction pattern.

The present invention also provides a process for preparing crystalline form of Quetiapine tosylate, which comprises treating Quetiapine with p-toluene sulfonic acid. The reaction is preferably carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting tosylate. Advantageously, both Quetiapine and the p-toluene sulfonic acid are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of Quetiapine and a solvent may be contacted with a p-toluene sulfonic acid, or conversely, a mixture, slurry, or solution of p-toluene sulfonic acid and a solvent may be contacted with Quetiapine. In another embodiment, both' partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for p-toluene sulfonic acid may be identical with or different from the solvent system used for the Quetiapine. The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two phase reaction scheme may be used wherein the Quetiapine and p-toluene sulfonic acid are primarily reacted in one phase and the resulting Quetiapine tosylate compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include water, a lower alcohol (Ci- C₆) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, di isoproipyl ether, dioxane and the like. The temperature of contact of Quetiapine and p-toluene sulfonic acid in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e. a slurry or two phase solution are also possible, though a single solution is generally preferred. The Quetiapine tosylate compound can be isolated or recovered from the salt forming reaction by any convenient means. For example, the Quetiapine tosylate can be precipitated out of a solution or reaction mixture. The precipitation may be spontaneous depending upon the solvent system used and the conditions. Alternatively, the precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent or by adding a contra solvent, i.e. a liquid miscible with the solvent in which the Quetiapine tosylate is less soluble. Seed crystals of Quetiapine tosylate may also be added to help induce precipitation. The precipitated Quetiapine tosylate compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure.

Alternatively, Quetiapine tosylate can be isolated by evaporating the solvent and collecting residue. Such a method generally leads to an oil or solid amorphous form of Quetiapine tosylate. Similarly, an amorphous solid form of the Quetiapine tosylate compound can be recovered by spray drying a solution containing the Quetiapine tosylate compound.

In the preferred embodiment, Quetiapine base (I) is dissolved in ethyl acetate and treated with p-toluene sulfonic acid to obtain Form III of Quetiapine tosylate. According to another aspect of the present invention relates to the crystalline form of Quetiapine tartrate. The crystalline form of Quetiapine tartrate is herein after designated as "Form IV". The Form IV of Quetiapine tartrate is characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 6.7, 9.4, 19.6, 20.6, 22.3 degrees. The Form IV of Quetiapine tartrate is further characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 15.3, 15.6, 20.8, 22.3, degrees. FIG. 4 shows typical Form IV x-ray powder diffraction pattern.

The Form IV of Quetiapine tartrate is characterized by its Differential Scanning Calorimetry (DSC), which shows peaks at about 154⁰C.

The present invention also provides a process for preparing crystalline form of Quetiapine tartrate, which comprises treating Quetiapine with tartaric acid.

The reaction is preferably carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting tartrate. Advantageously, both Quetiapine and the tartaric acid are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of Quetiapine and a solvent may be contacted with a tartaric acid, or conversely, a mixture, slurry, or solution of tartaric acid and a solvent may be contacted with Quetiapine. In another embodiment, both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for tartaric acid may be identical with or different from the solvent system used for the Quetiapine. The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two phase reaction scheme may be used wherein the Quetiapine and tartaric acid are primarily reacted in one phase and the resulting Quetiapine tartrate compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include water, a lower alcohol (Ci- C₆) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, diisoproipyl ether, dioxane and the like.

The temperature of contact of Quetiapine and tartaric acid in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is foπned in this step, i.e. a slurry or two phase solution are also possible, though a single solution is generally preferred.

The Quetiapine tartrate compound can be isolated or recovered from the salt forming reaction by any convenient means. For example, the Quetiapine tartrate can be precipitated out of a solution or reaction mixture. The precipitation may be spontaneous depending upon the solvent system used and the conditions. Alternatively, the precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent or by adding a contra solvent, i.e. a liquid miscible with the solvent in which the Quetiapine tartrate is less soluble. Seed crystals of Quetiapine tartrate may also be added to help induce precipitation. The precipitated Quetiapine tartrate compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure.

Alternatively, Quetiapine tartrate can be isolated by evaporating the solvent and collecting residue. Such a method generally leads to an oil or solid amorphous form of Quetiapine tartrate. Similarly, an amorphous solid form of the Quetiapine tartrate compound can be recovered by spray drying a solution containing the Quetiapine tartrate compound.

In the preferred embodiment, Quetiapine base (I) is dissolved in isopropanol and treated with tartric acid to obtain Form IV of Quetiapine tartrate.

