Hypromellose, Ethylcellulose, and Polyethylene Oxide Use in Hot Melt Extrusion

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Pharmaceutical Technology, Pharmaceutical Technology-01-02-2006, Volume 30, Issue 1

Hot melt extrusion (HME) formulation development depends heavily on choosing the appropriate polymers. This article reviews HME process parameters and highlights three polymers in HME: polyethylene oxide, ethylcellulose, and hypromellose.

Extrusion processing has been a preferred mode of fabrication in the plastics industry for nearly a century. It is widely used today to produce films, sheets, and pipes cost effectively. Single-screw extruders are an economical option for melt processing, but are not ideal for compounding mixtures of plastics with solids or liquids. Twin-screw extruders are preferred when compounding dissimilar materials, but a greater capital investment is required.

A hot-melt extrusion system (American Leistritz Extrusion Corporation) with a downstream film/sheet takeoff using The Dow Chemical Company's "POLYOX" N-80 poly(ethylene) oxide polymer.

The hot melt extrusion (HME) process is just now becoming accepted in the pharmaceutical industry. Building on knowledge from the plastics industry, formulators can extrude combinations of drugs, polymers, and plasticizers into various final forms to achieve desired drug-release profiles. The benefits of using HME over traditional processing techniques include (1):

  • fewer unit operations;

  • better content uniformity;

  • an anhydrous process;

  • a dispersion mechanism for poorly soluble drugs;

  • a low energy alternative to high-shear granulation;

  • less processing time compared with conventional wet granulation.

Several articles have provided overviews of HME technology and how it can be used to produce pharmaceutical dosage forms (2–6).

HME formulation development

Polymer choice is a critical factor to obtain the desired drug-release profile during formulation development for HME. Good polymer choice facilitates processing in the extruder. Many commercially available, pharmaceutical-grade polymers can be used in HME formulations. When choosing a polymer to use in a formulation, processing conditions and processing attributes of the raw materials should be considered. For example, processing conditions typically are chosen on the basis of the rheological and thermal properties of the materials to be extruded. The conditions chosen must generate an acceptable melt viscosity for processing, but they cannot result in the degradation of any raw materials. Torque, melt pressure, and drive-motor amperage are indirect measures of melt viscosity. Torque is the measure of mechanical work needed to move material through an extruder. Melt pressure is the force generated within the extruder as materials are compacted, melted, and forced through a restriction at the end of the extrusion system such as a die. Melt-pressure measurements are typically taken at the end of the extruder barrel. A drive-motor amperage measures how much energy is consumed by the motor when it rotates the extruder screws. Under a given set of processing conditions, higher viscosity materials result in higher values of torque, melt pressure, and drive-motor amperage. This is an important consideration because all extrusion equipment have maximum values of these attributes that should not be exceeded. Improper conditions may lead to degradation of the drug, excipient, or additives.

Extrusion processing

Processing conditions, equipment design, polymer selection, and the use of various additives in the formulation all effect HME.

Processing conditions. Processing conditions directly affect the system's melt viscosity because higher processing temperatures result in lower melt viscosity (7, 8). One example of the polymer's influence on processing conditions is the effect of polymer viscosity. At constant temperature, as the viscosity and molecular weight of the material to extrude increases, the torque in the extruder also increases. The torque, barrel pressure, and drive-motor amperage can be decreased by incorporating plasticizers in the formulation.

Additives. Plasticizers are added to HME formulations to facilitate the extrusion of the material and to increase the flexibility of the extrudate. Plasticizers work by lowering the glass transition temperature (Tg) and melt viscosity of the material. The net effect is that the material can be processed in the extruder at a lower or the same temperature with lower mechanical energy (9, 10). This approach may reduce the likelihood of degradation problems that are associated with temperature-sensitive drugs or polymers. In some formulations, the drug can act as a plasticizer during processing (11, 12). In others, traditional plasticizers must be added to provide the desired effects. The addition of plasticizers can alter the drug release rate, so there must be a balance to ensure that there is enough plasticizer to facilitate extrusion, while maintaining the desired drug-release profile (13).

Equipment. HME equipment can be modified to generate optimum final dosage forms. Some design modifications include the screw configuration, type of extruder (single versus twin screw), temperature-zone set points along the extruder, the method of loading material into the extruder hopper (starve versus flood fed), and rate of extrusion.

Polymer selection. As described previously, polymer and equipment selection, formulation, and processing conditions all play important roles in the success of a HME formulation. This review article will focus on polymer selection and highlight three polymers that are used in HME–polyethylene oxide, ethylcellulose, and hypromellose (HM). In this review article, HM will be used to refer to polymers previously designated as HPMC or hydroxypropyl methylcellulose.

