Pharmaceutical Excipients for Hot-Melt Extrusion

Hot-melt extrusion (HME) technology is prominent in the pharmaceutical industry. Of particular interest is the use of HME to disperse active pharmaceutical ingredients (APIs) in a matrix at the molecular level, thus forming solid solutions. This method is becoming more and more important because the percentage of poorly soluble new chemical entities in drug development is constantly increasing (1). Especially for BCS class II compounds, improved absorption and therapeutic efficacy can be realized by enhancing API solubility (2). An additional benefit of the HME technique is that it is a robust and continuous manufacturing process that can be run in practically any pharmaceutical plant.

However, as with other innovations, numerous obstacles have to be overcome before the technology and resulting dosage forms can be exploited commercially. Compared with other pharmaceutical technologies, such as granulation and compression, hot-melt extrusion is still an emerging method, and its potential has not been explored fully yet. The technology itself can be described as a process in which a material melts or softens under elevated temperature and pressure and is forced through an orifice by screws. Appropriate thermoplastic behavior is a prerequisite of any polymer to be used in hot-melt extrusion. However, the number of such polymers approved for pharmaceutical use is limited.

Purposes of HME

Within the pharmaceutical industry, HME has been used for the following purposes:

• To increase the drug's dissolution rate and bioavailability

• To control or modulate drug release

• To mask the drug's taste

• To stabilize the API

• To create parenteral depots and topical delivery systems.

Personnel can increase the dissolution rate and bioavailability of poorly soluble APIs through HME by forming a solid solution (i.e., solid dispersion) of a drug within hydrophilic excipients. The solid solution is the ideal type of solid dispersions for increasing drug release. In such a matrix, the drug is molecularly dissolved and has a lower thermodynamic barrier for dissolution compared with solid dispersions with crystalline drugs (see Figure 1) (3). Extruded solid solutions offer higher thermodynamic stability than those prepared by alternative processes, such as spray drying, solvent evaporation, and other hot-melt methods (4).

Figure 1: Relevant types of solid dispersions. (ALL FIGURES ARE COURTESY OF THE AUTHOR)

In comparison with other possible processes, HME is, by far, less complex and more cost effective because its manufacturing process requires only a few steps. HME presents the following advantages over solvent-based processes:

• It eliminates the need to handle explosive solvents

• It does not produce residual solvents

• It enables continuous processing

• It entails few process steps

• It yields high product density

• It produces nondusty pellets

• It is a water-free process

• It can be accomplished through small-scale equipment

• It requires a low investment in equipment.

Furthermore, the polymeric components used in the extrusion process may function as thermal binders, drug stabilizers, drug solubilizers or drug-release controlling excipients.

The choice of an adequate polymer as a matrix to form stable solid solutions is crucial in HME. Polymers with a high solubilization capacity are particularly suitable because they can dissolve large quantities of drugs. Some features, such as lipophilicity, hydrogen-bonding acceptors, or donors and amide groups, are basic prerequisites for a high solubilization capacity (5). This factor explains why povidone, copovidone, and PEG-VCap-VAc are highly suitable for HME. Copovidone and PEG-VCap-VAc, in particular, are more lipophilic than many other water-soluble polymers containing hydroxyl groups. Therefore, they are best suited to the lipophilicity of poorly soluble drugs (6, 7).

When the drug is incorporated in a supersaturated form, the whole mixture should have a rigid structure to minimize crystallization from the dissolved drug and from amorphous drug particles (8, 9). As a solid solution, the formulation dissolves in gastric or intestinal fluids, thus forming a supersaturated solution of the drug and enhancing dissolution and bioavailability (10).

In extruded drug-delivery systems, the polymer serves as a matrix. Larger quantities of polymer thus are required than when the polymer is used as a binder or coating agent. Consequently, it is crucial that the polymers be nontoxic and approved in various countries at high doses.

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.

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 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.

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.

Figure 3: Melt viscosity of pure polymers as a function of temperature.

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.

