WO2006056771A1 - Phosphoric acid salt of quetiapine - Google Patents
Phosphoric acid salt of quetiapine Download PDFInfo
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- WO2006056771A1 WO2006056771A1 PCT/GB2005/004501 GB2005004501W WO2006056771A1 WO 2006056771 A1 WO2006056771 A1 WO 2006056771A1 GB 2005004501 W GB2005004501 W GB 2005004501W WO 2006056771 A1 WO2006056771 A1 WO 2006056771A1
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- quetiapine
- salt
- phosphoric acid
- pharmaceutically acceptable
- salts
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D281/16—[b, f]-condensed
Definitions
- the present invention relates to novel heterocyclic compounds, to a process for their preparation, to pharmaceutical compositions containing them and to the use of the compounds in the treatment of psychotic disorders.
- the compounds are novel pharmaceutically acceptable salts of quetiapine, wherein the salt is derived from phosphoric acid.
- 2-[2-(4-Dibenzo[£>,/][1 ,4] thiazepin-11-yl-1-piperazinyl)ethoxy]ethano! hemifumarate also known as quetiapine hemifumarate
- quetiapine hemifumarate is an anti-psychotic drug belonging to a new chemical class of dibenzothiazepine derivatives. It is currently commercially available from AstraZeneca, sold under the trade name Seroquel ® . Quetiapine is currently supplied for oral administration in the form of its hemifumarate salt and is indicated for the treatment of schizophrenia.
- Quetiapine is described in U.S. Patent No. 4,879,288 together with its preparation in the form of hemifumarate, maleate and hydrochloride salts, as well as the preparation of pharmaceutical compositions for use in treating psychosis. Additional methods for the preparation of quetiapine hemifumarate are disclosed in European' Patent No. EP 282236, and International Publication No. WO 01/55125. A method for the purification of quetiapine hemifumarate is described in U.S. Patent No. 6,372,734.
- the invention provides a novel salt of quetiapine derived from phosphoric acid, a process for its preparation and pharmaceutical compositions containing it.
- the invention also provides a method of treating or preventing psychotic disorders in a human requiring such treatment which comprises administering an effective amount of a new salt of quetiapine derived from phosphoric acid.
- Figure 1 shows a representative X-ray powder diffraction (XRPD) pattern for a typical sample of crystalline quetiapine phosphate according to the invention.
- the XRPD pattern was determined using CuKa radiation on a powder sample collected using a PANalytical X'PertPRO powder diffractometer.
- the new quetiapine salts exist in crystalline form with specific and distinctive physical characteristics including melting point and X-ray diffraction patterns.
- the invention also provides a pharmaceutical composition that comprises a new salt of quetiapine with phosphoric acid together with one or more pharmaceutically acceptable excipients.
- the process for the preparation of novel quetiapine salts comprises the reaction of quetiapine base with phosphoric acidjn a suitable solvent or diluent, the isolation of the quetiapine salt with phosphoric acid in a crystalline form, and the drying of the crystalline salt thus obtained.
- phosphoric acid is a tribasic acid and that quetiapine may form salts in which one two or three molecules of quetiapine are present.
- the invention includes such salts and also mixed phosphate salts in which another counterion is present, for example an alkali metal or alkaline earth metal cation such as sodium, potassium, lithium, calcium or magnesium, is present in addition to a quetiapine ion.
- another counterion for example an alkali metal or alkaline earth metal cation such as sodium, potassium, lithium, calcium or magnesium, is present in addition to a quetiapine ion.
- the process may be carried out at a temperature in the general range for example 10 - 80 0 C and, more particularly in the general range 25-60 °C.
- solvents and diluents or mixtures thereof may be used for the process of the invention.
- suitable solvents or diluents include, for example, alkanols such as ethanol, propanol, isopropanol and butanol, hydrocarbons such as pentane, hexane, heptane, toluene and xylene, ethers such as di-isopropyl ether and tetrahydrofuran, esters such ethyl acetate and butyl acetate, and chlorinated hydrocarbons such as dichloromethane and tetrachloroethylene.
