The Basics of Compounding

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Compounding GelsGels have a variety of applications in the administration of

medications orally, topically, intranasally, vaginally and rectally.Nasal absorption of drugs from gels has been extensively investi-gated, with some reports of drugs administered by nasal gels show-ing better absorption than by oral administration. Gels can alsoserve as ointment bases. An example is Plastibase™ and mineral-oil gels made with aluminum monostearate. Some, such as pluroniclecithin organogel, can be used to enhance penetration of drugsinto the skin.

Some gel systems are as clear as water and others are turbid, sincethe ingredients involved may not be completely molecularly dis-persed or they may form aggregates, which disperse light. Theconcentration of the gelling agents is mostly less than 10%, usu-ally in the 0.5% to 2.0% range, with some exceptions. For best consumer appeal, gels should have clarity and sparkle. Most gelsare water washable, water soluble, water absorbing and greaselessand act as absorption bases. The gel should also maintain its vis-cosity and character over a wide temperature range.

DefinitionsGels, or jellies, are semisolid systems consisting of suspensions

made up of small inorganic particles or large organic moleculesinterpenetrated by a liquid. Where the gel mass consists of a network of small, discrete par tic les , the gel is classi fied as a two-phase system. In these two-phase systems, if the particle size of the dispersed phase is large, the product is referred to as a magma.Single-phase gels consist of organic macromolecules uniformly distributed throughout a liquid in such a manner that no appar-ent boundaries exist between the dispersed macromolecules andthe liquid. Single-phase gels may be made from synthetic macro-molecules or from natural gums (mucilages). The continuous phase

usually is aqueous, but it can also be alcoholic or oleaginous.Gels and jellies exhibit a number of different characteristics, i

cluding imbibition, swelling, syneresis and thixotropy. Imbibtion is the taking up of a certain amount of liquid withoutmeasurable increase in volume. Swelling is the taking up of a liuid by a gel, with an increase in volume. Only liquids that solvaa gel can cause swelling. The swelling of protein gels is influencby pH and the presence of electrolytes. Syneresis is a form of istability in aqueous and nonaqueous gels. It occurs when the iteraction between particles of the dispersed phase becomes so grethat, on standing, the dispersing medium is squeezed out in drople

and the gel shrinks. Thixotropy is a reversible gel-sol formati with no change in volume or temperature – a type of non-Newtonian flow. An interesting product, a xerogel, can be formed whethe liquid is removed from a gel and only the framework remainExamples would include gelatin sheets, tragacanth ribbons anacacia tears.

Classification of Gels Table 1 is a general classification of gels, listing two classific

tion schemes. The first divides gels into inorganic and organclassifications.

Inorganic gels are usually two-phase systems such as aluminuhydroxide gel and bentonite magma. Bentonite has also beeused as an ointment base in concentrations of about 10% to 25%Organic gels are usually single-phase systems and may inclusuch gelling agents as carbomer and tragacanth and those that cotain an organic liquid, such as Plastibase.

The second classification scheme c lassifies gels as hydrogels organogels, with some additional subcategories.

Hydrogels include ingredients that are dispersible as colloids

Loyd V. Allen, Jr., PhD, RPh

G E N E R A L I N T E R E S

TheBasics of

Compounding

3International Journal of Pharmaceutical Compounding

Vol.3 No.5 September/October 1999

Table 1. General Classification and Description of Gels.

Class Description Examples

Inorganic Usually two-phase systems Aluminum hydroxide gel, bentonite magma

Organic Usually single-phase systems Carbopol,® tragacanthHydrogels Contain water Silica, bentonite, pectin, sodium alginate, methylcellulose, alumina

Organogels Hydrocarbon type Petrolatum, mineral oil/polyethylene gel, Plastibase Animal/vegetable fats Lard, cocoa butterSoap-base greases Aluminum stearate with heavy mineral-oil gelHydrophilic organogels Carbowax bases (PEG ointment)

Hydrogels Organic hydrogels Pectin paste, tragacanth jelly Natural and synthetic gums Methylcellulose, sodium carboxymethylcellulose, Pluronic® F-127Inorganic hydrogels Bentonite gel (10% to 25%), Veegum®


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soluble in water and include organic hydrogels, natural and syn-thetic gums and inorganic hydrogels. Some examples are hy-

drophilic colloids such as silica, bentonite, tragacanth, pectin,sodium alginate, methylcellulose, sodium carboxymethylcelluloseand alumina, which in high concentrations form semisolid gels.Sodium alginate has been used to produce gels that can be em-ployed as ointment bases. In concentrations greater than 2.5%and in the presence of soluble calcium salts, a firm gel, stable be-tween pH 5 and 10, is formed. Methylcellulose, hydroxyethyl-cellulose and sodium carboxymethylcellulose are among thecommercially available cellulose products that may be used inointments. They are available in various viscosity types, usually high, medium and low.

