Pharmaceutical Thin Film Formulations with Controlled Crystal Polymorphism, Morphology, and Size
Guthrie, Stephanie, Chemical Engineering - School of Engineering and Applied Science, University of Virginia
Giri, Gaurav, EN-Chem Engr Dept, University of Virginia
Crystallization and formulation are critical steps for the creation of new therapeutics. Most drug products are formulated as solid tablets and capsules containing thousands of solid drug crystals. However, an increasing number of candidate drug molecules are not suitable for development in traditional tablet formulations due to poor physicochemical properties (e.g. solubility, dissolution rate, melting point) associated with the crystal forms. Solid form screening is performed to characterize crystal attributes (including polymorph, size and shape) and select the desired form for further development. Screening is one of many processes that contribute to long lead times and the significant development costs in the pharmaceutical industry. This motivates the development of new screening technologies that can improve understanding of pharmaceutical solid states. This dissertation discusses the development of a meniscus guided coating technology for the application of solid form screening and selection in pharmaceutical molecules. New formulation approaches are presented, including thin films, novel drug carriers and 3D printed drug loaded gel tablets.
In Chapter 2, crystalline thin films of glycine and acetaminophen were fabricated using evaporative meniscus guided coating. Films were characterized using polarized optical microscopy and X-ray diffraction to determine morphology and crystal structure. Simple process parameters, such as coating temperature and coating speed are shown to select different crystal morphologies and polymorphs while controlling film thickness. In Chapter 3, In situ grazing incidence X-ray diffraction was used to characterize glycine crystallization during the coating process. Through gaining spatial and temporal resolution of crystallization, I develop and propose a hypothesis for the crystallization of multiple crystal orientations during the coating process. In Chapter 4, a novel meniscus guided coating regime is accessed by utilizing substrate temperatures that exceed the boiling point of the solvent during flow coating. This is shown to isolate microcrystals, a highly desirable crystal size and shape for the pharmaceutical industry. Chapters 2-4 present a new technique for pharmaceutical solid form screening and selection.
Formulation typically encompasses incorporation of the active pharmaceutical compound with coatings and additives (e.g. polymer binders and excipients) to control drug release. Traditionally, a solid tablet is the preferred formulation. However, alternative strategies are being explored to control drug release timescales, and create customized doses for personalized healthcare. We explore metal organic frameworks (MOFs) as potential drug carriers in Chapter 5 and 3D printing for personalized dosing in Chapter 6.
MOFs are a porous material with demonstrated utility for storage of small molecules and proteins, thus motivating their use as drug carriers. The mechanism of transport within a MOF is complex and poorly understood, a critical property that must be characterized if MOFs are to be used for drug delivery. Chapter 5 of this dissertation presents a nanofluidic platform for crystallization of high-quality MOF crystals and subsequent loading with fluorescent small molecules. The device can be used to characterize diffusion of small molecules in the framework by tracking the fluorescence intensity.
Additive manufacturing, such as 3D printing, has great potential to create custom drug formulations. In chapter 6, we develop a polymer/drug gel that can be extruded from a syringe to create 3D printed tablets. Tablet size was changed by printing multiple layers sequentially. Crystal structure and bonding in the polymer matrix were characterized using X-ray diffraction and infrared spectroscopy. Tablet dissolution was assessed using ultraviolet-visible spectroscopy. This dissertation presents strides towards improving pharmaceutical development technologies, from solid form screening and selection to formulation design.
PHD (Doctor of Philosophy)
Crystallization, Pharmaceuticals, Small Molecules, Thin Films, Meniscus Guided Coating, Solid State Formulation