Crystallization behavior and microstructural characterization of drug/polymer systems
Abstract
Solid dispersions of the active pharmaceutical ingredient (API) in a polymeric matrix have received extensive attention as a potential approach to increase the dissolution rate of the API. Among different types of solid dispersions, polyethylene glycol (PEG) based semicrystalline solid dispersions have attracted considerable interest, for the reason that PEG enables the delivery of most APIs with low aqueous solubility. However, there are still limitations that restrict the application of this technique for drug formulations. One main concern is the reproducibility of the physicochemical properties of the solid dispersions during scale-up and storage. Additionally, the mechanism by which the dissolution rate is enhanced is still unclear. These are all related to the microstructure of the solid dispersions. Therefore, the purpose of this project is to have a fundamental understanding of the crystallization behavior and microstructural evolution of API/PEG solid dispersions. The model API was comelted with PEG and solidified at predetermined temperatures. The effect of the physicochemical properties of the APIs, polymer matrix and preparation conditions on the crystallization behavior and structure were investigated, using wide-angle X-ray scattering, small-angle X-ray scattering, scanning electron microscopy, atomic force microscopy and second harmonic imaging microscopy. When API/PEG solid dispersions were formed using different APIs, it was found that, for the fast crystallizing APIs (e.g. naproxen), the interaction between the API and the PEG matrix slowed down the crystallization rate of naproxen. For the slow crystallizing APIs (e.g. ibuprofen), crystalline PEG acted as heterogeneous nuclei to speed up the onset of crystallization. It was also found that, APIs with strong interaction in PEG (e.g. Naproxen/PEG) favored the interlamellar incorporation of naproxen in PEG matrix before naproxen crystallized. When the naproxen/PEG solid dispersions are prepared at 40°C, both the nucleation rate and overall crystallization rate was slower than that at 25°C, which resulted in larger NAP domains and slower dissolution rate. However, the effect of various polymer matrix on the structure evolution are much more complicated, as well as the corresponding dissolution behavior. The dissolution rate showed strong dependence on preparation conditions and polymer matrix. This study highlights the complex nature of API/Polymer dispersions and the interplay between API-polymer specific interactions, crystallization tendency and preparation temperature.
Degree
Ph.D.
Advisors
Harris, Purdue University.
Subject Area
Chemical engineering|Pharmaceutical sciences|Materials science|Organic chemistry
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