Surfactants Accelerate Crystallization of Amorphous Nifedipine by Similar Enhancement of Nucleation and Growth Independent of Hydrophilic-Lipophilic Balance.

Amorphous formulations, increasingly employed to deliver poorly soluble drugs, generally contain surfactants to improve wetting and dissolution. These surfactants are often liquids and can potentially increase the mobility of the drug and reduce its stability, but little is known about this effect. Here we investigate the effect of four common nonionic surfactants (Tween 80, Span 80, Triton X-100, and Poloxamer 407) on the crystallization of amorphous nifedipine (NIF). We find that the surfactants significantly enhance the rates of crystal nucleation and growth even at low concentrations, by up to 2 orders of magnitude at 10 wt %. The surfactants tested show similar enhancement effects independent of their structural details and hydrophilic-lipophilic balance (HLB), suggesting that surfactant adsorption at solid/liquid interfaces does not play a major role in crystal nucleation and growth. Importantly, the surfactants accelerate crystal nucleation and growth by a similar factor. This result mirrors the previous finding that a polymer dopant in a molecular glass-former causes similar slowdown of nucleation and growth. These results indicate that nucleation and growth in a deeply supercooled liquid are both mobility-limited, and a dopant mainly functions as a mobility modifier (enhancer or suppressor depending on the dopant). The common surfactants tested are all mobility enhancers and destabilize the amorphous drug, and this negative effect must be managed using stabilizers such as polymers. The effect of surfactants on nucleation can be predicted from the effect on crystal growth and the crystallization kinetics of the pure system, using the same principle previously established for drug-polymer systems. We show how the independently measured nucleation and growth rates enable predictions of the overall crystallization rates.