A novel pseudo-azeotrope mosquito repellent mixture

Abstract

Repellents play a key role in preventing mosquito-borne diseases such as malaria by reducing human-vector contact. The general mechanism of action relies on providing a repelling vapour around the applied area on the skin. Thus, the proper evaporation rate and consistency of the composition of the released vapour are factors determining the performance of repellent formulations. The formulation should evaporate fast enough to provide a sufficient level of repellence during its life time. However, if evaporation proceeds too fast, then it will be depleted rapidly so that activity is lost within a short period of time, which makes the repellent inefficient. Several controlled-release approaches have been developed to improve both the protection time and level. However, these techniques have inherent drawbacks from the industrial point of view. Moreover, these techniques mostly focus only on reducing the release rate, while the consistency of the vapour composition has not been addressed. In the present study, a novel approach towards controlling the evaporation behaviour of repellents is proposed. It is based on engineering the molecular interactions in order to design negative pseudo-azeotrope formulations. Negative pseudo-azeotrope mixtures are less volatile than the pure parent components and they do not undergo separation during evaporation. The feasibility of the idea was investigated by studying the molecular structure of generally available repellents. Among known molecular interactions, hydrogen bonding has the most likely impact on the formation of azeotropes and in particular pseudo-azeotropes. Thus, established repellents were classified based on their chemical structures and their capability to take part in hydrogen bonding. Next, a simple spectroscopic method for anticipating pseudoazeotropes formation was developed. Binary compositions of nonanoic acid and ethyl butylacetylaminopropionate (IR3535) showed a potential for forming pseudo-azeotrope mixtures. Hence R3535 and nonanoic acid were selected as model compounds to test the hypothesis. An experimental technique to confirm pseudo-azeotrope formation and to locate the composition of the probable pseudo-azeotrope point was required. To this end, an oven test was designed. The temporal mass loss, under an isothermal program, of a series of evaporating mixtures was measured. Simultaneously, the Fourier transform infrared (FTIR) spectra of the liquid remaining was recorded. Inverse analysis techniques were used to determine the composition of remaining liquid mixtures from the recorded FTIR spectra. The oven tests revealed that, as vaporisation progressed, the composition of the liquid remaining and the emitted vapour converged to a fixed IR3535 content of ca. 75 mol%. Mixtures close to this composition also featured the lowest volatility. Oven test also showed that the composition of the liquid mixtures diverged from the fixed IR3535 content of ca. 10 mol%. Mixtures close to this composition featured the highest volatility. These observations showed that IR3535 and nonanoic acid forms two pseudo-azeotrope compositions, i.e. a negative pseudo-azeotrope at an IR3535 content of ca. 75 mol%, and a positive pseudo-azeotrope at IR3535 content of ca. 10 mol%. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were applied to check these results. TGA confirmed that the negative pseudo-azeotrope mixture is less volatile while the positive pseudo-azeotrope is more volatile than the parent compounds. The DSC results revealed that in comparison with the pure compounds, negative pseudo-azeotrope had a lower boiling point onset while the positive pseudo-azeotrope had a higher boiling point. Although negative pseudo-azeotrope repellent formulations have the desired lower constant release rate, their repellent activity needed to be tested. This is due to the fact that mixing the ingredients to formulate a negative pseudo-azeotrope results in interactions among the components. As a consequence, the inherent repellence effect of the compounds might have been impaired in the mixture. The modified arm-in-cage test was used to test the repellence of the controlled-release repellent formulation i.e. the negative pseudo-azeotrope of the IR3535 + nonanoic acid system. Results showed that the mixture featured improved performance with respect to both repellence efficacy and persistence. Moreover, the negative pseudo-azeotrope also exhibited a knock down effect, even resulting in mortality of most of the test mosquitoes. The presence of two pseudo-azeotrope points at different composition in the IR3535 + nonanoic acid system is a rare occurrence, analogous to double azeotropy. Thus, molecular simulation techniques were used to explore the nature of system and the interactions responsible for this unique behaviour. Gibbs-Monte Carlo simulation results suggest that variations in the sizes of the molecular clusters present in the liquid at various compositions might be responsible. They revealed that IR3535 and nonanoic acid in neat form are both highly structured liquids. The break-down in the structure of IR3535 at high concentrations of the acid may be the origin of increased evaporation rate and formation of the positive pseudo-azeotrope. On the other hand, negative pseudo-azeotrope may be resulted from formation of bulkier clusters at the ration of 3:1 (IR3535: nonanoic acid).