CA2187128A1 - New and useful polymorph of anhydrous paroxetine hydrochloride - Google Patents
New and useful polymorph of anhydrous paroxetine hydrochlorideInfo
- Publication number
- CA2187128A1 CA2187128A1 CA002187128A CA2187128A CA2187128A1 CA 2187128 A1 CA2187128 A1 CA 2187128A1 CA 002187128 A CA002187128 A CA 002187128A CA 2187128 A CA2187128 A CA 2187128A CA 2187128 A1 CA2187128 A1 CA 2187128A1
- Authority
- CA
- Canada
- Prior art keywords
- paroxetine hydrochloride
- form iii
- anhydrous
- paroxetine
- schedule
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A new form of paroxetine hydrochloride anhydrous, designated as Form III, is provided having one or more of the following characteristics: Infrared spectra as shown in Schedules "A" and "B"; a DSC onset temperature of about 159°C; an X-ray powder diffraction pattern as shown in Schedule "D"; a melting point of between about 156°C to about 162°C; a bulk density exceeding about 0.6g/mL and a tapped density exceeding about 0.9g/mL.
Description
TITLE OF INVENTION
A NEW AND USEFUL POLYMORPH OF ANHYDROUS PAROXETINE
HYDROCHLORIDE
FIELD OF INVENTION
This invention relates to a new and useful polymorph of paroxetine hydrochloride (anhydrous) and its preparation thereof.
BACKGROUND OF THE INVENTION
Canadian Letters Patent 1,287,060 describes two distinct forms of paroxetine hydrochloride viz., an anhydrous form of paroxetine hydrochloride and the hemihydrate form of paroxetine hydrochloride (paroxetine hydrochloride 1/2 H20).
These two forms have been known for a substantial period of time, particularly the anhydrous form, which has a melting point of about 118C and which is very hygroscopic making this material extremely difficult to handle.
Coupled with this is the fact that the said anhydrous material is also light andfluffy, which further compounds the problems of handling (filtration and drying) and formulating the active into the final dosage form.
The hemihydrate form is purportedly stable. The purpose of the hemihydrate is to provide material which is less hygroscopic, however the 2 0 compound does include additional amounts of water. Preferably the paroxetine hydrochloride anhydrous should be easily handled with minimal difficulties with respect to the hygroscopic nature of the material and should not be light and fluffy. Preferably the paroxetine hydrochloride anhydrous is in a form having a dense crystalline structure which enables the raw active to be easily 2 5 formulated into final dosage form. Such dense material should, of course, also be easily filtered and readily dried to yield the bulk active and should be readily adapted for use in the commercial manufacture of anhydrous paroxetine hydrochloride, the active ingredient in the final formulation.
- 2- 2l87l28 It is therefore an object of this invention to provide such improved paroxetine hydrochloride anhydrous which overcomes the disadvantages of the prior form of the raw active which suffers from the above deficiencies, particularly the hygroscopic nature of the paroxetine hydrochloride having the 5 melting point of about 118C, the light fluffy nature of the said paroxetine hydrochloride anhydrous and the other deficiencies which would deter one from using paroxetine hydrochloride anhydrous and require such person to use the paroxetine hydrochloride hemihydrate in its place.
Further and other objects of the invention will be realized by those skilled 10 in the art from the following summary of the invention and detailed description of examples thereof.
SUMMARY OF THE INVENTION
In our research, we have determined that paroxetine hydrochloride anhydrous may exist in a number of polymorphic forms. For the purposes 15 herein, our research using differential scanning calorimetric (DSC) analysis has revealed various physical forms of paroxetine hydrochloride anhydrous. We have been able to distinguish between what we identify herein as Form I
paroxetine hydrochloride anhydrous having a DSC onset temperature of approximately 118C and a second polymorphic form (Form II) having a DSC
2 0 onset temperature of approximately 135C made by different processes from the process used to make Form I. In some instances, the processes carried out to produce Form I also produced combinations of Form I and Form II. The processes for making Form I were taught in Canadian Patent No. 1,287,060 and also by various other modified processes which emanated from our research.
2 5 The processes for making Form II also emanated from our research efforts to find a suitable stable polymorphic form of paroxetine hydrochloride (anhydrous).
