**1. Introduction**

Modern pharmaceutical technology could not exist without polymers, which play an integral role in the advancement of drug delivery (e.g., by providing controlled release of therapeutic agents, masking bitter taste of drugs, or serving as carriers in targeted therapy). They have a wide range of physicochemical characteristics according to their molecular weight and configuration. Therefore, polymers approved for use in medicines are receiving considerable attention as essential excipients in the development of di fferent drug dosage forms. Cellulose derivatives are an important group among the most commonly used polymers in pharmaceutical technology. Cellulose is one of the most abundant polymers in nature. It is produced by photosynthesis and constitutes a basic plant component. It is a linear polymer composed of glucopyranose residues, where the units are connected by 1,4-β-glycosidic bonds. It is a tasteless and odorless component with fibrous structure that is practically insoluble both in cold and hot water. Among the cellulose modifiers, its esters and ethers are of practical importance. Cellulose-based biomaterials are widely utilized as biocompatible templates for designing novel drug delivery systems with a wide range of pharmaceutical applications via di fferent routes and pharmacotherapeutic purposes [1–4].

Ethylcellulose (EC), an ethyl ether of cellulose, is a free-flowing, white to light-tan powder prepared from wood pulp or cotton that is used in pharmaceutical manufacturing industries. The European Pharmacopoeia (Ph. Eur.) and United States Pharmacopoeia (USP) monographs describe EC as partially O-ethylated cellulose [5–7]. EC with ethoxyl substitution molecular formula is C12 H23 O6(C12 H22 O5)*n*C12 H23 O5, where *n* can vary in order to provide a wide variety of molecular weights, which a ffect its properties. It is insoluble at any pH that occurs in organisms, but it undergoes swelling in the presence of gastric juice [3,4]. There is very limited data detailing possible side e ffects of EC, hence it is generally regarded as safe (GRAS) and included in the US Food and Drug Administration (FDA) Inactive Ingredients database as well as in the Canadian List of Acceptable Non-medicinal Ingredients to be utilized in oral capsules, suspensions, tablets, topical emulsions, and vaginal or ocular preparations. In contrast to other polymers which are insoluble in the gastrointestinal tract (e.g., nitrocellulose, cellulose acetate, Eudragit RL, or Eudragit RS), EC is characterized as a non-ionic material, having the advantage of being non-reactive. Moreover, safety data on utilizing cellulose acetate and methacrylic acid copolymers in pediatric preparations are limited, while EC is clinically tested and approved for use in pediatric formulations. EC is also allowed for use in non-parenteral medicines licensed in Europe. The polymer is accepted for use as a food additive because it is a non-calorific and metabolically inert substance following oral consumption. As EC is not considered to be a health hazard, the World Health Organisation (WHO) has not specified its acceptable daily intake [4,8,9]. According to the intended use, the commercially available EC can be classified in two categories of products: industrial grade and pharmaceutical grade. For the pharmaceutical grade, the quality standard should meet USP, Ph. Eur., Chinese Pharmacopoeia, and Japanese Pharmacopoeia standards [6,7,10,11].

#### **2. Physicochemical Characteristics of EC**

The polymer is obtained by synthesis (etherification) through the substitution of the cellulose hydroxyl groups with ethoxyl ones. The chemical reaction involves cellulose dissolution in sodium hydroxide aqueous solution, which leads to degradation of the cellulose's molecular structure. This results in the formation of an alkali cellulose and exposure of the cellulose hydroxyl group for reaction. Afterwards, ethyl chloride gas is added to the reaction medium, leading to bonding with the alkalized cellulose. EC, sodium chloride, and water are formed (Figure 1) [1–5].