Polyethylene oxide, ethylcellulose, and HM have been extrusion processed in nonpharmaceutical applications for many years. For example, Miller et al. taught the use of water as an extrusion aid for polyethylene oxide in a US patent issued in 1976 (14). Films, rods, and pipes are examples of extruded forms that can be processed. In 1941, Burrows et al. taught the use of extruded ethylcellulose as an insulating coating on wire (15). One use for HM in extrusion formulations is for its binding properties. For example, Chalasani and Johnson patented the use of HM in extruded honeycomb forms that are used in applications such as catalysts, adsorption, and filters (16).


Poly(ethylene) oxide

Poly(ethylene) oxide (PEO) is a white, free-flowing hydrophilic powder. It is a highly crystalline polymer available in 100,000-7,000,000-Da molecular weights. It is currently used in the pharmaceutical industry in applications such as controlled-release, solid-dose matrix systems, transdermal drug delivery systems, and mucosal bioadhesives. PEO is an ideal candidate for HME because of its broad processing window. The crystalline melting point of PEO is ~70 °C, depending upon molecular weight. Without plasticizers, PEO can be extruded at processing temperatures modestly higher than its melting point, subject to equipment limitations. Thermogravimetric analysis (TGA) data indicate that PEO does not exhibit significant weight loss until ~350 °C (see Table I) (17).

Table I: Thermal data summary.

The processing of PEO and the properties of the extrudate can be altered by using various additives. For example, Repka and McGinity included vitamin E TPGS in HME films containing PEO of molecular weight 1,000,000 in various blends with hydroxypropyl cellulose (HPC) (18). The films were produced on a single-screw microtruder (RCP-0750 Microtruder. Randcastle). The authors used a melt temperature that was optimum for each blend but was between 180 and 190 °C. The addition of vitamin E TPGS served as a plasticizer by lowering the Tg of the material. As reported, by adding 3% vitamin E TPGS to a 50:50 blend of PEO–HPC, the Tg was decreased by 11 °C compared with the same formulation without vitamin E TPGS. Vitamin E TPGS also helped in the processing of the PEO–HPC blends by decreasing melt viscosity, as evidenced by reductions in extrusion barrel (melt) pressure, drive-motor amperage, and torque. The physical properties of these 10–13-mm films were changed by the addition of vitamin E TPGS, with a measured decrease in tensile strength and increase in percent elongation.

Thermal stability. Since hot-melt extrusion exposes polymers to elevated temperatures, thermal stability of the polymers is crucial. In a study conducted by Crowley et al., lower molecular weight PEO degraded more rapidly than higher molecular weight PEO (19). This study used a single-screw microtruder (Model RC 0750, Randcastle) equipped with a rod-shaped die. The extruded material was manually cut into 250-mg tablets. Average molecular weight, measured using gel-permeation chromatography (GPC), was used to determine PEO degradation. Additional results reported for extruded matrix tablets of chlorpheniramine maleate (i.e., CPM, a freely water-soluble drug) showed that the addition of PEO with a molecular weight of 100,000 acts as a processing aid when added to PEO with a molecular weight of 1,000,000. The observed effect was a decrease in the extruder-drive amperage. Holding the percentage of CPM constant at 20%, PEO 100,000 was added at 10, 20, and 40% of the total formulation. The addition of PEO 100,000 did not significantly alter the release rate of CPM compared with using PEO 1,000,000 alone. The potential degradation of PEO during extrusion was reduced with the addition of vitamin E succinate, vitamin E, or vitamin E TPGS, which limit molecular weight loss of the PEO.

The benefits of PEO in hot melt extrusion (HME). Using PEO in HME has benefits over traditional pharmaceutical processes such as granulation and direct compression. Using PEO in HME formulations allows for a dry process and reduces processing steps. Moreover, no compressibility requirements are needed, and a continuous efficient operation is possible. In a study by Zhang and McGinity, PEO was extruded with CPM using PEG 3350 as a plasticizer (20). A single-screw extruder with a rod-shaped die was used and the extruded rod was manually cut into tablets 10 mm in diameter and 4.5 mm thick. The authors showed that CPM dispersed at the molecular level in the PEO and formed a solid solution within the PEO matrix. Content uniformity of the final tablets was within 99.0–101.0% of the theoretical amount, as reported by the authors. PEG was added to the formulation to prevent PEO degradation. It can also be used to modify drug release; adding PEG increased the CPM release rate from the extruded matrix tablets.

Repka et al. suggested that HME-produced dosage forms can improve patient compliance. They argued that HME can be used to produce higher-efficiency dosage forms, thereby decreasing dose frequency (21). This study involved PEO MW 100,000 in combination with HPC and the active ingredient polycarbophil (Noveon AA-1) to produce films with thicknesses of 0.34–0.36 mm. A single-screw extruder (Killion, KLB-100) with a film die was used. PEG 3350 was added to the formulation as a plasticizer with butylated hydroxytoluene and propyl gallate as antioxidants and clotrimazole (10% w/w) as an antifungal. The exact composition of the film was not disclosed. These films were reported to have excellent content uniformity. Wide-angle X-ray diffraction studies showed that clotrimazole was molecularly dispersed within the HME films. The clotrimazole showed zero-order release over 6 hours, and prolonged release over 10 hours.

