patent-us 008053579 b2-salts of clopidogrel and process for preparation
TRANSCRIPT
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8/10/2019 Patent-US 008053579 B2-Salts of Clopidogrel and Process for Preparation
1/10
US008053579B2
( 1 2 )
Ulllted
States
Patent
( 1 0 ) P a t e n t N 0 . :
U S 8 , 0 5 3 , 5 7 9
B2
Lohray t a ] . 4 5 )
Date o f P a t e n t : * N o v . 8 ,
2 0 1 1
( 5 4 ) SALTS
OF CLOPIDOGREL
AND
PROCESS
6 , 6 3 5 , 7 6 3 B2 1 0 / 2 0 0 3
P a n d e y
e t a 1 .
FORPREPARATION 6 , 7 6 7 , 9 1 3 B2 7 / 2 0 0 4 L i f s h i t Z e t a l .
2002/0177712 A1
1 1 / 2 0 0 2
Pandey t a 1 .
.
. _ 2005/0203122 A1 9/2005 Doser et
a l .
7 5 )
I n v e n t o r s :
B r a ]
Bhushan
L o h r a y ,
G u j a r a t
I N ) ,
Z o o s / 0 2 5 6 1 5 2
A 1
1 1 / 2 0 0 5
D o s e r
e t
a 1
Vldya B h l l s h a l l
L o h r a y , G 1 1 1 a r a t
( 1 N ) ;
2 0 0 6 / 0 2 6 4 6 3 6
A 1
1 1 / 2 0 0 6 L o h r a y
e t a 1 .
Mayank Ghanshyambhai
D a v e ,
2 0 0 7 / 0 0 3 7 8 4 2 Al 2 / 2 0 0 7 L o h r a y
e t
a 1 .
G u j a r a t
( 1 N )
2 0 0 7 / 0 0 8 2 9 2 4 A 1 4 / 2 0 0 7 L o h r a y
2009/0270448
A1
1 0 / 2 0 0 9
Rey t a 1 .
( 7 3 ) A s s i g n e e :
C a d i l a H e a l t h c a r e
L i m i t e d ,
G u j a r a t FOREIGN
PATENT
DOCUMENTS
( I N ) EP 1 9 0 0 3 5 8 3 / 2 0 0 8
WO
2004/013147 2 / 2 0 0 4
(
*
)
N o t i c e : S u b j e c t t o
any
d i s c l a i m e r , t h e
t e r m o f h i s
WO 2 0 0 4 / 0 7 2 0 8 4
8 / 2 0 0 4
p a t e n t i s
extended
o r a d j u s t e d
under 35 WO
2 0 0 4 / 0 7 2 0 8 5
8 / 2 0 0 4
U _ S _ C _
1 5 4 1 ) ) b y
( )
day,
WO 2 0 0 4 / 0 7 4 2 1 5
9 / 2 0 0 4
T h i s
p a t e n t
i s s u b j e c t t o a
t e r m i n a l
d i s - OTHER PUBLICATIONS
C l a l m e r ' A n o n y m o u s
S t a b i l i t y
r e p o r t
f o r C l o p i d o g r a l
b e s y l a t e
s u b s t a n c e
_ one page (2008).
( 2 1 )
A p p l ' NO 1 2 / 7 6 0 5 2 3 B y r n e t a l .
S o l i d - s t a t e
p h a r m a c e u t i c a l
c h e m i s t r y
C h e m .
o f
M a t e
. _ rials
611148-1158
( 1 9 9 4 ) .
( 2 2 ) F l l e d ' A p r 1 4 2010 B y r n e t a l . S o l i d - S t a t e
C h e m i s t r y o f
D r u g s , A c a d e m i c
P r e s s ,
p p . 3 - 2 7
. . . (1982).
( 6 5 )
Pnor P u b h c a t l o n
Data C a i r a
C r y s t a l l i n e p o l y m o r p h i s m o f
o r g a n i c c o m p o u n d s T o p i c s i n
Us 2 0 1 0 / 0 1 9 7 9 2 3 A1 A u g . 5 ,
2 0 1 0 C u r r ;
Chem 1 9 8 5 1 6 3 4 0 3 ( 1 9 9 8 )
DumtZ
e t
a l .
D 1 s a p p e a r 1 n g p o l y m o r p h s
A c c o u n t s
o f
Chem.
R e s .
. .
28:193-200
( 1 9 9 5 ) .
Related
U ' s ' Apphcatlon
Data F i e r s
v .
S u g a n o
2 5 USPQ2d 1 6 0 1 ,
7 p g s ( F e d .
C i r .
1 9 9 3 ) .
( 6 3 )
C o n t i n u a t i o n o f
a p p l i c a t i o n
N o .
1 0 / 5 5 4 , 3 6 7 ,
? l e d a s
K n a p m a n P o l y m o r p h i c
p r e d i c t i o n M o d e r n
D r u g D i s c o v e r y 3 : 5 3
a p p l i c a t i o n No. PCT/IN2004/000112 on A p r . 2 2 , 5 4 a n d 5 7 ( 2 0 0 0 )
2004 HOW pat NO_
7
732
608
R o s e n b e r g , P a t e n t Law
a s i c s ,
W e s t G r o u p p p . 9 - 5 8
a n d
9 - 5 9
( 2 0 0 0 ) .
s s
Rosenberg, P a t e n t Law
a s i c s , West
Group
p .
9-62
and
- 6 3 ( 2 0 0 0 ) .
R osenb erg , Patent
Law
asics, West Group p.
9-30
and 9 -3 1
(2000).
( 3 0 ) F o r e l g n Apphcatlon Pmnty
ata
I n t l S e a r c h R e p o r t
f o r
P C T / I N 2 0 0 4 / 0 0 0 1 1 2 , m a i l e d J a n .
2 5 ,
2 0 0 5 .
W r i t t e n O p i n i o n
f o r P C T / I N 2 0 0 4 / 0 0 0 1 1 2 ,
m a i l e d J a n .
2 5 ,
2 0 0 5 .
Apr' 2 5 2003 ( I N ) 4 1 3 / M U M / 2 0 0 3 I n t l P r e l i m i n a r y R e p o r t on P a t e n t a b i l i t y f o r PCT/IN2004/000112
( 5 1 ) I n t Cl m a i l e d S e p . 5 , 2 0 0 5 .
' rzmar
xammer
eW
osar
07D 513/02
(2006 01) P y E And
D
K
(52)
U . . S .
Cl. . . . . . . . . . . . . . . . .
. . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
.
