Compounding Topical and Transdermal Preps Materials

COMPOUNDING TECHNIQUES FOR TOPICAL AND TRANSDERMAL PREPARATIONS

Liz Fredrickson, PharmD, BCPS

Liz Fredrickson, PharmD, BCPS, is an Associate Professor of Pharmacy Practice and Pharmaceutical Sciences at Northeast Ohio Medical University College of Pharmacy. Liz Fredrickson is also the Course Director for the Basic Pharmaceutics Lab, Parenteral Products, and Parenteral Products lab courses.

Topic Overview

Pharmaceutical compounding is considered an art and science and involves preparing medications unique to an individual’s health needs. Compounded nonsterile preparations (CNSPs) encompass many dosage forms, including transdermal and topical preparations. These dosage forms have many benefits in the pharmaceutical care of patients, including convenience, ease of application, and improved medication adherence. Pharmacists and pharmacy technicians who compound topical and transdermal medications should be well-versed in compounding standards and skilled in the techniques needed to prepare compounds that are effective, safe, and high quality. This continuing education program will review the importance of topical and transdermal preparations, discuss United States Pharmacopeia (USP) standards pertaining to these dosage forms, and review techniques related to preparing ointments, creams, pastes, and gels.

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Universal Activity Number (UAN): The ACPE Universal Activity Number assigned to this activity is 

Pharmacist  0669-0000-24-111-H07-P

Pharmacy Technician  0669-0000-24-112-H07-T

Credits: 2 contact hour(s) (0.2 CEU(s)) of continuing education credit

Type of Activity: Knowledge

Media: Internet/Home study Fee Information: $6.99

Estimated time to complete activity: 2 contact hour(s) (0.2 CEU(s)), including Course Test and course evaluation

Release Date: July 31, 2024 Expiration Date: July 31, 2027

Target Audience: This educational activity is for pharmacists and pharmacy technicians

How to Earn Credit: From July 31, 2024, through July 31, 2027, participants must:

Read the “Learning Objectives” and “author and planning team disclosures;”

Study the section entitled “Educational Activity;” and

Complete the Course Test and Evaluation form. The Course Test will be graded automatically. Following successful completion of the Course Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)

Credit for this course will be uploaded to CPE Monitor®.

Learning Objectives: Upon completion of this educational activity, participants should be able to:

Discuss the importance of topical and transdermal dosage forms

Recall important considerations for preparing transdermal medications

Identify compounding techniques used to prepare ointments, creams, pastes, and gels

Disclosures

The following individuals were involved in developing this activity: Liz Fredrickson, PharmD, BCPS, and Pamela Sardo, PharmD, BS. Pamela Sardo and Liz Fredrickson have no conflicts of interest or financial relationships regarding the subject matter. There are no financial relationships or commercial or financial support relevant to this activity to report or disclose by RxCe.com or any of the individuals involved in the development of this activity.

© RxCe.com LLC 2024: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.

Educational Activity

Compounding Techniques for Topical and Transdermal Preparations Introduction

Pharmaceutical compounding is considered an art and science and involves preparing medications unique to an individual’s health needs. Compounded nonsterile preparations (CNSPs) encompass many dosage forms, including transdermal and topical preparations. These dosage forms have many benefits in the pharmaceutical care of patients, including convenience, ease of application, and improved medication adherence. Pharmacists and pharmacy technicians who compound topical and transdermal medications should be well-versed in compounding standards and skilled in preparing effective, safe, high-quality compounds. This continuing education program will review the importance of topical and transdermal preparations, discuss United States Pharmacopeia (USP) standards regarding these dosage forms, and review techniques related to preparing ointments, creams, pastes, and gels.