~ 3 ~ 2187128 Such processes include:
Example 1 for making Form II is set out below:
Paroxetine free base (36.8g) is dissolved in 10 volumes of toluene. To this solution is added 21.5g of a hydrochloric acid in 2-propanol solution (24.9% by 5 weight). At this point, 5 volumes of toluene are removed by distillation. Uponcooling, paroxetine hydrochloride of Form II had precipitated out. This materialwas isolated by filtration and dried in vacuo at 45-55C to provide 39.1g (95%
yield) of paroxetine hydrochloride (anhydrous). The melting range was 135.4-137.4C.
1 0 Example 2 for making Form II:
Paroxetine free base (41.8g) is dissolved in 15 volumes of toluene. To this solution was added 16.5mL of concentrated hydrochloric acid (10 M). After 30 minutes, 5 volumes of toluene are removed, the solution is cooled to 20-25C
and filtered. The product is dried under vacuum at 45-55C, furnishing 46.5g 1 5 (100% yield) of Form II paroxetine hydrochloride.
Form II may also be prepared using a similar experimental protocol with organic solvents (or solvent combinations) selected from an organic ketone such as methyl iso-butyl ketone or methyl ethyl ketone, a halogenated hydrocarbon such as dichloromethane, an alkyl acetate such as ethyl acetate, a hydrocarbon 2 0 such as toluene, or an ether such as methyl tert-butyl ether.
Form I paroxetine hydrochloride is prepared by recrystallization from organic ketones such as acetone, lower alcohols such as 2-propanol, or combinations of organic ketones and lower alcohols.
Our research unexpectedly revealed to us a new polymorphic form of 2 5 paroxetine hydrochloride anhydrous which was very dense (having the consistency of coarse sand), having a bulk density exceeding about 0.6g/mL and atapped density exceeding about 0.9g/mL and which is substantially non-hygroscopic. We have identified this Form as Form III. Form III did not retain, we discovered, residual solvent in excess of about 0.1% and even leaving the 4 2l87128 material exposed to open air for a period of five days, Form III did not take onmoisture more than 1% by weight. Form III, as well, was very stable and was distinguished from the other two forms previously described (Form I and Form II) by a DSC onset temperature of about 159C and a melting point between about 157-159C. Form III we have also determined is easily formulated into final dosage form and is easily manufactured in commercial quantities by processes described in the examples herein.
To complete the identification of Form III paroxetine hydrochloride anhydrous is the infrared spectrum of Form III in KBr and is attached as 1 0 Schedule "A". The infrared spectrum of Form III in Nujol is attached as Schedule "B". The DSC thermogram showing the determination of the DSC
onset temperature of Form III is attached as Schedule "C" and the X-ray powder diffraction pattern of Form III is attached as Schedule "D" (pages 1 and 2) to this application. Form III may be manufactured by the following examples:
1 5 Example 3 for making Form III
Anhydrous paroxetine hydrochloride (600g) is suspended in methyl iso-butyl ketone (3.0L). This solution is stirred and heated to 90-95C (internal temperature) under a nitrogen atmosphere. This temperature is maintained for 4-6 hours, then cooled to 20-25C and filtered. The filter cake is rinsed with 2 0 methyl iso-butyl ketone (0.5L) and transferred to a vacuum drying oven. The heat was increased to 50-90C and the product dried for 24-48 hours in vacuo at this temperature. Heating was discontinued and, after 6 hours, the material was removed, milled and stored in a dry atmosphere. This provided 581.7g of paroxetine hydrochloride (anhydrous) of Form III. The melting point range was 2 5 157.9-158.8C. The infrared spectra (KBr and Nujol), differential scanningcalorimetry thermogram and X-ray powder diffractogram are shown in Schedules "A", "B", "C", and "D", respectively and labeled as Form III.
Example 4 - Form III
Paroxetine free base is dissolved in methyl iso-butyl ketone (10 vol) and to this solution is added 20% HCl in isopropanol (1.2 eq) and 5 volumes of methyl iso-butyl ketone are removed. Seed crystals of Form III paroxetine hydrochloride5 are added and the resulting heterogeneous solution is stirred at 90-95C under a nitrogen atmosphere for 4-6 hours and filtered. The product is rinsed with methyl iso-butyl ketone (0.5 vol) and is dried for 24-48 hours at 50-90C and heating discontinued. After cooling to ambient temperature, the material was removed, milled and stored in a dry atmosphere. This provided paroxetine l 0 hydrochloride (anhydrous) of Form III.