According to another aspect of the present invention relates to the crystalline form of Quetiapine benzoate. The crystalline form of Quetiapine benzoate is herein after designated as "Form V". The Form V of Quetiapine benzoate is characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 6.2, 14.1, 14.8, 19.9, 21.1, 22.1, 23.0 degrees. The Form V of Quetiapine benzoate is further characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 11.0, 11.5, 16.0, 16.3, 18.7, 19.1, 23.6, 24.3 degrees. FIG. 5 shows typical Form V x-ray powder diffraction pattern. The Form V of Quetiapine benzoate is characterized by its Differential Scanning Calorimetry (DSC), which shows peaks at about 99⁰C.

The present invention also provides a process for preparing crystalline form of Quetiapine benzoate, which comprises treating Quetiapine with benzoic acid. The reaction is preferably carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting benzoate. Advantageously, both Quetiapine and the benzoic acid are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of Quetiapine and a solvent may be contacted with a benzoic acid, or conversely, a mixture, slurry, or solution of benzoic acid and a solvent may be contacted with Quetiapine. In another embodiment, both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for benzoic acid may be identical with or different from the solvent system used for the Quetiapine. The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two phase reaction scheme may be used wherein the Quetiapine and benzoic acid are primarily reacted in one phase and the resulting Quetiapine benzoate compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include water, a lower alcohol (Ci- C₆) such as methanol, ethanol, isopropanol, n- propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, diisoproipyl ether, dioxane and the like.

The temperature of contact of Quetiapine and benzoic acid in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e. a slurry or two phase solution are also possible, though a single solution is generally preferred. The Quetiapine benzoate compound can be isolated or recovered from the salt forming reaction by any convenient means. For example, the Quetiapine benzoate can be precipitated out of a solution or reaction mixture. The precipitation may be spontaneous depending upon the solvent system used and the conditions. Alternatively, the precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent or by adding a contra solvent, i.e. a liquid miscible with the solvent in which the Quetiapine benzoate is less soluble. Seed crystals of Quetiapine benzoate may also be added to help induce precipitation. The precipitated Quetiapine benzoate compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure.

Alternatively, Quetiapine benzoate can be isolated by evaporating the solvent and collecting residue. Such a method generally leads to an oil or solid amorphous form of Quetiapine benzoate. Similarly, an amorphous solid form of the Quetiapine benzoate compound can be recovered by spray drying a solution containing the Quetiapine benzoate compound.

In the preferred embodiment, Quetiapine base (I) is dissolved in ethyl acetate and treated with benzoic acid to obtain Form V of Quetiapine benzoate. According to another aspect of the present invention relates to the crystalline form of Quetiapine oxalate. The crystalline form of Quetiapine oxalate is herein after designated as "Form VI". The Form VI of Quetiapine oxalate is characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 7.3, 10.7, 11.8, 22.4 degrees. The Form VI of Quetiapine oxalate is further characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 16.6, 17.1, 19.7, 21.5, 22.0, 22.7 degrees. FIG. 6 shows typical Form VI x-ray powder diffraction pattern. The Form VI of Quetiapine oxalate is characterized by its Differential Scanning Calorimetry (DSC), which shows peaks at about HO⁰C. Fig. 8 shows typical Form VI DSC pattern. The present invention also provides a process for preparing crystalline form of

Quetiapine oxalate Form VI, which comprises treating Quetiapine with oxalic acid in ketonic solvent to give Form VI of Quetiapine oxalate. In the preferred embodiment, Quetiapine base (I) is dissolved in ketonic solvent and treated with oxalic acid to obtain Form VI of Quetiapine oxalate. Preferably, ketonic solvent can be selected form acetone, methyl ethyl ketone, methyl tert-butyl ketone and most preferably acetone.

According to another aspect of the present invention relates to the crystalline form of Quetiapine oxalate. The crystalline form of Quetiapine oxalate is herein after designated as "Form VII". The Form VII of Quetiapine oxalate is characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 9.6, 12.6, 14.5, 16.8, 24.1 degrees. The Form VI of Quetiapine oxalate is further characterized by its powder X-ray diffraction pattern having peaks expressed as 2θ at about 14.5, 16.8, 18.4, 20.2, 21.0, 22.6 degrees. FIG. 7 shows typical Form VII x-ray powder diffraction pattern.

