**3. Review of the use of cellulosics in compounding**

The use of cellulose and/or its derivatives as part of compounded formulations has been cited in a great number of studies in the literature. A review of their properties and usage in pharmaceutical preparations is presented in the following section. Focus is given to the products that require more elaborate techniques in compounding pharmacies.

## **3.1. Cellulose derivatives in oral liquid (suspensions) extemporaneous preparation**

It is well known that children and the elderly have difficulties in swallowing solid dosage forms, due to their size or texture. Such population groups benefit from oral liquid 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 preparations are compounded from drugs that are industrially produced.

148 Cellulose – Medical, Pharmaceutical and Electronic Applications

the number of daily administrations [29,30].

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

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].

products that require more elaborate techniques in compounding pharmacies.

The use of cellulose and/or its derivatives as part of compounded formulations has been cited in a great number of studies in the literature. A review of their properties and usage in pharmaceutical preparations is presented in the following section. Focus is given to the

**3.1. Cellulose derivatives in oral liquid (suspensions) extemporaneous preparation** 

It is well known that children and the elderly have difficulties in swallowing solid dosage forms, due to their size or texture. Such population groups benefit from oral liquid

**3. Review of the use of cellulosics in compounding** 

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 (amber) or not (transparent) from light.

Stability studies conducted at 4 °C and 25 °C for distinct drugs over at least 8 weeks are shown in Table 1 [42-52].

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 formulations provide satisfactorily safe and stable products.

Oral extemporaneous suspensions of other drugs (amiodarone, granisetron, trimethoprim, and verapamil salt) prepared in methylcellulose and simple syrup (MC:SS) were also reported to have adequate stability [14].


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

**Table 1.** Stability of different drugs in oral suspension extemporaneously prepared in a mixture of 1% methylcellulose:simple syrup (MC:SS) from commercial available products.

Another cellulose derivative frequently used as part of a vehicle in oral extemporaneous suspensions is sodium carboxymethylcellulose. It is a constituent of a commercial product, Ora-Plus®, which is employed in a 1:1 mixture with Ora-Sweet® (with sugar) or Ora-Sweet SF® (sugar free) [7,8]. Ora-Sweet® is a sugar-based citrus-berry flavoured syrup (see Table 2 footnote). Researchers have performed stability studies for various oral suspensions of drugs with this vehicle. The results of drug stability tests for periods of at least 8 weeks at refrigerated (3-5°C) and room (22-25°C) temperatures, are presented in Table 2 [43,46,49-77].

Cellulose and Its Derivatives Use in the Pharmaceutical Compounding Practice 151

**CMC or Ora-Plus added (1:1) of** 

Ora-Sweet® Ora-Sweet SF®

syrup

Ora-Sweet® Ora-Sweet SF®

syrup

Ora-Sweet® Ora-Sweet SF®

2.5 Ora-Sweet® 42e 28e

Ora-Sweet SF® 90e 7e

Ora-Sweet SF® 28h 28h

Ora-Sweet® 91d, 84c Ora-Sweet SF® 84c

Ora-Sweet SF® 60h 60h

Ora-Sweet SF® 60h 60h

1 Simple syrup 91c 91c

200) 1 91h 91h

Tablets (500) 50, 100 Ora-Sweet® 91d 91d

(10, 20) 4 Ora-Sweet® 91d 91d

(25, 50, 100) 2.5 Ora-Sweet® 91e 91e

2.5a Ora-Sweet®

**Stability (days) in different temperatures 3-5°C 22-25°C** 

> 1h unstable h 2h

60h 60h

57e 57e

60h 60h

90e 90e

56d 56d

60h 60h

**Suspension (mg/mL)** 

5

**Dosage form (mg)** 

> Tablets (100+25)

Capsules (250)

Naratriptan HCl [68] Tablets (1, 2.5) 0.5 Ora-Sweet®

Norfloxacin [69] Tablets (400) 20b Strawberry

(250, 375, 500) 50a

Propylthiouracil [46] Tablets (50) 5 91e 70e

60h 60 Quinidine sulphate [57] h Tablets (200, 300) 10a Rifabutin [70] Capsules (150) 20 Ora-Sweet® 84g 84g

240) <sup>5</sup>

(150, 300) 25a Ora-Sweet®

(25+25) (5+5)a Ora-Sweet®

Capsule/tablets

(25, 50, 100)