Example 5 - Form m Paroxetine free base (32.3g) is dissolved in methyl iso-butyl ketone (15 vol) and to this solution is added concentrated HCl (11.7 mL) (~10 M) (1.2 eq). Methyl iso-butyl ketone (10 vol) is removed by vacuum distillation. Seed crystals of 1 5 Form III (1% by weight) are added and the heterogeneous solution is then stirred at 90-95C under a nitrogen atmosphere for 4-6 hours and filtered. The product was dried for 24-48 hours at 50-90C and heating discontinued. After cooling to ambient temperature, the material was removed, milled and stored in a dry atmosphere. This provided 34.9g (97% yield) of paroxetine hydrochloride 2 0 (anhydrous) of Form III.
Example 6 - Form III
Paroxetine hydrochloride of Form I is dry-mixed with Form III paroxetine hydrochloride in a 1:1 ratio by weight. This polymorphic mixture is then placed in a drying oven and dried in vacuo at 50-90C for 24-48 hours. The oven is 2 5 cooled to 20-25C and the product removed to provide a quantitative recovery of paroxetine hydrochloride (anhydrous) of Form III.
Example 7 - Form III
Paroxetine hydrochloride hemihydrate is dry-mixed with anhydrous paroxetine hydrochloride of Form III in a 1:1 ratio by weight. This polymorphic - 6 - 218~12~
mixture is transferred to a vacuum oven and heated at 50-90C for 24-48 hours.
The oven is cooled to 20-25C and the product removed to provide a quantitative recovery of paroxetine hydrochloride (anhydrous) of Form III.
Our research has demonstrated that dry-mixing of Forms such as Form I, 5 Form II, hemihydrate form or combinations thereof with Form III seed crystals and heating to 60-90C, results in conversion of the various Forms of paroxetinehydrochloride to Form III paroxetine hydrochloride. This indicates that Form IIIparoxetine hydrochloride is the thermodynamically most stable Form.
Form III paroxetine hydrochloride may then be formulated into a 10 pharmaceutical composition in final dosage form with a suitable excipient or suitable excipients.
As many changes can be made to the invention without departing from the scope thereof, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.
~`~ 21 871 28 .
Schedule ~An _ Form III Paroxetine.~cl - IR 8pectrum - RBr ~r ~ 1 so .1' i . ! ~ ! I
!i ! !
n 4~ I p~ H~
A ! i d~ ~ V
10-- .
o ~oo ~00 3000 .D00 .0 1400 J2D0 luO0 ~oa 600 . o ~1 C~nc a ~ lr 4 . oo 1701 4000.00 600.00 1.49 30.06 4.00 ST 20 2.000 ~EF 4 ro f. ~ ~ 7~.6~
_4 6 . I -- ; ; 9 ~ 2 . I . 3 2l17 . 27 .:27 . 1~ . _ 6~-.t ~.~ . 4 .'7 24.~.51.~' IB ?.73. ~.
, . ~ . 7~ . ~ : ~ . 1 7 . ~ . 15 ~C ~
A NEW AND USEFUL POLYMORPH OF ANHYDROUS PAROXETINE
HYDROCHLORIDE
FIELD OF INVENTION
This invention relates to a new and useful polymorph of paroxetine hydrochloride (anhydrous) and its preparation thereof.
BACKGROUND OF THE INVENTION
Canadian Letters Patent 1,287,060 describes two distinct forms of paroxetine hydrochloride viz., an anhydrous form of paroxetine hydrochloride and the hemihydrate form of paroxetine hydrochloride (paroxetine hydrochloride 1/2 H20).
These two forms have been known for a substantial period of time, particularly the anhydrous form, which has a melting point of about 118C and which is very hygroscopic making this material extremely difficult to handle.
Coupled with this is the fact that the said anhydrous material is also light andfluffy, which further compounds the problems of handling (filtration and drying) and formulating the active into the final dosage form.
The hemihydrate form is purportedly stable. The purpose of the hemihydrate is to provide material which is less hygroscopic, however the 2 0 compound does include additional amounts of water. Preferably the paroxetine hydrochloride anhydrous should be easily handled with minimal difficulties with respect to the hygroscopic nature of the material and should not be light and fluffy. Preferably the paroxetine hydrochloride anhydrous is in a form having a dense crystalline structure which enables the raw active to be easily 2 5 formulated into final dosage form. Such dense material should, of course, also be easily filtered and readily dried to yield the bulk active and should be readily adapted for use in the commercial manufacture of anhydrous paroxetine hydrochloride, the active ingredient in the final formulation.
