**2.2. Cellulose ether derivatives**

## *2.2.1. Methylcellulose (MC)*

144 Cellulose – Medical, Pharmaceutical and Electronic Applications

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

filtration and spray-drying of the aqueous portion [12].

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

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

preparations.

sections.

**2.1. Cellulose** 

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

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

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

> In compounded medicines, MCs function as emulsifying agents (1-5%), suspending agents (1-2%), capsule disintegrants and viscosity increasing 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 drugs in the stomach [12].

## *2.2.2. Ethylcellulose (EC)*

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 glycoside linkages [12].

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

## *2.2.3. Hydroxyethylcellulose (HEC)*

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

weight. Some grades are modified so as to improve aqueous dispersion. HEC is insoluble in most organic solvents.

Cellulose and Its Derivatives Use in the Pharmaceutical Compounding Practice 147

It is available as calcium and sodium salt forms of a polycarboxymethyl (CH2COOX, X=Ca or Na) ether of cellulose. Only sodium CMC is commonly used in compounded preparations. The degree of substitution can be estimated by a sodium assay, which must be

CMC-Na acts as a capsule disintegrant and a stabilizing, a suspending, an emulsifying (0.25- 1%), a gel-forming (3-6%) and a viscosity-increasing (0.1-1%) agent in compounded medicines. In compounding pharmacies, CMC-Na has applications in oral (liquid, solid) and topical (liquid, gel, emulsion) formulations, primarily for its viscosity-increasing properties. Viscous aqueous solutions are used to suspend powders intended for either topical or oral use. In emulsions, CMC may be used as stabilizer. At higher concentrations, a CMC of intermediate-viscosity grade forms gels that are employed as a base for cosmetics or other drug formulations [12]. Similarly to microcrystalline cellulose, CMC-Na is also described as

This cellulose derivative has partially or completely acetylated (COCH3) hydroxyl groups. Cellulose acetate is available in a wide range of acetyl levels (29-44.8%) and chain lengths,

Cellulose acetate is used as a capsule diluent, a filler and as a taste-masking agent in

CAP acid form is a cellulose derivative obtained by the reaction of phthalic anhydride and a partial acetate ester of cellulose. It contains 21.5–26% of acetyl (COCH3) and 30-36% of

In compounded medicines, CAP confers gastro-resistance, and is thus used as an enteric

In compounding pharmacies, CAP has applications in oral solid dosage forms either by film coating from organic (ketones, esters, ether alcohols, cyclic ethers) or aqueous solvent systems. Such coatings resist prolonged contact with the strongly acidic gastric fluid, but dissolve in the mildly acidic or neutral intestinal environment. The addition of plasticizers improves the water resistance of such coating materials, making formulations with this

As mentioned, cellulose and its derivatives, primarily intended for use in the pharmaceutical industry, are also relevant in compounding practice. The common uses of cellulosics in compounding practices as a diluent in solid dosage forms, a thickening and a

*2.2.6. Carboxymethyl cellulose (CMC)* 

a constituent of vehicles used for oral suspension [27].

with molecular weights ranging from 30 000 to 60 000.

phthalyl (o-carboxybenzoyl, COC6H4COOH) groups.

**2.3. Cellulose ester derivatives** 

*2.3.1. Cellulose acetate* 

compounded medicines [12].

coating agent (0.5-9%) [12].

derivative more effective [12,29].

*2.3.2. Cellulose acetate phthalate (CAP)* 

between 6.5-9.5%.

In compounded medicines, HEC has the following functions: a suspending, a thickening and a viscosity-increasing agent.

It is widely employed in topical formulations (gel) and cosmetics due to its nonionic and water-soluble polymer characteristics. The main use is as a thickening agent [12].

