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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 560 days. This patent is subject to a terminal dis› claimer. 

(21) Appl. No.: 12/529,269 

(22) PCT Filed: Mar. 5, 2008 

(86) PCT No.: PCT /IL2008/000289 § 371 (c)(l), (2), ( 4) Date: Dec.16, 2009 

(87) PCT Pub. No.: WO2008/107887 PCT Pub. Date: Sep. 12, 2008 

## (65) Prior Publication Data 

US 2010/0099878 Al Apr. 22, 2010 

(60) Provisional application No. 60/893,749, filed on Mar. 8, 2007. 

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

(52) U.S. Cl. USPC .......................................................... 546/140 

( 58) Field of Classification Search USPC .......................................................... 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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# (IO) Patent No.: US 8,461,338 B2 

# (45) Date of Patent: *Jun. 11, 2013 

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Ariffin et al., Journal of Chromatograph, B (2006), 842(2), p. 91-97. * 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). 

Mistry et al. "Directly Coupled Chiral HPLC-NMR and HPLC-CD Spectroscopy as Complementary Methods for Structural and Enantiomeric Isomer Identification: Application to Atracurium Besylate," Analytical Chemistry, vol. 71, No. 14, pp. 2838-2843 (1999). 

Nehmer "Separation of cis-cis, cis-trans and trans-trans isomers of (.+-.)-atracurium besylate and cis and trans isomers of its major quaternary decomposition products and related impurity by reversed› phase high-performance liquid chromatography," Journal of Chro› matography, vol. 457, pp. 127-135 (1988). 

Stenlake et al.: "Biodegradable Neuromuscular Blocking Agents 6. Stereochemical Studies on Atracurium and Related Polyalkylene Diesters," European Journal of Medicinal Chemistry, Editions Scientifique Elsevier, Paris, FR, vol. 19, No. 5, pp. 441-450 (Jan. 1, 1984). 

Stenlake et al., "Neuromuscular Block Agents: Some approaches to short acting compounds," European Journal of Medicinal Chemistry, vol. 27, No. 5, pp. 463-477 (1992). 

Primary Examiner - Yong Chu 

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

## (57) ABSTRACT 

The present invention provides an improved method of chro› matographically separating the isomers of (lR,rR)-atracu› rium salts by high-performance liquid chromatography (HPLC), in the absence of a strong acid. The separation is preferably performed on a silica gel HPLC column using an eluent containing an organic solvent, a polar aprotic co-sol› vent and a weak organic acid. 

US0084613 3 8B2 

## FOREIGN PATENT DOCUMENTS 

## OTHER PUBLICATIONS 

(Continued) 

## 21 Claims, 3 Drawing Sheets 