USP <795> Pharmaceutical Compounding - Nonsterile Preparations

Pharmaceutical compounding is considered an art and science and involves preparing medications unique to an individual’s health needs.1 Compounded nonsterile preparations (CNSPs) encompass many different oral dosage forms, each with a specific purpose and associated patient benefits. The United States Pharmacopeia (USP) <795>, “Pharmaceutical Compounding, Nonsterile Preparations,” defines nonsterile compounding as combining, admixing, diluting, pooling, reconstituting other than as provided in the manufacturer’s labeling, or otherwise altering a drug product or bulk drug substance to create a nonsterile preparation.2 The chapter requirements are essential to minimize harm, including death, to human and animal patients that could result from:2

Excessive microbial contamination

Variability from the intended strength of correct ingredients

Physical and chemical incompatibilities

Chemical and physical contaminants and/or

Use of ingredients of inappropriate quality

The scope of the chapter pertains to numerous CNSPs, including the following:2

Solid oral preparations (such as capsules or tablets)

Liquid oral preparations (such as solutions or suspensions)

Rectal preparations

Vaginal preparations

Topical preparations (such as creams, gels, and ointments)

Nasal and sinus preparations intended for local application (such as nasal sprays and nasal irrigation)

Otic preparations (excluding use in perforated eardrums)

USP <795> requires personnel who compound such dosage forms to be competent in preparing them, including measuring and mixing, properly using equipment and devices, and handling and transporting components and CNSPs.2 Such skills are crucial to ensure the proper preparations of compounds for patients.

The Topical Route of Administration

Topical medications are applied directly to the body surface, including the skin and mucous membranes of the eyes, ears, nose, throat, or airway.3 They are typically intended to treat the localized area on which they are applied, though systemic absorption can occur, leading to unwanted side effects.3 The volume of the drug able to penetrate the skin as part of a semisolid formulation is dependent on a number of factors, including:1

The amount of pressure applied

The vigor with which preparation is rubbed into the skin

The amount of surface area covered

The condition of the patient’s skin

The type of ointment base used

Whether occlusive dressings are used

The advantages of topical medications include their usefulness for localized effects through direct application, beneficial for dermatologic and ophthalmologic preparations, and general convenience and ease of application.3 Disadvantages include limited absorption for drugs with high molecular weights, poor lipid solubility, and potential local side effects such as rash, irritation, and dermatitis.1,3

Compounded Topical Preparations

Compounded topical preparations are extremely common and allow for medication flexibility for many patients.4 These medications are common within the area of dermatology and may be prescribed for many reasons, including the following:4

The patient requires a different strength of a commercially available medication

The patient requires a medication in a topical dosage form

The patient requires a topical medication free of preservatives, irritants, or allergens

The drug requires preparation immediately before dispensing due to stability issues

Combination preparations are needed to improve patient adherence and convenience

Pharmacists should work with the prescribing physician and the patient to determine the optimal formulation for treatment.1 Many factors may come into play when deciding on the best dosage form. When choosing between an ointment, paste, or cream preparation, the extent of skin penetration needed and the characteristics of the affected area should be considered (Table 1).1

Table 1

Topical Dosage Form Descriptions

The Transdermal Route of Administration

The transdermal route of administration involves delivering drugs through the skin and into the general circulation to achieve a local or systemic effect.1 These medications are applied to the skin and absorbed into the bloodstream, avoiding first-pass metabolism.1 The amount of drug that can be administered through the skin can be measured through drug blood levels, the detection of the drugs or their metabolite in urine, or the patient's clinical response.1

For a drug to be absorbed percutaneously, it must penetrate the stratum corneum (SC).1 The stratum corneum is approximately 40% protein and 40% water.1 The remaining components include lipids such as cholesterol, triglycerides, and free fatty acids.1 These lipids are a key consideration of how well a drug will penetrate the skin.1 A drug’s rate of movement will depend on the concentration of the drug as well as its aqueous and lipid solubility characteristics.1

Compounded Transdermal Preparations

Compounding personnel should be aware of the factors that make active pharmaceutical ingredients (APIs) suitable for use in transdermal formulations. Important considerations include the physical and chemical properties of the drug (molecular weight, solubility, partition coefficient, dissociation constant, pKa, the carrier vehicle, and the skin's condition.1 The following are important considerations:1

