Method development and application of high resolution vibrational spectroscopic techniques to elucidate the microstructure of pharmaceutical powder formulations

Oral solid dosage forms play an important role in the pharmaceutical industry. In a quality by design (QbD) framework, the quality of a pharmaceutical drug product depends heavily on proactive science and risk-based formulation and process understanding. However, there are known knowledge gaps in the current pharmaceutical drug product manufacturing processes, particularly regarding the relationship between critical material attributes (CMAs), process parameters (CPPs) and quality attributes (CQAs). Often, these parameters are selected based on prior experience or a trial-and-error approach. Application of process analytical technology (PAT) tools to provide a thorough understanding of a pharmaceutical drug product microstructure has the potential to unlock this black box. Microstructure of a pharmaceutical drug product refers to the spatial and particle size distributions of different components as well as the void space present in the formulation. Finally, a determination of the microstructure-property relationship of a drug product for a certain set of material attributes and process parameters offers an interesting opportunity to fine-tune the material attributes and process parameters. This may eventually enable purposeful engineering of the microstructure for the desired performance attributes. Chemical imaging (CI) systems based on vibrational spectroscopy, mainly near-infrared (NIR) and Raman, are becoming increasingly popular PAT tools for determining the microstructure of pharmaceutical drug products, as part of QbD. CI allows the spatial characterization of the chemical composition and structure of a sample, at a particle level. In these tools, a microscope and vibrational spectroscopy hardware are integrated to obtain micro-scale vibrational spectra from different positions of the sample. The main aim of this dissertation is the development and implementation of Raman chemical imaging (RCI) for pharmaceutical tablets, based on a commercial RCI system, to answer the following key microstructural aspects: (1) accurate, robust, and time-efficient assessment of tablet microstructure, (2) impact of material attributes and process parameters on tablet microstructure, (3) influence of tablet microstructure on product performance attributes and (4) engineering of tablet microstructure. In-line/off-line NIR based spectrometers and scanning electron microscopy/energy dispersive x-ray spectroscopy (SEM/EDX) are also used in conjunction with the RCI system, wherever required. The specific aims of this work include state-of-the art case studies relevant to the manufacturing of oral solid dosage forms: Specific Aim 1: Developing a framework to determine the microstructure of pharmaceutical tablets using Raman chemical imaging. Specific Aim 2: Quantifying the effect of material attributes and processing parameters on API domain sizes in pharmaceutical tablets manufactured using direct compression. Specific Aim 3: Applying in-line NIR spectroscopy and Raman chemical imaging to monitor and characterize API agglomerates in low dose pharmaceutical powder formulations. Specific Aim 4: Investigating the feasibility to engineer the microstructure of pharmaceutical formulations for a desired dissolution performance.Ph.D.Includes bibliographical reference