THE APhA COMPLETE REVIEW FOR PHARMACY, 7th Ed

4. Compounding - Charles N. May, BSPh, MSHP

4-1. Introduction

Pharmacists extemporaneously compound medications to provide patients and prescribers more options for treatment and therapy than are provided by commercially available products. Patients need individualized custom-prepared medications for many reasons, including the following: (1) some therapeutic agents are not commercially manufactured; (2) some therapeutic agents are not manufactured in the form or size needed; (3) some manufactured therapeutic agents contain offending ingredients, such as dyes, preservatives, fillers, and binders; (4) some manufactured therapeutic agents contain offending flavors, fragrances, or colors; and (5) some patients do not fit into the standard categories that manufactured products treat. In addition, from time to time commercially manufactured products are unavailable for a variety of reasons, such as (1) the drug is recalled, (2) the manufacturing facility is closed down, (3) a strike or disaster occurs, (4) the product is no longer commercially profitable, or (5) the manufacturer no longer supplies the product for other corporate reasons. Several segments of the population are not properly served by pharmaceutical manufacturers, including pediatric patients, geriatric patients, veterinary patients, and patients with rare or very complicated disease states. Prescribers and pharmacists working very closely with patients improve the quality of life for those patients as no other practice can.

4-2. Philosophy of Compounding

• Compounding is extemporaneous per patient.

• It fulfills needs for unique dosage forms and sizes.

• The pharmacist works as part of a three-member team—the patient, the pharmacist, and the prescriber—to satisfy a patient's unique needs that cannot be satisfied by commercially available products.

• The pharmacist follows up with the patient, the prescriber, or both to determine if the compounded preparation needs further adjustment or refinement to completely satisfy the patient's needs.

4-3. Compounding versus Manufacturing

Compounding

• Compounded preparations are patient specific in conjunction with the prescriber.

• They are regulated by the state board of pharmacy.

• Compounded preparations are not advertised.

• Compounded preparations have beyond-use dates.

• Compounded preparations are not prepared in advance except in the case of documented usage or demand.

• Compounded preparations have no National Drug Code (NDC) number.

Manufacturing

• Products are subject to an approved New Drug Application (NDA).

• Products are subject to U.S. Food and Drug Administration (FDA)-approved labeling.

• Products are manufactured in FDA-approved plants in accordance with good manufacturing practices.

• Products may be advertised.

• Products carry an expiration date.

• Products carry an NDC number.

• Products are regulated by the FDA.

4-4. Guidelines for Compounding

The following are published guidelines pharmacists use in designing and carrying out their compounding activities. Pharmacists' compounding practices are regulated by the laws of the state board of pharmacy of the state in which the pharmacist practices.

Allen LV Jr. Extemporaneous prescription compounding. In: Remington: The Science and Practice of Pharmacy, 21st ed. Baltimore: Lippincott Williams & Wilkins; 2006:1903-12.

National Association of Boards of Pharmacy. Good Compounding Practices Applicable to State Licensed Pharmacies. Park Ridge, Ill.: National Association of Boards of Pharmacy; 1993.

U.S. Food and Drug Administration. Pharmacy compounding. In: Compliance Policy Guide, Compliance Policy Guidance for FDA Staff and Industry. Washington, D.C.; 2002. Section 460. 200.

U.S. Pharmacopeial Convention. Good compounding practices: chapter 1075. In: U.S. Pharmacopeia 32/National Formulary 27. Rockville, Md.: U.S. Pharmacopeial Convention; 2009:523-26.

U.S. Pharmacopeial Convention. Pharmaceutical calculations in prescription compounding: chapter 1160. In: U.S. Pharmacopeia 32/National Formulary 27. Rockville, Md.: U.S. Pharmacopeial Convention; 2009:674-83.

U.S. Pharmacopeial Convention. Pharmaceutical compounding-nonsterile preparations: chapter 795. In: U.S. Pharmacopeia 32/National Formulary 27. Rockville, Md.: U.S. Pharmacopeial Convention; 2009:314-18.

U.S. Pharmacopeial Convention. Prescription balances and volumetric apparatus: chapter 1176. U.S. Pharmacopeia 32/National Formulary 27. Rockville, Md.: U.S. Pharmacopeial Convention; 2009:691-92.

U.S. Pharmacopeial Convention. Quality assurance in pharmaceutical compounding: chapter 1163. In: U.S. Pharmacopeia 32/National Formulary 27. Rockville, Md.: U.S. Pharmacopeial Convention; 2009:684-86.

4-5. Requirements

Pharmacy

Space

• An appropriate amount is required; a dedicated area is ideal.

• Space should be properly arranged and maintained, with ingredients and equipment close at hand.

• A controlled atmosphere is necessary, with limited traffic flow and air flow away from operator.

• Separate areas are needed for sterile and nonsterile compounding.

• A source of potable water and purified water (i.e., sink) should be readily available.

• Facility should be constructed of materials that are as nonporous and seamless as possible; a well lit space with bright fixtures, walls, and floors gives a clean, professional appearance.

Equipment

• Appropriate measuring devices are required (e.g., graduated cylinders, pharmacy graduates, pipettes).

• Appropriate balances for weighing are necessary (e.g., an electronic balance or class A prescription balance).

• Appropriate mixing devices are required (e.g., Wedgwood, porcelain, and glass mortars and pestles, blenders).

• Appropriate counters and shelves are needed; sufficient countertop space must be available so that compounding will not be cramped, and shelving must be sufficient and appropriately located so that ingredients can be convenient and properly stored.

• Appropriate processing equipment is necessary (e.g., hot plates and magnetic stirrers, ointment mills, electronic mortar and pestle, tablet pulverizers).

• Appropriate safety equipment must be available (e.g., rubber gloves, face masks, hair covers, gowns, and goggles for personnel; devices that gently exhaust the air from the work area to keep the air free of contamination with ingredients; and containment areas for personnel who are working with light, fine, fluffy ingredients or ingredients that are irritating or foul smelling).

• Appropriate packaging equipment is required (e.g., capsule-filling machines, tube-sealing equipment, calibrated measuring and filling devices)

• Appropriate computer equipment should be available (e.g., for processing labels, profiles, and formulas and for maintaining required records regarding ingredients)

Formulas

Ingredient classification and quality

• USP/NF: United States Pharmacopeia/National Formulary (ingredients meet official standards and are suitable for human use)

• FCC: Food Chemicals Codex (food grade)

• ACS: American Chemical Society (reagent grade)

• AR: analytical reagent (high purity)

• CP: chemically pure (uncertain quality)

• Tech: technical (industrial quality)

Supplies

• Supplies include weigh boats, weighing paper (parchment and glassine), filter paper, ointment paper, spatulas (stainless steel and hard rubber), stirring rods (glass and polypropylene), rubber scrapers, beakers, flasks, funnels, casseroles, and containers of all types and sizes to properly package all the unique dosage forms and sizes patients require.