**Figure 1.** Schematic illustration of ethylcellulose (EC) obtainment.

EC contains 44–51% ethoxyl groups (-OC2H5) and is composed of β-anhydroglucose units joined together via acetal linkage. EC is a biocompatible, non-allergenic, nonirritant, colorless, odorless, and tasteless hydrophobic polymer soluble in a wide variety of organic solvents (alcohols, ketones, and polycyclic aromatic hydrocarbons), but does not dissolve in water, glycerin, or propylene glycol. EC that contains no less than 46.5% of ethoxyl groups is freely soluble in chloroform, ethanol, ethyl acetate, methanol, and toluene. EC is compatible with a wide array of excipients and most of the plasticizers used in pharmaceutical formulations, and therefore can be well mixed with many softeners, oils, and waxes (dibutyl phthalate, diethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetylated monoglyceride, butyl and glycol esters of fatty acids, refined mineral oils, oleic acid, stearic acid, stearyl alcohol, castor oil). It shows incompatibilities with para ffin and microcrystalline wax. EC exhibits a high degree of stability within pH 3–11, making it useful both in acidic and alkaline mixtures. EC is also slightly hygroscopic, absorbing very little water from humid

air or during immersion. In addition, it can form tough and tensile films and maintains flexibility even at low temperatures. It possesses good thermal stability and low ash content when burning [1,3–5].

The physical characteristic of EC types and their performance depends on the degree of etherification or substitution (ethoxyl content), molecular uniformity, and molecular weight of the cellulosic backbone. Solubility in organic solvents is achieved with degree of substitution (DS) values between 2.2 and 2.6. A range of commercial products is available with a degree of substitution between 2.15 and 2.60, corresponding to a range of ethoxyl contents from 43% to 50%. At low DS values (0.8–1.3), the replacement of some of the hydroxyl groups by ethoxyl groups reduces the hydrogen bonding across the cellulosic chains to such an extent that the material is soluble in water. Further replacement of hydroxyl groups by the less polar and more hydrocarbon ethoxyl groups increases the water resistance. Fully etherified EC is soluble only in non-polar solvents [1–5].

The molecular weight can be regulated by controlled degradation of the alkali cellulose in the presence of air. This can be done either before or during etherification. The molecular weight of commercial grades is usually expressed indirectly as viscosity. The completely etherified material with a degree of substitution of 3 has an ethoxyl content of 54.88%. The viscosities are determined using a capillary viscometer and recorded in millipascal-seconds (mPa·s) or centipoise (cP) synonymous for a 5% *w*/*w* solution in toluene/ethanol solvent mixture (80:20), being determined at 25 ◦C and expressed in mPa·s. For each viscosity grade of EC, the pharmacopoeial specification allows variation of 80–120% within the stated nominal viscosity (depending on manufacturer). Several types of EC (e.g., Ethocel ™ 4, Ethocel ™ 10, and Ethocel ™ 45) di ffer in the length of the polymer chains, the rate of dissolution, and the viscosity of their solutions. The mechanical properties are largely determined by chain length; softening point, hardness, water absorption, and solubility are rather more influenced by the degree of substitution [1–5,12,13].

EC viscosities increase with the increase in the polymeric backbone chain length. The impact of EC molecular weight variation (measured by viscosity) on the drug release was determined by Mehta et al. Metoprolol was selected as a model drug that is highly soluble in water and acetaminophen as one with low aqueous solubility. Drug-layered sugar spheres were coated with EC of di fferent viscosity grades at varying coating weight gains, and their drug release profiles were determined. The study revealed that viscosity variation within the manufacturer's specifications of EC (Ethocel ™ 10, 20, and 100 cP) had a minimal e ffect on release of model drugs. Acetaminophen multiparticulates exhibited slower drug release and longer lag time when compared to the metoprolol beads. The obtained results can be associated with the lower aqueous solubility of acetaminophen compared to metoprolol. Based on the study, it was concluded that all grades of EC were suitable for organic solvent coating of extended release barrier membrane multiparticulates [14]. In another study, sustained-release metformin hydrochloride nanoparticulate systems were developed, and the e ffect of di fferent viscosity EC grades on their in vitro characteristics was investigated. The sustainability of EC was enhanced by the increase in its apparent viscosity—the EC with higher viscosity grade sustained metformin release more e fficiently [15].