546 / 1 1 4 Assistant Examineri
aymond covington
( 5 8 ) F i e l d o f
C l a s s l ? c a t l o n
Search . . . . . . . . . . . . . 5 4 6 / 1 1 4 ( 7 4 ) A t t o r n e y ) A g e n t ]
o r
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& anderhye
PC
S e e
a p p l 1 c a t 1 o n
? l e f o r c o m p l e t e
s e a r c h h 1 s t o r y .
57
ABSTRACT
5 6 )
R e f e r e n c e s C i t e d
( )
U . S .
PATENT DOCUMENTS
4 , 5 2 9 , 5 9 6
A
7 / 1 9 8 5 A u b e r t e t
a 1 .
4 , 8 4 7 , 2 6 5 A 7 / 1 9 8 9 Badorc e t
a l .
6 , 4 2 9 , 2 1 0 B1
8 / 2 0 0 2
B o u s q u e t e t a l .
6 , 5 0 9 , 3 4 8
B1
1 / 2 0 0 3 O g l e t r e e
D i s c l o s e d
a r e
neW
s a l t s o f C l o p i d o g r e l
V i Z .
C l o p i d o g r e l
m e s y l a t e , C l o p i d o g r e l
b e s y l a t e a n d
C l o p i d o g r e l t o s y l a t e ,
m e t h o d s
f o r
t h e i r
p r e p a r a t i o n
a n d
p h a r m a c e u t i c a l c o m p o s i
t i o n s
c o n t a i n i n g them and h e i r
u s e
i n
m e d i c i n e .
9 C l a i m s , 5 Drawing S h e e t s
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1
SALTS OFCLOPIDOGREL
AND PROCESS
FOR
PREPARATION
T h i s
a p p l i c a t i o n
i s
a
c o n t i n u a t i o n
o f a p p l i c a t i o n S e r .
N o .
1 0 / 5 5 4 , 3 6 7 , ? l e d F e b . 1 ,
2006
now US.
a t .
N o . 7 , 7 3 2 , 6 0 8 ,
noW l l o w e d ; Which s a
US.
n a t i o n a l s t a g e under 35 U . S . C .
3 7 1 o f
n t l
P a t e n t A p p l i c a t i o n
N o . PCT/IN2004/000112
? l e d
A p r .
2 2 , 2 0 0 4 ; W h i c h c l a i m s p r i o r i t y b e n e ? t
o f
I n d i a n
A p p l i
c a t i o n
No. 413/MUM/2003;
t h e
e n t i r e
c o n t e n t s
o f a l l o f
W h i c h a r e h e r e b y i n c o r p o r a t e d b y
r e f e r e n c e
i n t h i s a p p l i c a
t i o n .
FIELD OF
INVENTION
The
p r e s e n t i n v e n t i o n
d e s c r i b e s
c e r t a i n s a l t s o f
C l o p i
d o g r e l
i n c l u d i n g
t h e i r h y d r a t e s
a n d
o t h e r
s o l v a t e s ,
b o t h
i n
a m o r p h o u s
a n d
c r y s t a l l i n e f o r m s ,
p r o c e s s e s f o r t h e i r
p r e p a
r a t i o n
a n d
p h a r m a c e u t i c a l c o m p o s i t i o n s
c o n t a i n i n g t h e m a n d
t h e i r
u s e
i n m e d i c i n e .
C l o p i d o g r e l i s marketed
a s
( S ) - ( + )
C l o p i d o g r e l
b i s u l f a t e ,
u s e f u l
a s a n
a n t i p l a t e l e t
d r u g f o r
t h e
t r e a t m e n t
o f
a t h e r o s c l e r o s i s , m y o c a r d i a l
i n f a r c t i o n ,
s t r o k e s
and
v a s c u l a r
d e a t h .
The
p r e s e n t i n v e n t i o n
a l s o
d e s c r i b e s
method
o f
t r e a t m e n t
o f
s u c h
c a r d i o v a s c u l a r d i s o r de r s
u s i n g
t h e
s a l t s o f
t h e
p r e s e n t
i n v e n t i o n
o r m i x t u r e s t h e r e o f , and
p h a r m a c e u t i c a l c o m p o s i t i o n s
c o n t a i n i n g
t h e m .
T h e p r e s e n t
i n v e n t i o n a l s o
r e l a t e s
t o t h e u s e
o f
t h e s a l t s
o f
C l o p i d o g r e l
d i s c l o s e d
h e r e i n a n d
p h a r m a c e u t i c a l c o m p o s i t i o n s
c o n t a i n
i n g
them
f o r t h e t r e a t m e n t
o f
c a r d i o v a s c u l a r d i s o r d e r s .
BACKGROUND
TO
THE
INVENTION
The
compounds o f t h e
i n v e n t i o n
r e f e r r e d
h e r e i n , a r e p h a r
m a c e u t i c a l l y a c c e p t a b le s a l t s o f t h e c o m p o u n d knoWn b y i t s
g e n e r i c name C l o p i d o g r e l
h a v i n g s t r u c t u r e
( I )
o
ocH3
n H
m
1 S
I t i s a v a i l a b l e i n
t h e
market
a s
i t s
b i s u l f a t e s a l t and i s
m a r k e t e d by
S a n o ? - S y n t h e l a b o
a s P l a v i x
h a v i n g
t h e g e n
e r a l f o r m u l a I I )
C l o p i d o g r e l
i s
a n i n h i b i t o r o f p l a t e l e t a g g r e g a t i o n a n d
i s
m a r k e t e d a s a n a n t i a n g i n a l
a g e n t ,
a n t i p l a t e l e t
a g e n t
a n d
i s
found
t o d e c r e a s e
morbid
e v e n t s i n p e o p l e W i t h e s t a b l i s h e d
a t h e r o s c l e r o t i c c a r d i o v a s c u l a r d i s e a s e and c e r e b r o v a s c u l a r
d i s e a s e s .
T h e
t h e r a p e u t i c
a p p l i c a t i o n
o f
C l o p i d o g r e l a s
b l o o d - p l a t e
l e t a g g r e g a t i o n i n h i b i t i n g
a g e n t s
a n d
a n t i t h r o m b o t i c
a g e n t
a n d
i t s p r e p a r a t i o n i s d i s c l o s e d i n US. P a t .
N o .
4 , 5 2 9 , 5 9 6 .
( I )
( I 1 )
20
25
30
35
4 0
45
50
55
60
6 5
2
US. P a t . No. 4 , 8 4 7 , 2 6 5
d e s c r i b e s
t h e p r o c e s s
f o r
t h e p r e p a
r a t i o n o f
t h e
h y d r o g e n
s u l f a t e
s a l t o f C l o p i d o g r e l .
P o l y m o r p h s
o f C l o p i d o g r e l b i s u l f a t e h a s
b e e n
d e s c r i b e d i n
US. P a t .
N o s .
