In one of our pregnane ring structure related product (Drospirenone), we are facing one impurity (i.e. 6-Methyl Drospirenone impurity) problem. The observed level of impurity is about 1% on USP HPLC RS method. We have done so many purification process trials in lab (Column chromatography, recrystallziation, fraction crystallization, combination of mixture of solvents, tried different adsorbents). But there is no success till date for removal of this impurity from product.
Kindly help us to for development of purification process for removal of this impurity from product. The product and impurity structure are attached.
Ketones form typical derivatives like DNPH, semicarbazones, oximes, etc. which may be purified, then regenerated into initial ketones. This is kind of old school chemistry... which maybe difficult, time consuming, inefficient, I don't know.
Dear Gang Chen,
This is the principle of the question section of RG to try helping for free young researchers and colleagues. I spent some time (time is money 😉) to write answers, eventually searching the literature ...
Regards,
J-F Gal
Drospirenone has a couple of strained 3-member rings. Look at your process to see if there are conditions (heat?) that opens one of the rings.
Dear J-F Gal,
Thanks for your valuable words and attention to my problem. Hoping you get favorable response soon after your search.
Thanks,
Deep
Hi Jack Silver,
Yes, absolutely right, this impurity formed at elevated temperature during synthesis of molecules. Control over impurity formation is found, but we need purification process for reduction of impurity in generated material.
Deep Chand Agrawal what is the retention difference between your desired compound and nearest impurity on your analytical column? You should be able to scale from analytical to prep.
In analytical column RRT is 1.3 and we already separated on Prep column. But we need commercial purification process. Preparative column process technique is very costly and not commercially viable.
What was the solvent system you used on your column to run your sample?
Hi Dauda Garba,
We are using acetonitrile (70%) and Water (30%) by HPLC analysis method.
But have you tried using a normal conventional column, i.e., silica gel chromatography? This will save you money. mounting a small column with a silica gel mesh size of 60/120 using hexane as an eluting solvent, then gradually introducing ethyl acetate by 2-5% while monitoring the process using a TLC plate.
Thanks Dauda Garba, We have tried 60/120, 100/200, 230-400 and 400-700 mesh size with pressure and without pressure. Minor separation observed in 230-400 silica gel mesh by using gradient mobile phase (Ethyl acetate: cyclohexane from 0 to 30% gradually). The separation is very poor. First we need to get separation over TLC method, the same method shall be applied to column. But unable to get better separation over TLC till date.
Sure sir, will share all details over mail shortly. Our product is freely soluble in Methylene Dichloride, Dimethyl formamide and Tetrahydrofuran, soluble in Methanol and Ethyl Acetate, insoluble in water and non-polar solvents (like cyclohexane, hexanes and n-Heptane)
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