WO2007048870A1 - Quetiapine hemifumarate purification by crystallization - Google Patents
Quetiapine hemifumarate purification by crystallization Download PDFInfo
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- WO2007048870A1 WO2007048870A1 PCT/FI2006/000344 FI2006000344W WO2007048870A1 WO 2007048870 A1 WO2007048870 A1 WO 2007048870A1 FI 2006000344 W FI2006000344 W FI 2006000344W WO 2007048870 A1 WO2007048870 A1 WO 2007048870A1
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- Prior art keywords
- quetiapine
- salt
- hemifumarate
- crystallization
- solvent
- Prior art date
Links
- 229960004431 quetiapine Drugs 0.000 title claims abstract description 80
- ZTHJULTYCAQOIJ-WXXKFALUSA-N quetiapine fumarate Chemical compound [H+].[H+].[O-]C(=O)\C=C\C([O-])=O.C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12.C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 ZTHJULTYCAQOIJ-WXXKFALUSA-N 0.000 title claims abstract description 34
- 238000002425 crystallisation Methods 0.000 title claims description 23
- 230000008025 crystallization Effects 0.000 title claims description 22
- 238000000746 purification Methods 0.000 title description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 238000004519 manufacturing process Methods 0.000 claims abstract 2
- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 claims description 74
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 3
- FLNQAPQQAZVRDA-UHFFFAOYSA-N 1-(2-(2-Hydroxyethoxy)ethyl)piperazine Chemical compound OCCOCCN1CCNCC1 FLNQAPQQAZVRDA-UHFFFAOYSA-N 0.000 claims description 2
- LECMBPWEOVZHKN-UHFFFAOYSA-N 2-(2-chloroethoxy)ethanol Chemical compound OCCOCCCl LECMBPWEOVZHKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 abstract description 10
- 239000001530 fumaric acid Substances 0.000 abstract description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 abstract description 4
- 239000012535 impurity Substances 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 239000013078 crystal Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- ABFPKTQEQNICFT-UHFFFAOYSA-M 2-chloro-1-methylpyridin-1-ium;iodide Chemical compound [I-].C[N+]1=CC=CC=C1Cl ABFPKTQEQNICFT-UHFFFAOYSA-M 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229960005197 quetiapine fumarate Drugs 0.000 description 6
- 229960004592 isopropanol Drugs 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000011343 solid material Substances 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 description 2
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- VNJOEUSYAMPBAK-UHFFFAOYSA-N 2-methylbenzenesulfonic acid;hydrate Chemical compound O.CC1=CC=CC=C1S(O)(=O)=O VNJOEUSYAMPBAK-UHFFFAOYSA-N 0.000 description 1
- 102000004108 Neurotransmitter Receptors Human genes 0.000 description 1
- 108090000590 Neurotransmitter Receptors Proteins 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000011928 denatured alcohol Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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 a novel process for the purification of quetiapine hemifumarate. More specifically, the purification comprises a crystallization process where quetiapine is crystallized consecutively as two different salts, the latter one being hemifumarate.
- Quetiapine hemifumarate is a psychoactive compound that is an antagonist for multiple neurotransmitter receptors in the brain. Quetiapine hemifumarate is used as an antipsychotic or neuroleptic. Quetiapine hemifumarate is described, for example, in patent publication US 4,879,288, which describes also the synthesis of quetiapine hemifumarate. Preparation of hemifumarate is described also e.g. in EP 0 282 236, and WO 01/55125. Different polymorphic forms of quetiapine hemifumarate and their preparation are described in WO 03/080065, WO 2004/076431 and WO 04/078735.
- quetiapine hemifumarate refers to 11-(4-[2-(2- hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,fj-l,4-thiazepine fumarate (2:1) salt.
- the starting material, quetiapine base or quetiapine hemifumarate, for the crystallization can be made by any method described in the literature, e.g. as in US 4,879,288 or EP 0 282 236.
- the process of the invention can be used e.g. if crystalline quetiapine hemifumarate does not fulfil the specifications on impurities and further purification is needed.
- IPCOM000041967D it has not been possible to remove this impurity by crystallization, but it has been necessary to remove 2-chloroethanol from the raw material by distillation.
- the method of the present invention it is possible to reduce the amount of the critical impurity by up to 90 % by varying the first salt and the solvent and depending on the amount of the impurity in the starting material.
