Liza M.

Walsh
Christine I. Gannon
CONNELL FOLEY LLP
85 Livingston Avenue
Roseland, New Jersey 07068-1765
(973) 535-0500
lwalsh@connellfoley.com
cgannon@connellfoley.com

Attorneys for Plaintiff
Bristol-Myers Squibb Company

IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF NEW JERSEY
BRISTOL-MYERS SQUIBB COMPANY,
Plaintiff,
v.
AUROBINDO PHARMA U.S.A., INC. and
AUROBINDO PHARMA LTD.,

Defendants.
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)
)
)
)
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)
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CA. No. __________




Electronically Filed

COMPLAINT FOR PATENT INFRINGEMENT
Plaintiff Bristol-Myers Squibb Company (BMS), through its attorneys, hereby alleges as
follows:
Nature of the Action
1. This is an action for patent infringement of United States Patent No. 6,087,383
(the 383 patent) against defendants Aurobindo Pharma Ltd. and Aurobindo Pharma U.S.A.,
Inc. (collectively Aurobindo). This action relates to Abbreviated New Drug Application
(ANDA) No. 204806 filed by Aurobindo Pharma Ltd. with the United States Food and Drug
Administration (FDA) for approval to market a generic version of BMSs Reyataz

drug
product. This action arises under the patent laws of the United States, 35 U.S.C. 100, et seq.
2

Parties
2. BMS is a Delaware corporation having its corporate headquarters at 345 Park
Avenue, New York, New York.
3. BMS is engaged in the business of creating, developing, and bringing to market
revolutionary biopharmaceutical products to help patients prevail in their fight against serious
diseases.
4. Upon information and belief, Aurobindo Pharma Ltd. is a company organized and
existing under the laws of India, having a place of business at Maitri Vihar, Plot #2, Ameerpet,
Hyderabad - 500038, Andhra Pradesh, India.
5. On information and belief, Aurobindo Pharma U.S.A., Inc. is a corporation
organized and existing under the laws of the State of Delaware, having its principal place of
business at 6 Wheeling Road, Dayton, New Jersey 08810 (Middlesex County). On information
and belief, Aurobindo Pharma U.S.A. is a wholly-owned subsidiary of Aurobindo Pharma Ltd.
Jurisdiction and Venue
6. This Court has jurisdiction over the subject matter of this action pursuant to 28
U.S.C. 1331, 1338(a), 2201, and 2202.
7. Venue is proper in this judicial district pursuant to, inter alia, 28 U.S.C. 1391(b)
and 1400(b).
8. This Court has jurisdiction over the defendants because, upon information and
belief, Aurobindo Pharma U.S.A., Inc. has a principal place of business in New Jersey and is the
subsidiary and agent of Aurobindo Pharma Ltd. Upon information and belief, Aurobindo Pharma
U.S.A., Inc. is acting as the agent of Aurobindo Pharma Ltd. with respect to ANDA No. 204806.
3

9. This Court has jurisdiction over Aurobindo Pharma Ltd. because it has corporate
offices in Dayton, New Jersey, and Dayton, New Jersey is also the center of its U.S. operations.
Aurobindo Pharma Ltd. has at least three significant subsidiaries based in Dayton, New Jersey.
10. In the alternative, this Court has jurisdiction over Aurobindo Pharma Ltd. because
the requirements of Federal Rule of Civil Procedure 4(k)(2)(A) are met.
11. This Court also has jurisdiction over the defendants because, inter alia, this action
arises from actions of the defendants directed toward New Jersey, and because the defendants have
purposefully availed themselves of the rights and benefits of New Jersey law by engaging in
systematic and continuous contacts with New J ersey. Upon information and belief, the defendants
regularly and continuously transact business within the state of New Jersey, including by selling
pharmaceutical products in New Jersey, either on their own or through affiliates. Upon
information and belief, the defendants derive substantial revenue from the sale of those products in
New Jersey and have availed themselves of the privilege of conducting business within the State of
New Jersey.
12. The defendants have previously been sued in this judicial district without objecting
on the basis of lack of personal jurisdiction and have availed themselves of New Jersey courts
through the assertion of counterclaims.
13. For these reasons, and for other reasons that will be presented to the Court if
jurisdiction is challenged, the Court has personal jurisdiction over the defendants.
BMSs Reyataz

Product and the 383 Patent

14. On July 11, 2000, the U.S. Patent and Trademark Office duly and legally issued the
383 patent, titled Bisulfide Salt of HIV Protease Inhibitor. A true and correct copy of the 383
patent is attached as Exhibit A. The claims of the 383 patent are valid and enforceable.
15. BMS is the owner of the 383 patent.
4

16. The expiration date of the 383 patent is December 21, 2018.
17. BMS is the holder of New Drug Application (NDA) No. 21-567, by which the
FDA granted approval for atazanavir sulfate capsules (Eq. 100 mg base, Eq., 150 mg base, Eq. 200
mg base, and Eq. 300 mg base). BMS markets and sells atazanavir sulfate capsules in the United
States under the trade name Reyataz

.
18. The Food and Drug Administration Center for Drug Equivalence Evaluations (the
Orange Book) lists the 383 patent for each of the strengths of Reyataz

approved by the FDA

under NDA No. 21-567.
Aurobindos ANDA Filing and Notice Letter
19. Upon information and belief, Aurobindo filed with the FDA ANDA No. 204806
(the Aurobindo ANDA) under Section 505(j) of the Federal Food, Drug and Cosmetic Act (21
U.S.C. 355(j)), seeking approval to engage in the commercial manufacture, use, or sale of
Atazanavir Sulfate Capsules (Eq. 100 mg, 150 mg, 200 mg, and 300mg base) (the Aurobindo
ANDA Products) generic versions of the FDA-approved Reyataz

