Impurity of Risedronate Sodium

[syx]

Dear Members,
Related to the post: Impurity makes a split peak, Risedronate.
Does anyone let me know where I could get the impurities for Risedronate sodium (in the post it is ortho risedronic acid)? I have tried to search in Sigma-Aldrich but they do not have it.

Thank you and best regards,
Siswanto Tanuatmojo

[syx]

First formula of our risedronate sodium was containing calcium salt as the inactive ingredients. That time, we only got result 40% in recovery. I asked formulator to remove the calcium from the formula.
Now the only 'metal' in the formula is Mg-stearate and we got approx 97% in recovery. I suggest that the Mg is the reason. How could we extract risedronate from the tablet in the present of Mg? Any idea?

[Mark Tracy]

The *dronate drugs are all pyrophosphate analogs. I would suggest adding excess pyrophosphate to compete for the metal ions.

The use of calcium or magnesium in the drug formulation will affect absorbtion by the body. I don't know which direction the effect will be, but removing calcium is a non-trivial change in formulation.

[syx]

where should I put the pyrophosphate? In diluent, mobile phase, or both?

[Mark Tracy]

In the context of sample extraction, I would use it in the extraction solution, at a 2-fold molar excess over the metal content. I always used the tetrasodium pyrophosphate because that is what we had in the lab, and it was of good quality. The tetrasodium salt is alkaline, so watch your pH. If you want to add it to the mobile phase to suppress metal effects, you only need 0.5 millimolar in the aqueous phase; it is not very soluble in water, and practically insoluble in pure MeCN. In the absence of biological activity, it is stable for at least a week. It is effective even in 0.1% TFA solution, where EDTA is not.

[syx]

I would use it in the extraction solution, at a 2-fold molar excess over the metal content.

For example, if we use 5 mg per tablet of magnesium stearate as lubricant, should we calculate it as the same portion in solution though it is insoluble in the solvent?

[Mark Tracy]

Yes. The idea is to lock up all the magnesium as the pyrophosphate so that it can't bind the risendronate.

[syx]

Thank you for the advise, Mark. I will try it... I will purchase the pyrophosphate today.