Separation of Unprecedented Degradants of Domperidone by Ultra-Performance Convergence Chromatography and Their Structure Elucidation.

Domperidone, a gastroprokinetic agent, is a common drug to treat emesis. It was subjected to acid, base-mediated hydrolysis, peroxide-mediated oxidation, photolysis and thermal degradation according to ICH guidelines to observe stability of the selected drug under the stress conditions. Although the drug is resistant to base hydrolysis, photolysis and thermal stressors, two degradants (DP-ISO1 and DP-ISO2) were formed in acid mediated hydrolysis. Oxidation with hydrogen peroxide also resulted in one product (DP-OX). All three degradants were isolated from the crude reaction mixture by preparative high-performance liquid chromatography and supercritical fluid chromatography. Structures of isolated compounds were unambiguously characterized as 5-chloro-1-(1-(3-(6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (DP-ISO1), 5-chloro-1-(3-(4-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)propyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (DP-ISO2), 4-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)piperidine 1-oxide (DP-OX) by analysis of mass spectrometry, 1D and 2D nuclear magnetic resonance spectra. To the best of our knowledge, DP-ISO1 and DP-ISO2 are new and DP-OX was previously reported as domperidone impurity.

Structure elucidation of novel degradation products of thiocolchicoside by NMR spectroscopy.

Thiocolchicoside is a natural product analogue often used for its spasmolytic action. To know more about its stability under various stress conditions, the drug was stirred in acid, base and peroxide solutions. In acid hydrolysis, two products were obtained and in both, the glucose got cleaved. In one of them the acetyl group also got cleaved. A set of two diastereomers were formed during the peroxide mediated hydrolysis. The base mediated hydrolysis resulted in formation of three novel degradants. They have six membered rings in their structures instead of a seven membered cycloheptatrienone. Structures of known and novel degradation products have been elucidated by extensive analysis of HRMS, 1D and 2D NMR spectroscopic techniques.

Degradation study of irbesartan: Isolation and structural elucidation of novel degradants.

To assess the stability of Irbesartan under stress conditions, and identify the degradation products, it was subjected to hydrolytic and oxidative stress, according to ICH guideline Q1A (R2). The drug showed degradation only in basic conditions, while it was stable to other stress conditions. Three degradation products were formed, which were separated on a C-8 column employing prep HPLC using gradient elution. The structures were established by extensive 1D and 2D NMR spectroscopic studies and mass spectra. The products were identified as (2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methanamine (DP-1), N-((2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)pentanamide (DP-2) and N-((2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1-pentanamidocyclopentane-1-carboxamide (DP-3). One of the three, DP-1, was reported earlier. However, its structure has not been elucidated by NMR. The other two degradants are novel and are being reported here for the first time.