POLYOX (Polyethylene Oxide) - Applications in Pharma Industry

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Abstract

The purpose of this review article is to describe the properties and applications of polyethylene oxide. Polyethylene oxide is a biocompatible polymer, which is marketed as "POLYOX TM". It is a non-ionic, water soluble resin, with good lubricating, binding and film forming properties. POLYOX TM retards the release rate of drug/s and hence are widely used in pharmaceutical formulations like controlled release dosage forms, hot-melt technology and mucoadhesive dosage forms. Depending on its molecular weight, various grades of POLYOX(tm)are available in market. Drug release mechanisms from dosage forms are based on swelling and erosion properties of the polymer. POLYOX TM plays a vital role in design of a novel drug delivery system for both highly and poorly soluble drug.

Keywords: Polymers, Polyethylene oxide, controlled drug delivery, POLYOX(tm), PEO

1. Introduction:

Since past few decades, pharmaceutical companies are booming ahead with innovations in formulation, research and development. These innovations aim at the quality and safety of the product, without compromising patient compliance. Scientists are working on novel drug delivery systems like liposomes, niosomes, nano-technology, magnetic delivery systems, and sonophoresis, but in such type of dosage forms its a challenge for research scientists and industrialists, to transfer pilot scale to production batches. So alternatively, controlled drug delivery systems, sustained delivery systems, orally disintegrating system, immediate release dosage forms etc., are used. The most important factor in all these release retarding dosage form is the use of polymers. Hence polymers like POLYOX(tm) is used in novel drug delivery systems [19 ] .

1.1 Controlled drug delivery (CDD) :

Release of drug from a CDD system proceeds at a kinetically predictable and reproducible rate. It produces a constant steady-state plasma level for prolonged duration. It can be defined as "Release of drug at a predetermined rate and/or to a location according to needs of body and disease rates for a definite time period". The release mechanism in controlled drug delivery system is mainly by reservoir or matrix systems. The three major types of materials used in there preparation of devices are insoluble plastics, hydrophilic polymers and fatty compounds. Plastic materials mainly include methyl acrylate, methyl methacrylate, polyvinyl chloride and polyethylene. Hydrophilic polymers include methyl cellulose (MC), hydroxy propyl methyl cellulose (HPMC), carbopol etc. Fatty compounds include carnauba wax, glyceryl tristearate[15]. In all types of novel drug delivery systems polymers play a significant role.

Few mechanisms involved in controlled release of drug are: diffusion controlled system; solvent activated system; chemically controlled system; and magnetically controlled system. Polymers, used in these drug delivery systems, can be mainly classified based on polymer-water interaction like hydrophobic polymers, hydrophilic polymers, water soluble polymers and hydrogels.

Swelling System: In this system, drug is dispersed throughout the polymer and has difficulty in diffusing out of polymer matrix. Biological fluid diffuses into matrix and causes its outer polymer layer to swell and because of that entrapped drug can release at predictable rate.

Erosion System: In this system, drug is dispersed throughout the polymer and rate of drug release depends on erosion rate of polymer [15, 18].

2. POLYOX(tm):

POLYOX(tm), water soluble resins, is also referred to as poly (ethylene oxide).

Characteristics: They are white, free-flowing hydrophilic crystalline powders supplied in a wide variety of molecular weight grades, ranging from one hundred thousand to eight million with an average particle size of around 150 mm. POLYOX(tm) NF water-soluble resins have applications in pharmaceutical products, such as in controlled release solid dose matrix systems, tablet binding, tablet coatings, transdermal drug delivery systems, and mucosal bioadhesives and gastro-retentive dosage forms [19, 21].

They exhibit film forming and water retention properties. It has high water solubility and low toxicity [11].

POLYOX(tm) resins can form associated compounds with many substances such as polystyrene, polycaprolactone, polyethylene, polypropylene and polylactides to produce unique blends and achieve a wide variety of additional, useful formulation properties.

Poly(ethylene oxide) (PEO) is a non-ionic linear homopolymer of ethylene oxide, which can be used as a matrix system for controlled release, a tablet binder for direct compression, a mucosal bioadhesive, a thickening agent, and a tablet coater [10].

2.1 Common structure:

(-O-CH2-CH2-)n OH. They have same chemical structure as PEG but higher molecular weights. n = average number of oxyethylene groups [16]. The ethylene oxide monomer is an epoxide ring. Two corners of the molecule consist of -CH2- linkages as shown in figure 1. The third corner is oxygen, -O-. In the presence of a catalyst the monomer forms a chain having the repeat unit -CH2-CH2-O- [22].

