Use of Carbodiimides as Stabilizing Agents to Deliver Water—Labile Active Ingredients in Liquid Systems Including Aqueous Medium—Amitraz as a Case Study

Abstract

Abstract Several active ingredients such as sulfonylureas and diimidines (Amitraz) are unstable in water. They undergo hydrolysis producing metabolites that are no longer biologically active. The rate of hydrolysis is a function of several factors, such as the solvent system, access to water, pH, temperature, ionic strength, and the types of emulsifiers used in the liquid matrices. Some of the active ingredients undergo rapid hydrolysis even with the residual water present in the emulsifier system in an organic emulsifiable concentrate formulation. It is therefore difficult to formulate such active ingredients in liquid delivery systems. Use of carbodiimides like Stabaxol I® (bis-2,6-diisopropylphenylcarbodiimide) as a water scavenger to stabilize oil-based formulations for Amitraz is well documented and is commercially practiced. We have found that unique combinations of carbodiimides with specific solvent-emulsifier-polymer blends in a buffered system can produce stable microemulsions of Amitraz in water. Such aqueous formulations with 200–500 ppm Amitraz in >99 % water, were stable with 95 % retention on accelerated storage at 50°C for two weeks. This data translates to greater than two years stability at room temperature. Such formulations may be extended to deliver sulfonylureas. We also observed that the concentrate and the matrix containing Stabaxol I® and emulsifiers can produce gels on storage, adversely affecting physical stability. We have identified several additives and alternatives to prevent gel formation enabling long-term storage stability of the matrix and the concentrate. Examples with supporting data will be provided. A rationale and proposed mechanism for the enhanced stability and potential biological activity will be discussed.