john e. flaherty ravin r. patel mccarter & english llp · 3/25/2016 · the claims of the...

John E. Flaherty

Ravin R. Patel

McCARTER & ENGLISH LLP

Four Gateway Center

100 Mulberry Street

Newark, New Jersey 07102

(973) 622-4444

Counsel for Plaintiffs AstraZeneca AB,

Aktiebolaget Hassle, AstraZeneca LP,

and Zeneca Inc.

Einar Stole

Edward H. Rippey

COVINGTON & BURLING LLP

One CityCenter

850 Tenth St., NW

Washington, DC 20001

(202) 662-6000

Of Counsel for Plaintiffs

IN THE UNITED STATES DISTRICT COURT

FOR THE DISTRICT OF NEW JERSEY

ASTRAZENECA AB, AKTIEBOLAGET

HÄSSLE, ASTRAZENECA LP, and

ZENECA INC.,

Plaintiffs,

v.

MACLEODS PHARMACEUTICALS LTD.

and MACLEODS PHARMA USA, INC.,

Defendants.

Civil Action No. ____________

COMPLAINT FOR

PATENT INFRINGEMENT

AND CERTIFICATION PURSUANT TO

LOCAL CIVIL RULE 11.2

Case 3:16-cv-01682-MLC-TJB Document 1 Filed 03/24/16 of 16 PageID: 1

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Plaintiffs AstraZeneca AB, Aktiebolaget Hassle, AstraZeneca LP, and Zeneca Inc.

(collectively, “Plaintiffs”), by their attorneys, for their Complaint against Macleods

Pharmaceuticals Ltd. (“Macleods”) and Macleods Pharma USA, Inc. (“Macleods USA”), allege

as follows:

NATURE OF THE ACTION

1. This is a civil action for patent infringement arising under the patent laws of the

United States, 35 U.S.C. § 100 et seq., and in particular under 35 U.S.C. § 271(e). This action

relates to Abbreviated New Drug Application (“ANDA”) No. 208511 filed by or for the benefit

of Macleods and Macleods USA (collectively, “Defendants”) with the United States Food and

Drug Administration (“FDA”) for approval to market generic versions of Plaintiffs’ NEXIUM®

pharmaceutical products that are sold in the United States.

THE PARTIES

2. Plaintiff AstraZeneca AB (“AZ AB”) is a corporation operating and existing

under the laws of the Sweden, with its principal place of business at S-151 85 Södertälje,

Sweden.

3. Plaintiff Aktiebolaget Hässle (“Hässle”) is a corporation organized and existing

under the laws of Sweden, having its principal place of business at Mölndal, Sweden.

4. Plaintiff AstraZeneca LP (“AZ LP”) is a limited partnership operating and

existing under the laws of the State of Delaware, with its principal place of business at 1800

Concord Pike, Wilmington, Delaware 19803. AZ LP holds an approved New Drug Application

from the FDA for an esomeprazole magnesium formulation which it sells under the name

NEXIUM®.


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5. Plaintiff Zeneca Inc. (“Zeneca”) is a Delaware corporation having its principal

place of business at Wilmington, Delaware. Zeneca has exclusive rights in the United States to

market and sell products covered by United States Patent Nos. 6,369,085; 7,411,070; and

8,466,175.

6. Upon information and belief, Macleods is an Indian company having its principal

place of business at Atlanta Arcade, Marol Church Road, Andheri (East), Mumbai, India 400059.

Upon information and belief, Macleods is in the business of developing, manufacturing,

marketing, and selling generic drugs.

7. Upon information and belief, Macleods USA is a wholly-owned subsidiary of

Macleods.

8. Upon information and belief, Macleods USA is a corporation organized under the

laws of the State of Delaware, with its principal place of business at 666 Plainsboro Road,

Building 200, Suite 230, Plainsboro, New Jersey 08536. Upon information and belief, Macleods

USA is in the business of marketing, distributing, and selling, in the State of New Jersey and

throughout the United States, pharmaceutical drugs, including generic pharmaceutical drugs

manufactured by Macleods.

9. Upon information and belief, Defendants collaborate to manufacture, import,

market, distribute, and sell generic pharmaceutical products in the State of New Jersey and the

throughout the United States.

10. Upon information and belief, following any FDA approval of ANDA No. 208511,

Macleods itself and through its U.S. agent, Macleods USA, will make, use, offer to sell, and/or

sell the generic drug products that are the subject of ANDA No. 208511 throughout the United

States, and/or import such generic drug products into the United States.


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BACKGROUND

The NDA

11. AZ LP is the holder of New Drug Application (“NDA”) No. 21153 for

NEXIUM® Esomeprazole Magnesium Delayed-Release Capsules, in 20 mg and 40 mg dosage

forms. NEXIUM® is a prescription drug approved for use to relieve the symptoms of acid reflux

disease and treat erosive esophagitis. Esomeprazole magnesium trihydrate is the active

ingredient in NEXIUM®.

The Patents-in-Suit

12. United States Patent No. 6,369,085 (“the ’085 patent”), entitled “Form of S-

Omeprazole,” was duly and legally issued by the United States Patent and Trademark Office

(“the USPTO”) on April 9, 2002 to AZ AB, upon assignment from the inventors Hanna Cotton,

Anders Kronstrom, Anders Mattson, and Eva Möller. The ’085 patent claims, inter alia,

magnesium salts of esomeprazole trihydrate, pharmaceutical compositions comprising the

claimed salts, methods of treatment using the claimed salts, and processes for preparing the

claimed salts. A true and correct copy of the ’085 patent is attached as Exhibit A.

13. Plaintiff AZ AB has been and still is the owner of the ’085 patent. The ’085

patent will expire on May 25, 2018, and pediatric exclusivity relating to the ’085 patent expires

on November 25, 2018.

14. United States Patent No. 7,411,070 (“the ’070 patent”), entitled “Form of S-

omeprazole,” was duly and legally issued by the USPTO on August 12, 2008 to AZ AB upon

assignment from inventors Hanna Cotton, Anders Kronstrom, Anders Mattson, and Eva Moller.

The claims of the ’070 patent are directed to, inter alia, magnesium salts of esomeprazole


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trihydrate and processes for preparing the claimed salts. A true and correct copy of the ’070

patent is attached as Exhibit B.




16. United States Patent No. 8,466, 175 (“the ’175 patent”), entitled “Form of S-

omeprazole,” was duly and legally issued by the USPTO on June 18, 2013 to AZ AB upon

assignment from inventors Hanna Cotton, Anders Kronstrom, Anders Mattson, and Eva Moller.

The claims of the ’175 patent are directed to, inter alia, methods of treating Heliobacter

infections comprising administration of magnesium salts of esomeprazole trihydrate. A true and

correct copy of the ’175 patent is attached as Exhibit C.




The ANDA

18. On information and belief, Macleods filed ANDA No. 208511 with the FDA

under 21 U.S.C. § 355(j) to obtain FDA approval for the commercial manufacture, use,

importation, offer for sale, and sale in the United States of esomeprazole magnesium delayed-

release pellets, 20 mg and 40 mg (“Macleods’s Esomeprazole Magnesium Delayed-Release

Pellets”), which are generic versions of Plaintiffs’ NEXIUM® Esomeprazole Magnesium

Delayed-Release Capsules, in 20 mg and 40 mg dosage forms.

19. By letter dated February 8, 2016 (the “ANDA Notice Letter”), Macleods notified

Plaintiffs that Macleods had filed ANDA No. 208511 seeking approval to market Macleods’s


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Esomeprazole Magnesium Delayed-Release Pellets and that Macleods was providing

information to Plaintiffs pursuant to 21 U.S.C. § 355(j)(2)(B) and 21 C.F.R. § 314.95.

Macleods’s ANDA Notice Letter failed to provide “the name and address of an agent in the

United States authorized to accept service of process” for applicants that, like Macleods, do not

reside or have a place of business in the United States. See 21 C.F.R. § 314.95(c)(7).

JURISDICTION AND VENUE

20. Subject matter jurisdiction over this action is proper pursuant to the provisions of

Title 28, United States Code, Sections 1331 and 1338(a).

21. Upon information and belief, Macleods is an Indian company having its principal

place of business at Atlanta Arcade, Marol Church Road, Andheri (East), Mumbai, India 400059.

Upon information and belief, Macleods is in the business of developing, manufacturing,

marketing, and selling generic drugs.

22. On information and belief, Macleods, either directly or through one or more of its

wholly owned subsidiaries and/or agents, develops, manufactures, distributes, markets, offers to

sell, and sells generic drug products for sale and use throughout the United States, including

within the judicial district.

23. Upon information and belief, Macleods purposefully has conducted and continues

to conduct business, directly or indirectly, in this judicial district, and this judicial district is a

likely destination of Macleods’s generic products. Upon information and belief, Macleods is a

“truly global pharmaceutical company” that has grown at an average rate of 22% over the last

five years. See http://www.macleodspharma.com/default.asp. Upon information and belief,

“Macleods has received FDA approval on 9 Abbreviated New Drug Applications and has


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another 60 filed and awaiting approval.” See

http://www.macleodspharma.com/UnitedStates.asp.

24. On information and belief, Macleods USA is a corporation organized and existing

under the laws of the State of Delaware, with its principal place of business at 666 Plainsboro

Road, Building 200, Suite 230, Plainsboro, New Jersey 08536. Macleods has designated

Macleods Pharma USA, Inc., located in New Jersey, to accept service of process for this matter.

25. On information and belief, Macleods USA is in the business of marketing,

distributing, and selling, in the State of New Jersey and throughout the United States,

pharmaceutical drugs, including generic pharmaceutical drugs manufactured by Macleods.

26. On information and belief, Defendants acted in concert to develop Macleods’s

Esomeprazole Magnesium Delayed-Release Pellets and to seek approval from the FDA to sell

Macleods’s Esomeprazole Magnesium Delayed-Release Pellets throughout the United States,

including within this judicial district.

27. On information and belief, and as stated in the ANDA Notice Letter, Macleods

prepared and filed ANDA No. 208511.

28. On information and belief, and as stated in the ANDA Notice Letter, the FDA

received ANDA No. 208511 from Macleods.

29. On information and belief, by virtue of, inter alia, Macleods’s preparation and/or

filing of ANDA No. 208511 and sales-related activities in New Jersey, including but not limited

to the substantial, continuous, and systematic distribution, marketing, and/or sales of

pharmaceutical products to residents of New Jersey, this Court has personal jurisdiction over

Macleods. See, e.g., Acorda Therapeutics Inc. v. Mylan Pharm. Inc., No. 15-1456, slip op. at 14

(Fed. Cir. Mar. 18, 2016) (holding that minimum-contacts requirement for specific personal


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jurisdiction is established where Defendant’s “ANDA filings and its distribution channels

establish that [the Defendant] plans to market its proposed drugs in [the State where the

complaint was filed] and the lawsuit is about patent constraints on such in-State marketing.”)

30. On information and belief, Macleods has previously been sued in this district and

has not challenged personal jurisdiction. See, e.g., AstraZeneca Pharmaceuticals LP et al. v.

Macleods Pharmaceuticals, Ltd. et al., Civ. Action No. 2:15-cv-01513-CCC-MF (D.N.J.);

Otsuka Pharmaceutical Co., Ltd. v. Macleods Pharmaceuticals, Ltd. et al., Civ. Action No. 1:15-

cv-5109-JBS-KMW (D.N.J.).

31. On information and belief, Macleods has availed itself of the jurisdiction of this

court by asserting counterclaims in this district. See, e.g., Otsuka Pharmaceutical Co., Ltd. v.

Macleods Pharmaceuticals, Ltd. et al., Civ. Action No. 1:15-cv-5109-JBS-KMW (D.N.J.).

32. Venue is proper in this District pursuant to the provisions of Title 28, United

States Code, Sections 1391(c) and (d), and 1400 (b).

COUNT 1: INFRINGEMENT OF THE ’085 PATENT

33. Plaintiffs incorporate by reference paragraphs 1-32 of this Complaint as if fully

set forth herein.

34. On information and belief, Defendants submitted ANDA No. 208511 to the FDA

under 21 U.S.C. § 355(j) in order to obtain approval to market their Esomeprazole Magnesium

Delayed-Release Pellets in the United States before the expiration of the ’085 patent.

35. By their ANDA Notice Letter, Defendants informed Plaintiffs that they had

submitted to the FDA, pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV), a certification alleging that

the ’085 patent is invalid, unenforceable, or will not be infringed by the commercial


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manufacture, use, sale, offer for sale, or importation into the United States of Macleods’s

Esomeprazole Magnesium Delayed-Release Pellets.

36. Under 35 U.S.C. § 271(e)(2)(A), the submission by Defendants to the FDA of

ANDA No. 208511 to obtain approval for the commercial manufacture, use, sale, offer for sale,

or importation into the United States of Macleods’s Esomeprazole Magnesium Delayed-Release

Pellets before the expiration of the ’085 patent constitutes infringement of one or more claims of

the ’085 patent, either literally or under the doctrine of equivalents.

37. On information and belief, Macleods’s Esomeprazole Magnesium Delayed-

Release Pellets, if approved by the FDA, will be prescribed and administered to human patients

in a therapeutically effective amount to inhibit gastric acid secretion and for the treatment of

gastrointestinal inflammatory disease. On information and belief, this administration will occur

at Defendants’ active behest and with their intent, knowledge, and encouragement. On

information and belief, Defendants will actively encourage, aid and abet this administration with

knowledge that it is in contravention of Plaintiffs’ rights under the ’085 patent.

38. The ANDA Notice Letter, which is required by statute and regulation to provide a

full and detailed explanation regarding all defenses, provides only a bare allegation of invalidity

and unenforceability of the ’085 patent’s claims without any explanation or identifying any legal

basis or supporting facts. Because Defendants allege that the ’085 patent is invalid or

unenforceable without any explanation or identifying any legal basis or supporting facts,

Defendants effectively admit that the ’085 patent is both valid and enforceable.

39. Plaintiffs will be substantially and irreparably harmed by the infringing activities

described above unless those activities are precluded by this Court. Plaintiffs have no adequate

remedy at law.


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set forth herein.


under 21 U.S.C. § 355(j) in order to obtain approval to market Macleods’s Esomeprazole

Magnesium Delayed-Release Pellets in the United States before the expiration of the ’070 patent.














gastrointestinal inflammatory disease. On information and belief, this administration will occur

at Defendants’ active behest and with their intent, knowledge, and encouragement. On

information and belief, Defendants will actively encourage, aid and abet this administration with

knowledge that it is in contravention of Plaintiffs’ rights under the ’070 patent.


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remedy at law.



set forth herein.


under 21 U.S.C. § 355(j) in order to obtain approval to market Macleods’s Esomeprazole

Magnesium Delayed-Release Pellets in the United States before the expiration of the ’175 patent.










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gastrointestinal inflammatory disease, including Heliobacter infection. On information and

belief, this administration will occur at Defendants’ active behest and with their intent,

knowledge, and encouragement. On information and belief, Defendants will actively encourage,

aid and abet this administration with knowledge that it is in contravention of Plaintiffs’ rights

under the ’175 patent.









remedy at law.