- the amount of the critical impurity may be reduced using the herein described crystallization method even below quantitation limit. In comparison the effectivity of conventional recrystallization to remove the critical impurity in ethanol is typically only around 10%.
- the salts which can be used as first crystallization salts are e.g. tosylate or hydrohalic acid salts, preferably hydrochloride is used as the first salt.
- the present invention relates to a novel process for the preparation of crystalline quetiapine hemifumarate which comprises crystallizing first quetiapine as e.g. as hydrohalic acid salt and converting it to the hemifumarate.
- the present invention provides a process for crystallizing quetiapine hemifumarate comprising a) dissolving quetiapine base in a solvent; b) converting quetiapine to the first quetiapine salt; c) cooling the mixture to precipitate the first quetiapine salt; d) isolating the first quetiapine salt; and e) converting the first quetiapine salt to quetiapine hemifumarate salt.
- the present invention provides a process for purifying quetiapine hemifumarate comprising a) dissolving quetiapine hemifumarate in a solvent; b) optionally liberating quetiapine base from quetiapine hemifumarate c) converting quetiapine to the first quetiapine salt; d) cooling the mixture to precipitate the first quetiapine salt; e) isolating the first quetiapine salt; and f) converting the first quetiapine salt to quetiapine hemifumarate.
- Suitable solvents in the first crystallization step include but are not limited to, methanol, ethanol, n-propanol, iso-propanol, ethylene glycol, mixtures of alcohol with water or acetone depending on the salt to be formed, e.g. if hydrochloride is made, the preferred solvent is ethanol, butanol, isopropanol or acetone, and if tosylate is made, the preferred solvent is acetone.
- the typical crystallization process of the first salt includes the steps of heating a solution of quetiapine base, which may be obtained from the hemifumarate using a suitable base, in a crystallization solvent with the acid used for the the salt formation for a time sufficient to dissolve the quetiapine base; crystallization using a typical cooling profile with cooling rate from 1 °C /h to 20 0 C /h; and isolating the quetiapine first salt and washing and drying it.
- the crystallization may optionally be initiated with the aid of seed crystals.
- the ratio of quetiapine to treating solvent is not critical. Typically 1-10 times of volume of solvent per gram of quetiapine base is used.
- the heating time is not critical. The skilled artisan will know to optimize the time depending on, among other things, the quetiapine used as a starting material, the reagent for the salt formation and the ratio of quetiapine to treating solvent.
- the temperature of the solution is decreased during the crystallization. Usually a linear cooling system is used, but also other systems are possible. When the typical crystallization cooling profile is used the temperature is decreased to about 20°C to O 0 C. In particular, the temperature is decreased gradually over a period of time. Optionally also seeding crystals may be used.
- Crystallization time is not critical but can vary from about 1 to about 20 hours, with 3 to 10 hours being typical. The skilled artisan will know to adjust the crystallization time according to the relative amounts of quetiapine, salt forming reagent, crystallization solvent and the equipment used.
- the first crystalline quetiapine salt is isolated by suitable means known to the skilled artisan and routiner alike, for example, filtration or centrifugation.
- the isolated solid quetiapine first salt can be dried, or used as such to make fumarate salt or be re-crystallized if necessary.
- the first quetiapine salt is transferred to the hemifumarate in a similar way.
- the base is liberated from the first salt using a suitable inorganic or organic base, e.g.NaOH, KOH, Na 2 CO 3 or K 2 CO 3 can be used.
- the hemifumarate can be made as described in prior art using fumaric acid and isolated by methods known in the art.
- quetiapine fumarate or quetiapine base used in examples can be made by processes known in the art, e.g. as described in US 4,879,288 or EP O 282 236.
- Quetiapine base 8 g (HPLC -purity 96,87 a-% and critical impurity 0,16 a-%) was dissolved to ethanol 16 ml and heated to reflux. Ethanol -HCl solution 15 w-% 5 g was added to hot ethanol quetiapine mixture and allowed to cool to O 0 C. Cooling rate was 10 °C / h and the mixture was stirred for Ih at 0°C. The crystals were filtered of and dried. The yield of quetiapine hydrochloride was 6,0 g and HPLC- purity 99,65%. Critical impurity was not detected.
