Abstract
All activities should aim to eliminate genotoxic impurities and/or protect the API against degradation. There is a necessity to monitor impurities from all classification groups, hence ivabradine forced degradation studies were performed. Ivabradine was proved to be quite durable active substance, but still new and with insufficient stability data. Increased temperature, acid, base, oxidation reagents and light were found to cause its degradation. Degradation products were determined with the usage of HPLC equipped with Q-TOF-MS detector. Calculations of pharmacological and toxicological properties were performed for six identified degradation products. Target prediction algorithm was applied on the basis of Hyperpolarization-activated cyclic nucleotide-gated cation channels, as well as more general parameters like logP and aqueous solubility. Ames test and five cytochromes activities were calculated for toxicity assessment for selected degradation products. Pharmacological activity of photodegradation product (UV4), which is known as active metabolite, was qualified and identified. Two other degradation compounds (Ox1 and N1), which were formed during degradation process, were found to be pharmacologically active.
Highlights
Guidelines for assessing the quality of active pharmaceutical ingredient (API) and medicinal products has been developed by ICH, FDA, WHO or EMA, which are focused to the greatest extent, firstly to verify the stability of the API through the establishment of various tests and the way there are conducted (ICH Q1A, 1993)
For a comprehensive evaluation process associated with the pharmaceutical stability, there is a need to perform various tests, which results should be the answer whether the drug substance is stable
Photostability tests are characterized by particular specificity and are an integral part of stability tests that are included in standard, ICH Q1A (1993)
Summary
Guidelines for assessing the quality of active pharmaceutical ingredient (API) and medicinal products has been developed by ICH, FDA, WHO or EMA, which are focused to the greatest extent, firstly to verify the stability of the API through the establishment of various tests and the way there are conducted (ICH Q1A, 1993). Studies are performed to explore various paths of the potential degradation of the API, evaluating the rate of changes under the influence of various factors. For a comprehensive evaluation process associated with the pharmaceutical stability, there is a need to perform various tests, which results should be the answer whether the drug substance is stable. The most important for the drug substance are so-called stress tests, which involve overly intense exposure to factors such as: strong acid, base, hydrogen peroxide, high temperature or light, Forced Degradation Studies of Ivabradine in a manner individual to the different drugs (ICH Q1A (R2), 2003; Waterman and Adami, 2005). There is a special need to recognize all possibilities of degradation of new pharmaceutical compound especially those, which are not recognized in Pharmacopeia yet
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