Article révisé par les pairs
Résumé : Substrate-inducedpolymorphism(SIP)representsapromisingstrategyfordirectingthecrystallizationpathwaysofactivepharmaceutical ingredients(APIs),yetitsapplicationtomolecularsystemsremainsrelativelylimited.Here,weexamineSIPinFenofibrate, focusingontheinfluenceofsubstratechemistryandsolutionconcentrationonthepolymorphicoutcome.Onpristinesilicone substrates with native silicon oxide (SiO2), the resulting polymorphic formwas primarily determined by solutionconcentration.LowsolutionconcentrationsfavortheconcomitantnucleationofmetastableFormIVandstableFormI,whilehigherconcentrations favor the stableFormI.Toexplore the roleof surfacechemistry, SiO2 substrateswere covalentlygraftedwithmonolayersofFenofibratederivatives,whichsignificantlyalteredthenucleationbehaviorandpolymorphselectioncomparedwiththepristineSiO2.Surfaces functionalizedwithmonofunctionalorganosilane-FenofibrateconsistentlypromotedexclusiveformationofFormI,whereasthosemodifiedwithpolyfunctionalorganosilane-FenofibratesupportedthecrystallizationofstableFormIaswellasmetastableFormsII, III, andIV,dependingonsolutionconcentrationandsurfacehydrophobicity.Thesefindingsdemonstratethat engineeredmolecular interfaces candirect crystallizationkinetics andpolymorph selection, establishingSIPas apowerfulapproachforstabilizingbothstableandmetastableAPI forms.Althoughnonewpolymorphswereobtained, theseresultsestablishthatgraftedmolecular interfacescanmodulateboththekineticsandoutcomeofAPIcrystallization.SIPthusrepresentsaversatilestrategyforselectivelystabilizingdesiredpolymorphsandtailoringcrystallizationprocesses throughrational surfacedesign.

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