- Quetiapine hydrochloride (6 g) was added to a mixture of water (10 ml) and methanol (10 ml). The mixture was stirred for ca.lO min to dissolve solid material. Toluene 30 ml was added and the pH of the solution was adjusted to 13-14 by addition of 50% NaOH solution. The mixture was heated to 40-50 0 C and stirred for 10 min. The toluene phase was separated and washed once with water (10 ml). The toluene solution was evaporated under reduced pressure. The remaining residue was dissolved to 80 % ethanol (24 ml) and fumaric acid (0,85 g) was added to the solution. The mixture was heated to reflux for 10 min and cooled to 0 0 C. The solid material was filtered to give pure white crystals of quetiapine fumarate 4,92 g.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT The present invention relates to a process for preparing and purifying crystalline quetiapine hemifumarate, which comprises preparing crystalline quetiapine hemifumarate via a crystalline salt, which is not a salt of fumaric acid.
Description
QUETIAPINE HEMIFUMARATE PURIFICATION BY CRYSTALLIZATION
FIELD OF THE INVENTION
The present invention relates to a novel process for the purification of quetiapine hemifumarate. More specifically, the purification comprises a crystallization process where quetiapine is crystallized consecutively as two different salts, the latter one being hemifumarate.
BACKGROUND OF THE INVENTION
1 l-(4-[2-(2-Hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,fj-l,4-thiazepine, is a well established drug substance known under the INN name quetiapine. It is used as its hemifumarate salt having the structure or formula (1)
(1)
Quetiapine hemifumarate is a psychoactive compound that is an antagonist for multiple neurotransmitter receptors in the brain. Quetiapine hemifumarate is used as an antipsychotic or neuroleptic. Quetiapine hemifumarate is described, for example, in patent publication US 4,879,288, which describes also the synthesis of quetiapine hemifumarate. Preparation of hemifumarate is described also e.g. in EP 0 282 236, and WO 01/55125. Different polymorphic forms of quetiapine hemifumarate and their preparation are described in WO 03/080065, WO 2004/076431 and WO 04/078735. The crystallization of quetiapine base and its use in the preparation of quetiapine hemifumarate is described in US 6,372,734. There industrial methylated spirit is used as a solvent and it is said that crystalline fumarate salt is obtained in
good purity and high yield without by-products of other salts. Anyhow, no information about the purity of the product is given.
SUMMARY OF THE INVENTION
Applicants have discovered that it is possible to improve the purity of quetiapine hemifumarate significantly if it is first crystallized as a different salt and then converted to the hemifumarate. The term different salt or first salt is used here to refer to any other salt of quetiapine than the salts of fumaric acid.
It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel possibility to improve the purity of quetiapine hemifumarate obtained by the crystallization process. As used herein and unless otherwise indicated, quetiapine hemifumarate refers to 11-(4-[2-(2- hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,fj-l,4-thiazepine fumarate (2:1) salt. The starting material, quetiapine base or quetiapine hemifumarate, for the crystallization can be made by any method described in the literature, e.g. as in US 4,879,288 or EP 0 282 236. Thus the process of the invention can be used e.g. if crystalline quetiapine hemifumarate does not fulfil the specifications on impurities and further purification is needed.
Applicants have surprisingly discovered that crystallizing quetiapine first as some other salt and then converting it to the hemifumarate improves the purity of the product better than ordinary re-crystallization. An especially difficult impurity to remove by normal purification methods like re-crystallization is 2-(4- dibenzo[b,fjthiazepin-l l-yl-piperazin-l-yl)ethanol. The term critical impurity is used herein to refer to this impurity. This impurity is formed when 2-chloroethanol is present as an impurity in the 2-(2-chloroethoxy)ethanol or in 2- hydroxyethoxyethylpiperazine used as raw material. According to IP.com publication no. IPCOM000041967D it has not been possible to remove this
impurity by crystallization, but it has been necessary to remove 2-chloroethanol from the raw material by distillation. Now it has been surprisingly noticed that by the method of the present invention it is possible to reduce the amount of the critical impurity by up to 90 % by varying the first salt and the solvent and depending on the amount of the impurity in the starting material. The amount of the critical impurity may be reduced using the herein described crystallization method even below quantitation limit. In comparison the effectivity of conventional recrystallization to remove the critical impurity in ethanol is typically only around 10%. The salts which can be used as first crystallization salts are e.g. tosylate or hydrohalic acid salts, preferably hydrochloride is used as the first salt.