The present invention also provides a process for preparing crystalline form of Quetiapine oxalate Form VII, which comprises treating Quetiapine with oxalic acid in alcohols to give Form VII of Quetiapine oxalate. In the preferred embodiment, Quetiapine base (I) is dissolved in alcoholic solvent and treated with oxalic acid to obtain Form VII of Quetiapine oxalate. Preferably, alcoholic solvent can be selected form methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol and most preferably isopropranol.

According to another aspect of the present invention relates to the crystalline form of Quetiapine hydrobromide. The crystalline form of Quetiapine hydrobromide is herein after designated as "Form VIII". The Form VIII of Quetiapine hydrobromide is characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 5.6, 16.6, 23.8, 24.8 and 26.4. FIG. 8 shows typical Form VIII x-ray powder diffraction pattern. The present invention also provides a process for preparing crystalline form of Quetiapine hydrobromide, which comprises treating Quetiapine with hydrobromic acid. The Form VIII of Quetiapine hydrobromide is characterized by its Differential Scanning Calorimetry (DSC) having peak at about 163.6 and about 191.7.

The reaction is preferably carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting hydrobromide. Advantageously, both Quetiapine and the hydrobromic acid are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of Quetiapine and a solvent may be contacted with a hydrobromic acid, or conversely, a mixture, slurry, or solution of hydrobromic acid and a solvent may be contacted with Quetiapine. In another embodiment, both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for hydrobromic acid may be identical with or different from the solvent system used for the Quetiapine. The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two phase reaction scheme may be used wherein the Quetiapine and hydrobromic acid are primarily reacted in one phase and the resulting Quetiapine hydrobromide compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include water, a lower alcohol (C₁- C₆) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert- butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, diisoproipyl ether, dioxane and the like.

The temperature of contact of Quetiapine and hydrobromic acid in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e. a slurry or two phase solution are also possible, though a single solution is generally preferred.

The Quetiapine hydrobromide compound can be isolated or recovered from the salt forming reaction by any convenient means. For example, the Quetiapine hydrobromide can be precipitated out of a solution or reaction mixture. The precipitation may be spontaneous depending upon the solvent system used and the conditions. Alternatively, the precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent or by adding a contra solvent, i.e. a liquid miscible with the solvent in which the Quetiapine hydrobromide is less soluble. Seed crystals of Quetiapine hydrobromide may also be added to help induce precipitation. The precipitated Quetiapine hydrobromide compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure. Alternatively, Quetiapine hydrobromide can be isolated by evaporating the solvent and collecting residue. Such a method generally leads to an oil or solid amorphous form of Quetiapine succinate. Similarly, an amorphous solid form of the Quetiapine hydrobromide compound can be recovered by spray drying a solution containing the Quetiapine hydrobromide compound. In the preferred embodiment, Quetiapine base (I) is dissolved in acetone and treated with hydrobromic acid to obtain Form VIII of Quetiapine hydrobromide.

The novel salts and process for its preparation described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of invention.

The novel Quetiapine salts of the present invention having better solubility properties over the known Quetiapine fumarate salt as it is highly soluble in water, which requires special care during formulation. It is well known fact in the pharmaceutical technology field that the solubility of the drug plays a major role in drug dissolution and bioavalability profile. The result of the solubility profile of the novel quetiapine salt is mentioned in below Table -1.

Table - 1

Examples:

Example 1: Preparation of Quetiapine Benzoate

Dissolved Quetiapine freebase (1.1 g) in Ethyl acetate (5.5 rnL) and Benzoic Acid (0.38 g) was added. The reaction mixture was stirred at room temperature for 3 h; the precipitated solid product was filtered and washed with Ethyl acetate (5.5 mL). Solid product was dried at 5O⁰C for 3 h. Thus, obtained Quetiapine Benzoate "Form I" exhibits XRD as shown is Figure -1. Example 2: Preparation of Quetiapine Benzoate

Dissolved Quetiapine freebase (1.1 g) in Isopropanol (5.5 mL) and Benzoic Acid (0.38 g) was added. The reaction mixture was stirred at room temperature for 3 h; the precipitated solid product was filtered and washed with Isopropanol (5.5 mL). Solid product was dried at 5O⁰C for 3 h. Thus, obtained Quetiapine Benzoate "Form I" exhibits XRD as shown is Figure -1. Example 3: Preparation of Quetiapine Tartrate

Dissolved Quetiapine freebase (1.1 g) in Ethyl Acetate (5.5 mL) and Tartaric acid (0.24 g) was added. The reaction mixture was stirred at room temperature for 1 h; the precipitated solid product was filtered and washed with Ethyl Acetate (5.5 mL). Solid product was dried at 5O⁰C for 3 h. Thus, obtained Quetiapine tartrate "Form IV" exhibits XRD as shown is Figure -4.