Figure 1: Synthesis of PEO

Synthesis of PEO

2.2 Grades of POLYOX(tm) water soluble resins:

POLYOX(tm) water soluble resins are supplied with variety of molecular weight grades and are

formulated as NF and other official grade compounds. Different grades of POLYOX(tm) water soluble resins and its pharmaceutical applications are cited in table 1[19]. As per inactive ingredient guide (published by the division of drug information resources, the Food and Drug Administration, as last updated April 2009), the highest level of polyethylene oxide in an oral drug form currently being used is approximately 543 mg/tablet.

Table:1 POLYOX(tm) Water-Soluble Resins NF for Pharmaceutical Applications

POLYOX(tm) Water-Soluble Resin NF Product

Approximate Molecular Weight

Viscosity Range at 25degC, cP

5% Solution

2% Solution

1% Solution

WSR N-10

100,000

30 - 50

WSR N-80

200,000

55 - 90

WSR N-750

300,000

600 - 1,200

WSR N-205

600,000

4,500 - 8,800

WSR N-1105

900,000

8,800 - 17,600

WSR N-12K

1,000,000

400 - 800

WSR N-60K

2,000,000

2,000 - 4,000

WSR-301

4,000,000

1,650 - 5,500

WSR Coagulant

5,000,000

5,500 - 7,500

WSR-303

7,000,000

7,500 - 10,000

*(tm) Trademark of the Dow Chemical Company ("Dow") or an affiliated company of Dow.

2.3 General properties [19]:

High binding efficiency - POLYOX(tm) water-soluble resins have high-binding efficiency for pigments, fillers, and metal powders. These binders easily burn off at low temperatures with little or no tendency to char.

Form novel complexes - The strong hydrogen bonding affinity of POLYOX(tm) water-soluble resins accounts for the association of these polyether with various polar compounds, such as phenolic resins, mineral acids, halogens, urea, lignin sulfonic acids and poly (carboxylic acids).

Crosslink ability - POLYOX(tm) water-soluble resins can be cross-linked to form gels that are highly water-retentive.

Emollient - When applied to the skin and hair, POLYOX(tm) water-soluble resins produce a soft and silky feel.

Film former excipient - POLYOX(tm) water-soluble resins can be formed into flexible films both by thermoplastic processing and casting techniques. Such films may be made of POLYOX(tm) water-soluble resins alone or blended with a wide variety of other polymers, such as polyethylene, polystyrene, polycaprolactone, ethylene vinyl acetate, nylon, etc.

Low toxicity - POLYOX(tm), water-soluble resins, shows very low order of toxicity in animal studies by all routes of exposure. At the maximum practical oral dose to rates of about 2 g/kg of body weight neither death nor signs of toxicity are observed [20]. Because of their high molecular weights, the resins are poorly absorbed from the gastrointestinal tract and are completely and rapidly eliminated. These resins are neither skin irritants nor sensitizers, nor do they cause eye irritation as the dry powder or as aqueous solutions.

Flocculant activity - High molecular weight grades of POLYOX(tm) water-soluble resins effectively adsorb onto many colloidal materials and perform as efficient flocculating agents. They exhibit a high affinity for a variety of materials, including silica, clays, oxidized coal fines, lignins and paper fines.

Lubricity - POLYOX(tm) water-soluble resins impart a high degree of lubricity when in contact with water.

Solubility/Thickening of many organic solvents - POLYOX(tm) water-soluble resins are readily soluble in and will thicken wide variety of organic solvents at various temperatures. Organic solvents include most halogenated hydrocarbons, various ketones, alcohols, aromatic hydrocarbons and esters. POLYOX(tm) water-soluble resins are not generally soluble in aliphatic hydrocarbon solvents, glycols, diols and aliphatic ethers.

Thermoplasticity - As thermoplastics, POLYOX(tm) water-soluble resins are readily calendered, extruded, injection molded, or cast. Sheets and films of this material are heat-sealable and can be oriented to develop high strength. Films are inherently flexible, tough and resistant to most oils and greases. These resins are compatible with many natural and synthetic polymers. The combination of thermo plasticity and aqueous solubility and compatibility with "hydrophobic" polymers (e.g. polyethylene, polycaprolactone, ethylene vinyl acetate, nylon, etc.) makes POLYOX(tm) water-soluble resins a valuable asset for degradable plastics applications.

Wet tack - POLYOX(tm) water-soluble resins exhibit a high degree of wet tack and, thus, are useful as wet adhesives. The dried residue is non-tacky.

