**1. Introduction**

140 Cellulose – Medical, Pharmaceutical and Electronic Applications

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For centuries, the pharmaceutical profession has provided services of fundamental value to society, such as the procurement, storage, compounding and dispensing of drugs. In recent decades, the focus of the pharmacist's role has shifted from compounding medicines to ensuring their safe and effective use by providing information and advice [1,2]. Although compounding activity has decreased over time, it is incontestable that this service is essential in certain patient specific situations, where industrially produced medicine is not available or is inappropriate for a particular reason [3,4]. Thus, compounded medicines are mainly important for paediatric and geriatric patients, and patients with special needs such as those with dermatological diseases [3,5,6,7,8]. In many countries, nowadays, the activity of compounding is a complementary practice to the production of medicines in alternative amounts and diversified dosage forms (liquid, semi-solid, solid) in community pharmacies (United States of America, The Netherlands), as well as in hospital pharmacies (Canada, France, Belgium, Croatia, Denmark, England, Finland, Germany, Ireland, Italy, Norway, Scotland, Slovenia, Spain, Sweden, Switzerland) [3,4,8-10].

Interestingly, compounded medicines were estimated to make up 10-15% of all dispensed drugs in the Netherlands in the early 90's, 5.5% in 1994 and 6.6% in 1995. By the year 2000 this estimate was 3.7-5.5% [3]. On the other hand, the compounding field appears to have been a considerable and growing business since the 1990's in the United States. These products represented around 1% of all prescriptions dispensed yearly and according to this estimate, 30 million medications would have been compounded in 2003 [4]. This shows that the population has recognized that compounding pharmacies can provide individualized drug therapy benefits [11].

The practice of compounding requires not only the drug(s) (active pharmaceutical ingredient, API), but also, the excipient(s) (pharmacological inert component) in order to

© 2013 Dias Marques-Marinho and Duarte Vianna-Soares et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Dias Marques-Marinho and Duarte Vianna-Soares et al., licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. obtain the final medicine. The excipients are chosen according to the characteristics of the required dosage form [5]. Each excipient exerts specific functions in the formulation, as, for instance, a diluent for hard capsules or powders, a coating agent for solid oral dosage forms, a suspending, thickening or stabilizing agent for oral liquids, etc. The excipient function depends on the concentration in a particular pharmaceutical formulation [12,13].

Cellulose and Its Derivatives Use in the Pharmaceutical Compounding Practice 143

forms, II, III and IV. Cellulose II is the allomorph that is thermodynamically most stable [16,23-24]. Cellulose III can be prepared by liquid ammonia or (mono, di, tri) amine treatment of cellulose I and II [25]. The cellulose IV crystalline form is obtained by immersion in glycerol and heating of cellulose III [26]. Cellulose is an excipient widely employed by both pharmaceutical companies (tablet processing) and compounding pharmacies; it is available in powdered (n500) and microcrystalline (n220) forms, the latter being obtained by acid hydrolysis of the amorphous regions of the cellulose

Cellulosics, such as methyl, ethyl, hydroxyethyl, hydroxyethylmethyl, hydroxypropyl (HP), hydroxypropyl methyl (HPM, also denominated hypromellose) and carboxymethyl ethers cellulose (Figure 2) are formed by hydroxyl etherification with the appropriate alkyl halide (R-Cl, see Figures 2, 3) from previously alkalinized cellulose usually obtained from wood pulp [16]. The degree of substitution (DS) in these ether derivatives indicates the average number of R groups present in each glucan unit along the chain. The maximum DS is three, since it is the number of hydroxyl groups that can be substituted on each glucan unit. DS

Cellulose derivatives are employed as excipients in pharmaceutical industrial products for oral, topical or parenteral administration [12,16,27]. Their most relevant application, as observed in pharmaceutical industrial products, is to create matrix systems for solid oral dosage forms. Due to their aqueous swelling, the drug release is controlled by its diffusion through the hydrogel layers that are formed. For instance, the use of carboxymethyl cellulose (CMC) sodium salt as an excipient sustains the release in solid oral dosage forms.