Organogels include the hydrocarbons, animal/vegetable fats,soap-base greases and hydrophilic organogels. Included in thehydrocarbon type is Jelene, or Plastibase, a combination of min-eral oils and heavy hydrocarbon waxes with a molecular weight of about 1300. Petrolatum is a semisolid gel consisting of a liquidcomponent together with a “protosubstance” and a crystalline waxy fraction. The crysta lline fraction provides rigidity to thestructure, while the protosubstance or gel former stabilizes thesystem and thickens the gel . The hydrophi l ic , or polar ,organogels include the polyethylene glycols of high molecular weight, the carbowaxes. They are soluble to about 75% in waterand are completely washable. The gels look and feel like petrola-tum. They are nonionic and stable.

Jell ies are a class of gels in which the structural coherent matrixcontains a high proportion of liquid, usually water. They usually are formed by adding a thickening agent such as tragacanth or

carboxymethyl cellulose to an aqueous solution of a drug sub-stance. The resultant product is usually clear and of a uniformsemisolid consistency. Jellies are subject to bacterial contamina-tion and growth and, thus, most are preserved with antimicrobials. Jell ies should be stored with tight closures s ince water may evap-orate, drying out the product.

Gel-forming AgentsExamples of gelling agents include acacia, alginic acid, bentonite,

carbomer, carboxymethylcellulose sodium, cetostearyl alcohol,

colloidal silicon dioxide, ethylcellulose, gelatin, guar gum, hy-droxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, magnesium aluminum silicate, maltodextrin,methylcellulose, polyvinyl alcohol, povidone, propylene carbon-ate, propylene glycol alginate, sodium alginate, sodium starch gly-colate, starch, tragacanth and xanthan gum. A few of the morecommon ones will be discussed later.

Preparation Different techniques can be used to prepare gels, depending

upon the characteristics of the gelling agent. Carbopol can beadded to rapidly agitated water and allowed to set for the escapeof air bubbles; when the neutralizer is added, the gel thickens. The active drug may be added before or after the gel is formed.

If the active drug does not interfere with the gelling process, itis best to add it prior to gelling. If the active drug interferes withgelling, it should be added after gelling occurs. Bentonite is addedto nonagitated water in small portions. Each portion is allowedto hydrate and settle in the container. The product can be leftundisturbed overnight, and the next day it is thoroughly agitated.

As a general rule, one obtains easier and more uniform disper-sion of the drug if it is added to the dispersion medium prior togelling, if no interference occurs. Otherwise, the drug is addedafter gelling and it requires more effort and usually results in theincorporation of air into the product. One easy method of prepa-ration is to add the gel to a plastic bag along with the active drug. The bag is kneaded to thoroughly mix the drug. After the prod-

uct is finished, use scissors to snip off one corner of the bag andthen squeeze the product into the dispensing container, similar tothe method used for decorating cakes.

In gel preparation, the powdered polymers, when added to wa-ter, may form temporary gels that slow the process of dissolution. As water diffuses into these loose clumps of powder, their exteri-ors frequently turn into clumps of solvated particles encasing drypowder. The clumps of gel dissolve very slowly because of theirhigh viscosity and the low diffusion coefficient of the macro-molecules. Use of glycerin or other liquid as a wetting/dispersingagent minimizes this occurrence.

Aqueous polymer solutions, especially of cellulose derivatives,are stored for approximately 48 hours after dissolution to promotefull hydration, maximum viscosity and clarity. If salts are to be

added, they are added at this point rather than being dissolved in water prior to adding polymer; otherwise, the solutions may notreach their full viscosity and clarity.

Common Ingredients Alginic acid is obtained from seaweed throughout the world and

the prepared product is a tasteless, practically odorless, white to yellowish-white, fibrous powder. It is used in concentrations ofbetween 1% and 5% as a thickening agent in gels. It swells in water to about 200 to 300 times its own weight without dissolv-

G E N E R A L I N T E R E S T



Continuing EducationGoal: To assist pharmacists, pharmacy students and pharmacy

technicians with the basics of compounding gels, includingthe steps required for their successful preparation.Objectives: After reading and studying the article, the reader will be able to:1. Briefly discuss the use and appropriate application of gels.2. Select an appropriate method of preparing gels, based upon

the active drug and the type of gel to be prepared.3. Prepare gels using appropriate equipment and techniques.4. List at least four different gelling agents and discuss their

characteristics.


