Quartz Crystal Microbalance Technique for Analysis of Cooling Crystallization
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In chapter 1, background of crystallization and quartz crystal microbalance were introduced. In chapter 2, a quartz crystal microbalance (QCM) technique is developed for the in situ analysis of the cooling crystallization processes of crystal nucleation and growth. In contrast to conventional techniques based on property changes in the solid or solution phase, the proposed QCM technique simultaneously exploits property changes in both the solid and solution phases, such as the solid mass and liquid viscosity, to analyze the crystallization processes. When initial cooling the solution, an increase in the solution viscosity is reflected in the QCM responses for the resonant frequency and resonant resistance. With further cooling, the resonant frequency and resonant resistance sharply change at the induction point of crystal nucleation, as the viscous liquid film on the sensor suddenly shifts to an elastic solid phase. Thereafter, the QCM responses are mainly controlled by the suspension viscosity due to simultaneous crystal nucleation and growth with further cooling. As a result, the QCM responses allow accurate measurement of the induction point and metastable zone width during the cooling crystallization. Additional mechanistic information on the crystallization, including molecular cluster formation, crystal nucleation, and crystal growth, is also extracted from a resonant frequency-resistance plot (F-R plot) of the QCM responses when varying the cooling conditions. In chapter 3, the cooling crystallization and reverse heating dissolution of sulfamerazine were analyzed in real time using a quartz crystal microbalance (QCM). The resonant frequency and resonant resistance of the QCM response were registered to extract information on the nucleation, crystal growth, crystal dissolution, and viscosity change during the crystallization process. The instantaneous nucleation of sulfamerazine crystals on the QCM sensor surface during the cooling crystallization triggered a dramatic drop in the resonant frequency, followed by a further decrease during crystal growth. Meanwhile, during the mild dissolution process, the approach of equilibrium, followed by a solution viscosity diminution during the heating process were also revealed by the QCM in real time based on its inherent distinctive response to a rigid mass and the liquid phase. The F-R model, which has already been shown to reveal conformational information on the interface, was utilized to analyze the distinctive phenomena of cooling crystallization and reverse heating dissolution, in particular, the accumulation of supersaturation, instantaneous burst of nuclei, approach of equilibrium, and viscosity change. In addition, the dissolution rate was estimated through a slope analysis of the F-R plots. The equilibrium temperature measured by the QCM and focused beam reflectance measurements (FBRM) exhibited a discrepancy that originated from their respective working principles, and this discrepancy was further studied using a series of heating rates. A solubility curve was constructed by plotting the equilibrium point obtained in real time by the QCM against the concentration and found to be accurate when evaluated using a thermodynamic gravimetric method. Thus, as a solubility determining strategy, the QCM achieved a high level of accuracy with minimal effort based on simple temperature cycling, thereby avoiding calibration and sampling. Plus, its independence of the heating rate promises a high efficiency. In chapter 4, a novel in-situ supersaturation analyzing strategy was explored through application of functionalized quartz crystal microbalance (QCM) in cooling crystallization. Quantitative analysis of supersaturation profile was realized by exclusively detection of liquid property in cooling crystallization. Due to absence of hydrogen bond formation, –NH2 self-assembled on sensor was found able to forbid sulfamerazine crystal formation on sensor surface, allowing QCM response exclusively to liquid property change. A linear relation was found between the QCM resonant frequency response and liquid composition, attributed to the correlation with liquid viscosity. In cooling crystallization, concentration decrease was induced by nucleation and crystal growth, accompanied with consumption of liquid sulfamerazine molecules. The in-situ concentration variation was revealed by resonant frequency shift and further converted to in-situ supersaturation profile with the knowledge of solubility. In chapter 5, based on capability of simultaneously characterizing both solid and liquid phases, quartz crystal microbalance (QCM) was applied to analyze the polymorphic nucleation and phase transformation in cooling crystallization. Sulfamerazine has two polymorphs of metastable phase of form-I and stable phase of form-II, with dominant face (020) and (002) respectively. The QCM sensor was self-assembled with 11-amino-1-undecanethiol, providing a layer of – NH2. The formation of form-I crystal on sensor surface was prevented, however form-II was allowed. Thus, two polymorphs can be distinguished by QCM response. The mechanism lied on hydrogen bonding ability of each polymorph with the - NH2 on sensor surface. Dominant group aromatic N of form-II can form hydrogen bond with - NH2 on sensor surface, whereas difficult for form-I with dominant group of – NH2. The hydrogen bond formation supposal was supported by the morphology change of crystal form-I nucleated on –COOH functionalized surface. In cooling crystallization, QCM responded to the nucleation of form-I as a resonant frequency elevation due to concentration depletion in liquid phase. As for form-II, a significant decrease of resonant frequency was induced at induction point due to crystal formation on sensor surface. The in-situ result of polymorphic nucleation and phase transformation profile by QCM were confirmed by Raman spectroscopy.