thin film on top of the substrate
Chapter 2 Materials and methods
2.2.5 EUDRAGIT ® EPO
EUDRAGIT® EPO is a cationic copolymer which is composed of dimethylaminoethyl methacrylate and neutral methacrylic ester units as shown in Figure 2.5. It is a pH-dependent soluble polymer that dissolves at the pH below 5. EUDRAGIT® EPO is naturally amorphous with a glass transition temperature of approximately 50oC (33). EUDRAGIT® EPO has been widely applied in pharmaceutical industry in taste masking via the preparation of solid dispersions or microspheres with bitter drugs (13, 34-36). Due to its non-hygroscopicity, EUDRAGIT® EPO was
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also used to protect amorphous solid dispersions from moisture uptake to enhance the physical stability (7).
Figure 2.5: Chemical structure of EUDRAGIT® EPO.
Recently, EUDRAGIT® EPO was used in amorphous solid dispersions to increase the dissolution rate of poorly water-soluble drugs (15, 37, 38). An ibuprofen tablet prepared from compressing ibuprofen-EUDRAGIT® EPO melt extrudates was reported to show a similar dissolution profile to the commercial Nurofen® (39). Increasing the drug loadings in the tablet (up to 40% w/w) a faster dissolution rate was observed and it was attributed to the faster disintegration of the tablet due to the higher loading of talc (39). In another research, an efravirenz-EUDRAGIT® EPO melt extrudate was prepared and compared with the physical mixture with the same drug-polymer ratio, the dissolution rate from the solid dispersions increased two times higher (15). These studies demonstrated the feasibility of EUDRAGIT® EPO in the hot melt extrusion and its ability of dissolution enhancement of some poorly water-soluble drugs.
In addition, phase separation behaviour of EUDRAGIT® EPO based amorphous solid dispersions was also studied (13, 17, 36, 40, 41). Hot melt extrudates prepared with paracetamol and EUDRAGIT® EPO were studied by Qi et al, and it was reported that crystalline drug could be detected even in 10% (w/w) drug loading sample (17). Phase separation including molecular drug-polymer dispersion and crystalline drug were very likely to present in the solid dispersions (17).
Felodipine-EUDRAGIT® EPO solid dispersions prepared by hot melt extrusion was studied by the same group (41). After 2 month aging under 20%RH/40oC, only little amount of crystalline felodipine was detected in 70% (w/w) drug loading sample. These finds indicate that drug-polymer solid solubility is drug-dependent and different drugs formulated with the same polymer can present significantly different physical stability. In addition, a very recent study on the investigation of the physical stability of spin coated solid dispersions showed that EUDRAGIT® EPO can strongly protect solid dispersions from phase separation under stressed humidity in comparison to PVP K30 and Soluplus. This was attributed to the low hygroscopicity of EUDRAGIT® EPO and moisture uptake has been suggested as a key factor causing physical instability of the studied solid dispersions (7). Consequently, based on the good processibility of EUDRAGIT® EPO in hot melt extrusion and its low-hygroscopicity nature, it was selected as the
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main model polymer to formulate solid dispersions with model drugs by hot melt extrusion in this project.
2.2.6 Kollidon® VA64
Kollidon® VA64 (PVPVA64) is a hydrophylic polymer which is composed of 6 parts of N-vinylpyrrolidone and 4 parts of vinyl acetate (Figure 2.6). It is an amorphous polymer with a glass transition temperature of 106oC (42). Kollidon® VA64 was originally invented as a binder for wet granulation or dry binder for direct compression. Due to the suitable glass transition temperature and good thermoplasticity, Kollidon® VA64 was introduced as polymeric carriers in hot melt extrusion (43). Amorphous solid dispersions prepared by hot melt extrusion with Kollidon® VA64 have been reported to show enhanced dissolution performance (44-46). In a study regarding the improvement of a model poorly water-soluble drug (a cannabinoid antagonist, newly synthesised), the formulation prepared with 10% w/w drug and 90% (w/w) Kollidon® VA64 showed 100% drug release whereas only 3% of the pure drug dissolved under non-sink condition within the same time period (21). The formulation was still confirmed as amorphous after 15 days aged under 75%RH/40oC. In another study, bifendate was prepared into melt extrudates with Kollidon® VA64 (47). In comparison to the commercial product, a significant increase of dissolution rate was observed in the melt extrudates with 10% (w/w) drug loading. In addition, a relative bioavailability of 145.3±35.3% compared with commercial product was achieved.
Figure 2.6: Chemical structure of Kollidon® VA64
As can be seen in the chemical structure (Figure 2.6), Kollidon® VA64 contains exposed carbonyl groups indicating its strong potential as an acceptor to form hydrogen bonding with drugs contain donor groups (i.e. NH or OH) in solid dispersions. This may lead to a high drug-polymer solubility in amorphous solid dispersions (48). Although in comparison to PVP K30, 40% of hydrophilic components, vinylpyrrolidone, has been replaced by hydrophobic group, vinyl acetate, moisture uptake by solid dispersions prepared with Kollidon® VA64 was reported (49, 50). In this project, Kollidon® VA64 was used with EUDRAGIT® EPO as an immiscible polymer blend matrix to stabilise melt extruded solid dispersions with felodipine. The hypothesis can be described as follows. Firstly, the ability of Kollidon® VA64 to form hydrogen bonding with model drugs may potential increase the overall drug-polymer solubility. Secondly, moisture uptake of solid
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dispersions prepared with Kollidon® VA64 can be reduced with the addition of EUDRAGIT® EPO.
Therefore, combined the two effects, the physical stability of amorphous solid dispersions can be enhanced if formulated with the immiscible polymer blends. The application of the immiscible polymer blends is discussed in Chapter 7.
2.3 Methods
Solid dispersions were prepared by hot melt extrusion and spin coating in this study. In order to investigate drug-polymer miscibility and solubility as well as characterise model drugs and solid dispersions, several conventional characterisation technologies were used in this study including MTDSC, ATR-FTIR and PXRD. Modulated temperature differential scanning calorimetry (MTDSC) has been widely used in the pharmaceutical industry to provide the thermal properties of materials in heating. Attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR) has been used to gain chemical information on drug-polymer solid dispersions. Powder X-Ray diffraction (PXRD) can be used to distinguish a system from crystalline to amorphous state.
Besides these technologies mentioned above which provide bulk properties of solid dispersions, microscopy based technology including scanning electronic microscopy (SEM) and atomic force microscopy (AFM) combined with local thermal analysis (LTA) and photothermal microscopy (PT-MS) were also used in this study to understand the form, distribution and physical stability occurred on a spatially resolved basis.
2.3.1 Preparation of drug-polymer solid dispersions