Determination of Impurities in Drug Substances

Abstract

The present investigation involves a study of the characterization and determination of the major degradation impurities in selected drug substances and formulated products, i.e. bromazepam, diazepam, Cefixime trihydarte, cefazolin sodioum, simvastatin and lovastatin.. High Performance Liquid Chromatographic (HPLC) method has been used for the characterization of impurities present in a certain drug substance on comparison with the retention times of the reference standards. A complete separation of the individual drug substances and their major impurities has been achieved before a consideration of their determination. The tR values of the parent compounds are in the range of 2.71-9.22 and those of the impurities in the range of 1.23-20.57 min. Thus the separation and determination of these compounds can be carried out within 20 minutes. The HPLC assay method has been used to determine the parent compounds and their impurities after validation of the European Pharmacopoeal method used in this study. The validation of the HPLC method for the parent drugs and their degradation impurities involved the study of the parameters like specificity, linearity, precision and accuracy. In order to apply this method to the individual drug substances and their impurities all these parameters have been studied for each compound and the relevant data are presented. The overall recoveries of the parent drug substances and their impurities are in the range of 98 – 102%. The reproducibility of the method lies within 3% under the conditions used in this study. It needs to be emphasized that under pharmacopoeal requirements and guidelines of regulatory agencies it is mandatory to determine the impurities in excess of 0.1 % for the safety, efficacy and quality of the drugs. It is also important with a view point of the effect of variations in the synthetic routes of different manufacturers as well as due to the effects of packaging, shipment, and storage conditions. In addition to this the formulation adjuvants may also play a role in the formation of degradation impurities. The % contents of the selected drugs and their major degradation impurities in raw materials and formulated products have been determined and the range of the level of these impurities has been stated. In all cases the % content of the parent drugs and the formulated products are within the prescribed limits. However, the degradation impurities in the raw material as well as in the formulated product appear to exceed the level prescribed by ICH and other regulatory agencies. This could possibly result from variations in the manufacturing synthetic processes of different manufacturers for the raw materials and the manufacturing procedures and drug-excipient interactions for the formulated products. An attempt has been made to conduct forced degradation studies on these drug substances to predict the formation of different degradation products under stress conditions. This study includes the acid and alkaline hydrolysis and oxidation using H2O2. In acid solution the degradation appears to be higher than that observed in the alkaline medium (80 ± 0C). The major route of degradation of these compounds is hydrolytic cleavage of the molecule which may result from the effects of drug- excipient interactions and the environmental factors. The present study provides useful information to the formulator in the design of formulation strategies to minimize the formation of degradation impurities so as to achieve a better quality and efficacy of the formulated products. It also establishes the importance of the effects of variations in synthetic routes, process parameter and role of excipients on the formation of impurities.