Tablets

Levofloxacin [65] Tablets (200, 500, 750) 50 Strawberry

(2.5, 5, 10) 1a

(50, 100) 10a

Hydralazine HCl [55] Tablets (10, 25, 50, 100) 4a

Ketoconazole [61] Tablets (200) 20a

Labetalol HCl [62] Tablets (100, 200, 300) 40a

Moxifloxacin [66] Tablets (400) 20

Pyrazinamide [57] Tablets (500) 10a

Lamotrigine [63] Tablets (25, 100, 150,

Metolazone [61] Tablets

Metoprolol tartrate [62] Tablets

Nifedipine [44] Capsules

Rifampin [57] Capsules

Sildenafil citrate [49] Tablets

Spironolactone [61,71] Tablets

Sotalol HCl [50,51] Tablets (80, 120, 160,

**Drug [Ref.]** 

Levodopa + carbidopa

Mycophenolate mofetil

Procainamide HCl

Spironolactone + hydrochlorothiazide [62]

[45,61]

[64]

[67]



Acetazolamide [53,54] Tablets

Allopurinol [54] Tablets

Clonazepam [54] Tablets

Dapsone [58] Tablets

Dolasetron mesylate [59] Tablets

Famotidine [60] Tablets

Flecainide acetate [56] Tablets

Flucytosine [54] Tablets

Alprazolam [55] Tablets (0.25, 0.5, 1, 2) 1a

Baclofen [56] Tablets (10, 20) 10a

Cisapride [55] Tablets (10, 20) 1a

Diltiazem HCl [56] Tablets (30, 60, 90, 120) 12a

**Drug [Ref.]** 

[57]

[55]

Chloroquine phosphate

Another cellulose derivative frequently used as part of a vehicle in oral extemporaneous suspensions is sodium carboxymethylcellulose. It is a constituent of a commercial product, Ora-Plus®, which is employed in a 1:1 mixture with Ora-Sweet® (with sugar) or Ora-Sweet SF® (sugar free) [7,8]. Ora-Sweet® is a sugar-based citrus-berry flavoured syrup (see Table 2 footnote). Researchers have performed stability studies for various oral suspensions of drugs with this vehicle. The results of drug stability tests for periods of at least 8 weeks at refrigerated (3-5°C) and room (22-25°C) temperatures, are presented in Table 2 [43,46,49-77].

> **Suspension (mg/mL)**

**CMC or Ora-Plus added (1:1) of** 

Ora-Sweet®

Ora-Sweet® Ora-Sweet SF®

2 Ora-Sweet® 91e 91e

Ora-Sweet SF® 60h 60h

Ora-Sweet®

Strawberry syrup Ora-Sweet SF®

Ora-Sweet® Ora-Sweet SF®

(0.5, 1, 2) 0.1a 60g 60g

(10, 20, 40) 8 Ora-Sweet® NE 95h

(250, 500) 10a 60g 60g

Ora-Sweet SF® 60g 60g

**Stability (days) in different temperatures 3-5°C 22-25°C** 

60h 60h

60h 60h

90e 90e

60h 60h

**Dosage form (mg)** 

Tablets

Tablets

(25, 100)

Enalapril maleate [55] Tablets (2.5, 5, 10, 20) 1a Ora-Sweet®

(125, 250) 25a

(100, 300) 20a

(5, 10, 25, 50) 5a

(250, 500) 15a

Azathioprine [54] Tablets (50) 50a 60g 60g

60h 60h Bethanechol chloride

Captopril [56] Tablets (12.5, 25, 50, 100) 0.75a <10h <10h

Ora-Sweet SF® 60h 60 Dipyridamole [56] h Tablets (25, 50, 75) 10a

(50, 100) <sup>10</sup>

(50, 100, 150) 20a

Gabapentin [43] Capsules (100, 300, 400) 100 Ora-Sweet® 91e 56e


Cellulose and Its Derivatives Use in the Pharmaceutical Compounding Practice 153

**3.2. Cellulose and its derivatives in oral solid dosage forms** 

cellulose as excipients for delivering a paediatric medication [81].

*3.2.2. Cellulose ether derivatives in sustained/controlled release* 

*3.2.2.1. Carboxymethylcellulose and hydroxypropylmethylcellulose* 

flowable plant extracts.

inferior concentration (< 6%) [12].

