In this project, the breakthrough new technique of nanoscale infrared (IR) spectroscopy, pioneered by Anasys Instruments, will be adapted and refined for Pharmaceutical and biological systems. The technique has numerous applications such as Polymorph screening; sub-cellular spectroscopy and Drug-Polymer composites. In this research proposal, we will focus on demonstrating proof of concept of the nanoscale IR platform to fully characterize the micro- and nanostructure of drug- polymer systems where Prof Taylor of Purdue is an expert. The measurement technique is based on the capability of an atomic force microscope (AFM) probe to detect the thermal expansion of samples in contact with an attenuated total reflectance (ATR) prism, following absorption of evanescent mid-IR waves. Using the technique, both localized mid-IR spectra as well as images collected at a specific wavelength can be obtained. This breakthrough technique has the potential to fully characterize the micro- and nanostructure of drug-polymer systems. Hence, an in-depth understanding of the dispersion state of the systems can be obtained. This can fill the current gap in understanding the relationship between manufacturing and formulation variables and resulting product performance of drug-polymer systems. The project aims at maximizing both spatial (the resolution associated with the imaging process as such) and chemical (the ability to chemically differentiate domains based on subsequent analytical processing of imaging data) resolution of the technique. The model systems selected will consist of a representative set of drug-polymer composites. The model polymers will cover a range of polymer types including those used for oral delivery (polyethylene oxide, cellulose based polymers), biodegradable polymers (polylactic acid, polylactic glycolic acid), and non-erodable device coating polymers (polyethylene-co-vinylacetate, poly n-butyl methacrylate). Model drugs will include itraconazole and griseofulvin (combined with oral delivery polymers), dexamethasone and naltrexone (combined with biodegradable polymers), and sirolimus and paclitaxel (combined with device coating polymers). By varying manufacturing and formulation conditions, molecularly, nano- and microdispersed systems will be obtained. Samples of varying thickness will be prepared using a (cryogenic) microtome as well as with a spin-coater. Their thickness will be determined and they will be characterized using nanoscale infrared spectroscopy. The effects of sample thickness and measurement conditions on spatial resolution will be evaluated. This will result in a general optimized sampling protocol by which a maximum spatial resolution can be achieved. Using these optimized sampling conditions, chemical resolution of the technique will be further improved by applying advanced data processing techniques. Uni- and multivariate analysis will be employed on drug-polymer systems with different dispersion states. Using the data processing techniques identified to generate maximized chemical resolution, the influence of manufacturing and formulation on resulting dispersion will be rationalized.
Public Health Relevance: In this project, the breakthrough new technique of nanoscale infrared (IR) spectroscopy, pioneered by Anasys Instruments, will be adapted and refined for Pharmaceutical and biological systems. The technique has numerous applications such as Polymorph screening; sub-cellular spectroscopy and Drug- Polymer composites. In this research proposal, we will focus on demonstrating proof of concept of the nanoscale IR platform to fully characterize the micro- and nanostructure of drug-polymer systems where Prof Taylor of Purdue is an expert.