capsules, Eq. 100 mg, 150

mg, 200 mg, and 300 mg base before the expiration date of the 383 patent.
20. Upon information and belief, the Aurobindo ANDA Products contain atazanavir
bisulfate.
21. Upon information and belief, the Aurobindo ANDA Products will be manufactured
by, or at the direction of, Aurobindo.
22. Upon information and belief, Aurobindo intends to directly or indirectly
manufacture, use, market, sell, offer for sale, and distribute the Aurobindo ANDA products,
including within this District, upon regulatory approval.
23. By letter dated April 24, 2014 (Aurobindo Notice Letter), Aurobindo notified
BMS that it had filed an ANDA for the Aurobindo ANDA Products, including a Paragraph IV
5

certification asserting that the 383 patent is invalid, unenforceable, and/or will not be infringed
by the commercial manufacture, use, and sale of the Aurobindo ANDA products, and that it sought
approval of its ANDA prior to the expiration date of the 383 patent.
24. BMS received the Aurobindo Notice Letter on or about April 25, 2014.
25. This action is being commenced before the expiration of forty-five days from the
date BMS received the Aurobindo Notice Letter.
Count 1

(Infringement of United States Patent No. 6,087,383)
26. BMS incorporates the preceding paragraphs as if fully set forth herein.
27. Aurobindos submission of the Aurobindo ANDA to obtain approval to engage in
the commercial manufacture, use, offer to sell, or sale of the Aurobindo ANDA Products prior to
the expiration of the 383 patent constitutes infringement of claims 1 and 2 of the 383 patent under
35 U.S.C. 271(e)(2)(A).
28. Aurobindos commercial manufacture, use, offer to sell, sale, or importation of the
Aurobindo ANDA Products prior to the expiration of the 383 patent, and its inducement of and/or
contribution to such conduct, would further infringe claims 1 and 2 of the 383 patent under 35
U.S.C. 271(a), (b) and/or (c).
29. Upon FDA approval of the Aurobindo ANDA, Aurobindo will infringe claims 1
and 2 of the 383 patent by making, using, offering to sell, selling, or importing the Aurobindo
ANDA Products in the United States, and by actively inducing and/or contributing to infringement
by others, unless enjoined by this Court.
30. BMS will be irreparably harmed if Aurobindos infringement is not enjoined. BMS
does not have an adequate remedy at law.
6

PRAYER FOR RELIEF
WHEREFORE, Plaintiffs pray that this Court grant the following relief:
A. A declaration that the 383 patent is valid and enforceable;
B. A declaration that Aurobindo has infringed a claim or claims of the 383
patent by submitting the aforesaid ANDA and certification, and that
Aurobindos making, using, offering to sell, selling, or importing the
Aurobindo ANDA Products and its inducement of and/or contribution to
such conduct by others, will infringe the 383 patent;
C. An Order providing that the effective date of any approval of the Aurobindo
ANDA shall be a date which is not earlier than the expiration of the 383
patent and all exclusivities to which Plaintiff is or becomes entitled;
D. An Order permanently enjoining Aurobindo and its affiliates and
subsidiaries, and each of its officers, agents, servants, and employees, from
making, using, offering to sell, selling, or importing the Aurobindo ANDA
Products and from inducing or contributing to such conduct by others, until
after expiration of the 383 patent and all exclusivities to which Plaintiff is
or becomes entitled;
E. Damages or other monetary relief to BMS if Aurobindo engages in the
commercial manufacture, use, offer to sell, sale, or importation of the
Aurobindo ANDA Products, or inducing or contributing to such conduct by
others, prior to expiration of the 383 patent and all exclusivities to which
Plaintiff is or becomes entitled, and that any such damages or monetary
relief be awarded to BMS with prejudgment interest; and,
F. Such further and other relief as this Court deems proper and just, including
any appropriate relief under 35 U.S.C. 285.

7

Dated: June 4, 2014 CONNELL FOLEY LLP
/s/ Liza M. Walsh











OF COUNSEL:

Amy K. Wigmore
Amanda Major
Tracey C. Allen
Wilmer Cutler Pickering Hale
and Dorr LLP
1875 Pennsylvania Avenue, N.W
Washington, DC 20006
(202) 663-6000
Liza M. Walsh
Christine I. Gannon
85 Livingston Avenue
Roseland, New Jersey 07068
973-535-0500
lwalsh@connellfoley.com

Attorneys for Plaintiff
Bristol-Myers Squibb Company



8

RULE 11.2 CERTIFICATION
I hereby certify that, to the best of my knowledge, the matter in controversy is not the
subject of any other pending or anticipated litigation in any court or arbitration proceeding, nor are
there any non-parties known to Plaintiff that should be joined to this action. In addition, I
recognize a continuing obligation during the course of this litigation to file and to serve on all other
parties and with the Court an amended certification if there is a change in the facts stated in this
original certification.
Dated: June 4, 2014 CONNELL FOLEY LLP
/s/ Liza M. Walsh











OF COUNSEL:

Amy K. Wigmore
Amanda Major
Tracey C. Allen
Wilmer Cutler Pickering Hale
and Dorr LLP
1875 Pennsylvania Avenue, N.W
Washington, DC 20006
(202) 663-6000
Liza M. Walsh
Christine I. Gannon
85 Livingston Avenue
Roseland, New Jersey 07068
973-535-0500
lwalsh@connellfoley.com
cgannon@connellfoley.com

Attorneys for Plaintiff
Bristol-Myers Squibb Company


9

RULE 201.1 CERTIFICATION
I hereby certify that the above-captioned matter is not subject to compulsory arbitration in
that the Plaintiff seeks, inter alia, injunctive relief.