PRAYER FOR RELIEF

WHEREFORE, Plaintiffs respectfully request the following relief:

A. A judgment that the claims of the ’085, ’070, and ’175 patents are valid and

enforceable;


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B. A judgment that the submission of ANDA No. 208511 by Defendants infringes

one or more claims of each of the ’085, ’070, and ’175 patents under 35 U.S.C. § 271(e)(2);

C. A judgment providing that, pursuant to 35 U.S.C. § 271(e)(4)(A), the effective

date of any FDA approval of Macleods’s ANDA No. 208511 shall be no earlier than the latest

expiration date of the Patents-in-Suit and any additional periods of exclusivity;

D. A judgment pursuant to 35 U.S.C. § 271(e)(4)(B) permanently enjoining

Defendants, and all persons acting in concert with Defendants, from making, using, selling,

offering to sell, or importing the esomeprazole magnesium product described in Defendants’

ANDA No. 208511 prior to the latest expiration of the Patents-in-Suit and any additional periods

of exclusivity;

E. Attorneys’ fees in this action pursuant to 35 U.S.C. § 285;

F. Costs and expenses in this action; and

G. Such further and other relief as this Court may deem just and proper.

Dated: March 24, 2016 Respectfully submitted,

s/ John E. Flaherty

John E. Flaherty

Ravin R. Patel


Four Gateway Center

100 Mulberry Street


(973) 622-4444



and Zeneca Inc.


14

Einar Stole

Edward H. Rippey


One CityCenter

850 Tenth St., NW


(202) 662-6000



15

CERTIFICATION PURSUANT TO L. CIV. R. 11.2

Pursuant to Local Civil Rule 11.2, I hereby certify that the matter in controversy is

related to the subject matter of the following actions:

ASTRAZENECA AB, AKTIEBOLAGET HÄSSLE, ASTRAZENECA LP, KBI INC., and KBI-E

INC. v. MYLAN LABORATORIES LTD. and MYLAN, INC., C.A. No. 3:12-cv- 01378-MLC-

TJB (District of New Jersey)


INC. v. WATSON LABORATORIES, INC. – FLORIDA, C.A. No. 3:13-cv-01669- MLC-TJB

(District of New Jersey)


INC. v. WOCKHARDT LIMITED and WOCKHARDT USA LLC, C.A. No. 3:13- cv-04854-

MLC-TJB (District of New Jersey)


INC. v. AUROBINDO PHARMA LIMITED and AUROBINDO PHARMA USA Inc., C.A. No.

3:13-cv-7298-MLC-TJB (District of New Jersey)


INC. v. KREMERS URBAN PHARMACEUTICALS, KREMERS URBAN DEVELOPMENT

CO., and KREMERS URBAN LLC, C.A. No. 3:13-cv-7299-MLC-TJB (District of New

Jersey)


INC. v. ZYDUS PHARMACEUTICALS (USA) INC., and CADILA HEALTHCARE LTD. (dba

ZYDUS CADILA), C.A. No. 3:14-cv-4782-MLC-TJB (District of New Jersey)

ASTRAZENECA AB, AKTIEBOLAGET HÄSSLE, ASTRAZENECA LP, and ZENECA INC. v.

ACTAVIS LABORATORIES FL, INC., and ACTAVIS PHARMA, INC., C.A. No. 3:14-cv-

7870-MLC-TJB (District of New Jersey)


ANDRX LABS, LLC, ANDRX CORPORATION, and ACTAVIS, INC., C.A. No. 3:14-cv-8030-



PERRIGO COMPANY PLC, PERRIGO COMPANY, L. PERRIGO COMPANY, and

PADDOCK LABORATORIES, LLC, C.A. No. 3:15-cv-1057-MLC-TJB (District of New

Jersey)


HEC PHARM CO., LTD., HEC PHARM GROUP, and HEC PHARM USA INC., C.A. No.



16


LUPIN LTD. and LUPIN PHARMACEUTICALS INC.,, C.A. No. 3:15-cv-06092-MLC-TJB



ALKEM LABORATORIES LTD., and ASCEND LABORATORIES, LLC., C.A. No. 3:15-cv-


ASTRAZENECA AB, AKTIEBOLAGET HÄSSLE, ASTRAZENECA LP, and ZENECA INC. v. ZYDUS PHARMACEUTICALS (USA) INC., and CADILA HEALTHCARE LTD. (dba ZYDUS

CADILA), C.A. 3:15-cv-07415-MLC-TJB (District of New Jersey)


DR. REDDY’S LABORATORIES, LTD. and DR. REDDY’S LABORATORIES, INC., C.A. No.


Date: March 24, 2016 By: s/ John E. Flaherty

John E. Flaherty

Ravin R. Patel


Four Gateway Center

100 Mulberry Street


(973) 622-4444



and Zeneca Inc.

Einar Stole

Edward H. Rippey


One CityCenter

850 Tenth St., NW


(202) 662-6000



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VI. CAUSE OF ACTION

E16'#6/'#F)")#E1(12#"676=6'#=89'4#B/10/#A3=#74'#:1218>#(Do not cite jurisdictional statutes unless diversity4Q

#

[41':#9'5041<6138#3:#07=5'Q

VII. REQUESTED IN

COMPLAINT:

! EUPEg#RJ#.UR"#R"#S#CLASS ACTION

FNMP&#&FKP#+XC#J)&)E()L)

DEMAND $ EUPEg#hP"#382A#1:#9';789'9#18#03;<27186Q

JURY DEMAND: ! h'5 ! N3

VIII. RELATED CASE(S)

IF ANY!";;$7@>O8DIO7C@>4S

!FMWP MOEgP.#NFT[P&

MS.P "RWNS.F&P#OJ#S..O&NPh#OJ#&PEO&M

FOR OFFICE USE ONLY

&PEPRL.#i STOFN. SLLKhRNW#RJL !FMWP TSW)#!FMWP

Hon. Mary L. Cooper, U.S.D.J.

Hon. Tonianne J. Bongiovanni, U.S.M.J.

ASTRAZENECA AB, AKTIEBOLAGET HÄSSLE, ASTRAZENECA LP,and ZENECA INC.

Sweden

John E. Flaherty, Esq.McCarter & English, LLP, Four Gateway Center, 100 Mulberry Street,Newark, NJ, 07102. Tel: 973-622-4444 Email: [email protected]

MACLEODS PHARMACEUTICALS LTD. and MACLEODS PHARMAUSA, INC.

Mumbai, India

35 U.S.C. §271

Patent Infringement (ANDA)

Please see attached

03/24/2016 s/ John E. Flaherty

Case 3:16-cv-01682-MLC-TJB Document 1-1 Filed 03/24/16 Page 1 of 1 PageID: 17

CIVIL COVER SHEET ATTACHMENT

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EXHIBIT A

Case 3:16-cv-01682-MLC-TJB Document 1111111111111111111111111111111111111111111111111111111iUS006369085131

(12) United States Patent (10) Patent No.: US 6,369,085 B1Cotton et al. (45) Date of Patent: Apr. 9, 2002

(54) FORM OF S-OMEPRAZOLE FOREIGN PATENT DOCUMENTS

(75) Inventors: Hanna Cotton; Anders Kronstrom; CN 1136564 11/1996EP 0005129 10/1979Anders Mattson; Eva Willer, all ofEP 0124495 11/1984

Södertälje (SE) EP 0247983 12/1987WO 9427988 12/1994

(73) Assignee: AstraZeneca AB, Sodertalje (SE) WO WO 95/01977 1/1995WO 9601623 1/1996

Notice: Subject to any disclaimer, the term of this WO 9602535 2/1996patent is extended or adjusted under 35U.S.C. 154(b) by 0 days. OTHER PUBLICATIONS

(21) Appl. No.: 09/077,719 Japanese Chemical Society, Experimental Chemical Semi-nar, vol. 18, p. 55 (translation), 1958.*

(22) PCT Filed: May 5, 1998An Introduction to Crystal Chemistry by Evans Cambridge

(86) PCT No.: PCT/SE98/00974 At the Univ. Press. 1964.*

371 Date: Jun. 8, 1998 von Unge, S. et al. "Stereochemical assignment of theenantiomers of omeprazole from X–ray analysis of a fenchy-

102(e) Date: Jun. 8, 1998 loxylmethyl derivative of (+)–(R)–omeprazole", Tetrahe-dron Asymmetry, vol. 8, No. 12, pp. 1967-1970 (1997).(87) PCT Pub. No.: W098/54171

PCT Pub. Date: Dec. 3, 1998 cited by examiner

(30) Foreign Application Priority Data Primary Examiner—Jane Fan

May 30, 1997 (SE) 9702065 (74) Attorney, Agent, or Firm—White & Case LLP

(51) Int. Cl.7 A61K 31/4439; CO7D 401/12 (57) ABSTRACT

(52) U.S. Cl. 514/338; 546/273.7 The present invention relates to a novel form of the(58) Field of Search 514/338; 546/273.7 enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-

pyridinyl)-methyl]sulfinyl]-1H-benzimidazole, i.e.(56) References Cited S-omeprazole. More specifically, it relates to a novel form of

U.S. PATENT DOCUMENTS the magnesium salt of the S-enantiomer of omeprazoletrihydrate. The present invention also relates to processes for

4,738,974 A 4/1988 Brandstrom 514/338 preparing such a form of the magnesium salt of5,530, 160 A 6/1996 Nore et al. 562/571 S-omeprazole and pharmaceutical compositions containing5,690,960 A 11/1997 Bengtsson et al. 514/338 it. Furthermore, the present invention also relates to new5,693,818 A 12/1997 Vion Unge 514/338.intermediates used in the process.5,714,504 A 2/1998 Lindberg et al. 514/3385,877, 192 A 3/1999 Lindberg et al. 514/3385,900,424 A 5/1999 Kallstrom et al. 514/338 12 Claims, 5 Drawing Sheets

Case 3:16-cv-01682-MLC-TJB Document 1-3 Filed 03/24/16 Page 3 of 14 PagelD: 22

U.S. Patent Apr. 9, 2002 Sheet 1 of 5 US 6,369,085 B1

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US 6,369,085 B12

FORM OF S-OMEPRAZOLE of the dihydrate shown in FIG. 3 (See Example 6). Thismagnesium salt of S-omeprazole dihydrate has been pre-

This application is a 371 of PCT/SE98/00974, May 5, pared and can be used in the preparation of the magnesium1998 now WO 9854171 Dec. 3, 1998. salt of S-omeprazole trihydrate according to the present

5 invention.FIELD OF THE INVENTION FIG. 5 shows X-ray powder diffractogram of the magne-

The present invention relates to a novel form of the sium salt of S-omeprazole prepared according to example A

(—)-enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl- in WO 96/01623.2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole, i.e.

DESCRIPTION OF THE INVENTIONS-omeprazole. More specifically, it relates to a novel form of 10

the magnesium salt of the S-enantiomer of omeprazole It has surprisingly been found that the magnesium salt oftrihydrate. The present invention also relates to processes for S-omeprazole occurs in a number of structurally different

preparing such a form of the magnesium salt of forms. It is an object of the present invention to provide a

S-omeprazole and pharmaceutical compositions containing substantially pure magnesium salt of S-omeprazoleit. Furthermore, the present invention also relates to inter- 15 trihydrate, hereinafter referred to as the compound of themediates used in the process, and their preparation. invention. This trihydrate can be obtained as a well defined

compound. The present invention also provides a process toBACKGROUND OF THE INVENTION AND obtain and a method of differentiating the magnesium salt of

PRIOR ART S-omeprazole trihydrate from other forms of magnesiumThe compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl- 20 salts of S-omeprazole.

2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, having the The compound of the invention is advantageous becausegeneric name omeprazole, and therapeutically acceptable it is more stable than the corresponding magnesium saltsalts thereof, are described in EP 5129. The specific alkaline compounds in prior art and is therefore easier to handle andsalts of omeprazole are disclosed in EP 124 495. Omepra- store. The compound of the invention is also easier tozole is a proton pump inhibitor, i.e. effective in inhibiting 25 characterize because it exists in a well defined state.

gastric acid secretion, and is useful as an antiulcer agent. In Additionally, the compound of the invention is easier toa more general sense, omeprazole may be used for preven- synthesize in a reproducible manner and thereby easier totion and treatment of gastric-acid related diseases in mam- handle in a full scale production.mals and especially in man. The magnesium salt of S-omeprazole trihydrate obtained

Omeprazole is a sulfoxide and a chiral compound, 30according to the present invention is substantially free from

wherein the sulfur atom being the stereogenic center. Thus, magnesium salts of R-omeprazole. The magnesium salt ofomeprazole is a racemic mixture of its two single S-omeprazole trihydrate obtained according to the presentenantiomers, the R and S-enantiomer of omeprazole, herein invention is also substantially free from other forms ofreferred to as R-omeprazole and S-omeprazole. The absolute magnesium salts of S-omeprazole, such as the correspond-configurations of the enantiomers of omeprazole have been ing magnesium salt compounds described in prior art, anddetermined by an X-ray study of an N-alkylated derivative dihydrates used in the preparation of the trihydrate com-

of the (+)-enantiomer in non-salt form. The (+)-enantiomer pound according to the present invention.of the non-salt form and the (—)-enantiomer of the non-salt The compound of the invention is characterized by theform were found to have R and S configuration, respectively, positions and intensities of the major peaks in the X-rayand the (+)-enantiomer of the magnesium salt and the 40

powder diffractogram, but may also be characterized by(—)-enantiomer of the magnesium salt were also found to conventional FT-IR spectroscopy. These characteristics arehave R and S configuration, respectively. The conditions for not exhibited by any other form of magnesium salt ofthe optical rotation measurement for each of these enanti- S-omeprazole and accordingly, the magnesium salt ofomers are described in WO 94/27988.

45 S-omeprazole trihydrate is easily distinguishable from anyCertain salts of single enantiomers of omeprazole and other crystal form of the magnesium salt of S-omeprazole

their preparation are disclosed in WO 94/27988. These disclosed in prior art. The compound of the invention iscompounds have improved pharmacokinetic and metabolic characterized by being highly crystalline, i.e. having a

properties which will give an improved therapeutic profile higher crystallinity than any other form of magnesium salt ofsuch as a lower degree of interindividual variation.

50 S-omeprazole disclosed in the prior art. With the expressionWO 96/02535 discloses a process for the preparation of "any other form" is meant anhydrates, hydrates, solvates,

the single enantiomers of omeprazole and salts thereof, and and polymorphs or amorphous forms thereof disclosed in theWO 96/01623 discloses a suitable tableted dosage forms of prior art. Examples of any other forms of magnesium salt offor instance magnesium salts of R- and S-omeprazole. S-omeprazole includes, but are not limited to, anhydrates,

monohydrates, dihydrates, sesquihydrates, trihydrates,BRIEF DESCRIPTION OF THE DRAWINGS 55alcoholates, such as methanolates and ethanolates, and poly-

FIG. 1 shows a X-ray powder diffractogram of the mag- morphs or amorphous forms thereof.nesium salt of S-omeprazole trihydrate prepared according The compound of the invention may also be characterizedto the present invention, by its unit cell.