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ing. Crosslinking with increased viscosity occurs upon the addi-tion of a calcium salt, such as calcium citrate. Alginic acid can bedispersed in water vigorously stirred for approximately 30 min-utes. Premixing with another powder or with a water-miscibleliquid aids in the dispersion process.

Bentonite, a naturally occurring hydrated aluminum silicate,can be used to prepare gels by sprinkling it on the surface of hot water and allowing this to stand 24 hours, sti rring occasionally after the bentonite has become wetted. Glycerin or a similarliquid can be used to prewet the bentonite prior to mixing with

water. Aqueous bentonit e suspensions re ta in thei r vi scos ityabove pH 6 but are precipitated by acids. Alkaline materials, suchas magnesium oxide, increase gel formation. Alcohol in signifi-cant amounts can precipitate bentonite and, since bentonite isanionic, the antimicrobial efficacy of cationic preservatives may be reduced. Bentonite exhibits thixotropy: it may form a semi-rigid gel that reverts to a sol when agita ted. The sol will reformto a gel upon standing.

Carbomer (Carbopol) resins were first described in the litera-ture in 1955 and are currently ingredients in a variety ofpharmaceutical dosage systems. They were previously discussedin IJPC 1997;1:(4).

Carboxymethylcellulose in concentrations of 4% to 6% of themedium-viscosity grades can be used to produce gels; glycerin may

be added to prevent drying. Precipitation can occur at pH valuesless than 2; it is most stable at pH levels between 2 and 10, withmaximum stability at pH 7 to 9. It is incompatible with ethanol.

Carboxymethylcellulose sodium/sodium carboxymethyl-cellulose is soluble in water at all temperatures. Its sodium salt can be dispersed with high shear in cold water before the parti-cles can hydrate and swell to sticky gel grains agglomerating intolumps. Once the powder is well dispersed, the solution is heated with moderate shear to about 60˚C for fastest dissolution. Thesedispersions are sensitive to pH changes because of the carboxy-

late group. The viscosity of the product is decreased markedly blow pH 5 or above pH 10.

Colloidal silicon dioxide can be used to prepare transparegels when used with other ingredients of similar refractive indeColloidal silicon dioxide adsorbs large quantities of water witout liquefying. The viscosity is largely independent of temperture. Changes in pH may affect the viscosity: it is most effectiat pH values up to about 7.5. At higher levels, the viscosity-icreasing properties are reduced at a pH greater than 10.7 and thsilicon dioxide dissolves to form silicates with no viscosity-in

creasing properties. Colloidal silicon dioxide (fumed silica) wform a gel when combined with 1-dodecanol and n-dodecan These are prepared by adding the silica to the vehicle and soncating for about one minute to obtain a uniform dispersion, seaing and storing at about 40°C overnight to complete gelation. Thgel is more hydrophobic in nature than the others.

Gelatin can be used to prepare gels by dispersing the gelatin hot water followed by cooling. As an alternative, moisten the gelat with about three to five part s of an organic liquid that will nswell the polymer, such as ethyl alcohol or propylene glycol folowed by the addition of the hot water and cooling. Magnesium aluminum silicate , Veegum, in concentrations

about 10%, forms firm, thixotropic gels. The material is inert anhas few incompatibilities but is best used above pH 3.5. It m

bind to some drugs and limit their availability. Methylcel lulose is a long-chain-substituted cellulose that c

be used to form gels in concentrations up to about 5%. Sinmethylcellulose hydrates slowly in hot water, the powder is dipersed with high shear in about one third of the required amouof water at 80 to 90°C. Once the powder is finely dispersed, threst of the water is added cold or as ice with moderate stirring cause prompt dissolution. Anhydrous alcohol or propylene glycmay be used to help prewet the powders. Maximum clarity, fullehydration and highest viscosity will be obtained if the gel




Table 2. Typical Properties of Selected Carbopol Pharmaceutical Resins.