Thickening power (aqueous) - POLYOX(tm) water-soluble resins are nonionic and completely water-soluble at all temperatures upto the boiling point of water. Unlike most other high molecular weight, water-soluble resins, they do not exhibit an inverse solubility-temperature relationship, except near the boiling point. POLYOX(tm) water-soluble resins are extremely effective thickening agents in both fresh and salt water. Aqueous solutions are pseudoplastic (i.e. shear thinning).

Drag reduction/Drift control - Very low concentrations of the higher molecular weight POLYOX(tm) water-soluble resins can reduce the turbulent frictional drag of the water in which they are dissolved by as much as 80 percent.

Viscoelasticity - The flexibility of ether linkages combined with the extremely high molecular weight of POLYOX(tm) water-soluble resins produces solutions with elastic behavior.

Flow property - All grades of POLYOX(tm) water soluble resins flow relatively the same. POLYOX(tm) contains silica (~1.5%) to help with the flow ability.

Glass transition temperature - The glass transition temperature (Tg) of the family of poly (ethylene oxide) products ranges from -50 to -57degC. Molecular weight does not have a significant impact on the Tg within the family of products.

Water soluble - POLYOX(tm) resins can be controlled over a wide range through blending with other thermoplastics. Packaging materials, personal care products, and other items manufactured from POLYOX(tm) resins are easily disposable and environmental friendly.

Timed release - Unique swelling properties coupled with the controlled rate of dissolution make POLYOX(tm) resins an ideal choice for time-release formulations. Devices that provide a time-release of fragrance, colors, surfactants, reagents, etc., can be extruded using POLYOX(tm) resins.Several pharmaceutical time-release formulations are currently based on POLYOX(tm) resins.

Nontoxic and degradable -POLYOX(tm) water-soluble resins are nontoxic and have received FDA approvals for a number of food and drug applications. Aqueous solutions of POLYOX(tm) resins are environmentally degradable due to oxidation and aerobic biodegradation.
Because of their many unique properties, POLYOX(tm) resins are particularly suited for the following processes:

  • Casting
  • Extrusion
  • Injection molding
  • Blown film [19]

2.4 Typical physical property

Properties of POLYOX(tm) are shown in below table 2[19].

Table 2(1): Typical Property of POLYOX TM

Appearance

Off-white powder

Crystalline Melting Point (2) (X-ray and DSC), degC

62-67

Odor

Slightly smells like ammonia

Melt Flow Temperature, degC

>98

Volatiles Content, as packaged, % by wt (at 105degC)

<1.0

Alkaline Earth Metals, % by wt as CaO, max

1.0

Powder Bulk Density, lb/ft3 (kg/m3)

19-37 (304-593)

Polymer Density, g/cc

1.15-1.26

Moisture Content, as Packaged, %

<1

Heat of Fusion, cal/gm

33

Solution pH

8-10

Particle size, % by wt

Average through 10-mesh ( U.S. standard)

Average through 20-mesh

100

96

(1) Data listed here are considered to be typical properties, not specifications.

(2) At temperature far above the crystalline melting point, high polymers of POLYOX(tm) water soluble resins still retain a very high degree of crystalline character.

3.Preparation of POLYOX(tm) solution [19]:

POLYOX(tm) solution is water soluble. If POLYOX(tm) powder is not dispersed properly; agglomeration and gel formation takes place. These insoluble agglomerates will hinder the formulations. Organic solvents can be used to avoid such problems.

Three techniques provide good dispersion of POLYOX(tm):

* Simple direct addition to water.

* Predispersion in water-miscible non-solvents.

* Use of mechanical devices that achieve dispersion with minimal shear.

Technique used will depend on the final viscosity and volume required. For laboratory and less than drum quantities, direct addition of the POLYOX(tm) water-soluble resins to water, or non-solvent predispersion of POLYOX(tm) water-soluble resins, is recommended. For large volumes or continuous operation, special mechanical devices are used. Aqueous solutions of POLYOX(tm) water-soluble resins are pseudoplastic. The degree of pseudoplasticity increases as the molecular weight increases. Therefore, the viscosity of a given aqueous solution is a function of the shear rate used for the measurement [7]. This relationship between viscosity and shear rate for solutions of various molecular weight poly (ethylene oxide) resins is presented in the figure. 2 [19]

The key to dissolution is good initial dispersion. In entire dissolving operation of POLYOX(tm) water-soluble resins, it dissolves completely in first few seconds by separating the individual resin particles from each other. High-shear agitators are not necessary and should be avoided. In water, POLYOX(tm) water-soluble resins are instantly wettable. If the POLYOX(tm) water-soluble resin powder is not properly dispersed, the partially dissolved, wetted particles will agglomerate and form gels that may never dissolve. High-speed agitation of dissolved POLYOX(tm) water-soluble resins must be avoided to prevent shear degradation of the resin. Organic solvents, because of their lower polarity, do not solvate (wet) POLYOX(tm) water-soluble resins as rapidly as water. As a result, particle agglomeration and gel formation are generally not a problem when dissolving POLYOX(tm) water-soluble resins in organic solvents [19].