- alkanols such as ethanol, propanol, isopropanol and butanol
- hydrocarbons such as pentane, hexane, heptane, toluene and xylene
- ethers such as di-isopropyl ether and tetrahydrofuran
- One preferred novel salt of the invention is quetiapine phosphate.
- the new salts of quetiapine of the present invention can be used in the preparation of rapid, controlled, and sustained release pharmaceutical compositions, suitable for oral, rectal, parenteral, transdermal, buccal, nasal, sublingual, subcutaneous or intravenous administration.
- the compositions are preferably administered orally, in the form of rapid or controlled release tablets, microparticles, mini tablets, capsules and oral solutions or suspensions, or powders for the preparation thereof.
- a composition of the present invention for oral preparation may optionally include various standard pharmaceutical carriers and excipients, such as binders, fillers, buffers, lubricants, glidants, disintegrants, odorants, sweeteners, surfactants and coatings.
- excipients may have multiple roles in the formulations, for example they may act as both binders and disintegrants.
- Suitable pharmaceutically acceptable disintegrants include, but are not limited to starch, pre-gelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, croscarmellose sodium, microcrystalline cellulose, alginates, resins, surfactants, effervescent compositions, aqueous aluminum silicates and crosslinked polyvinylpyrrolidone.
- Suitable pharmaceutically acceptable binders include, but are not limited to, acacia; cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethylcellulose; gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pre-gelatinized starch, tragacanth, xanthane resin, alginates, magnesium aluminum silicate, polyethylene glycol and bentonite.
- acacia cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethylcellulose
- gelatin glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pre-gelatinized starch, tragacanth, xanthane resin, alginates,
- suitable pharmaceutically acceptable fillers include, but are not limited to, iactose, anhydrolactose, lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (particularly microcrystalline cellulose), dihydro- or anhydro-calcium dihydrogenphosphate, calcium carbonate and calcium sulfate.
- Suitable pharmaceutically acceptable lubricants include, but are not limited to, magnesium stearate, talc, polyethylene glycol, polymers of ethylene oxide, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine and colloidal silicon dioxide
- suitable pharmaceutically acceptable odorants include, but are not limited to, synthetic aromas and natural aromatic oils such as extracts of oils, flowers, fruits and combinations thereof.
- Preferable are vanilla and fruit aromas, including banana, apple, sour cherry, peach and similar aromas. Their use depends on many factors, the most important being the organoleptic acceptability for the population that will be taking the pharmaceutical formulations.
- suitable pharmaceutically acceptable dyes include, but are not limited to, synthetic and natural dyes such as titanium dioxide, beta-carotene and extracts of grapefruit peel.
- Examples of useful pharmaceutically acceptable coatings typically used to facilitate swallowing, modify the release properties, improve the appearance, and/or mask the taste of the formulations include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose and acrylate-methacrylate copolymers.
- Suitable examples of pharmaceutically acceptable sweeteners include, but are not limited to, aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, lactose and sucrose.
- Suitable examples of pharmaceutically acceptable buffers include, but are not limited to, citric acid, sodium citrate, sodium bicarbonate, magnesium oxide, calcium carbonate and magnesium hydroxide.
- Suitable examples of pharmaceutically acceptable surfactants include, but are not limited to, sodium lauryl sulfate and polysorbates.
- Formulations of the new salts of quetiapine of the present invention can also be administered intravenously or intraperitoneally, by infusion or injection.
- Dispersions can also be prepared in a liquid carrier or intermediate, such as glycerin, liquid polyethylene glycols, triacetin oils, and mixtures thereof. To improve storage stability, such preparations may also contain a preservative to prevent the growth of microorganisms.