FIG. 2 shows a X-ray powder diffractogram of the potas- 60 In a further aspect, the present invention provides pro-sium salt of S-omeprazole prepared and used in the present cesses for the preparation of the magnesium salt ofapplication (See examples 2 and 3) S-omeprazole trihydrate which comprises;

FIG. 3 shows a X-ray powder diffractogram of a magne- a) treating a magnesium salt of S-omeprazole of any form,sium salt of S-omeprazole dihyclrate prepared and used in for example prepared according to procedures knownthe present application (See example 5) 65 in the art such as Example A in WO 96/01623 which is

FIG. 4 shows a X-ray powder diffractogram of a magne- incorporated herein by reference, with water at a suit-sium salt of S-omeprazole dihyclrate which is a polymorph able temperature for a suitable time. By a suitable


US 6,369,085 B1

3 4temperature is meant a temperature which induces the pound of the invention may also be used in patients intransformation of starting material to product without intensive care situations, in patients with acute upper gas-decomposing any of these compounds. Examples of trointestinal bleeding, pre- and postoperatively to preventsuch suitable temperatures include, but are not limited aspiration of gastric acid and to prevent and treat stress

to, room temperature and above. By a suitable time is 5 ulceration. Further, the compound of the invention may bemeant a time that results in high conversion of the useful in the treatment of psoriasis as well as in the treatment

starting material into product without causing any of Helicobacter infections and diseases related to these. The

decomposition of either compounds, i.e. results in a compound of the invention may also be used for treatment

good yield. This suitable time will vary depending onof inflammatory conditions in mammals, including man.

Athe temperature used in a way well known to people in 10ny suitable route of administration may be employed for

the art. The higher the temperaturethe shorter time is providing the patient with an effective dosage of the mag-nesium salt of S-omeprazole trihydrate, according to theneeded to give the desired conversion. The amount ofinvention. For example, peroral or parental formulations and

water is not crucial and will depend on the process the like may be employed. Dosage forms include capsules,conditions used. The magnesium salt of S-omeprazole tablets, dispersions, suspensions and the like.trihydrate is thereafter separated from the aqueous is It is further provided a pharmaceutical composition com-

slurry, for example by filtration or centrifugation and prising the magnesium salt of S-omeprazole trihydratethereafter dried to constant weight; or according to the invention, as active ingredient, in associa-

b) oxidizing 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- tion with a pharmaceutically acceptable carrier, diluent or

pyridinyl)methyl]thio]-1H-benzimidazole, with an oxi- excipient and optionally other therapeutic ingredients. Com-

dizing agent and a chiral titanium complex, optionally 20 positions comprising other therapeutic ingredients are espe-in the presence of a base. The oxidation is carried out cially of interest in the treatment of Helicobacter infections.in an organic solvent, for example toluene or dichl- The invention also provides the use of the magnesium salt ofromethane. S-omeprazole trihydrate of the invention in the manufacture

The crude product is converted to the corresponding of a medicament for use in the treatment of a gastric-acidpotassium salt by treatment with a potassium source, such as 25 related condition and a method of treating a gastric-acidmethanolic potassium hydroxide or methanolic potassium related condition which method comprises administering to

methylate, followed by isolation of the formed salt. a subject suffering from said condition a therapeuticallyThe resulting potassium salt of S-omeprazole is thereafter effective amount of the magnesium salt of S-omeprazole

converted to the corresponding magnesium salt by treatment trihydrate according to the invention.with a magnesium source, such as magnesium sulfate in a 30 The compositions of the invention include compositionslower alcohol, such as methanol. The solution is optionally suitable for peroral or parental administration. The most

filtered and the precipitation is initialized by addition of a preferred route is the oral route. The compositions may benon-solvent such as acetone. The product is filtered off and conveniently presented in unit dosage forms, and preparedoptionally washed with water and further processed as is by any methods known in the art of pharmacy.described in a) above. Alternatively, the potassium salt may 35 In the practice of the invention, the most suitable route ofbe treated with a magnesium source, such as magnesium administration as well as the magnitude of a therapeutic dosesulfate in water, and isolation of the magnesium salt of of the magnesium salt of S-omeprazole trihydrate accordingS-omeprazole trihydrate, or any other conventional tech- to the invention in any given case will depend on the nature

nique for transforming a potassium salt to the corresponding and severity of the disease to be treated. The dose, and dose

magnesium salt can be used and is within the scope of the 40 frequency, may also vary according to the age, body weight,present invention, and response of the individual patient. Special requirements

Yet a further aspect of the present invention is to provide may be needed for patients having Zollinger-Ellisona suitable intermediate used in the preparation of the com- syndrome, such as a need for higher doses than the averagepound of the invention, as well as a process for its prepa- patient. Children and patients with liver diseases generallyration. The potassium salt of S-omeprazole is found to be 45 will benefit from doses that are somewhat lower than thesuch a suitable intermediate. The potassium salt of average. Thus, in some conditions it may be necessary to use

S-omeprazole may also be used as an active component of doses outside the ranges stated below, for example long term

a pharmaceutical formulation to be used in the treatment of treatments may request lower dosage. Such higher and lower

gastrointestinal diseases. doses are within the scope of the present invention. SuchThe compound of the invention, i.e. the magnesium salt of 50 daily doses may vary between 5 mg to 300 mg.

S-omeprazole trihydrate, prepared according to the present In general, a suitable oral dosage form of the compoundinvention may be analyzed by XRPD, a technique which is of the invention may cover a dose range from 5 mg to 300known per se. mg total daily dose, administered in one single dose or

The amount of water in the magnesium salt of equally divided doses. A preferred dosage range is from 10

S-omeprazole trihydrate is determined by thermogravimet- 55 mg to 80 mg.ric analysis, a technique which is known per se. The compound of the invention may be combined as the

The compound of the invention is effective as a gastric active component in intimate admixture with a pharmaceu-acid secretion inhibitor, and is useful as an antiulcer agent. tical carrier according to conventional techniques, such as

In a more general sense, it can be used for prevention and the oral formulations described in WO 96/01623 and EP 247treatment of gastric-acid related conditions in mammals and 60 983, the disclosures of which are hereby incorporated as a

especially in man, including e.g. reflux esophagitis, gastritis, whole by reference.duodenitis, gastric ulcer and duodenal ulcer. Furthermore, it Combination preparations comprising the magnesium salt

may be used for treatment of other gastrointestinal disorders of S-omeprazole trihydrate and other active ingredients maywhere gastric acid inhibitory effect is desirable e.g. in also be used. Examples of such active ingredients include,patients on NSAID therapy, in patients with Non Ulcer 65 but are not limited to anti-bacterial compounds, non-

Dyspepsia, in patients with symptomatic gastro-esophageal steroidal anti-inflammatory agents, antacid agents, alginatesreflux disease, and in patients with gastrinomas. The com- and prokinetic agents.


US 6,369,085 B1

5 6The examples which follow will further illustrate the (0.05 ml, 2,8 mmol) and D-(-)-diethyl tartrate (2.02 g, 9.82

preparation of the compound of the invention, according to mmol) were added. The reaction mixture was stirred for 20different process routes and including new intermediates. minutes. Titanium(IV)isopropoxide (1.34 g, 4.68 mmol) was

These examples are not intended to limit the scope of the added and the reaction mixture was stirred for 45 minutes.invention as defined hereinabove or as claimed below. 5 The mixture was cooled to 30° C. and diisopropylethy-

lamine (0.91 g, 7.01 mmol) was added followed by cumene

EXAMPLES hydroperoxide (9.52 g, 51.89 mmol). The resultant mixturewas stirred at 30° C. for 3 hours. Methanol (40 ml) was

Example 1 added followed by potassium hydroxide (3.05 g, 46.8 mmol)S-5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2-pyridiny1)- 10 in methanol (30 ml). Seed crystals were added and themethyl]sulfiny1]-1H-benzimidazole magnesium salt trihy- reaction mixture was stirred at 35° C. overnight. The pre-drate cipitated product was filtered off, washed with methanol and

Water (157 kg) was added to the wet crystals of the toluene and dried in vacuo. Yield: 9.74 g (54%).magnesium salt of S-omeprazole, prepared according to

Example 4, below. The mixture was heated to 38° C. with is Example 3stirring and left for 3 hours. The crystals were filtered off and S-5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2-pyridiny1)-dried in vacuo. Yield: 31.6 kg methyl]sulfiny1]-1H-benzimidazole potassium salt

X-ray powder diffraction analysis was performed on a

sample of the crystals prepared above according to standardWater (157.6 gl) was added to a solution of 5-methoxy-

24(4-methoxy-3,5-dimethy1-2-pyridinyl)methyl]thio]-1H-methods, which can be found in e.g. Kitaigorodsky, A. I. 20 benzimidazole in toluene (370 ml; 211.5 g/l) with a water(1973), Molecular Crystals and Molecules, Academic Press

content of 0.031% (w/w), followed by addition of D-(-)-New York; Bunn, C. W. (1948), Chemical Crystallography, diethyl tartrate (8.55 ml). The solution was heated to 50° C.Clarendon Press, London; or Klug, H. P. & Alexander, L. E.

and stirred at this temperature for 20 minutes. Titanium(IV)(1974), X-Ray Diffraction Procedures, John Wiley and Sons, isopropoxide (7.15 ml) was added and reaction was left atNew York. The analysis gave the diffractogram depicted in 25 50° C. for 45 minutes. The temperature was lowered to 30°FIG. 1. The main peaks, with positions and relativeintensities, have been extracted from the diffractogram in

C. and diisopropylethylamine (6.2 ml) was added. Cumene

hydroperoxide was added at an appropriate speed to main-FIG. 1 and is given below in table 1. The relative intensities

n the temperature from 28° C. to 34° C. The temperatureare less reliable and instead of numerical values the follow- laiwas raised to 35° C. after 2 hours and potassium methoxideing definitions are used. 30 (24.55 g) in methanol (222 ml) was added. The mixture was

filtered after 14 hours and the crystals were washed withmethanol:toluene (240 ml; 1:1) and methanol (120 ml) and

Relative Intensity Definition dried. Yield: 79 g (74%), ee>99.9%. [av0=+28.7° (c=1%,water); Assay: 89% is S-5-methoxy-2-[[(4-methoxy-3,5-

25-100 vs (very strong) 35 dimethy1-2-pyridiny1)-methyl]sulfiny1]-1H-benzimidazole10-25 s (strong)3-10 m (medium) potassium salt (11% is methanol).1-3 w (weak) 1H-NMR (200 MHz, DMSO-d6, 8 ppm): 2.23 (s, 3H),<1 vw (very weak) 2.24 (s, 3H), 3.71 (s, 3H), 3.75 (s 3H), 4.40 (d, 1H), 4.78 (d,

1H), 6.58 (dd, 1H), 7.00 (d, 1H), 7.35 (d, 1H), 8.25 (s, 1H.40

Some additional very weak peaks found in the diffractogram The products from Examples 2 and 3 were analysed usinghave been omitted from table 1. X-ray powder diffraction as described in Example 1 and

gave the diffractogram depicted in FIG. 2 and given below

TABLE 1 inTable 2. Some additional very weak peaks found in the

Positions and intensities of the major peaks in the XRP-diffractogram of 45diffractogram have been omitted from Table 2.

the magnesium salt of S-omeprazole trihydrate.

d-value A Relative Intensity TABLE 2

2.67 m Positions and intensities of the major peaks in the XRP-diffractogram of2.79 m 50 the potassium salt of S-omeprazole.3.27 m

3.52 s. Relative d-value/ Relative3.82 s d-value/A intensity (A) intensity3.96 vs

4.14 m 13.6 vs 3.52 m

5.2 m 55 10.6 vw 3.42 w

5.6 m 7.8 m 3.38 w

6.7 vs 6.8 m 3.34 m

6.9 s 6.5 m 3.28 w

8.3 w 6.2 w 3.20 m

16.6 vs 6.1 m 3.12 w

605.8 s 3.06 w

5.4 m 3.03 w

5.3 w 2.97 w al 1.54060 AExample 2 5.2 w 2.93 vw

S-5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2-pyridinyl) 5.0 vw 2.89 w

4.75 m 2.85 m

methyl]sulfiny1]-1H-benzimidazole potassium salt4.71 w 2.76 w

A solution of 5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2- 65 4.52 w 2.71 vw

pyridinyl)methyl]thio]-1H-benzimidazole (15.4 g, 46.8 4.42 w 2.66 vw

mmol) in toluene (70 ml) was heated to 50° C. and water


US 6,369,085 B1

7 8

TABLE 2-continued TABLE 3-continued

Positions and intensities of the major peaks in the XRP-diffractogram of Positions and intensities of the major peaks in the XRP-diffractogram ofthe potassium salt of S-omeprazole. the magnesium salt of S-omeprazole dihydrate, Form B.

5

Relative d-value/ Relative d-value/A Relative Intensityd-value/A intensity (A) intensity

8.1 s

4.32 w 2.58 w 11.0 m

4.27 m 2.57 w 11.8 m

3.98 vw 2.56 w 10 14.9 vs

3.92 w 2.52 vw

3.89 w 2.47 vw

3.87 w 2.45 vw Convertion of magnesium salt of S-omeprazole dihydrate to3.81 w 2.43 vw trihydrate3.74 m 2.40 vw This material was subsequently processed to S-5-3.60 m 2.38 vw 15 methoxy-2-[[(4-methoxy-3, 5-dimethy1-2-pyridiny1)-3.55 m 2.31 vw

methyl]sulfiny1]-1H-benzimidazole magnesium salt trihy-drate according to the procedure described for the moistsubstance in Example 1.

Example 4Example 6

S-5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2-pyridiny1)- 20 S-5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2-pyridiny1)-methyl]sulfinyl]-1H-benzimidazole magnesium saltmethyl]sulfiny1]-1H-benzimidazole magnesium salt dihy-Methanol (148 kg) was added to S-5-methoxy-2-[[(4- drate

methoxy-3,5-dimethy1-2-pyridiny1)-methyl]sulfinyl]-1H- A methanolic solution of S-5-methoxy-2-[[(4-methoxy-3,benzimidazole potassium salt (71 kg, methanol content= 5 -dimethy1-2 -pyridiny1)-methyl]sulfiny1]-1H-13%). MgSO4x7 H20 (40 kg) was added to the mixture 25 benzimidazole magnesium salt was prepared as is describedwhile stirring. After 70 minutes the mixture was filtered and in Example 4. Such a solution of S-5-methoxy-2-[[(4-the filtrate was washed with methanol (46 kg). The solution methoxy-3,5-dimethy1-2-pyridiny1)-methyl]sulfinyl]-1H-was concentrated to a volume of 100 liter, acetone (253 kg) benzimidazole magnesium salt (1.86 g) in 5 ml methanolwas added and the resulting mixture was left for 4 hours. The was concentrated by evaporation until 1.58 ml methanolprecipitated product was filtered off, washed with acetone 30 remained. Then, a mixture of 1.6 ml water and 6.32 mland water. The wet crystals were immediately used as is aceton was added. The solution was allowed to crystallizedescribed in Example 1. during 26 h at room temperature. The resulting crystals were

filtered off and dried at 400 C. under reduced pressure givingExample 5 1.17 g of S-5-methoxy-24(4-methoxy-3,5-dimethy1-2-

S-5-methoxy-24(4-methoxy-3,5-dimethyl-2-pyridiny1)- 35 pyridiny1)-methyl]sulfiny1]-1H-benzimidazole magnesiummethyl]sulfiny1]-1H-benzimidazole magnesium salt dihy- salt dihydrate, named form A.drate The product was analyzed using X-ray powder diffration

5.0 g of the moist product from Example 4 with an as described in Example 1 and gave the diffractogramapproximate dry content of 74%, was dried in vacuum at 35° depicted in FIG. 4 and given below in Table 4. SomeC. over night to yield 3.58 g (2.68 mmol) of 5-5-methoxy- 40 additional peaks with low intensities found in the diffracto-24(4-methoxy-3,5-dimethy1-2-pyridiny1)-methyl]sulfinyl]- gram have been omitted from Table 4.1H-benzimidazole magnesium salt dihydrate, named FormB. TABLE 4

The product was analyzed using X-ray powder diffractionas described in Example 1, and the analyze gave the dif- 45 Positions and intensities of the major peaks in the XRP-diffractogram of

the magnesium salt of S-omeprazole dihydrate, Form A.fractogram depicted in FIG. 3 and given below in Table 3.Some additional peaks with low intensities found in the d-value/A Relative Intensitydiffractogram have been omitted from Table 3.