Cellulosics, such as the cellulose esters acetate, acetate trimellitate, acetate phthalate (CAP), HPM phthalate, HPM acetate succinate are formed by hydroxyl esterification with either acetic, trimellitic, dicarboxylic phthalic or succinic acids, or a combination of them, as represented in Figure 3. The reaction usually occurs in the presence of a strong acid that

Among these cellulosics, CAP was one of the earliest and most effective solutions to pHcontrolled release, and its use still continues today [15]. These cellulosics are usually resistant to acid environments such as that of the stomach and are thus very useful as enteric coatings for capsules or tablets [12,16]. Cellulose esters require plasticizers (acetylated monoglyceride, butyl phtalylbutyl glycolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalylethyl glycolate, glycerin, propylene glycol, triacetin, triacetin

affects cellulose derivatives' physical properties such as solubility [12].

**Figure 2.** Chemical structure of cellulose ether derivatives.

promotes the acid catalysis.

nanofibrils.

Cellulose (Figure 1) and its derivatives (ether and ester) are among the excipients frequently used in pharmaceutical compounded and industrialized products with various purposes. Among their uses, the most frequently reported are as suspending agents in oral liquid extemporaneous preparation and as viscosity increasing agents in topical formulations, exemplified in Tables 1, 2 [5,7,8,14]. Particularly, in oral solid dosage forms, cellulose and its derivatives (also known as cellulosics) can render distinct drug delivery property patterns: immediate, controlled/sustained or delayed release [15,16]. In addition, cellulosics show several interesting characteristics such as low cost, reproducibility, biocompatibility, and recyclability [16]. The latter is currently an important aspect considering the need for green technology.

**Figure 1.** The chemical structure of cellulose with two β-1,4 linked anhydroglucose units.

Cellulose is the most abundant biopolymer. It is present in the cell walls of a great diversity of organisms, from bacteria (Cyanobacteria), prokaryotes (*Acetobacter, Rhizobium, Agrobacterium*) to eukaryotes (fungis, amoebae, green algae, freshwater and marine algae, mosses, ferns, angiosperms, gymnosperms). It is also produced by some animals, the tunicates (urochordates), members of the subphylum Tunicata in the Chordata phylum [17- 19]. Native cellulose made by biosynthesis in living organisms is composed only of glucose monomers, as anhydroglucose (AGU) or glucan units (C6H10O5, n) with -1,4 linkages (Figure 1). It usually exists as cellulose I (in most plants) and rarely as cellulose II (in several algae and some bacteria) allomorphs, in which the glucan chains are oriented parallel and antiparallel respectively [20, 21]. Cellulose allomorphs (I, II, IIII, IIIII, IVI, IVII) have structural variations regarding unit cell dimensions, degree of intra/interchain hydrogen bonding per unit cell and polarity of adjacent cellulose sheets [22]. Cellulose I allomorphs consist of distinct numbers of parallel glucan chains arranged to form nanofibrils. Native crystalline cellulose I has two suballomorphs, and , which exist as a single chain triclinic unit cell and a two chain monoclinic unit cell, respectively. Cellulose I is rarely synthesized in nature as a pure form (except by tunicates) and is more thermodynamically stable [20]. Cellulose I can be altered by a strong alkali treatment in order to produce other crystalline forms, II, III and IV. Cellulose II is the allomorph that is thermodynamically most stable [16,23-24]. Cellulose III can be prepared by liquid ammonia or (mono, di, tri) amine treatment of cellulose I and II [25]. The cellulose IV crystalline form is obtained by immersion in glycerol and heating of cellulose III [26]. Cellulose is an excipient widely employed by both pharmaceutical companies (tablet processing) and compounding pharmacies; it is available in powdered (n500) and microcrystalline (n220) forms, the latter being obtained by acid hydrolysis of the amorphous regions of the cellulose nanofibrils.

Cellulosics, such as methyl, ethyl, hydroxyethyl, hydroxyethylmethyl, hydroxypropyl (HP), hydroxypropyl methyl (HPM, also denominated hypromellose) and carboxymethyl ethers cellulose (Figure 2) are formed by hydroxyl etherification with the appropriate alkyl halide (R-Cl, see Figures 2, 3) from previously alkalinized cellulose usually obtained from wood pulp [16]. The degree of substitution (DS) in these ether derivatives indicates the average number of R groups present in each glucan unit along the chain. The maximum DS is three, since it is the number of hydroxyl groups that can be substituted on each glucan unit. DS affects cellulose derivatives' physical properties such as solubility [12].