- Pharmaceutical formulations suitable for injection or infusion may be in the form of a sterile aqueous solution, dispersion or a sterile powder that contains the active ingredient, adjusted, if necessary, for preparation of such a sterile solution or dispersion suitable for infusion or injection. This may optionally be encapsulated into liposomes. In all cases, the final preparation must be sterile, liquid, and stable under production and storage conditions.
- the liquid carrier or intermediate can be a solvent or liquid dispersive medium that contains, for example, water, ethanol, a polyol (e. g. glycerol, propylene glycol or the like), vegetable oils, non-toxic glycerine esters and suitable mixtures thereof. Suitable flowability may be maintained, by generation of liposomes, administration of a suitable particle size in the case of dispersions, or by the addition of surfactants. Prevention of the action of micro-organisms can be achieved by the addition of various antibacterial and antifungal agents, e. g. paraben, chlorobutanol, or sorbic acid. In many cases isotonic substances are recommended, e. g. sugars, buffers and sodium chloride to assure osmotic pressure similar to those of body fluids, particularly blood. Prolonged absorption of such injectable mixtures can be achieved by introduction of absorption- delaying agents, such as aluminum monostearate or gelatin.
- absorption- delaying agents such as aluminum monoste
- Sterile injectable solutions can be prepared by mixing a new salt of quetiapine with an appropriate solvent and one or more of the aforementioned excipients, followed by sterile filtering.
- a new salt of quetiapine may also be used for the preparation of locally acting, topical formulations.
- Such formulations may also contain other pharmaceutically acceptable excipients, such as polymers, oils, liquid carriers, surfactants, buffers, preservatives, stabilizers, antioxidants, moisturizers, emollients, colorants, and odorants.
- Examples of pharmaceutically acceptable polymers suitable for such topical formulations include, but are not limited to, acrylic polymers; cellulose derivatives, such as carboxymethylcellulose sodium, methylcellulose or hydroxypropylcellulose; natural polymers, such as alginates, tragacanth, pectin, xanthan and cytosan.
- suitable pharmaceutically acceptable oils include, but are not limited to, mineral oils, silicone oils, fatty acids, alcohols and glycols.
- suitable pharmaceutically acceptable liquid carriers include, but are not limited to, water, alcohols or glycols such as ethanol, isopropanol, propylene glycol, hexylene glycol, glycerol and polyethylene glycol, or mixtures thereof in which the new salt of quetiapine is dissolved or dispersed, optionally with the addition of non-toxic anionic, cationic or non-ionic surfactants, and inorganic or organic buffers.
- Suitable examples of pharmaceutically acceptable preservatives include, but are not limited to, various antibacterial and antifungal agents such as solvents, for example ethanol, propylene glycol, benzyl alcohol, chlorobutanol, quaternary ammonium salts, and parabens (such as methyl paraben, ethyl paraben, propyl paraben, etc.).
- solvents for example ethanol, propylene glycol, benzyl alcohol, chlorobutanol, quaternary ammonium salts, and parabens (such as methyl paraben, ethyl paraben, propyl paraben, etc.).
- Suitable examples of pharmaceutically acceptable stabilizers and antioxidants include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), thiourea, tocopherol and butyl hydroxyanisole.
- EDTA ethylenediaminetetraacetic acid
- thiourea thiourea
- tocopherol thiourea
- butyl hydroxyanisole ethylenediaminetetraacetic acid
- Suitable examples of pharmaceutically acceptable moisturizers include, but are not limited to, glycerine, sorbitol, urea and polyethylene glycol.
- Suitable examples of pharmaceutically acceptable emollients include, but are not limited to, mineral oils, isopropyl myristate, and isopropyl palmitate.
- the use of dyes and odorants in topical formulations of the present invention depends on many factors of which the most important is organoleptic acceptability to the population that will be using the pharmaceutical formulations.
- the quantity of new quetiapine salt of the invention administered for therapeutic purposes may vary, dependent on the selected salt, the mode of administration, treatment conditions, age and status of the patient, and the preference of the clinician involved.