The amount of drug absorbed per unit of surface area per time interval increases with an increase in concentration of drug

The larger the area of application, the larger the quantity of drug absorbed

A drug needs to have a greater physiochemical attraction to the skin than to the formulation vehicle

Drugs with a molecular weight (MW) of 100-800 daltons and good lipid and aqueous solubility can permeate the skin (the ideal MW is less than 400 daltons)

Good skin hydration favors percutaneous absorption

The longer the medication remains in contact with the skin, the more drug absorption

Advantages of the transdermal route include ease of application, avoidance of first-pass metabolism, and assistance with compliance by changing some oral forms to transdermal.1

However, there is a limited number of drugs that meet the criteria to be formulated as transdermal medications.1 Counseling points for transdermal medications are provided in Table 2 below.1

Table 2

Patient Counseling Points for Transdermal Medications1

Compounding Techniques for Nonsterile Topical Dosage Forms

Compounding starts with understanding general compounding techniques. Additional compounding techniques can then be applied to topical dosage forms, including ointments, creams, pastes, and gels.

General Techniques

Compounding personnel should be familiar with general compounding techniques related to particle size reduction and mixing methods when formulating nonsterile topical dosage forms. Perfecting these skills will help

ensure that preparations are compounded accurately. Particle size reduction, also known as comminution, helps ensure ingredients are in the same particle size range, and there are various methods for achieving this.1 Manual methods of comminution are defined in Table 3.1 The method used will be dependent on the API characteristics.1

Table 3

Manual Comminution Methods1,5

Understanding methods to mix the components of preparations is also vital, as this helps ensure homogeneity and even dose distribution.1 Geometric dilution is a manual mixing method that starts with the ingredient of the smallest quantity.1 Other ingredients are added to the mixture in order of quantity required by doubling the mixed portion each time.1

Ultimately, the primary objective in mixing ingredients is to achieve homogeneity in the final product, which is essential for optimal therapeutic outcomes. Mixing equipment may include a mortar and pestle (Figure 1) or an ointment slab with a spatula (Figure 2).

Figure 1 Mortar and Pestle

Figure 2 Ointment Slab

Techniques for Topical Dosage Form Preparation Ointments

Ointments are semisolid preparations applied externally to the skin or mucous membranes.1 They are used to deliver drugs topically to the skin, protect injured areas, provide hydration, or produce an emollient effect.1 These dosage forms provide ease of administration, leading to good patient adherence, though some patients may not prefer the greasiness.1

An essential component of compounding ointments is selecting an appropriate ointment base.1 The ointment base serves many vital roles. First, they provide a vehicle to deliver medication either locally or systemically.4 They can also hydrate the skin and offer protection from the environment, chemicals, and physical irritants.4 Compounding personnel have a variety of ointment bases from which to choose, all of which have varying functions and characteristics that should be reviewed and considered before selection. Drug- specific factors include whether the API is physically and chemically stable in the selected base and if the API will be bioavailable in the formulation.4

Regarding the ointment base itself, pharmacy personnel should also consider the spreadability and occlusive nature of the base. Spreadability is how easily a substance can be applied over the skin.4 Patients tend to prefer spreadability because it tends to be less greasy.4 Spreadability is especially important when compounding with lipid-containing oleaginous, absorption, and water-in-oil (W/O) emulsion bases.4 Occlusiveness is defined as a water retention characteristic of a topical preparation that prevents the evaporation of moisture from the skin.4 Occlusiveness is particularly beneficial for patients who require extended contact with the drug and skin.4 Hydrocarbons have the most occlusive character among the four general classes of lipids, and oleaginous hydrophobic bases have excellent occlusiveness.4 Examples include white petrolatum and white ointment. There are also patient-specific factors to consider.4 These include whether the patient is sensitive to different preservatives or has a skin condition that may require using a base that avoids dryness.4

Table 4 details the level of skin penetration of varying ointment bases, and Table 5 provides the polarity and spreadability of common lipid components of ointment bases.1,4 Table 6 describes the five types of ointment bases with regard to varying characteristics, such as water washability.1,4