3.04 s

3.14 sTABLE 3 50 3.18 m

4.05 s

Positions and intensities of the major peaks in the XRP-diffractogram of 4.19 s

the magnesium salt of S-omeprazole dihydrate, Form B. 4.32 m

4.54 s

d-value/A Relative Intensity 4.69 vs

55 5.2 s4.19 m

5.3 s4.45 m

5.8 s4.68 m

6.2 vs4.79 s

6.6 s4.91 s 15.5 vs4.98 s

605.1 m

5.4 s

5.5 m Example 75.6 m S-5-methoxy-24(4-methoxy-3,5-dimethy1-2-pyridiny1)-5.8 m

methyl]sulfiny1]-1H-benzimidazole magnesium salt trihy-6.3 m

6.7 s 65 drate7.9 m 22,0 g (29,1 mmol) of S-5-methoxy-2-[[(4-methoxy-3,5-

dimethy1-2-pyridinyHmethyl]sulfinylPH-benzimidazole


US 6,369,085 B1

9 10potassium salt was dissolved in 40 mL of water. The solutionwas seeded with 0,11 g (0,1 mmol) S-5-methoxy-2-[[(4- TABLE 5-continuedmethoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole magnesium salt trihydrate. 22 mL (69,6 Positions and intensities of the major peaks in the XRP-diffractogram

mmol) of MgSO4 (aq) was added under a 3 h period. The 5shown in FIG. 5.

slurry was filtered off and the precipitate was elutriated in d-value/A Relative Intensitywater for approximately 30 minutes and the crystals were

filtered off and dried (35° C., vacuum). 6.8

Yield: 9,15 g (11,6 mmol; 80%). The substance had a7.88.4 vs

purity (HPLC):99,8 area Mg content: 3,40% (w/w) and io 10.8

ee: 99,8%. 12.2

The product was analyzed using X-ray powder diffraction 15.1 vs

and the result complies with s FIG. 1 and Table 1.

WReference Example A hat is claimed is:15 1. The magnesium salt of S-omeprazole trihydrate,S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-

methyl]sulfinyl]-1H-benzimidazole magnesium salt wherein the compound is characterized by the following(The method used is in accordance with the method major peaks in its X-ray diffractogram:

described in Example A in WO 96/01623)Magnesium (0.11 g, 4.5 mmol) was dissolved and reacted

20with methanol (50 ml) at 40° C. with a catalytic amount of d-value A Relative Intensitymethylene chloride. The reaction was run under nitrogen andwas finished after five hours. At room temperature a mixture 2.67

of the two enantiomers [90%(-)-isomer and 10%(+)-isomer] 2.79

of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) 3.273.52

methyl]sulfinyl]-1H-benzimidazole (2.84 g, 8.2 mmol) was25

3.82added to the magnesium methoxide solution. The mixture 3.96 vs

was stirred for 12 hours whereupon a small amount of water 4.14

(0.1 ml) was added in order to precipitate inorganic mag- 5.2

nesium salts. After 30 minutes stirring, these inorganic salts 5.6

were filtered off and the solution was concentrated on a 306.7 vs

6.9rotavapor. The residue was now a concentrated methanolic 8.3solution of the enantiomeric mixture (i.e. the title compound 16.6 vs

contaminated with the (+)-isomer), with an optical purity(enantiomeric excess, e.e.) of 80%. This mixture was dilutedwith acetone (100 ml) and after stirring at room temperature

2. The magnesium salt of S-omeprazole trihydrate accord-35

for 15 minutes, a white precipitate was obtained. Additional ing to claim 1, wherein the compound is in a highlystirring for 15 minutes and thereafter filtration afforded 1.3 crystalline form.

g (50%) of the title compound as white crystals. Chiral 3. The magnesium salt of S-omeprazole trihydrate accord-ianalyses of the crystals and mother liquor were performed ng to claim 1, wherein the compound is in a stable form.

by chromatography on an analytical chiral column. The 4. A process for the preparation of the magnesium salt of4

optical purity of the crystals and mother liquor was found to0 S-omeprazole trihydrate according to any of claims 1, 2 or

be 98.4 e.e. and 64.4% e.e., respectively. Thus, the optical 3 which comprises treating a magnesium salt of

purity (ee.) has been enhanced from 80% to 98.4% simply S-omeprazole any other form with water.

by crystallizing the Mg-salt from a mixture of acetone and 5. A process for the preparation of the magnesium salt of

methanol. The product was crystalline as shown by powder S-omeprazole trihydrate according to any of claims 1, 2 or

X-ray diffraction and the magnesium content was 3.44% as45 3 which comprises the following steps:

shown by atomic absorption spectroscopy. [a]D20=-131.50 a) mixing a potassium salt of S-omeprazole with an

(c=0.5%, methanol). organic solvent;The product was analyzed using X-ray powder diffraction b) converting the potassium salt of S-omeprazole into a

as described in Example 1 and gave the diffractogramdepicted in FIG. 5 and given below in Table 5. Some 50 corresponding magnesium salt of S-omeprazole byadditional very weak peaks found in the diffractograms have treating the potassium salt with a magnesium source;

been omitted from Table 5. c) precipitating the magnesium salt of S-omeprazole byaddition of a non-solvent;

TABLE 5 d) isolating the obtained magnesium salt of S-omeprazole;55 e) treating the obtained magnesium salt of S-omeprazolePositions and intensities of the major peaks in the XRP-diffractogram

shown in FIG. 5. with water, and

f) isolating and drying the obtained magnesium salt ofd-value/A Relative Intensity S-omeprazole trihydrate.

2.90 6. The process according to claim 5, wherein the organic3.41

60 solvent of step a) is methanol.3.90 s 7. The process according to claim 5, wherein the non-4.13 solvent of step c) is acetone.4.79 vs

5.00 vs8. The process according to claim 5 wherein steps a) to e)

5.4 vsare replaced by the following single step: converting the

5.7 65 potassium salt of S-omeprazole into a corresponding mag-6.3 s nesium salt of S-omeprazole by treating the potassium salt

with a magnesium source in water.


US 6,369,085 B111 12

9. The process according to claim 5, wherein the magne- 12. A method of treating a gastric acid related conditionsium source is magnesium sulfate. which method comprises administering to a subject suffering

10. The process according to claim 8, wherein the mag- from said condition a therapeutically effective amount of thenesium source is magnesium sulfate.

magnesium salt of S-omeprazole trihydrate according to any11. A pharmaceutical composition comprising the mag- 5nesium salt of S-omeprazole trihydrate according to any of of claims 1, 2 or 3.

claims 1, 2 or 3 as active ingredient and a pharmaceuticallyacceptable carrier.

Case 3:16-cv-01682-MLC-TJB Document 1-3 Filed 03/24/16 Page 14 of 14 PapelD: 33UNITED STATES PATENT AND TRADEMARK OFFICE

CERTIFICATE OF CORRECTION

PATENT NO.: 6,369,085 B1 Page 1 of 1DATED: April 9, 2002

INVENTOR(S): Cotton et al.

It is certified that error appears in the above-identified patent and that said Letters Patent ishereby corrected as shown below:

Title page,Item [22] PCT Filed, delete "May 5, 1998" and insert therefor May 25, 1998

Column 10,Line 42, insert of after "S-omeprazole".

Signed and Sealed this

JAMES E. ROGANDirector of the United States Patent and Trademark Office

A

Eighth Day of April, 2003


EXHIBIT B

Case 3:16-cv-01682-MLC-TJB Document11111111111111111111111211111111111111111 35

US007411070B2

(12) United States Patent (10) Patent No.: US 7,411,070 B2Cotton et al. (45) Date of Patent: *Aug. 12, 2008

(54) FORM OF S-OMEPRAZOLE EP 0247983 12/1987EP WO 95/01977 1/1995

(75) Inventors: Hanna Cotton, Södertälje (SE); Anders IN 1344/DEL/98 5/1998

Kronström, Södertälje (SE); Anders WO 9427988 12/1994

Mattson, Södertälje (SE); Eva Möller, WO 9501977 1/1995

Södertälje (SE) WO 9601623 1/1996WO 9602535 2/1996

(73) Assignee: AstraZeneca AB, Sodertalje (SE)OTHER PUBLICATIONS

Notice: Subject to any disclaimer, the term of this

patent is extended or adjusted under 35 Japanese Chemical Society, Experimental Chemical Seminar. vol.U.S.C. 154(b) by 0 days. 18. p. 55 (translation), 1958.*

An Introduction to Crystal Chemistry by Evans Cambridge At theThis patent is subject to a terminal dis- Univ. Press, 1914.*

claimer. Erlandsson, P. Et al., "Resolution of the enantiomers of omeprazoleand some of its analogues by liquid chromatography on a

(21) Appl. No.: 10/672,936 trisphenylcarbamoyl cellulose-based stationary phase", Journal of

Chromatography, 532 (1990) 305-319.

(22) Filed: Sep. 25, 2003 von Unge, S. et al. "Stereochemical assignment ofthe enantiomers of

omeprazole fromX-ray analysis ofa fenchyloxylmethyl derivative of

(65) Prior Publication Data (+)-(R)-omeprazole", Tetrahedron Asymmetry, vol. 8, No. 12, pp.1967-1970 (1997).

US 2005/0075369 Al Apr. 7, 2005 An Introduction to Crystal Chemistry by Evans Cambridge at theUniv. Press, 1964.

Related U.S. Application Data Opposition filed by Ranbaxy Laboratories Limited against IndianPatent Application No. 1344/DEL/98.

(60) Continuation of application No. 10/076,711, filed on Opposition filed by Torrent Pharmaceuticals Limited against IndianFeb. 14, 2002, now Pat. No. 6, 677,455, which is a Patent Application No. 1344/DEL/98.division of application No. 09/077,719, filed as appli- X-ray powder diffraction pattern of Mg-salt of S-omeprazolecation No. PCT/5E98/00974 on May 25, 1998, now trihydrate depicted by Torrent obtained by method ofWO 94/27988.Pat. No. 6,369,085. NDA 21-153/S-020 for Nexium® (esomeprazole magnesium)

Delayed Release Capsule.(30) Foreign Application Priority Data NDA 21-153/21-154 entitled "Medical Review(s)".

May 30, 1997 (SE) 9702065 Statement with Exhibits A-C on Behalf ofthe Applicant, AstraZeneca

AB, to the Opposition filedby Ranbaxy Laboratories Limited against

(51) Int. Cl.Indian Patent Application No. 1344/DEL/98.Statement with Exhibits A-D on Behalf of the Applicant,CO7D 401/12 (2006.01) AstraZeneca AB, to the Opposition filed by Torrent Pharmaceuticals

A61K 31/4439 (2006.01) Limited against Indian Patent Application No. 1344/DEL/98.(52) U.S. Cl. 546/273.7; 514/338 Decision of the Pre-grant Opposition filed by Ranbaxy Laboratories

(58) Field of Classification Search 514/338; Limited against Indian Patent Application No. 1344/DEL/98.546/273.7 Decision of the Pre-grant Opposition filed by Torrent Pharmaceuti-

See application file for complete search history. cals Limited against Indian Patent Application No. 1344/DEL/98.Notice of Allegation, dated Nov. 13, 2007, pursuant to the Patented

(56) References Cited Medicines (Notice ofCompliance) Regulations with respect to Cana-dian Letters Patent No. 2, 290,963.

U.S. PATENT DOCUMENTS

4,255,431 A 3/1981 Junggren et al. 424/263 cited by examiner

4,738,974 A 4/1988 Brandstrom 514/338 Primary Examiner Charanjit S Aulakh4,786,505 A 11/1988 Lovgren et al. 424/468

5, 530, 160 A 6/1996 Nore et al. 562/571 (74) Attorney, Agent, or Firm White & Case LLP

5,676,884 A 10/1997 Tiers et al. 252/582f„,

5,690,960 A 11/1997 Bengtsson et al. 514/338 ABSTRACT

5,693,818 A 12/1997 Vion Unge 514/338

5,714,504 A 2/1998 Lindberg et al. 514/338 The present invention relates to a novel form of the5, 817,338 A 10/1998 Bergstrand et al. 424/468

enantiomer of 5-methoxy-2[[(4-methoxy-3, 5-dimethy1-2-5, 877, 192 A 3/1999 Lindberg et al. 514/338

5,900,424 A 5/1999 Källström et al. 514/338 pyridinyl)-methyl]sulfinyl]-1H-benzimidazole, i.e. 5-ome-

6,369,085 B1 4/2002 Cotton et al. 514/338 prazole. More specifically, it relates to a novel form of the

6,677,455 B2 1/2004 Kronstrom et al. magnesium salt of the S-enantiomer of omeprazole trihy-6,747, 155 B2 6/2004 Kronstrom et al. drate. The present invention also relates to processes for pre-

paring such a form of the magnesium salt of S-omeprazoleFOREIGN PATENT DOCUMENTS and pharmaceutical compositions containing it. Furthermore,

CN 1136564 11/1996 the present invention also relates to new intermediates used in

DE 4 035 455 5/1992 the process.

EP 0005129 10/1979EP 0124495 11/1984 4 Claims, 5 Drawing Sheets


U.S. Patent Aug. 12, 2008 Sheet 1 of 5 US 7,411,070 B2

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US 7,411,070 B22

FORM OF S-OMEPRAZOLE FIG. 3 shows a X-ray powder diffractogram of a magne-sium salt ofS-omeprazole dihydrate prepared and used in the

This application is a continuation of U.S. patent applica- present application (See example 5)tion Ser. No. 10/076,711, filed Feb. 14, 2002, now U.S. Pat. FIG. 4 shows a X-ray powder diffractogram of a magne-No. 6, 667,455 which is a divisional ofU.S. patent application 5 sium salt ofS-omeprazole dihydrate which is a polymorph ofSer. No. 09/077,719, filed Jun. 8, 1998, now U.S. Pat. No. the dihydrate shown in FIG. 3 (See Example 6). This magne-6,369,085, which was the National Stage of International sium salt of S-omeprazole dihydrate has been prepared andApplication No. PCT/5E98/00974, filed May 25, 1998. can be used in the preparation of the magnesium salt of

S-omeprazole trihydrate according to the present invention.FIELD OF THE INVENTION

10 FIG. 5 shows X-ray powder diffractogram of the magne-sium salt of S-omeprazole prepared according to example A

The present invention relates to a novel form of thein WO 96/01623.

enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2-pyridiny1)-methyl]sulfinyl]-1H-benzimidazole, i.e. S-ome-

DESCRIPTION OF THE INVENTIONprazole. More specifically, it relates to a novel form of the

15magnesium salt of the S-enantiomer of omeprazole trihy- It has surprisingly been found that the magnesium salt ofdrate. The present invention also relates to processes for pre-paring such a form of the magnesium salt of S-omeprazole S-omeprazole occurs in a number of structurally different

forms. It is an object of the present invention to provide aand pharmaceutical compositions containing it. Furthermore,substantially pure magnesium salt of S-omeprazole trihy-the present invention also relates to intermediates used in the

20 drate, hereinafter referred to as the compound of the inven-process, and their preparation. tion. This trihydrate can be obtained as a well defined com-

BACKGROUND OF THE INVENTION AND pound. The present invention also provides a process to

PRIOR ART obtain and a method ofdifferentiating the magnesium salt of

S-omeprazole trihydrate from other forms of magnesiumThe compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl- 25 salts of S-omeprazole.