Dated: June 4, 2014 CONNELL FOLEY LLP
/s/ Liza M. Walsh











OF COUNSEL:

Amy K. Wigmore
Amanda Major
Tracey C. Allen
Wilmer Cutler Pickering Hale
and Dorr LLP
1875 Pennsylvania Avenue, N.W
Washington, DC 20006
(202) 663-6000
Liza M. Walsh
Christine I. Gannon
85 Livingston Avenue
Roseland, New Jersey 07068
973-535-0500
lwalsh@connellfoley.com
cgannon@connellfoley.com

Attorneys for Plaintiff
Bristol-Myers Squibb Company



EXHIBIT A
United S ta tes Pa tent [ 1 9 ]
S ing h et a l .
US 006087383A
6, 087, 383
J u l . 1 1 , 2 000
[ 1 1 ] Pa tent Nu mber:
[ 4 5 ] Da te o f Pa tent:
[ 5 4 ] BIS ULFATE S ALT OF HIV PROTEAS E
INHIBITOR
[ 75 ] Inv ento rs : J a na k S ing h , La W renc ev il l e;
Ma dh u s u dh a n Pu dip eddi, Pl a ins bo ro ;
Ma rk D. Lindru d, Ba s k ing Ridg e, a l l
o f NJ .
[ 73] As s ig nee: Bris to l - My ers S q u ibb C o mp a ny ,
Princ eto n, NJ .
[ 2 1 ] Ap p l . No . : 09 / 2 1 7, 5 38
[ 2 2 ] Fil ed: Dec . 2 1 , 1 9 9 8
Rel a ted US . Ap p l ic a tio n Da ta
[ 60] Pro v is io na l a p p l ic a tio n No . 60/ 071 , 9 68, J a n. 2 0, 1 9 9 8.
[ 5 1 ] Int. C l . 7 . . . . . . . . . . . . . . . . . . . . . . . . . A61 K 31 / 4 4 ; C 07D 2 1 3/ 5 6
[ 5 2 ] US . C l . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 1 4 / 35 7; 5 4 6/ 332
[ 5 8] Fiel d o f S ea rc h . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4 6/ 332 ; 5 1 4 / 35 7
[ 5 6] Ref erenc es C ited
U. S . PATENT DOC UMENTS
5 , 84 9 , 9 1 1 1 2 / 1 9 9 9 Fa s s l er et a l . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4 4 / 335
FOREIGN PATENT DOC UMENTS
W O9 7/ 4 002 9 1 0/ 1 9 9 7 W IPO .
Prima ry Exa minerBerna rd DentZ
Atto rney , Ag ent, o r FirmDa v id M. Mo rs e
[ 5 7] ABS TRAC T
Th e p res ent inv entio n p ro v ides th e c ry s ta l l ine bis u l f a te s a l t
o f th e f o rmu l a
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dis s o l u tio n ra te a nd o ra l bio a v a il a bil ity rel a tiv e to th e f ree
ba s e f o rm o f th is a Z a p ep tide HIV p ro tea s e inh ibito r c o m
p o u nd.
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BISULFATE SALT OF HIV PROTEASE
INHIBITOR
Th i s a p p l i c a t i o n c l a i m s p r i o r i t y f r o m Pr o v i s i o n a l Ap p l i
c a t i o n 6 0 / 0 7 1 , 9 6 8 ? l e d J a n . 2 0 , 1 9 9 8 .
BACKGROUND OF THE INVENTION
1 . Fi e l d o f t h e In v e n t i o n
Th 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 t h e n o v e l c r y s t a l l i n e b i s u l
f a t e s a l t o f t h e a Z a p e p t i d e HIV p r o t e a s e i n h i b i t o r o f t h e
f o r m u l a
o c H3
E
\N
H
H3 CO N
H
W h i c h e x h i b i t s u n e x p e c t e d l y s u p e r i o r a q u e o u s s o l u b i l i t y /
d i s s o l u t i o n b e h a v i o r c o m p a r e d t o o t h e r s a l t s , a n d s i g n i ?
c a n t l y i m p r o v e d o r a l b i o a v a i l a b i l i t y i n a n i m a l s c o m p a r e d t o
t h e f r e e b a s e . Th e b i s u l f a t e s a l t i s t h u s u s e f u l f o r p h a r m a
c e u t i c a l d o s a g e f o r m s o f t h e a b o v e - i n d i c a t e d p r o t e a s e
i n h i b i t o r , p a r t i c u l a r l y o r a l d o s a g e f o r m s .
2 . Ba c k g r o u n d Ar t
Pu b l i s h e d PCT p a t e n t a p p l i c a t i o n W O 9 7 / 4 0 0 2 9 d i s c l o s e s
a s e r i e s o f a Z a p e p t i d e HIV p r o t e a s e i n h i b i t o r s r e p o r t e d t o
h a v e a h i g h d e g r e e o f i n h i b i t o r y a c t i v i t y a g a i n s t t h e HIV
v i r u s . On e o f t h e a g e n t s i n c l u d e d W i t h i n t h e s c o p e o f W O
9 7 / 4 0 0 2 9 i s t h e c o m p o u n d h a v i n g t h e s t r u c t u r a l f o r m u l a
a n d t h e c h e m i c a l n a m e [ 3 S- ( 3 R* , 8 R* , 9 R* , 1 2 R* ) ] - 3 , 1 2
b i s ( 1 , 1 - d i m e t h y l e t h y l ) - 8 - h y d r o x y - 4 , 1 1 - d i o x o - 9
( p h e n y l m e t h y l ) - 6 - [ [ 4 - ( 2 - p y r i d i n y l ) p h e n y l m e t h y l ] - 2 , 5 , 6 , 1 0 ,
1 3 - p e n t a a Z a t e t r a d e c a n e d i o i c ] a c i d , d i m e t h y l e s t e r a n d i s
u n d e r e v a l u a t i o n a s a p o s s i b l e s e c o n d g e n e r a t i o n HIV p r o
t e a s e i n h i b i t o r .
W O 9 7 / 4 0 0 2 9 d i s c l o s e s t h e f r e e b a s e f o r m o f a Z a p e p t i d e
d e r i v a t i v e s s u c h a s c o m p o u n d I a n d a l s o v a r i o u s 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 a c i d a d d i t i o n s a l t s . W h i l e s e v e r a l
