Effect of Surfactants on Posaconazole Crystallization and Polymorphism: Tween 80 vs Span 80

A surfactant is often present in a pharmaceutical formulation and can accelerate the crystallization of the active component. We investigate the effects of two common surfactants with different hydrophilic-lipophilic balance, Span 80 and Tween 80, on the crystallization of posaconazole (POS) in its two polymorphic forms (I and II). At 0-10 wt %, the two surfactants similarly increase the growth rates of both polymorphs, but have different effects on their nucleation rates, without exhibiting the proportional-modification behavior observed for many other amorphous systems. The classical nucleation theory (CNT) can quantitatively describe the nucleation kinetics in the pure POS melt and in the surfactant-doped melts, where the surfactants are treated as ideal diluents of POS. The two surfactants' effects on the nucleation rate form a single trend in the CNT analysis, yielding the nucleus/liquid interfacial tension σ = 0.019 J/m² for Form I and 0.012 J/m² for Form II. The σ value of 0.019 J/m² for Form I nucleating from a doped melt exceeds that for nucleating from a pure melt (0.012 J/m²), possibly reflecting a greater structural difference between a chemically pure crystal and an impure melt. This work has provided a strong test of the CNT by applying it to both pure and doped melts where the crystallization driving force is varied through temperature in the pure system and through concentration in the doped system, and yielded a simple picture for two chemically distinct surfactants on the crystallization in a polymorphic system.