No analytical method can be proven able to identify all potential impurities in a sample. What can be demonstrated is that a refined method can separate more impurities more completely from the pure substance than others. To develop such a method one needs an impure sample of the desired product containing as many of the process’s potential impurities as possible. This material is called the resolution standard. Besides being used to choose an appropriate analytic protocol, this material is used to show that the analytical equipment is functioning as required by the protocol before samples are run.
How to Make a Resolution Standard
Batches of synthetic API that are quite evidently impure, made by the envisioned process, using whatever unvalidated methods have been used in process development, are selected. As large a sample of each batch is taken as can be sacrificed, and these samples are combined, mixed, and as large a portion as will fit is packed into a mechanical blender. An anti-solvent is added to cover and completely moisten the solid, and the mixture is blended thoroughly but without substantially raising the temperature of the mass. The blending is stopped, and the mass is left for several hours. The wet mass is filtered to remove all the triturated solid. The clear filtrate was concentrated to dryness under vacuum, keeping any warming to a minimum. This solid from the evaporation will be a material with intensified impurities. If a further increase in the proportion of impurities is desired, the same procedure should be repeated, triturating this sample identically.
The method is called swishing.