• Supplies also include all sizes of prescription bottles, powder jars, capsule vials, and ointment jars as well as ointment tubes, troche molds, plastic suppository molds, powder paper boxes, suppository boxes, "ride-up" tubes, and so forth.

Records

• An exact record of each compounded prescription must be made and maintained.

• A chronological record of each day's compounding activity should be made and kept for future reference and use.

• A Master Formula card must be in place for each preparation compounded, and it must be approved by and signed and dated by the pharmacist in charge.

Policies and procedures

• Standard operating procedures (SOPs)

• Material safety data sheets (MSDSs)

• Certificates of analysis (COAs)

• Quality assurance checks

• Other policies and procedures

The Pharmacist

• Interest: A distinct interest in being creative, solving difficult patient problems, working closely with prescribers and patients, and formulating and compounding special customized medications is very important.

• Education: The emphasis on compounding varies among colleges of pharmacy. Even graduates of programs that require students to compound a wide variety of formulations may find that they need more training.

• Training: Additional training is often obtained through continuing education courses, seminars, professional development programs, or professional associations.

• Experience: Experience in compounding is perhaps the key to how effective a pharmacist can be in creating special formulations that make a significant difference in a patient's life when everything else up to that point has failed. It enables the pharmacist to suggest to the prescriber a therapeutic agent in a unique dosage form that has a better chance of solving the patient's problem. Conversely, a pharmacist with less-than-optimal experience and interest may compound a medication that is not effective and thus not satisfy the patient's need—and perhaps may even undermine the prescriber's confidence in all compounded medications. Pharmacists who compound must be certain that they possess the appropriate requisites for the level of compounding they perform.

• Compounding support: Compounding pharmacists should join professional organizations that support compounding such as the International Academy of Compounding Pharmacists. They should subscribe to journals that focus on compounding such as the International Journal of Pharmaceutical Compounding or the U.S. Pharmacist. They should also use the professional resources of the companies that fulfill their compounding needs.

Professional Considerations

• Is there a commercially available product in the exact dosage, size, form, and package needed?

• Is there an alternative product that will completely satisfy the patient's requirements?

• Can I do the required pharmaceutical calculations to make and package the preparation?

Quality Control Requirements

• Accurate calculations

• Accurate weights

• Accurate measurements

• Proper processing techniques

• Proper packaging

• Proper records

• Proper labeling, including beyond-use date

Beyond-Use Dates

• Pharmacists assign beyond-use dates to compounded preparations to provide patients with guidance in the proper use of the preparation.

• The goal is to provide a beyond-use date that will allow the patient enough time to fully use the amount of preparation dispensed, but not enough time to allow the preparation to degrade or lose potency or be stored for future use.

• If the pharmacist does not have a reference on stability of the specific dosage form or if experience with it is insufficient, the USP guidelines are followed.

4-6. Compounded Preparations

Solutions

• Definition: Solutions are chemically and physically homogenous mixtures of two or more substances.

• Types: Solutions can be syrups, elixirs, aromatic waters, tinctures, spirits, nonaqueous, and so forth.

• Properties: Solutions are hypertonic, isotonic, hypotonic, osmolar, osmolal, and so forth.

• Stability: Stability of solutions is enhanced by adjusting pH or adding preservatives, antioxidants, and so forth.

• Rate of dissolution: The rate of dissolution is enhanced by stirring, heat, particle-size reduction, and so forth.

• Beyond-use dates: Aqueous solutions have short beyond-use dates.

• Testing: Organoleptic, pH, and other testing is performed.

An example of an isotonic aqueous solution follows:

Ephedrine sulfate

1%

 

Sodium chloride

qs

 

Purified water, qs ad

30 mL

 

M.ft. isotonic solution

 
 

Steps in compounding are as follows:

1. Calculate the required quantity of each ingredient (NaCl equivalent of ephedrine sulfate is 0.2).

2. Accurately weigh or measure each ingredient.

3. Dissolve the solid ingredients in about 25 mL of purified water.

4. Add sufficient purified water to measure 30 mL.

The following is an example of a nonaqueous solution:

Urea

10 g

 

Salicylic acid

5 g

 

Coal tar solution

5 mL

 

Propylene glycol, qs ad

100 mL

 

Steps in compounding are as follows:

1. Accurately weigh or measure each ingredient.

2. Dissolve the urea and salicylic acid in about 75 mL of propylene glycol.

3. Add the coal tar solution and mix well.

4. Add sufficient propylene glycol to measure 100 mL.

Note: If using a mechanical stirrer, it may take significant time to dissolve the urea and salicylic acid.

Suspensions

• Definition: A suspension is a two-phased system containing a finely divided solid in a vehicle.

• Requirement: Drug is uniformly dispersed throughout vehicle.

• Concentration: Suspending agents are typically used in a concentration of 0.5-6.0%.

• Viscosity: The vehicle has enough viscosity to keep drug particles suspended separately.

• Insolubility: The active ingredient is insoluble in vehicle.

• Tip: Wet insoluble powder with vehicle-miscible liquid.

• Advantage: A suspension allows the preparation of a liquid form of an insoluble drug.

• Stability: Stability is enhanced by adding a preservative.

• Testing: Organoleptic, pH, and other testing is performed.

Categories of suspending agents

• Natural hydrocolloids: Acacia, alginic acid, gelatin, guar gum, sodium alginate, tragacanth, xanthan gum

• Semisynthetic hydrocolloids: Ethylcellulose, methylcellulose, sodium carboxymethylcellulose

• Synthetic hydrocolloids: Carbomers (Carbopol), poloxamers (Pluronic), polyvinyl alcohol, polyvinylpyrrolidone

• Clays: Bentonite, magnesium aluminum silicate (Veegum)

An example of an oral suspension follows:

Progesterone, micronized

1.2 g

 

Glycerin

3 mL

 

Methylcellulose 2% solution

30 mL

 

Flavored syrup, qs ad

60 mL

 

Steps in compounding are as follows:

1. Accurately weigh or measure each ingredient.

2. In a glass mortar, wet the progesterone with the glycerin, making a thick paste.

3. Slowly add the methylcellulose solution while triturating.

4. When mixed thoroughly, pour into a graduate.

5. Add small amounts of syrup in mortar, mix, and add to graduate until the desired volume is reached.

Emulsions

• Definition: An emulsion is a two-phase system of two immiscible liquids, one of which is dispersed throughout the other as small droplets.

