Improved 3D-imaging of a sirolimus/probucol eluting stent coating using laser postionization secondary neutral mass spectrometry and time-of-flight secondary ion mass spectrometry

Implantable drug delivery systems that provide controlled and sustained release of a therapeutic agent are used in a wide variety of applications. Drug eluting stents, which are used to treat coronary artery disease, are among the most widespread of these devices, with an estimated 3 x 10(6) implants annually worldwide. Controlling the rate of drug release from these devices relies on precise control of the three dimensional (3D)-distribution of the drug, so methods for measuring this distribution are of great importance. The aims of this work were to determine how 3D-imaging of polymer-free sirolimus/probucol drug eluting stent coatings could be improved through the use of laser postionization secondary neutral mass spectrometry (Laser-SNMS) and Ar cluster sputtering with time-of-flight secondary ion mass spectrometry (ToF-SIMS) and to optimize conditions for this analysis. In this study, 3D-imaging of a sirolimus/probucol dual drug eluting stent has been investigated using Laser-SNMS and ToF-SIMS. Laser-SNMS studies of pure sirolimus and probucol were undertaken using 30 keV Bi-3(+) primary ions and a 157 nm excimer postionization laser. Under optimal conditions, a greater than 100-fold increase in detected ion yield was observed for Laser-SNMS when compared to ToF-SIMS, although ToF-SIMS provided equal or greater yields for higher mass characteristic ions. Although the optimal laser power density for detecting probucol (5 x 10(6) W/cm(2)) was significantly lower than the optimum for sirolimus (7 x 10(7) W/cm(2)), an intermediate laser power density of 1 x 10(7) W/cm(2) was sufficient to allow imaging of both drugs. Using individual selected ion signals, ToF-SIMS and Laser-SNMS produced similar images of the two drug species. When using, however, a multivariate approach (maximum autocorrelation factors), Laser-SNMS provided significant improvements in image contrast and small area detection when compared to ToF-SIMS. Following optimization of the technique, 3D-images of the dual drug eluting stent coating were obtained using 10 keV Ar-2000(+) cluster ions for sputtering and 30 keV Bi-3(+) cluster ions for analysis for both ToF-SIMS and Laser-SNMS. This work demonstrates the advantages of Laser-SNMS for 3D-imaging of pharmaceutical devices, which has not been previously published. Both ToF-SIMS and Laser-SNMS revealed that the outermost surface of the drug eluting coating contained pure sirolimus to a depth of a few tens of nanometers, with a few channels of sirolimus extending to a depth of around 1 mu m. Below about 1 mu m, the two drugs were uniformly mixed. Using the 10 keV Ar-2000(+) sputter beam, the authors were able to sputter through the complete drug coating (similar to 6 mu m) without observing any accumulated damage in the organic layer. The two techniques showed complementary strengths: ToF-SIMS offers faster data collection and better detected ion yield for larger characteristic ions than Laser-SNMS, and Laser-SNMS offers significantly enhanced detected ion yield for smaller fragment ions, allowing for improved image contrast and resolution of smaller features. (C) 2016 American Vacuum Society.