Example 4: Preparation of Quetiapine Tartrate

Dissolved Quetiapine freebase (1.1 g) in Isopropanol (5.5 mL) and Tartaric acid

(0.24 g) was added. The reaction mixture was stirred at room temperature for 3 h; the precipitated solid product was filtered and washed with Isopropanol (5.5 mL). Solid product was dried at 5O⁰C for 3 h. Thus, obtained Quetiapine tartrate "Form IV" exhibits XRD as shown is Figure -A.

Example 5: Preparation of Quetiapine Tartrate

Dissolved Quetiapine freebase (1.1 g) in Acetone (5.5 mL) and Tartaric acid (0.24 g) was added. The reaction mixture was stirred at room temperature for 1 h; the precipitated solid product was filtered and washed with Acetone (5.5 mL). Solid product was dried at 5O⁰C for 3 h. Thus, obtained Quetiapine tartrate "Form IV" exhibits XRD as shown is Figure -4.

Example 6: Preparation of Quetiapine Oxalate Dissolved Quetiapine freebase (1.1 g) in Acetone (5.5 mL) and Oxalic acid

(0.20 g) was added. The reaction mixture was stirred at room temperature for 1 h; the precipitated solid product was filtered and washed with Acetone (5.5 mL). Solid product was dried at 5O⁰C for 3 h. Thus, obtained Quetiapine oxalate "Form VI" exhibits XRD as shown is Figure -6. Example 7: Preparation of Quetiapine Oxalate

Dissolved Quetiapine freebase (1.1 g) in Isopropanol (5.5 mL) and Oxalic acid

(0.20 g) was added. The reaction mixture was stirred at room temperature for 1 h; the precipitated solid product was filtered and washed with Isopropanol (5.5 mL). Solid product was dried at 5O⁰C for 3 h. Thus, obtained Quetiapine oxalate "Form VI" exhibits XRD as shown is Figure -6.

Example S: Preparation of Quetiapine Tosylate

Dissolved Quetiapine freebase (1.1 g) in Ethyl Acetate (5.5 mL) and p-

Toluenesulfonic acid (0.6 g) was added. The reaction mixture was stirred at room temperature for 5 h, Cyclohexane (5.5 mL) was added to the reaction mixture and reaction mixture was further stirred for 18 h at room temperature. The precipitated solid product was filtered and washed with Ethyl Acetate (5.5 mL). Solid product was dried at 5O⁰C for 3 h. Thus, obtained Quetiapine tosylate "Form III" exhibits XRD as shown is Figure -3. Example 9: Preparation of Quetiapine Succinate

Dissolved Quetiapine freebase (1.1 g) in Acetone (5.5 mL) and p- Toluenesulfonic acid (0.19 g) was added. The reaction mixture was stirred at room temperature for 1 h; the precipitated solid product was filtered and washed with Acetone (5.5 mL). Solid product was dried at 5O⁰C for 3 h. Thus, obtained Quetiapine succinate "Form II" exhibits XRD as shown is Figure -2. Example 10: Preparation of Quetiapine Succinate

Dissolved Quetiapine freebase (1.1 g) in Ethyl Acetate (5.5 mL) and p- Toluenesulfonic acid (0.19 g) was added. The reaction mixture was stirred at room temperature for 1 h; the precipitated solid product was filtered and washed with Ethyl Acetate (5.5 mL). Solid product was dried at 5O⁰C for 3 h. Thus, obtained Quetiapine succinate "Form II" exhibits XRD as shown is Figure -2. Example 11: Preparation of Quetiapine Succinate

Dissolved Quetiapine freebase (1.1 g) in Isopropanol (5.5 mL) and p- Toluenesulfonic acid (0.19 g) was added. The reaction mixture was stirred at room temperature for 1 h; the precipitated solid product was filtered and washed with Isopropanol (5.5 mL). Solid product was dried at 5O⁰C for 3 h. Thus, obtained Quetiapine succinate "Form II" exhibits XRD as shown is Figure -2. Example 12: Preparation of Quetiapine hydrobromide