• Components: An emulsion has a dispersion medium or external or continuous phase, an internal or discontinuous or dispersed phase, and an emulsifying agent.

• Type: Types are oil in water (o/w) and water in oil (w/o), depending on which is the internal and which is the external phase

• Emulsifying agents: Emulsifying agents can be natural gums (acacia, agar, chondrus, pectin, tragacanth) or hydrophilic or lipophilic agents (the esters of sorbitan)

• Lipophilic agents: Trade names for lipophilic agents include Arlacel and Span

• Hydrophilic agents: Trade names for hydrophilic agents include Myrj and Tween

• Hydrophilic-lipophilic balance: A lower hydrophilic-lipophilic balance (HLB) value favors a w/o emulsion; a higher HLB value favors an o/w emulsion. Agents with an HLB value of 1-9 are considered to be lipophilic; agents with an HLB value of 10 and above are considered to be hydrophilic.

• Other agents: Other agents include bentonite, cholesterol, gelatin, lecithin, methylcellulose, soaps of fatty acids, sodium docusate, sodium lauryl sulfate, and triethanolamine.

• Equipment: Equipment includes mortar and pestle, homogenizers, colloid mill, mechanical mixers, agitators, and ultrasonic vibrators.

• Solids: Solid ingredients should be dissolved before they are incorporated into the emulsion, or if a sizable quantity is added, a levigating or wetting agent may be needed.

• Flavors: Flavors should be incorporated into the external phase.

• Preservatives: Preservatives should be added in the aqueous phase; they may also be added in the oily phase, if necessary.

• Stability: Emulsions either cream or crack.

• Continental method: The Continental or dry gum method of preparing an emulsion nucleus involves using the oil:water:dry gum emulsifier in a 4:2:1 ratio.

• Advantages: An emulsion can be used to mask taste, improve palatability, increase absorption, and enhance bioavailability.

• Testing: Organoleptic testing is performed.

An example of preparing an emulsion by the Continental or dry gum or 4:2:1 method follows:

Cod liver oil

50 mL

 

Acacia

12.5 g

 

Syrup

10 mL

 

Flavor oil

0.4 mL

 

Purified water, qs ad

100 mL

 

Steps in compounding are as follows:

1. Accurately weigh or measure each ingredient.

2. Place the cod liver oil in a dry mortar.

3. Add the acacia and give it a very quick mix.

4. Add 25 mL of purified water and immediately triturate rapidly to form the thick, white, homogenous emulsion nucleus.

5. Add the flavor and mix thoroughly.

6. Add the syrup and mix thoroughly.

7. Add sufficient purified water to measure 100 mL.

Capsules

• Definition: This dosage form incorporates ingredients into a shell called a capsule.

• Procedure: Triturate powders to reduce particle size, mix powders by geometric dilution, incorporate diluent by geometric dilution, calculate total weight to fit a certain size capsule, and clean the outside of the filled capsules.

• Advantages: Capsules mask unpleasant taste; allow the mixture of ingredients that could not be mixed in other vehicles; alter the release rate of ingredients; incorporate several ingredients into one dosage form; provide an accurate dosage size for liquids, semisolids, and powders; and provide a dosage form that is easier to swallow and more acceptable to the patient.

• Methods of filling: Hand punch from powder on pill tile; use a capsule-filling machine.

• Sizing: Determining the size of capsule to use for a particular dosage size involves assessing the density or fluffiness of the powder, comparing it to known weights of various reference powders with published capsule size capacities, and then actually weighing the capsule. If the requested dosage does not fill a specific size capsule, a filler should be added.

• Testing: Organoleptic, weight percent error, weight variance, and other testing is performed.

An example of an altered-release capsule follows:

Progesterone, micronized

25 mg

 

Methocel E4M

50%

 

Lactose, qs ad

 
 

M.ft. capsules

Make 15 doses

 

Steps in compounding are as follows:

1. Select capsule size and calculate the required quantity of each ingredient.

2. Accurately weigh each ingredient.

3. If necessary, reduce particle size, and mix thoroughly.

4. Fill capsules.

5. Weigh capsules, calculate average weight, and determine percentage of error.

Tablet Triturates (Sublingual or Molded Tablets)

• Definition: A tablet triturate is a small tablet that is made in a mold and intended for sublingual administration. It usually weighs about 30-250 mg.

• Advantages: A tablet triturate rapidly dissolves under the tongue, is rapidly absorbed, avoids first pass through liver, and provides a rapid therapeutic response.

• Components: Tablet triturates consist of an active ingredient and a base, which may consist of lactose, sucrose, dextrose, mannitol, and so forth.

• Formulation: On the basis of the size of the mold cavities, mix the active ingredient with the base, which often consists of four parts lactose and one part sucrose. Thoroughly triturate powders, mix by geometric dilution, and then moisten with a solution containing four parts alcohol and one part purified water until the powder mixture is adhesive. Press into mold.

• Testing: Organoleptic, weight percent error, weight variance, and other testing is performed.

• Tip: Tablets may be flavored and colored by adding flavor and color to the wetting solution.

An example of a tablet triturate follows:

Testosterone

3 mg

 

Base, qs ad

 
 

M.ft. tabs

 
 

Steps in compounding are as follows:

1. The base may consist of a 1:4 mixture of sucrose and lactose.

2. The wetting solution may consist of a 1:4 mixture of water and alcohol.

3. On the basis of the size mold and the number of tablets it makes, calculate the required quantity of each ingredient.

4. Accurately weigh or measure each ingredient.

5. Reduce particle size and mix ingredients by geometric dilution.

6. In a glass mortar, gradually moisten the powder mixture until it becomes adhesive. Note: Drop the wetting solution onto the powder a few drops at a time and triturate after each addition until powder becomes moist and adhesive.

7. Press moist powder evenly into all holes in the tablet triturate mold plate.

8. Place the mold plate on the base plate and press down until the tablets rest on top of the pegs.

9. Let tablets air dry.

10. Very gently remove dried tablets from pegs.

Troches, Lozenges, and Lollipops (Suckers)

• Definition: Troches, lozenges, and lollipops are solid dosage forms intended to be slowly dissolved in the mouth for local or systemic effects.

• Formulation: Troches, lozenges, and lollipops are composed of an active ingredient and a base that may consist of (1) sugar and other carbohydrates that produce a hard candy troche, (2) polyethylene glycols and other ingredients that produce a softer troche, or (3) a glycerin-gelatin combination that produces a chewable troche.