- suitable doses will generally be similar to those currently used for quetiapine hemifumarate, commercially available as Seroquel ® , which is supplied for oral administration as 25 mg, 100 mg, 200 mg, and 300 mg tablets.
- Quetiapine hemifumarate is generally administered with an initial dose of 25 mg bid, with increases in increments of 25-50 mg to a target dose range of 300 to 400 mg daily.
- Example 1 The invention is illustrated by the following non-limiting Examples in which Example I describes the preparation of starting quetiapine free base.
- Quetiapine free base (1.0 g; 2.61 mmol) was dissolved in ethanol (10 mL) and phosphoric acid was added in equimolar amount. The reaction mixture was heated until dissolution occurred and stirred for 3 hours at room temperature and 1 hour at 0 0 C. The precipitate was separated by filtration, washed with ethanol (5 mL) and dried in a vacuum oven at 55 0 C for 1.5 hour to give quetiapine phosphate salt (0.83g).
- This salt gave the following DSC measurements, recorded on Mettler Toledo 822 e /500 DSC instrument, operating with MettlerSTAR 8 system: melting point (Peak, 0 C): 149.54; heat of fusion (DH, J/g) -61.10
- This quetiapine phosphate salt of the invention also possesses a characteristic X-Ray Powder Diffraction (XRPD) patterns, a typical example of which is shown in Figure 1 attached hereto.
- XRPD X-Ray Powder Diffraction
- the XRPD was measured using CuKa radiation on a powder sample collected using a PANalytical X'PertPRO powder diffractometer.
- the solubility of the novel quetiapine phosphate salt (100 mg) was tested in comparison with the known quetiapine hemifumarate, in 900 mL degassed water using US Pharmacopoeia 2 apparatus with device for intrinsic testing, at 100 rpm, in order to determine their intrinsic dissolution rate (IDR).
- IDR intrinsic dissolution rate
- quetiapine hemifumarate salt has IDR of 0.158 mg/min/cm 2 while quetiapine phosphate salt was dissolved up to 38% within 5 minutes which made it impossible to calculate the IDR.
- the phosphate salt showed a much faster dissolution than the corresponding hemifumarate salt.
Abstract
The invention relates to new salts of 2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy] ethanol derived from phosphoric acid and obtainable in crystalline form, to a process for their preparation and to pharmaceutical compositions containing them. The new salts are useful in the treatment or prevention of psychotic disorders.
Description
PHOSPHORIC ACID SALT OF QUETIAPINE
FIELD OF THE INVENTION
The present invention relates to novel heterocyclic compounds, to a process for their preparation, to pharmaceutical compositions containing them and to the use of the compounds in the treatment of psychotic disorders. Specifically, the compounds are novel pharmaceutically acceptable salts of quetiapine, wherein the salt is derived from phosphoric acid.
BACKGROUND TO THE INVENTION
2-[2-(4-Dibenzo[£>,/][1 ,4] thiazepin-11-yl-1-piperazinyl)ethoxy]ethano! hemifumarate, also known as quetiapine hemifumarate, is an anti-psychotic drug belonging to a new chemical class of dibenzothiazepine derivatives. It is currently commercially available from AstraZeneca, sold under the trade name Seroquel®. Quetiapine is currently supplied for oral administration in the form of its hemifumarate salt and is indicated for the treatment of schizophrenia.
Quetiapine is described in U.S. Patent No. 4,879,288 together with its preparation in the form of hemifumarate, maleate and hydrochloride salts, as well as the preparation of pharmaceutical compositions for use in treating psychosis. Additional methods for the preparation of quetiapine hemifumarate are disclosed in European' Patent No. EP 282236, and International Publication No. WO 01/55125. A method for the purification of quetiapine hemifumarate is described in U.S. Patent No. 6,372,734.