Solution properties of POLYOX(tm) water soluble resins

Figure 2 [19]: Solution properties of POLYOX(tm) water soluble resins.

The pH of a POLYOX(tm) water-soluble resin solution is 8 - 10. POLYOX(tm) resin solutions will be most stable at neutral to slightly alkaline pH. At pH > 12, POLYOX(tm) resins will precipitate out. At pH < 2, the polymer will degrade since ethers undergo acidic hydrolysis. This is evidenced by a loss of solution viscosity over time [19].As the concentration of POLYOX(tm) water-soluble resin is increased, solution viscosity increases rapidly. The viscosities produced by several grades of POLYOX(tm) at various concentrations are cited in the figure 3 [19].

Figure 3 [19]: Relationship between Viscosity and concentration of resins.

Relationship between Viscosity and concentration of resins

Solution Characteristics of POLYOX(tm) in different solvents: POLYOX(tm), water soluble resins, is readily soluble and becomes thick in a wide variety of organic solvents at various temperatures. Organic solvents include most halogenated hydrocarbons, various ketones, alcohols, aromatic hydrocarbons and esters. POLYOX(tm) is not soluble in aliphatic hydrocarbon solvents, glycols, diols and aliphatic ethers. POLYOX(tm) will not form solutions with 1, 3-Butanediol, ethylene glycol, diethylene glycol and glycerol.

3.1 Mechanism of release:

POLYOX(tm) water-soluble resin is uniformly incorporated throughout the tablet. Upon contact with water, it hydrates the outer tablet surface to form a gel layer. The rate of diffusion out of the gel layer and the rate of tablet erosion control the overall dissolution rate and delivery of the active substance [19]. The POLYOX(tm) product should be selected based on the molecular weight (MW) needed to obtain the release profile desired. A lower MW polymer will release faster than a high MW grade. For a robust and reproducible release profile the amount of POLYOX(tm) should be 20 - 90% of the tablet weight [19].

The drug release from the high molecular weight PEO tablets is governed by the swelling of the polymer rather than by the erosion of the polymer, leading to anomalous release kinetics. However, the drug release from the low molecular weight PEO is controlled primarily by the swelling/erosion of the polymer, resulting in front synchronization and a constant release rate. It is observed that drug loading and drug solubility do not influence the release of drugs from low molecular weight PEO tablets. The pH of the dissolution medium and the stirring rate do not affect the drug release regardless of the molecular weight of the PEO [20].

High molecular weight linear poly (ethylene oxide) (PEO) has shown a great potential as a material for controlled drug delivery systems. Matrix tablets based on PEO can be manufactured readily, because of good compressibility of this polymer [17]. The polyether chains of PEO can form strong hydrogen bonds with water; therefore, when solid matrices are brought into contact with an aqueous medium, the polymer tends to hydrate, forming a superficial gel which eventually erodes as the polymer dissolves. Drug release from such matrices may be controlled by polymer swelling or erosion, or drug diffusion in the hydrated gel or by these processes altogether. Hence, a variety of release patterns can be obtained, depending on the PEO molecular mass and the drug physicochemical properties. Several studies on PEO based controlled-release matrices for oral application have been reported [1, 2, 3, 8, 9, 13, and 17]. Also, applications of PEO as a carrier or component of oral, mucosal and transdermal drug delivery systems are documented by numerous patents. Good mucoadhesive properties [19] and lack of irritancy to the rabbit eye [4] makes this polymer as an interesting candidate material for controlled-release erodible ocular inserts.

3.2 Degradation of POLYOX(tm):

POLYOX(tm), water soluble resins, is oxidatively degradable polymers. Degradation can be monitored by gel permeation chromatography or else viscosity of POLYOX(tm) solution is used to determine degradation. Degradation of POLYOX(tm) occurs due to aliphatic ethers present in POLYOX(tm). This reacts with oxidizing agent such as oxygen and hydrogen peroxide to form hydroperoxides. Further degradation results in chain scission. Various metal ions like silver, ferrous, cupric also cause decomposition. This degradation can be prevented by use of antioxidants, bubbling nitrogen through solution and storing POLYOX(tm) under cool condition [19].