• Formulations made in a sucker mold complete with sticks are called lollipops or suckers.

• Formulations must be calculated to fit the size mold that will be used.

• Flavors and colors are added just before the molds are filled.

• Advantages: Troches, lozenges, and lollipops are easy to administer, are convenient for patients who cannot swallow oral dosage forms, maintain a constant level of drug in the oral cavity and throat, and have a pleasant taste.

• Testing: Organoleptic, weight percent error, weight variance, and other testing is performed.

An example of a troche follows:

Gelatin

4.68 g

 

Glycerin

16.70 mL

 

Purified water

2.30 mL

 

Acacia

0.50 g

 

Bentonite

0.50 g

 

Benzocaine

0.30 g

 

Citric acid

0.66 g

 

Saccharin sodium

0.17 g

 

Flavor and color

qs

 

Steps in compounding are as follows:

1. Depending on the size of the mold to be used and the number of troches to be made, calculate the required quantity of each ingredient.

2. Accurately weigh or measure each ingredient.

3. Heat the glycerin in a boiling water bath for several minutes.

4. Add the water and heat for a few more minutes.

5. While stirring, very slowly add the gelatin. Note: Gelatin must be lump free; the mixture must be homogeneous.

6. Triturate and thoroughly mix the powders.

7. Add the powders to the warm liquid and mix thoroughly.

8. Add flavor and color, mix, pour into the mold, and let cool.

Transdermal Gels

• Definition: Transdermal gels move medications through the skin in quantities sufficient to produce a therapeutic effect.

• Components: Transdermal gels have the following components:

• Active ingredient or ingredients

• Gelling agents: the carbomers (e.g., Carbopol 934P); methylcellulose; the poloxamers (e.g., Pluronic F-127); sodium carboxymethylcellulose; and so forth

• Wetting or levigating agents: propylene glycol, glycerin, and so forth

• Penetration-enhancing agents: water, alcohol, lecithin, dimethyl sulfoxide, isopropyl myristate, isopropyl palmitate, propylene glycol, polyethylene glycol, and so forth

• Suspending or dispersing agents: bentonite, silica gel, and so forth

• Testing: Organoleptic testing is performed.

• Advantages: Transdermal gels are convenient and effective, have great acceptability to patients, and avoid problems other dosage forms have such as gastrointestinal irritation from oral dosages, pain from injections, and undesirability of suppositories

• Formulation: Use proper techniques for creating the gel, adjust the pH for carbomer gels, respect the temperature for poloxamer gels, use small amounts of nonaqueous solvents, and if possible keep electrolyte ingredients to a minimum.

• Tip: Do not use transdermal gels for the systemic use of antibiotics, and do not try to get large molecules such as proteins through the skin via transdermal gels.

An example of a transdermal gel using carbomer as the base follows:

Ketoprofen

5%

 

Carbomer 934P

2%

 

Alcohol

qs

 

Trolamine

2 mL

 

Purified water, qs ad

30 mL

 

Steps in compounding are as follows:

1. Calculate the required quantity of each ingredient.

2. Accurately weigh or measure each ingredient.

3. Triturate the carbomer 934P in a glass mortar.

4. While triturating, gradually add about 18 mL of purified water.

5. Be sure the carbomer and water are thoroughly mixed and the mixture is homogenous.

6. Dissolve the ketoprofen in about 10 mL of alcohol.

7. While triturating, add this solution to the carbomer-water mixture, and mix thoroughly.

8. If necessary, add purified water to make about 28 mL and pour into the ointment jar.

9. Add trolamine and stir quickly with a stirring rod until the gel is thoroughly formed.

Note: A trade name for carbomer 934P is Carbopol 934P.

An example of a transdermal gel using organogel (PLO) as the base follows:

Ketoprofen

5%

 

Propylene glycol

10%

 

Lecithin isopropyl palmitate liquid

20%

 

Poloxamer 407 20% gel, qs ad

100 mL

 

Steps in compounding are as follows:

1. Calculate the required quantity of each ingredient.

2. Accurately weigh or measure each ingredient.

3. In a glass mortar, triturate the ketoprofen with the propylene glycol.

4. Make a smooth uniform paste.

5. Add the lecithin isopropyl palmitate liquid and mix well.

6. Add sufficient poloxamer 407 20% gel to measure 100 mL.

7. Triturate until a high-quality gel is produced.

8. Package in a light-resistant container.

Note: The lecithin isopropyl palmitate liquid and the poloxamer 407 20% gel should be prepared ahead of time so that they are ready for use.

The lecithin isopropyl palmitate liquid may be prepared as follows:

Soy lecithin, granular

10.0 g

 

Isopropyl palmitate

10.0 g

 

Sorbic acid

0.2 g

 

1. Accurately weigh or measure each ingredient.

2. Add the soy lecithin granules and the sorbic acid to the isopropyl palmitate, mix well, and allow to set overnight at room temperature.

3. The next morning, very gently stir to ensure complete mixing.

Note: Isopropyl myristate may be used in place of isopropyl palmitate.

The poloxamer 407 20% gel may be prepared as follows:

Poloxamer 407

20.0 g

 

Potassium sorbate

0.2 g

 

Purified water, qs ad

100 mL

 

1. Accurately weigh or measure each ingredient.

2. Add the poloxamer 407 and the potassium sorbate to a portion of the purified water, mix well, and add purified water to make 100 mL.

3. Mix thoroughly, ensuring that the poloxamer 407 is completely wet.

4. Allow to set overnight in the refrigerator.

5. The next morning, stir slowly to be sure mixing is complete.

6. Store in the refrigerator.

Note: A trade name for poloxamer 407 is Pluronic F-127.

Suppositories

• Definition: Suppositories are solid dosage forms for insertion into the rectum, vagina, or urethra to provide localized therapy or systemic therapy.

• Sizes: Rectal suppositories are approximately 2 g, vaginal suppositories are 3-5 g; and urethral suppositories are 2 g (female) or 4 g (male). Note: Urethral suppositories were formerly called bougies.

• Formulation: Suppositories are usually made by fusion with either a fatty or water-miscible base. They can also be hand molded or made by compression.

• Suppositories are usually made in a metal or plastic mold.

• The active ingredients in powder form should be triturated (comminuted) to reduce particle size and should be levigated with a levigating or wetting agent before incorporation into the melted base.

• The melted formulation should be poured continuously into the mold to prevent layering.