o r g a n i c a n d i n o r g a n i c a c i d s a r e m e n t i o n e d a s p o s s i b l e s a l t
1 0
2 0
2 5
3 0
3 5
4 5
5 5
6 0
6 5
2
f o r m i n g a g e n t s , i n c l u d i n g s u l f u r i c a c i d , t h e r e i s n o m e n t i o n
o f t h e p a r t i c u l a r b i s u l f a t e s a l t W h i c h i s t h e s u b j e c t o f t h e
p r e s e n t a p p l i c a t i o n .
SUMMARY OF THE INVENTION
Th 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 t h e b i s u l f a t e s a l t o f c o m
p o u n d I a b o v e h a v i n g t h e s t r u c t u r a l f o r m u l a
0 OH
H
N
H3 CO N
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o
o
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/ N\ N N OCH3 'H2 SO4
H T
0
DETAILED DESCRIPTION OF THE
INVENTION
Co m p o u n d I a s d i s c l o s e d a b o v e i s a W e a k o r g a n i c b a s e
W i t h a n a q u e o u s s o l u b i l i t y o f l e s s t h a n 1 p g / m L a t 2 4 1 3 C.
Th e c r y s t a l l i n e f r e e b a s e f o r m a s a s u s p e n s i o n i n W a t e r o r o i l
h a s p o o r o r a l b i o a v a i l a b i l i t y i n a n i m a l s , p r o b a b l y b e c a u s e o f
i t s e x t r e m e l y l o W s o l u b i l i t y i n t h e s e v e h i c l e s .
Fo r d e v e l o p m e n t o f p h a r m a c e u t i c a l f o r m u l a t i o n s , p a r t i c u
l a r l y o r a l d o s a g e f o r m s , t h e a c t i v e i n g r e d i e n t m u s t h a v e
s u f f i c i e n t o r a l b i o a v a i l a b i l i t y . Si n c e t h e f r e e b a s e f o r m o f
c o m p o u n d I d i d n o t p o s s e s s s u c h b i o a v a i l a b i l i t y , a c i d a d d i
t i o n s a l t s W e r e e x p l o r e d b y t h e p r e s e n t i n v e n t o r s . A n u m b e r
o f c o m m o n l y u s e d a c i d a d d i t i o n s a l t s s u c h a s t h e
h y d r o c h l o r i d e , b e n Z e n e s u l f o n a t e , m e t h a n e s u l f o n a t e ,
p - t o l u e n e s u l f o n a t e , p h o s p h a t e , n i t r a t e , 1 , 2
e t h a n e d i s u l f o n a t e , i s e t h i o n a t e a n d s u l f a t e W e r e e v a l u a t e d , i n
a d d i t i o n t o t h e b i s u l f a t e s a l t o f t h e p r e s e n t i n v e n t i o n . Al l o f
t h e s e s a l t s i n t h e i r c r y s t a l l i n e f o r m e x h i b i t e d l o W e r a q u e o u s
s o l u b i l i t y ( 1 3 m g / m L o r l e s s a t 2 4 1 3 C. ) t h a n t h e b i s u l f a t e
W h i c h h a d a s o l u b i l i t y u n d e r t h e s a m e c o n d i t i o n s o f a p p r o x i
m a t e l y 4 5 m g / m L.
So l i d s t a t e t r a n s f o r m a t i o n W a s o b s e r v e d W h e n t h e o t h e r
a c i d a d d i t i o n s a l t s m e n t i o n e d a b o v e W e r e s u s p e n d e d i n
W a t e r , p r o b a b l y d u e t o t h e i r d i s s o c i a t i o n t o f o r m t h e f r e e
b a s e . In t h e m a j o r i t y o f c a s e s , t h i s t r a n s f o r m a t i o n W a s
a c c o m p a n i e d b y g e l f o r m a t i o n . Un l i k e t h e o t h e r s a l t s m e n
t i o n e d a b o v e , t h e e x t r a p r o t o n o f t h e b i s u l f a t e s a l t p r e v e n t s
t h e c o n v e r s i o n t o t h e f r e e b a s e W h i c h , a s m e n t i o n e d a b o v e ,
i s v e r y i n s o l u b l e i n W a t e r a n d h a s p o o r o r a l b i o a v a i l a b i l i t y .
Th e u n u s u a l s o l u b i l i t y b e h a v i o r o f t h e b i s u l f a t e s a l t i n W a t e r
i s f u r t h e r e l a b o r a t e d i n t h e f o l l o W i n g .
6 , 0 8 7 , 3 8 3
3
I n g e n e r a l , c o n v e r s i o n o f s a l t s t o t h e u n i o n i z e d f o r m o r
v i c e v e r s a c a n be e x p l a i n e d o n t h e ba s i s o f p H - s o l u bi l i t y
t h e o r y . Th e s o l u bi l i t y o f t h e f r e e ba s e i n W a t e r W a s d e t e r
mi n e d a s a f u n c t i o n o f p H a t 2413 C . a n d i s s h o W n be l o W .
Th e p H a t W h i c h t h e c o mp o u n d e x h i bi t s t h e h i g h e s t s o l u
bi l i t y i s r e f e r r e d t o a s p H mwc a n d W a s f o u n d t o be a p p r o x i
ma t e l y 1. 2. I t h a s be e n r e p o r t e d i n t h e l i t e r a t u r e t h a t a t
p H >p H ma x o f a W e a k l y ba s i c o r g a n i c c o mp o u n d , t h e e q u i
l i br i u m s o l i d p h a s e i n a n a q u e o u s s u s p e n s i o n o f t h e c o m
p o u n d i s t h e f r e e ba s e . A t p H <p H mwc t h e e q u i l i br i u m s o l i d
