Synthesis of the impurities during the manufacture of bulk drug midazolam and separation of these impurities by HPLC

Abstract

Impurities can be closely related to the product that is formed during the synthesis of a bulk drug or it can be decomposition product formed during the storage of the drug. The International Conference on Harmonization (ICH) has published guidelines on impurities in new drug substances, products and residual solvents. According to ICH guidelines, an impurity should not exceed 0.1 % and total impurity should not exceed 1.0 % in manufacturing each batch of the drug (1, 2). Impurities present in excess of 0.1 % During the manufacture of bulk drug midazolam various impurities arised that can be the related products or degradation products. Structures of eight impurities that can arise during the manufacture of bulk drug midazolam were proposed. In the present work, synthesis of these impurities and their characterization by different spectroscopic techniques have been done. HPLC method was developed for the separation of impurities from the bulk drug. The developed method separates midazolam from its eight impurities/degradation products within a run time of 45 min.

Purification and Concentration of Minor Impurity in the Bulk Drug by Step-Gradient Twin-Column Recycling Chromatography

“…Run Col (8) where Pr represents the productivity of the critical impurity, C Feed represents the concentration of the critical impurity in the feed solution and is the product of its initial content in raw material and the total concentration (C Bulk ), t Run is the total time of a whole operation process including feeding, valve switching, and product recovery, and V Col is the column volume.…”

“…The common methods to obtain impurities include straightforward chemical or biological synthesis and chromatographic separation. Straightforward synthesis requires multiple steps including characterization of the impurity structure, speculation about its possible source, design of a feasible formation pathway, and verification of the as-synthesized product so that the whole process is complex, and the as-obtained raw impurity usually still needs further purification. , Therefore, it is more economical to isolate impurities in bulk drug through chromatography directly. , There are two main difficulties in the chromatographic separation: first, as the physical and chemical properties of some critical impurities are very close to API, it is very difficult to isolate the critical impurities with standard chromatographic techniques; second, the impurity with low original content is continuously diluted in the separation process due to band broadening, resulting in extremely low concentrations of the qualified fraction, and the target impurity would be easily decomposed and deteriorated during evaporation and recovery.…”