• Calculations: The capacity in grams of the suppository mold must be known to determine the quantity of base needed. (If this capacity is not known, the capacity must be determined by filling the mold with the suppository base and weighing the resulting suppositories.) The space in the suppository occupied by the active ingredient or ingredients must calculated using the density factor of each active ingredient. (If the density factor is not known, it can be calculated by making a suppository containing a known amount of the active ingredient.)

• Advantages: Suppositories deliver medication for local or systemic effects. (The systemically absorbed medication avoids the first pass through the liver.) They can be used when patients cannot take medication orally or by injection.

• Testing: Organoleptic, weight percent error, weight variance, and other testing is performed.

An example of a rectal suppository follows:

Progesterone, micronized

25 mg

 

Polyethylene glycol base

qs

 

M.ft. supp

dtd #12

 

Use the following formula for the polyethylene glycol base:

Polyethylene glycol 300

50%

 

Polyethylene glycol 6000

50%

 

Steps in compounding are as follows:

1. On the basis of the size of the mold, calculate the required amount of each ingredient.

2. Accurately weigh or measure each ingredient.

3. Carefully heat the polyethylene glycol 6000 until it melts.

4. Add the polyethylene glycol 300 and mix well.

5. Very slowly add the micronized progesterone and mix thoroughly.

6. Pour the mixture into the suppository mold.

Note: When using the plastic molds (shells), the liquid mixture must not be too hot.

Powders

• Definition: Powders are fine particles that result from the comminution of dry substances. Particle sizes are usually determined by the size sieve they will pass through and may be described as very coarse, coarse, moderately coarse, fine, and very fine.

• Mixtures: Mixtures of powders should have the same size or similar size particles, and mixing should be accomplished by geometric dilution.

• Preparation: Comminution is the process of reducing particle size in powders. It is accomplished manually by trituration, levigation, or pulverization by intervention and mechanically by grinders and various types of mills.

• Uses: Powders taken by mouth may provide systemic effects. Powders are applied topically for local effects. Powders that contain mucoadhesive ingredients, when insufflated into body cavities, will adhere to moist body surfaces.

• Advantages: Because they are dry, powders often have greater stability, and they may not react with ingredients with which they are otherwise incompatible (except explosive mixtures). Once in the gastrointestinal tract, they are ready to be absorbed, and they tend to have longer beyond-use dates.

• Testing: Organoleptic testing is performed.

An example of a powder for external use follows:

 
 

Zinc oxide, of each

8%

 

Red mercuric oxide

1%

 

Magnesium oxide, heavy, qs ad

60 g

 

M.ft. powder

 
 

Steps in compounding are as follows:

1. Calculate the required amount of each ingredient.

2. Accurately weigh each ingredient.

3. Thoroughly mix the powders by geometric dilution.

4. If using a mortar and pestle, use a porcelain mortar and begin with the ingredient having the smallest weight.

5. Use the "spread test" to determine when the mixture is totally homogeneous.

Powder Papers (Charts)

• Definition: Powders or mixtures of powders are enfolded in papers containing one dose each and dispensed in an appropriate box or container.

• Preparation: Powders are finely subdivided (comminuted) and mixed by geometric dilution, and a dose of the appropriate size is placed on a powder paper and properly folded. The appropriate size can be obtained by weighing. An alternate method is to place all the powder on a pill tile and to "block and divide" the powder into the proper number of doses, placing one dose on each powder paper.

• Advantages: For patients who cannot swallow, those who have difficulty swallowing certain tablets or capsules, and those who have indwelling nasogastric tubes, powder papers provide an ideal dosage form. Several medications can be given as one dose. The medication is in powder form and ready to be absorbed once it is in the gastrointestinal tract. For patients who have many medications to take each day, they may be combined into a smaller number of powder papers. Powder papers have longer beyond-use dates than many other compounded dosage forms.

• Testing: Organoleptic, weight percent error, weight variance, and other testing is performed.

An example of a powder paper (chart) follows:

Aspirin

3.5 grains

 

Acetaminophen

2.5 grains

 

Caffeine

0.5 grains

 

M.ft. chart

dtd #12

 

Steps in compounding are as follows:

1. Calculate the required quantity of each ingredient.

2. Accurately weigh each ingredient.

3. Triturate each ingredient separately to reduce particle size.

4. Thoroughly mix the ingredients by geometric dilution.

5. Weigh the correct amount for each chart on a separate paper.

6. Properly fold each paper and place it in the powder box.

Ointments and Creams

• Definition: Ointments and creams are semisolid dosage forms for external application. Properties are typically characteristic of the base selected (e.g., white petrolatum, hydrophilic petrolatum, cold cream, hydrophilic ointment, polyethylene glycol ointment). Ointments and creams protect the skin and mucous membranes, moisturize the skin, and provide a vehicle for various types of medications. Types and classifications include oleaginous or hydrocarbon, absorption, emulsion, and water soluble.

• Characteristics of an oleaginous or hydrocarbon ointment base: Such a base

• Is occlusive—white petrolatum

• Is greasy—white ointment

• Is an emollient—vegetable shortening

• Is not water washable

• Will not absorb water

• Is insoluble in water

• Characteristics of an absorption ointment base: Such a base

• Is occlusive—hydrophilic petrolatum

• Is greasy—lanolin, USP (anhydrous)

• Is an emollient—Aquaphor

• Is not water washable—Aquabase

• Can absorb water

• Is insoluble in water

• Characteristics of an emulsion, w/o ointment base: Such a base

• Is occlusive—cold cream

• Is greasy—rose water ointment

• Is an emollient—Eucerin

• Is not water washable—hydrous lanolin

• Will absorb water—hydrocream

• Is insoluble in water—Nivea

• Characteristics of an emulsion, o/w ointment base: Such a base

• Is nonocclusive—hydrophilic ointment

• Is nongreasy—acid mantle cream

• Is water washable—Cetaphil

• Will absorb water—Dermabase

• Is insoluble in water—Keri lotion, Lubriderm, Neobase, Unibase, vanishing cream, Velvachol

• Characteristics of water-soluble ointment bases

• Is nonocclusive—polyethylene glycol ointment

• Is nongreasy—Polybase

• Is water washable

• Will absorb water

• Is water soluble

• Preparation: Ointments are typically prepared by fusion or levigation. Powders should be comminuted to fine particles; some powders may be dissolved. If using the fusion method, use only enough heat to melt the ingredient with the highest melting point. For the levigation method, an ointment slab and metal spatula usually work well. Levigating agents should be carefully selected, considering both the ingredient or ingredients to be incorporated and the base.

Table 4-1 shows commonly used levigating agents grouped by type and matched with the appropriate group of ointment base classifications.