Microcrystalline cellulose is reported as an excipient (diluent) in oral powder and capsules extemporaneously compounded for paediatric use. Capsules and powders were prepared from commercial tablets containing 10 mg of nifedipine, which was mixed with different amounts of lactose or microcrystalline cellulose in a mortar with pestle using standard geometric dilution. Capsules were filled by a hand-operated capsule-filling machine. The oral powders and capsules containing extemporaneously prepared nifedipine showed acceptable quality regarding content uniformity, but considerable loss of the active ingredient occurred during the compounding process for both preparations. The authors demonstrated that oral powders of nifedipine (a light sensitive drug) can be replaced by capsules, which were adequately safe with either lactose monohydrate or microcrystalline

Recently, microcrystalline cellulose and two other common pharmaceutical excipients (starch and lactose) were investigated with regards to the choice of the best diluent for *Gymnema sylvestre* extract (a plant used as an adjuvant in the treatment of diabetes mainly in China) used to compound capsules. The *Gymnema sylvestre* extract is available as powder that presents low flowability due to its small particle size which causes problems in the filling of the hard capsules. An evaluation of these excipients was also performed in the presence of different lubricants (magnesium stearate or talc). The study showed that microcrystalline cellulose is a better diluent than lactose or starch, because it produces the most uniform particle size distribution when added to *Gymnema sylvestre* extract and also reduces the percentage of fine particles resulting in acceptable variation of the weight among the capsules (RSD< 4%). On the other hand, starch and lactose increase the number of small particles that worsen the flowability of the powder mixture. Furthermore, microcrystalline cellulose associated with 1% lubricant renders a powder mixture ready for encapsulation of *Gymnema sylvestre* extract in hard gelatin capsules, since flow agents optimize the capsule filling in the compounding routine practices [82]. The foregoing suggests that microcrystalline cellulose can be an appropriate diluent in formulating similar

Some studies reveal improper use of cellulosic excipients. For example, using a high percentage (30% w/w) of CMC-Na (anionic polymer) as a diluent in the compounding of capsules of simvastatin has a deleterious effect. These capsules showed serious drug release problems in pharmaceutical tests because they did not disintegrate or dissolve at all [83]. In this case, CMC-Na should have been used as a capsule disintegrating agent at a much

*3.2.1. Mycrocrystalline cellulose in immediate release* 

a: storage in the dark, b: at fluorescent lighting, c: amber glass, d: plastic, e: amber plastic, f: polyvinyl chloride, g: polyethylene terephthalate (PET), h: amber PET; i: amber high density polyethylene bottles; NE, not evaluated; HCl, hydrochloride.

Ora-Plus® constituents: CMC-Na, citric acid, flavouring, methylparaben, microcrystalline glucose, potassium sorbate, purified water, simethicone, sodium phosphate, xanthan gum, pH 4.2. Ora-Sweet® constituents: citric acid, flavouring, glycerin, methylparaben, purified water, sodium phosphate, sorbitol, sucrose, potassium sorbate, pH 4.2. Ora-Sweet SF® constituents: citric acid, flavouring, glycerin, methylparaben, propylparaben, potassium sorbate, purified water, sodium saccharin, sodium citrate, sorbitol, xanthan gum, pH 4.2. Sugar-free.

**Table 2.** Stability of different drugs in oral suspension extemporaneously prepared from commercially available sodium carboxymethylcellulose (CMC-Na) in Ora-Plus® and/or other vehicle constituents.

Most of the suspensions prepared presented no substantial changes in pH, odour or physical appearance, showing that CMC-Na base usually provides products with a satisfactory safety and stability (drug content equal or superior to 90% of the original concentration) over a period of 8 weeks.

The use of Ora-Plus® extemporaneous oral suspension has provided satisfactory stability for aminophylline, cyclophosphamide, domperidone, granisetron, itraconazole, ursodiol and tramadol hydrochloride associated with acetaminophen [14,78]. However, for captopril, hydralazine hydrochloride and tetracycline hydrochloride, the suspensions were reported as not having enough stability. The problem of stability with captopril is due to its oxidative degradation, which can be solved by the addition of EDTA disodium [79]. Although, these studies are important, most of them have not evaluated the microbiological stability, an essential criterion for liquid dosage forms.

In addition to MC and CMC-Na, HPMC has also been employed in extemporaneous oral suspension. For instance, nifedipine tablets or drug powder, prepared with HPMC 1% solution in order to obtain a suspension of 1 mg/mL concentration, was stable for at least 4 weeks when stored at room or refrigerated temperatures and protected from light [80].

There is no doubt that these drug stability results are important for providing formulations for both paediatric patients and the geriatric populations that have difficulty in swallowing capsules or tablets.

## **3.2. Cellulose and its derivatives in oral solid dosage forms**

## *3.2.1. Mycrocrystalline cellulose in immediate release*

152 Cellulose – Medical, Pharmaceutical and Electronic Applications

Tacrolimus [73-75] Capsules

Tetracycline HCl [57] Capsules

concentration) over a period of 8 weeks.

essential criterion for liquid dosage forms.

capsules or tablets.

