within drug substance synthesis Dr Michael Burns Senior Scientist - - PowerPoint PPT Presentation
Controlling a cohort Understanding the risk of nitrosamines within drug substance synthesis Dr Michael Burns Senior Scientist michael.burns@lhasalimited.org Outline Purge approach for nitrosamine risk assessments Exploring
Senior Scientist michael.burns@lhasalimited.org Dr Michael Burns
reagents or by-products) then risk is deemed low/non-existent.
significant risk of formation.
conditions)
control options.
from triethylamine and DMF degradation.
there is no realistic possibility of NaNO2 being present in the same stage as an amine.
also exists in the subsequent stages.
In-depth understanding of the process conditions is vital, as this allows appropriate use of purge values.
8
Barber et al, Regul. Toxicol. Pharmacol., 2017, 90, 22-28
expectations for purge calculations, with further conservatism built in.
as a guide to the risk of formation at a concerning level * Assumes quantitative conversion of the amine precursor into a nitrosamine, in itself highly unlikely. Linked to control limits for Sartans in Article 31 Predicted Purge Purge Ratio (1 ppm limit) Purge Ratio (30 ppb limit*) Triethyl amine 8.1 × 108 16200 486 DMF 7.3 × 109 36500 1095 Predicted Purge Purge Ratio (1 ppm limit) Triethyl amine 8.1 × 108 16200 DMF 7.3 × 109 36500
Initially
150 ppb)
Now
ppb)
This work has now been published: Org. Process Res. Dev. Just Accepted Manuscript, doi.org/10.1021/acs.oprd.0c00264
The chemistry of Amino, Nitroso and Nitro compounds and their derivative 1982, 1151-1223.
Strongest evidence of purge Evidence of purge – but limited quantity Variable purge – highly dependant on conditions and/or competition
20 40 60 80 100 120 140 NaBH4/Lewis acid H2/metal catalyst Fe/aqueous acid Zn/aqueous acid LiAlH4
Number of reported yields for reducing agents
WO2019236710A1 WO2003106457A1
Synthesis 1976, 548-550
Synthesis 1976, 548-550
Tetrahedron 1997, 38, 619-620
J Med Chem 1984, 27, 1710 - 1717
Strongest evidence of purge Available evidence suggests limited purge No data available
Majority of evidence of oxidation to nitramines is with peroxide reagents:
Synthesis, 1985, 1985, 677-679 US20090286994A1
Limited evidence of nitrosamine oxidation with inorganic reagents:
Chem Res Tox., 2000, 13, 72-81
Number of examples with reported yields 20 40 60 80 100 120 140 160 180 200 HClO4 chlorosulfonyl isocyanate HCl/CuCl HOAC H2SO4 TFA HCl
Nitroso nitrogen alkylation followed by α-carbon alkylation with excess Grignard reagent to form trisubstituted hydrazines.
Farina PR et al., J. Org. Chem., 1975, 40, 1070-1074
Nitroso nitrogen alkylation followed by α-carbon alkylation with excess Grignard reagent to form trisubstituted hydrazines.
Farina PR et al., J. Org. Chem., 1975, 40, 1070-1074
Violent reaction with diethylzinc:
Lachman A, Am. Chem. J., 1899, 21, 433-446
No reaction with diethylzinc:
Farina PR et al., J. Org. Chem., 1973, 38, 4259-4263 Vazquez AJ et al., Synth. Commun., 2009, 39, 3958-3972
Nitroso nitrogen alkylation, followed by dimerization to form hexahydrotetrazines. Nitroso nitrogen alkylation, followed by α-carbon alkylation to form trialkylhydrazines.
There is limited good quality data in the literature for nitrosamine reactivity – only 4 main transformations.
Hydrogen peroxide Hydrogen peroxide and acetic acid/trifluoroacetic acid
In the absence of a nucleophile, Y = NO2
pH, [HNO2] and Y -
Synthesis 2006, 2371-2375
Oxidative Nitrosating agents Imidoyl halide + nitrate Partial reduction
Metal amide nitrosation
Mirabilis 3
Mirabilis 4
Conditions identified
Risk reviewed
Warning Secondary amines are known to generate nitrosamines under acidic conditions when in the presence of a source of nitrite [Ref]
Justification
Conditions identified
Conditions identified
their control in line with ICH M7
within a risk assessment
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