- 2- 2l87l28 It is therefore an object of this invention to provide such improved paroxetine hydrochloride anhydrous which overcomes the disadvantages of the prior form of the raw active which suffers from the above deficiencies, particularly the hygroscopic nature of the paroxetine hydrochloride having the 5 melting point of about 118C, the light fluffy nature of the said paroxetine hydrochloride anhydrous and the other deficiencies which would deter one from using paroxetine hydrochloride anhydrous and require such person to use the paroxetine hydrochloride hemihydrate in its place.
Further and other objects of the invention will be realized by those skilled 10 in the art from the following summary of the invention and detailed description of examples thereof.
SUMMARY OF THE INVENTION
In our research, we have determined that paroxetine hydrochloride anhydrous may exist in a number of polymorphic forms. For the purposes 15 herein, our research using differential scanning calorimetric (DSC) analysis has revealed various physical forms of paroxetine hydrochloride anhydrous. We have been able to distinguish between what we identify herein as Form I
paroxetine hydrochloride anhydrous having a DSC onset temperature of approximately 118C and a second polymorphic form (Form II) having a DSC
2 0 onset temperature of approximately 135C made by different processes from the process used to make Form I. In some instances, the processes carried out to produce Form I also produced combinations of Form I and Form II. The processes for making Form I were taught in Canadian Patent No. 1,287,060 and also by various other modified processes which emanated from our research.
2 5 The processes for making Form II also emanated from our research efforts to find a suitable stable polymorphic form of paroxetine hydrochloride (anhydrous).
~ 3 ~ 2187128 Such processes include:
Example 1 for making Form II is set out below:
Paroxetine free base (36.8g) is dissolved in 10 volumes of toluene. To this solution is added 21.5g of a hydrochloric acid in 2-propanol solution (24.9% by 5 weight). At this point, 5 volumes of toluene are removed by distillation. Uponcooling, paroxetine hydrochloride of Form II had precipitated out. This materialwas isolated by filtration and dried in vacuo at 45-55C to provide 39.1g (95%
yield) of paroxetine hydrochloride (anhydrous). The melting range was 135.4-137.4C.
1 0 Example 2 for making Form II:
Paroxetine free base (41.8g) is dissolved in 15 volumes of toluene. To this solution was added 16.5mL of concentrated hydrochloric acid (10 M). After 30 minutes, 5 volumes of toluene are removed, the solution is cooled to 20-25C
and filtered. The product is dried under vacuum at 45-55C, furnishing 46.5g 1 5 (100% yield) of Form II paroxetine hydrochloride.
Form II may also be prepared using a similar experimental protocol with organic solvents (or solvent combinations) selected from an organic ketone such as methyl iso-butyl ketone or methyl ethyl ketone, a halogenated hydrocarbon such as dichloromethane, an alkyl acetate such as ethyl acetate, a hydrocarbon 2 0 such as toluene, or an ether such as methyl tert-butyl ether.
Form I paroxetine hydrochloride is prepared by recrystallization from organic ketones such as acetone, lower alcohols such as 2-propanol, or combinations of organic ketones and lower alcohols.
Our research unexpectedly revealed to us a new polymorphic form of 2 5 paroxetine hydrochloride anhydrous which was very dense (having the consistency of coarse sand), having a bulk density exceeding about 0.6g/mL and atapped density exceeding about 0.9g/mL and which is substantially non-hygroscopic. We have identified this Form as Form III. Form III did not retain, we discovered, residual solvent in excess of about 0.1% and even leaving the 4 2l87128 material exposed to open air for a period of five days, Form III did not take onmoisture more than 1% by weight. Form III, as well, was very stable and was distinguished from the other two forms previously described (Form I and Form II) by a DSC onset temperature of about 159C and a melting point between about 157-159C. Form III we have also determined is easily formulated into final dosage form and is easily manufactured in commercial quantities by processes described in the examples herein.
