Experimental methods
Materials.
The authors studied copovidone (Kollidon VA 64), polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer
(Soluplus; abbr.: PEG-VCap-VAc), povidone grades (Kollidon 12 PF, Kollidon 17 PF, Kollidon 30, and Kollidon 90 F), polyvinyl
acetate–povidone (Kollidon SR; abbr.: PVAc+PVP), methacrylic acid–ethacrylate copolymer 1:1 (Kollicoat MAE 100P; abbr.: MA–EA),
macrogol polyvinyl alcohol grafted copolymer (Kollicoat IR; abbr.: PEG–VA), macrogol polyvinyl alcohol grafted copolymer +
poly(vinyl alcohol) (Kollicoat Protect; abbr.: PEG–VA+PVA), poloxamer 407 (Lutrol F 127 and Lµtrol micro 127). Poloxamer 188
(Lutrol F 68 and Lµtrol micro 68), macrogolglycerol hydroxystearate 40 (Cremophor RH 40; abbr.: MGHS 40), and PEG 1500 (Pluriol
E 1500 Powder K) were used as plasticizers. BASF supplied all materials.
Extrusion.
Melt extrusion was performed using a twin-screw extruder (ZSK 25, Coperion Werner & Pfleiderer) with a screw diameter of 25
mm and a length-to-diameter ratio of 34. Extrusion parameters included throughput from 2.5 to 5 kg/h, extrusion temperatures
of 60–200 °C and screw speed from 100 to 150 rpm.
Film casting.
The polymer and plasticizer were dissolved in water. The solution was cast (Coatmaster, Erichsen Testing Equipment) using
scrapers with different die gaps of 150–500 μm and dried at 40 °C.
Differential scanning calorimetry (DSC).
DSC studies were performed with a Q2000 TA Instruments. DSC scans were recorded at a heating rate of 20 K/min in the second
heating run.
Thermo gravimetric analyses (TGA).
TGA studies were performed using a Netzsch STA 409 C/CD instrument. TGA scans were recorded at a heating rate of 5 K/min until
the ambient temperature reached 450 °C.
General physicochemical characteristics of polymers
Polymers for HME must exhibit appropriate thermoplastic characteristics to enable the HME process, and they must be thermally
stable at extrusion temperatures. Other relevant characteristics include a glass-transition or melting temperature (T
g
or T
m
) of 50–180 °C, low hygroscopicity, and no toxicity (2). The extrudability of a polymer is mainly determined by T
g
or T
m
and melt viscosity (11). Polymers with a high molecular weight exhibit high melt viscosity and are difficult to extrude.
Moreover, a high T
g
or T
m
requires a high processing temperature that can degrade sensitive APIs (12). As a general rule, an extrusion process should
be run at temperatures of 20–40 °C above the T
g
. Most polymers demonstrate thixotropic behavior, which means that their viscosity decreases with increasing shear stress.
The glass-transition temperature of povidone homopolymers increases from 90 °C to 156 °C as a function of molecular weight.
The relatively low glass-transition temperature of copovidone results from the soft monomer vinyl acetate. The low glass-transition
temperature of PEG–VCap–VAc results from the covalently bound PEG moiety. PEG–VCap–VAc therefore can be regarded as an internally
plasticized molecule. The PEGs and poloxamers exhibit glass-transition temperatures below 0 °C, therefore the authors give
only their melting points.
In principle, all organic materials can be degraded by increasing temperature. TGA is a suitable tool for examining the thermal
sensitivity of a polymer. At least at the extrusion temperature, which is usually 100–200 °C, the polymer must be stable.
Even if TGA is not capable of delivering detailed information about cross-linking of the polymer chains and other possible
reactions, it provides an idea about the changes that take place upon heating. Thus, it enables users to observe changes in
mass with increasing temperature and the kind of reactions (i.e., endothermic or exothermic). Personnel also must consider
the length of time the material is exposed to the temperature. Long heat exposure might lead to decomposition, although the
material might be stable for a short time at the same temperature.
Figure 2: Comparison of the glass-transition temperature (Tg) or melting temperature (Tm) by differential scanning calorimetry with the temperature of degradation (Tdeg) by thermo gravimetric analyses of pure polymers.
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T
g
or T
m
and temperature of degradation (T
deg
) measured by TGA indicate the range within which the extrusion can be performed, from a processability and stability point
of view. The broadest processing range can be found with PEG–VCap–VAc, followed by copovidone and povidone 12 (see Figure
2). A large range between T
g
(T
m
) and T
deg
is highly beneficial because it offers great freedom for the development of the extrusion process and also serves as a prerequisite
for a reliable and reproducible formulation.
Figure 3: Melt viscosity of pure polymers as a function of temperature.
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As temperature increased, the dynamic viscosity of all tested polymers decreased. Only PEG–VA showed a slightly higher viscosity
at 190 °C compared with its viscosity at 180 °C. This result probably can be explained by the cross-linking of polymer chains.
All the values presented in Figure 3 were determined at 16 rad/s.
Melt viscosity is influenced by molecular weight and interactions between the functional groups of the polymer chains. The
authors found significant differences between the various polymers. Melt viscosity increased strongly from povidone 12 (~2500
Da) to povidone 17 (~9000 Da), povidone 30 (~50,000 Da), and povidone 90 (1,250,000 Da). Despite a high molecular weight,
PEG–VCap–VAc (118,000 Da) results in a similar viscosity to that of copovidone (~55,000 Da). For a small-scale extruder, the
limitation is at approximately 10,000 Pa*s because higher viscosities generate too much torque. On the other hand, a low-viscosity
polymer could cause problems for downstream processing.
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