**Figure 2.** Chemical structure of cellulose ether derivatives.

142 Cellulose – Medical, Pharmaceutical and Electronic Applications

technology.

obtain the final medicine. The excipients are chosen according to the characteristics of the required dosage form [5]. Each excipient exerts specific functions in the formulation, as, for instance, a diluent for hard capsules or powders, a coating agent for solid oral dosage forms, a suspending, thickening or stabilizing agent for oral liquids, etc. The excipient function

Cellulose (Figure 1) and its derivatives (ether and ester) are among the excipients frequently used in pharmaceutical compounded and industrialized products with various purposes. Among their uses, the most frequently reported are as suspending agents in oral liquid extemporaneous preparation and as viscosity increasing agents in topical formulations, exemplified in Tables 1, 2 [5,7,8,14]. Particularly, in oral solid dosage forms, cellulose and its derivatives (also known as cellulosics) can render distinct drug delivery property patterns: immediate, controlled/sustained or delayed release [15,16]. In addition, cellulosics show several interesting characteristics such as low cost, reproducibility, biocompatibility, and recyclability [16]. The latter is currently an important aspect considering the need for green

depends on the concentration in a particular pharmaceutical formulation [12,13].

**Figure 1.** The chemical structure of cellulose with two β-1,4 linked anhydroglucose units.

Cellulose is the most abundant biopolymer. It is present in the cell walls of a great diversity of organisms, from bacteria (Cyanobacteria), prokaryotes (*Acetobacter, Rhizobium, Agrobacterium*) to eukaryotes (fungis, amoebae, green algae, freshwater and marine algae, mosses, ferns, angiosperms, gymnosperms). It is also produced by some animals, the tunicates (urochordates), members of the subphylum Tunicata in the Chordata phylum [17- 19]. Native cellulose made by biosynthesis in living organisms is composed only of glucose monomers, as anhydroglucose (AGU) or glucan units (C6H10O5, n) with -1,4 linkages (Figure 1). It usually exists as cellulose I (in most plants) and rarely as cellulose II (in several algae and some bacteria) allomorphs, in which the glucan chains are oriented parallel and antiparallel respectively [20, 21]. Cellulose allomorphs (I, II, IIII, IIIII, IVI, IVII) have structural variations regarding unit cell dimensions, degree of intra/interchain hydrogen bonding per unit cell and polarity of adjacent cellulose sheets [22]. Cellulose I allomorphs consist of distinct numbers of parallel glucan chains arranged to form nanofibrils. Native crystalline cellulose I has two suballomorphs, and , which exist as a single chain triclinic unit cell and a two chain monoclinic unit cell, respectively. Cellulose I is rarely synthesized in nature as a pure form (except by tunicates) and is more thermodynamically stable [20]. Cellulose I can be altered by a strong alkali treatment in order to produce other crystalline Cellulose derivatives are employed as excipients in pharmaceutical industrial products for oral, topical or parenteral administration [12,16,27]. Their most relevant application, as observed in pharmaceutical industrial products, is to create matrix systems for solid oral dosage forms. Due to their aqueous swelling, the drug release is controlled by its diffusion through the hydrogel layers that are formed. For instance, the use of carboxymethyl cellulose (CMC) sodium salt as an excipient sustains the release in solid oral dosage forms.

Cellulosics, such as the cellulose esters acetate, acetate trimellitate, acetate phthalate (CAP), HPM phthalate, HPM acetate succinate are formed by hydroxyl esterification with either acetic, trimellitic, dicarboxylic phthalic or succinic acids, or a combination of them, as represented in Figure 3. The reaction usually occurs in the presence of a strong acid that promotes the acid catalysis.

Among these cellulosics, CAP was one of the earliest and most effective solutions to pHcontrolled release, and its use still continues today [15]. These cellulosics are usually resistant to acid environments such as that of the stomach and are thus very useful as enteric coatings for capsules or tablets [12,16]. Cellulose esters require plasticizers (acetylated monoglyceride, butyl phtalylbutyl glycolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalylethyl glycolate, glycerin, propylene glycol, triacetin, triacetin

citrate, triethylcitrate, tripropionin) soluble in organic solvents (ketones, esters, ether alcohols, cyclic ethers) or in their mixtures, such as methanol/chloroform and ethyl acetate/isopropanol in order to produce more effective coating films [12,28,29]. Some of the cellulose esters are employed either in industrial or compounded pharmaceutical preparations.

