By Courtaney Davis, BBA, PCCA Senior Formulation Specialist, and Stacey Lemus, BS, CPhT, PCCA Senior Formulation Specialist

In general, a gel consists of two parts: water, alcohol or other solvents (such as propylene glycol) along with a hydrophilic polymer. Most gels use water, and the hydrophilic polymer acts as a gelling agent. Several types of gelling agents are available with varying characteristics. The major difference is the degree of viscosity they provide given the percentage of gelling agent used. However, those that form a stiffer gel often leave it susceptible to breaking or collapsing. Some work better than others at certain pH ranges, and there are some incompatibilities as well.

In other words, there are a number of variables when preparing medicated gels for patients. In this article, we’ll list the major factors you should consider when compounding gels and help you troubleshoot one of the most common problems with preparing them. We’ll also provide important information about the most common gelling agents for compounding and cover frequently asked questions about them.

What to Consider When Choosing the Appropriate Gelling Agent

• What vehicle is being used to compound the gel (water, alcohol, propylene glycol, DMSO, etc.)?
• What is the route of administration (oral, topical, mucosal, etc.)?
• What active pharmaceutical ingredients (APIs) are being included?
• Are the component ingredients compatible with each other, the pH of the preparation, etc.?

These questions will help you determine the ideal gelling agent to use in your compounded preparation. You can use them in conjunction with the information we’ve provided about gelling agents below to help determine the appropriate one.

What to Do If Your Compounded Gel Is Clumping

This is one of the more common issues when compounding gels. If a gelling agent is added to the dispersing vehicle too quickly, it tends to clump. The outer molecules of the gelling agent contact the vehicle first and hydrate, forming a layer with a gelled surface that is more difficult for the vehicle to penetrate. Eventually the clumps will hydrate and the gel will smooth out, but it takes more time. One compounding technique that you can use to minimize clumping is to vigorously stir the vehicle and slowly sift the gelling agent into the vortex of it. The use of a strainer helps to ensure small particle size.

Another way to help speed up the hydration process and smooth out your gel is to use a glass stirring rod to break up the gel clump(s) into smaller pieces, then rapidly mix using a magnetic stirrer until it is all hydrated. You may also transfer the contents to an electronic mortar and pestle (EMP) jar and mix for two minutes on a medium setting. The sheer force used when mixing in the EMP will help to break up the clumps, which will enable the gel to hydrate more quickly. However, it could take a longer time for the bubbles to subside after mixing in the EMP.

Common Gelling Agents in Pharmacy Compounding

Carbomer 940 NF and Carbomer 934P NF

• Also referred to as Carbopol^®
• Gels are clear and colorless
• Concentration range is 0.2–2.5%
• The pH range is 6.5–11
• Approximately 30% lower viscosity when using carbomer 934P compared to carbomer 940
• Hydrates best in water or combination of alcohol and water, but propylene glycol (70%) and glycerin (70%) can also be used
• Incompatible with phenol, cationic polymers, strong acids and high levels of electrolytes
• 100 mL hydrates and forms a gel immediately when pH adjusted
• The pH must be adjusted to approximately 6.5 or higher using trolamine or sodium hydroxide to create a gel
• Route of administration for carbomer 940: topical use only
• Routes of administration for carbomer 934P: topical, oral, mucosal

Carboxymethylcellulose Sodium USP (Medium Viscosity)

• Also referred to as CMC
• Gels are clear and colorless to pale beige
• Concentration range is 0.5–5%
• The pH range should be 7–9 for maximum viscosity, but fairly stable at pH range of 4–10
• Incompatible with zinc, aluminum, and soluble salts of iron
• Hydrates best in water
• 100 mL hydrates in 30–60 minutes
• Routes of administration: oral, nasal, vaginal, rectal, ophthalmic, injection

Hydroxyethyl Cellulose NF (4500-6500 CPS, 2%, 25C)

• Also referred to as HEC
• Gels are clear and colorless
• Concentration range is 0.5–5%
• The pH range is 2–12, but less stable below pH of 5 (due to hydrolysis)
• Hydrates best in water
• 100 mL hydrates in 30–60 minutes
• Incompatible with parabens, leading to compromised preservative effectiveness
• Routes of administration: topical, oral, vaginal, ophthalmic, urethral

Hydroxypropyl Cellulose NF (1500-3000 CPS, 1%, 25C)

• Also referred to as HPC
• Gels are clear and colorless to slightly hazy
• Concentration range is 0.5–5%
• The pH should be 6–8 for best stability
• Hydrates best in alcohol or propylene glycol 
• incompatible with parabens, leading to compromised preservative effectiveness
• Routes of administration: topical, oral, otic