There is a need for alternative salts of quetiapine to improve on the properties of the existing known salts especially the hemifumarate which is used clinically. We have now discovered various new salts of quetiapine which can be isolated in crystalline form and which have improved properties in relation to those of the salts already known. These improved properties include for example higher solubility in aqueous media.
SUMMARY OF THE INVENTION
The invention provides a novel salt of quetiapine derived from phosphoric acid, a process for its preparation and pharmaceutical compositions containing it. The invention also provides a method of treating or preventing psychotic disorders in a human requiring such treatment which comprises administering an effective amount of a new salt of quetiapine derived from phosphoric acid.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a representative X-ray powder diffraction (XRPD) pattern for a typical sample of crystalline quetiapine phosphate according to the invention. The XRPD pattern was determined using CuKa radiation on a powder sample collected using a PANalytical X'PertPRO powder diffractometer.
DETAILED DESCRIPTION OF THE INVENTION
According to the invention there is provided a novel salt of quetiapine derived from phosphoric acid..
In a preferred embodiment, the new quetiapine salts exist in crystalline form with specific and distinctive physical characteristics including melting point and X-ray diffraction patterns.
In another feature of the invention there is provided a process for the preparation of a novel quetiapine salt, derived from phosphoric acid
The invention also provides a pharmaceutical composition that comprises a new salt of quetiapine with phosphoric acid together with one or more pharmaceutically acceptable excipients.
According to the invention, the process for the preparation of novel quetiapine salts comprises the reaction of quetiapine base with phosphoric acidjn a suitable solvent or diluent, the isolation of the quetiapine salt with phosphoric acid in a crystalline form, and the drying of the crystalline salt thus obtained.
It will be appreciated that phosphoric acid is a tribasic acid and that quetiapine may form salts in which one two or three molecules of quetiapine are present. Accordingly the invention includes such salts and also mixed phosphate salts in which another counterion is present, for example an alkali metal or alkaline earth metal cation such as sodium, potassium, lithium, calcium or magnesium, is present in addition to a quetiapine ion.
The process may be carried out at a temperature in the general range for example 10 - 80 0C and, more particularly in the general range 25-60 °C.
A wide range of solvents and diluents or mixtures thereof may be used for the process of the invention. As an illustration, suitable solvents or diluents include, for example, alkanols such as ethanol, propanol, isopropanol and butanol, hydrocarbons such as pentane, hexane, heptane, toluene and xylene, ethers such as di-isopropyl ether and tetrahydrofuran, esters such ethyl acetate and butyl acetate, and chlorinated hydrocarbons such as dichloromethane and tetrachloroethylene.
One preferred novel salt of the invention is quetiapine phosphate.
It is an object of the invention to provide compounds and compositions useful for the treatment and prevention of psychotic disorders, such as, but not limited to, schizophrenia, mania associated with bipolar disorders and hyperactivity. Because of their useful properties, the new salts of quetiapine of the present invention can be used in the preparation of rapid, controlled, and sustained release pharmaceutical compositions, suitable for oral, rectal, parenteral, transdermal, buccal, nasal, sublingual, subcutaneous or intravenous administration. The compositions are preferably administered orally, in the form of rapid or controlled release tablets, microparticles, mini tablets, capsules and oral solutions or suspensions, or powders for the preparation thereof.
In addition to the new salt of quetiapine defined above, a composition of the present invention for oral preparation may optionally include various standard
pharmaceutical carriers and excipients, such as binders, fillers, buffers, lubricants, glidants, disintegrants, odorants, sweeteners, surfactants and coatings. Some excipients may have multiple roles in the formulations, for example they may act as both binders and disintegrants. Examples of suitable pharmaceutically acceptable disintegrants include, but are not limited to starch, pre-gelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, croscarmellose sodium, microcrystalline cellulose, alginates, resins, surfactants, effervescent compositions, aqueous aluminum silicates and crosslinked polyvinylpyrrolidone. Examples of suitable pharmaceutically acceptable binders include, but are not limited to, acacia; cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethylcellulose; gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pre-gelatinized starch, tragacanth, xanthane resin, alginates, magnesium aluminum silicate, polyethylene glycol and bentonite.