• Uses: Ointments or creams are an effective dosage form for treating skin and mucous membranes. On occasion, an ointment or cream will move sufficient quantities of medication through the skin to produce a systemic effect. Some formulations provide effective protection for the skin and mucous membranes.

[Table 4-1. Levigating Agents by Type and Ointment Base Classification]

• Packaging: Typically, ointments and creams are packaged in ointment jars. The tube is often an ideal alternative package because it protects the preparation until it is squeezed out and used.

• Testing: Organoleptic, homogenicity, and other testing is performed.

An example of a nongreasy ointment follows:

Benzoyl peroxide

10%

 

Sulfur

1%

 

Polyethylene glycol base, qs ad

30 g

 

Steps in compounding are as follows:

1. Calculate the required quantity of each ingredient. Benzoyl peroxide, hydrous, USP contains about 26% water. The polyethylene glycol base consists of

Polyethylene glycol 400

65%

 

Polyethylene glycol 3350

35%

 

2. Accurately weigh or measure each ingredient.

3. Triturate each powder to a fine particle size.

4. Melt the polyethylene glycol 3350 and remove it from the heat source.

5. Add the polyethylene glycol 400 and mix thoroughly.

6. Add the powders and mix thoroughly.

7. Before the preparation begins to harden, stir thoroughly and pour into the ointment jar.

An example of a greasy ointment follows:

Salicylic acid

3%

 

White petrolatum, qs ad

30 g

 

Steps in compounding are as follows:

1. Calculate the required quantity of each ingredient.

2. Accurately weigh each ingredient.

3. Triturate the salicylic acid to reduce particle size.

4. Levigate with a small quantity of mineral oil.

5. By geometric dilution, incorporate the levigated salicylic acid into the white petrolatum.

The following is an example of a cream:

Almond oil

56.0 g

 

White wax

12.0 g

 

Light mineral oil

10.0 g

 

Cetyl esters wax

2.5 g

 

Sodium borate

0.5 g

 

Purified water

19.0 g

 

Total

100.0 g

 

M.ft. cream, S.A.

 
 

Steps in compounding are as follows:

1. Accurately weigh or measure each ingredient.

2. Melt the white wax.

3. Add the cetyl esters wax, almond oil, and light mineral oil.

4. Bring to a temperature of 70°C.

5. Dissolve the sodium borate in the purified water.

6. Bring to a temperature of 70°C.

7. With both liquids at 70°C, mix and stir.

8. Stir until the cream is completely formed.

9. Package in a tube or jar.

Sticks

• Definition: This topical dosage form is made in the shape of a rod or stick or variation thereof and packaged in a container that allows it to be advanced upward as it is used or consumed.

• Advantages: Sticks are an effective, convenient method of applying a topical agent exactly in the location desired. They can deliver a variety of agents—including those that are therapeutic, protective, and cosmetic—and they are very portable.

• Preparation: Select a semisolid vehicle from a variety of polyethylene glycols, waxes, and oils that will produce the consistency desired. Triturate solid ingredients, wet them with an appropriate wetting or levigating agent, and add them along with any liquid ingredients to the melted vehicle. Mix thoroughly. Pour into an appropriate "ride-up" container.

• Testing: Organoleptic testing is performed.

• Tip: Sticks can usually be considered a stable dosage form and assigned a corresponding beyond-use date.

An example of a stick follows:

Menthol

1.00%

 

Camphor

0.50%

 

Phenol

0.25%

 

Flavor

qs

 

Color

qs

 

Polyethylene glycol 400

7 g

 

Polyethylene glycol 4500

3 g

 

Steps in compounding:

1. Calculate the required quantity of each ingredient.

2. Accurately weigh or measure each ingredient.

3. Melt the polyethylene glycol 4500.

4. Remove from heat source.

5. Add the polyethylene glycol 400 and mix thoroughly.

6. Mix the menthol, camphor, and phenol together; they will liquefy, forming a eutectic mixture.

7. Add the eutectic mixture and the other ingredients and mix thoroughly.

8. Pour into a "ride-up" lip balm tube and let cool.

4-7. Quality Assurance and Preparation Testing

The assurance of high quality influences every facet of compounding. The atmosphere, the area design, the fixtures, the equipment and apparatus, the components, the containers, the expertise and experience of the personnel, the policies and procedures, and many other factors play important roles for achieving the highest quality possible in the compounding of individualized, customized preparations. Perhaps the most important element is commitment—the commitment of each individual who plays any role in the compounding process. This commitment must be of such intensity that the individual will not vary from the correct way of performing every function every time in everything.

Preparation testing must be in place for every compounded preparation. Chapter 1163 in the U.S. Pharmacopeia 32/National Formulary 27 has a table that shows what types of tests can be performed on every type of compounded preparation. The compounding process of each type of dosage form should include all applicable tests that must be performed each time the dosage form is compounded.

The ultimate test of quality for a compounded preparation consists of having the preparation analyzed by a competent analytical laboratory. The typical goal is to have the contents of the preparation vary no more than plus or minus 5% of the potency stated on the label.

An indicator that the compounding pharmacy is committed to a high-quality practice is accreditation by the Pharmacy Compounding Accreditation Board (PCAB). The PCAB is national in scope, and it very carefully evaluates all aspects of the pharmacy operation and ensures that policies and procedures are in place and operational for a very high-quality practice.

PCAB accreditation is currently the only benchmark available to attest to the quality of a compounding pharmacy. PCAB accreditation should be the goal of every pharmacy that provides compounded preparations.

4-8. Key Points

• Each extemporaneously compounded prescription is for a specific patient.

• Three parties are involved in extemporaneous compounding: the prescriber, the patient, and the pharmacist.

• A thorough knowledge of and proficiency in pharmacy math is required for the extemporaneous compounding of prescriptions.

• The sensitivity of the pharmacy balance must be determined, and the minimum weighable quantity calculated for that particular balance.

• All weighing and measuring must be accurate. Avoid errors of 5% or more.

• Once an ingredient is removed from the stock container, it may not be returned to the stock container.

• Trituration is used to reduce the particle size of powders so that a greater surface area will be available, to uniformly mix powders using geometric dilution, and to dissolve solutes in solvents.

• Levigation is the process of mixing or triturating a powder with a liquid in which it is insoluble to reduce particle size and aid in incorporating the powder into the ointment base.

• The pharmacist must choose a levigating agent that is miscible with the ointment base.

• Mineral oil is an appropriate levigating agent for a hydrophobic ointment base such as white petrolatum.

• Up to 5% of levigating agent is usually sufficient unless the amount of powder is large.