Methylcellulose

• Gels are clear and colorless
• Concentration range is 0.25–5%
• Lower affinity for hydration than other gelling agents, but highest tolerance to a variety of chemicals and pH ranges
• The pH range is 3–11
• Not soluble in alcohol
• Incompatible with parabens, leading to compromised preservative effectiveness
• Routes of administration: topical, oral, ophthalmic

Methocel^® E4M Premium CR (Hypromellose USP)

• Also referred to as hydroxypropyl methylcellulose
• Gels are clear and colorless
• Concentration range is 0.25–5%
• The pH range is 3–11
• Greater gelling capacity than methylcellulose, but a lower tolerance for positively charged ions and low pH ranges
• 100 mL hydrates in 45 minutes refrigerated
• Formulas require heating ½ amount of purified water USP to 65–70° C and combining it with ½ refrigerated purified water USP to disperse and hydrate well
• Incompatible with parabens, leading to compromised preservative effectiveness
• Routes of administration: topical, oral, nasal, ophthalmic

Poloxamer 407 NF

• Also referred to as Pluronic^®
• Gels are clear and colorless
• Concentration range is 0.2–30%
• Hydrates best in refrigerated water
• 100 mL hydrates in 12–24 hours refrigerated
• Routes of administration: topical, oral, nasal, ophthalmic, rectal

Frequently Asked Questions

Can hydroxyethyl cellulose NF (HEC) be used as a substitute for hydroxypropyl cellulose NF (HPC)?

In some cases, yes. However it may take much longer to hydrate and form a gel. It will also depend on the pH (HPC is best at pH 6–8). If substituting, it may also be necessary to increase the amount of HEC to achieve the same viscosity. Remember that HEC hydrates best in water, whereas HPC hydrates best in anhydrous vehicles, such as alcohol or propylene glycol.

Can hydroxypropyl cellulose NF (HPC) be used as a substitute for hydroxyethyl cellulose NF (HEC)?

In some cases, yes. However it may take much longer to hydrate and form a gel. It will also depend on pH (HPC is best at pH 6–8). For example, 100 mL of an HEC 2% aqueous gel, which uses water as the vehicle, typically hydrates in 30–60 minutes. Making the same formula using HPC 2% takes four hours (three hours to hydrate, and one additional hour for the air bubbles to clear). Remember that HEC hydrates best in water, whereas HPC hydrates best in anhydrous vehicles, such as alcohol or propylene glycol.

Can hydroxypropyl cellulose NF (HPC) and hydroxyethyl cellulose NF (HEC) be used interchangeably? 

Probably for most cases, but see the differences outlined above.

Can Methocel K100M be used as a substitute for Methocel E4M?

This is not recommended. Methocel K100M is primarily used in sustained-release capsules and rarely in gels.

Can Carbomer 934P be used as a substitute for Carbomer 940?

Yes, but carbomer 940 cannot always be used as a substitute for carbomer 934P since carbomer 940 cannot be used orally or on mucous membranes.

Can poloxamer 188 NF be used as a substitute for poloxamer 407 NF?

They have very different viscosities, so substitution is not recommended.

PCCA members with Clinical Services support can find a list of related formulas in our formula database.

Courtaney Davis, BBA, is a Senior Formulations Specialist and technical consultant with more than 18 years’ combined experience in the pharmacy compounding industry. She joined PCCA’s Formulation Development department in 2005, where she assists in the creation of new formulas as well as continually updating and revising existing formulas. She works closely with the Quality Control team to ensure that PCCA’s chemicals and devices continue to perform to our highest standards in our formulas. In addition to this, Courtaney takes technical calls from our members regarding such topics as calculations, formula troubleshooting and equipment usage and works closely with our Research and Development team to bring technologically advanced and innovative products to our membership. Prior to joining PCCA’s staff, she worked for a member pharmacy as a certified technician.

Stacey Lemus, BS, CPhT, became a compounding technician in 2000. She worked with a PCCA member pharmacy for more than 10 years before joining the PCCA Formulation Development team in 2012. Her work at PCCA focuses on new formula development as well as updating and testing existing formulations. Her experience with equipment, compounding techniques and calculations makes her a valuable resource for member technical calls. She received her BS in biology and chemistry from Texas A&M University – Kingsville.

References

1. Allen, L. V., Jr. (2020). The art, science, and technology of pharmaceutical compounding (6th ed.). American Pharmacists Association.
2. Kibbe, A. H. (Ed.). (2000). Handbook of pharmaceutical excipients (3rd ed.). Pharmaceutical Press.
3. Shrewsbury, R. P. (2020). Applied pharmaceutics in contemporary compounding (4th ed.). Morton.
4. Thompson, J. E., & Davidow, L. W. (2003. A practical guide to contemporary pharmacy practice (2nd ed.). Lippincott Williams & Wilkins.