Cellulose and Its Derivatives Use in the Pharmaceutical Compounding Practice 145

In compounded medicines, powdered cellulose and microcrystalline cellulose are used as an adsorbent, a suspending agent, a capsule diluent (5-30% and 20-90%, respectively).

The applications of the powdered cellulose and the microcrystalline cellulose in compounding pharmacies include the oral solid dosage form (capsules) as a bulking agent to increase the mass in formulations containing small amounts of the active ingredient. The powdered cellulose is a base material for powder dosage forms, a suspending agent for aqueous peroral delivery and an adsorbent and thickening agent for topic preparations [12]. Moreover, the

In this cellulose ether derivative approximately 27–32% of hydroxyl groups are changed to the methyl ether (CH3O) form. MC is practically insoluble in most organic solvents. Various grades of MC can be found with degrees of polymerization in the range of 50 to 1000 and

In compounded medicines, MCs function as emulsifying agents (1-5%), suspending agents

In compounding pharmacies, MCs of different viscosity grades, low and high, have been applied in oral liquid (oil emulsions, suspensions, solutions) and topical (creams, gels) formulations respectively. MC is often used instead of sugar-based syrups and other suspension bases. MC delays the settling of suspensions and increases the contact time of

This cellulose derivative is partially or completely ethoxylated, yielding 44-51% of ethoxyl groups (OCH2CH3). Full substitution (DS=3) of cellulose units produce C12H23O6(C12H22O5)nC12H23O5, where *n* can vary, thus providing a wide variety of molecular weights. EC is a long-chain polymer of ethyl-substituted -glucan units joined together by

In compounded medicines, EC functions as a flavouring and as a viscosity increasing agent. In compounding pharmacies, EC finds applications in oral and topical (creams, lotions, gels) formulations. For oral use, it works as an active delivering agent and for topical dosage

This cellulose derivative is a partially substituted hydroxyethyl (CH2CH2OH) ether of cellulose. It is found in various viscosity grades, with respect to the DS and molecular

forms as a thickening agent. It has been evaluated as a stabilizer for emulsions [12].

microcrystalline cellulose is a constituent of the vehicle used for oral suspension [27].

molecular weights (number average) in the range 10 000 to 220 000 Da [12].

(1-2%), capsule disintegrants and viscosity increasing agents.

Powdered cellulose is also used as a thickening agent.

**2.2. Cellulose ether derivatives** 

*2.2.1. Methylcellulose (MC)* 

drugs in the stomach [12].

*2.2.2. Ethylcellulose (EC)* 

glycoside linkages [12].

*2.2.3. Hydroxyethylcellulose (HEC)* 

Some cellulosics, if they are to be applied in distinct drug delivery formulations, may require special large scale processing and equipment normally only installed in pharmaceutical industry plants. This is one of the reasons why not all commercially available cellulosics are employed in compounding pharmacies. A description of some cellulosics and their applications in compounded medicines is presented in the following sections.

**Figure 3.** Chemical structures of cellulose ester derivatives.

#### **2. Cellulose and its derivatives in compounded medicines**

#### **2.1. Cellulose**

Powdered cellulose and microcrystalline cellulose come from -cellulose (cellulose free of hemi-celluloses and lignin) pulp from fibrous plant materials; they differ in regard to their manufacturing processes. Powdered cellulose is obtained by -cellulose purification and mechanical size reduction. Crystalline cellulose is obtained by controlled hydrolysis of cellulose with mineral acid solutions (2 to 2.5 N), followed by hydrocellulose purification by filtration and spray-drying of the aqueous portion [12].

In compounded medicines, powdered cellulose and microcrystalline cellulose are used as an adsorbent, a suspending agent, a capsule diluent (5-30% and 20-90%, respectively). Powdered cellulose is also used as a thickening agent.

The applications of the powdered cellulose and the microcrystalline cellulose in compounding pharmacies include the oral solid dosage form (capsules) as a bulking agent to increase the mass in formulations containing small amounts of the active ingredient. The powdered cellulose is a base material for powder dosage forms, a suspending agent for aqueous peroral delivery and an adsorbent and thickening agent for topic preparations [12]. Moreover, the microcrystalline cellulose is a constituent of the vehicle used for oral suspension [27].