c o n v e r t s t o t h e c o r r e s p o n d i n g s a l t f o r m. Th e t e r m e q u i l i b
r i u m s o l i d p h a s e r e f e r s t o t h e u n d i s s o l v e d o r e x c e s s s o l i d i n
a s u s p e n s i o n o f t h e c o mp o u n d i n W a t e r a f t e r s u f ? c i e n t
e q u i l i br a t i o n t i me . W h e n a s a l t o f a W e a k ba s e i s e q u i l i br a t e d
i n W a t e r i n a n a mo u n t e x c e e d i n g i t s s o l u bi l i t y l i mi t ( i . e . , a
s u s p e n s i o n o f t h e s a l t i n W a t e r ) , t h e r e s u l t i n g p H o f t h e
s u s p e n s i o n ma y f a l l o n e i t h e r s i d e o f t h e p H mwc d e p e n d i n g
o n t h e s t r e n g t h o f t h e a c i d a mo n g o t h e r f a c t o r s . W h e n t h e
r e s u l t i n g p H i s g r e a t e r t h a n t h e p H t h e s u s p e n d e d s o l i d
c o n v e r t s t o t h e f r e e ba s e .
S t u d i e s c o n d u c t e d W i t h me t h a n e s u l f o n a t e a n d h y d r o c h l o
r i d e s a l t s , i n p a r t i c u l a r , o f t h e f r e e ba s e c o n ? r me d t h e a bo v e
d e s c r i be d g e n e r a l ? n d i n g s r e p o r t e d i n t h e l i t e r a t u r e .
A mo u n t s i n e x c e s s o f t h e s o l u bi l i t y o f t h e s e s a l t s W e r e
e q u i l i br a t e d i n W a t e r a t 2413 C . f o r a t l e a s t 24 h o u r s . Th e
p H o f t h e s u s p e n s i o n s a f t e r e q u i l i br a t i o n W a s 2110 . 1 W h i c h
i s g r e a t e r t h a n t h e p H ma x . Th e u n d i s s o l v e d s o l i d s f r o m t h e s e
s u s p e n s i o n s W e r e i s o l a t e d , a i r - d r i e d , a n d c h a r a c t e r i Z e d . By
t h e r ma l a n d e l e me n t a l a n a l y s i s t h e u n d i s s o l v e d s o l i d s f r o m
t h e s e s u s p e n s i o n s W e r e i d e n t i ? e d a s t h e f r e e ba s e . Th i s
be h a v i o r W a s e x p e c t e d ba s e d o n t h e p H - s o l u bi l i t y p r o ? l e
s h o W n i n F I G . 1 a n d t h e s t u d i e s r e p o r t e d i n t h e l i t e r a t u r e .
W h e n a n e x c e s s a mo u n t o f t h e bi s u l f a t e s a l t W a s e q u i l i
br a t e d i n W a t e r a mo d i ? c a t i o n o c c u r r e d i n t h e s o l i d p h a s e i n
e q u i l i br i u m W i t h s o l u t i o n . H o W e v e r , t h e u n d i s s o l v e d s o l i d
p h a s e a f t e r e q u i l i br a t i o n W a s n o t t h e f r e e ba s e , a l t h o u g h t h e
p H ( 19 10 . 2) o f t h e s u s p e n s i o n W a s g r e a t e r t h a n t h e p H mwc
a n d c o mp a r a bl e t o t h e p H o f t h e s u s p e n s i o n s o f me t h a n e
s u l f o n a t e a n d h y d r o c h l o r i d e s a l t s d e s c r i be d a bo v e . Th e s o l i d
p h a s e a f t e r a t l e a s t 24 h o u r s o f e q u i l i br a t i o n W a s i d e n t i ? e d
by e l e me n t a l a n a l y s i s a s a h y d r a t e d f o r m o f 2: 1 s a l t o f t h e
f r e e ba s e f o r m a n d s u l f u r i c a c i d ( r e f e r r e d t o a s t h e s u l f a t e
s a l t ) . Th i s be h a v i o r o f t h e bi s u l f a t e s a l t i s u n e x p e c t e d ba s e d
o n p H - s o l u bi l i t y t h e o r y .
W h e n a n e x c e s s a mo u n t o f t h e s u l f a t e s a l t , i n t u r n , W a s
e q u i l i br a t e d i n W a t e r a mo d i ? c a t i o n o c c u r e d i n t h e s o l i d
p h a s e i n e q u i l i br i u m W i t h s o l u t i o n . Th e u n d i s s o l v e d s o l i d
f r o m t h i s s u s p e n s i o n W a s i s o l a t e d , a i r - d r i e d , a n d c h a r a c t e r
i Z e d . Th e r ma l a n d e l e me n t a l a n a l y s i s o f t h i s u n d i s s o l v e d
s o l i d p h a s e W a s s i mi l a r t o t h a t o f t h e f r e e ba s e a l t h o u g h t h e
c o n v e r s i o n o f t h e s u l f a t e s a l t t o t h e f r e e ba s e W a s n o t a s
d e ? n i t i v e a s t h a t o f t h e me t h a n e s u l f o n a t e a n d h y d r o c h l o r i d e
s a l t s . F r o m a p h a r ma c e u t i c a l p o i n t o f v i e W t h e p r o p e n s i t y o f
s a l t s t o c o n v e r t t o t h e f r e e ba s e i n a n a q u e o u s e n v i r o n me n t
i s n o t d e s i r a bl e d u e t o t h e l o W o r a l bi o a v a i l a bi l i t y o f t h e f r e e
ba s e . Th u s , t h e bi s u l f a t e s a l t d u e i t s u n i q u e s o l u bi l i t y be h a v
i o r i n W a t e r o f f e r e d u n e x p e c t e d s u p e r i o r i t y .