Schachter et al. investigated PEO MW 100,000 for preparing solid-melt dispersions with ketoprofen (22). PEO and ketoprofen were mixed together, wet granulated with water, blended in a Plasticorder (Brabender), then melt-pressed into plaques. Neat ketoprofen has a strong melting transition. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis on the blended material suggested that ketoprofen dissolved in the amorphous phase of PEO. The dispersion was stable, as indicated by XRD analysis of the samples stored at accelerated conditions (40 °C and 75% RH) for one month. The authors also tested the ability of PEO to form solid dispersions with other drug structures. DSC results indicated that ibuprofen, tolbutamide, sulfathiazole, and hydroflumethazide can potentially form solid dispersions in PEO. Schachter and colleagues also used solid-state nuclear magnetic resonance (SSNMR) to characterize molecular structure and mobility of dispersions of ketoprofen in PEO (23). Samples were prepared following the procedure previously described. SSNMR results showed the PEO–ketoprofen interactions were strong enough to disrupt the crystalline lattice of ketoprofen, even at temperatures below the melting point of either component. The authors reported an increase in mobility of ketoprofen in the blend relative to the neat crystalline structure. These results confirmed the ability of PEO to form solid dispersions with ketoprofen at low temperatures.


Ethylcellulose (EC) is a hydrophobic ethyl ether of cellulose. EC is currently used in pharmaceutical applications for microencapsulation of actives, controlled-release matrix systems, taste masking, solvent and extrusion granulation, tablet binding, and as a controlled-release coating for tablets and beads. EC is available in various molecular weights, and has a Tg of 129–133 °C and a crystalline melting point ~180 °C. EC is a good candidate for extrusion because it exhibits thermoplastic behavior at temperatures above its glass transition temperature and below the temperature at which it exhibits degradation (~250 °C) (17).

Typically, plasticizers are added to polymers to reduce their Tg and therefore permit processing at lower temperatures. Some drugs can act as plasticizers to polymers and eliminate the need to add plasticizers to the formulation. For example, DeBrabander et al. found that extruded films of ibuprofen with EC have a lower Tg than films containing EC alone (11). These films were made on a laboratory-scale co-rotating twin-screw extruder. The authors ground the extrudate into fine powders to perform thermal analysis. An increase in the amount of ibuprofen decreased the Tg. For example, when 5% ibuprofen was added to EC, the Tg was in the range of 105.8–109.2 °C. When 20% ibuprofen was added, the Tg dropped to 52.8–66.2 °C. The authors also report complete miscibility between ibuprofen and EC as indicated by a single Tg of the extruded films.

DeBrabander et al. studied modifying the release rate of ibuprofen from EC by adding hydrophilic excipients (HM) (24). They used a co-rotating twin-screw extruder with a 3-mm die to produce mini-matricies. The extrudate was manually cut into dosage forms 2 mm in length. Varying the ratio of HM to EC in the formulation varied the drug-release rate, with release rates increasing as the ratio of HM increased. The authors also studied the thermal stability of ibuprofen after it was extruded with polymers. The authors found that 98.9% of the ibuprofen amount remained after extrusion, as determined by high-performance liquid chromatography.

In another study, by DeBrabander et al. studied the addition of hydrophilic excipients, HM, and xanthan gum to EC and ibuprofen mini-matrices (25). On the basis of an in-vivo study, the group reported a more constant drug absorption pattern with HME produced mini-matrices than with a commercially available product. The authors produced the mini-matricies with a laboratory-scale co-rotating, twin-screw extruder with a 3-mm cylindrical die. The extrudate was manually cut into tablets 2 mm in length.

Crowley et al. compared matrix tablets comprised of 30% guaifenesin and 70% EC, produced by HME with those made using direct compression (26). HME tablets were made using a single-screw extruder with a 6-mm rod-shaped die. The extrudate was manually cut into 250-mg tablets. A smaller particle size of EC in the tablets resulted in a slower release rate using both HME and direct compression. Smaller particle size EC yielded smaller median pore radius direct compression tablets. These tablets were less porous and more tortuous than those made with larger particle size EC. The authors reported that release rates from tablets prepared using HME were slower than those prepared using direct compression, with the HME prepared tablets having a smaller median pore radius and overall lower porosity. The authors also examined the effect of extrusion temperature on drug-release rate. They found that extruding at higher temperatures (90–110 °C) produced tablets that were less porous and more tortuous than extruding at lower temperatures (80–90 °C). Higher temperature processing decreased the drug release rate.