All POLYOX(tm) water-soluble resins contains some level of BHT (butylated hydroxytoluene) antioxidant. Additional BHT is added as per our requirement. The pharmaceutical grades of POLYOX(tm) resin contain 100 - 1000 ppm (industrial grades contain 0.1% max) BHT with the exact level depending on the molecular weight of the polymer [20]. Vitamin E is also used in pharmaceutical applications as an oxidative stabilizer. Typical use level is 500-1000 ppm. To achieve good mixing of vitamin E into the POLYOX(tm) powder, vitamin E is dissolved in a small amount of isopropyl alcohol before mixing it with the POLYOX(tm) powder [19]. In solution, the use of alcohols or glycols (isopropyl alcohol, propylene glycol, and glycerol) at approximately 5 - 10% wt has the benefit of reducing the loss of solution viscosity on aging since these solvents behave as solution viscosity stabilizers [19].

In industrial applications, sodium thiosulphate (0.1%w/v) can be used as a solid stabilizer. Sodium thiosulphate acts as a chlorine scavenger and is most useful for processes using municipal (treated) water [21].

4. Standard retest frequency for POLYOX(tm):

  • Mid to high molecular weight grades - 6 months
    [WSR N-3000, 205, 1105, 12K, 60K, 301, Coagulant, 303, and N-750 ]
  • Low molecular weight grades - 2 years
    [WSR N-10 and N-80]

POLYOX(tm) water soluble resins do not have a shelf-life per se; however, it is recommend that it is good to retest the material periodically to ensure suitability in any application. Retesting of batches of material is done to ensure viscosity specification compliance [19].

5.0 Comparison of low molecular weight (LMW) and high molecular weight (HMW) POLYOX(tm):

Despite of release mechanism, both LMW and HMW differ from strength of gel formation. PEO forms strong gel upon contact with water. The strength of gel is decreased as water content is increased. As compared to LMW PEO, HMW PEO has higher cohesive strength, holds extrudate better together and also prevents it from sticking to the extrudent. Swelling is dependent on both the type of polymer as well as molecular weight, whereas erosion is mainly dependant on molecular weight [20].

5.1 Formulation variables with POLYOX(tm) matrices:

Polymer viscosity

Polymer concentration

Polymer particle size

pH effect

Formulation stability [20]

6.0 Applications in Pharmaceutical Industries:

POLYOX(tm) offers a history of successful use in extended release applications of osmotic pump technologies, hydrophilic matrices, gastro-retentive dosage forms and other drug delivery systems such as transdermal and mucoadhesive technologies.

POLYOX(tm) resins also provide a number of benefits:

  • Wide range of molecular weights offers formulation flexibility
  • Versatile application in direct compression and granulation
  • Rapid hydration and swelling for use in osmotic pump technologies
  • Fast hydration and gel formation for use in hydrophilic matrices
  • Meets requirements of the United States Pharmacopoeia (USP) and compliance with US Food Chemicals Codex [20].

6.1 Controlled release matrix systems -

POLYOX(tm) water soluble resins NF are very versatile polymers for controlled release applications. Upon exposure to water or gastric juices, they hydrate and swell rapidly to form hydrogels with properties ideally suited for controlled drug-delivery vehicles. POLYOX(tm) water-soluble resins NF are nonionic, has no interaction between drug and polymers which are used in CDDS.

6.2 Direct compression tablet binding -

POLYOX(tm) water soluble resins NF acts as binders in direct compression systems. They often provide better flow and compaction properties than other binders and their lubricity also assists tableting operations.

6.3 Mucosal bioadhesives -

POLYOX(tm) water-soluble resins NF offers number of important properties for mucoadhesion - water solubility, hydrophilicity, high molecular weight, hydrogen bonding functionality and good biocompatibility. These resins have a long linear chain structure which allows them to form a strong interpenetrating network with mucus. Data indicates that molecular weights of 4,000,000 and higher have the highest level of adhesion.

6.4 Melt extrusion -

POLYOX(tm) water soluble resins NF provide good flow characteristics and can be used in conventional equipment [20].

7.0 Disadvantages:

They have property to impart lubricity and water solubility to the end product. But when relatively small constant stress is applied to POLYOX(tm) products crazing and tensile failure can occur [20].

Crystallization is also observed with polymer and especially more and faster in lower molecular weight POLYOX(tm), because water absorbing capacity is increased with decreased molecular weight. Because of high water absorption by LMW POLYOX(tm), a glassy rubbery transition can be observed on SEM photomicrographs and so it must be more in case of POLYOX(tm) LMW. These structural changes occur due to physical aging not only effect pure substance but also dosage form. Mechanical and drug release property can change which might result in stability problem in long term. In order to avoid problem, it is advisable to monitor possible structural changes [10].