Th e s o l u bi l i t y be h a v i o r o f t h e bi s u l f a t e s a l t i n W a t e r W a s
a l s o u n e x p e c t e d c o n s i d e r i n g t h e i n t e r a c t i o n o f c o mp o u n d I
f r e e ba s e a n d s u l f u r i c a c i d i n W a t e r . F o r e x a mp l e , t h e f r e e
ba s e e x h i bi t e d a s o l u bi l i t y o f l e s s t h a n 1 mg /mL i n W a t e r a t
a p H o f ~ 1. 8 a d j u s t e d W i t h s u l f u r i c a c i d , c o mp a r e d t o 4 5
mg /mL s o l u bi l i t y o f t h e bi s u l f a t e s a l t i n W a t e r a t c o mp a r a bl e
p H c o n d i t i o n s . Ba s e d o n p H - s o l u bi l i t y t h e o r y t h e f r e e ba s e
a n d t h e s a l t a r e e x p e c t e d t o e x h i bi t s i mi l a r s o l u bi l i t y a t a
g i v e n p H .
Th e e n h a n c e d s o l u bi l i t y /d i s s o l u t i o n be h a v i o r o f t h e bi s u l
f a t e c o n t r i bu t e s t o i t s i mp r o v e d o r a l bi o a v a i l a bi l i t y i n a n i
ma x ,
10
15
20
25
3 0
3 5
40
45
5 5
6 0
6 5
4
ma l s r e l a t i v e t o t h e f r e e ba s e . Th e a bs o l u t e o r a l bi o a v a i l
a bi l i t y o f t h e bi s u l f a t e s a l t W a s f o u n d t o be a p p r o x i ma t e l y
20 % i n d o g s W h e n a d mi n i s t e r e d i n u n f o r mu l a t e d s o l i d f o r m
p l a c e d i n a g e l a t i n c a p s u l e . I n c o mp a r i s o n , t h e c r y s t a l l i n e
f r e e ba s e h a d mi n i ma l o r a l bi o a v a i l a bi l i t y i n d o g s .
I n a d d i t i o n t o o p t i ma l s o l u bi l i t y , s a t i s f a c t o r y p h y s i c a l
s t a bi l i t y i n t h e s o l i d - s t a t e i s a n o t h e r d e s i r a bl e p r o p e r t y o f
p h a r ma c e u t i c a l s a l t f o r ms . Th e t e r m p h y s i c a l s t a bi l i t y i n d i
c a t e s t h e a bi l i t y o f t h e s a l t f o r m t o r e t a i n i t s c r y s t a l s t r u c t u r e
( i n c l u d i n g s o l v e n t s o f c r y s t a l l i Z a t i o n , i f a n y ) u n d e r s t o r a g e /
s t r e s s c o n d i t i o n s . S i g n i ? c a n t c h a n g e s i n t h e p h y s i c a l n a t u r e
o f t h e s a l t f o r m a s i n d i c a t e d by t h e r ma l me t h o d s s u c h a s
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 me t r y a r e u n d e s i r a bl e . Th e bi s u l
f a t e s a l t e x h i bi t e d e x c e l l e n t s o l i d - s t a t e p h y s i c a l s t a bi l i t y
W h e n s t o r e d a t 40 C . /7 5 % r e l a t i v e h u mi d i t y ( RH ) f o r a s
l o n g a s 9 mo n t h s a s s h o W n i n F I G . 2a . 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 me t r y r e v e a l e d n o s i g n i ? c a n t c h a n g e s i n t h e t h e r ma l
be h a v i o r o f t h e s t r e s s e d s a mp l e o f t h e bi s u l f a t e s a l t c o m
p a r e d t o t h a t o f t h e u n s t r e s s e d s a mp l e ( s t o r e d a t 2 8 C . i n
a c l o s e d c o n t a i n e r ) . Th e me t h a n e s u l f o n a t e , h y d r o c h l o r i d e ,
a n d t h e s u l f a t e s a l t s , o n t h e o t h e r h a n d , s h o W e d s i g n i ? c a n t
c h a n g e s i n t h e i r t h e r ma l be h a v i o r W h e n s t o r e d a t 40 C . /7 5 %
RH f o r a s l i t t l e a s t W o W e e k s a s s h o W n i n F I G S . 2b, c , a n d
d . W h i l e d i f f e r e n c e s i n p h y s i c a l s t a bi l i t y o f s a l t f o r ms i s n o t
u n u s u a l , t h e p r o p e n s i t y o f a p a r t i c u l a r s a l t t o f o r m s o l v a t e s
( o r c r y s t a l mo d i ? c a t i o n s ) a n d i t s a bi l i t y t o r e t a i n t h e s o l v e n t
o f c r y s t a l l i Z a t i o n ( t h e p h y s i c a l s t a bi l i t y o f c r y s t a l
mo d i ? c a t i o n s ) u n d e r s t o r a g e /s t r e s s c o n d i t i o n s c a n n o t be
p r e d i c t e d a p r i o r i .
F I G . 2a r e p r e s e n t s P h y s i c a l s t a bi l i t y o f t h e bi s u l f a t e s a l t .
Th e s o l i d l i n e r e p r e s e n t s t h e u n s t r e s s e d ma t e r i a l . Th e d o t t e d
l i n e r e p r e s e n t s t h e ma t e r i a l s t r e s s e d a t 40 C . /7 5 % RH f o r 9
mo n t h s .
F I G . 2b r e p r e s e n t s P h y s i c a l S t a bi l i t y o f t h e h y d r o c h l o r i d e
s a l t . Th e s o l i d l i n e r e p r e s e n t s t h e u n s t r e s s e d ma t e r i a l . Th e
d o t t e d l i n e r e p r e s e n t s t h e ma t e r i a l s t r e s s e d a t 40 C . /7 5 %
RH f o r t W o W e e k s .