• Heat should be used sparingly in compounding. Use only enough heat to melt ingredients, effect solution, enhance a reaction, and so forth—never any extra.

• Use of a water bath normally prevents overheating ingredients when compounding.

• Care must be taken to never lose or waste any ingredients in the preparation process because doing so can alter the concentration of active ingredients in the finished preparation and produce a subpotent or superpotent preparation.

• To promote accuracy in the compounding process, place all unused stock containers on the left side of the workstation. As each one is used, place it on the right side.

• The dry gum (or Continental) method of preparing an emulsion uses oil, purified water, and gum (e.g., acacia) in a ratio of 4:2:1, respectively.

• The extemporaneously compounded preparation has no NDC number.

4-9. Questions

1.

When water is an ingredient in a nonsterile compounded preparation and the type of water is not specified, the pharmacist is correct to use

A. tap water.

B. potable water.

C. purified water.

D. water for injection.

E. sterile water for injection.

 

2.

When alcohol is an ingredient in a nonsterile compounded preparation and the type and percent alcohol is not specified, the pharmacist is correct to use

A. ethyl alcohol 100%.

B. ethyl alcohol 95%.

C. ethyl alcohol 70%.

D. ethyl alcohol 50%.

E. isopropyl alcohol 70%.

 

3.

Ingredients that soften the skin and make it more flexible when applied topically are called

A. keratolytics.

B. emollients.

C. rubefacients.

D. counterirritants.

E. astringents.

 

4.

To increase the stability of potassium iodide oral solution (SSKI),____________________ may be used as an antioxidant to prevent the release of free iodine.

A. sodium alginate

B. sodium borate

C. sodium glycinate

D. sodium succinate

E. sodium thiosulfate

 

5.

In preparing diluted hydrochloric acid, the pharmacist notes a temperature change. The reaction is called

A. hypothermic.

B. hyperthermic.

C. endothermic.

D. exothermic.

E. isothermic.

 

6.

Ingredients that tend to tighten or shrink tissues when applied topically are called

A. astringents.

B. emollients.

C. keratolytic agents.

D. occlusive agents.

E. suspending agents.

 

7.

A solution expressed as 35% w/w has the following:

A. 35 mg of solute dissolved in 100 mL of solution

B. 35 g of solute dissolved in 100 g of solvent

C. 35 mg of solute dissolved in 100 g of solvent

D. 35 g of solute dissolved in 100 g of solution

E. 35 mL of solute dissolved in 100 mL of solution

 

8.

When dissolving potassium iodide in purified water, the pharmacist notes a temperature change. The reaction is called

A. hypothermic.

B. hyperthermic.

C. endothermic.

D. exothermic.

E. isothermic.

 

9.

A solution expressed as 35% w/v has the following:

A. 35 mg of solute dissolved in 100 mL of solvent

B. 35 g of solute dissolved in 100 mL of solution

C. 35 mg of solute dissolved in 100 mL of solution

D. 35 g of solute dissolved in 100 mL of solvent

E. 35 mL of solute dissolved in 100 g of solution

 

10.

Hydrophilic ointment, USP, is an o/w type of ointment base; therefore, it possesses the property of being

A. emollient.

B. greasy.

C. occlusive.

D. water washable.

E. anhydrous.

 

11.

When compounding an emulsion that contains a flavoring agent, the flavoring agent should be in

A. the continuous (external) phase.

B. the discontinuous (internal) phase.

C. the aqueous phase.

D. the oil phase.

E. the emulsifier.

 

The next four questions pertain to the following compounded prescription:

Mineral oil

60 mL

 

Acacia

qs

 

Syrup

12 mL

 

Flavor

qs

 

Purified water, qs ad

120 mL

 

M.ft. emulsion using dry gum method

12.

Mineral oil is in the

I. internal phase.

II. external phase.

III. discontinuous phase.

A. I only

B. II only

C. I and III only

D. II and III only

E. I, II, and III

 

13.

Acacia is the

A. primary active ingredient.

B. preservative.

C. emulsifying agent.

D. wetting agent.

E. coloring agent.

 

14.

How much acacia is needed for this preparation?

A. 5 g

B. 10 g

C. 15 g

D. 30 g

E. 35 g

 

15.

How much purified water is needed to make the initial emulsion?

A. 5 mL

B. 10 mL

C. 15 mL

D. 30 mL

E. 48 mL

 

16.

When cocoa butter is used as a suppository base, its melting point can pose a problem. To overcome this problem, the compounding pharmacist can replace _____________ of the cocoa butter with white wax.

A. 5%

B. 10%

C. 15%

D. 20-25%

E. 30%

 

17.

When cocoa butter is used as a suppository base, its melting point can pose a problem. To overcome this problem, the compounding pharmacist can replace ______________ of the cocoa butter with cetyl esters wax.

A. 5%

B. 10%

C. 15%

D. 20-25%

E. 30%

 

18.

Hydrophilic petrolatum, USP, is used as an ointment base. It possesses the characteristic or characteristics of being

I. emollient.

II. occlusive.

III. greasy.

A. I only

B. II only

C. I and III only

D. II and III only

E. I, II, and III

 

19.

When lime water and olive oil are processed together to form an emulsion, a reaction occurs that produces the emulsifying agent, which is

A. lime oil.

B. lime oxide.

C. calcium oxide.

D. calcium oleate.

E. olive oxide.

 

20.

The advantage or advantages of sublingual tablets as a dosage form are

I. quick absorption into the bloodstream.

II. rapid onset of action.

III. avoidance of the first pass through the liver.

A. I only

B. II only

C. I and III only

D. II and III only

E. I, II, and III

 

The next question pertains to the following compounded prescription:

Camphor

1.0%

 

Menthol

1.0%

 

Thymol

0.5%

 

White petrolatum, qs ad

30 g

 

M.ft. oint

 
 

21.

To prepare this compounded prescription, the pharmacist should

A. dissolve the camphor, menthol, and thymol in alcohol and incorporate them into the white petrolatum by geometric dilution.

B. dissolve the camphor, menthol, and thymol in glycerin and incorporate them into the white petrolatum by geometric dilution.

C. dissolve the camphor, menthol, and thymol in propylene glycol and incorporate them into the white petrolatum by geometric dilution.

D. form a eutectic mixture and incorporate it into the white petrolatum by geometric dilution.

E. alter the formula to avoid incompatibilities.

 

22.

The advantage or advantages of capsules as a dosage form are that they

I. provide an accurate dose.

II. mask unpleasant tastes.

III. provide an immediate therapeutic response.

A. I only

B. II only

C. I and II only

D. II and III only

E. I, II, and III

 

The next question pertains to the following compounded prescription:

Salicylic acid

5%

 

White petrolatum, qs ad

30 g

 

23.