6 , 5 0 4 , 0 4 0 and
6 , 4 2 9 , 2 1 0 . We
a v e d i s c l o s e d
n o v e l p o l y m o r p h s
o f
C l o p i d o g r e l b i s u l f a t e i n o u r
PCT I n t e r
n a t i o n a l A p p l i c a t i o n N o .
PCT/IN03/
0 0 5 3 .
The
p r e s e n t a p p l i c a n t
h a s
a l s o d i s c l o s e d
n o v e l p r o c e s s e s
f o r p r e p a r i n g C l o p i d o g r e l
b a s e i n US. a t . N o . 6 , 6 3 5 , 7 6 3 .
US. P a t . N o . 4 , 8 4 7 , 2 6 5 d i s c l o s e s t h a t t h e d e x t r o r o t a t o r y
e n a n t i o m e r o f
f o r m u l a I )
o f C l o p i do g r e l h a s a n e x c e l l e n t
a n t i a g r e g a n t p l a t e l e t a c t i v i t y , W h e r e a s t h e c o r r e s p o n d i n g
l e v o r o t a t o r y e n a n t i o m e r
o f
F o r m u l a I ) i s
l e s s
t o l e r a t e d
o f
t h e
tWo e n a n t i o m e r s and i s l e s s a c t i v e . US. P a t . No. 4 , 8 4 7 , 2 6 5
a l s o
d e s c r i b e s v a r i o u s o t h e r s a l t s
o f h e
compound f f o r m u l a
( I ) , l i k e i t s h y d r o c h l o r i d e , c a r b o x y l i c a c i d
a n d s u l f o n i c a c i d s
s a l t s . S p e c i ? c a l l y ,
s a l t s
o f a c e t i c ,
b e n Z o i c , f u m a r i c , m a l e i c ,
c i t r i c , t a r t a r i c ,
g e n t i s i c , m e t h a n e s u l f o n i c ,
e t h a n e s u l f o n i c ,
b e n Z e n e s u l f o n i c
a n d ,
l a u r y l
s u l f o n i c a c i d s W e r e
p r e p a r e d .
H o W e v e r , a c c o r d i n g
t o
t h i s
p a t e n t ,
t h e s e s a l t s u s u a l l y p r e c i p i
t a t e d
i n
a m o r p h o u s f o r m a n d / o r t h e y W e r e
h y g r o s c o p i c
mak
i n g them i f ? c u l t t o h a n d l e
i n an n d u s t r i a l
s c a l e . A l s o ,
no
d a t a
c o r r e s p o n d i n g t o a n y o f t h e s e
s a l t s a r e r e p o r t e d .
The s p e c i ?
c a t i o n
a l s o
d e s c r i b e s
s a l t s
o f d o b e s i l i c a c i d ( m . p . : 7 0 o C . ) a n d
p a r a - t o l u e n e s u l f o n i c a c i d ,
h a v i n g
a
m e l t i n g
p o i n t o f 5 1 0 C . ,
t h e p u r i ? c a t i o n
o f W h i c h , a s a c c e p t e d
i n t h e
p a t e n t , p r o v e d
t o
be d i f ? c u l t .
T h u s ,
t h e r e r e m a i n s
a
need o p r e p a r e
s a l t s o f C l o p i d o g r e l
Which a r e
s t a b l e ,
e a s y
t o
h a n d l e , can
be
puri?ed and
can
be
e x p l o i t e d on
an
i n d u s t r i a l s c a l e .
We
h e r e b y d i s c l o s e
c e r t a i n p h a r m a c e u t i c a l l y
a c c e p t a b l e
s a l t s o f C l o p i d o g r e l p a r t i c u l a r l y t h e s a l t s
o f
p - t o l u e n e s u l f o n i c
a c i d ,
b e n Z e n e s u l f o n i c
a c i d a n d m e t h a n e s u l f o n i c a c i d s
b o t h i n
c r y s t a l l i n e
a n d
a m o r p h o u s f o r m s , i n c l u d i n g t h e i r
h y d r a t e s
a n d
o t h e r s o l v a t e s Which r e
W e l l
c h a r a c t e r i z e d , f r e e ? o W i n g ,
e a s y
t o h a n d l e a n d h a v i n g h i g h p u r i t y .
OBJECTS OFTHE INVENTION
I t i s
t h e r e f o r e , a n o b j e c t
o f
t h e p r e s e n t i n v e n t i o n
t o p r e p a r e
neW p h a r m a c e u t i c a l l y
a c c e p t a b l e s a l t s o f C l o p i d o g r e l .
More
p a r t i c u l a r l y ,
t h e
p r e s e n t i n v e n t i o n
a i m s
t o
p r o v i d e neW f o r m s
o f C l o p i d o g r e l p - t o l u e n e s u l f o n a t e , C l o p i d o g r e l b e n Z e n e
s u l f o n a t e a n d
C l o p i d og r e l m e t h a n e s u l f o n a t e ,
i n c l u d i n g
t h e i r
h y d r a t e s a n d o t h e r
s o l v a t e s
i n
b o t h
c r y s t a l l i n e a n d
a m o r p h o u s
f o r m s .
A n o t h e r o b j e c t
o f
t h e p r e s e n t
i n v e n t i o n
i s t o p r o v i d e p r o
c e s s e s f o r
p r e p a r i n g
t h e neW a l t s d e s c r i b e d h e r e i n .
A u r t h e r o b j e c t o f t h e
p r e s e n t i n v e n t i o n i s t o
p r o v i d e t h e
s a l t s i n p u r e , e a s y t o h a n d l e , f r e e ?oWing a n d s t a b l e
f o r m .
A u r t h e r o b j e c t
i s
t o p r o v i d e a
p r o c e s s
o f p r e p a r a t i o n o f h e
p h a r m a c e u t i c a l l y
a c c e p t a b l e s a l t s
o f t h e p r e s e n t i n v e n t i o n on
an
i n d u s t r i a l s c a l e .
I t i s a l s o a n
o b j e c t
o f
t h e p r e s e n t
i n v e n t i o n
t o
p r o v i d e
f o r
p h a r m a c e u t i c a l c o m p o s i t i o n s o f t h e p h a r m a c e u t i c a l l y
a c c e p t a b l e s a l t s o f C l o p i d o g r e l o f
t h e
p r e s e n t i n v e n t i o n , a s
d e s c r i b e d h e r e i n .
Another
o b j e c t i s t o p r o v i d e a
method
o f
t r e a t m e n t
o f
c a r d i o v a s c u l a r d i s o r d e r s ,
c o m p r i s i n g
a d m i n i s t e r i n g , f o r
e x a m p l e ,
o r a l l y a
c o m p o s i t i o n
c o n t a i n i n g t h e
p h a r m a c e u t i
c a l l y a c c e p t a b l e s a l t s
o f
t h e p r e s e n t i n v e n t i o n i n a
t h e r a p e u
t i c a l l y
e f f e c t i v e a m o u n t .