F I G . 2c r e p r e s e n t s P h y s i c a l s t a bi l i t y o f t h e me t h a n e
s u l f o n a t e s a l t . Th e s o l i d l i n e r e p r e s e n t s t h e u n s t r e s s e d ma t e
r i a l . Th e d o t t e d l i n e r e p r e s e n t s t h e ma t e r i a l s t r e s s e d a t 40
C . /7 5 % RH f o r t W o W e e k s
F I G . 2a ' r e p r e s e n t s P h y s i c a l s t a bi l i t y o f t h e s u l f a t e s a l t .
Th e s o l i d l i n e r e p r e s e n t s t h e u n s t r e s s e d ma t e r i a l . Th e d o t t e d
l i n e r e p r e s e n t s t h e ma t e r i a l s t r e s s e d a t 40 C . /7 5 % RH f o r
t W o W e e k s .
Th e bi s u l f a t e s a l t ma y be p r e p a r e d by f o r mi n g a s o l u t i o n
o f f r e e ba s e o f c o mp o u n d I W i t h s u l f u r i c a c i d i n s o l v e n t s
s u c h a s a c e t o n i t r i l e , i s o p r o p a n o l , e t h a n o l , o r a c e t o n e a n d
t h e n i s o l a t i n g t h e s o - p r o d u c e d bi s u l f a t e s a l t .
Be c a u s e o f i t s h i g h bi o a v a i l a bi l i t y a s W e l l a s i t s g o o d
c r y s t a l l i n i t y a n d s t a bi l i t y , t h e bi s u l f a t e s a l t i s v e r y u s e f u l i n
p r e p a r i n g o r a l d o s a g e f o r ms o f c o mp o u n d I . Th e e x a mp l e s
W h i c h f o l l o W i l l u s t r a t e p r e p a r a t i o n o f r e p r e s e n t a t i v e o r a l
f o r mu l a t i o n s .
Th e bi s u l f a t e s a l t , a n d f o r mu l a t i o n s t h e r e o f , a r e u s e d a s
d e s c r i be d i n W O 9 7 /40 0 29 f o r t h e t r e a t me n t o f d i s e a s e s
c a u s e d by v i r u s e s , e s p e c i a l l y r e t r o v i r u s e s s u c h a s t h e H I V
v i r u s .
D ES C RI P TI ON OF S P EC I F I C EMBOD I MENTS
Ex a mp l e 1
P r e p a r a t i o n o f Bi s u l f a t e S a l t f r o m Et h a n o l
To a 5 0 0 mL t h r e e - n e c k e d r o u n d bo t t o me d ? a s k e q u i p p e d
W i t h a n o v e r h e a d s t i r r e r a n d d r o p p i n g f u n n e l , 15 . 0 13 g
6 , 0 8 7 , 3 8 3
5
( 0 . 0 2 1 3 m o l e ) o f f r e e b a s e co m po und I a nd 1 1 3 m L o f 2 0 0
pr o o f e t h a no l W e r e a dde d W i t h s t i r r i ng . T o t h i s s us pe ns i o n,
1 . 2 8 m L co nce nt r a t e d s ul f ur i c a ci d W a s a dde d dr o pW i s e o v e r
90 s e co nds . A f t e r t h e a ddi t i o n o f s ul f ur i c a ci d, a cl e a r
a m b e r -co l o r e d s o l ut i o n W a s o b t a i ne d. T h e s o l ut i o n W a s
po l i s h ? l t e r e d us i ng # 1 W h a t m a n ? l t e r pa pe r a nd W a s h e d
W i t h 5 m L o f 2 0 0 pr o o f e t h a no l . T o t h i s s o l ut i o n W a s a dde d
5 8 m L o f h e pt a ne a nd 3 7 . 5 m g ( 0 . 2 5 W t %) o f s e e d cr y s t a l s
o f t h e co m po und o f f o r m ul a I I f o l l o W e d b y 5 5 m L o f
a ddi t i o na l h e pt a ne . T h e r e s ul t i ng m i x t ur e W a s s t i r r e d f o r 6
h o ur s a t 3 0 0 r pm . T h e r e s ul t i ng cr y s t a l s l ur r y W a s ? l t e r e d
a nd W a s h e d W i t h 5 0 m L e t h a no l / h e pt a ne ( 1 : 1 ) s o l ut i o n a nd
dr i e d unde r v a cuum a t 6 0 C . o v e r ni g h t t o a f f o r d 1 5 . 1 1 g o f
t h e de s i r e d cr y s t a l l i ne b i s ul f a t e s a l t ( 8 8 . 4 m o l e % y i e l d)
h a v i ng f o r m ul a I I a b o v e .
C h a r a ct e r i z i ng P r o pe r t i e s o f B i s ul f a t e S a l t
A na l . C a l cd. f o r C 3 8 H 5 2 N 6 O . 1 . 0 H 2 S O 4 : C , 5 6 . 8 4 ; H ,
6 . 7 8 ; N , 1 0 . 3 7 ; S , 3 . 99. F o und: C , 5 6 . 7 2 ; H , 6 . 6 5 ; N , 1 0 . 4 1 ;
S , 3 . 8 3 . m . p. 1 95 . 0 , H 2 O =0 . 2 8 %
E x a m pl e 2
P r e pa r a t i o n o f B i s ul f a t e S a l t f r o m A ce t o ne
5 M H ZS O 4 ( 8 . 5 2 m L, 4 2 . 6 m M) W a s a dde d dr o pW i s e t o
a s us pe ns i o n o f t h e f r e e b a s e co m po und o f f o r m ul a I ( 3 0 . 0
g . , 4 2 . 6 m M) i n a ce t o ne ( 2 1 3 m L) s t i r r e d m e ch a ni ca l l y i n a
5 0 C . o i l -b a t h . A cl e a r s o l ut i o n W a s o b t a i ne d a l m o s t i m m e
di a t e l y . T h e s o l ut i o n W a s s e e de d W i t h cr y s t a l s o f t h e f r e e
b a s e co m po und o f f o r m ul a I I . A f t e r t W o m i nut e s , a pr e ci pi
t a t e f o r m e d W h i ch b e ca m e a pa s t e . T h e m i x t ur e W a s s t i r r e d
a t 5 0 C . f o r o ne h o ur , a t 2 5 C . f o r 3 0 m i nut e s a nd a t 0 C .
