I am trying to validate an LCMS instrument with clinical drugs.

When most of my analytes look good, I have a about 8 drugs which does not pass the validation for lower calibrators if I use the corresponding IS.....but they seem to pass if I use an IS from another group of analytes. For example, for cotinine when I use the nicotine IS, the lower calibrators are not passing but if I use 6-MAM-D3 they seem to pass. Similarly, for Methylphenidate, when I use Ritanalic acid IS, lower calibrators do not pass but when I use Desipramine IS they pass. 

Any thoughts on this....any recommendations how to correct.

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