To complete the identification of Form III paroxetine hydrochloride anhydrous is the infrared spectrum of Form III in KBr and is attached as 1 0 Schedule "A". The infrared spectrum of Form III in Nujol is attached as Schedule "B". The DSC thermogram showing the determination of the DSC
onset temperature of Form III is attached as Schedule "C" and the X-ray powder diffraction pattern of Form III is attached as Schedule "D" (pages 1 and 2) to this application. Form III may be manufactured by the following examples:
1 5 Example 3 for making Form III
Anhydrous paroxetine hydrochloride (600g) is suspended in methyl iso-butyl ketone (3.0L). This solution is stirred and heated to 90-95C (internal temperature) under a nitrogen atmosphere. This temperature is maintained for 4-6 hours, then cooled to 20-25C and filtered. The filter cake is rinsed with 2 0 methyl iso-butyl ketone (0.5L) and transferred to a vacuum drying oven. The heat was increased to 50-90C and the product dried for 24-48 hours in vacuo at this temperature. Heating was discontinued and, after 6 hours, the material was removed, milled and stored in a dry atmosphere. This provided 581.7g of paroxetine hydrochloride (anhydrous) of Form III. The melting point range was 2 5 157.9-158.8C. The infrared spectra (KBr and Nujol), differential scanningcalorimetry thermogram and X-ray powder diffractogram are shown in Schedules "A", "B", "C", and "D", respectively and labeled as Form III.
Example 4 - Form III
Paroxetine free base is dissolved in methyl iso-butyl ketone (10 vol) and to this solution is added 20% HCl in isopropanol (1.2 eq) and 5 volumes of methyl iso-butyl ketone are removed. Seed crystals of Form III paroxetine hydrochloride5 are added and the resulting heterogeneous solution is stirred at 90-95C under a nitrogen atmosphere for 4-6 hours and filtered. The product is rinsed with methyl iso-butyl ketone (0.5 vol) and is dried for 24-48 hours at 50-90C and heating discontinued. After cooling to ambient temperature, the material was removed, milled and stored in a dry atmosphere. This provided paroxetine l 0 hydrochloride (anhydrous) of Form III.
Example 5 - Form m Paroxetine free base (32.3g) is dissolved in methyl iso-butyl ketone (15 vol) and to this solution is added concentrated HCl (11.7 mL) (~10 M) (1.2 eq). Methyl iso-butyl ketone (10 vol) is removed by vacuum distillation. Seed crystals of 1 5 Form III (1% by weight) are added and the heterogeneous solution is then stirred at 90-95C under a nitrogen atmosphere for 4-6 hours and filtered. The product was dried for 24-48 hours at 50-90C and heating discontinued. After cooling to ambient temperature, the material was removed, milled and stored in a dry atmosphere. This provided 34.9g (97% yield) of paroxetine hydrochloride 2 0 (anhydrous) of Form III.
Example 6 - Form III
Paroxetine hydrochloride of Form I is dry-mixed with Form III paroxetine hydrochloride in a 1:1 ratio by weight. This polymorphic mixture is then placed in a drying oven and dried in vacuo at 50-90C for 24-48 hours. The oven is 2 5 cooled to 20-25C and the product removed to provide a quantitative recovery of paroxetine hydrochloride (anhydrous) of Form III.
Example 7 - Form III
Paroxetine hydrochloride hemihydrate is dry-mixed with anhydrous paroxetine hydrochloride of Form III in a 1:1 ratio by weight. This polymorphic - 6 - 218~12~
mixture is transferred to a vacuum oven and heated at 50-90C for 24-48 hours.
The oven is cooled to 20-25C and the product removed to provide a quantitative recovery of paroxetine hydrochloride (anhydrous) of Form III.
Our research has demonstrated that dry-mixing of Forms such as Form I, 5 Form II, hemihydrate form or combinations thereof with Form III seed crystals and heating to 60-90C, results in conversion of the various Forms of paroxetinehydrochloride to Form III paroxetine hydrochloride. This indicates that Form IIIparoxetine hydrochloride is the thermodynamically most stable Form.
Form III paroxetine hydrochloride may then be formulated into a 10 pharmaceutical composition in final dosage form with a suitable excipient or suitable excipients.
As many changes can be made to the invention without departing from the scope thereof, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.
~`~ 21 871 28 .
Schedule ~An _ Form III Paroxetine.~cl - IR 8pectrum - RBr ~r ~ 1 so .1' i . ! ~ ! I
!i ! !
n 4~ I p~ H~
A ! i d~ ~ V
10-- .
o ~oo ~00 3000 .D00 .0 1400 J2D0 luO0 ~oa 600 . o ~1 C~nc a ~ lr 4 . oo 1701 4000.00 600.00 1.49 30.06 4.00 ST 20 2.000 ~EF 4 ro f. ~ ~ 7~.6~
_4 6 . I -- ; ; 9 ~ 2 . I . 3 2l17 . 27 .:27 . 1~ . _ 6~-.t ~.~ . 4 .'7 24.~.51.~' IB ?.73. ~.
