Title: Investigation of the applicability of poly(ethyleneglycol-g-vinylalcohol) as a carrier in the formulation of solid dispersions of poorly water-soluble drugs.
Other Titles: Onderzoek naar de toepasbaarheid van poly(ethyleenglycol-g-vinylalcohol) in de formulering van vaste dispersies van slecht oplosbare geneesmiddelen.
Authors: Guns, Sandra
Issue Date: 5-Oct-2012
Abstract: A general background about solid dispersions as a strategy to improve the solubility and dissolution rate of poorly soluble compounds is provided in chapter I. Commonly used carriers for the manufacturing of solid dispersions were listed and discussed. In addition, a short description of the copolymer poly(ethyleneglycol-g-vinylalcohol) (EG/VA) and the model drug miconazole used during this research project was given. In chapter II the general objectives of this project are described. In short, we investigated the potential of EG/VA as a new carrier for the formulation of solid dispersions. Therefore different aspects needed to be addressed. A first important step is to understand the phase behavior of this copolymer before, during and after processing via spray-drying and hot-melt extrusion (chapter III). In the first part of this chapter we used modulated differential scanning calorimetry (MDSC) and X-ray powder diffraction (XRPD). The results showed that EG/VA consists of two semi-crystalline fractions: a polyethylene glycol (PEG) fraction (Tg = ca. -57 &#176;C and Tm = 15 &#176;C) and a polyvinylalcohol (PVA) fraction (T g= ca. 45 &#176;C and Tm = 212 &#176;C). Spray-drying induced amorphization of the PVA fraction (if the inlet temperature was 140 &#176;C or lower), while hot-melt extrusion increased the crystallinity of the same fraction, as a result of both shear forces and increased temperature. In both cases the PEG fraction is not influenced. Since this observed increase in crystallinity can potentially lead to demixing of the drug and polymer during solidification after hot-melt extrusion, the benefit of applying forced cooling after hot-melt extrusion was explored in a second part of this chapter. With high Performance DSC and ultra-fast chip calorimetry we applied controlled quench cooling from the melt at different cooling rates. The PEG fraction was amorphous after cooling at 300 &#176;C/s, but to make the PVA fraction completely amorphous a cooling rate of at least 3000 &#176;C/s was necessary, indicating that applying normal forced cooling after extrusion in order to make the extrudates completely amorphous will be insufficent. Because the ultimate goal is to mix this copolymer with small organic molecules like drug molecules, we also investigated the mixing behavior of three different plasticizers in chapter III. Depending on the type and the concentration of the compounds, a different preference for one of the two amorphous phases occurred. This suggested that also different drug molecules may preferentially mix with one of the two amorphous phases of EG/VA during solid dispersion manufacturing, hence leading to different physical stability profiles, depending on which amorphous phase is involved in mixing. Since chapter III showed that EG/VA could be processed by both hot-melt extrusion and spray-drying, we investigated the effect of the manufacturing method on the kinetic miscibility of a drug and EG/VA in chapter IV. Miconazole was chosen as model drug. Additionally the effect of heat pre-treatment of solutions used for spray-drying and the use of spray-dried copolymer as excipient for hot-melt extrusion was investigated as well. Again MDSC and XRPD were used to study the phase behavior of the resulting solid dispersions with different drug-polymer ratio’s. Miconazole either mixed with the PEG fraction of the copolymer or crystallized in the same or a different polymorph as the starting material. The kinetic miscibility was higher for the solid dispersions obtained from solutions which were pre-heated compared to those spray-dried from solutions at ambient temperature. Hot-melt extrusion resulted in an even higher degree of mixing. Here the use of the spray-dried copolymer did not show any benefit concerning the kinetic miscibility of the drug and copolymer, but it resulted in a remarkable decrease in the torque experienced by the extruder allowing extrusion at lower temperature and torque. The latter could be an advantage when working with heat labile compounds. The results for hot-melt extrusion in chapter III &amp; IV were obtained after extrusion with a lab scale extruder with simple screw design and an internal circulation channel. Extruders used for production at large scale have a different design as they work via continuous throughput and have a modular screw design, which allows the introduction of mixing elements in the screw configuration. Because of the difference in design and few literature reports, we tried to scale up the extrusion process in chapter V. The same model drug was chosen and two series of solid dispersions were made with a lab scale and a pilot scale extruder. Efforts were made to match the operating parameters as close as possible (residence time, extrusion temperature and screw speed). The samples were analyzed with MDSC straight after production and after exact 24 h and 15 days of storage at &#8209;26 &#176;C. The kinetic miscibility of the samples prepared with the lab scale extruder was slightly higher than the samples prepared with the pilot scale extruder. As the solid dispersions with high drug load were unstable over time, demixing occurred, slightly faster for the samples prepared with the lab scale extruder. After 15 days, the levels of molecular mixing were comparable, pointing to the predictive value of samples prepared on laboratory scale. In chapter VI the phase behavior of EG/VA, miscibility of the model drug miconazole in EG/VA and the partitioning of miconazole between PEG and PVA amorphous phases after hot-melt extrusion were studied into more detail with solid-state 1H and 13C NMR methods. The crystallinity of PVA fraction of the copolymer as received by the manufacturer was here determined to be 45% &plusmn; 10% w/w and hot-melt extrusion causes only a slight increase in PVA crystallinity. The bi-modal description of the phase behavior (crystalline-amorphous) was refined in this chapter by the use of 1H NMR transverse magnetization relaxation (T</>2 relaxation) methods. Four T2 relaxation components could be described, which were assigned to: (1) rigid amorphous and crystalline fractions (2) semi-rigid amorphous fraction with largely restricted chain mobility (3) mobile amorphous fraction (4) highly mobile fraction with chain mobility which is typical for rubbery materials. These phases should not be understood as four distinct phases, but rather as heterogeneity in chain dynamics in the amorphous PEG and PVA fractions due to the absence of sharp borders between different phases as expected for graft copolymers. The partitioning of miconazole molecules in the different phases of the copolymer was studied by high-resolution 13C NMR spectroscopy. The T1H and T1rH revealed that miconazole is molecularly dispersed in the melt-extruded EG/VA; the average cluster size was determined at approximately 1.6 nm. In chapter VII a general discussion is provided of the most important findings described in this thesis. The different observations are discussed and linked to relevant literature. Finally some critical remarks and perspectives were postulated.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Chemistry - miscellaneous
Polymer Chemistry and Materials
Centre for Surface Chemistry and Catalysis
Drug Delivery and Disposition

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