The investigation of pharmaceutical liquid crystals: Formation, stability and phase behavior (2011)

This dissertation is primarily focused on the study of pharmaceutical liquid crystals, their formation, physico-chemical characterization, stability, and phase transformation in the context of drug formulation and development. In addition, a novel screening approach of drop levitation with online X-ray monitoring is explored in an attempt to evaluate the recrystallization tendency of amorphous pharmaceuticals, either alone or dispersed within polymer. As a separate topic, a research project aiming at detecting counterfeit medications via their potentially unique impurity profiles was investigated using analytical techniques such as liquid chromatography, gas chromatography and mass spectrometry. The first chapter provides the theory and background of liquid crystals in general, including their definitions and classifications. The two principle types of liquid crystal, lyotropic and thermotropic, are reviewed in detail separately and pharmaceutical examples of each type are presented. The research objectives for liquid crystal studies are also outlined at the end of this chapter. Chapter 2 and Chapter 3 focus on the study of thermotropic liquid crystals of two model compounds—sodium deoxycholate (NaDC) and itraconazole, respectively. In chapter two, the solid-state properties and physical stability of three disordered materials of NaDC, a thermotropic liquid crystal, a lyophile, and spray-dried amorphous, are studied. Results from stability test are contrary to the conventional notion that liquid crystals possess intermediate degree of order and thus intermediate level of stability compared to crystalline and amorphous materials. Despite the higher structural order, the thermotropic liquid crystal phase of NaDC formed by dehydration is physically less stable than the amorphous form under both temperature and moisture stress. This discovery suggests that kinetics, rather than thermodynamics, is the dominating factor for crystallization in this system. In chapter three, both thermotropic liquid crystal and amorphous forms of itraconazole are prepared, and show different optical and thermal properties. Significant increase in apparent solubility was observed by conversion of the crystalline formto the liquid crystal. More importantly, the solubility enhancement lasted for a much longer period than that of any other pharmaceutical liquid crystals being reported. Chapter four studies the lyotropic liquid crystal system of NaDC in water. In this chapter, the phases of the NaDC-water binary system are investigated as a function of concentration and temperature. The phase of the liquid crystal form is assigned by synchrotron X-ray analysis. Phase diagram of the system is refined and shows significant differences from the literature report. As a technique to understand the liquid crystal/amorphous formation during solvent evaporation, chapter five describes a newly developed study of drop levitation using synchrotron X-ray. Results from preliminary study performed to date are consistent with those obtained from larger scales by spray-drying. The method shows the potential for rapid amorphous/liquid crystal screening with minimal sample requirement. On a separate study, chapter six describes a project using analytical methods to detect counterfeit medications. The study shows that certain mass spectrometry methods, such as ESI-MS and GC-MS, are able to detect and identify trace amounts of impurities related to the drug molecules from genuine tablet products by different drug manufacturers. Impurity profiles developed herein in some cases can distinguish the drug manufacturers of the same drug product, thus providing a potential tool to detect true counterfeits.