Tiagabine HCl [52] Tables (2, 4, 6, 8, 10, 12,

**Dosage form (mg)** 

Theophylline [77] Capsules (125, 200, 300) <sup>5</sup>Ora-Sweet®

purified water, sodium saccharin, sodium citrate, sorbitol, xanthan gum, pH 4.2. Sugar-free.

**Suspension (mg/mL)** 

(0.5, 1, 5) 0.5 Simple syrup

(250, 500) 25a Ora-Sweet®

Sunitinib malate [72] Capsules (50) 10 Ora-Sweet® 60c 60c

Terbinafine HCl [76] Tablets (250) 25 Ora-Sweet® 42h 42i

a: storage in the dark, b: at fluorescent lighting, c: amber glass, d: plastic, e: amber plastic, f: polyvinyl chloride, g: polyethylene terephthalate (PET), h: amber PET; i: amber high density polyethylene bottles; NE, not evaluated; HCl,

Ora-Plus® constituents: CMC-Na, citric acid, flavouring, methylparaben, microcrystalline glucose, potassium sorbate, purified water, simethicone, sodium phosphate, xanthan gum, pH 4.2. Ora-Sweet® constituents: citric acid, flavouring, glycerin, methylparaben, purified water, sodium phosphate, sorbitol, sucrose, potassium sorbate, pH 4.2. Ora-Sweet SF® constituents: citric acid, flavouring, glycerin, methylparaben, propylparaben, potassium sorbate,

**Table 2.** Stability of different drugs in oral suspension extemporaneously prepared from commercially available sodium carboxymethylcellulose (CMC-Na) in Ora-Plus® and/or other vehicle constituents.

Most of the suspensions prepared presented no substantial changes in pH, odour or physical appearance, showing that CMC-Na base usually provides products with a satisfactory safety and stability (drug content equal or superior to 90% of the original

The use of Ora-Plus® extemporaneous oral suspension has provided satisfactory stability for aminophylline, cyclophosphamide, domperidone, granisetron, itraconazole, ursodiol and tramadol hydrochloride associated with acetaminophen [14,78]. However, for captopril, hydralazine hydrochloride and tetracycline hydrochloride, the suspensions were reported as not having enough stability. The problem of stability with captopril is due to its oxidative degradation, which can be solved by the addition of EDTA disodium [79]. Although, these studies are important, most of them have not evaluated the microbiological stability, an

In addition to MC and CMC-Na, HPMC has also been employed in extemporaneous oral suspension. For instance, nifedipine tablets or drug powder, prepared with HPMC 1% solution in order to obtain a suspension of 1 mg/mL concentration, was stable for at least 4 weeks when stored at room or refrigerated temperatures and protected from light [80].

There is no doubt that these drug stability results are important for providing formulations for both paediatric patients and the geriatric populations that have difficulty in swallowing

**CMC or Ora-Plus added (1:1) of** 

Ora-Sweet SF®

16) 1 Ora-Sweet® 91d 70e

**Stability (days) in different temperatures 3-5°C 22-25°C** 

> 28g 28h 10g 7h

NF NE 56c,e

Ora-Sweet SF® NE 90e

**Drug [Ref.]** 

hydrochloride.

Microcrystalline cellulose is reported as an excipient (diluent) in oral powder and capsules extemporaneously compounded for paediatric use. Capsules and powders were prepared from commercial tablets containing 10 mg of nifedipine, which was mixed with different amounts of lactose or microcrystalline cellulose in a mortar with pestle using standard geometric dilution. Capsules were filled by a hand-operated capsule-filling machine. The oral powders and capsules containing extemporaneously prepared nifedipine showed acceptable quality regarding content uniformity, but considerable loss of the active ingredient occurred during the compounding process for both preparations. The authors demonstrated that oral powders of nifedipine (a light sensitive drug) can be replaced by capsules, which were adequately safe with either lactose monohydrate or microcrystalline cellulose as excipients for delivering a paediatric medication [81].

Recently, microcrystalline cellulose and two other common pharmaceutical excipients (starch and lactose) were investigated with regards to the choice of the best diluent for *Gymnema sylvestre* extract (a plant used as an adjuvant in the treatment of diabetes mainly in China) used to compound capsules. The *Gymnema sylvestre* extract is available as powder that presents low flowability due to its small particle size which causes problems in the filling of the hard capsules. An evaluation of these excipients was also performed in the presence of different lubricants (magnesium stearate or talc). The study showed that microcrystalline cellulose is a better diluent than lactose or starch, because it produces the most uniform particle size distribution when added to *Gymnema sylvestre* extract and also reduces the percentage of fine particles resulting in acceptable variation of the weight among the capsules (RSD< 4%). On the other hand, starch and lactose increase the number of small particles that worsen the flowability of the powder mixture. Furthermore, microcrystalline cellulose associated with 1% lubricant renders a powder mixture ready for encapsulation of *Gymnema sylvestre* extract in hard gelatin capsules, since flow agents optimize the capsule filling in the compounding routine practices [82]. The foregoing suggests that microcrystalline cellulose can be an appropriate diluent in formulating similar flowable plant extracts.