Table 4

Ointment Base by Skin Penetration

Table 5

Polarity and Spreadability of Common Lipid Components of Ointment Bases

Table 6

Types of Ointment Bases, Properties, and Examples

Compounding Techniques for Ointments

When preparing an ointment, the initial step involves triturating the solid materials to reduce particle size.1,4 This will also prevent any grittiness in the final preparation. Particle size reduction can be done using a mortar pestle.1,4 Next, the API will need to be incorporated into the ointment. Manual and mechanical methods are available to accomplish this. Mechanical methods are typically preferred as they allow for better reproducibility and keep the preparation more hygienic.6 Equipment for manual methods includes using an ointment tile, ointment pad, or mortar and pestle.1,4 Ointment tiles tend to be preferred. These pieces of equipment are composed of either glass or porcelain, and their construction offers a suitable material for mixing that is non-absorbable.1,4 An angled metal spatula helps incorporate the API into the ointment, allowing for more dexterity and strength of mixing during incorporation.1,4 Using a rubber or plastic spatula typically is not helpful as it won’t allow the application of enough pressure for thorough mixing. They may be warranted if the ingredients used in the preparation would react with metal.1,4

For mechanical mixing, an electronic mortar and pestle (Unguator) can be utilized. This piece of equipment allows the mixtures, such as suspension ointments, to be prepared in the same container in which they will be dispensed.6 Benefits of EMP technology include easy and efficient loading of jars onto the machine, compact size and reduced height of the equipment, which allows for ease of placement in compounding areas, and validation routines that enhance the quality assurance aspect of the compounding process.6

A common technique for incorporating an API into an ointment base is to use levigation.1,4 As noted above, levigation encompasses reducing the particle size of a drug by triturating (or spatulating) it with a small quantity of either a melted ointment base or an insoluble liquid.1,4 This process is crucial, as it helps to mix the solid into the ointment base and ensure the final preparation is smooth, consistent in texture, and non-gritty.1,4 The choice of levigating agent will depend on their compatibility with the ointment base. The formulation may already include an ingredient that could be used as a levigating agent and, in this case, can be selected as the agent of choice.1,4

Geometric dilution should be used to incorporate the API in the base.1 This is crucial to dilute the drug and ensure the final preparation is homogenous. Heat needs to be used when preparing bases that have ingredients with high melting points.1 In these cases, either a water bath or direct heat can be used.1 Water baths are preferred for applications that need lower temperatures, while direct heat is useful when higher temperatures are needed.1 This can be accomplished using a hot plate while being cautious not to burn the preparation. When using heat, the ingredients with the highest melting points are added first, followed in descending order of melting points.1

Once all ingredients have been added, the preparation is mixed and thoroughly cooled.1 If the preparation is cooled too rapidly, it could become lumpy and lack pharmaceutical elegance for the patient.1 General tips for the preparation of ointments are detailed in Table 7.1 There is also an example of ointment preparation in Table 8.1

Table 7

To transfer an ointment directly from plastic bags into packaging, cut one corner of the plastic bag and squeeze the contents into the ointment tube or jar

Two or more ointments can be combined by mixing them in a plastic bag

Tips for Preparing Ointments1

Table 8

Example of Ointment Preparation: Formulation: Hydrophilic Petrolatum1

Steps:

Calculate the required quantity of each ingredient for the total amount of ointment to be prepared

Accurately weigh or measure each ingredient

Place the stearyl alcohol, white wax, and white petrolatum in a suitable container and melt the ingredients using a water bath

Add the cholesterol, and stir until the mixture is blended completely

Remove the mixture from the bath and stir until congealed

Package and label the preparation

Pastes

Pastes are thick, stiff ointments that do not melt at body temperature.1 They contain a higher percentage of solid material (often 20-50%) compared to ointments.1 Pastes are less greasy and more absorptive, making them suitable for protective and absorptive functions.1 They are used to protect skin areas from irritation and moisture, such as in diaper rash or to provide a protective barrier in conditions like psoriasis.1 Tips for preparing pastes are provided in Table 9.1