8.0 Comparison of POLYOX(tm) with other polymers:

Although HPC has a greater number of H-bonding group than PEO but PEO films demonstrated higher bioadhesion than HPC films. Because PEO hydrates faster, takes up more water and swell more than HPC. The swollen polymer maximizes space between polymer molecule increasing flexibility which leads to more entanglements, interpenetration and consequently adhesion strength. Physical stability of drug and PEO in HME films increased with increase HPC concentration but bioadhesion and flexibility of PEO films decreased with increased HPC concentration. PEO films shows higher bioadhesion than HPC films because extremely flexible PEO structure. Moisture content present in PEO films has no significant effect on mechanical property of films stored below 60% RH [14]. HMW PEO can be used as alternative to HPMC as tablet binder in direct compression [12].

The swelling ratio of PEO was approximately twice as that of HPMC in acidic and neutral testing media. The swelling behavior of PEO hydrogels is not influenced by the pH or ionic strength of medium and, therefore, showed a similar bioadhesive trend in acidic and neutral pH environments. Carbopol, in contrast, has pH dependant swelling pattern, which results in variations in its bioadhesion at different locations. The pH independent swelling and bioadhesion behavior of PEO makes it a reliable polymer for bioadhesion in stomach [20].

9.0 Current status:

PEO can be used for matrix tablets for the sustain release of a large amount of a highly water-soluble drug, due to the significant diffusion of drug. Effective restricted diffusion of drug is achieved because of opposite charge on other polymer and drug [11].

Poly(ethyleneoxide) is a biocompatible eroding polymer available in a number of molecular weights, which is receiving growing attention as sustained-release bioadhesive platform due to its safety, ease of processing (direct compression is feasible) and possibility to control drug release. Depending on the molecular weight of PEO, different dissolution and water swelling rates, viscoelastic behaviour of the swollen gel as well as extent and duration of bioadhesion can be achieved. PEO has been used in oral sustained-release tablets [1, 2, 3, 8, 9] and ocular inserts [4].

Zero-order release kinetics can be achieved with PEO tablets for drugs for which solubility is below 1%. PEO tablets provided zero-order release for poorly water-soluble drugs (below 0.2%) at 39% drug loading. Zero-order release kinetics can be attained with PEO tablets using a drug which has a solubility of less than 0.1% [8, 9].

PEO can be used for poor water solubility drug in melt processed blend. The drug containing carboxylic group form hydrogen bond with ether group of POLYOX(tm), which provides high miscibility and increased dissolution. So, POLYOX(tm) is helpful for drug which has low bioavailability [13].

Incorporation of cyclodextrins in a PEO-based hydrophilic matrix intended for the delivery of poorly soluble drugs can be a suitable strategy to optimize the release features of the system while maintaining good bioadhesive properties [2].

Recently, it has been established that non-cross linked low molecular weight poly (ethylene oxide) (PEO) ensures constant release rate by means of forming a homogeneous gel of even thickness. When the drug is loaded onto the model matrices, based on PEO of higher molecular weight, the release is controlled by the swelling of the polymer, not by its erosion. This leads to the inconstant rate of release, induced by the diffusion of the drug through the swollen gel layer [8, 9]. Being harmless and stable, makes PEO a suitable carrier for drug delivery systems. Its good compressibility allows the preparation of hydrogel matrices by direct compression [5].

High molecular weight POLYOX(tm) polymers can retard the release rate of both poorly and high soluble drugs from capsule formulations. It appears that swelling depends on the polymer molecular weight and the amount of polymer present in the formulation. POLYOX(tm) polymers can be good candidate for oral sustained (capsules) drug delivery systems filled with drug of different solubility, especially for poorly soluble drugs [6].

10.0 Case study [21]:

The influence of different dissolution methods and hydrodynamic conditions in the dissolution

vessel on the release of a high solubility drug, metformin hydrochloride (metformin HCl), from an ER matrix formulation containing PEO as the rate-controlling polymer was carried out. The formulation was prepared which contained 50% w/w metformin HCl, BCS class II drug, 30% w/w PEO (POLYOX WSR-1105), 19% w/w microcrystalline cellulose, 0.5% w/w fumed silica and 0.5% w/w magnesium stearate.

Tablets were manufactured by direct compression with a target weight of 1000 mg and checked for dissolution. Drug release was measured at 50, 100, 150 and 200 rpm using different dissolution techniques like USP I (baskets), USP II (paddle), USP II (paddle) with sinkers, 2.38 mm stationary quadrangular baskets (QBs). QBs were positioned within the dissolution vessel using perpendicular or parallel to the shaft of the paddle and in a low, middle or high position above the paddle.

Figure:Position of QBs in the dissolution vessel relative to the paddle.

