Solid-State Physical Form Detection and Quantitation of Pharmaceuticals in Formulations

Abstract

The majority of pharmaceutical dosage forms are marketed as solids, and the active pharmaceutical ingredient (API) can exist in various physical forms. These physical forms can be either crystalline or amorphous, and will have different physical properties. The physical form of the API is selected to provide the appropriate solubility, stability, and bioavailability for the formulation. However, processing steps involved in the production of the formulation can induce changes in the physical form of the API and thus impact the performance of the formulation. Therefore, it is critical to characterize the physical form of the API in the formulation, and to monitor it for any changes in the physical form during storage. Multiple solid-state characterization techniques are typically employed in order to identify and quantitate physical forms of APIs. However, most of these techniques suffer from significant issues related to the interference of excipient signals with API signals when analyzing formulations. Additionally, in order to perform quantitative measurements pure standards are needed and calibration curves must be generated for most of these characterization techniques. This dissertation demonstrates the superior ability of solid-state nuclear magnetic resonance (SSNMR) spectroscopy to both detect and quantitate physical forms of APIs within formulations, relative to other solid-state characterization techniques. Specifically, SSNMR has been used to understand the dehydration of levofloxacin hemihydrate, including the discovery of a previously unreported anhydrous polymorph. Three formulations for pulmonary delivery have been characterized by both differential scanning calorimetry (DSC) and SSNMR. DSC could not clearly identify the physical form of the APIs in the formulations, but SSNMR was able to unambiguously determine the physical forms of the APIs in all cases. The work presented in the dissertation also demonstrates that SSNMR can be used to quantitate the relative amounts of physical forms of APIs within formulations without pure standards or calibration curves. Finally, the relative ability of SSNMR and other solid-state characterization techniques were compared and clearly illustrate that SSNMR is considerably more powerful in the relative quantitation of API physical form in both pure materials and formulations.