Monitoring and control of genotoxic impurity acetamide in the synthesis of zaurategrast sulfate

Organic Process Research and Development

Volumn 14, Issue 4, 2010, Pages 1008-1014

  Schülé, Arnaud ^a   Ates, Célal ^a   Palacio, Magali ^a   Stofferis, Jimmy ^a   Delatinne, Jean Pierre ^a   Martin, Bruno ^b   Lloyd, Steven ^a  

^a UCB PHARMA   (Belgium)

^b Analytical Development and Industrialisation   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

ACCEPTANCE CRITERIA; ANALYTICAL METHOD; ANALYTICAL TOOL; CHEMICAL PROCESS DESIGN; DEVELOPMENT PHASE; DRUG CANDIDATES; GENOTOXIC IMPURITIES; MONITORING AND CONTROL; PROJECT DEVELOPMENT;

PROCESS ENGINEERING;

CHEMICAL ANALYSIS;

EID: 77955369019     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op900330e     Document Type: Article

References (35)

1. Pierson, D. A.; Olsen, B. A.; Robbins, D. K.; DeVries, K. M.; Varie, D. L. Org. Process Res. Dev. 2009, 13, 285-291
2. Teasdale, A.; Eyley, S. C.; Delaney, E.; Jacq, C.; Taylor-Worth, K.; Lipczynski, A.; Reif, V.; Elder, D. P.; Facchine, K. L.; Golec, S.; Schulte Oestrich, R.; Sandra, P.; David, F. Org. Process Res. Dev. 2009, 13, 429-433
3. Yang, Q.; Haney, B. P.; Vaux, A.; Riley, D. A.; Heidrich, L.; He, P.; Mason, P.; Tehim, A.; Fisher, L. E.; Maag, H.; Anderson, N. G. Org. Process Res. Dev. 2009, 13, 786-791
4. Guidelines on the Limits of Genotoxic Impurities. CPMP/SWP/5199/02 EMEA/CHMP/QWP/251344/2006; European Medicines Agency (EMEA), Committee for Medicinal Products for Human Use (CHMP): London, June 28, 2006.
5. Questions & Answers on the CHMP Guideline on the Limits of Genotoxic Impurities. EMA/CHMP/SWP/431994/2007, revision 2; European Medicines Agency (EMEA), CHMP SAFETY WORKING PARTY (SWP): London, December 2009.
6. GTI impurity may be a reactant, an intermediate, or a by-product.
7. NTC00484536. Double-blind, Placebo-controlled, Randomized, Parallel-group Phase II Study in Subjects With Relapsing Forms of Multiple Sclerosis (MS) to Evaluate the Safety, Tolerability, and Effects of CDP323. http://clinicaltrials. gov/ct2/show/NCT00484536?term=CDP323&rank=1; accessed 12/11/2009
8. Glowienke, S.; Frieauff, W.; Allmendinger, Th.; Martus, H.-J.; Sutter, W.; Mueller, L. Mutat. Res. 2005, 581, 23-34
9. Summary and Evaluation Diethyl Sulfate; International Agency for Research on Cancer (IARC): 1992; Vol. 54, p 213, http://www.inchem.org/documents/iarc/ vol54/04-diethyl-sulfate.html.
10. Basu, M. K.; Luo, F.-T. Efficient Transformation of Nitrile into Amide under Mild Conditions Tetrahedron Lett. 1998, 39, 3005-3006
11. Wilgus, C. P.; Downing, S.; Molitor, E.; Bains, S.; Pagni, R. M.; Kabalka, G. W. The Acid-Catalyzed and Uncatalyzed Hydrolysis of Nitriles on Unactivated Alumina Tetrahedron Lett. 1995, 36, 3469-3472
12. Krieble, V. K.; Smellie, R. H. Process for hydrolyzing organic nitriles and dehydrating ethers. U.S. Patent 2,441,114, 1948.
13. Liler, M.; Kosanovic, D. J. J. Chem. Soc. 1958, 1084-1090
14. Travagli, G. Gazz. Chim. Ital. 1957, 87, 682-687 and 830-836.
15. 2O) x Clusters J. Catal. 2000, 191, 200-217
16. 5 Polyhedron 1996, 15 (11) 1817-1821
17. 4 with ethanol
18. According to FDA's EAFUS (Everything Added to Food in the US) database, The EAFUS list of substances contains ingredients added directly to food that FDA has either approved as foods additives or listed or affirmed as GRAS (Generally Recognized as Safe). In this table acetamide is listed in the EAF category, meaning There is reported use of the substance, but it has not yet been assigned for toxicology literature search.
19. The Flavor and Extracts Manufacturers Association Expert Panel, an independent organization, has included acetamide in the GRAS (Generally Recognized as Safe) list with the average maximum use level of 5 ppm for baked goods.
20. IARC ((1999) Monogr. Eval. Carcinog. Risks Hum.: Acetamide, Vol 71, 1211- 1220.
21. Dybing, E.; Soderlung, E. G.; Gordon, W. P.; Holme, J. A.; Christensen, T.; Becher, G.; Rivedal, E.; Thorgeirsson, S. S. Studies on the mechanism of acetamide hepatocarcinogenicity Pharmacol. Toxicol. 1987, 60, 9-16
22. Frutos, R. P.; Rodriguez, S.; Patel, N.; Johnson, J.; Saha, A.; Krisshnamurthy, D.; Senanayake, C. H. Org. Process Res. Dev. 2007, 11, 1076-1078
23. Li, B.; Buzon, R. A.; Zhang, Z. Org. Process Res. Dev. 2007, 11, 951-955
24. Li, X.; Jain, N.; Russell, R. K.; Ma, R.; Branum, S.; Xu, J.; Sui, Z. Org. Process Res. Dev. 2006, 10, 354-360
25. Zanka, A.; Kubota, A.; Hirabayashi, S.; Nakamura, H. Org. Process Res. Dev. 1988, 2, 71-77
26. 4Br.
27. NBS could be purchased at an approximate price of 15 a-/kg at ton scale.
28. The Merck Index, 14th ed.; https://themerckindex.cambridgesoft.com/ TheMerckIndex (accessed 12/11/2009).
29. Synthetic Reagents; John Wiley: New York, 1974; 2, pp 1- 63.
30. A FTIR monitoring study comparison between NBS solution addition and portion-wise solid NBS addition showed that solid NBS addition favored the formation of the over-brominated impurity, UCB1191133.
31. The NBS solution was prepared by dissolving 1 mol equiv of NBS in a mixture of acetonitrile/water (2.6 vol/0.4 vol) with respect to starting material UCB1193394.
32. A batch size of 245 kg of UCB1193394 involved a NBS solution addition time of 3 h 38 min at a rate of 3.0 kg/min, maintaining the internal temperature at-2.3 °C to-2.6 °C.
33. International Chemical Safety Cards, www.cdc.gov/niosh/ipcsnfrn/nfrn0233. html (accessed 12/01/2009).
34. At the time these data were generated, the analytical method was neither fully developed nor qualified yet.
35. The 2.7 ppm acetamide contained in the crude API is likely to be removed in the mother liquors of the step 5 final recrystallization based on data obtained for the crude API isolation at step 4. In that case 80% of acetamide spiked was removed in the mother liquors (11 vol). For step 5, 2.7 ppm (1.4% acetamide spiked) diluted in approximately the same volume of solvent (9 vol) makes its quantification not possible by the analytical method. This explains why the amount of 2.7 ppm acetamide is neither detected nor reported.