Table 9

Tips for Preparing Pastes1

Creams

Creams are defined as opaque, soft solids or thick liquids that are used externally.1 Formulations include medications dissolved or suspended in a water-soluble or vanishing cream base.1 Preparations can be classified as oil- in-water or water-in-oil.1 Tips for preparing creams are provided in Table 10.1

Table 10

Tips for Preparing Creams1

Gels

Gels (Table 11) are semisolid systems consisting of small inorganic particles or large organic molecules interpenetrated by a liquid.1 They can be classified into two types: single-phase and two-phase systems.1 Single-phase gels contain no discrete particles and are formed by macromolecules uniformly distributed throughout a liquid.1 Two-phase gels, or magmas, contain small discrete particles.1

Gels are useful for delivering various topically used drugs due to their high water content and ability to provide a cooling effect upon application.1 They are particularly beneficial for inflammatory skin conditions and for delivering medications that require a high degree of local penetration.1 These formulations include gelling agents and are a versatile delivery system compatible with many different types of drugs and relatively easy for compounding personnel to prepare.1

Table 111

Classification and Description of Gels

Preparations of Compounded Gels

When compounding a gel preparation, compounding personnel should recognize that the characteristics of the gelling agent will determine the technique used to make the compound.1 General preparation techniques are summarized in Table 12, and a description of preparing aqueous dispersions of carbomer gels is described below.

Table 121

General Gel Preparation Techniques

Being familiar with the techniques used to prepare aqueous dispersions of carbomer gels is recommended. Carbomer resins are typically used in aqueous systems.1 To quickly achieve dispersion of the carbomer during preparation, it is recommended that compounding personnel slowly add the carbomer powder into the vortex of a liquid while stirring rapidly. This can be

accomplished using a sieve to distribute the powder into the rapidly stirred liquid.1 A greater rate of agitation is preferred, but extremely high shear mixers should be avoided as they can break down polymers and reduce gel viscosity.1 Instead, a variable-speed mixer can be used. This device is useful as it incorporates less air into the gel.1 Once the powder has been fully incorporated, the stirring speed can be reduced, and mixing should continue for 10-15 minutes to avoid trapping excess air.1

Once the carbomer has been dispersed, the next step is to add a neutralizer.1 Sodium hydroxide or potassium hydroxide may be selected if the dispersion contains less than 20% alcohol.1 If it contains up to 50% ethanol, triethanolamine can be used.1 The neutralizing agent will thicken the preparation.1 It is important to remove any air bubbles that may be present before adding this agent.1 This can be done simply by allowing the preparation to stand or using an ultrasonic unit.1 Table 13 provides an example of a gel formulation.

Table 13

Example Gel Formulation: Formulation: Estradiol 2 mg/mL Vaginal Gel

Steps:

Calculate the quantity of each ingredient required for the prescription

Accurately weigh or measure each ingredient

Levigate the estradiol with the polysorbate 80

Geometrically add the methylcellulose 2% gel and mix thoroughly.

Package and label the product.

Additional Resources

Compounding pharmacists and pharmacy technicians who wish to learn more about this topic may find the following references useful.

Remington

Martindale

The Art, Science, and Technology of Pharmaceutical Compounding

The International Journal of Pharmaceutical Compounding

compoundingtoday.com

The Role of the Pharmacy Technician

Nonsterile compounding is a specialized skill of pharmacy technicians. They can assist with preparing safe, quality, and effective topical compounds by utilizing skills related to weighing, mixing, and measuring, in addition to techniques specific to each dosage form. Pharmacy technicians can also assist pharmacists in determining if a patient has experienced any issues with their compounded medications.

Summary

Nonsterile compounding encompasses a variety of dosage forms, each with a specific purpose and associated benefits for patients. Compounding personnel, including pharmacists and pharmacy technicians, should be skilled in preparing various dosage forms to produce safe, quality, and effective topical and transdermal medications. This includes skills to prepare ointments, creams, pastes, and gels.