#### *3.2.2. Cellulose ether derivatives in sustained/controlled release*

#### *3.2.2.1. Carboxymethylcellulose and hydroxypropylmethylcellulose*

Some studies reveal improper use of cellulosic excipients. For example, using a high percentage (30% w/w) of CMC-Na (anionic polymer) as a diluent in the compounding of capsules of simvastatin has a deleterious effect. These capsules showed serious drug release problems in pharmaceutical tests because they did not disintegrate or dissolve at all [83]. In this case, CMC-Na should have been used as a capsule disintegrating agent at a much inferior concentration (< 6%) [12].

CMC-Na and HPMC (nonionic polymer) were evaluated by *in vitro* release studies with regards to ibuprofen (non-steroidal anti-inflammatory) extended-release from hard gelatin capsules. The study showed that different grades of CMC-Na and HPMC could control ibuprofen release to a substantial degree when used as diluents. Furthermore, the molecular weight of the polymer group that is directly related to the viscosity grade affects the drug release: the higher the molecular weight is, the slower the drug release is [40]. One year later, these researchers evaluated ibuprofen bioavailability (healthy volunteers) from hard gelatin capsules containing different grades of HPMC (K100 and K15M) and CMC-Na (low, medium, high viscosity). These capsules were prepared by filling the shells with the simple mixture of the powders (drug and polymer). The study showed that different viscosities of HPMC can modify the absorption rate of ibuprofen from hard gelatin capsules, in close correlation with a previous *in vitro* study. In particular, a higher viscosity HPMC (K15M) was a better diluent in sustained-release. On the other hand, the use of the CMC-Na with different viscosity grades did not allow for the control of the absorption rate of ibuprofen and did not correspond to *in vitro* results. However, none of the polymers seemed to have any effect on the bioavailability of the ibuprofen from hard gelatin capsules [39].

Cellulose and Its Derivatives Use in the Pharmaceutical Compounding Practice 155

batches of each) were compounded in a local pharmacy employing 40% HPMC (E4M Premium CR) and lactose as excipients and a specific machine for capsule-filling. The authors observed that the release of the active ingredients from the compounded capsules after 0.5, 4 and 12 h were less than 23%, 85% and 98%, demonstrating that HPMC is an adequate excipient for preparing slow-release capsules of morphine sulphate and oxycodone hydrochloride. The authors recommend that the ratio of active ingredient to polymer should remain constant regardless of the capsule size in order to achieve similar release rates, provided there is some degree of compression within the capsule shell. *In vitro*  performance showed small intra-batch variations as well as inter-batch variations which were not statistically significant. Thus the compounding of slow release capsules yielded reproducible formulations. However, the authors mention that clinical evaluation is needed

A variety of drugs, especially natural bioidentical hormones, have been exploited in compounding using matrix systems since 2002. Hydrophilic matrix systems were mentioned as being successfully used in slow-release capsules. The authors report that a good response of patients in a dose-related manner was observed in response to all micronized hormones

Polymers of HPMC (K100MPRCR, K15MPRCR and E4MCR) in different proportions from 15 to 35% w/w were also used as extended-release excipients in the compounding of capsules containing 100 mg of theophylline. The polymers of HPMC were employed to prepare capsules by volumetric method for powder filling in a manual encapsulator. The extended drug release was evaluated using USP apparatus I for industrially-produced batches and for those obtained by compounding process. The dissolution profile obtained for the higher ratio (35% w/w) of HPMC (E4MCR) met USP specifications. Furthermore, reproducibility was observed with ten other compounded batches. HPMC was efficient in controlling the release of theophylline from the matrix of the capsules prepared by compounding. However, extendedrelease capsules containing 100 mg of theophylline (pellets) available in the market did not

To summarize, CMC-Na does not seem to be an adequate slow-releasing agent for preparing the capsules regardless of its viscosity. On the other hand, HPMC is a promising agent for prolonging the release of drugs, since it has been used before with success. The results suggest a relationship between degree of viscosity of HPMC and slow release (ibuprofen, morphine). However, reproducibility is an important requisite, and may not be assured for all formulations. In addition, studies of therapeutic efficacy are also scarce for

Cellulose ester derivatives are used for enteric coatings of capsules, making them resistant to dissolution in low pH environments, such as the stomach, but allowing for their rapid disintegration in higher pH environments, such as the intestine. The efficiency of the coating is limited by the smooth and nonporous surface of the hard capsules. Studies into anti-

in order to determine whether the small differences are significant [37].

show prolonged release when submitted to the same test conditions [38].

administered in slow-release capsules [36].

such compounded products.