Examples of suitable pharmaceutically acceptable fillers include, but are not limited to, iactose, anhydrolactose, lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (particularly microcrystalline cellulose), dihydro- or anhydro-calcium dihydrogenphosphate, calcium carbonate and calcium sulfate.
Examples of suitable pharmaceutically acceptable lubricants include, but are not limited to, magnesium stearate, talc, polyethylene glycol, polymers of ethylene oxide, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine and colloidal silicon dioxide
Examples of suitable pharmaceutically acceptable odorants include, but are not limited to, synthetic aromas and natural aromatic oils such as extracts of oils, flowers, fruits and combinations thereof. Preferable are vanilla and fruit aromas, including banana, apple, sour cherry, peach and similar aromas. Their use depends on many factors, the most important being the organoleptic
acceptability for the population that will be taking the pharmaceutical formulations.
Examples of suitable pharmaceutically acceptable dyes include, but are not limited to, synthetic and natural dyes such as titanium dioxide, beta-carotene and extracts of grapefruit peel.
Examples of useful pharmaceutically acceptable coatings, typically used to facilitate swallowing, modify the release properties, improve the appearance, and/or mask the taste of the formulations include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose and acrylate-methacrylate copolymers.
Suitable examples of pharmaceutically acceptable sweeteners include, but are not limited to, aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, lactose and sucrose.
Suitable examples of pharmaceutically acceptable buffers include, but are not limited to, citric acid, sodium citrate, sodium bicarbonate, magnesium oxide, calcium carbonate and magnesium hydroxide.
Suitable examples of pharmaceutically acceptable surfactants include, but are not limited to, sodium lauryl sulfate and polysorbates.
Formulations of the new salts of quetiapine of the present invention can also be administered intravenously or intraperitoneally, by infusion or injection.
Dispersions can also be prepared in a liquid carrier or intermediate, such as glycerin, liquid polyethylene glycols, triacetin oils, and mixtures thereof. To improve storage stability, such preparations may also contain a preservative to prevent the growth of microorganisms. Pharmaceutical formulations suitable for injection or infusion may be in the form of a sterile aqueous solution, dispersion or a sterile powder that contains the active ingredient, adjusted, if necessary, for preparation of such a sterile solution or dispersion suitable for infusion or injection. This may optionally be encapsulated into liposomes. In all cases, the final preparation must be sterile, liquid, and stable under production and storage conditions.
The liquid carrier or intermediate can be a solvent or liquid dispersive medium that contains, for example, water, ethanol, a polyol (e. g. glycerol, propylene glycol or the like), vegetable oils, non-toxic glycerine esters and suitable mixtures thereof. Suitable flowability may be maintained, by generation of liposomes, administration of a suitable particle size in the case of dispersions, or by the addition of surfactants. Prevention of the action of micro-organisms can be achieved by the addition of various antibacterial and antifungal agents, e. g. paraben, chlorobutanol, or sorbic acid. In many cases isotonic substances are recommended, e. g. sugars, buffers and sodium chloride to assure osmotic pressure similar to those of body fluids, particularly blood. Prolonged absorption of such injectable mixtures can be achieved by introduction of absorption- delaying agents, such as aluminum monostearate or gelatin.
Sterile injectable solutions can be prepared by mixing a new salt of quetiapine with an appropriate solvent and one or more of the aforementioned excipients, followed by sterile filtering.
A new salt of quetiapine may also be used for the preparation of locally acting, topical formulations. Such formulations may also contain other pharmaceutically acceptable excipients, such as polymers, oils, liquid carriers, surfactants, buffers, preservatives, stabilizers, antioxidants, moisturizers, emollients, colorants, and odorants.
