Thermal and Structural Characterization of Fipronil

Abstract

Fipronil is a widely used insecticide which exerts selective toxicity towards the GABA receptors of insects and has no known pesticide resistance in target insects. This, in turn, has led to the increase in the usage of fipronil as an alternative to commonly used pesticides in residential, industrial, commercial and agricultural settings. In this study, fipronil was considered for use as the chemical active in a controlled-release polymer system applied as alternative to indoor residual spraying in the fight against malaria. However, before incorporating the insecticide in a polymer, the vaporization and polymorphic behaviour of fipronil had to be studied. This information is important in providing guidance for the implementation of suitable safety measures during polymer processing to prevent exposure or contact to substances which could potentially harm one's health. On the other hand, polymorphism affects various physicochemical properties like the melting point, solubility, stability and manufacturability of a compound, which are extremely important for quality control and assurance. Differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD) and single crystal X-ray diffraction (SCXRD) were used to study the vaporisation and polymorphic behaviour of fipronil. Sublimation and evaporation rates were determined using isothermal TGA. From these results, vapour pressures were deduced on the assumption that the fumes behaved like ideal gases and that mass loss was controlled by diffusion through the gas present in the partially-filled crucible. For the latter process, the diffusion coefficient was estimated using the Fuller correlation. Results obtained using benzoic acid as the calibration standard suggested that it is possible to estimate vapour pressures to within 12% with this TGA method. The enthalpies of sublimation and of evaporation were determined as 120 ± 4 and 72 ± 5 kJ mol-1, respectively. Polymorphic behaviour was studied through a systematic comparison of the thermal and structural properties of different crystal forms, including those obtained in this study and in literature. DSC was particularly useful in differentiating between two different crystal forms found in the as-received neat fipronil. Two polymorphs were successfully separated through sublimation of neat fipronil. A metastable, lower melting polymorph and a thermodynamically stable, higher melting form were obtained in the sublimate and residue, respectively. The lower melting polymorph was found to be unstable at high heating rates, with evidence suggesting a solid-solid phase transition to the stable form at low heating rates. Solvent recrystallization of neat fipronil in acetonitrile, acetone, ethyl acetate and methanol yielded five different crystal forms of fipronil. TGA curves revealed that all five crystal forms, except for the acetone-derived sample, were solvate pseudo-polymorphs exhibiting solvent loss between 60 and 100 °C. The acetone-derived sample was found to be a hemihydrate exhibiting mass loss at 120 °C. SCXRD studies revealed that three of the five forms had similar structural characteristics, while the other two forms differed notably from each other and the rest of the structures. Despite these differences, all five forms exhibited near-identical intra- and intermolecular hydrogen bond networks. The sublimation and evaporation enthalpies were successfully determined and the data indicates that fipronil will likely sublime at polymer processing conditions above 150 °C. The study also demonstrated, by DSC analysis, that the lower melting form in the neat, as-received fipronil would be converted to the high melting, thermodynamically stable form at the polymer processing conditions.