*3.2.3. Cellulose ester derivatives in delayed release* 

Slow-release morphine (opioid analgesic used for the relief of pain) capsules extemporaneously prepared were investigated regarding their dissolution profile. Three batches of capsules prepared by a pharmacist were compared with each other and with tablets acquired in the market. The authors describe how similar slow-release profiles were found for tablets and compounded capsules, though the latter showed a faster release-rate for morphine sulphate. Despite small variations from batch to batch, the authors describe that compounded capsules showed a remarkably consistent slow-release profile in *in vitro* studies [34].

Another study of compounded capsules containing 300 mg of morphine sulphate (a dosage unavailable in the market) reported the use of HPMC in sustained-release. There has been considerable controversy about the advisability of this practice. Release studies, performed according to the United States Pharmacopeia (USP) using a dissolution apparatus of type III, showed that almost half of the morphine was released in the first hour and that the release of the remainder was not adequately sustained. As verified in other studies, the increase of HPMC prolonged release and reduced drug release in the first hour. Other formulations prepared by placing compressed pellets in capsules showed a sustained release significantly beyond that of the pellets' original formulation. Considering that the medication can be taken after a meal, the agitation of the gastrointestinal tract would have increased, resulting in the reduction of the sustained release period and in a slight increase of the drug amount during the first hour after administration. In the first formulation, the capsules did not exhibit sustained-release that could be adequate for most applications. Formulations with a greater percentage of the HPMC are preferred. Furthermore, the pelleted formulation was superior, but it may not be feasible because it is too labour-intensive [35].

Slow-release capsules of morphine sulphate (15, 60, 200 mg) and oxycodone hydrochloride (10, 80, 200 mg) were evaluated *in vitro* by USP dissolution apparatus II. All capsules (three batches of each) were compounded in a local pharmacy employing 40% HPMC (E4M Premium CR) and lactose as excipients and a specific machine for capsule-filling. The authors observed that the release of the active ingredients from the compounded capsules after 0.5, 4 and 12 h were less than 23%, 85% and 98%, demonstrating that HPMC is an adequate excipient for preparing slow-release capsules of morphine sulphate and oxycodone hydrochloride. The authors recommend that the ratio of active ingredient to polymer should remain constant regardless of the capsule size in order to achieve similar release rates, provided there is some degree of compression within the capsule shell. *In vitro*  performance showed small intra-batch variations as well as inter-batch variations which were not statistically significant. Thus the compounding of slow release capsules yielded reproducible formulations. However, the authors mention that clinical evaluation is needed in order to determine whether the small differences are significant [37].

A variety of drugs, especially natural bioidentical hormones, have been exploited in compounding using matrix systems since 2002. Hydrophilic matrix systems were mentioned as being successfully used in slow-release capsules. The authors report that a good response of patients in a dose-related manner was observed in response to all micronized hormones administered in slow-release capsules [36].

Polymers of HPMC (K100MPRCR, K15MPRCR and E4MCR) in different proportions from 15 to 35% w/w were also used as extended-release excipients in the compounding of capsules containing 100 mg of theophylline. The polymers of HPMC were employed to prepare capsules by volumetric method for powder filling in a manual encapsulator. The extended drug release was evaluated using USP apparatus I for industrially-produced batches and for those obtained by compounding process. The dissolution profile obtained for the higher ratio (35% w/w) of HPMC (E4MCR) met USP specifications. Furthermore, reproducibility was observed with ten other compounded batches. HPMC was efficient in controlling the release of theophylline from the matrix of the capsules prepared by compounding. However, extendedrelease capsules containing 100 mg of theophylline (pellets) available in the market did not show prolonged release when submitted to the same test conditions [38].

To summarize, CMC-Na does not seem to be an adequate slow-releasing agent for preparing the capsules regardless of its viscosity. On the other hand, HPMC is a promising agent for prolonging the release of drugs, since it has been used before with success. The results suggest a relationship between degree of viscosity of HPMC and slow release (ibuprofen, morphine). However, reproducibility is an important requisite, and may not be assured for all formulations. In addition, studies of therapeutic efficacy are also scarce for such compounded products.