Product Viscosity* Properties and Uses

Carbopol 910, NF 3,000-7,000 Effective in low concentrations; good ion tolerance

Carbopol 934, NF 30,500-39,400 Good stabil ity at high vi scos ity; good for thick formulations, such as medium-

to high-viscosity gels, emulsions and suspensions; good for zero-order release

Carbopol 934P, NF 29,400-39,400 of products, such as oral and mucoadhesive applications; excellent for

Carbopol 974P, NF 29,400-39,400 transdermals and topicals

Carbopol 940, NF 40,000-60,000 Excellent thickening efficiency at high viscosities and very good clarity; produce

sparkling clear water or hydroalcoholic topical gels

Carbopol 941, NF 4,000-11,000 Produces low-viscos ity, sparkling, c lear gels; good stabi lizer for emuls ions;

Carbopol 981, NF 4,000-11,000 effect ive in moderately ionic systems; more ef ficient than 934 and 940

at low-to-moderate concentrations

* Typical viscosities of 0.5% solutions, pH 7.5


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cooled to 0 to 10°C for about an hour. A pr es er va ti ve shou ld be ad de d. A 2%solution of methylcellulose 4000 has a gelpoint at about 50°C. High concentrationsof electrolytes will salt out the macro-molecules and increase their viscosity,ultimately precipitating the polymer.

Plastibase/Jelene is a 5% low-molecu-lar-weight polyethylene/95% mineral-oilmixture. The polymer is soluble in min-eral oil above 90°C, close to its meltingpoint. When cooled below 90°C, the poly-mer precipitates and causes gelation. Themineral oil is immobilized in the network of entangled and adhering insolublepolyethylene chains, which probably evenassociate into small crystalline regions. Thisgel can be heated to about 60°C without substantial loss of consistency.

Poloxamer , or Pluronic, gels are madefrom selected forms of polyoxyethylenepolyoxypropylene copolymers in concen-trations ranging from 15% to 50%. Polox-amers generally are white, waxy, free-flowinggranules that are practically odorless andtasteless. Aqueous solutions of poloxamersare stable in the presence of acids, alkalisand metal ions. However, they do support mold growth and should be preserved. Com-monly used poloxomers include the 124 (L-

44 grade), 188 (F-68 grade), 237 (F-87 grade),338 (F-108 grade) and 407 (F-127 grade)types, which are freely soluble in water. The“F” designation refers to the flake form of the product. The trade name Pluronic is usedin the United States by BASF Corporationfor pharmaceutical and industrial-gradepoloxamers. Pluronic F-127 has good sol-ubilizing capacity and optical properties andlow toxicity and is a good medium for top-ical drug-delivery systems.

Polyvinyl alcohol is used at concentra-tions of about 2.5% in the preparation of various jellies that dry rapidly when appliedto the skin. Borax is a good agent that willgel polyvinyl alcohol solutions. For bestresults, disperse polyvinyl alcohol in cold

water, followed by hot water. It is less sol-uble in the cold water.

Povidone, in the higher-molecular-weightforms, can be used to prepare gels in con-centrations up to about 10%. It has the ad- vantage of being compatible in solution witha wide range of inorganic salts, natural andsynthetic resins and other chemicals. It hasalso been used to increase the solubility ofa number of poorly soluble drugs.

Propylene glycol alginate is used as agelling agent in concentrations of 1% to5%, varying depending upon the specificapplication. The preparations are most sta-ble at a pH of 3 to 6 and should contain apreservative.

Sodium alginate can be used to producegels in concentrations up to 10%. Aque-ous preparations are most stable betweenpH values of 4 and 10; below pH 3, alginicacid is precipitated. Sodium alginate gelsfor external use should be preserved, forexample, with 0.1% chloroxylenol or theparabens. If the preparation is acidic, ben-zoic acid may be used. High concentrations

G E N E R A L I N T E R E S T



Lubricating Jelly Formula

Methylcellulose, 4000 cps 0.8%

Carbopol 934 0.24%

Propylene glycol 16.7%

Methylparaben 0.015%

Sodium hydroxide qs pH 7

Purified water qs ad 100%

1. Calculate the quantity of each in-gredient for the total amount to beprepared.

2. Accurately weigh or measure eachingredient.

3. Disperse the methylcellulose in 40mL of hot (80 to 90°C) water.

4. Chill overnight in a refrigerator toeffect solution.

5. Disperse the Carbopol 934 in 20mL water.

6. Adjust the pH of the dispersion to7.0 by adding sufficient 1% sodiumhydroxide solution (about 12 mL isrequired) and bring the volume to 40mL with purified water.

7. Dissolve the methylparaben in thepropylene glycol.

8. Mix the methylcellulose, Carbopol934 and propylene glycol fractionsusing caution to avoid incorporat-ing air.

9. Package and label.

Clear Carbomer Gel

Carbomer 934 0.5 g Triethanolamine 1.2 gGlycerin 34.2 gPropylene glycol 2.0 gPurified water qs 100 g



3. Disperse the Carbopol 934 in 20 mL

water.4. Add the triethanolamine and bringthe volume to 40 mL with purified water.