, . ~ . 7~ . ~ : ~ . 1 7 . ~ . 15 ~C ~
3 . 3 . ~ .. 52 z . 4~. A~ ,' 95 4~.~ 7 .~-.04 ; ~ 12. ~ 65. ~ , -,, ,~, 6~. 71.~ 6: ..37 E~l 5; PEAKl J F01~
- ~ ,~ -~
^ ` ~
- ~ 2187128 8chedule ~B" - Form III Paroxetlne.HCl - IR 8pectrum - Nu~ol 1lO.O ¦ H
! !
JJ I i 1 1 n 40- J P~~
30- NL~ ~ I ~ !
a~ ~
ll 0.0 ~ ._ . A
400 o 3500 3000 ~ioo ~00 0 ~oo 1600 l400 1200 1000 ~00 600 0 ~701 4000.00 600.00 0.03 ~0.03 4.00 ~ 20 2.000 F
~ 4''0 ~ 00' .77 '907. .; '85 '. . q754. ' .~ ~ . ~ 2: ,17 ~ ~-1, 3, ' I . .2.4 1 J . ~ . ~.2 I , ?.... '4 ~ . 4. ;~
: 67~ '3.~- ~.; "'. ..... E
- ~ ,~ -~
^ ` ~
- ~ 2187128 8chedule ~B" - Form III Paroxetlne.HCl - IR 8pectrum - Nu~ol 1lO.O ¦ H
! !
JJ I i 1 1 n 40- J P~~
30- NL~ ~ I ~ !
a~ ~
ll 0.0 ~ ._ . A
400 o 3500 3000 ~ioo ~00 0 ~oo 1600 l400 1200 1000 ~00 600 0 ~701 4000.00 600.00 0.03 ~0.03 4.00 ~ 20 2.000 F
~ 4''0 ~ 00' .77 '907. .; '85 '. . q754. ' .~ ~ . ~ 2: ,17 ~ ~-1, 3, ' I . .2.4 1 J . ~ . ~.2 I , ?.... '4 ~ . 4. ;~
: 67~ '3.~- ~.; "'. ..... E
5~ pEA,~I!`) FOUO
~, ~ 7'.~
~c 218712~
8chedule ~C" - Fonm III Paroxetine.~Cl - DSC Prof~le Heat Flow (~W) ~
o ~no ~n o ~n -- o o o o O O O
O
o o o O_ ~ .
,_ -O _ ~D
,_ tD I
~ ~a o _ ~ n~
O ~ W~
a O
' F --' ~ - ~
SCHEDULE "D" (page 1) ~ 2 1 8 7 1 2 ~ ~
For~ III Paroxetine Hydrochloride (A.nhydrous) _- X-Ray Powder ~iffraction Pattern n ~ N ~ J~ ~n C cn O O O O O ~ O
O O ' O O O ~D O
O O O O O O 'J O
"~
' . ' F
..
' ~' :~
--~ .
.
~=
n~
~ ~ . ' - .
, o ~ r ~e 21 8712~3 ~
SC~EDULE "D" (page 2) Form III Paroxetine H~d,ochloride (Anhydrous) X-Ray Diffraction Pattern Degrees 20 VqO Degrees20 ~qo 10.02 1 25.86 8 11.62 1 26.17 26 12.03 8 26.84 7 13.02 7 27.38 6 14.15 6 27.87 11 15.04 1 28.53 14 15.59 <1 28.97 4 16.27 6 29.22 15 17.35 8 30.63 3 17.58 10 31.99 6 18.29 19 32.67 2 18.74 4 33.56 2 19.26 15 35.16 19.76 5 35.47 2 20.23 6 35.98 20.67 100 36.53 6 20.99 10 36.89 3 22.18 2 37.85 4 22.75 7 38.34 23.17 5 38.90 2 23.55 24 39.17 2 24.32 4 39.73 3 24.64 2 , .
~, ~ 7'.~
~c 218712~
8chedule ~C" - Fonm III Paroxetine.~Cl - DSC Prof~le Heat Flow (~W) ~
o ~no ~n o ~n -- o o o o O O O
O
o o o O_ ~ .
,_ -O _ ~D
,_ tD I
~ ~a o _ ~ n~
O ~ W~
a O
' F --' ~ - ~
SCHEDULE "D" (page 1) ~ 2 1 8 7 1 2 ~ ~
For~ III Paroxetine Hydrochloride (A.nhydrous) _- X-Ray Powder ~iffraction Pattern n ~ N ~ J~ ~n C cn O O O O O ~ O
O O ' O O O ~D O
O O O O O O 'J O
"~
' . ' F
..