## *3.2.3. Cellulose ester derivatives in delayed release*

154 Cellulose – Medical, Pharmaceutical and Electronic Applications

studies [34].

CMC-Na and HPMC (nonionic polymer) were evaluated by *in vitro* release studies with regards to ibuprofen (non-steroidal anti-inflammatory) extended-release from hard gelatin capsules. The study showed that different grades of CMC-Na and HPMC could control ibuprofen release to a substantial degree when used as diluents. Furthermore, the molecular weight of the polymer group that is directly related to the viscosity grade affects the drug release: the higher the molecular weight is, the slower the drug release is [40]. One year later, these researchers evaluated ibuprofen bioavailability (healthy volunteers) from hard gelatin capsules containing different grades of HPMC (K100 and K15M) and CMC-Na (low, medium, high viscosity). These capsules were prepared by filling the shells with the simple mixture of the powders (drug and polymer). The study showed that different viscosities of HPMC can modify the absorption rate of ibuprofen from hard gelatin capsules, in close correlation with a previous *in vitro* study. In particular, a higher viscosity HPMC (K15M) was a better diluent in sustained-release. On the other hand, the use of the CMC-Na with different viscosity grades did not allow for the control of the absorption rate of ibuprofen and did not correspond to *in vitro* results. However, none of the polymers seemed to have

any effect on the bioavailability of the ibuprofen from hard gelatin capsules [39].

Slow-release morphine (opioid analgesic used for the relief of pain) capsules extemporaneously prepared were investigated regarding their dissolution profile. Three batches of capsules prepared by a pharmacist were compared with each other and with tablets acquired in the market. The authors describe how similar slow-release profiles were found for tablets and compounded capsules, though the latter showed a faster release-rate for morphine sulphate. Despite small variations from batch to batch, the authors describe that compounded capsules showed a remarkably consistent slow-release profile in *in vitro*

Another study of compounded capsules containing 300 mg of morphine sulphate (a dosage unavailable in the market) reported the use of HPMC in sustained-release. There has been considerable controversy about the advisability of this practice. Release studies, performed according to the United States Pharmacopeia (USP) using a dissolution apparatus of type III, showed that almost half of the morphine was released in the first hour and that the release of the remainder was not adequately sustained. As verified in other studies, the increase of HPMC prolonged release and reduced drug release in the first hour. Other formulations prepared by placing compressed pellets in capsules showed a sustained release significantly beyond that of the pellets' original formulation. Considering that the medication can be taken after a meal, the agitation of the gastrointestinal tract would have increased, resulting in the reduction of the sustained release period and in a slight increase of the drug amount during the first hour after administration. In the first formulation, the capsules did not exhibit sustained-release that could be adequate for most applications. Formulations with a greater percentage of the HPMC are preferred. Furthermore, the pelleted formulation was

Slow-release capsules of morphine sulphate (15, 60, 200 mg) and oxycodone hydrochloride (10, 80, 200 mg) were evaluated *in vitro* by USP dissolution apparatus II. All capsules (three

superior, but it may not be feasible because it is too labour-intensive [35].

Cellulose ester derivatives are used for enteric coatings of capsules, making them resistant to dissolution in low pH environments, such as the stomach, but allowing for their rapid disintegration in higher pH environments, such as the intestine. The efficiency of the coating is limited by the smooth and nonporous surface of the hard capsules. Studies into anti-

inflammatory and anti-secretory (H+ pumps inhibitors) drugs, such as diclofenac and pantoprazole sodium salts, respectively, show that these drug formulations must be coated because they can irritate the stomach walls or degrade in acid environments [84,85].

Cellulose and Its Derivatives Use in the Pharmaceutical Compounding Practice 157

especially for extemporaneous use; however, a great effort is still necessary in this field in order to assure quality, safety and efficacy for several other drugs. This aspect is even more relevant when these products require specific pharmaceutical features (such as delayed release) and, consequently, adequate techniques for achieving drug therapy success. It points towards the need for more research into ways to properly disseminate the appropriate use of cellulose derivatives in compounding pharmacies. A greater attention should be paid to this field because compounding is a growing practice in many countries as a result of pharmaceutical care that prioritizes the person in his/her individuality, as opposed to the average population usually targeted by companies. For all these reasons, cellulose derivatives and their applications in compounding practice were reviewed, with an emphasis on their use in solid dosage forms with modified release. Addressing the use of the cellulose derivatives, such as cellulose acetate phthalate, can be critical in the coating of

 and Cristina Duarte Vianna-Soares *Department of Pharmaceutical Products, Federal University of Minas Gerais, Belo Horizonte, MG,* 

To CAPES for the fellowship to Marques-Marinho FD, to Lima AA and Reis IA for the

[1] Anderson S. Making Medicines- A Brief History of Pharmacy and Pharmaceuticals.