Position of QBs in the dissolution vessel relative to the paddle

Purified water was used as dissolution medium (1000 ml) at 37.0+-0.5oC. Samples were analysed with dual beam spectrophotometer at a wavelength of 233nm. Triplicate samples were measured at each time point and mean and standard deviation (SD) values were calculated. Result shows that for all dissolution testing methods, reproducible first-order drug profile was obtained. At 100 rpm, metformin HCl release from PEO matrices was slightly faster when QBs or paddles with sinkers were used as compared to paddles without sinkers or basket method. SD value obtained was less when using QBs as compared to paddles. The reason behind it is some PEO matrices were found stick to the bottom of the dissolution chamber or float onto the surface of the dissolution medium and so its resulted in variable drug release.

Figure 5: The influence of dissolution method on metformin HCl release from PEO ER matrices (100 rpm)

The influence of dissolution method on metformin

Positions of the QBs at middle and high above the paddle show slightly faster drug release as compared to lower position.

Figure 6: The influence of QBs position relative to the shaft of the paddle on metformin HCl release from PEO ER matrices (100 rpm)

The influence of QBs position relative to the shaft of the paddle

Figure 7: The influence of QBs position above the paddle on metformin HCl release from PEO ER matrices (100 rpm)

The influence of QBs position above the paddle on metformin HCl

Release of the drug becomes faster as the rotational speed increases from 50 rpm to 100 rpm.

Figure 8: The influence of paddle speed on metformin HCl release from PEO ER matrices using quadrangular baskets.

The influence of paddle speed on metformin HCl release

Conclusion:

POLYOX(tm) has very good advantage in novel drug delivery system. As it is non-ionic in nature, there is no any interaction with other excipients. Poly(ethyleneoxide) is a biocompatible eroding polymer available in a number of molecular weights, which is receiving growing attention as sustained-release bioadhesive platform due to its safety, ease of processing (direct compression is feasible) and possibility to control drug release. Depending on the molecular weight of PEO, different dissolution and water swelling rates, viscoelastic behaviour of the swollen gel as well as extent and duration of bioadhesion can be achieved. PEO has been used in oral sustained-release tablets. HMW POLYOX(tm) shows release by swelling instead of erosion, leads to anomalous release kinetics. PEO hydrates faster so its swelling rate is high. As per current status, it is very helpful polymer in novel drug delivery system for both highly soluble and poorly soluble drug.

Acknowledgements: We thank Prof. R.S Gaud, Dean Pharm.Sciences, SVKM's NMIMS for his valuable support.

Abbreviations:-

NDDS: Novel Drug Delivery System

MC: Methyl Cellulose

HPMC: Hydroxy Propyl Methyl Cellulose

NF: National Formulary

PEO: Polyethylene Oxide

PEG: Polyethylene Glycol

MW: Molecular Weight

BHT: Butylated Hydroxytoluene

LMW: Lower Molecular Weight

HMW: Higher Molecular Weight

USP: United States Pharmacopoeia

CDDS: Controlled Drug Delivery System

SCM: Scanning Electron Microscop

HPC: Hydroxy Propyl Cellulose

HME: Hot-Melt Extrusion

References:

1.Apicella A., Cappello B., Del Nobile M.A., La Rotonda M.I., Mensitieri G., Nicolais L. Poly (ethylene oxide) (PEO) and different molecular weight PEO blends monolithic devices for drug release. Biomaterials 14, 1993, 83-90.

2.Cappello B.,Del Nobile A.M., La Rotonda M.I., Mensitieri G., Miro A., Nicolais L., 1994. Water soluble drug delivery system based on a non-biological bioadhesive polymeric system. II Farmaco 49, 809-818.

3.Cappello B., De Rosa G., Giannini L., 2006. Cyclodextrin-containing poly(ethylene oxide) tablets for the delivery of poorly soluble drugs: Potential as buccal delivery system. International Journal of Pharmaceutics 319, 63-70.

4. Di Colo G., Burgalassi S., Chetoni P., 2001. Gel-forming erodible inserts for ocular controlled delivery of ofloxacin. International Journal of Pharmaceutics, Vol. 215, Issues 1-2, Pages 101-111.

5.Dimitrov M., Lambov N., 1999. Study of verapamil hydrochloride release from compressed hydrophilic Polyox-Wsr tablets. International Journal of Pharmaceutics 189, 105-111.

6.Efentakis M., Vlachou M., July 2000. Evaluation of high molecular weight polyox polymer: Studies of flow properties and release rates of furosamide and captopril from controlled release hard gelatin capsules, Pharmaceutical Development and Technology, Vol. 5, Issue 3, pages 339-346.