2-pyridinyl)methyl]sulfiny1]-1H-benzimidazole, having the The compound ofthe invention is advantageous because itgeneric name omeprazole, and therapeutically acceptable is more stable than the corresponding magnesium salt com-

salts thereof, are described in EP 5129. The specific alkaline pounds in prior art and is therefore easier to handle and store.salts of omeprazole are disclosed in EP 124 495. Omeprazole The compound of the invention is also easier to characterizeis a proton pump inhibitor, i.e. effective in inhibiting gastric 30 because it exists in a well defined state. Additionally, theacid secretion, and is useful as an antiulcer agent. In a more compound of the invention is easier to synthesize in a repro-general sense, omeprazole may be used for prevention and ducible manner and thereby easier to handle in a full scaletreatment of gastric-acid related diseases in mammals and production.especially in man. The magnesium salt of S-omeprazole trihydrate obtained

Omeprazole is a sulfoxide and a chiral compound, wherein 35according to the present invention is substantially free from

the sulfur atom being the stereogenic center. Thus, omepra- magnesium salts of R-omeprazole. The magnesium salt ofzole is a racemic mixture of its two single enantiomers, the R S-omeprazole trihydrate obtained according to the presentand S-enantiomer of omeprazole, herein referred to as invention is also substantially free from other forms ofmag-R-omeprazole and S-omeprazole. The absolute configura- nesium salts of S-omeprazole, such as the correspondingtions ofthe enantiomers ofomeprazole have been determined 40

magnesium salt compounds described in prior art, and dihy-by an X-ray study of an N-alkylated derivative of the drates used in the preparation of the trihydrate compoundenantiomer in non-salt form. The (+)-enantiomer of the non- according to the present invention.salt form and the (—)-enantiomer of the non-salt form were The compound of the invention is characterized by thefound to have R and S configuration, respectively, and the

45 positions and intensities of the major peaks in the X-ray(+)-enantiomer ofthe magnesium salt and the (—)-enantiomer powder diffractogram, but may also be characterized by con-of the magnesium salt were also found to have R and S ventional FT-IR spectroscopy. These characteristics are notconfiguration, respectively. The conditions for the optical exhibited by any other form ofmagnesium salt of S-omepra-rotation measurement for each of these enantiomers are zole and accordingly, the magnesium salt of S-omeprazoledescribed in WO 94/27988.

50 trihydrate is easily distinguishable from any other crystalCertain salts of single enantiomers ofomeprazole and their form of the magnesium salt of S-omeprazole disclosed in

preparation are disclosed in WO 94/27988. These compounds prior art. The compound of the invention is characterized byhave improved pharmacokinetic and metabolic properties being highly crystalline, i.e. having a higher crystallinity thanwhich will give an improved therapeutic profile such as a

any other form ofmagnesium salt ofS-omeprazole disclosedlower degree of interindividual variation.

55 in the prior art. With the expression "any other form" is meantWO 96/02535 discloses a process for the preparation ofthe anhydrates, hydrates, solvates, and polymorphs or amor-

single enantiomers of omeprazole and salts thereof, and WO phous forms thereof disclosed in the prior art. Examples of96/01623 discloses a suitable tableted dosage forms of for

any other forms ofmagnesium salt ofS-omeprazole includes,instance magnesium salts of R- and S-omeprazole. but are not limited to, anhydrates, monohydrates, dihydrates,

BRIEF DESCRIPTION OF THE DRAWINGS 60 sesquihydrates, trihydrates, alcoholates, such as methano-lates and ethanolates, and polymorphs or amorphous formsthereof.FIG. 1 shows a X-ray powder diffractogram of the magne-

sium salt of S-omeprazole trihydrate prepared according to The compound of the invention may also be characterized

the present invention, by its unit cell.

FIG. 2 shows a X-ray powder diffractogram of the potas- 65 In a further aspect, the present invention provides pro-sium salt of S-omeprazole prepared and used in the present cesses for the preparation of the magnesium salt of S-ome-

application (See examples 2 and 3) prazole trihydrate which comprises;


US 7,411,070 B2

3 4a) treating a magnesium salt of S-omeprazole of any form, where gastric acid inhibitory effect is desirable e.g. in patients

for example prepared according is to procedures known on NSAID therapy, in patients with Non Ulcer Dyspepsia, inin the art such as Example A in WO 96/01623 which is patients with symptomatic gastro-esophageal reflux disease,incorporated hereinby reference, with water at a suitable and in patients with gastrinomas. The compound ofthe inven-

temperature for a suitable time. By a suitable tempera- 5 tion may also be used in patients in intensive care situations,ture is meant a temperature which induces the transfor- in patients with acute upper gastrointestinal bleeding, pre-mation of starting material to product without decom- and postoperatively to prevent aspiration ofgastric acid and to

posing any of these compounds. Examples of such prevent and treat stress ulceration. Further, the compound ofsuitable temperatures include, but are not limited to, the invention may be useful in the treatment of psoriasis as

room temperature and above. By a suitable time is meant io well as in the treatment of Helicobacter infections and dis-a time that results in high conversion of the starting eases related to these. The compound of the invention maymaterial into product without causing any decomposi- also be used for treatment of inflammatory conditions intion of either compounds, i.e. results in a good yield, mammals, including man.

This suitable time will vary depending on the tempera- Any suitable route ofadministration may be employed forture used in a way well known to people in the art. The 15 providing the patient with an effective dosage of the magne-higher the temperature, the shorter time is needed to give sium salt of S-omeprazole trihydrate, according to the inven-the desired conversion. The amount of water is not cm- tion. For example, peroral or parental formulations and thecial and will depend on the process conditions used. The like may be employed. Dosage forms include capsules, tab-magnesium salt of S-omeprazole trihydrate is thereafter lets, dispersions, suspensions and the like.separated from the aqueous slurry, for example by fil- 20 It is further provided a pharmaceutical composition com-tration or centrifugation and thereafter dried to constant prising the magnesium salt of S-omeprazole trihydrateweight; or according to the invention, as active ingredient, in association

b) oxidizing 5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2- with a pharmaceutically acceptable carrier, diluent or excipi-pyridinyl)methyl]thio]-1H-benzimidazole, with an oxi- ent and optionally other therapeutic ingredients. Composi-dizing agent and a chiral titanium complex, optionally in 25 tions comprising other therapeutic ingredients are especiallythe presence of a base. The oxidation is carried out in an of interest in the treatment of Helicobacter infections. Theorganic solvent, for example toluene or dichlo- invention also provides the use of the magnesium salt ofromethane. S-omeprazole trihydrate of the invention in the manufacture

The crude product is converted to the corresponding potas- of a medicament for use in the treatment of a gastric-acidsium salt by treatment with a potassium source, such as 30 related condition and a method of treating a gastric-acidmethanolic potassium hydroxide or methanolic potassium related condition which method comprises administering to a

methylate, followed by isolation of the formed salt. subject suffering from said condition a therapeutically effec-The resulting potassium salt of S-omeprazole is thereafter tive amount ofthe magnesium salt ofS-omeprazole trihydrate

converted to the corresponding magnesium salt by treatment according to the invention.with a magnesium source, such as magnesium sulfate in a 35 The compositions of the invention include compositionslower alcohol, such as methanol. The solution is optionally suitable for peroral or parental administration. The most pre-filtered and the precipitation is initialized by addition of a ferred route is the oral route. The compositions may be con-non-solvent such as acetone. The product is filtered off and

veniently presented in unit dosage forms, and prepared by anyoptionally washed with water and further processed as is methods known in the art of pharmacy.described in a) above. Alternatively, the potassium salt may 40In the practice of the invention, the most suitable route ofbe treated with a magnesium source, such as magnesium administration as well as the magnitude ofa therapeutic dosesulfate in water, and isolation of the magnesium salt of

of the magnesium salt of S-omeprazole trihydrate accordingS-omeprazole trihydrate, or any other conventional techniqueto the invention in any given case will depend on the naturefor transforming a potassium salt to the corresponding mag-

nesium salt can be used and is within the scope ofthe present 45and severity of the disease to be treated. The dose, and dose

invention, frequency, may also vary according to the age, body weight,and response of the individual patient. Special requirementsYet a further aspect of the present invention is to provide a

suitable intermediate used in the preparation ofthe compound may be needed for patients having Zollinger-Ellison syn-

of the invention, as well as a process for its preparation. The drome, such as a need for higher doses than the averageatient. Children and patients with liver diseases generallypotassium salt of S-omeprazole is found to be such a suitable so p.

will benefit from doses that are somewhat lower than theintermediate. The potassium salt of S-omeprazole may alsobe used as an active component of a pharmaceutical formu- average. Thus, in some conditions it may be necessary to use

doses outside the ranges stated below, for example long termlation to be used in the treatment of gastrointestinal diseases.treatments may request lower dosage. Such higher and lowerThe compound of the invention, i.e. the magnesium salt of

S-omeprazole trihydrate, prepared according to the present 55doses are within the scope ofthe present invention. Such dailydoses may vary between 5 mg to 300 mg.invention may be analyzed by XRPD, a technique which is

known per se. In general, a suitable oral dosage form ofthe compound of

The amount of water in the magnesium salt of S-omepra- the invention may cover a dose range from 5 mg to 300 mgzole trihydrate is determined by thermogravimetric analysis, total daily dose, administered in one single dose or equallya technique which is known per se. 60 divided doses. A preferred dosage range is from 10 mg to 80

The compound ofthe invention is effective as a gastric acid mg.secretion inhibitor, and is useful as an antiulcer agent. In a The compound of the invention may be combined as themore general sense, it can be used for prevention and treat- active component in intimate admixture with a pharmaceuti-ment ofgastric-acid related conditions in mammals and espe- cal carrier according to conventional techniques, such as the

cially in man, including e.g. reflux esophagitis, gastritis, 65 oral formulations described in WO 96/01623 and EP 247 983,duodenitis, gastric ulcer and duodenal ulcer. Furthermore, it the disclosures ofwhich are hereby incorporated as a whole

may be used for treatment of other gastrointestinal disorders by reference.


US 7,411,070 B2

5 6Combination preparations comprising the magnesium salt

of S-omeprazole trihydrate and other active ingredients may TABLE 1-continuedalso be used. Examples of such active ingredients include, butare not limited to anti-bacterial compoundsnon-steroidal Positions and intensities of the major peaks in the XRP-diffractogram

of the magnesium salt of S-omeprazole trihydrate.anti-inflammatory agents, antacid agents, alginates and pro- 5

kinetic agents. d-value/A Relative IntensityThe examples which follow will further illustrate the

8.3preparation of the compound of the invention, according to

16.6 vs

different process routes and including new intermediates.These examples are not intended to limit the scope of the 10

invention as defined hereinabove or as claimed below.Example 2

EXAMPLESS-5-methoxy-2-[[(4-methoxy-3, 5-dimethy1-2-pyridi-

Example 1 15 nyl)methyl]sulfiny1]-1H-benzimidazole PotassiumSalt

S-5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2-pyridi-ny1)-methyl] sulfiny1]-1H-benzimidazole Magnesium A solution of 5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2-

Salt Trihydrate pyridinyl)methyl]thio]-1H-benzimidazole (15.4 g, 46.820 mmol) in toluene (70 ml) was heated to 50° C. and water (0.05

Water (157 kg) was added to the wet crystals of the mag- ml, 2.8 mmol) and D-(-)-diethyl tartrate (2.02 g, 9.82 mmol)nesium salt ofS-omeprazole, prepared according to Example were added. The reaction mixture was stirred for 20 minutes.

4, below. The mixture was heated to 38° C. with stirring and Titanium(IV)isopropoxide (1.34 g, 4.68 mmol) was added

left for 3 hours. The crystals were filtered off and dried in and the reaction mixture was stirred for 45 minutes. The

vacuo. Yield: 31.6 kg. 25 mixture was cooled to 30° C. and diisopropylethylamineX-ray powder diffraction analysis was performed on a (0.91 g, 7.01 mmol) was added followed by cumene hydrop-

eroxide (9.52 g, 51.89 mmol). The resultant mixture wassample of the crystals prepared above according to standardmethods, which can be found in e.g. Kitaigorodsky, A. I. stirred at 30° C. for 3 hours. Methanol (40 ml) was added

followed by potassium hydroxide (3.05 g, 46.8 mmol) in(1973), Molecular Crystals and Molecules, Academic Press,New York; Bunn, C. W. (1948), Chemical Crystallography, 30 methanol (30 m1). Seed crystals were added and the reaction

mixture was stirred at 35° C. overnight. The precipitatedClarendon Press, London; or Klug, H. P. & Alexander, L. E.p(1974), X-Ray Diffraction Procedures, John Wiley and Sons, roduct was filtered off, washed with methanol and toluene

New York. The analysis gave the diffractogram depicted in and dried in vacuo. Yield: 9.74 g (54%).FIG. 1. The main peaks, with positions and relative intensi-ties, have been extracted from the diffractogram in FIG. 1 and 35 Example 3

is given below in table 1. The relative intensities are lessreliable and instead ofnumerical values the following defini- S-5-methoxy-2-[[(4-methoxy-3, 5-dimethy1-2-pyridi-tions are used. ny1)-methyl] sulfiny1]-1H-benzimidazole Potassium

Salt40

Water (157.6 pi) was added to a solution of 5-methoxy-2-Relative Intensity Definition (4-methoxy-3, 5 -dimethy1-2-pyridinyl)methyl] thio] -1H-

25-100 vs (very strong) benzimidazole in toluene (370 ml; 211.5 g/l) with a water

10-25 s (strong) content of 0.031% (w/w), followed by addition of D-(-)-3-10 m (medium) 45 diethyl tartrate (8.55 m1). The solution was heated to 50° C.1-3 w (weak) and stirred at this temperature for 20 minutes. Titanium(IV)<1 vw (vely weak)

isopropoxide (7.15 ml) was added and reactionwas left at 50°C. for 45 minutes. The temperature was lowered to 30° C. and

Some additional very weak peaks found in the diffracto- diisopropylethylamine (6.2 ml) was added. Cumene hydrop-50

gram have been omitted from table 1. eroxide was added at an appropriate speed to maintain the

temperature from 28° C. to 34° C. The temperature was raisedTABLE 1 to 35° C. after 2 hours and potassium methoxide (24.55 g) in

methanol (222 ml) was added. The mixture was filtered afterPositions and intensities of the major peaks in the XRP-diffractogram 14 hours and the crystals were washedwith methanol:toluene

of the magnesium salt of S-omeprazole trihydrate. 55 (240 ml; 1:1) and methanol (120 ml) and dried. Yield: 79 gd-value/A Relative Intensity (74%), ee>99.9%.