## *2.2.4. Hydroxypropylcellulose (HPC)*

This cellulose derivative is partially hydroxypropylated, yielding 53.4–80.5% of hydroxypropyl groups [OCH2CH(OH)CH3]. Because the added hydroxypropyl contains a hydroxyl group which can also be etherified during the preparation, the degree of substitution of hydroxypropyl groups can be higher than three. HPC is found in different grades that provide solutions with various viscosities. Its molecular weight has a range of 50 000 to 1 250 000. HPC with an value of moles of substitution of approximately four is necessary in order to have good water solubility.

In compounded medicines, HPC is used as an emulsifying, a stabilizing, a suspending, a thickening or a viscosity-increasing agent.

In compounding pharmacies, HPC is also employed in topical formulations (gel) and especially in cosmetics, as an emulsifier and a stabilizer [12].

## *2.2.5. Hydroxypropylmethylcellulose (HPMC)*

This cellulose derivative, also called hypromellose, is a partly O-methylated and O-(2 hydroxypropylated) cellulose. HPMC is found in various grades with different viscosities and extents of substitution. The content of methoxyl (OCH3) and hydroxypropyl groups [OCH2CH(OH)CH3] affects the HPMC molecular weight, which ranges from 10 000 to 1 500 000.

HPMC has many different functions in compounded medicines as a dispersing, an emulsifying, a foaming, a solubilizing, a stabilizing, a suspending (0.25-5%) and a thickening (0.25-5%) agent. In addition, HPMC can be applied as a controlled-release and sustainedrelease agent.

In compounding pharmacies, HPMC has found application for nasal (liquid) and topical (gel, ointment) formulations as a thickening, a suspending, an emulsifying and a stabilizing agent. The aqueous solution produced with HPMC presents greater clarity and fewer undissolved fibres compared with MC. HPMC can prevent droplets and particles from coalescing or agglomerating, thus inhibiting the formation of sediment. In addition, it is also widely used in cosmetics [12].

## *2.2.6. Carboxymethyl cellulose (CMC)*

146 Cellulose – Medical, Pharmaceutical and Electronic Applications

most organic solvents.

and a viscosity-increasing agent.

*2.2.4. Hydroxypropylcellulose (HPC)* 

necessary in order to have good water solubility.

*2.2.5. Hydroxypropylmethylcellulose (HPMC)* 

1 500 000.

release agent.

widely used in cosmetics [12].

especially in cosmetics, as an emulsifier and a stabilizer [12].

thickening or a viscosity-increasing agent.

weight. Some grades are modified so as to improve aqueous dispersion. HEC is insoluble in

In compounded medicines, HEC has the following functions: a suspending, a thickening

It is widely employed in topical formulations (gel) and cosmetics due to its nonionic and

This cellulose derivative is partially hydroxypropylated, yielding 53.4–80.5% of hydroxypropyl groups [OCH2CH(OH)CH3]. Because the added hydroxypropyl contains a hydroxyl group which can also be etherified during the preparation, the degree of substitution of hydroxypropyl groups can be higher than three. HPC is found in different grades that provide solutions with various viscosities. Its molecular weight has a range of 50 000 to 1 250 000. HPC with an value of moles of substitution of approximately four is

In compounded medicines, HPC is used as an emulsifying, a stabilizing, a suspending, a

In compounding pharmacies, HPC is also employed in topical formulations (gel) and

This cellulose derivative, also called hypromellose, is a partly O-methylated and O-(2 hydroxypropylated) cellulose. HPMC is found in various grades with different viscosities and extents of substitution. The content of methoxyl (OCH3) and hydroxypropyl groups [OCH2CH(OH)CH3] affects the HPMC molecular weight, which ranges from 10 000 to

HPMC has many different functions in compounded medicines as a dispersing, an emulsifying, a foaming, a solubilizing, a stabilizing, a suspending (0.25-5%) and a thickening (0.25-5%) agent. In addition, HPMC can be applied as a controlled-release and sustained-

In compounding pharmacies, HPMC has found application for nasal (liquid) and topical (gel, ointment) formulations as a thickening, a suspending, an emulsifying and a stabilizing agent. The aqueous solution produced with HPMC presents greater clarity and fewer undissolved fibres compared with MC. HPMC can prevent droplets and particles from coalescing or agglomerating, thus inhibiting the formation of sediment. In addition, it is also

water-soluble polymer characteristics. The main use is as a thickening agent [12].

