Digital Pulsed Force Mode AFM and Confocal Raman Microscopy in Drug-Eluting Coatings Research
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Digital Pulsed Force Mode AFM and Confocal Raman Microscopy in Drug-Eluting Coatings Research G. Haugstad1 and K. Wormuth2 1 Characterization Facility, University of Minnesota, Minneapolis, MN, U.S.A. 2 Surmodics, Eden Prairie, MN, U.S.A. ABSTRACT Controlled release of amorphous drug from a polymer matrix depends intimately upon the degree of mixing of drug and polymer, the susceptibility of the drug to crystallization, and the ability of the drug to dissolve and diffuse through water-swollen polymer. Characterization methods ideally would follow these processes on the molecular level in situ and in real time. We move closer to this ideal state of characterization through application of two imaging methods: digital pulsed force mode atomic force microscopy (D-PFM AFM) and confocal Raman microscopy (CRM). We examine model spin-coated films ~1 μm thick containing the drug dexamethasone dispersed in poly(n-alkyl methacrylate) homopolymer and blend coatings. We report aqueous-immersion studies of surface and subsurface structural changes due to drug elution over time frames ranging from very fast (a few minutes) to slow (tens of hours). INTRODUCTION One particularly successful application of amorphous drug/polymer mixtures is as coatings on drug eluting stents. Controlled release of an anti-proliferative drug from the coating minimizes restenosis after a stent is placed to prop open a blocked artery. Despite successful application, the nature of amorphous drug elution from stent coatings remains incompletely understood. Open questions revolve around potential crystallization of the drug upon exposure to body fluids, diffusion of water and salts into the coating, and migration of drug out of the coating. Upon exposure of amorphous drug/polymer mixtures to an aqueous medium, water likely plasticizes the drug/polymer mixture and solubilizes the drug. Upon plasticization, drug mobility increases and the probability for drug crystallization rises. However, the presence of polymer may arrest crystallization or kinetically stabilize amorphous drug [1,2]. Here we directly examine drug-polymer coatings immersed in water and watch drug elution and crystallization employing atomic force microscopy for high-resolution (~1-10 nm) surface sensitivity and confocal Raman microscopy for lower resolution (~250-500 nm) but with 3D spatial sensitivity. EXPERIMENT Coatings of drug/polymer mixtures containing dexamethasone drug in (a) poly(butyl methacrylate) (PBMA),a 50:50 ratio, or (b) PBMA/poly(lauryl methacrylate) (PLMA) blends, a 43.5:43.5:13 ratio (minority PLMA, of rubbery character), were prepared by spin coating (50 mg solids per ml THF solvent) at 3000 rpm on silicon wafers (native oxide surface) with no further thermal or chemical treatment. Coated wafers were cleaved to provide pieces approximately 2x2cm in size, large enough to comprise the floor of an open AFM liquid cell. An Agilent Technologies 5500 scanning probe microscope with an attached digital pulsed force mode controller (D-PFM, WITec, GmbH) allowed the surfaces of the
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