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Browsing by Subject "X-ray powder diffractometry"

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  • Mikkonen, Heidi (2014)
    One way to improve the solubility of a poorly-water-soluble drug is to make amorphous solid dispersion of it with one or several carrier polymers. However, the amorphous solid dispersions are often unstable. Stability and amorphisation of drug substance depend on e.g. the miscibility of the components in dispersion. Moreover, in the early stage of drug development there is available only limited amount of active substance and time to the analyses. In this study, the primary goal was to develop a method combining the preparing (solvent method) and the analyzing (MTDSC, modulated temperature differential scanning calorimetry) methods. In the method developing part, the possible effect of analyzing parameters of MTDSC to the results was also tested. Amorphous solid dispersions were prepared and analyzed with the invented method. The dispersions were made of poorly-watersoluble itraconazole with hydroxypropylmethylcellulose acetate succinate (HPMC-AS) and/or polyvinylpyrrolidone (PVP K30). X-ray powder diffraction (XRPD) and polarized light microscopy (PLM) were also used to make the interpretation of results easier and more reliable. By analyzing the prepared dispersions the differences in the miscibilities of the used polymers with itraconazole were examined and it was also studied how the miscibility affected to the amorphicity of the prepared dispersion. As a secondary goal, it was tested if combining the two polymers would improve the miscibility and amorphicity of the prepared dispersion. In many cases, with the developed method it was possible to make mixed and amorphous solid dispersion with 10-20 % itraconazole concentration. Used small amount of drug was roughly enough to the detection limit of the used analyzing techniques. The analyzing parameters of MTDSC were not seen to affect to the results in this study which makes the use of this method easier. The results of used analyses were in some part contradictory and that is why it is recommended to use several analyzing techniques or methods that combine different kinds of techniques. In the study, it was seen that in the most part of the prepared dispersions there was more HPMC-AS than PVP K30. This was speculated to be caused by the ionic bonds between the basic itraconazole molecules and acidic succinyl groups in HPMC-ASs and also because of more hygroscopic nature of PVP K30 which increases mobility which in turn increases probability of collision of itraconazole molecules. The use of two polymers in the same time was useful especially in the case of 90/10 HPMC-AS/PVP K30 polymer ratio. This was speculated to be caused by different vaporization rates of the used solvents (DCM and methanol) and too slow evaporation phase. To explain and examine this observation more thoroughly, nuclear magnetic resonance (NMR) -measurements were done. When analyzing the prepared dispersions and itraconazole alone, it was observed that with used amorphisation method (solvent method) itraconazole was in a form that differs from the original polymorph. This form of itraconazole was probably some kind of liquid crystal and was examined further by heating the sample and analyzing it by XRPD. Although there are some other studies to support this hypothesis, this interpretation needs some confirmatory analyses with other methods: with high temperature SAXS (small angle X-ray scattering) and NMR.