2.67 [a]D20=+28.7° (c=1%, water); Assay: 89% is 5-5-meth-

2.79 m oxy-2-[[(4-methoxy-3,5-dimethy1-2-pyridiny1)-methyl]3.27 m

60 sulfiny1]-1H-benzimidazole potassium salt (11% is metha-3.52 nol).3.823.96 vs 1H-NMR (200 MHz, DMSO-d6, 8 ppm): 2.23 (s, 3H), 2.244.14 m (s, 3H), 3.71 (s, 3H), 3.75 (s, 3H), 4.40 (d, 1H), 4.78 (d, 1H),5.2 m 6.58 (dd, 1H), 7.00 (d, 1H), 7.35 (d, 1H), 8.25 (s, 1H).5.66.7 vs 65 The products from Examples 2 and 3 were analysed using6.9 s X-ray powder diffraction as described in Example 1 and gave

the diffractogram depicted in FIG. 2 and given below in Table


US 7,411,070 B2

7 82. Some additional very weak peaks found in the diffracto- was added and the resulting mixture was left for 4 hours. The

gram have been omitted from Table 2. precipitated product was filtered off, washed with acetone

and water. The wet crystals were immediately used as isTABLE 2 described in Example 1.

5Positions and intensities of the major peaks in the XRP-diffractogram Example 5

of the potassium salt of S-omeprazole.

Relative S-5-methoxy-2-[[(4-methoxy-3, 5-dimethy1-2-pyridi-d-value/A intensity ny1)-methyl]sulfiny1]-1H-benzimidazole Magnesium

10 Salt Dihydrate13.6 vs

10.6 vw

7.8 m 5.0 g ofthe moist product from Example 4 with an approxi-6.8 m mate dry content of 74%, was dried in vacuum at 35° C. over6.5 m night to yield 3.58 g (2.68 mmol) of S-5-methoxy-2-[[(4-6.2 w

6.1 m 15 methoxy-3,5-dimethy1-2-pyridiny1)-methyl] sulfinyl] -1H-

5.8 s benzimidazole magnesium salt dihydrate, named Form B.5.4 m The product was analyzed using X-ray powder diffraction5.3 w

as described in Example 1, and the analyze gave the diffrac-5.2 w

5.0 vw togram depicted in FIG. 3 and given below in Table 3. Some

4.75 m 20 additional peaks with low intensities found in the diffracto-4.71 w gram have been omitted from Table 3.4.52 w

4.42 w

4.32 w TABLE 34.27 m

3.98 vw 25Positions and intensities of the major peaks in the XRP-diffractogram

3.92 w of the magnesium salt of S-omeprazole dihydrate, Form B.

3.89 w

3.87 w d-value/A Relative Intensity3.81 w

3.74 m4.19 m

3.60 m4.45 m

3.55 m30 4.68 m

3.52 m4.79 s

3.42 w4.91 s

3.38 w4.98 s

3.34 m5.1 m

3.28 w5.4 s

3.20 m 35 5.5 m

3.12 w5.6 m

3.06 w5.8 m

3.03 w6.3 m

2.97 w6.7 s

2.93 vw7.9 m

s2.89 w 40 8.1

2.85 m11.0 m

2.76 w11.8 m

2.71 vw14.9 vs

2.66 vw

2.58 w

2.57 w 45 Conversion of Magnesium Salt of S-omeprazole Dehydrate2.56 w

to Trihydrate2.52 vw

2.47 vw This material was subsequentlyprocessed to 5-5-methoxy-2.45 vw 2-[[(4-methoxy-3,5-dimethy1-2-pyridiny1)-methyl]sulfinyTh2.43 vw 1H-benzimidazole magnesium salt trihydrate according to2.40 vw

50 the procedure described for the moist substance in Example 1.2.38 vw

2.31 vw

Example 6al 1.54060 A

S-5-methoxy-2-[[(4-methoxy-3, 5-dimethy1-2-pyridi-Example 4 55 ny1)-methyl]sulfiny1]-1H-benzimidazole Magnesium

Salt DihydrateS-5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2-pyridi-ny1)-methyl]sulfinyl]-1H-benzimidazole Magnesium A methanolic solution of S-5-methoxy-2-[[(4-methoxy-3,

Salt 5-dimethy1-2-pyridinyl)methyl]sulfiny1]-1H-benzimidazole60 magnesium salt was prepared as is described in Example 4.

Methanol (148 kg) was added to S-5-methoxy-2-[[(4- Such a solution of S-5-methoxy-2-[[(4-methoxy-3,5-dim-

methoxy-3,5-dimethy1-2-pyridinyl)methyl]sulfiny1]-1H- ethy1-2-pyridinyl)methyl]sulfiny1]-1H-benzimidazole mag-benzimidazole potassium salt (71 kg, methanol con- nesium salt (1.86 g) in 5 ml methanol was concentrated bytent=13%). MgSO4x7H20 (40 kg) was added to the mixture evaporation until 1.58 ml methanol remained. Then, a mix-while stirring. After 70 minutes the mixture was filtered and 65 ture of 1.6 ml water and 6.32 ml aceton was added. Thethe filtrate was washed with methanol (46 kg). The solution solution was allowed to crystallize during 26 h at room tem-

was concentrated to a volume of 100 liter, acetone (253 kg) perature. The resulting crystals were filtered off and dried at


US 7,411,070 B2

9 1040° C. under reduced pressure giving 1.17 g ofS-5-methoxy- of5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2-pyridinyl)me-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyTh thyl]sulfiny1]-1H-benzimidazole (2.84 g, 8.2 mmol) was

1H-benzimidazole magnesium salt dihydrate, named formA. added to the magnesium methoxide solution. The mixtureThe product was analyzed using X-ray powder diffration as was stirred for 12 hours whereupon a small amount of water

described in Example 1 and gave the diffractogram depicted 5 (0.1 ml) was added in order to precipitate inorganic magne-in FIG. 4 and given below in Table 4. Some additional peaks sium salts. After 30 minutes stirring, these inorganic saltswith low intensities found in the diffractogram have been were filtered off and the solution was concentrated on a

omitted from Table 4. rotavapor. The residue was now a concentrated methanolicsolution of the enantiomeric mixture (i.e. the title compound

TABLE 4 10 contaminated with the (+)-isomer), with an optical purity(enantiomeric excess, e.e.) of 80%. This mixture was diluted

Positions and intensities of the major peaks in the XRP-diffractogram with acetone (100 ml) and after stirring at room temperatureof the magnesium salt of S-omeprazole dihydrate, Form A. for 15 minutes, a white precipitate was obtained. Additional

d-value/A Relative Intensity stirring for 15 minutes and thereafter filtration afforded 1.3 g15 (50%) ofthe title compound as white crystals. Chiral analyses

3.04 5 of the crystals and mother liquor were performed by chroma-3.143.18 m tography on an analytical chiral column. The optical purity of4.05 s the crystals and mother liquor was found to be 98.4 e.e. and4.19 5 64.4% e.e., respectively. Thus, the optical purity (e.e.) has4.32 rn

20 been enhanced from 80% to 98.4% simply by crystallizing4.544.69 vs

the Mg-salt from a mixture of acetone and methanol. The5.2 s product was crystalline as shown by powderX-ray diffraction5.3 5 and the magnesium content was 3.44% as shown by atomic5.8 absorption spectroscopy. [a]D2o__131.50 (c=0.5%, metha-6.2 vs

6.6 25 nol).15.5 vs The product was analyzed using X-ray powder diffraction

as described in Example 1 and gave the diffractogramdepicted in FIG. 5 and given below in Table 5. Some addi-

Exame 7 tional very weak peaks found in the diffractograms have beenpl30 omitted from Table 5.

S-5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2-pyridi-ny1)-methyl]sulfiny1]-1H-benzimidazole Magnesium TABLE 5

Salt Trihydrate Positions and intensities of the major peaksin the XRP-diffractogram shown in FIG. 5.

22.0 g (29, 1 mmol) of S-5-methoxy-2-[[(4-methoxy-3,5- 35

dimethy1-2-pyridinyl) methyl]sulfiny1]-1H-benzimidazole d-value/A Relative Intensity

potassium salt was dissolved in 40 mL of water. The solution 2.90 s

was seeded with 0.11 g (0, 1 mmol) S-5-methoxy-2-[[(4- 3.41 s

methoxy-3, 5-dimethy1-2-pyridiny1)-methyl] sulfinyl] -1H- 3.90 s

413 sbenzimidazole magnesium salt trihydrate. 22 mL (69, 6 40

4..79 vs

mmol) of Mg504 (aq) was added under a 3 h period. The 5.00 vs

slurry was filtered off and the precipitate was elutriated in 5.4 vs

5.7 swater for approximately 30 minutes and the crystals weres

filtered off and dried (35° C. vacuum).6.36.8 s

Yield: 9.15 g (11,6 mmol; 80%). The substance had a45

7.8 s

purity (HPLC):99.8 area Mg content: 3.40% (w/w) and ee: 8.4 vs

99.8%. 10.8 s

12.2 s

The product was analyzed using X-ray powder diffraction 15.1 vs

and the result complies with FIG. 1 and Table 1.50

Reference Example A The invention claimed is:1. The magnesium salt of S-omeprazole trihydrate.

S-5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2-pyridi- 2. The magnesium salt ofS-omeprazole trihydrate accord-

ny1)-methyl] sulfiny1]-1H-benzimidazole Magnesium ing to claim 1 represented by FIG. 1.

Salt55 3. A process for the preparation of the magnesium salt of

S-omeprazole trihydrate according to claim 1 which com-

(The method used is in accordance with the method prises treating a magnesium salt ofS-omeprazole ofany other

described in Example A in WO 96/01623) form with water.

4. A process for the preparation of the magnesium salt ofMagnesium (0.1 lig, 4.5 mmol) was dissolved and reacted 6 S-omeprazole trihydrate according to claim 2 which com-

with methanol (50 ml) at 40° C. with a catalytic amount ofprises treating a magnesium salt ofS-omeprazole ofany other

methylene chloride. The reaction was run under nitrogen andwas finished after five hours. At room temperature a mixture

form with water.

of the two enantiomers [90%(-)-isomer and 10%(+)-isomer]


EXHIBIT C

Case 3:16-cv-01682-MLC-TJB DocumentlE111111111111911111111111111111119"US008466175B2

(12) United States Patent (10) Patent No.: US 8,466, 175 B2Cotton et al. (45) Date of Patent: *Jun. 18, 2013

(54) FORM OF S-OMEPRAZOLE 5, 948,913 A 9/1999 Yamamoto et al.

6, 022,985 A 2/2000 Authelin et al.

(75) Inventors: Hanna Cotton, Södertälje (SE); Anders 6, 132,771 A 10/2000 Depui et al.

Kronström, Södertälje (SE); Anders 6, 136,344 A 10/2000 Depui et al.

Mattson, Södertälje (SE); Eva Möller, 6, 183,776 B1 2/2001 Depui et al.

Södertälje (SE) 6, 365, 184 B1 4/2002 Depui et al.

6, 369,085 B1 4/2002 Cotton et al. 514/338

(73) Assignee: AstraZeneca AB, Sodertalje (SE) 6, 613,354 B2 9/2003 Depui et al.

6, 677,455 B2 1/2004 Kronstrom et al.

Notice: Subject to any disclaimer, the term of this6, 747, 155 B2 6/2004 Kronstrom et al.

7,411,070 B2 8/2008 Cotton et al.patent is extended or adjusted under 35 7,488,497 B2 2/2009 Depui et al.U.S.C. 154(b) by 0 days. 7, 745,466 B2 6/2010 Cotton et al.

This patent is subject to a terminal dis- 8, 076,361 B2 12/2011 Cotton et al. 514/338

claimer.2007/0122470 Al 5/2007 Johansson et al.2008/0255363 Al 10/2008 Cotton et al.

(21) Appl. No.: 13/298,3732009/0297594 Al 12/2009 Depui et al.

FOREIGN PATENT DOCUMENTS(22) Filed: Nov. 17, 2011 CN 1136564 11/1996

DE 4 035 455 5/1992(65) Prior Publication Data EP 0005129 10/1979

EP 0124495 11/1984US 2012/0252847 Al Oct. 4, 2012 EP 0247983 12/1987

IN 1344/DEL/98 5/1998Related U.S. Application Data WO 9427988 12/1994

WO 9501977 1/1995(60) Continuation of application No. 12/784,881, filed on WO 9601623 1/1996

May 21, 201 0, now Pat. No. 8,076, 3 61, which is a WO 9602535 2/1996

continuation of application No. 11/853,3 23, filed on

Sep. 11, 2007, now Pat. No. 7,745,466, which is a OTHER PUBLICATIONScontinuation of application No. 1 0/672,93 6, filed on

Sep. 25, 2003, now Pat. No. 7,411,070, which is aErlandsson, P. Et al., "Resolution of the enantiomers of omeprazole

continuation of application No. 1 0/076,711, filed onand some of its analogues by liquid chromatography on a

Feb. 14, 2002, now Pat. No. 6, 677,455, which is a trisphenylcarbamoyl cellulose-based stationary phase", Journal of

division of application No. 09/077,71 9, filed as Chromatography, 532 (1990) 305-319.

application No. PCT/5E98/00974 on May 25, 1998, von Unge, S. et al. "Stereochemical assignment ofthe enantiomers of

now Pat. No. 6,3 69,085. omeprazole fromX-ray analysis ofa fenchyloxylmethyl derivative of

(+)-(R)-omeprazole", Tetrahedron Asymmetry, vol. 8, No. 12, pp.

(30) Foreign Application Priority Data 1967-1970 (1997).Japanese Chemical Society, Experimental Chemical Seminar. vol.

May 30, 1997 (SE) 9702065 18. p. 55 (translation), 1958.

An Introduction to Crystal Chemistry by Evans Cambridge at the

(51) Int. Cl. Univ. Press, 1964.

A 61K 31/4439 (2006.01)(52) U.S. Cl. (Continued)

USPC 514/338; 514/337

(58) Field of Classification Search Primary Examiner Charanjit AulakhUSPC 514/33 8, 337See application file for complete search history. (74) Attorney, Agent, or Firm David Gryte

(56) References Cited(57) ABSTRACT

U.S. PATENT DOCUMENTS The present invention relates to a novel form of the4,255,431 A 3/1981 Junggren et al. 424/263 enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2-4,738,974 A 4/1988 Brändström 514/3384,786,505 A 11/1988 Lovgren et al. 424/468 pyridiny1)-methyl]sulfinyl]-1H-benzimidazole, i.e. 5-ome-

5,204, 118 A 4/1993 Goldman et al. prazole. More specifically, it relates to a novel form of the5,244,891 A 9/1993 Kaplan et al. magnesium salt of the S-enantiomer of omeprazole trihy-5,417,980 A 5/1995 Goldman et al. drate. The present invention also relates to processes for pre-5, 530, 160 A 6/1996 Nore et al. 562/5715,676,884 A 10/1997 Tiers et al. 252/582 paring such a form of the magnesium salt of S-omeprazole5,690,960 A 11/1997 Bengtsson et al. 514/338 and pharmaceutical compositions containing it. Furthermore,5,693,818 A 12/1997 von Unge 546/273.7 the present invention also relates to new intermediates used in5,714,504 A 2/1998 Lindberg et al. 514/338 the process.5, 817,338 A 10/1998 Bergstrand et al. 424/4685, 840, 552 A 11/1998 Holt et al.5, 877, 192 A 3/1999 Lindberg et al. 514/3385,900,424 A 5/1999 Källström et al. 514/338 14 Claims, 5 Drawing Sheets


US 8,466,175 B2Page 2

OTHER PUBLICATIONS Theophylline", International Journal of Pharmaceutics 135 (1996)151-160.