' ~' :~
--~ .
.
~=
n~
~ ~ . ' - .
, o ~ r ~e 21 8712~3 ~
SC~EDULE "D" (page 2) Form III Paroxetine H~d,ochloride (Anhydrous) X-Ray Diffraction Pattern Degrees 20 VqO Degrees20 ~qo 10.02 1 25.86 8 11.62 1 26.17 26 12.03 8 26.84 7 13.02 7 27.38 6 14.15 6 27.87 11 15.04 1 28.53 14 15.59 <1 28.97 4 16.27 6 29.22 15 17.35 8 30.63 3 17.58 10 31.99 6 18.29 19 32.67 2 18.74 4 33.56 2 19.26 15 35.16 19.76 5 35.47 2 20.23 6 35.98 20.67 100 36.53 6 20.99 10 36.89 3 22.18 2 37.85 4 22.75 7 38.34 23.17 5 38.90 2 23.55 24 39.17 2 24.32 4 39.73 3 24.64 2 , .
Claims (9)
1. Paroxetine hydrochloride anhydrous designated as Form III having at least one of the characteristics selected from the group consisting of:
a) Infrared spectra as shown in Schedules "A" and "B", b) A DSC onset temperature of about 159°C, c) An X-ray powder diffraction pattern as shown in Schedule "D"
(pages 1 and 2), d) A melting point of between about 156°C to about 162°C, e) A bulk density exceeding about 0.6g/mL and a tapped density exceeding about 0.9g/mL.
a) Infrared spectra as shown in Schedules "A" and "B", b) A DSC onset temperature of about 159°C, c) An X-ray powder diffraction pattern as shown in Schedule "D"
(pages 1 and 2), d) A melting point of between about 156°C to about 162°C, e) A bulk density exceeding about 0.6g/mL and a tapped density exceeding about 0.9g/mL.
2. Form III paroxetine hydrochloride having infrared spectra as shown in Schedule "A" (KBr) and "B" (Nujol).
3. Form III paroxetine hydrochloride anhydrous having a DSC onset temperature of about 159°C.
4. Form III Paroxetine hydrochloride anhydrous having the following X-ray powder diffraction pattern as shown in Schedule "D".
5. Form III paroxetine hydrochloride anhydrous having a melting point of between about 156°C to about 162°C.
6. Form III paroxetine hydrochloride anhydrous having a bulk density exceeding about 0.6g/mL and a tapped density exceeding about 0.9g/mL.
7. Use of anhydrous paroxetine hydrochloride Form III for the manufacture of a pharmaceutical formulation.
8. A pharmaceutical composition comprising paroxetine hydrochloride Form III as described in claim 1 together with a pharmaceutically acceptable excipient.
9. The anhydrous crystalline Form III of paroxetine hydrochloride characterized by peaks in a powder X-ray diffraction pattern at the approximate values of 10.02°; 11.62°; 12.03°; 13.02°; 14.15°; 15.04°; 15.59°; 16.27°; 17.35°; 17.58°;
18.29°; 18.74°; 19.26°; 19.76°; 20.23°; 20.67°; 20.99°; 22.18°; 22.75°; 23.17°; 23.55°;
24.32°; 24.64°; 25.86°; 26.17°; 26.84°; 27.38°; 27.87°; 28.53°; 28.97°; 29.22°; 30.63°;
31.99°; 32.67°; 33.56°; 35.16°; 35.47°; 35.98°; 36.53°; 36.89°; 37.85°; 38.34°; 38.90°;
39.17°; and 39.73°; of two theta.