Dissolved Quetiapine freebase (1.0 g) in Acetone (5.5 mL) and hydrobromic acid 2ml was added. The reaction mixture was stirred at room temperature for 1.5 h; the precipitated solid product was filtered and washed with acetone (10 mL). Solid product was dried at 5O⁰C for 2 h. Thus, obtained Quetiapine hydrobromide "Form VIII" exhibits XRD as shown is Figure -8. Example 13: Preparation of Quetiapine hydrobromide Dissolved Quetiapine freebase (1.0 g) in Isopropanol (5.5 mL) and hydrobromic acid 2ml was added. The reaction mixture was stirred at room temperature for 1.5 h; the precipitated solid product was filtered and washed with Isopropanol (10 mL). Solid product was dried at 5O⁰C for 2 h. Thus, obtained Quetiapine hydrobromide "Form VIII" exhibits XRD as shown is Figure -8.

Claims

Claims:

1. Salts of Quetiapine of formula (II)

(H) wherein S represents an acid selected from the group consisting of benzoic acid, tartaric acid, oxalic acid, p-toluene sulfonic acid, naphthalene sulfonic acid, succinic acid, malic acid, hydrobromic acid; which forms a salt with Quetiapine. 2. Quetiapine salts as claimed in claim 1 selected from

(i) Quetiapine malate "Form I" characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 7.1, 9.0, 16.0, 21.0 degrees; (ii) Quetiapine succinate "Form II" characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 7.4, 9.3, 20.0, 22.5 degrees;

(iii) Quetiapine tosylate "Form III" characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 11.3, 12.2, 12.7, 13.3, 17.3 degrees;

(iv) Quetiapine tartrate "Form IV" characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 6.7, 9.4, 19.6, 20.6, 22.3 degrees;

(v) Quetiapine benzoate "The Form V" characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 6.

2, 14.1, 14.8,

19.9, 21.1, 22.1, 23.0 degrees; (vi) Quetiapine oxalate "Form VI" characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 7.3, 10.7, 11.8, 22.4 degrees; (vii) Quetiapine oxalate "Form VII" characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 9.6, 12.6, 14.5,

16.8, 24.1 degrees and (viii) Quetiapine hydrobromide "Form VIII" is characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 5.6, 16.6, 23.8, 24.8 and 26.4.

3. Quetiapine salts as claimed in claim 4, wherein (i) Quetiapine malate "Form I" is further characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 11.4, 14.7, 15.1, 16.5, 17.4, 21.6, 22.1, 23.1 degrees;

(ii) Quetiapine succinate "Form II" further characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 11.8, 13.5, 16:7, 17.5, 21.3, 25.2 degrees;

(iii) Quetiapine tosylate "Form III" further characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 14.6, 14.9, 20.6, 21.1, 22.9, 23.1, 23.6 degrees

(iv) Quetiapine tartrate "Form IV" further characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 15.3, 15.6, 20.8,

22.3, degrees;

(v) Quetiapine benzoate "Form V" further characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 11.0, 11.5, 16.0, 16.3, 18.7, 19.1, 23.6, 24.3 degrees; (vi) Quetiapine oxalate "Form VI" further characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 16.6, 17.1, 19.7, 21.5, 22.0, 22.7 degrees and ;

(vii) Quetiapine oxalate "Form VII" further characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 14.5, 16.8, 18.4, 20.2, 21.0, 22.6 degrees.

4. A pharmaceutical composition comprising compound of Quetiapine of formula (II)

(H) wherein S represents an acid selected from the group consisting of benzoic acid, tartaric acid, oxalic acid, p-toluene sulfonic acid, naphthalene sulfonic acid , succinic acid, malic acid, hydrobromic acid; which forms a salt with Quetiapine and pharmaceutically acceptable excipients.

5. A process for preparing salts of Quetiapine of formula (II)

(H) wherein S represents acid selected from the group consisting of benzoic acid, tartaric acid, oxalic acid, p-toluene sulfonic acid, naphthalene sulfonic acid, succinic acid, malic acid, hydrobromic acid, which comprises reacting Quetiapine of formula (I) with an acid selected from the group consisting of benzoic acid, tartaric acid, oxalic acid, p- toluene sulfonic acid, naphthalene sulfonic acid, succinic acid, malic acid, hydrobromic acid to give the novel salts of formula (II).

6. A process as claimed in claim 5, wherein reaction of Quetiapine of formula (II) with said acid is carried out in suitable solvent.

7. A process as claimed in claim 6, wherein said solvent is selected from group comprising of water, a lower alcohol (Ci- C₆) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, diisoproipyl ether, dioxane or mixtures thereof.