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# c12) United States Patent 

# Arad et al. 

# (54) (lR,l’R)-ATRACURIUM SALTS SEPARATION PROCESS 

(75) Inventors: Oded Arad, Rehovot (IL); Elena Ostrovsky, Rishon Le-Zion (IL) 

(73) Assignee: CHEMAGIS Ltd., Bnei Brak (IL) 

( *) Notice: Subject to any disclaimer, the term ofthis patent is extended or adjusted under 35 U.S.C. 154(b) by 460 days. This patent is subject to a terminal dis› claimer. 

(21) Appl. No.: 12/601,734 

(22) PCT Filed: Mar. 5, 2008 

(86) PCT No.: PCT /IL2008/000290 § 371 (c)(l), (2), ( 4) Date: Nov. 24, 2009 

(87) PCT Pub. No.: WO2008/155752 

PCT Pub. Date: Dec. 24, 2008 

## (65) Prior Publication Data 

US 2010/0174082Al Jul. 8, 2010 

(60) Provisional application No. 60/944,597, filed on Jun. 18, 2007. 

(51) Int. Cl. A61K 3114725 (2006.01) C07D 401112 (2006.01) 

(52) U.S. Cl. ........................................ 546/140; 514/308 

(58) Field of Classification Search .................. 514/308; 546/140 See application file for complete search history. 

## (56) References Cited 

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## Related U.S. Application Data 

## U.S. PATENT DOCUMENTS 

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# (10) Patent No.: US 8,357,805 B2 

# (45) Date of Patent: *Jan. 22, 2013 

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## FOREIGN PATENT DOCUMENTS 

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ICH Guideline, International Conference on Harmonization of Tech› nical Requirements of Registration of Pharmaceuticals for Human Use (ICH), ICH Q3CR4 residual solvents MEDIA5254 (Feb. 2009). 

European Patent Office, International Search Report in International Patent Application No. PCT/IL2008/000291 (Jul. 4, 2008). 

European Patent Office, International Search Report in International Patent Application No. PCT/IL2008/000290 (Jul. 7, 2008). 

European Patent Office, International Search Report in International Patent Application No. PCT/IL2008/000289 (Sep. 5, 2008). 

European Patent Office, International Search Report in International Patent Application No. PCT/IL2008/000586 (Aug. 27, 2008). 

European Patent Office, International Search Report in International Patent Application No. PCT/IL2008/000589 (Aug. 21, 2008). 

European Patent Office, International Search Report in International Patent Application No. PCT/IL2008/000590 (Aug. 29, 2008). 

European Patent Office, International Search Report in International Patent Application No. PCT/IL2008/001329 (Feb. 4, 2009). 

U.S. Patent & Trademark Office, International Search Report in International Patent Application No. PCT/IL2009/000452 (Aug. 12, 2009). 

Lindon et al. "Directly coupled HPLC-NMR and HPLC-NMR-MS in pharmaceutical research and development," Journal of Chromatog› raphy B : Biomedical Applications, Elsevier Science Publishers, NL, vol. 748, No. 1, pp. 233-258 (Oct. 1, 2000). 

Liu et al. "High-performance liquid chromatography of atracurium besylate," Yao Hsueh Hsueh Pao-Acta Pharmaceutica Sinica, Beijing, CN, vol. 29, No. 1, pp. 68-73 (Jan. 1, 1994). 

Primary Examiner - Joseph Kosack 

Assistant Examiner - Matthew Coughlin 

(74) Attorney, Agent, or Firm - Leydig, Voit & Mayer, Ltd. 

## (57) ABSTRACT 

The present invention provides an improved method for obtaining cisatracurium besylate, which preferably chro› matographically separating cisatracurium besylate from a mixture of (1 R, 1 ’R)-atracurium isomers via flash chromatog› raphy. 

US008357805B2 

## OTHER PUBLICATIONS 

(Continued) 

## 12 Claims, No Drawings 

