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Hydroxylamine reacts with benzonitrile 6 during Stage 2 to form the benzimidamide 7 (Figure 3.4). A 2.5 molar excess of the reagent is used to assure reaction completion, and therefore, as much as 1.5 equivalents might remain within the Stage 2 process after formation of 7.

Hydroxylamine has an ADI of 23 μg/day that equates to a permitted limit of ≤ 38 333 μg/g of GW641597X and correlates to a required purge factor of 39.1 (1 500 000/38 333 = 39.1).

With respect downstream purging, hydroxylamine free base has a low boiling point (58°C), and it is reasonable to expect losses through evaporation during higher temperature processing as well as during isolation and drying through volatilization. Despite this, a conservative approach was taken and volatility was not scored for the entire process. Hydroxylamine can be considered to purge through solubility within processes to prepare 7, 8, 9, and GW641597X, and reactivity was anticipated during Stages 3 and 4 for the preparation of 8 and 9 through reaction with chloroacetyl chloride and alkyl chloride 8, respectively. Even with the application of a highly conservative approach i.e. assuming a starting concentration of 1.5 equivalents and discounting likely volatility, the predicted purge factor was significant, 1 × 10⁸ (Table 3.8). The purge ratio is significantly greater than 1000, which justifies an ICH M7 Option 4 control rationale without recourse to additional experimental data and simply reporting “unlikely to persist” should be sufficient for a regulatory submission as per the published guidance [19].

Table 3.8 Purge predictions for hydroxylamine.

Stage	Reactivity	Solubility	Volatility	Total	Rationale
2	1	10	1	10	2.5 Equivalents used in Stage 2 – anticipate 1 equivalent would react as reaction is high yielding. Hydroxylamine anticipated to be highly soluble in the isolation solvent (aqueous ethanol). Volatility during isolation and drying expected but not included within the prediction.
3	100	10	1	1000	Expected reaction with chloroacetyl chloride. Anticipated solubility during extraction process (aqueous acid). Volatility during “put and take” drying process expected but not included within the prediction.
4	100	10	1	1000	Expected reaction with alkyl chloride 8 and solubility within isolation solvents (aqueous ethanol). Volatility during isolation and drying expected but not included within the prediction.
5	1	10	1	10	Anticipated solubility within the crystallization/isolation solvent (denatured ethanol). Volatility during isolation and drying expected but not included within the prediction.
Predicted purge factor (Required purge)	1 × 108 (39) Purge ratio = 2.56 × 106 (informs ICH M7 Option 4 control)