Notice of Allegation, filed Nov. 13, 2007, pursuant to the patented Stephen Byrn et al., "Pharmaceutical Solids: A Strategic Approach toMedicines (Notice ofCompliance) Regulations with respect to Cana- regulatory Consideration", Pharmaceutical Research, vol. 12, No. 7dian Letters Patent No. 2,290, 963. (1995), 945-954.

Rajendra K. Khankari et al., "Pharmaceutical hydrates", Kenneth M. Harmon et al., Hydrogen bonding Part 43. IR and ther-Thermochimca Acta 248 (1995) 61-79. modynamic study of the stoichiometry and stability of hydrates ofAbstract of CN1136564: Aomeilazole salt hydrate for gastric acid triethylenediamine oxide. Journal of Molecular Structure, v.268, n.

inhibitor and its preparing method, Nov. 27, 2006. 1-3, p. 87-96, 1992.

Haijian Zhu et al. "Influence of water activity in organic solvent +

water mixtures on the nature of the crystallizing drug phase. 1 cited by examiner


U.S. Patent Jun. 18, 2013 Sheet 1 of 5 US 8,466,175 B2

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US 8,466, 175 B22

FORM OF S-OMEPRAZOLE BRIEF DESCRIPTION OF THE DRAWINGS

This application is a continuation of U.S. patent applica- FIG. 1 shows a X-ray powder diffractogram ofthe magne-tion Ser. No. 12/784,881, filed 21 May 2010 now U.S. Pat. sium salt of S-omeprazole trihydrate prepared according to

No. 8,076,361, which is a continuation of U.S. patent appli- 5 the present invention.cation Ser. No. 11/853,323, filed 11 Sep. 2007, now U.S. Pat. FIG. 2 shows a X-ray powder diffractogram of the potas-No. 7,745,466, which is a continuation of U.S. patent appli- sium salt of S-omeprazole prepared and used in the presentcation Ser. No. 10/672,936, filed 25 September 2003, now application (See examples 2 and 3)U.S. Pat. No. 7,411,070, which is a continuation of U.S. FIG. 3 shows a X-ray powder diffractogram of a magne

10patent application Ser. No. 10/076,711, filed 14 Feb. 2002, sium salt ofS-omeprazole dihydrate prepared and used in thenow U.S. Pat. No. 6,677,455, which is a divisional of U.S, present application (See example 5)patent application Ser. No. 09/077,719, filed 8 Jun. 1998, now FIG. 4 shows a X-ray powder diffractogram of a magne-U.S. 6,369,085, which was the National Stage of Interim- sium salt ofS-omeprazole dihydrate which is a polymorph oftional Application No. PCT/5E98/00974, tiled 25 May 1998.

15the dihydrate shown in FIG. 3 (See Example 6). This magne-sium salt of S-omeprazole dihydrate has been prepared and

FIELD OF THE INVENTION can be used in the preparation of the magnesium salt of

S-omeprazole trihydrate according to the present invention.The present invention relates to a novel form of the FIG. 5 shows X-ray powder diffractogram of the magne-

enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2- 20 sium salt of S-omeprazole prepared according to example Apyridiny1)-methyl]sulfiny1]-1H-benzimidazole, i.e. S-ome- in WO 96/01623.prazole. More specifically, it relates to a novel form of the

magnesium salt of the S-enantiomer of omeprazole trihy- DESCRIPTION OF THE INVENTIONdrate. The present invention also relates to processes for pre-paring such a form of the magnesium salt of S-omeprazole 25 It has surprisingly been found that the magnesium salt ofand pharmaceutical compositions containing it. Furthermore, S-omeprazole occurs in a number of structurally differentthe present invention also relates to intermediates used in the forms. It is an object of the present invention to provide a

process, and their preparation. substantially pure magnesium salt of S-omeprazole trihy-drate, hereinafter referred to as the compound of the inven-

BACKGROUND OF THE INVENTION AND 30 tion. This trihydrate can be obtained as a well defined com-

PRIOR ART pound. The present invention also provides a process to

obtain and a method ofdifferentiating the magnesium salt of

The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl- S-omeprazole trihydrate from other fauns ofmagnesium salts

2-pyridinyl)methyl]sulfiny1]-1H-benzimidazole, having the of S-omeprazole.generic name omeprazoleand therapeutically acceptable 35 The compound ofthe invention is advantageous because it

salts thereof, are described in EP 5129. The specific alkaline is more stable than the corresponding magnesium salt com-

pounds in prior art and is therefore easier to handle and store.salts of omeprazole are disclosed in EP 124 495. Omeprazole The compound of the invention is also easier to characterizeis a proton pump inhibitor, i.e. effective in inhibiting gastric because it exists in a well defined state. Additionally, theacid secretion and is useful as an antiulcer agent. In a more

40 compound of the invention is easier to synthesize in a repro-general sense, omeprazole may be used for prevention and ducible manner and thereby easier to handle in a full scaletreatment of gastric-acid related diseases in mammals and production.especially in man. The magnesium salt of S-omeprazole trihydrate obtained

Omeprazole is a sulfoxide and achiral compound, wherein according to the present invention is substantially free fromthe sulfur atom being the stereogenic center. Thus, omepra- 45 magnesium salts of R-omeprazole. The magnesium salt ofzole is a racemic mixture of its two single enantiomers, the R S-omeprazole trihydrate obtained according to the presentand S-enantiomer of omeprazole, herein referred to as invention is also substantially free from other forms ofmag-R-omeprazole and S-omeprazole. The absolute configura- nesium salts of S-omeprazole, such as the correspondingtions ofthe enantiomers ofomeprazole have been determined magnesium salt compounds described in prior art, and dihy-by an X-ray study of an N-alkylated derivative of the so drates used in the preparation of the trihydrate compoundenantiomer in non-salt form. The (+)-enantiomer of the non- according to the present invention.salt form and the (—)-enantiomer of the non-salt form were The compound of the invention is characterized by thefound to have R and S configuration, respectively, and the positions and intensities of the major peaks in the X-ray(+)-enantiomer ofthe magnesium salt and the (—)-enantiomer powder diffractogram, but may also be characterized by con-

of the magnesium salt were also found to have R and S 55 ventional FT-IR spectroscopy. These characteristics are not

configuration respectively. The conditions for the optical exhibited by any other form ofmagnesium salt of S-omepra-rotation measurement for each of these enantiomers are zole and accordingly, the magnesium salt of S-omeprazoledescribed in WO 94/27988. trihydrate is easily distinguishable from any other crystal

Certain salts of single enantiomers ofomeprazole and their form of the magnesium salt of S-omeprazole disclosed in

preparation are disclosed in WO 94/27988. These compounds 60 prior art. The compound of the invention is characterized byhave improved pharmacokinetic and metabolic properties being highly crystalline i.e. having a higher crystallinity thanwhich will give an improved therapeutic profile such as a any other form ofmagnesium salt ofS-omeprazole disclosedlower degree of interindividual variation, in the prior art. With the expression "any ether form" is meant

WO 96/02535 discloses a process for the preparation ofthe anhydrates, hydrates, solvates, and polymorphs or amor-

single enantiomers of omeprazole and salts thereof, and WO 65 phous forms thereof disclosed in the prior art. Examples of96/01623 discloses a suitable tableted dosage forms of for any other forms ofmagnesium salt ofS-omeprazole includes,instance magnesium salts R- and S-omeprazole. but are not limited to, anhydrates, monohydrates, dihydrates,


US 8,466, 175 B2

3 4sesquihydrates, trihydrates, alcoholates, such as methano- The compound ofthe invention is effective as a gastric acidlates and ethanolates, and polymorphs or amorphous forms secretion inhibitor, and is useful as an antiulcer agent. In a

thereof more general sense, it can be used for prevention and treat-

The compound of the invention may also be characterized ment ofgastric-acid related conditions in mammals and espe-

by its unit cell. 5 cially in man, including e.g. reflux esophagitis, gastritis,In a further aspect, the present invention provides pro- duodenitis, gastric ulcer and duodenal ulcer. Furthermore, it

may be used for treatment of other gastrointestinal disorderscesses for the preparation of the magnesium salt of S-ome-

where gastric acid inhibitory effect is desirable e.g. in patientsprazole trihydrate which comprises;a) treating a magnesium salt ofS-omeprazole ofany form, for on NSAID therapy, in patients with Non Ulcer Dyspepsia, in

10 patients with symptomatic gastro-esophageal reflux disease,example prepared according is to procedures known in theand in patients with gastrinomas. The compound ofthe inven-

art such as Example A in WO 96/01623 which is incorpo- tion may also be used in patients in intensive care situations,rated herein by reference, with water at a suitable tempera- in patients with acute upper gastrointestinal bleeding, pre-ture for a suitable time. By a suitable temperature is meant and postoperatively to prevent aspiration ofgastric acid and toa temperature which induces the transformation of starting 15 prevent and treat stress ulceration. Further, the compound ofmaterial to product without decomposing any of these the invention may be useful in the treatment of psoriasis as

compounds. Examples of such suitable temperatures well as in the treatment of Helicobacter infections and dis-include, but are not limited to, room temperature and eases related to these. The compound of the invention mayabove. By a suitable time is meant a time that results in high also be used for treatment of inflammatory conditions inconversion of the starting material into product without 20 mammals, including man.

causing any decomposition of either compounds, i.e. Any suitable route ofadministration may be employed forresults in a good yield. This suitable time will vary depend- providing the patient with an effective dosage of the magne-ing on the temperature used in a way well known to people sium salt of S-omeprazole trihydrate, according to the inven-in the art. The higher the temperature, the shorter time is tion. For example, peroral or parental formulations and theneeded to give the desired conversion. The amount ofwater 25 like may be employed. Dosage founts include capsules, tab-is not crucial and will depend on the process conditions lets, dispersions, suspensions and the like.used. The magnesium salt of S-omeprazole trihydrate is It is further provided a pharmaceutical composition com-

thereafter separated from the aqueous slurry, for example prising the magnesium salt of S-omeprazole trihydrateby filtration or centrifugation and thereafter dried to con- according to the invention, as active ingredient, in associationstant weight; or 30 with a pharmaceutically acceptable carrier, diluent or excipi-

b) oxidizing 5-methoxy-2-[[(4-methoxy-3, 5-dimethy1-2-py- ent and optionally other therapeutic ingredients. Composi-ridinyl)methyl]thio]-1H-benzimidazole, with an oxidizing tions comprising other therapeutic ingredients are especiallyagent and a chiral titanium complex, optionally in the pres- of interest in the treatment of Helicobacter infections. Theence of a base. The oxidation is carried out in an organic invention also provides the use of the magnesium salt ofsolvent, for example toluene or dichloromethane. 35 S-omeprazole trihydrate of the invention in the manufactureThe crude product is converted to the corresponding potas- of a medicament for use in the treatment of a gastric-acid

sium salt by treatment with a potassium source, such as related condition and a method of treating a gastric-acidmethanolic potassium hydroxide or methanolic potassium related condition which method comprises administering to a

methylate, followed by isolation of the formed salt. subject suffering from said condition a therapeutically effec-The resulting potassium salt of S-omeprazole is thereafter 40 tive amount ofthe magnesium salt ofS-omeprazole trihydrate

converted to the corresponding magnesium salt by treatment according to the invention.with a magnesium source, such as magnesium sulfate in a The compositions of the invention include compositionslower alcohol, such as methanol. The solution is optionally suitable for peroral or parental administration. The most pre-filtered and the precipitation is initialized by addition of a ferred route is the oral route. The compositions may be con-

non-solvent such as acetone. The product is filtered off and 45 veniently presented in unit dosage forms, and prepared by anyoptionally washed with water and further processed as is methods known in the art of pharmacy.described in a) above. Alternatively, the potassium salt may In the practice of the invention, the most suitable route ofbe treated with a magnesium source, such as magnesium administration as well as the magnitude ofa therapeutic dosesulfate in water, and isolation of the magnesium salt of of the magnesium salt of S-omeprazole trihydrate accordingS-omeprazole trihydrate, or any other conventional technique so to the invention in any given case will depend on the nature

for transforming a potassium salt to the corresponding mag- and severity of the disease to be treated. The dose, and dosenesium salt can be used and is within the scope ofthe present frequency, may also vary according to the age, body weight,invention, and response ofthe individual patients. Special requirements

Yet a further aspect of the present invention is to provide a may be needed for patients having Zollinger-Ellison syn-suitable intermediate used in the preparation ofthe compound 55 drome, such as a need for higher doses than the averageof the invention, as well as a process for its preparation. The patient. Children and patients with liver diseases generallypotassium salt of S-omeprazole is found to be such a suitable will benefit from doses that are somewhat lower than theintermediate. The potassium salt of S-omeprazole may also average. Thus, in some conditions it may be necessary to use

be used as an active component of a pharmaceutical formu- doses outside the ranges stated below, for example long term

lation to be used in the treatment of gastrointestinal diseases. 60 treatments may request lower dosage. Such higher and lowerThe compound of the invention, i.e. the magnesium salt of doses are within the scope ofthe present invention. Such daily

S-omeprazole trihydrate, prepared according to the present doses may vary between 5 mg to 300 mg.invention may be analyzed by XRPD, a technique which is In general, a suitable oral dosage form ofthe compound ofknown per se. the invention may cover a dose range from 5 mg to 300 mg

The amount of water in the magnesium salt of S-omepra- 65 total daily dose, administered in one single dose or equallyzole trihydrate is determined by thermogravimetric analysis, divided doses. A preferred dosage range is from 10 mg to 80a technique which is known per se. mg.


US 8,466, 175 B2

5 6The compound of the invention may be combined as the TABLE 1-continued

active component in intimate admixture with a pharmaceuti-cal carrier according to conventional techniques, such as the Positions and intensities of the major peaks in the XRP-diffractogram

of the magnesium salt of S-omeprazole trihydrate.oral formulations described inWO 96/01623 and EP 247 983,the disclosures of which are hereby incorporated as a whole 5 d-value/A Relative Intensityby reference.

3.82Combination preparations comprising the magnesium salt 3.96 vs

of S-omeprazole trihydrate and other active ingredients may 4.14

also be used. Examples of such active ingredients include, but 5.2

are not limited to anti-bacterial compounds, non-steroidal 10 5.66.7 vs

anti-inflammatory agents, antacid agents, alginates and pro- 6.9kinetic agents. 8.3

The examples which follow will further illustrate the 16.6 vs

preparation of the compound of the invention, according to

different process routes and including new intermediates. 15

These examples are not intended to limit the scope of the Example 2invention as defined hereinabove or as claimed below.