7. Hong S.I., Oh S. Y., 2008. Dissolution kinetics and physical characterization of three layered tablet with poly (ethylene oxide) core matrix capped by Carbopol. Int. J.Pharm. 5, 121-129.

8.Kim C., 1995. Drug release from compressed hydrophilic POLYOX-WSR tablets, J. Pharm. Sci. 84, 303-306.

9.Kim C., 1998. Effects of drug solubility, drug loading, and polymer molecular weight on drug release from Polyox tablets, Drug Dev. Ind. Pharm. 24, 645-651.

10.Kiss D., Karoly S., Marek T., 2006. Tracking the physical aging of poly (ethylene oxide): A technical note. AAPS PharmSciTech. 7(4) Article 95.

11. Kojima H., Yoshihara K., Sawada T., 2008. Extended release of a large amount of highly water-soluble diltiazem hydrochloride by utilizing counter polymer in polyethylene oxides (PEO)/polyethylene glycol (PEG) matrix tablets. European Journal of Pharmaceutics and Biopharmaceutics 70, 556-562.

12.Maggi L., Bruni R., Conte U., 2000. High molecular weight polyethylene oxides (PEOs) as an alternative to HPMC in controlled release dosage forms. International Journal of Pharmaceutics 195, 229-238.

13. Moroni A., Ghebresellassie I., 1995. Application of Poly (oxyethylene) homopolymers in sustained- release solid formulations. Drug Dev. Ind. Pharm. 21, 1411-1428.

14. Proddutari S., Urman K.L., 2007. Stabilization of Hot-Melt Extrusion formulations containing solid solutions using polymer blends. AAPS PharmSciTech; 8(2) Article 50.

15. Remington. The Science and Practice of Pharmacy, 21st edition, Vol. I pg no. 939-964

16. USP/ NF 2009 pg no. 1312.

17. Yang L., Venkatesh G., Fassihi R., 1996. Characterization of compressibility and compactibility of poly (ethylene oxide) polymers for modified release application by compaction simulator. J. Pharm. Sci. 85, 1085-1090 50.

18. Yie W. C. Novel Drug Delivery System, 2nd edition, Revised and Expanded, Vol. 50 Marcel Dekker, New York pg no. 3-45.

19. www.dow.com

20. www.polyox.com

21. www.colorcon.com

22. www.ncsu.edu

About Authors:

A.P. Shah *, S.R. Bhandary

A.P. Shah

A.P. Shah

Department of Pharmaceutics, School of Pharmacy and Technology Management, SVKM's NMIMS, Vile Parle (w) Mumbai, India - 400 056
E-mail: ashish.shah999@gmail.com, sarithabhandary@gmail.com, Telephone no.: +91- 022-42332000

S.R. Bhandary

S.R. Bhandary

Pursuing Phd in Pharmaceeutical Sciences from School of Pharmacy and Technology Management, SVKM's NMIMS, Mumbai

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Comments

umapratyusha's picture

Dear Madam, I have come across the word, polyethylene oxide many times in my text books but I haven't known that this one has so much importance. I wanted to ask you a small doubt,what does TM in the superscript of the word polyox stand for?

Regards

Uma Pratyusha

Event co-ordinator.

Saritha R Bhandary's picture

Dear Uma! Glad to see your comment. Please read the article completely. You will understand and gain more about polyethylene oxide applications in your formulation development. Its a water soluble resin and TM stands for the trademark symbol in superscript form.For more details you can check out for IPR related topics in which you will understand more about trademarks.
Dixon Thomas's picture

Good presentation. Best regards,

Mr. Dixon Thomas, M. Pharm, M. S., RPh Assoc. Prof., RIPER 

 

deepankargupta143's picture

Hello Ma'm,

 

I am developing an analytical method (both Assay & RS) for a Polyox based ER tablet. The Avg Wt. of tablet is 210 mg. I am cutting the tablets, as the Polyox liquifies upon trituration, and adding to respective volumetric flasks. 24 mg equivalent of sample is taken in a 100ml VF for RS and 12 mg equivalent in 200ml for Assay. The grades of Polyox that has been used in the formulation are WSR Coagulant (~70mg/tablet) and Polyox WSR N80 (~4mg/tablet). The diluent which I have been using is a mixture of pH 2.0 Buffer and ACN (60:40v/v). I am keeping the samples on mechanical shaker as the impurities are increasing on sonication. It takes around 10-12 to completely disperse the polyox and the solution is highly viscous and can' t be filtered. Also, the reproducibility of this method is doubtful.

How can I improve the solubility of the Polyox while reducing the sample preparation time?