#### **3. Pharmaceutical Characteristics of EC**

EC has been widely used in the pharmaceutical industry for decades, being utilized in oral and topical pharmaceutical formulations for various purposes. It has the potential to modulate and improve the physiological performance of drug dosage forms because of its hydrophobic nature and swelling capacity. The main goal of EC utilization is the development of drug dosage forms with modified release (MR), as EC ensures drug dissolution in the entire gastrointestinal tract, providing constant drug concentration and eliminating the necessity of taking several doses a day, hence improving pharmacotherapeutic e ffectiveness. Because it is an inert hydrophobic polymer and possesses properties such as lack of toxicity, stability during storage, and good compressibility, it is suitable for designing sustained-release preparations [1–5,16]. EC provides the formation of hydrophobic coatings, filaments, or backing layers; masks unpleasant medicine tastes; creates matrices and nanostructures for the

preparation of bioactive materials or is used as an encapsulation excipient for the preparation of sustained-release microparticles; and serves as moisture protector or binder. It can also be used as a dispersing, stabilizing, and water-retaining agen<sup>t</sup> to prevent drugs from getting wet and to promote the safe storage of drugs. Shell tablets can be obtained by suspending drug in the gastrointestinally insoluble carrier. EC has also been used as a matrix in the preparation of both water-soluble and sparingly water-soluble drugs using solid dispersion technique. It is ubiquitously utilized as a coating material in sustained-release preparations due to its film-forming properties and good mechanical strength. Also, in the coating context, its important feature is insolubility at any physiological pH. However, the polymer exhibits swelling in the presence of gastric juice, making it permeable for water and permitting extended modified drug release [4,17–22]. EC-coated beads have also demonstrated the ability to absorb pressure and hence protect the coating from fracture during compression. Drug release from EC-based film coatings depends on the coating level, drug solubility, and the form in which the polymer is applied in the coating process (e.g., as powder, aqueous dispersion, or organic solution). It is also common to employ blending polymers to ge<sup>t</sup> suitable and desired results, as using a single polymer may not give the desired drug release profile. Owing to its hydrophobic properties, EC reduces the penetration of water into the solid polymeric matrix, hence reducing drug release [4,23].

EC can be found in di fferent forms, such as powders with various viscosity grades or aqueous dispersions. Examples of organic solids are Ethocel ™ or Aqualon ™, and aqueous dispersions include Surelease ®, Aquacoat ® ECD, Aquarius ™ Control ECD, and AshaKote ® (Table 1, Figure 2) [12,24–28]. Commercially available types of EC (e.g., Ethocel ™ 4, Ethocel ™ 10, and Ethocel ™ 45) di ffer in the length of the polymer chains, the rate of dissolution, molecular weights, and hence the viscosity of their solutions (ranging from 3 to 110 mPa·s) [12].

> **Table 1.** Characteristics of commercially available EC \*.


## **Aqualon** ™ **ethylcellulose**

During preparation, the substitution of ethoxyl groups is controlled to obtain commercially useful range of 48–52% ethoxyl (or 2.3–2.6 ethoxyl groups out of a theoretical maximum of 3.0) per anhydroglucose unit. Over this ethoxyl range, Aqualon ™ ethylcellulose is classified into three ethoxyl types: N (low substitution), T (mid substitution), and X (high substitution). The improved compressible grade (Aqualon ™ T10) was developed with optimized compactability (high ethoxyl content and low viscosity) and good powder flow. The grades of Aqualon ™ ethylcellulose are compliant with the monograph requirements of the United States Pharmacopoeia (USP) and the European Pharmacopoeia (Ph. Eur.) [24].

> **Aqueous dispersion of ethylcellulose**

**Table 1.** *Cont.*