Thus, the present invention relates to a novel process for the preparation of crystalline quetiapine hemifumarate which comprises crystallizing first quetiapine as e.g. as hydrohalic acid salt and converting it to the hemifumarate.
hi another aspect, the present invention provides a process for crystallizing quetiapine hemifumarate comprising a) dissolving quetiapine base in a solvent; b) converting quetiapine to the first quetiapine salt; c) cooling the mixture to precipitate the first quetiapine salt; d) isolating the first quetiapine salt; and e) converting the first quetiapine salt to quetiapine hemifumarate salt.
hi another aspect, the present invention provides a process for purifying quetiapine hemifumarate comprising a) dissolving quetiapine hemifumarate in a solvent; b) optionally liberating quetiapine base from quetiapine hemifumarate c) converting quetiapine to the first quetiapine salt; d) cooling the mixture to precipitate the first quetiapine salt; e) isolating the first quetiapine salt; and f) converting the first quetiapine salt to quetiapine hemifumarate.
Suitable solvents in the first crystallization step include but are not limited to, methanol, ethanol, n-propanol, iso-propanol, ethylene glycol, mixtures of alcohol
with water or acetone depending on the salt to be formed, e.g. if hydrochloride is made, the preferred solvent is ethanol, butanol, isopropanol or acetone, and if tosylate is made, the preferred solvent is acetone.
The typical crystallization process of the first salt includes the steps of heating a solution of quetiapine base, which may be obtained from the hemifumarate using a suitable base, in a crystallization solvent with the acid used for the the salt formation for a time sufficient to dissolve the quetiapine base; crystallization using a typical cooling profile with cooling rate from 1 °C /h to 200C /h; and isolating the quetiapine first salt and washing and drying it. The crystallization may optionally be initiated with the aid of seed crystals.
The ratio of quetiapine to treating solvent is not critical. Typically 1-10 times of volume of solvent per gram of quetiapine base is used.
Similarly, the heating time is not critical. The skilled artisan will know to optimize the time depending on, among other things, the quetiapine used as a starting material, the reagent for the salt formation and the ratio of quetiapine to treating solvent.
The temperature of the solution is decreased during the crystallization. Usually a linear cooling system is used, but also other systems are possible. When the typical crystallization cooling profile is used the temperature is decreased to about 20°C to O0C. In particular, the temperature is decreased gradually over a period of time. Optionally also seeding crystals may be used.
Crystallization time is not critical but can vary from about 1 to about 20 hours, with 3 to 10 hours being typical. The skilled artisan will know to adjust the crystallization time according to the relative amounts of quetiapine, salt forming reagent, crystallization solvent and the equipment used.
Following treatment, the first crystalline quetiapine salt is isolated by suitable means known to the skilled artisan and routiner alike, for example, filtration or centrifugation. The isolated solid quetiapine first salt can be dried, or used as such to make fumarate salt or be re-crystallized if necessary.
The first quetiapine salt is transferred to the hemifumarate in a similar way. The base is liberated from the first salt using a suitable inorganic or organic base, e.g.NaOH, KOH, Na2CO3 or K2CO3 can be used. The hemifumarate can be made as described in prior art using fumaric acid and isolated by methods known in the art.
The invention will be further clarified by the following nonlimiting examples, which are intended to be purely exemplary of the invention. The quetiapine fumarate or quetiapine base used in examples can be made by processes known in the art, e.g. as described in US 4,879,288 or EP O 282 236.
EXAMPLES
Preparation of quetiapine hydrochloride from quetiapine fumarate
Example 1
Crude quetiapine fumarate (HPLC purity 99,89 a-%, critical impurity 0,08 a-%) 1Og was suspended to ethanol (20 ml) and heated at 6O0C. 15 w-% EtOH-HCl solution (8 ml ) was added to the stirred mixture at 600C. The mixture was stirred until all solid material was dissolved and stirred at 60°C for 30 min. The reaction mixture was cooled to 00C, cooling rate 10°C/h and stirred Ih at 00C. Quetiapine hydrochloride crystals were collected by filtration and washed once with cold ethanol. The product 7, 95g was obtained as white crystals having HPLC purity of 99,98 %, critical impurity was not detected.
Example 2
Crude quetiapine fumarate (1Og, HPLC purity 99,70 a-%, critical impurity 0,08 a- %) was suspended to isopropanol (30 ml) and heated at 700C. 30 w-% HCl solution (2,5 ml ) was added to stirred reaction mixture at 700C. The mixture was stirred until all solid material was dissolved and stirred at 700C for 30 min. The reaction mixture was cooled to 0°C, cooling rate 10°C/h and stirred Ih at O0C. Quetiapine hydrochloride crystals were collected by filtration and washed once with
cold isopropanol to obtain 8,28 g white crystals having HPLC purity of 99,89 %, critical impurity was not detected.