Hypromellose (HM)

HM is a hydrophilic cellulose ether that is available in a range of viscosities and substitutions. It is used in pharmaceutical applications such as controlled-release matrices, tablet coatings, and granulation binders. HM has a Tg of 160–210 °C and shows significant degradation at temperatures in excess of 250 °C, depending upon the substitution (17). It has proven challenging to extrude because of its high Tg and low degradation temperature, which gives HM a narrow processing window. One way to broaden the processing window is to incorporate high amounts of plasticizer in the formulation as described by Alderman and Wolford (27). The authors suggested using at least 30% by weight of a plasticizer in an extruded matrix formulation.

Verreck, Six, and colleagues studied solid dispersions of itraconazole (a Class II drug) and HM (27, 28). Solvent-cast films were evaluated to determine the best drug–polymer ratio on the basis of drug dissolution rates and DSC analyses. Initial results indicated an amorphous solid dispersion of itraconazole in HM was formed. HME was used to study blends of 40% itraconazole and 60% HM. A co-rotating twin-screw extruder was used for the studies. Samples produced by HME and then milled released 90% of the itraconazole in 120 min. Samples made with a physical mixture of the drug and the polymer released only 2% of the intraconazole in the same time period. In a study to improve the dissolution rate of itraconazole, the extrudate was milled and then sieved to exclude particles larger than 355 mm. In a formulation comprising 25% itraconazole, 75% HM, 80% of the drug was dissolved within 30 min. These results are in contrast with dissolution of crystalline and glassy itraconazole, which had 0% and 5% drug release after 30 min, respectively.

Rambali et al. optimized a HME formulation containing itraconazole, HM, and hydroxypropyl-β-cyclodextrin (HP-β-CD) (12). The authors reported that itraconazole acted as a plasticizer for the melt because formulations with higher drug loading had a lower torque. For example, a formulation with 60% HM, 20% (HP-β-CD), and 20% itraconazole had a torque of 45%. When the percentage of itraconazole was increased to 43%, with 37% HM and 20% (HP-β-CD), the torque was reduced to 34%. A twin screw co-rotating extruder with a 3.0-mm rod-shaped die was used to generate these observations.

EC and HM can be combined in unique dosage forms to deliver active pharmaceuticals. One of these dosage forms used an EC outer pipe and a separately prepared HM core (30). The EC pipe was produced using HME with a laboratory-scale twin-screw co-rotating extruder with an annular die with a metal insert to produce the pipes. The core was manually prepared by heating the components until molten, followed by homogenization. The core material was manually filled into the pipe. The authors suggest that the entire process could be automated in a full-scale HME production operation. The goal of this study was to eliminate the burst effect that is sometimes seen in HMmatrix tablets. It was reported that with a 5% drug loading of theophylline monohydrate (medium soluble, aqueous solubility 8.33 g/L), propranolol HCl (freely water soluble, aqueous solubility 50 g/L), or hydrochlorothiazide (poorly soluble, 0.1 N HCl solubility 0.25 g/L) drug solubility did not affect release rate. Instead, the dissolution profiles indicated erosion-controlled, zero-order drug release for all three drugs. The authors also examined the effect of viscosity grade and substitution type of HM used in the inner core. The authors found that for the same HM viscosity, there was no difference in release rates. Nonetheless, replacing HM with methylcellulose (MC) resulted in faster release rates.

Another study by Mehuys et al. reported an increase in the bioavailability of propranolol HCl when an EC pipe with HM–Gelucire core was used instead of the core alone (31). The EC pipes were produced with a laboratory-scale co-rotating twin-screw extruder with an annular die with metal insert to produce the pipes. The pipes had a 5-mm internal diameter, a 1-mm wall thickness, and were cut into 12-mm lengths. The core materials were heated until molten and then homogenized. The pipe cores were manually filled with the separately prepared HM–Gelucire core material. The authors reported that hydrodynamics, mechanical stress, and the dissolution medium had little effect on drug-release rates. Results indicated that the HME-produced matrix in cylinder propranolol HCl had better bioavailability in dogs compared with the Inderal (Wyeth) sustained-release formulation. The authors reported the relative bioavailability of the matrix in cylinder system was ~400% better than Inderal, measured by the mean AUC0-24.


Many published examples have described the use of polyethylene oxide, ethylcellulose, and hypromellose in pharmaceutical dosage forms produced using hot-melt extrusion. The use of these polymers is anticipated to grow as hot melt extrusion technology becomes more widely practiced within the pharmaceutical industry.

Karen A. Coppens* is an application development specialist, Mark J. Hall is asenior application development specialist, Shawn A. Mitchell is an application development specialist, and Michael D. Read is a research leader, at The Dow Chemical Company, 16450 N. Swede Road, Midland MI, 48574.

*To whom all correspondence should be addressed.


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