Examples of pharmaceutically acceptable polymers suitable for such topical formulations include, but are not limited to, acrylic polymers; cellulose derivatives, such as carboxymethylcellulose sodium, methylcellulose or hydroxypropylcellulose; natural polymers, such as alginates, tragacanth, pectin, xanthan and cytosan.
Examples of suitable pharmaceutically acceptable oils include, but are not limited to, mineral oils, silicone oils, fatty acids, alcohols and glycols.
Examples of suitable pharmaceutically acceptable liquid carriers include, but are not limited to, water, alcohols or glycols such as ethanol, isopropanol, propylene glycol, hexylene glycol, glycerol and polyethylene glycol, or mixtures thereof in which the new salt of quetiapine is dissolved or dispersed, optionally with the
addition of non-toxic anionic, cationic or non-ionic surfactants, and inorganic or organic buffers.
Suitable examples of pharmaceutically acceptable preservatives include, but are not limited to, various antibacterial and antifungal agents such as solvents, for example ethanol, propylene glycol, benzyl alcohol, chlorobutanol, quaternary ammonium salts, and parabens (such as methyl paraben, ethyl paraben, propyl paraben, etc.).
Suitable examples of pharmaceutically acceptable stabilizers and antioxidants include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), thiourea, tocopherol and butyl hydroxyanisole.
Suitable examples of pharmaceutically acceptable moisturizers include, but are not limited to, glycerine, sorbitol, urea and polyethylene glycol.
Suitable examples of pharmaceutically acceptable emollients include, but are not limited to, mineral oils, isopropyl myristate, and isopropyl palmitate. The use of dyes and odorants in topical formulations of the present invention depends on many factors of which the most important is organoleptic acceptability to the population that will be using the pharmaceutical formulations.
The quantity of new quetiapine salt of the invention administered for therapeutic purposes may vary, dependent on the selected salt, the mode of administration, treatment conditions, age and status of the patient, and the preference of the clinician involved. However, suitable doses will generally be similar to those currently used for quetiapine hemifumarate, commercially available as Seroquel®, which is supplied for oral administration as 25 mg, 100 mg, 200 mg, and 300 mg tablets. Quetiapine hemifumarate is generally administered with an initial dose of 25 mg bid, with increases in increments of 25-50 mg to a target dose range of 300 to 400 mg daily.
The invention is illustrated by the following non-limiting Examples in which Example I describes the preparation of starting quetiapine free base.
EXAMPLES Example 1
Quetiapine hemifumarate (10.00 g; 22.65 mmol) was suspended in water (100 mL) and dichloromethane (100 ml_). Solution of sodium hydroxide (0.95 g; 23.75 mmol) in water (18 mL) was slowly added to the suspension and dissolution occurred. The reaction mixture was stirred for 1.5 hours at room temperature and organic layer separated and washed with water (3x50 mL). After drying the organic layer with anhydrous Na2SO4, the solvent was evaporated under vacuum, to give 8.04 g of quetiapine free base as an oily substance. Example 2
Quetiapine free base (1.0 g; 2.61 mmol) was dissolved in ethanol (10 mL) and phosphoric acid was added in equimolar amount. The reaction mixture was heated until dissolution occurred and stirred for 3 hours at room temperature and 1 hour at 0 0C. The precipitate was separated by filtration, washed with ethanol (5 mL) and dried in a vacuum oven at 55 0C for 1.5 hour to give quetiapine phosphate salt (0.83g).
This salt gave the following DSC measurements, recorded on Mettler Toledo 822e/500 DSC instrument, operating with MettlerSTAR8 system: melting point (Peak, 0C): 149.54; heat of fusion (DH, J/g) -61.10 This quetiapine phosphate salt of the invention also possesses a characteristic X-Ray Powder Diffraction (XRPD) patterns, a typical example of which is shown in Figure 1 attached hereto.
