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Title: Badanie kinetyki rekrystalizacji oraz dynamiki molekularnej w kontekście stabilności fizycznej amorficznych związków farmaceutycznie czynnych : w formie spójnego tematycznie cyklu artykułów opublikowanych w czasopismach naukowych
Authors: Kołodziejczyk-Jaszczak, Karolina
Advisor: Paluch, Marian
Grzybowska, Katarzyna
Keywords: rekrystalizacja; farmacja; badania; spektroskopia; leki
Issue Date: 2016
Publisher: Katowice : Uniwersytet Śląski
Abstract: This dissertation presents a collection of scientific articles (1-3) devoted to recrystallization of the amorphous of pharmaceutically active ingredients (API), the possible causes of this phenomenon and methods of preventing recrystallization process. The phenomenon of recrystallization is exemplified by two pharmaceutically active substances, salol and sildenafil characterized by a high instability in the amorphous phase. To monitoring process of recrystallization it was used a large variety of research techniques, that are: broadband dielectric spectroscopy (BDS), differential scanning calorimetry (DSC), infrared spectroscopy (FTIR), X-ray diffraction (XRD) and microscopy technique (OM). Moreover, in order to best reflect the conditions of manufacture and storage of amorphous material, the study of recrystallization were carried out in an isothermal and non-isothermal condition. To describe the experimental data, it was used Avrami, Avrami-Avramov and Ozawa model, which allowed estimation of kinetics crystallization parameters, such as: dimensionality of crystal (n), rate of crystallization (k), time of crystallization (cr) and induction time (t0) and the barrier of activation (Ea) this process. The results show that the application of those models provide to obtain a very similar values of crystallization parameters and that the models can be used interchangeably to describe the mechanism of this process. It is widely recognized that the main cause of recrystallization from an amorphous state is the a molecular mobility. This is evidence by data presented in Article 1 and 2, where it was found a correlation between the relaxation times of -process () and crystallization time cr estimated from Avrami-Avramov model. Moreover, it was also discovery of relation between the number of dynamic correlated molecules, Nc and induction time, t0 and also between Nc and cr. It was shown, that the -relaxation of sildenafil cannot be classified as the JG process, which is often expected to play a potential role in devitrification. Therefore, influence of secondary process on physical stability in case of amorphous sildenafil seem to be not significant. It was also proved that the sildenafil is stable for 6 months during long-term storage. However, the theoretical prediction of physical stability in the glass state by using the Adam – Gibbs model extended does not confirm this results. Additionally, it was presented the possibility of physical stabilization of amorphous system. To achieve this purpose it was used an inorganic porous matrix made of aluminum oxide (AAO membrane). The results show (publication 3) that the crystallization of salol did not occur when the pores diameters of AAO membranes are less than 73 nm. Moreover, it was shown that the AAO templates can be an effective tool for manipulation of geometry formed crystals, what may be useful in the future to develop new ways of producing crystals with tailor-made physicochemical properties.
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