SUMMARY
OFTHE INVENTION
The
p r e s e n t i n v e n t i o n
d e s c r i b e s
c e r t a i n
p h a r m a c e u t i c a l l y
a c c e p t a b l e
s a l t s
o f C l o p i d o g r e l i n c l u d i n g
t h e i r
h y d r a t e s a n d
o t h e r s o l v a t e s ,
b o t h i n
c r y s t a l l i n e
a n d
a m o r p h o u s
f o r m s ,
p r o
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8 , 0 5 3 , 5 7 9 B2
3
c e s s
f o r
t h e i r p r e p a r a t i o n
a n d
p h a r m a c e u t i c a l
c o m p o s i t i o n s
c o n t a i n i n g them n d
t h e i r
u s e
i n
m e d i c i n e . More a r t i c u l a r l y ,
t h e
p r e s e n t i n v e n t i o n de s c r i b e s neW f o r m s o f C l o p i d o g r e l
p - t o l u e n e s u l f o n a t e o r
C l o p i d o g r e l t o s y l a t e ) , C l o p i d o g r e l
b e n Z e n e s u l f o n a t e o r C l o p i d o g r e l
b e s y l a t e ) a n d
C l o p i d o g r e l
m e t h a n e s u l f o n a t e o r C l o p i d o g r e l
m e s y l a t e ) . A l s o
d e s c r i b e d
a r e
p r o c e s s e s
f o r
t h e i r
p r e p a r a t i o n
and
p h a r m a c e u t i c a l
com
p o s i t i o n s c o n t a i n i n g t h e same and h e i r u s e i n m e d i c i n e .
DESCRIPTIONOF FIGURES
F I G . 1 : XRD
f
a m o r p h o u s C l o p i d o g r e l b e s y l a t e
F I G . 2 : XRD
f
c r y s t a l l i n e C l o p i d o g r e l b e s y l a t e
F I G . 3 : DSC o f c r y s t a l l i n e
C l o p i d o g r e l
b e s y l a t e
F I G . 4 : XRD
f
a m o r p h o u s C l o p i d o g r e l m e s y l a t e
F I G .
5 :
XRD
f
a m o r p h o u s C l o p i d o g r e l
t o s y l a t e
DETAILED DESCRIPTION
T h e p r e s e n t
i n v e n t i o n
p r o v i d e s c e r t a i n p h a r m a c e u t i c a l l y
a c c e p t a b l e
s a l t s
o f C l o p i d o g r e l h a v i n g t h e g e n e r l f o r m u l a
( I I I )
g i v e n b e l o w :
( 1 1 1 )
o
ocH3
H
\
\
0 6 6
NH \ R s o 3
0 1 S
W h e r e i n R
e p r e s e n t s 4 - m e t h y l p h e n y l ,
p h e n y l
o r a m e t h y l
g r o u p .
More p a r t i c u l a r l y ,
t h e
p r e s e n t i n v e n t i o n
d e s c r i b e s
s t a b l e
f o r m s o f C l o p i d o g r e l
p - t o l u e n e s u l f o n a t e ,
C l o p i d o g r e l b e n Z e
n e s u l f o n a t e
a n d
C l o p i do g r e l m e t h a n e s u l f o n a t e .
T h e s e
s a l t s
i n
t h e i r
h y d r a t e d o r o t h e r s o l v a t e d
f o r m s
i s a l s o
encompassed
W i t h i n
t h e p r e s e n t i n v e n t i o n .
The
a l t s may b e p r e s e n t e i t h e r
i n c r y s t a l l i n e o r a m o r p h o u s f o r m . The
a l t s may b e p r e p a r e d
b y r e a c t i n g
C l o p i d o g r e l
b a s e W i t h t h e
c o r r e s p o n d i n g
a c i d s
( p - t o l u e n e s u l f o n i c
a c i d ,
b e n Z e n e s u l f o n i c
a c i d a n d m e t h a n e
s u l f o n i c a c i d
r e s p e c t i v e l y ) i n a s u i t a b l e s o l v e n t ,
a t
a tempera
t u r e
r a n g i n g from 3 0
C . t o
5 0 C . ,
and u b s e q u e n t l y , remov
i n g t h e s o l v e n t . The s u i t a b l e
s o l v e n t s
c a n b e
W a t e r ,
m e t h a n o l ,
e t h a n o l ,
a c e t o n e ,
p r o p a n o l ,
n - b u t a n o l , n - p e n t a n o l ,
n - h e x a n o l ,
n - h e p t a n o l , d i c h l o r o m e t h a n e , d i m e t h y l f o r r n a m i d e , d i m e t h y l
a c e t a m i d e ,
l , 4 - d i o x a n e ,
t e t r a h y d r o f u r a n , e t h e r , h e x a n e , h e p
t a n e , a c e t o n i t r i l e o r m i x t u r e s t h e r e o f .
The
removal of
t h e
s o l v e n t
can
be done p r e f e r a b l y
a t
reduced p r e s s u r e .
I n a p r e f e r r e d
e m b o d i m e n t ,
t h e C l o p i d o g r e l
b a s e may b e
p r e p a r e d a c c o r d i n g t o t h e p r o c e s s e s di s c l o s e d i n US. a t .
N o .
6 , 6 3 5 , 7 6 3 .
The s a l t s may
x i s t
i n a
s o l v e n t - f r e e form
o r i t may be
i s o l a t e d a s
a h y d r a t e
o r
a
s o l v a t e . The y d r a t e s and o l v a t e s
of
t h e s a l t s o f t h e p r e s e n t i n v e n t i o n form
a n o t h e r
a s p e c t o f t h e
i n v e n t i o n .
The s a l t s
c a n b e
c h a r a c t e r i z e d
by
s u i t a b l e t e c h n i q u e s
knoWn
i n
t h e
a r t .
T h e
a m o r p h o u s C l o p i d o g r e l
p - t o l u e n e
s u l f o n a t e C l o p i
d o g r e l t o s y l a t e ) h a s a m e l t i n g p o i n t i n
b e t W e e n
t h e r a n g e o f
7 0 - 9 5 C .
T h e
a m o r p h o u s
C l o p i d o g r e l
b e n Z e n e
s u l f o n a t e
C l o p i
d o g r e l b e s y l a t e ) o f h e p r e s e n t i n v e n t i o n h a s a m e l t i n g p o i n t i n
betWeen
h e
r a n g e
o f 8 5 C . - 9 5 C .
20
25
30
35
4 0
45
50
55
60
6 5
4
T h e c r y s t a l l i n e
C l o p i d o g r e l
b e n Z e n e s u l f o n a t e C l o p i
d o g r e l b e s y l a t e ) o f h e p r e s e n t
i n v e n t i o n
h a s a m e l t i n g p o i n t i n
betWeen
h e r a n g e o f 1 2 4 C . - l 3 2 C .
T h e a m o r p h o u s
C l o p i d o g r e l
m e t h a n e s u l f o n a t e C l o p i
d o g r e l
m e s y l a t e ) h a s a m e l t i n g p o i n t o f i n
b e t W e e n
t h e r a n g e
of
0 C . - 7 0 C .
T h e
f o l l oW i n g n o n - l i m i t i n g
e x a m p l e s i l l u s t r a t e
t h e
i n v e n
t o r s
p r e f e r r e d
m e t h o d s
f o r
p r e p a r i n g t h e
d i f f e r e n t
s a l t s
o f
S ( + ) C l o p i d o g r e l d i s c u s s e d i n t h e i n v e n t i o n a n d s h o u l d n o t b e
c o n s t r u e d t o
l i m i t
t h e s c o p e
of
h e i n v e n t i o n i n
any
W a y .
EXAMPLE
P r e p a r a t i o n o f C l o p i d o g r e l
T o s y l a t e
A m o r p h o u s
Form
C l o p i d o g r e l base
Was
d i s s o l v e d
i n
a c e t o n e
t o o b t a i n
a
c l e a r
s o l u t i o n . To
i t Was added
p - t o l u e n e
s u l f o n i c a c i d
a t room
t e m p e r a t u r e . The
r e a c t i o n mixture
Was
h e a t e d t o
re?ux tem
p e r a t u r e f o r 2 t o
1 0
h r s . The
o l v e n t
Was
v a p o r a t e d
t o d r y n e s s
u n d e r r e d u c e d p r e s s u r e
t o
o b t a i n
a m o r p h o u s C l o p i d o g r e l
t o s y l a t e .
m . p . : 7 5 - 9 3
C .
( s o f t e n )
XRD:
A m o r p h o u s
DSC:
No m e l t i n g
p e a k
a t e r :
0 . 5 - 4 % b y W e i g h t ( o b t a i n e d i n d i f f e r e n t b a t c h e s ) .
EXAMPLE
P r e p a r a t i o n o f C l o p i d o g r e l
T o s y l a t e
A m o r p h o u s
Form
C l o p i d o g r e l
base
Was
d i s s o l v e d
i n
methanol t o o b t a i n a
c l e a r
s o l u t i o n . To i t Was added
p - t o l u e n e s u l f o n i c a c i d a t 2 0
C .
The e a c t i o n m i x t u r e Was
h e a t e d
t o re?ux
t e m p e r a t u r e
f o r
2
t o
1 0
h r s .
The s o l v e n t Was
e v a p o r a t e d t o
d r y n e s s
under
reduced
p r e s s u r e
t o
o b t a i n
a
p o W d e r .
m . p : 7 3 - 9 3 C . s o f t e n )
XRD:
A m o r p h o u s
DSC:
No
m e l t i n g
p e a k
a t e r :
0 . 5 - 4 % b y W e i g h t ( o b t a i n e d i n d i f f e r e n t b a t c h e s ) .
S i m i l a r l y ,
t h e
same
a l t
Was
p r e p a r e d u s i n g
THF,
a c e t o n i
t r i l e and o t h e r s i m i l a r s o l v e n t s e i t h e r a l o n e o r a s a
mixture of
tWo o r more o l v e n t s d e s c r i b e d elseWhere
n
t h e s p e c i ? c a t i o n .
EXAMPLE
P r e p a r a t i o n o f
C l o p i d o g r e l T o s y l a t e
A m o r p h o u s
Form
C l o p i d o g r e l
b a s e Was d i s s o l v e d
i n m e t h a n o l . p - T o l u e n e
s u l p h o n i c a c i d Was
added o
t h e
s o l u t i o n
a t 20
C . The
r e a c
t i o n m i x t u r e Was h e a t e d t o
re?ux
t e m p e r a t u r e
f o r
2
h r s . The
s o l u t i o n Was cooled t o room
temperature and
Was a dded
d r o p - W i s e
t o d i e t h y l e t h e r .
The s u s p e n s i o n Was
s t i r r e d a t
R T .
The
s o l i d Was
? l t e r e d and d r i e d a t
about
50
C . i n
a
v a c u u m
o v e n
t o g i v e
C l o p i d o g r e l t o s y l a t e s i m i l a r
t o
t h a t o b t a i n e d
a b o v e .
S i m i l a r l y , same s a l t Was p r e p a r e d u s i n g a c e t o n e , a c e t o n i
t r i l e and
o t h e r
s i m i l a r s o l v e n t s e i t h e r a l o n e o r a s a mixture
of
tWo o r more o l v e n t s d e s c r i b e d
elseWhere n
t h e s p e c i ? c a t i o n .
EXAMPLE
P r e p a r a t i o n o f
C l o p i d o g r e l T o s y l a t e A m o r p h o u s
Form
C l o p i d o g r e l
b a s e Was d i s s o l v e d i n
m e t h a n o l , p - T o l u e n e
s u l p h o n i c
a c i d Was added o t h e
s o l u t i o n
a t
20
C . The r e a c
-
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8 , 0 5 3 , 5 7 9 B2
5
t i o n m i x t u r e
Was
h e a t e d
t o re?ux
t e m p e r a t u r e f o r 2
h r s . The
s o l u t i o n Was cooled
o
r o o m temperature
and h e
methanolic
s o l u t i o n Was added
d r o p W i s e
t o h o t t o l u e n e . The r e s u l t i n g
s o l u t i o n Was re?uxed o r an d d i t i o n a l 20 i n u t e s . The s o l u
t i o n Was
cooled t o
room temperature and
Was
s t i r r e d
f o r
24
h r s .
The s o l v e n t
Was
e v a p o r a t e d
under reduced p r e s s u r e t o
d r y n e s s t o
o b t a i n
C l o p i d o g r e l t o s y l a t e ,
s i m i l a r
t o t h a t
o b t a i n e d
a b o v e .
S i m i l a r l y , t h e
same
a l t
Was
p r e p a r e d
u s i n g
a c e t o n e , a c e t o
n i t r i l e
and
o t h e r s i m i l a r s o l v e n t s e i t h e r alone o r a s a
mixture
of tWo o r more s o l v e n t s d e s c r i b e d e l s e W h e r e
i n
t h e s p e c i ? c a
t i o n .