Course Test

Which of the following describes why a patient may require a compounded topical dosage form?

They require a different strength from a commercially available topical medication

They require a less expensive version of a commercially available topical medication

They require a topical medication without a prescription from their physician

They require a topical medication that will decrease their medication adherence

Which of the following is an advantage of transdermal medications?

They are easy for patients to apply

They undergo first-pass metabolism

There are numerous drugs that can be formulated as transdermal medications

They are not associated with any local side effects

Which of the following best describes how a topical medication may benefit a patient?

It is useful for drugs with poor lipid solubility

It can minimize the risk of rash and irritation compared to oral medications

It is useful for its localized effects

It is useful for drugs with high molecular weights

Which of the following makes an active pharmaceutical ingredient suitable for transdermal formulation?

High physiochemical attraction to the formulation vehicle

Low concentration of drug in the formulation

Molecular weight of 300

A high degree of irritation

Which of the following describes grinding an insoluble substance to a fine powder while wet?

Pulverization by intervention

Trituration

Geometric dilution

Levigation

A compounding pharmacist wants to select a nonocclusive and nongreasy ointment base. Which of the following is the best selection?

Petrolatum

White ointment

Anhydrous lanolin

PEG ointment

Which of the following is a tip for preparing ointments?

Always use a rubber or plastic spatula

Use heat to soften ointments and make packaging easier

Avoid mineral oil with drugs that build up electrostatic forces

The first step in preparing an ointment is always adding the levigating agent

Which of the following is true regarding creams?

They are thick, stiff ointments that do not melt at body temperature

They contain 50% solid materials

They are opaque soft solids or thick liquids used externally

They should have high levels of clarity and sparkle

Which of the following is true regarding the preparation of gels?

The active drug must always be added before the gel is formed

Premixing gelling agents with other powders can assist the dispersion process

pH is not a major consideration regarding the viscosity of carbomer gels

Natural gums need to hydrate for 1 hour to ensure homogeneity

True or False: A compounder may leave air bubbles in a carbomer gel preparation before adding a neutralizing agent.

True

False

References

Allen, Lloyd. The Art, Science, and Technology of Pharmaceutical Compounding, 6th Edition. APhA. October 2020.

General Chapter: USP. Pharmaceutical Compounding - Nonsterile Preparations <795>. In: USP–NF. Rockville, MD: USP; Dec 1, 2020

Benson HAE, Grice JE, Mohammed Y, Namjoshi S, Roberts MS. Topical and Transdermal Drug Delivery: From Simple Potions to Smart Technologies. Curr Drug Deliv. 2019;16(5):444-460. doi:10.2174/1567201816666190201143457

Nagel K, Ali F, Al-Khudari S, Khan A, Patel K, Patel N, Desai A. Extemporaneous compounding of medicated ointments. Int J Pharm Compd. 2010 Nov-Dec;14(6):472-8. PMID: 23965650.

PharmLabs. The Pharmaceutics and Pharmaceutical Compounding Laboratory. https://pharmlabs.unc.edu/. Accessed July 31, 2024.

Standridge R. Mixing In a Compounding Pharmacy in the 21st Century.

Int J Pharm Compd. 2015 Nov-Dec;19(6):479-84. PMID: 26891562.

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The information provided in this course is general in nature, and it is solely designed to provide participants with continuing education credit(s). This course and materials are not meant to substitute for the independent, professional judgment of any participant regarding that participant’s professional practice, including but not limited to patient assessment, diagnosis, treatment, and/or health management. Medical and pharmacy practices, rules, and laws vary from state to state, and this course does not cover the laws of each state; therefore, participants must consult the laws of their state as they relate to their professional practice.

Healthcare professionals, including pharmacists and pharmacy technicians, must consult with their employer, healthcare facility, hospital, or other organization, for guidelines, protocols, and procedures they are to follow. The information provided in this course does not replace those guidelines, protocols, and procedures but is for academic purposes only, and this course’s limited purpose is for the completion of continuing education credits.

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