EXAMPLESS-5-methoxy-2-[[(4-methoxy-3, 5-dimethy1-2-pyridi-

20 nyl)methyl] sulfiny1]-1H-benzimidazole potassiumsalt

Example 1

S-5-methoxy-2-[[(4-methoxy-35-dimethy1-2-pyridi-A solution of 5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2-ny1)-methyl] sulfiny1]-1H-benzimidazole magnesium pyridinyl)methyl]thio]-1H-benzimidazole (15.4 g, 46.8

salt trihydrate 25 mmol) in toluene (70 ml) was heated to 50° C. and water (0.05ml, 2.8 mmol) and D-(-)-diethyl tartrate (2.02 g, 9.82 mmol)

Water (157 kg) was added to the wet crystals of the mag- were added. The reaction mixture was stirred for 20 minutes.

nesium salt ofS-omeprazole, prepared according to Example Titanium(IV)isopropoxide (1.34 g, 4.68 mmol) was added

4, below. The mixture was heated to 38° C. with stirring and and the reaction mixture was stirred for 45 minutes. The

left for 3 hours. The crystals were filtered off and dried in 30 mixture was cooled to 30° C. and diisopropylethylaminevacuo. Yield: 31.6 kg (0.91 g, 7.01 mmol) was added followed by cumene hydrop-

X-ray powder diffraction analysis was performed on a eroxide (9.52 g, 51.89 mmol). The resultant mixture was

sample of the crystals prepared above according to standard stirred at 30° C. for 3 hours. Methanol (40 ml) was added

methods, which can be found in e.g. Kitaigorodsky, A. I. followed by potassium hydroxide (3.05 g, 46.8 mmol) in

(1973), Molecular Crystals and Molecules, Academic Press, 35 methanol (30 m1). Seed crystals were added and the reactionNew York; Bunn, C. W. (1948), Chemical Crystallography, mixture was stirred at 35° C. overnight. The precipitatedClarendon Press, London; or Klug, H. P. & Alexander, L. E. product was filtered off, washed with methanol and toluene

(1974), X-Ray Diffraction Procedures, John Wiley and Sons, and dried in vacuo. Yield: 9.74 g (54%).New York. The analysis gave the diffractogram depicted inFIG. 1. The main peaks, with positions and relative intensi- 40 Example 3

ties, have been extracted from the diffractogram in FIG. 1 andis given below in table 1. The relative intensities are less S-5-methoxy-2-[[(4-methoxy-3, 5-dimethy1-2-pyridi-reliable and instead ofnumerical values the following defini- ny1)-methyl] sulfiny1]-1H-benzimidazole potassiumtions are used. salt

45

Water (157.6 pi) was added to a solution of 5-methoxy-2-[[(4-methoxy-3, 5-dimethy1-2-pyridinyl)methyl]thio]-1H-

Relative Intensity Definition benzimidazole in toluene (370 ml; 211.5 g/l) with a water

25-100 vs (very strong)content of 0.031% (w/w), followed by addition of D-(-)-

10-25 s (strong) 50 diethyl tartrate (8.55 m1). The solution was heated to 50° C.3-10 m (medium) and stirred at this temperature for 20 minutes. Titanium(IV)1-3 w (weak) isopropoxide (7.15 ml) was added and reactionwas left at 50°<1 vw (vely weak) C. for 45 minutes. The temperature was lowered to 30° C. and

diisopropylethylamine (6.2 ml) was added. Cumene hydrop-Some additional very weak peaks found in the diffracto- 55 eroxide was added at an appropriate speed to maintain the

gram have been omitted from table 1. temperature from 28° C. to 34° C. The temperature was raisedto 35° C. after 2 hours and potassium methoxide (24.55 g) in

TABLE 1 methanol (222 ml) was added. The mixture was filtered after14 hours and the crystals were washedwith methanol:toluene

Positions and intensities of the major peaks in the XRP-diffractogram 60 (240 ml; 1:1) and methanol (120 ml) and dried. Yield: 79 gof the magnesium salt of S-omeprazole trihydrate. (74%), ee >99.9%. [a]D2°=+28.7° (c=1%, water); Assay:d-value/A Relative Intensity 89% is S-5-methoxy-2-[[(4-methoxy-3, 5-dimethy1-2-pyridi-

ny1)-methyl]sulfinyl] -1H-benzimidazole potassium salt2.67

(11% is methanol).2.793.27 m 65 (200 MHz, DMSO-d6, 8 ppm): 2.23 (s, 3H), 2.243.52 s (s, 3H), 3.71 (s, 3H), 3.75 (s, 3H), 4.40 (d, 110, 4.78 (d, 1H),

6.58 (dd, 1H), 7.00 (d, 1H), 7.35 (d, 1H), 8.25 (s, 1H).


US 8,466, 175 B2

7 8The products from Examples 2 and 3 were analysed using The product was analyzed using X-ray powder diffraction

X-ray powder diffraction as described in Example 1 and gave as described in Example 1, and the analyze gave the diffrac-the diffractogram depicted in FIG. 2 and given below in Table togram depicted in FIG. 3 and given below in Table 3. Some2. Some additional very weak peaks found in the diffracto- additional peaks with low intensities found in the diffracto-

gram have been omitted from Table 2. 5 gram have been omitted from Table 3.

TABLE 2 TABLE 3

Positions and intensities of the major peaks in the XRP- Positions and intensities of the major peaks in the XRP-diffractogramdiffractogram of the potassium salt of S-omeprazole. 10 of the magnesium salt of S-omeprazole dihydrate, Form B.

Relative Relatived-value/A intensity d-value/(A) intensity d-value/A Relative Intensity

13.6 vs 3.52 m 4.19 m

10.6 vw 3.42 w

7.8 m 3.38 w 15 4.45 m

6.8 m 3.34 m 4.68 m

6.5 m 3.28 w 4.79 s

6.2 w 3.20 m 4.91 s

6.1 m 3.12 w 4.98 s

5.8 s 3.06 w5.1 m

5.4 m 3.03 w 205.3 w 2.97 w 5.4 s

5.2 w 2.93 vw 5.5 m

5.0 vw 2.89 w 5.6 m

4.75 m 2.85 m5.8 m

4.71 w 2.76 w

4.52 w 2.71 VW 256.3 m

4.42 w 2.66 vw 6.7 s

4.32 w 2.58 w 7.9 m

4.27 m 2.57 w8.1 s

3.98 vw 2.56 w

3.92 w 2.52 VW 11.0 m

3.89 w 2.47 vw 11.8 m30

3.87 w 2.45 VW 14.9 vs

3.81 w 2.43 vw

3.74 m 2.40 vw

3.60 m 2.38 vw

3.55 m 2.31 vw Conversion of Magnesium Salt of S-Omeprazole Dihydrateal 1.54060 A 35

to TrihydrateThis material was subsequentlyprocessed to 5-5-methoxy-

2-[[(4-methoxy-3,5-dimethy1-2-pyridiny1)-methyl]sulfinyThExample 4 1H-benzimidazole magnesium salt trihydrate according to

the procedure described for the moist substance in Example 1.S-5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2-pyridi- 40

ny1)-methyl]sulfiny1]-1H-benzimidazole magnesiumsalt Example 6

Methanol (148 kg) was added to S-5-methoxy-2-[[(4- S-5-methoxy-2-[[(4-methoxy-3, 5-dimethy1-2-pyridi-methoxy-3, 5-dimethy1-2-pyridiny1)-methyl] sulfinyl] -1H- 45 ny1)-methyl]sulfiny1]-1H-benzimidazole magnesiumbenzimidazole potassium salt (71 kg, methanol content 13%). salt dihydrateMgSO4x7H20 (40 kg) was added to the mixture while stir-

ring. After 70 minutes the mixture was filtered and the filtrateA methanolic solution of S-5-methoxy-2-[[(4-methoxy-3,was washed with methanol (46 kg). The solution was concen-

50 5-dimethy1-2-pyridiny1)-methyl]sulfinyl]-1H-benzimidazoletrated to a volume of 100 liter, acetone (253 kg) was addedand the resulting mixture was left for 4 hours. The precipi- magnesium salt was prepared as is described in Example 4.

Such a solution of S-5-methoxy-2-[[(4-methoxy-3,5-dim-tated product was filtered off, washed with acetone and water.

The wet crystals were immediately used as is described in ethy1-2-pyridiny1)-methyl]sulfinyl]-1H-benzimidazole mag

Example 1.nesium salt (1.86 g) in 5 ml methanol was concentrated by

55 evaporation until 1.58 ml methanol remained. Then, a mix-

Example 5 ture of 1.6 ml water and 6.32 ml aceton was added. Thesolution was allowed to crystallize during 26 h at room tem-

S-5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2-pyridi- perature. The resulting crystals were filtered off and dried at

ny1)-methyl]sulfiny1]-1H-benzimidazole magnesium 40° C. under reduced pressure giving 1.17 g of 5-5-methoxy-60

salt dihydrate 2-[[(4-methoxy-3,5-dimethy1-2-pyridiny1)-methyl]sulfinyl]-1H-benzimidazole magnesium salt dihydrate, named formA.

5.0 g ofthe moist product from Example 4 with an approxi- The product was analyzed using X-ray powder diffractionmate dry content of 74%, was dried in vacuum at 35° C. over as described in Example 1 and gave the diffractogramnight to yield 3.58 g (2.68 mmol) of S-5-methoxy-2-[[(4- 65 depicted in FIG. 4 and given below in Table 4. Some addi-

methoxy-3, 5-dimethy1-2-pyridiny1)-methyl] sulfinyl] -1H- tional peaks with low intensities found in the diffractogrambenzimidazole magnesium salt dihydrate, named Form B. have been omitted from Table 4.


US 8,466, 175 B2

9 10TABLE 4 for 15 minutes, a white precipitate was obtained. Additional

stirring for 15 minutes and thereafter filtration afforded 1.3 gPositions and intensities of the major peaks in the XRP-diffractogram (50%) ofthe title compound as white crystals. Chiral analyses

of the magnesium salt of S-omeprazole dihydrate, Form A.of the crystals and mother liquor were performed by chro-

d-value/A Relative Intensity 5 matogaphy on an analytical chiral column. The optical purityofthe crystals and mother liquorwas found to be 98.4 e.e. and

3.04 s

3.14 s 64.4% e.e., respectively. Thus, the optical purity (e.e.) has3.18 m been enhanced from 80% to 98.4% simply by crystallizing4.05 s

10the Mg-salt from a mixture of acetone and methanol. The

4.19 s

4.32 m product was crystalline as shown by powderX-ray diffraction4.54 s and the magnesium content was 144% as shown by atomic4.69 vs absorption spectroscopy. [a]D20__131.5° (c=0.5%, metha-5.2 s

5.3 s nol).5.8 s

15The product was analyzed using X-ray powder diffraction

6.2 vs as described in Example 1 and gave the diffractogram15..66 s

depicted in FIG. 5 and given below in Table 5. Some addi-5 vs

tional very weak peaks found in the diffractograms have beenomitted from Table 5.

Example 7 20

TABLE 5

5-5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2-pyridi- Positions and intensities of the major peaksny1)-methyl]sulfiny1]-1H-benzimidazole magnesium in the XRP-diffractogram shown in FIG. 5.

salt trihydrate 25 d-value/A Relative Intensity

22.0 g (29.1 mmol) of S-5-methoxy-2-[[(4-methoxy-3,5- 2.90 s

3.41 s

dimethy1-2-pyridinyl)methyl]sulfiny1]-1H-benzimidazole 3.90 s

potassium salt was dissolved in 40 mL of water. The solution 4.13 s

was seeded with 0.11 g (0.1 mmol) S-5-methoxy-2-[[(4- 304.79 vs

5.00 vs

methoxy-3, 5-dimethy1-2-pyridiny1)-methyl] sulfinyl] -1H- 5.4 vs

benzimidazole magnesium salt trihydrate. 22 mL (69.6 5.7 s

mmol) of Mg504 (aq) was added under a 3 h period. The 6.3 s

6.8 s

slurry was filtered off and the precipitate was elutriated in7.8 s

water for approximately 30 minutes and the crystals were 35 8.4 vs

filtered off and dried (35° C., vacuum). 10.8 s

Yield: 9.15 g (11.6 mmol; 80%). The substance had a 12.2 s

15.1 vs

purity (HPLC): 99.8 area Mg content: 3,40% (w/w) andee: 99.8%.

The product was analyzed using X-ray powder diffraction 40

and the result complies with FIG. 1 and Table 1. The invention claimed is:1. A method of treating Helicobacter infections compris-

Reference Example A ing the administration of an effective amount of the magne-sium salt of S-omeprazole trihydrate and an antibacterial

S-5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2-pyridi- 45 compound to a patient in need thereofny1)-methyl]sulfmy1]-1H-benzimidazole magnesium 2. The method according to claim 1, wherein the magne-salt sium salt ofS-omeprazole trihydrate is represented by FIG. 1.

3. The method according to claim 1, wherein the magne-(The method used is in accordance method described in sium salt of S-omeprazole trihydrate is characterized by theExample A in WO 96/01623) 50 following peaks in its X-ray diffractogram:Magnesium (0.11 g, 4.5 mmol) was dissolved and reactedwith methanol (50 ml) at 40° C. with a catalytic amount of

methylene chloride. The reaction was run under nitrogen andwas finished after five hours. At room temperature a mixture d-value/A Relative Intensityofthe two enantiomers [90% (-)-isomer and 10% (+)-isomer] 55

2.67 mof5-methoxy-2-[[(4-methoxy-3, 5-dimethy1-2-pyridinyl)me- 2.79 m

thyl]sulfiny1]-1H-benzimidazole (2.84 g, 8.2 mmol) was 3.27 m

added to the m-agnesium methoxide solution. The mixture 3.52 s

was stirred for 12 hours whereupon a small amount ofwater 3.82 s

3.96 vs

(0.1 ml) was added in order to precipitate inorganic magne- 604.14 m

sium salts. After 30 minutes stirring, these inorganic salts 5.2 m

were filtered off and the solution was concentrated on a 5.6 m

rotavapor. The residue was now a concentrated methanolic 6.7 vs

6.9 ssolution of the enantiomeric mixture (i.e. the title compound 8.3 w

contaminated with the (+)-isomer), with an optical purity 65 16.6 vs.

(enantiomeric excess, e.e.) of 80%. This mixture was dilutedwith acetone (100 ml) and after stirring at room temperature


US 8,466, 175 B211 12

4. The method according to claim 1, wherein the magne-sium salt of S-omeprazole trihydrate is in a highly crystallineform.

5. The method according to claim 1, wherein the magne-sium salt of S-omeprazole trihydrate is in a stable form. 5

6. The method according to claim 1, wherein the magne-sium salt of S-omeprazole trihydrate is suitable for oraladministration.

7. The method according to claim 6, wherein the antibac-terial compound is suitable for oral administration. 10

8. The method according to claim 6, wherein the antibac-terial compound is suitable for parenteral administration.

9. The method according to claim 1, wherein the magne-sium salt of S-omeprazole trihydrate is suitable for parenteraladministration. 15

10. The method according to claim 9 wherein the antibac-terial compound is suitable for oral administration.

11. The method according to claim 9, wherein the antibac-terial compound is suitable for parenteral administration.

12. The method according to claim 1, wherein the antibac- 20

terial compound is suitable for oral administration.13. The method according to claim 1, wherein the antibac-

terial compound is suitable for parenteral administration.14. The method according to claim 1, wherein the total

daily dose of the magnesium salt of S-omeprazole trihydrate 25

is from 10 mg to 80 mg.

john e. flaherty ravin r. patel mccarter & english llp · 3/25/2016 · the claims of the...

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