[2] Kremers E., Sonnedecker, G., editors. Kremers and Urdang's History of Pharmacy.

[3] Buurma H, De Smet PA, van den Hoff OP, Sysling H, Storimans M, Egberts AC. Frequency, Nature and Determinants of Pharmacy Compounded Medicines in Dutch

[4] Galston SK. Federal and State Role in Pharmacy Compounding and Reconstitution. In:

[5] Jew RK, Soo-hoo W, Erush SC. Extemporaneous Formulations for Pediatric, Geriatric, and Special Needs Patients. Bethesda: American Society of Health-System Pharmacists;

http://www.fda.gov/NewsEvents/Testimony/ucm115010.htm (accessed 26 February

Madison: American Institute of the History of Pharmacy; 1986.

Community Pharmacies. Pharm. World Sci. 2003;25(6): 280-7.

US Food and Drug Administration; 2003. Available:

capsules by hand.

**Author details** 

*Brazil* 

Flávia Dias Marques-Marinho\*

important initial collaboration.

Great Britain: Pharmaceutical Press; 2005.

**Acknowledgement** 

**5. References** 

2013)

2010.

Corresponding Author

 \*

#### *3.2.3.1. Cellulose acetate phthalate*

CAP and other agents (formaldehyde, methacrylic acid copolymer) have been used to compound delayed-release capsules of diclofenac using specific small-scale machinery or manual immersion in order to evaluate the efficiency of these enteric coating processes [32]. Capsules coated with CAP (using acetone as solvent) prepared with either small machinery or twofold manual immersion showed adequate gastro-resistance, for which the release of the drug was less than 10% in acid and greater than 75% in buffered conditions. However, the capsules coated by machinery had a poorer visual aspect than those coated by the manual process [32]. In spite of this difference, the authors did not suggest which method was the most adequate to compound delayed-release capsules of diclofenac.

A simple, quick and easily reproducible method for compounding enteric-release capsules containing diclofenac has also been described. Twenty-two batches of diclofenac sodium capsules (n=60) were divided into three groups, which were submitted to different processes of coating. A small-scale machine and an enteric coating by atomization (spraying) of organic solutions of polymers (5% CAP in a mix of acetone and alcohol) were employed for ten and six batches, respectively. Before coating, the capsules' hemi receptacles were sealed by treatment with 50% v/v hydroalcoholic solution. The dissolution test results were statistically compared inter-batch and also with reference commercial product (Voltaren® DR). Most of the batches (>75%) met the pharmacopeial requirements for enteric release, in both acid (less than 10%) and buffered (greater than 80%) conditions [33]. Results confirmed that CAP is an effective enteric coating agent in compounding practice and that the application of adequate techniques in pharmacies is important.

Delayed release capsules obtained by compounding and coating with organic solutions of CAP have been evaluated for pro-drug sodium pantoprazole, a proton pump inhibitor that undergoes degradation in the acid environment of the stomach [31,84,85]. Quality control tests were performed on capsules locally acquired in compounding pharmacies. Dissolution studies for gastro-resistance evaluation were performed with granules of pantoprazole coated with CAP and encapsulated, as well as with capsules coated with CAP or other agents (formaldehyde, shellac, methacrylic acid copolymer). However, all the samples prepared by coating with CAP (capsules or granules) released their content in an acid environment and did not show adequate gastro-resistance [31]. These results reveal the need for suitable coating techniques for compounding gastro-resistant capsules, since CAP is admittedly an effective agent for enteric coating.

## **4. Conclusion**

Cellulose and its derivatives are very important excipients in compounded medicines. Many compounded preparations containing such excipients have been investigated since 1992, especially for extemporaneous use; however, a great effort is still necessary in this field in order to assure quality, safety and efficacy for several other drugs. This aspect is even more relevant when these products require specific pharmaceutical features (such as delayed release) and, consequently, adequate techniques for achieving drug therapy success. It points towards the need for more research into ways to properly disseminate the appropriate use of cellulose derivatives in compounding pharmacies. A greater attention should be paid to this field because compounding is a growing practice in many countries as a result of pharmaceutical care that prioritizes the person in his/her individuality, as opposed to the average population usually targeted by companies. For all these reasons, cellulose derivatives and their applications in compounding practice were reviewed, with an emphasis on their use in solid dosage forms with modified release. Addressing the use of the cellulose derivatives, such as cellulose acetate phthalate, can be critical in the coating of capsules by hand.