Physicochemical characteristics of polymer–plasticizer combinations

T_g can be reduced by adding plasticizers. An investigation on polymers used in combination with poloxamer 188, MGHS 40, and PEG 1500 was performed to observe the influence of these plasticizers on T_g, temperature range of polymers for extrusion, and melt viscosity (see Figures 4 and 5).

Figure 4: Glass-transition temperature (Tg) of pure polymers in comparison with polymer–plasticizer combinations (extrudate, 9:1, w/w%).

The additives tested acted in different ways. PEG 1500 and MGHS 40 decreased T_g in all systems significantly, but poloxamer 188 had no effect on several polymers. From these results, it can be concluded that PEG 1500 and MGHS 40 dissolve more homogeneously in most of the polymers tested than poloxamer 188 does. This result can be related to the higher molecular weight of the poloxamer.

Figure 5: Glass-transition temperature (Tg) of pure polymers in comparison with polymer–plasticizer combinations [extrudate and film (*), 9:1, w/w%], another color in the bar represents the presence of second Tg.

Processability

Taking the T_g or T_m, the melt viscosity, the T_deg, and the determination of the lowest and highest processing temperatures by HME into consideration, the pure polymers copovidone, PEG-VCap-VAc, povidone 12, and poloxamer 407 demonstrated excellent suitability for extrusion (see Figure 6). Povidone 17, PVAc+PVP, PEG–VA, and PEG–VA + PVA were difficult to extrude because of their high T_g or T_m, melt viscosities, and the small difference between T_deg and T_g. PVPs of higher molecular weight (povidone 30 and povidone 90) and MA-EA as pure polymers were not processed by HME because of their degradation.

Figure 6: Temperature range of polymers and PEG 1500 combinations for extrusion (9:1, w/w%).

Three plasticizers (poloxamer 188, MGHS 40, and PEG 1500) were investigated in combination with these polymers. In general, 10 % (w/w) of the plasticizers was sufficient to decrease extrusion temperatures significantly (see Figure 6). Poloxamer 188 and PEG 1500 could be added in powder form using a separate powder feeder. MGHS 40 was added in molten form using a melt pump. The temperature range for extrusion was determined according to the method employed for the pure polymers.

All the polymer–plasticizer combinations could be processed below the processing temperatures of the pure polymers. However, this reduction in temperature was not the same for all polymers. The highest reduction of 50 °C was observed for PVAc+PVP with all three plasticizers. This result is consistent with previous studies on the plasticizing effects in film coatings based on polyvinyl acetate, where small amounts also showed a tremendous effect.

The type of plasticizer also had a significant effect; PEG 1500 decreased the extrusion temperatures more than the other plasticizers. This result probably can be attributed to the low molecular weight of this plasticizer.

Conclusion

Suitable T_g (T_m), T_deg, and melt viscosity are relevant physicochemical parameters of the polymer in HME. A large range between T_g (T_m) and T_deg of the polymer is highly beneficial because it offers freedom for developing the extrusion process. PEG–VCap–VAc is characterized by the widest temperature range for extrusion, followed by povidone 12, and copovidone.

The type of plasticizer has a major influence on T_g, melt viscosity, and the temperature range of the polymer in the HME process. A plasticizer principally enables extrusion processes to occur at low temperatures.

The knowledge of polymer and plasticizer characteristics and their effects on the extrusion process and resulting extrudates is an important prerequisite for the quick and successful development of an extruded drug-delivery system.

Matthias Karl* and Dejan Djuric, PhD, are managers of research and development for pharmaceutical ingredients, and Karl Kolter, PhD, is head of research and development for pharmaceutical ingredients, all at BASF, G-ENP/MD - H 201, 67056 Ludwigshafen, Germany, tel. +49 621 60 92337, fax +49 621 60 97370, matthias.karl@basf.com.

*To whom all correspondence should be addressed.

Submitted: Feb. 17, 2011. Accepted: Apr. 1, 2011.

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Citation: When referring to this article, please cite it as "M.Karl, D. Djuric, K.Kolter, "Pharmaceutical Excipients for Hot-Melt Extrusion," Pharmaceutical Technology 35 (5) 74-82 (2011)."