It is available as calcium and sodium salt forms of a polycarboxymethyl (CH2COOX, X=Ca or Na) ether of cellulose. Only sodium CMC is commonly used in compounded preparations. The degree of substitution can be estimated by a sodium assay, which must be between 6.5-9.5%.

CMC-Na acts as a capsule disintegrant and a stabilizing, a suspending, an emulsifying (0.25- 1%), a gel-forming (3-6%) and a viscosity-increasing (0.1-1%) agent in compounded medicines.

In compounding pharmacies, CMC-Na has applications in oral (liquid, solid) and topical (liquid, gel, emulsion) formulations, primarily for its viscosity-increasing properties. Viscous aqueous solutions are used to suspend powders intended for either topical or oral use. In emulsions, CMC may be used as stabilizer. At higher concentrations, a CMC of intermediate-viscosity grade forms gels that are employed as a base for cosmetics or other drug formulations [12]. Similarly to microcrystalline cellulose, CMC-Na is also described as a constituent of vehicles used for oral suspension [27].

## **2.3. Cellulose ester derivatives**

## *2.3.1. Cellulose acetate*

This cellulose derivative has partially or completely acetylated (COCH3) hydroxyl groups. Cellulose acetate is available in a wide range of acetyl levels (29-44.8%) and chain lengths, with molecular weights ranging from 30 000 to 60 000.

Cellulose acetate is used as a capsule diluent, a filler and as a taste-masking agent in compounded medicines [12].

## *2.3.2. Cellulose acetate phthalate (CAP)*

CAP acid form is a cellulose derivative obtained by the reaction of phthalic anhydride and a partial acetate ester of cellulose. It contains 21.5–26% of acetyl (COCH3) and 30-36% of phthalyl (o-carboxybenzoyl, COC6H4COOH) groups.

In compounded medicines, CAP confers gastro-resistance, and is thus used as an enteric coating agent (0.5-9%) [12].

In compounding pharmacies, CAP has applications in oral solid dosage forms either by film coating from organic (ketones, esters, ether alcohols, cyclic ethers) or aqueous solvent systems. Such coatings resist prolonged contact with the strongly acidic gastric fluid, but dissolve in the mildly acidic or neutral intestinal environment. The addition of plasticizers improves the water resistance of such coating materials, making formulations with this derivative more effective [12,29].

As mentioned, cellulose and its derivatives, primarily intended for use in the pharmaceutical industry, are also relevant in compounding practice. The common uses of cellulosics in compounding practices as a diluent in solid dosage forms, a thickening and a

suspending agent in liquid dosage forms, an emulsifying agent in semi-solid preparations and others require well known manufacturing techniques, which do not need sophisticated apparatus [5]. Nevertheless, specific equipment may be necessary when cellulosics are employed to impart special dosage form properties, such as in modified release systems. Among the modified drug delivery systems, mostly delayed and controlled (extended or slow) release have been described in compounding practice. In the former, the systems are frequently employed to prevent drug degradation in acid environments after oral administration, to protect the stomach mucosa from drug irritation and to release the drug in the intestine. In controlled release, systems are used to prevent side effects and to reduce the number of daily administrations [29,30].

Cellulose and Its Derivatives Use in the Pharmaceutical Compounding Practice 149

administration; hence, this is a preferred means of administration. Frequently, drugs in a concentration appropriate for paediatric use are unavailable or extemporaneous preparations from commercial products become a necessity. Thus, patients with special needs can be provided with drugs easily administered in the hospitals if extemporaneous