Preparation of quetiapine hydrochloride from quetiapine free base
Example 3.
Quetiapine base 8 g (HPLC -purity 96,87 a-% and critical impurity 0,16 a-%) was dissolved to ethanol 16 ml and heated to reflux. Ethanol -HCl solution 15 w-% 5 g was added to hot ethanol quetiapine mixture and allowed to cool to O0C. Cooling rate was 10 °C / h and the mixture was stirred for Ih at 0°C. The crystals were filtered of and dried. The yield of quetiapine hydrochloride was 6,0 g and HPLC- purity 99,65%. Critical impurity was not detected.
Conversion of quetiapine hydrochloride to quetiapine fumarate
Example 4.
Quetiapine hydrochloride (6 g) was added to a mixture of water (10 ml) and methanol (10 ml). The mixture was stirred for ca.lO min to dissolve solid material. Toluene 30 ml was added and the pH of the solution was adjusted to 13-14 by addition of 50% NaOH solution. The mixture was heated to 40-500C and stirred for 10 min. The toluene phase was separated and washed once with water (10 ml). The toluene solution was evaporated under reduced pressure. The remaining residue was dissolved to 80 % ethanol (24 ml) and fumaric acid (0,85 g) was added to the solution. The mixture was heated to reflux for 10 min and cooled to 00C. The solid material was filtered to give pure white crystals of quetiapine fumarate 4,92 g.
Conversion of quetiapine free base to quetiapine tosylate
Example 5.
Solution of toluenesulfonic acid monohydrate (1.13 g) in acetone (10 ml) was added to quetiapine base (prepared from 2.61 g of hemifumarate HPLC purity 99,40 and the amount of critical impurity was 0,13 %) dissolved in toluene (15 ml) under stirring. The formed oily mixture was slightly warmed to dissolve the oil and left at
room temperature for 4 h and then at 0°C overnight. The precipitate was filtered off to obtain Q«TsOH salt in 3.05 g amount (HPLC purity 99,88 and critical impurity 0,01 %.
Examples of the decrease in the amount of the critical impurity obtained by the method of the invention are presented in table 1.
Table 1. The amount of 2-(4-dibenzo[b,fJthiazepin-l l-yl-piperazin-l-yl) ethanol as an impurity in quetiapine hemifumarate before and after re-crystallization via first quetiapine salt.
* 2-(4-dibenzo[b,f] thiazepin-11-yl-piperazin-l-yl) ethanol
Claims
1. A process for preparing crystalline quetiapine hemifumarate comprising the steps: a) crystallizing quetiapine first salt from a suitable solvent and; b) converting the first salt to quetiapine hemifumarate.
2. A process for crystallizing quetiapine hemifumarate comprising a) dissolving quetiapine base in a solvent; b) converting quetiapine to the first quetiapine salt; c) cooling the mixture to precipitate the first quetiapine salt; d) isolating the first quetiapine salt; and e) converting the first quetiapine salt to quetiapine hemifumarate.
3. A process according to claim 1 or 2 wherein the first quetiapine salt is quetiapine hydrochloride.
4. A process according to claim 1 or 2, wherein the first quetiapine salt is quetiapine tosylate.
5. A process of claim 1 or 2 wherein the first quetiapine salt is quetiapine hydrochloride and the crystallization solvent is ethanol, butanol, isopropanol or acetone.
6. A process of claim 1 or 2 wherein the first quetiapine salt is quetiapine tosylate and the crystallization solvent is acetone.
7. A process for purifying quetiapine hemifumarate comprising a) dissolving crude quetiapine hemifumarate in a solvent; b) optionally liberating quetiapine base from quetiapine hemifumarate; c) converting quetiapine to the first quetiapine salt; d) cooling the mixture to precipitate the first quetiapine salt; e) isolating the first quetiapine salt; and f) converting the first quetiapine salt to quetiapine hemifumarate.
8. A process according to claim 7 wherein the first quetiapine salt is quetiapine hydrochloride.
9. A process according to claim 7 wherein the first quetiapine salt is quetiapine tosylate.
10. A process of claim 7 wherein the first quetiapine salt is quetiapine hydrochloride and the crystallization solvent is ethanol, butanol, isopropanol or acetone.
