HPLC separation of related impurities in etiprednol dicloacetate, a novel soft corticosteroid.
Etiprednol dicloacetate (ethyl 17alpha-dichloroacetoxy-11beta-hydroxy-androsta-1,4-diene-3-one-17beta-carboxylate, code-named: BNP-166) has been prepared in a 3-step synthesis from prednisolone as starting material. The primary aim of the present work was to develop HPLC methods for the separation of all the impurities found in experimental pilot plant batches of BNP-166 at concentrations > or = 0.10 area %. Besides BNP-166, a total of 19 compounds, eight of them potential impurities, were involved in the HPLC studies in which several HPLC systems were examined and tested to optimize the separation. Of the parameters influencing chromatographic behaviour column type, the nature and composition of the mobile phase and column temperature were varied, while the pH of the eluent was kept constant at 4.5, a pH value at which stability of the BNP-166 ester bonds was found to be the highest. A comparison of the RRT values obtained allowed some conclusions to be drawn concerning the physico-chemical forces governing separation. The isocratic reversed-phase HPLC system (V02) chosen to be used for various GXP studies on BNP-166 affords baseline separation of nearly all the compounds concerned, and also the quantitation of the drug candidate (BNP-166). By means of this system, it was shown that the target compound prepared by the standardized synthesis method on a pilot plant scale, never contained more than 2-3 impurities with area % values higher than 0.10.
Patthy
M
M
IVAX Drug Research Institute Ltd., Budapest, Hungary. Miklos.Patthy@idri.hu
Seres
G
G
Csanádi
A
A
Szekeres
T
T
Zubovics
Z
Z
Bodor
N
N
D000305:Adrenal Cortex Hormones / Q000737:chemistry*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D003460:Crystallization; D004340:Drug Contamination
D000305:Adrenal Cortex Hormones; C450000:etiprednol dicloacetate