5. Add the other ingredients and mix well: add sufficient purified water to100 g.

6. Package and label.

Poloxamer Gel Base

Pluronic F-127, NF 20 g to 50 gPotassium sorbate, NF 0.2 gPurified water/buffer qs 100 mL



3. Add the powders and water to abottle and shake well.

4. Store in a refrigerator and the gel

will form.5. Package and label.

Examples


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will result in increased viscosity up to a point where the sodium alginate is salted out, oc-curring at about 4% with sodium chloride. Tragacanth gum has been used to pre-

pare gels that are most stable at pH 4 to 8. These gels must be preserved with either0.1% benzoic acid or sodium benzoate ora combination of 0.17% methylparabenand 0.03% propylparaben. These gels may be sterilized by autoclaving. Since pow-dered tragacanth gum tends to form lumps when added to water, aqueous dispersions

are prepared by adding the powder to vig-orously stirred water. Also, the use of ethanol,glycerin or propylene glycol to prewet thetragacanth is very effective. If other pow-ders are to be incorporated into the gel,they can be premixed with the tragacanthin the dry state.

Liqua-Gel™ (Paddock) is a nongreasy, water-soluble, liquid lubricating gel that can be used to dissolve or suspend a vari-ety of topically applied dermatologicalagents. It contains purified water, propy-lene glycol, glycerin, hydroxypropylmethylcellulose, and potassium sorbate.Sodium phosphate and boric acid are usedto buffer the gel to a pH of about 5.0.Diazolidinyl urea, methylparaben andpropylparaben are included as preserva-tives. Its viscosity is about 80,000 cpsat 25˚C; it is a clear, colorless, viscous gel

with a faint, characteristic odor.Quality Control

Quality control procedures include ap-pearance, uniformity, weight/volume, vis-cosity, clarity, pH and smell.

StorageGels should be stored at refrigerated or

room temperatures in tight containers. They

should be labeled to be kept tightly close

StabilityPhysical observations for gels inclu

shrinkage, separation of liquid from the gdiscoloration and microbial contaminatio Many gels will neither promote bacterior mold growth nor prevent it. Consquently, they should either be autoclavor contain preservatives. Gelling agents the dry state are usually not a problem.

Beyond-use dates for water-containinformulations are not later than 14 day when stored at cold temperatures, for proucts prepared from ingredients in solid form This is extended if there is supporting valscientific stability information. ■




Piroxicam 0.5%in an Alcoholic Gel

Hydroxypropylcellulose 1.75 g

70% isopropyl alcohol 98.25 mL

Propylene glycol 4.1 mL

Polysorbate 80 1.7 mL

Piroxicam 20-mgcapsules 25 capsule

No te : Piroxi cam powder can be used if

available.

1. Calculate the quantity of each ingredient for the total amount to be

prepared.2. Accurately weigh or measure each

ingredient.3. Make the hydroxypropylcellulose ge

by mixing the hydroxypropylcellu-lose in the alcohol until a clear geresults.

4. Make a paste with the piroxicam pow-der (from capsules), the propyleneglycol and the polysorbate 80.

5. Using geometric dilution, add thehydroxypropylcellulose gel and qsto 100 g.

6. Package and label. Note: It is important to use an alcoholicwater mixture, such as 70% isopropyalcohol, or a gel may not form.

Pluronic Lecithin Organogel(PLO Gel)

Lecithin and isopropylpalmitate liquid* 20 mL

Pluronic 20% gel 80 mL



3. Mix the two viscous liquids together well . A number of different tech-

niques can be used, including mix-ing in plastic bags, pushing back andforth between two syringes fitted witha syringe adapter or simply mixingin a mortar with a pestle. Minimizethe incorporation of air.

* The lecithin and isopropyl palmitateliquid consists of:Soy lecithin, granular 10 gIsopropyl pa lmitate, NF 10 g


2. Accurately weigh or measure eachingredient.3. Add the soy lecithin granules to the

isopropyl palmitate liquid and allow to set overnight.

4. Mix by rolling or gentle agitation,not shaking. Since the density ofthe isopropyl palmitate is about0.855, a volume of 11.7 mL can bemeasured.

Methylcellulose Gels

Methylcellulose 1500 cps 1% to 5%Purified water qs 100%



3. Add the methylcellulose to about 50mL of boiling purified water and dis-perse well.

4. Add the remaining purified water, ice

cold, to make a 100-mL volume of gel.5. Stir until uniform and thickened.6. Package and label.

The Basics of Compounding

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