18.29°; 18.74°; 19.26°; 19.76°; 20.23°; 20.67°; 20.99°; 22.18°; 22.75°; 23.17°; 23.55°;
24.32°; 24.64°; 25.86°; 26.17°; 26.84°; 27.38°; 27.87°; 28.53°; 28.97°; 29.22°; 30.63°;
31.99°; 32.67°; 33.56°; 35.16°; 35.47°; 35.98°; 36.53°; 36.89°; 37.85°; 38.34°; 38.90°;
39.17°; and 39.73°; of two theta.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002187128A CA2187128A1 (en) | 1996-10-04 | 1996-10-04 | New and useful polymorph of anhydrous paroxetine hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002187128A CA2187128A1 (en) | 1996-10-04 | 1996-10-04 | New and useful polymorph of anhydrous paroxetine hydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2187128A1 true CA2187128A1 (en) | 1997-06-26 |
Family
ID=4159025
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002187128A Abandoned CA2187128A1 (en) | 1996-10-04 | 1996-10-04 | New and useful polymorph of anhydrous paroxetine hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2187128A1 (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5874447A (en) * | 1997-06-10 | 1999-02-23 | Synthon B. V. | 4-Phenylpiperidine compounds for treating depression |
| WO1999032484A1 (en) * | 1997-12-19 | 1999-07-01 | Smithkline Beecham Plc | Process for the preparation of paroxetine hydrochloride |
| WO2000001693A1 (en) * | 1998-07-07 | 2000-01-13 | Medichem, S.A. | Paroxetine maleate polymorph and pharmaceutical compositions containing it |
| US6063927A (en) * | 1998-07-02 | 2000-05-16 | Smithkline Beecham Plc | Paroxetine derivatives |
| WO2000032592A1 (en) * | 1998-11-28 | 2000-06-08 | Smithkline Beecham Plc | Process for the preparation of paroxetine hydrochloride |
| WO2001012623A1 (en) * | 1999-08-12 | 2001-02-22 | Smithkline Beecham P.L.C. | Process for the preparation of paroxetine hydrochloride |
| US6436956B1 (en) | 1996-12-24 | 2002-08-20 | Brantford Chemicals Inc. | Useful form of anhydrous paroxetine hydrochloride |
| WO2002102382A1 (en) * | 2001-06-14 | 2002-12-27 | Teva Pharmaceutical Industries Ltd. | A PROCESS FOR PREPARING PAROXETINE HCl WHICH LIMITS FORMATION OF PINK COLORED COMPOUNDS |
| WO2005019209A2 (en) * | 2003-06-12 | 2005-03-03 | Cadila Healthcare Limited | Crystalline anhydrous paroxetine hydrochloride |
-
1996
- 1996-10-04 CA CA002187128A patent/CA2187128A1/en not_active Abandoned
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6436956B1 (en) | 1996-12-24 | 2002-08-20 | Brantford Chemicals Inc. | Useful form of anhydrous paroxetine hydrochloride |
| US6900327B2 (en) | 1997-06-10 | 2005-05-31 | Synthon Bct Technologies, Llc | 4-phenylpiperidine compounds |
| US5874447A (en) * | 1997-06-10 | 1999-02-23 | Synthon B. V. | 4-Phenylpiperidine compounds for treating depression |
| US7598271B1 (en) | 1997-06-10 | 2009-10-06 | Noven Therapeutics, Llc | Crystalline paroxetine methane sulfonate |
| WO1999032484A1 (en) * | 1997-12-19 | 1999-07-01 | Smithkline Beecham Plc | Process for the preparation of paroxetine hydrochloride |
| US6063927A (en) * | 1998-07-02 | 2000-05-16 | Smithkline Beecham Plc | Paroxetine derivatives |
| WO2000001693A1 (en) * | 1998-07-07 | 2000-01-13 | Medichem, S.A. | Paroxetine maleate polymorph and pharmaceutical compositions containing it |
| ES2138937A1 (en) * | 1998-07-07 | 2000-01-16 | Medichem Sa | Paroxetine maleate polymorph and pharmaceutical compositions containing it |
| US6440459B1 (en) | 1998-07-07 | 2002-08-27 | Medichem, S.A. | Paroxetine maleate polymorph and pharmaceutical compositions containing it |
| WO2000032592A1 (en) * | 1998-11-28 | 2000-06-08 | Smithkline Beecham Plc | Process for the preparation of paroxetine hydrochloride |
| WO2001012623A1 (en) * | 1999-08-12 | 2001-02-22 | Smithkline Beecham P.L.C. | Process for the preparation of paroxetine hydrochloride |
| WO2002102382A1 (en) * | 2001-06-14 | 2002-12-27 | Teva Pharmaceutical Industries Ltd. | A PROCESS FOR PREPARING PAROXETINE HCl WHICH LIMITS FORMATION OF PINK COLORED COMPOUNDS |
| WO2005019209A3 (en) * | 2003-06-12 | 2005-05-12 | Cadila Healthcare Ltd | Crystalline anhydrous paroxetine hydrochloride |
| WO2005019209A2 (en) * | 2003-06-12 | 2005-03-03 | Cadila Healthcare Limited | Crystalline anhydrous paroxetine hydrochloride |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |