patent-us 008053579 b2-salts of clopidogrel and process for preparation

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 )

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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 ,

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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

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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

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(2006 01) P y E And

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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 ]

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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


2/10

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Patent

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1

0 1 5 US

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B2

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B2

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A n a l y t i c a l R e s e a r c h ,

ZRC

Peak

=

132595 C

Onset = 124.397 C

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5/10

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Patent

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, 0 5 3 , 5 7 9

B2

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w a m

8

s a w

? m a u v3 . 2 5


6/10

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Patent N o v . 8 , 2 0 1 1 S h e e t 5 o f 5

U S 8 , 0 5 3 , 5 7 9

B2

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1

SALTS OFCLOPIDOGREL

AND PROCESS

FOR

PREPARATION

T h i s


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 ) - ( + )


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


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


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


d i s c l o s e d

h e r e i n a n d


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 )


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


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 ,


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


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


d e s c r i b e s

c e r t a i n


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


a n d

a m o r p h o u s

f o r m s ,

p r o


8/10

US

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


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


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


and


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


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


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


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 ,


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


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


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


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


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


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


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 :


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


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


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


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


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


9/10

US

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


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


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


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


base

Was

d i s s o l v e d

i n


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 :


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


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


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


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


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


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


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


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


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


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 ) .


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 ,


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


o f C l o p i d o g r e l B e s y l a t 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


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


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 ) .


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



M e s y l a t e

A m o r p h o u s

Form


base

Was d i s s o l v e d

i n


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


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


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


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


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 .


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


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



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


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


n o n - s o l v a t e d


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



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 .

patent-us 008053579 b2-salts of clopidogrel and process for preparation

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