Make very accurate solutions without weighing

I am currently facing a hen-egg problem. For a LC-MS method development I need to prepare reference solutions which are used to calibrate the method. Since the method is to be used for quantification in the pg/mL range, the reference solutions should have the most accurate concentrations possible. Of course I know how to prepare exact solutions in volumetric flasks, but here substance quantities are used which can be weighed easily and also quite exactly. In my case, only a few milligrams of the substance are available to me, which is why I cannot weigh high masses. The precision balance that I have at my disposal has a lower weighing limit of 1 mg, which is about the same as the mass that I would have to weigh. However, since the lower limit is very error-prone, I do not like this method. Unfortunately, I cannot think of an alternative solution that would allow me to create an exact solution without weighing. One could of course dissolve any amount of substance in the desired solvent and then determine the concentration by LC-MS, but this is exactly where the hen-egg problem mentioned above occurs. I cannot quantify via LC-MS until I have a suitable method and an internal standard. Are there any other ideas how to get exact concentrations using small amounts of the desired substance?

• Is what you are trying to weigh a salt? eg if a sodium salt then you could analyze the solution for sodium for which you could prepare standards by weighing a different salt and diluting.
– MaxW
Jun 22, 2020 at 8:25
• No, unfortunately not.
– Sam
Jun 22, 2020 at 8:30
• Is it possible for you to describe a little further about the nature of this reference substance? Molweight (roughly, say 100, 200, 500, 1000 g/mol)? What about mixing your compound with something down the road equally is diluted enough to not not interfere badly with your LC-MS, but initially eases the weight-in? E.g., murexide (en.wikipedia.org/wiki/Murexide) is mixed 1:250 or even 1:500 with Na2SO4 and still then it is a powerful indicator for heavy metals. Then an aliquote could be electrochemically analyzed (if reversibly responsive) by redox and cyclic voltammetry. Jun 22, 2020 at 13:32
• What is the nature of your sample (peptide / protein / oligomer / dye)? In similar tune to @MaxW, researcher isolating natural products / determining LC50 values work with small quantities (e.g., doi 10.1039/C3NP20106F finally mentions a prep GC to yield just 2.22 mg of Caratol (MW < 200)). Then, the folks in radiochemistry equally use tiny amounts of matter only. Jun 22, 2020 at 13:52
• @Buttonwood The reference substances are steroid hormones of an MW-range of 270 to 400 g/mol. As we have a common weighing room, the other labs won't have balances that are more precise and I even don't know anyone of my circle of acquaintances who has access to such a device. Your idea of mixing the compound could be an idea, I'll have a closer look into this. Thanks!
– Sam
Jun 22, 2020 at 15:12