Coherent anti-Stokes Raman scattering microscopy for pharmaceutics

Abstract

This dissertation demonstrates coherent anti-Stokes Raman scattering (CARS) microscopy as a tool in pharmaceutical solid state development. CARS microscopy is a nonlinear optical imaging technique that uses inelastic scattering of light to provide chemically specific imaging. CARS microscopy is suitable for early stage pharmaceutical development, analyzing pure API powders as well as late stage analysis of more complex dosage forms. The strengths and weaknesses of CARS microscopy are explored in the context of pharmaceutical analysis over a wide range of samples covering a number of commonly used pharmaceutical formulation strategies. Chapter one is an introduction to the area of traditional pharmaceutical solid state analysis and provides a background to the area of CARS microscopy. Chapter two introduces and discusses hyperspectral CARS microscopy as a tool for determining pharmaceutical solid state form capable of distinguishing between hydrous and anhydrous polymorphic forms as well as between crystalline and amorphous forms. Chapter three presents CARS and hyperspectral CARS as a tool for dissolution analysis capable of correlating visualized changes on the surface of a dosage form with changes observed in the dissolution rate. Chapter three begins with details about the design and building of the dissolution setup and is followed by results obtained from a number of theophylline containing oral dosage forms. Chapter four introduces the area of inhalation medicine and looks at the capabilities of CARS microscopy to provide useful information about the formulation strategy known as adhesive mixtures. The chapter begins with analyzing drug distribution followed by particle size calculations and ends with correlative imaging combining CARS with scanning electron microscopy (SEM). Chapter five looks at a drug loaded mesoporous silica particles, which is a formulation strategy aimed at stabilizing the amorphous form of poorly water soluble drugs. CARS and hyperspectral CARS were utilized to firstly identify the three dimensional drug distribution of the loaded silica particles and secondly to confirm the amorphous nature of the loaded drug. Finally more correlative CARS and SEM imaging was performed to confirm that the loaded drug was contained within the pores of the silica.