EXPERIMENT
P r e p a r a t i o n
o f C l o p i d o g r e l B e s y l a t e A m o r p h o u s
Form
C l o p i d o g r e l
base
Was
d i s s o l v e d i n
a c e t o n e
t o o b t a i n a c l e a r
s o l u t i o n . Then b e n Z e n e s u l f o n i c
a c i d Was added
t o
t h e
s o l u
t i o n
a t 200 C . The r e a c t i o n mixture Was heated t o re?ux
t e m p e r a t u r e
f o r
2
t o
1 0
h r s .
The
s o l v e n t
Was
e v a p o r a t e d
t o
d r y n e s s under reduced
p r e s s u r e
t o
o b t a i n
t h e t i t l e s a l t a s a
p o W d e r .
m . p : 8 6 - 9 5
C .
( s o f t e n )
XRD:
A m o r p h o u s
D S C : No m e l t i n g
p e a k s
a t e r :
0 . 5 -4% y W e i g h t , ( o b t a i n e d i n d i f f e r e n t b a t c h e s ) .
EXAMPLE
P r e p a r a t i o n
o f
C l o p i d o g r e l B e s y l a t e A m o r p h o u s
Form
C l o p i d o g r e l
base
Was
d i s s o l v e d
i n
methanol t o o b t a i n a
c l e a r
s o l u t i o n .
BenZenesulfonic
a c i d
Was
added
t o
t h e s o l u
t i o n
a t 200 C . The r e a c t i o n mixture Was heated
t o
re?ux
t e m p e r a t u r e f o r
2
t o
1 0
h r s . The
s o l v e n t
Was e v a p o r a t e d t o
d r y n e s s u n d e r r e d u c e d p r e s s u r e t o o b t a i n t h e t i t l e compound.
m . p . :
8 4 - 9 3 C .
( s o f t e n )
XRD:
A m o r p h o u s
D S C : No m e l t i n g p e a k
a t e r :
0 . 5 - 4 % b y W e i g h t ( o b t a i n e d i n d i f f e r e n t b a t c h e s ) .
S i m i l a r l y , t h e same
s a l t
Was p r e p a r e d i n THF,
a c e t o n i t r i l e
and o t h e r
s i m i l a r s o l v e n t s
e i t h e r alone o r a s a mixture of tWo
o r more s o l v e n t s d e s c r i b e d e l s e W h e r e i n t h e s p e c i ? c a t i o n .
EXAMPLE
P r e p a r a t i o n
o f
C l o p i d o g r e l B e s y l a t e
A m o r p h o u s
Form
C l o p i d o g r e l b a s e Was
d i s s o l v e d i n
m e t h a n o l . Benzene s u l
p h o n i c a c i d Was added o t h e s o l u t i o n a t 2 0 0 C . The
r e a c t i o n
m i x t u r e Was h e a t e d
t o re?ux
t e m p e r a t u r e f o r 2
h r s . The
s o l u
t i o n Was cooled t o room
temperature
and Was added drop
W i s e
t o
d i e t h y l e t h e r . The s u s p e n s i o n Was
s t i r r e d
a t R T . The
s o l i d Was ? l t e r e d and
d r i e d
i n a
va c u um
oven
t o g i v e Clopi
d o g r e l b e s y l a t e , s i m i l a r t o t h a t
o b t a i n e d
a b o v e .
S i m i l a r l y , t h e same a l t Was p r e p a r e d
u s i n g
a c e t o n e , a c e t o
n i t r i l e and
o t h e r s i m i l a r
s o l v e n t s
e i t h e r
alone
o r a s a
mixture
of tWo o r more s o l v e n t s d e s c r i b e d
e l s e W h e r e
i n t h e s p e c i ? c a
t i o n .
20
25
30
35
4 0
45
50
55
60
6 5
6
EXAMPLE
P r e p a r a t i o n o f C l o p i d o g r e l B e s y l a t e A m o r p h o u s
Form
C l o p i d o g r e l b a s e
Was d i s s o l v e d i n
m e t h a n o l . Benzene s u l
p h o n i c
a c i d
Was
added
o
t h e s o l u t i o n
a t
2 0 0
C .
The
r e a c t i o n
m i x t u r e
Was
e a t e d
t o re?ux
t e m p e r a t u r e f o r 2
h r s . The s o l u
t i o n Was
cooled
t o
room temperature
and t h e
methanolic
s o l u t i o n
Was added
d r o p - W i s e t o t h e b o i l i n g
t o l u e n e . The
r e s u l t i n g s o l u t i o n Was re?uxed f o r an a d d i t i o n a l 20 m i n u t e s .
The
s o l u t i o n Was cooled
o
r o o m
temperature and
Was s t i r r e d
a t
t h i s
t e m p e r a t u r e
f o r
extended h o u r s . The s o l v e n t Was
e v a p o r a t e d u n d e r r e d u c e d
p r e s s u r e t o d r y n e s s
t o
o b t a i n
C l o
p i d o g r e l b e s y l a t e , s i m i l a r t o t h a t o b t a i n e d a b o v e .
S i m i l a r l y , t h e same a l t Was p r e p a r e d
u s i n g
a c e t o n e , a c e t o
n i t r i l e and
o t h e r s i m i l a r
s o l v e n t s
e i t h e r
alone
o r a s a
mixture
of tWo o r more s o l v e n t s d e s c r i b e d
e l s e W h e r e
i n
t h e s p e c i ? c a
t i o n .
EXAMPLE
P r e p a r a t i o n
o f
C l o p i d o g r e l B e s y l a t e
C r y s t a l l i n e
Form
C l o p i d o g r e l b e s y l a t e a m o r p h o u s W a s s t i r r e d i n d i e t h y l
e t h e r a t 2 0 0 C . The
o b t a i n e d
W h i t e
s o l i d Was c o l l e c t e d by
? l t r a t i o n , Washed
W i t h
d i e t h y l
e t h e r and d r i e d , i n
a
vacuum
o v e n
t o
o b t a i n
C l o p i d o g r e l b e s y l a t e
i n
c r y s t a l l i n e
f o r m .
mp: 2 6 - 1 3 0 0 C . ( r a n g e
o b t a i n e d f r o m
d i f f e r e n t
b a t c h e s ) .
XRD: C r y s t a l l i n e
DSC:
l 2 7 . 5 - l 3 2 . 9 C .
a t e r : 0 . l - 0 . 3 %
b y
W e i g h t ( r a n g e o b t a i n e d f r o m d i f f e r
e n t b a t c h e s ) .