Methylcellulose (1%) and simple syrup NF (as described in the United States Pharmacopeia National Formulary monograph) mixtures have been used as a vehicle for many extemporaneous oral drug suspensions prepared from commercial products (tablets or capsules) [27,41]. Compounded oral preparations can be obtained by finely grinding tablets or the content of capsules in a mortar and pestle, with the gradual addition of small volumes of the vehicle being mixed. The final volume can be adjusted in a graduated glass cylinder. Afterwards, the suspension is transferred to an appropriate plastic or glass bottle protected

Stability studies conducted at 4 °C and 25 °C for distinct drugs over at least 8 weeks are

In such listed studies, suspensions containing MC did not show substantial changes in pH, odour or physical appearance in the period during which the drug content was assayed and found not to be less than 90% of the original concentration. This is a demonstration that MC

Oral extemporaneous suspensions of other drugs (amiodarone, granisetron, trimethoprim, and verapamil salt) prepared in methylcellulose and simple syrup (MC:SS) were also

Clonazepam [42] Tablets (0.5, 1, 2) 0.1 NI 60c NE

Nifedipine [44] Capsules (10, 20) 4 1:13 91b 91b

Propylthiouracil [46] Tablets (50) 5 1:1 91c 70c Pyrazinamide [47] Tablets (500) 100 1:1 60b 60b Pyrimethamine [48] Tablets (25) 2 1:1 91a,c 91a,c Sildenafil citrate [49] Tablets (25, 50, 100) 2.5 1:1 91c 91c

[50,51] Tablets (80, 120, 160, 240) 5 1:9 91b 91b

Tiagabine hydrochloride [52] Tablets (2, 4, 6, 8, 10, 12, 16) 1 1:6 91c 42c

**Table 1.** Stability of different drugs in oral suspension extemporaneously prepared in a mixture of 1%

**Suspension (mg/mL)** 

(250, 375, 500) 5, 50 70:30 Cherry

(100, 300, 400) 100 1:1 91c 56c

**MC:SS ratio** 

syrup

**Stability (days) in different temperatures 4 C 25 C** 

180b 180b

2.4:1 84a 84a

**Drug dosage form (mg)** 

Capsules, tablets

a: amber glass, b: plastic; c: amber plastic bottles; NI, not informed; NE, not evaluated.

methylcellulose:simple syrup (MC:SS) from commercial available products.

preparations are compounded from drugs that are industrially produced.

(amber) or not (transparent) from light.

reported to have adequate stability [14].

Gabapentin [43] Capsules

Procainamide hydrochloride

Sotalol hydrochloride

formulations provide satisfactorily safe and stable products.

shown in Table 1 [42-52].

**Drug [Ref.]** 

[45]

CAP is the cellulosic most frequently mentioned in compounded delayed-release dosage forms [31-33]. The use of sodium carboxymethylcellulose or hydroxypropyl methylcellulose have also been reported in extended or slow-release systems [34-40]. These systems are most commonly obtained by the simple mixing of the drug with an appropriate inert matrix [39]. The Food and Drug Administration (FDA) warns that in some instances, compounders may lack sufficient control techniques and resources (equipment, training, testing or facilities) to assure product quality or to compound more elaborated products such as modified release drugs [4]. Since obtaining high quality, safe and effective products is fundamental, compounding techniques must be developed and standardized. Thus, coating techniques used to obtain delayed release compounded capsules by the beaker flask method, by dipping or by spraying have been proposed [41]. In beaker flask coating, a small amount of coating material is added to the beaker and heated until melted. Subsequently, a few capsules are added away from the heat and the beaker is manually rotated to coat them. Small quantities of coating material are continuously added in order to prevent the capsules from sticking. The immersion or dipping method consists of heating the coating material in a recipient that permits the dipping of the capsules with the aid of tweezers in the coating solution and subsequent hardening. This process is repeated until all the capsules have a homogenous film. The vaporization or atomization method, also called spraying, consists in preparing a solution of the coating material in alcohol, ether, or keto-alcoholic solvents and transferring it to a spray bottle. The capsules are held over a screen, under ventilation. The coating solution is applied in multiple thin layers that are allowed to dry between applications. A small scale piece of machinery exists for this coating process [33].