f o r 2 h o ur s . T h e s o l i d W a s ? l t e r e d a nd t h e ? r s t ? l t r a t e W a s
us e d t o t r a ns f e r t h e r e m a i ni ng m a t e r i a l i n t h e ? a s k t o t h e
? l t r a t i o n f unne l . T h e pr o duct W a s W a s h e d W i t h a ce t o ne , t h e n
h e pt a ne , a nd dr i e d unde r v a cuum o v e r ni g h t t o g i v e 3 1 . 4 8 g
( co r r e ct e d y i e l d 92 %) o f t h e b i s ul f a t e s a l t o f f o r m ul a I I , m . p.
1 98 1 99 C . de c.
A na l . C a l cd. C 3 8 H 5 2 N 6 O 7 1 0 H 2 S O 4 . 0 . 2 H 2 O : c, 5 6 . 5 9;
H , 6 . 8 0 ; N , 1 0 . 4 2 , s , 3 . 98 ; H 2 O , 0 . 4 5 . F o und: c, 5 6 . 6 6 ; H ,
6 . 7 8 ; N , 1 0 . 5 0 , s , 4 . 2 0 , H 2 O , 0 . 4 5 ( K F ) .
E x a m pl e 3
P r e pa r a t i o n o f B i s ul f a t e S a l t f r o m I s o pr o pa no l
A que o us s ul f ur i c a ci d ( 5 . 0 M, 0 . 2 0 m L, 1 m M) W a s a dde d
t o a s us pe ns i o n o f t h e f r e e b a s e co m po und o f f o r m ul a I
( 0 . 7 0 4 g , 1 . 0 0 m M) i n i s o pr o pa no l ( 4 . 0 m L) ch i l l e d i n a n
i ce -b a t h . T h e i ce -b a t h W a s r e m o v e d a nd t h e m i x t ur e s t i r r e d
a t r o o m t e m pe r a t ur e . T h e s us pe ns i o n h a d di s s o l v e d a f t e r 1 5
m i nut e s . T h e s o l ut i o n W a s s e e de d W i t h cr y s t a l s pr e pa r e d a s
i n E x a m pl e s 1 o r 2 a b o v e a nd s t i r r e d f o r 5 h o ur s . T h e s o l i d
W a s ? l t e r e d a nd t h e ? l t r a t e W a s us e d t o t r a ns f e r t h e s o l i d
f r o m t h e ? a s k t o t h e f unne l . T h e pr o duct W a s W a s h e d W i t h
h e pt a ne a nd dr i e d unde r v a cuum t o g i v e 0 . 7 5 2 g o f cr y s t a l
l i ne b i s ul f a t e s a l t o f f o r m ul a I I , y i e l d 90 %, m p. 1 6 0 1 90
C . , de c.
A na l . C a l cd. f o r C 3 8 H 5 2 N 6 O 7 1 0 H 2 S O 4 . 2 . 0 H 2 O ; C ,
5 4 . 4 0 ; H , 6 . 97 ; N , 1 0 . 0 2 ; S , 3 . 8 2 ; H 2 O , 4 . 2 9. F o und: C ,
5 4 . 2 5 ; H , 6 . 7 3 ; N , 1 0 . 0 2 ; S , 3 . 6 7 ; H 2 O , 4 . 5 3
T h e cr y s t a l s o b t a i ne d f r o m i s o pr o pa no l s h o W e d a po W de r
x -r a y di f f r a ct i o n pa t t e r n di f f e r e nt f r o m t h e cr y s t a l s o b t a i ne d
1 0
1 5
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6 0
6
f r o m a ce t o ni t r i l e , e t h a no l -h e pt a ne o r a ce t o ne . T h e y a r e no W
r e f e r r e d t o a s T y pe -I I cr y s t a l s . T h e T y pe -I cr y s t a l s a ppe a r t o
b e a n a nh y dr o us / de s o l v a t e d cr y s t a l l i ne m a t e r i a l W h i l e t h e
T y pe -I I cr y s t a l s a r e a h y dr a t e d, h y g r o s co pi c cr y s t a l l i ne
f o r m .
E x a m pl e 4
P r e pa r a t i o n o f C a ps ul e F o r m ul a t i o ns o f B i s ul f a t e
S a l t
A . C a ps ul e s ( 5 0 a nd 2 0 0 m g f r e e b a s e e qui v a l e nt )
C a ps ul e s a r e pr o v i de d f o r o r a l a dm i ni s t r a t i o n i n W h i ch t h e
ca ps ul e i s a s i Ze # 0 , g r a y , o pa que , h a r d g e l a t i n ca ps ul e
co nt a i ni ng t h e b i s ul f a t e s a l t o f f o r m ul a I I f o r m ul a t e d a s a
W e t g r a nul a t i o n W i t h l a ct o s e , cr o s po v i do ne a nd m a g ne s i um
s t e a r a t e .
B . C a ps ul e s ( 1 0 0 m g f r e e b a s e e qui v a l e nt )
C a ps ul e s a r e pr o v i de d f o r o r a l a dm i ni s t r a t i o n i n W h i ch t h e
ca ps ul e i s a s i Ze # 0 , g r a y , o pa que , h a r d g e l a t i n ca ps ul e
co nt a i ni ng t h e b i s ul f a t e s a l t o f f o r m ul a I I s us pe nde d i n
G e l uci r e 4 4 / 1 4 . G e l uci r e 4 4 / 1 4 i s a s a t ur a t e d po l y g l y co l i Ze d
g l y ce r i de co ns i s t i ng o f m o no -, di - a nd t r i g l y ce r i de s a nd
m o no - a nd di -f a t t y a ci d e s t e r s o f po l y e t h y l e ne g l y co l . C a p
s ul e s a r e pr e pa r e d b y m e l t i ng G e l uci r e 4 4 / 1 4 a t 4 5 7 0 C .
f o l l o W e d b y a ddi t i o n o f t h e b i s ul f a t e s a l t W i t h s t i r r i ng . T h e
m o l t e n m i x t ur e i s ? l l e d i nt o h a r d g e l a t i n ca ps ul e s a nd
a l l o W e d t o co o l a nd s o l i di f y .
W e cl a i m :
1 . T h e b i s ul f a t e s a l t h a v i ng t h e f o r m ul a
O O E
H 3 C O N
H
?
o
H
/ N \ N N \ " / O C H 3 ' H 2 S O 4 .
H
o
2 . A ph a r m a ce ut i ca l do s a g e f o r m co m pr i s i ng t h e b i s ul f a t e
s a l t o f cl a i m 1 a nd a ph a r m a ce ut i ca l l y a cce pt a b l e ca r r i e r .