Rapid polymorphic screening using sessile microdroplets: competitive nucleation of mannitol polymorphs

We developed a rapid polymorphic screening approach based on contracting sessile microdroplets, which offers several advantages: (1) achieves very high supersaturation to facilitate formation of metastable forms; (2) allows systematic labeling of samples; (3) gives access to the statistical distribution of polymorphic selectivity as a function of experimental conditions; (4) ensures the formation of crystal for each droplet, addressing the problem of uncrystallized droplets in traditional microfluidics. We studied the competitive nucleation of d -mannitol polymorphs and investigated the effect of droplet volume on polymorphic selectivity. We showed that our observed polymorph distributions at different volumes are qualitatively consistent with the predictions of classical nucleation theory except for very small volumes where thermodynamic confinement or surface effects could play a substantial role. Overall, our microfluidic approach can be a promising tool not only for routine screening of pharmaceutical polymorphs in the industrial context but also in the fundamental understanding of the mechanisms underlying the competitive nucleation of polymorphs. Using microdroplets, we developed an approach to rapidly measure the nucleation statistics of polymorphs. It can be useful in the routine screening of pharmaceutical solid forms, and in the study of the competitive nature of polymorphic nucleation.