The pharmacist has on hand 2% salicylic acid ointment to use in preparing this prescription. When using it, the pharmacist should

A. weigh 0.5 g of salicylic acid powder and qs to 30 g with 2% salicylic acid ointment, incorporating the salicylic acid powder by geometric dilution.

B. weigh 0.5 g of salicylic acid powder, levigate it with 5 mL of alcohol, and qs to 30 g with 2% salicylic acid ointment, incorporating the salicylic acid by geometric dilution.

C. weigh 1.5 g of salicylic acid powder, levigate it with 6 mL of mineral oil, and qs to 30 g with 2% salicylic acid ointment, incorporating the salicylic acid by geometric dilution.

D. weigh 1.5 g of salicylic acid powder and qs to 30 g with 2% salicylic acid ointment, incorporating the salicylic acid powder by geometric dilution.

E. weigh 1 g of salicylic acid powder, levigate it with 4.5 mL of mineral oil (SpGr 0.89), and incorporate it into 25 g of 2% salicylic acid ointment by geometric dilution.

 

24.

The advantage or advantages of a transdermal gel as a dosage form is/are

I. convenience of administration or application.

II. quick therapeutic response.

III. patient acceptance.

A. I only

B. II only

C. I and II only

D. II and III only

E. I, II, and III

 

25.

One gram of iodine is soluble in 3,000 mL of water. In Lugol's solution (strong iodine solution), 1 g of iodine is dissolved in 20 mL of solution. Lugol's solution contains 5% iodine and 10% potassium iodide. The phenomenon by which the potassium iodide increases the solubility of iodine is known as

A. alligation.

B. coalescence.

C. comminution.

D. complexation.

E. diffusion.

 

4-10. Answers

1.

C. For nonsterile compounding, the USP specifies that purified water be used.

 

2.

B. When type or percentage of alcohol is not specified, alcohol, USP, is used, and it is 95% ethyl alcohol.

 

3.

B. Ingredients that make the skin soft and pliable when applied locally are called emollients.

 

4.

E. Sodium thiosulfate is the antioxidant that prevents the iodide ion from oxidizing to form free iodine.

 

5.

D. When diluted hydrochloric acid is prepared, heat is generated, and the reaction is called exothermic.

 

6.

A. Ingredients that shrink or tighten the skin when applied locally are called astringents.

 

7.

D. W/w means weight in weight. Consequently, 35 g of solute must be contained in 100 g of solution to have a 35% w/w solution.

 

8.

C. When potassium iodide is dissolved in purified water, the solution becomes distinctively cold and the reaction is called endothermic.

 

9.

B. W/v means weight in volume. Consequently, 35 g of solute must be contained in 100 mL of solution to have a 35% w/v solution.

 

10.

D. Hydrophilic ointment is water washable but does not possess the other properties listed.

 

11.

A. For the flavoring agent to be tasted, it must be in the external or continuous phase.

 

12.

C. Mineral oil is in the internal or discontinuous phase and should not be tasted.

 

13.

C. Acacia is the emulsifying agent forming an oil-in-water emulsion.

 

14.

C. Given the 4:2:1 ratio, the 1 part or 15 g is the acacia.

 

15.

D. Given the 4:2:1 ratio, the 2 parts or 30 mL is the water for the initial emulsion.

 

16.

A. Five percent cocoa butter replaced by white wax will overcome the low melting point problem.

 

17.

D. Twenty to twenty-five percent cocoa butter replaced by cetyl esters wax will overcome the low melting point problem.

 

18.

E. Hydrophilic petrolatum is greasy, occlusive, and emollient.

 

19.

D. The lime water is calcium hydroxide solution and the olive oil contains oleic acid. The two react together to form calcium oleate, which is the emulsifying agent that forms a water-in-oil emulsion.

 

20.

E. All three items are advantages of sublingual tablets as dosage forms.

 

21.

D. Camphor, menthol, and thymol are three ingredients that, when mixed together, will liquefy, forming what is called a eutectic mixture. This liquid mixture is then gradually incorporated into the white petrolatum by geometric dilution.

 

22.

C. Capsules do not provide an immediate therapeutic response; the other two choices are correct.

 

23.

E. Your compounded preparation must contain 1.5 g of salicylic acid. Twenty-five grams of your 2% ointment contain 500 mg. You must weigh out 1 g of salicylic acid powder. The remaining ingredients must not contain any salicylic acid. The remaining weight can be made up with the levigating agent or a combination of the levigating agent and white petrolatum.

 

24.

E. All three choices are correct.

 

25.

D. In solution, potassium iodide ionizes into potassium and the iodide ion. The iodide ion complexes with elemental iodine to form the soluble I3 complex.

 

4-11. References

The following are references that should be available in the compounding pharmacy to provide assistance as the pharmacist formulates the variety of dosage forms that customized medications require:

Allen LV Jr. The Art, Science, and Technology of Pharmaceutical Compounding. 3rd ed. Washington, D.C.: American Pharmacists Association; 2008.

Ansel HC, Allen LV Jr, Popovich NG. Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. 8th ed. Baltimore: Lippincott Williams & Wilkins; 2005.

Ansel HC, Stoklosa MJ. Pharmaceutical Calculations. 11th ed. Baltimore: Lippincott Williams & Wilkins; 2001.

Hendrickson R, ed. Remington: The Science and Practice of Pharmacy. 21st ed. Baltimore: Lippincott Williams & Wilkins; 2006.

O'Neil MJ, ed. The Merck Index. 14th ed. Whitehouse Station, N.J.: Merck & Co.; 2006.

Shrewsbury R. Applied Pharmaceutics in Contemporary Compounding. Englewood, Colo.: Morton; 2001.

Sweetman SC, ed. Martindale: The Complete Drug Reference. 36th ed. London: Pharmaceutical Press; 2009.

Thompson JE, Davidow LW. A Practical Guide to Contemporary Pharmacy Practice. 2nd ed. Baltimore: Lippincott Williams & Wilkins; 2004.

Trissel LA. Stability of Compounded Formulations. 4th ed. Washington, D.C.: American Pharmacists Association; 2009.

U.S. Pharmacopeial Convention. U.S. Pharmacopeia 32/National Formulary 73. Rockville, Md.: U.S. Pharmacopeial Convention; 2009.

U.S. Pharmacopeial Convention. USP Pharmacists' Pharmacopeia. 2nd ed. Rockville, Md.: U.S. Pharmacopeial Convention; 2008.