11. A process of claim 7 wherein the first quetiapine salt is quetiapine tosylate and the crystallization solvent is acetone.
12. The use of quetiapine hemifumarate made by any of claims 1 to 11 in the preparation of pharmaceuticals.
13. Quetiapine hemifumarate not containing detectable amount of 2-(4- dibenzo[b,f]thiazeρin-l 1-yl-piρerazin-l-yl) made by using 2-(2-chloroethoxy)ethanol or 2-hydroxyethoxyethylpiperazine as raw material.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP06807971A EP1948628A1 (en) | 2005-10-28 | 2006-10-26 | Quetiapine hemifumarate purification by crystallization |
| US12/083,975 US8044039B2 (en) | 2005-10-28 | 2006-10-26 | Quetiapine hemifumarate purification by crystallization |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US73084305P | 2005-10-28 | 2005-10-28 | |
| US60/730,843 | 2005-10-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2007048870A1 true WO2007048870A1 (en) | 2007-05-03 |
Family
ID=37762371
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/FI2006/000344 WO2007048870A1 (en) | 2005-10-28 | 2006-10-26 | Quetiapine hemifumarate purification by crystallization |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US8044039B2 (en) |
| EP (1) | EP1948628A1 (en) |
| WO (1) | WO2007048870A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007102074A2 (en) * | 2006-03-07 | 2007-09-13 | Cadila Healthcare Limited | Salts of quetiapine |
| WO2009004480A2 (en) * | 2007-05-07 | 2009-01-08 | Actavis Group Ptc Ehf | Quetiapine salts and their polymorphs |
| CZ300451B6 (en) * | 2006-07-03 | 2009-05-20 | Farmak, A. S. | Process for preparing salts of 2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]ethanol (quetiapine) and purification process of such salts |
| 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 |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9993486B1 (en) | 2017-06-19 | 2018-06-12 | Tlc Therapeutics, Llc | Oral quetiapine suspension formulations with extended shelf life and enhanced bioavailability |
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 |
| US20060063927A1 (en) * | 2004-09-22 | 2006-03-23 | Olga Etlin | Processes for preparing quetiapine and salts thereof |
-
2006
- 2006-10-26 EP EP06807971A patent/EP1948628A1/en not_active Withdrawn
- 2006-10-26 WO PCT/FI2006/000344 patent/WO2007048870A1/en active Application Filing
- 2006-10-26 US US12/083,975 patent/US8044039B2/en not_active Expired - Fee Related
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 |
| US20060063927A1 (en) * | 2004-09-22 | 2006-03-23 | Olga Etlin | Processes for preparing quetiapine and salts thereof |
Non-Patent Citations (1)
| Title |
|---|
| RAVIKUMAR K ET AL: "Quetiapine hemifumarate", ACTA CRYSTALLOGRAPHICA, SECTION E: STRUCTURE REPORTS ONLINE, XX, XX, vol. E61, no. 10, 14 September 2005 (2005-09-14), pages 3245 - 3248, XP002412734, ISSN: 1600-5368 * |
Cited By (8)
| 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 |
| WO2007102074A2 (en) * | 2006-03-07 | 2007-09-13 | Cadila Healthcare Limited | Salts of quetiapine |
| WO2007102074A3 (en) * | 2006-03-07 | 2008-02-07 | Cadila Healthcare Ltd | Salts of quetiapine |
| CZ300451B6 (en) * | 2006-07-03 | 2009-05-20 | Farmak, A. S. | Process for preparing salts of 2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]ethanol (quetiapine) and purification process of such salts |
| WO2009004480A2 (en) * | 2007-05-07 | 2009-01-08 | Actavis Group Ptc Ehf | Quetiapine salts and their polymorphs |
| WO2009004480A3 (en) * | 2007-05-07 | 2009-11-05 | Actavis Group Ptc Ehf | Quetiapine salts and their polymorphs |
| US8101597B2 (en) | 2007-05-07 | 2012-01-24 | Actavis Group Ptc Ehf | Quetiapine salts and their polymorphs |
| 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 |
|---|---|
| US20090156802A1 (en) | 2009-06-18 |
| US8044039B2 (en) | 2011-10-25 |
| EP1948628A1 (en) | 2008-07-30 |
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