T h e a b o v e
p r o c e s s f o r p r e p a r i n g c l o p i d o g r e l b e s y l a t e
c r y s
t a l l i n e
f o r m ,
i s c a r r i e d o u t u s i n g d i f f e r e n t
e t h e r s
W h e r e i n e a c h
a l k y l r a d i c a l o f
t h e e t h e r
i s i n d e p e n d e n t l y
s e l e c t e d f r o m
t h e
g r o u p
c o n s i s t i n g
o f
m e t h y l ,
e t h y l ,
p r o p y l , i s o p r o p y l ,
b u t y l ,
l - b u t y l , 2 - b u t y l
a n d
t - b u t y l o r m i x t u r e s t h e r e o f .
EXAMPLE
0
P r e p a r a t i o n
o f
C l o p i d o g r e l B e s y l a t e C r y s t a l l i n e
Form
C l o p i d o g r e l b e s y l a t e a m o r p h o u s
W a s s t i r r e d
i n n - h e p t a n e
a t
2 0 0
C . The o b t a i n e d
W h i t e
s o l i d Was c o l l e c t e d by
? l t r a t i o n ,
Washed With
- h e p t a n e ,
and d r i e d
i n
a
va c u um
oven o
o b t a i n
c l o p i d o g r e l b e s y l a t e i n c r y s t a l l i n e
f o r m .
mp: 1 2 5 - 1 3 0 0 C . ( ra n g e o b t a i n e d f r o m
d i f f e r e n t
b a t c h e s ) .
XRD: C r y s t a l l i n e
DSC:
l 2 5 . 5 - l 3 0 . 9
C .
a t e r : 0 . l - 0 . 3 %
b y
W e i g h t ( r a n g e o b t a i n e d
f r o m
d i f f e r
e n t b a t c h e s ) .
S i m i l a r l y ,
C l o p i d o g r e l
b e s y l a t e c r y s t a l l i n e
f o r m
W a s
p r e
p a r e d i n h e x a n e ,
n - h e p t a n e ,
c y c l o h e x a n e , p e t r o l e u m e t h e r a s
s o l v e n t s a s Well a s
t h e i r
mixtures.
EXAMPLE 1
P r e p a r a t i o n
o f C l o p i d o g r e l B e s y l a t e
C r y s t a l l i n e
Form
C l o p i d o g r e l b a s e Was d i s s o l v e d i n d i e t h y l e t h e r a t 2 0 - 2 5 0
C . To t h i s Was added benZene s u l p h o n i c a c i d d i s s o l v e d i n
d i e t h y l
e t h e r .
The e a c t i o n m i x t u r e Was t i r r e d a t 2 5 - 3 0 C . f o r
2 4 - 3 0 h r s .
The
h i t e s o l i d
Was
c o l l e c t e d by l t r a t i o n ,
Washed
-
8/10/2019 Patent-US 008053579 B2-Salts of Clopidogrel and Process for Preparation
10/10
US
8 , 0 5 3 , 5 7 9 B2
7
With
d i e t h y l e t h e r , and d r i e d a t 50-600 C . i n a va c u um oven
o
o b t a i n
C l o p i d o g r e l
b e s y l a t e
c r y s t a l l i n e f o r m .
mp: 2 4 - 1 3 0 0 C . ( r a n g e o b t a i n e d f r o m d i f f e r e n t b a t c h e s ) .
XRD: C r y s t a l l i n e
DSC:
1 2 8 . 9 - 1 3 2 . 7 C .
a t e r : 0.2%
T h e
a b o v e p r o c e s s f o r p r e p a r i n g
c l o p i d og r e l b e s y l a t e
c r y s
t a l l i n e
f o r m , i s
c a r r i e d
o u t
u s i n g d i f f e r e n t e t h e r s
W h e r e i n
e a c h
a l k y l r a d i c a l , o f t h e e t h e r i s i n d e p e n d e n t l y s e l e c t e d f r o m t h e
g r o u p
c o n s i s t i n g
o f
m e t h y l , e t h y l , p r o p y l ,
i s o p r o p y l , b u t y l ,
l - b u t y l , 2 - b u t y l
a n d t - b u t y l
o r
m i x t u r e s t h e r e o f .
EXAMPLE
2
P r e p a r a t i o n o f C l o p i d o g r e l M e s y l a t e A m o r p h o u s
Form
C l o p i d o g r e l base Was d i s s o l v e d
i n
a c e t o n e t o o b t a i n
a
c l e a r
s o l u t i o n . Methanesulfonic
a c i d
Was added t o t h e s o l u t i o n
a t
200
C .
The e a c t i o n
m i x t u r e
Was
h e a t e d
t o re?ux
e m p e r a t u r e
f o r 2 t o 1 0 h r s .
The
s o l v e n t
Was
e v a p o r a t e d t o
d r y n e s s
under
r e d u c e d p r e s s u r e
t o
o b t a i n
t h e
t i t l e
compound.
mp:
6 0 - 7 0 0
C . ( s o f t e n )
XRD:
A m o r p h o u s
D S C :
No m e l t i n g p e a k
W a t e r :
0 . 5 - 4 % b y
W e i g h t ( o b t a i n e d
f r o m
d i f f e r e n t
b a t c h e s ) .
EXAMPLE
3
P r e p a r a t i o n o f
C l o p i d o g r e l
M e s y l a t e
A m o r p h o u s
Form
C l o p i d o g r e l
base
Was d i s s o l v e d
i n
methanol t o o b t a i n a
c l e a r
s o l u t i o n . Methanesulfonic
a c i d Was added
t o t h e s o l u
t i o n
a t 200 C . The r e a c t i o n
mixture
Was heated t o re?ux
t e m p e r a t u r e f o r
2
t o
1 0
h r s . The
s o l v e n t
Was
e v a p o r a t e d
t o
d r y n e s s u n d e r r e d u c e d p r e s s u r e t o o b t a i n t h e t i t l e compound.
mp: 6 0 - 7 0 0
C .
( s o f t e n )
XRD:
A m o r p h o u s
D S C : No
m e l t i n g
p e a k
W a t e r :
0 . 5 - 4 % b y
W e i g h t . ( o b t a i n e d f r o m d i f f e r e n t
b a t c h e s ) .
S i m i l a r l y , t h e
same s a l t Was
p r e p a r e d
i n THE, a c e t o n i t r i l e
and o t h e r
s i m i l a r s o l v e n t s
e i t h e r alone
o r
a s a mixture of tWo
o r
more
s o l v e n t s
d e s c r i b e d
e l s e W h e r e
i n t h e s p e c i ? c a t i o n .
A l l t h e s e s a l t s
a r e
f r e e
?oWing, e a s y t o handle
and can be
manufactured
i n
l a r g e s c a l e
a s
W e l l
a s can be used i n t h e
p r e p a r a t i o n
o f u i t a b l e p h a r m a c e u t i c a l
c o m p o u n d s o r
d o s a g e
f o r m s . The
s a l t s of
t h e p r e s e n t i n v e n t i o n may a l s o e x i s t a s
d i f f e r e n t s o l va t e s c o r r e s p o n d i n g t o t h e d i f f e r e n t s o l v e n t s u s e d
i n t h e i r p r e p a r a t i o n .
