Imidacloprid Crystal Polymorphs for Disease Vector Control and Pollinator Protection

Abstract

Imidacloprid, the world’s leading insecticide, has been approved recently for controlling infectious disease vectors; yet, in agricultural settings, it has been implicated in the frightening decline of pollinators. This argues for strategies that sharply reduce the environmental impact of imidacloprid. When used as a contact insecticide, the effectiveness of imidacloprid relies on physical contact between its crystal surfaces and insect tarsi. Herein, seven new imidacloprid crystal polymorphs are reported, adding to two known forms. Anticipating that insect uptake of imidacloprid molecules would depend on the respective free energies of crystal polymorph surfaces, measurements of insect knockdown times for the metastable crystal forms were as much as nine times faster acting than the commercial form against Aedes, Anopheles, and Culex mosquitoes as well as Drosophila (fruit flies). These results suggest that replacement of commercially available imidacloprid crystals (a.k.a. Form I) in space-spraying with any one of three new polymorphs, Forms IV, VI, IX, would suppress vector-borne disease transmission while reducing environmental exposure and harm to nontarget organisms.

Crystallography of Contemporary Contact Insecticides

“…We also observed identical trends for newly discovered polymorphs of deltamethrin (DM) and imidacloprid (IMI) [ 1 , 2 ], among the most widely used insecticides today. A second DM polymorph, denoted Form II after structural characterization by our laboratory [ 1 ], was found to be nine and twelve times faster acting than Form I against Aedes aegypti and Anopheles quadrimaculatus mosquitoes, respectively [ 1 ].…”

“…Whilst much effort has been expended in the development of new compounds with improved efficacy, little attention has been paid to the solid-state structure of crystals that the insects encounter. Recent reports from our laboratory have revealed that the insecticidal activity of a particular contact poison depends on the crystal structures and associated free energies of its solid forms, also known as polymorphs, which often are accessible under ambient conditions [ 1 , 2 , 3 , 4 , 5 ]. Some crystal forms of a given contact insecticide can knock down mosquitoes twelve times faster than the commercially available form [ 1 , 2 ]…”

“…The two polymorphs not only differ with respect to the molecular arrangement in the solid state and the molecular presentations at their crystal surfaces, but they also differ with respect to the conformation of the DM molecules in the crystal lattice ( Figure 1 ). Subsequently, we discovered new polymorphs of imidacloprid with different molecular conformations [ 2 ], the least stable polymorph exhibiting nine times greater activity against these mosquitoes than the commercial thermodynamically stable form. Importantly, these metastable forms were found to be stable against transformation to the thermodynamically stable form for at least six months, meeting World Health Organization guidelines for practical use in the field.…”

Direct Structure Determination from Spherulites using 3D Electron Diffraction

“…Recently, we established a general strategy for cultivating single crystals from melt microdroplets 38 . Despite a high success rate in our lab 21,32,34,39 and other groups 22,24,40,41 , this method is incompatible with metastable polymorphs that undergo a solid-solid phase transition when heated.…”

“…Melt crystallization has recently shown great potential for its application in pharmaceutical polymorph screening [21][22][23][24][25][26][27][28][29][30][31][32][33][34] , as it can suppress nucleation whilst giving a large driving force to provide a crystallization pathway to access regions of the potential energy landscape inaccessible by traditional methods 35 . For example, nicotinamide, a naturally occurring form of vitamin B3, yields nine polymorphs from melts 21 , whereas only two polymorphs can crystallize from solution 36 .…”