Substrate-induced polymorphism (SIP) represents a promising strategy for directing the crystallization pathways of active pharmaceutical ingredients (APIs), yet its application to molecular systems remains relatively limited. Here, we examine SIP in Fenofibrate, focusing on the influence of substrate chemistry and solution concentration on the polymorphic outcome. On pristine silicone substrates with native silicon oxide (SiO2), the resulting polymorphic form was primarily determined by solution concentration. Low solution concentrations favor the concomitant nucleation of metastable Form IV and stable Form I, while higher concentrations favor the stable Form I. To explore the role of surface chemistry, SiO2 substrates were covalently grafted with monolayers of Fenofibrate derivatives, which significantly altered the nucleation behavior and polymorph selection compared with the pristine SiO2. Surfaces functionalized with monofunctional organosilane-Fenofibrate consistently promoted exclusive formation of Form I, whereas those modified with polyfunctional organosilane-Fenofibrate supported the crystallization of stable Form I as well as metastable Forms II, III, and IV, depending on solution concentration and surface hydrophobicity. These findings demonstrate that engineered molecular interfaces can direct crystallization kinetics and polymorph selection, establishing SIP as a powerful approach for stabilizing both stable and metastable API forms. Although no new polymorphs were obtained, these results establish that grafted molecular interfaces can modulate both the kinetics and outcome of API crystallization. SIP thus represents a versatile strategy for selectively stabilizing desired polymorphs and tailoring crystallization processes through rational surface design.
Sundareswaran et al. (Tue,) studied this question.