Such o b v i o u s
s o l v a t e s a r e a l s o i n t e n d e d
t o b e encompassed
W i t h i n
t h e s c o p e o f t h e p r e s e n t
i n v e n t i o n .
T h e
s a l t s
o f
C l o p i d o g r e l
d r u g
s u b s t a n c e
o f
t h e p r e s e n t
i n v e n t i o n p r e p a r e d a c c o r d i n g t o
a n y
p r o c e s s d e s c r i b e d
a b o v e
or
any o t h e r
process
can be administered t o
a person
i n need
20
25
30
35
4 0
45
50
8
o f
i t
e i t h e r W i t h o u t f u r t h e r f o r m u l a t i o n ,
o r
f o r m u l a t e d i n t o
s u i t a b l e f o r m u l a t i o n s and dosage forms a s a r e W e l l knoWn.
I n
a n o t h e r
embodiment o f
t h e p r e s e n t i n v e n t i o n a
method
o f t r e a t m e n t and
s e
o f
t h e
p h a r m a c e u t i c a l l y
a c c e p t a b l e s a l t s
o f C l o p i d o g r e l d e s c r i b e d i n t h e p r e s e n t
i n v e n t i o n
f o r
t h e
t r e a t m e n t o f c a r d i o v a s c u l a r
d i s o r d e r s
& n h i b i t i n g p l a t e l e t
a g g r e g a t i o n i s p r o v i d e d , c o m p r i s i n g a d m i n i s t e r i n g , f o r
e x a m p l e ,
o r a l l y
o r
i n
a n y
o t h e r
s u i t a b l e
d o s a g e
f o r m s ,
a
c o m p o s i t i o n
c o n t a i n i n g
t h e
neW
a l t s o f t h e
p r e s e n t i n v e n t i o n
i n a t h e r a p e u t i c a l l y e f f e c t i v e amount.
We l a i m :
1 . C r y s t a l l i n e C l o p i d o g r e l b e s y l a t e ,
W h i c h
s n o t s o l v a t e d .
2 . C r y s t a l l i n e n o n - s o l v a t e d C l o p i d o g r e l b e s y l a t e a s
c l a i m e d
i n c l a i m 1 , Which
h a s
a d i f f e r e n t i a l
s c a n n i n g
c a l o r i
m e t r i c t h e r r n o g r a m h a v i n g a n e n d o t h e r m i c p e a k a t a b o u t
124-1340
C .
3 .
C r y s t a l l i n e
n o n - s o l v a t e d C l o p i d o g r e l b e s y l a t e
a s
c l a i m e d i n c l a i m 1 , Which c o n t a i n s from
a b o u t
0 . 1 - 0 . 3 %
W a t e r b y W e i g h t .
4 . A
r o c e s s f o r p r e p a r i n g
c r y s t a l l i n e n o n - s o l v a t e d C l o p i
d o g r e l b e s y l a t e
a s
c l a i m e d i n
c l a i m
1 , c o m p r i s i n g :
i ) d i s s o l v i n g / c o n t a c t i n g C l o p i d o g r e l b a s e i n one
o r more
s o l v e n t s ;
i i )
t r e a t i n g t h e
p r o d u c t
o f s t e p ( i ) W i t h
b e n Z e n e s u l f o n i c
a c i d ; a n d
i i i ) r e m o v i n g
t h e
s o l v e n t s t o o b t a i n c r y s t a l l i n e n o n - s o l
v a t e d C l o p i d o g r e l b e s y l a t e .
5 . The
p r o c e s s
a s
claimed i n
claim 4 , Wherein
t h e
one o r
more o l v e n t s a r e s e l e c t e d from h e group c o n s i s t i n g of a t e r ,
n - h e p t a n e ,
c y c l o h e x a n e , p e t r o l e u m e t h e r ,
a n d e t h e r s W h e r e i n
e a c h
a l k y l r a d i c a l o f t h e e t h e r
i s i n d e p e n d e n t l y
s e l e c t e d f r o m
t h e g r o u p c o n s i s t i n g
o f
m e t h y l , e t h y l ,
p r o p y l , i s o p r o p y l ,
b u t y l , l - b u t y l , 2 - b u t y l a n d t - b u t y l , a n d m i x t u r e s t h e r e o f .
6 .
A
r o c e s s f o r p r e p a r i n g
c r y s t a l l i n e n o n - s o l v a t e d C l o p i
d o g r e l
b e s y l a t e
a s
c l a i m e d i n
c l a i m
1 , c o m p r i s i n g :
i )
d i s s o l v i n g / c o n t a c t i n g a m o r p h o u s
C l o p i d o g r e l
b e s y l a t e
i n one
or more
solvents and
i i )
r e m o v i n g
t h e s o l v e n t s
t o
o b t a i n
c r y s t a l l i n e
n o n - s o l v a t e d
C l o p i d o g r e l
b e s y l a t e .
7 . The p r o c e s s
a s
claimed i n
claim 6 , Wherein
t h e
one o r
more
s o l v e n t s a r e s e l e c t e d
t h e
group
c o n s i s t i n g
o f W a t e r ,
m e t h a n o l ,
e t h a n o l ,
p r o p a n o l ,
n - b u t a n o l , a c e t o n e ,
a c e t o n i t r i l e ,
h e x a n e ,
n - h e p t a n e ,
c y c l o h e x a n e ,
p e t r o l e u m e t h e r , a n d e t h e r s
W h e r e i n e a c h
a l k y l r a d i c a l
o f
t h e e t h e r
i s i n d e p e n d e n t l y
s e l e c t e d f r o m
t h e
g r o u p
c o n s i s t i n g
o f m e t h y l ,
e t h y l , p r o p y l ,
i s o p r o p y l , b u t y l , l - b u t y l ,
2 - b u t y l
a n d t - b u t y l , a n d m i x t u r e s
t h e r e o f .
8 . The
p r o c e s s
a s
claimed
i n
c l a i m 6 ,
Wherein
s a i d
amor
p h o u s
C l o p i d o g r e l b e s y l a t e h a s a
p o W d e r
X - r a y d i f f r a c t i o n
p a t t e r n s u b s t a n t i a l l y a s d e p i c t e d i n F I G . 1 .
9 .
The p r o c e s s
a s
claimed i n c l a i m 6 ,
Wherein
s a i d amor
p h o u s C l o p i d o g r e l b e s y l a t e c o n t a i n s f r o m a b o u t
0 . 5 - 4 %
W a t e r
b y
W e i g h t .