An Overview on Chemical Derivatization and Stability Aspects of Selected Avermectin Derivatives

• Published in: Chemical & pharmaceutical bulletin Vol. 60; no. 8; pp. 931 - 944
• Main Authors: Awasthi, Atul, Razzak, Majid, Al-Kassas, Raida, Harvey, Joanne, Garg, Sanjay
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 2012; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Animals; Anthelmintics - chemistry; avermectin; chemical stability; degradation mechanism; Drug Stability; Hydrogen-Ion Concentration; Ivermectin - analogs & derivatives; Ivermectin - chemistry; macrocyclic lactone; Molecular Structure; natural product; Oxidation-Reduction; related substance
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c12-00258

Naturally occurring avermectins (AVMs) and its derivatives are potent endectocide compounds, well-known for their novel mode of action against a broad range of nematode and anthropod animal parasites. In this review, chemical and pharmaceutical aspects of AVM derivatives are described including stability, synthetic and purification processes, impurities and degradation pathways, and subsequent suggestions are made to improve the chemical stability. It has been found out that unique structure of AVM molecules and presence of labile groups facilitated the derivatization of AVM into various compounds showing strong anthelmintic activity. However, the same unique structure is also responsible for labile nature related to sensitive stability profile of molecules. AVMs are found to be unstable in acidic and alkaline conditions. In addition, these compounds are sensitive to strong light, and subsequently presence of photo-isomer in animals treated topically with AVM product is well known. The pharmacoepial recommendations for addition of antioxidant into drug substance, as well as its products, arises from the fact that AVM are very sensitive to oxidation. Formations of solvates, salts, epoxides, reduction of double bonds and developing liquid formulation around pH 6.2, were some chemical approaches used to retard the degradation in AVM. This coherent review will contribute towards the better understanding of the correlation of chemical processes, stability profile and biological activity; therefore, it will help to design the shelf-life stable formulations containing AVMs.