The XRPD was measured using CuKa radiation on a powder sample collected using a PANalytical X'PertPRO powder diffractometer. The solubility of the novel quetiapine phosphate salt (100 mg) was tested in comparison with the known quetiapine hemifumarate, in 900 mL degassed water using US Pharmacopoeia 2 apparatus with device for intrinsic testing, at 100 rpm, in order to determine their intrinsic dissolution rate (IDR).. In this test quetiapine hemifumarate salt has IDR of 0.158 mg/min/cm2 while quetiapine
phosphate salt was dissolved up to 38% within 5 minutes which made it impossible to calculate the IDR. However the phosphate salt, showed a much faster dissolution than the corresponding hemifumarate salt.
Claims
1. A novel salt of quetiapiπe derived from phosphoric acid.
2. Crystalline quetiapine phosphate.
3. Quetiapine phosphate having an XRPD pattern substantially as shown in
Figure 1.
4. Quetiapine phosphate having a melting point at or about 180 0C.
5. A process for the preparation of a quetiapine salts as claimed in claim 1 which comprises (a) reacting quetiapine free base with phosphoric acid, (b) isolating the corresponding quetiapine salt in a crystalline form, and (c) drying the said crystalline form.
6. A pharmaceutical composition comprising a novel quetiapine salt as claimed in any of claims 1-4 together with one or more pharmaceutically acceptable excipients.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0425729A GB0425729D0 (en) | 2004-11-23 | 2004-11-23 | Heterocyclic compounds |
| GB0425729.1 | 2004-11-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2006056771A1 true WO2006056771A1 (en) | 2006-06-01 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB2005/004501 WO2006056771A1 (en) | 2004-11-23 | 2005-11-23 | Phosphoric acid salt of quetiapine |
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| GB (1) | GB0425729D0 (en) |
| WO (1) | WO2006056771A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7687622B2 (en) | 2005-04-14 | 2010-03-30 | Teva Pharmaceutical Industries, Ltd | Process for preparing quetiapine fumarate |
| WO2010100623A1 (en) | 2009-03-04 | 2010-09-10 | Ranbaxy Laboratories Limited | Process for the preparation of quetiapine fumarate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0282236A1 (en) * | 1987-03-10 | 1988-09-14 | Imperial Chemical Industries Plc | Process for the preparation of a thiazepine compound |
| WO1999006381A1 (en) * | 1997-08-01 | 1999-02-11 | Zeneca Limited | A crystalline dibenzothiazepine derivative and its use as an antipsychotic agent |
| WO2001055125A1 (en) * | 2000-01-25 | 2001-08-02 | EGIS Gyógyszergyár Rt. | A process for the preparation of quetiapine and intermediates therefor |
-
2004
- 2004-11-23 GB GB0425729A patent/GB0425729D0/en not_active Ceased
-
2005
- 2005-11-23 WO PCT/GB2005/004501 patent/WO2006056771A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0282236A1 (en) * | 1987-03-10 | 1988-09-14 | Imperial Chemical Industries Plc | Process for the preparation of a thiazepine compound |
| WO1999006381A1 (en) * | 1997-08-01 | 1999-02-11 | Zeneca Limited | A crystalline dibenzothiazepine derivative and its use as an antipsychotic agent |
| WO2001055125A1 (en) * | 2000-01-25 | 2001-08-02 | EGIS Gyógyszergyár Rt. | A process for the preparation of quetiapine and intermediates therefor |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7687622B2 (en) | 2005-04-14 | 2010-03-30 | Teva Pharmaceutical Industries, Ltd | Process for preparing quetiapine fumarate |
| WO2010100623A1 (en) | 2009-03-04 | 2010-09-10 | Ranbaxy Laboratories Limited | Process for the preparation of quetiapine fumarate |
Also Published As
| Publication number | Publication date |
|---|---|
| GB0425729D0 (en) | 2004-12-22 |
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