Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
2187128
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.
2187128
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.
1 5
~`~ 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
0
4-00
~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
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: 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
3 W
O_
~ .
,_
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O _
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o _ ~ n~
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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
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,
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~ 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
, .
