Citation: Bassett D, Barnes D, “Excipient Choices and Why They Matter in Topical Formulations”. ONdrugDelivery Online, November 30, 2021.
Daryl Bassett and David Barnes show how the choice of common excipients can have a material impact on manufacturing success, quality and, ultimately, commercial success for topical formulations, which generally require the incorporation of more excipients than other products to deliver their API payload effectively.
Topically applied therapeutics are a prominent, growing segment of the pharmaceutical industry, and consequently, it continues to attract a large number of product developers and manufacturers to compete in the sector. Industry analysts attribute the growth to the rising demand for treatments for chronic conditions like eczema, psoriasis, and skin cancer, as well as common infections, skin conditions, and muscular/joint treatments.
A staple of drug delivery, topical therapeutics remain a dominant category with millions of prescription, generic, and OTC doses being manufactured every day. In 2020, the market for topical pharmaceuticals was valued at US$95 billion (£84 billion) and is projected to grow to more than $155 billion by 2028.1
“Topical formulations are often inherently semi-solid in nature and typically contain more types of excipients than most other finished drug products. Many of these excipients, if specified without due consideration and analysis or formulated improperly, can adversely impact topical drug manufacturing processes.”
To meet demand, pricing, and other cost-of-goods economies, manufacturers are looking to produce topicals in increasingly larger volumes. However, as with many “all eggs in one basket” approaches to drug manufacturing, if process variability and chemistries can’t be controlled well in large commercial batches, they can’t be validated, and the product can’t be released. When scaling from clinical to commercial scale, every excipient must be characterised and evaluated carefully to assess its impact on formulation, production economies, process stability, resource efficiency, and quality.
Drug formulators have a wide variety of excipients to choose from, but failure to select the right one for the formulation in question can negatively impact outcomes.
EXCIPIENTS IN TOPICAL FORMULATION TRULY MATTER
Topical formulations are often inherently semi-solid in nature (Figure 1) and typically contain more types of excipients than most other finished drug products. Many of these excipients, if specified without due consideration and analysis or formulated improperly, can adversely impact topical drug manufacturing processes.
Formulators have at their disposal a broad range of excipients with which to achieve desired therapeutic outcomes, improve absorbability, and the shelf life of topical drug products including:
- Polymers to control viscosity
- Surface active agents to help solubilise APIs in the formulation
- Preservatives to improve shelf life and microbiological stability
- Penetration enhancers to promote absorption.
Larger topical drug manufacturing volumes can present the following challenges to processors:
- Longer processing times
- Material addition challenges (route of addition, uniformity in batch, ergonomics, etc)
- Matching and/or optimising process parameters from smaller scales.
If an excipient requires more steps to process (adding to timelines) or requires extra inputs of solvents, energy, or control (adding to cost and complexity), those aspects must be factored in accordingly.
For today’s topical drug manufacturers, to overcome these challenges a disciplined analytical approach is required to obtain the economies of scale and quality control needed to keep product prices competitive and affordable.
Broadly, formulators use polymers to enhance viscosity for improved suspension/retention characteristics. Most all polymers used in commercial pharma manufacturing can be divided into three classes:
- Fermented (e.g. Xanthan gum)
- Synthetic (e.g. hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), carbomer)
- Natural (e.g. acacia, starch).
However, natural polymers are no longer used in semi-solid product development and therefore have no relevant impact on current commercial formulation approaches. Regardless, fermented and synthetic polymers provide both pros and cons in the application.
“Low-cost, high availability fermented polymers give manufacturers economies at scale and other positive processing attributes. However, the compound in formulation might have drawbacks that may or may not make them a good choice depending on the process, equipment and formulation.”
Fermented Polymers Offer Flexibility & Economies of Scale
Low-cost, high availability fermented polymers offer manufacturers good economies at scale and other positive processing attributes. However, the compound in formulation might have drawbacks that may or may not make them a good choice depending on the process, equipment and formulation including:
- Poorly controlled viscosity range
- High bioburden
- Supports microbial growth
- Single rate of solvation.
Synthetic Polymers for Viscosity & Solvation Rate Control
Typified by HPMC, HPC and carbomer, commercially available synthetic polymers are extensively relied on by topical drug formulators and offer several benefits:
- Supports product differentiation and brand strategy
- Offers tight control of viscosity
- Provides a flexible range of solvation rates
- Offers low bioburden, inhibiting microbial growth.
“Synthetic polymer excipients come at a premium price and that is their central drawback, especially at large volumes.”
However synthetic polymer excipients come at a premium price and that is their central drawback, especially at large volumes. A thorough cost analysis should reveal if the processing efficiencies and utility of these compounds offset their extra cost.
Preservatives in Perspective
Preservative choices can also have a tremendous impact on large scale batch manufacturing economies and quality. Preservatives are a key component and are required to preserve it over time. In the US, methyl- and propylparaben are the preservatives most commonly incorporated into topical formulations.
Many preservatives have low-aqueous solubility and generally take longer to dissolve at room temperature. For topical formulators and processors, these excipients present several manufacturing trade-offs and compromises including a requirement to:
- Increase stirring shear rate
- Raise the temperature of the vessel
- Dissolve the preservative in a suitable solvent (e.g. propylene glycol) and add the solution to the product.
Each approach in the context of batch volume and process time offers pros and cons. Depending on how sensitive the formulation is to physical forces or heat, that may steer the choice of preservatives in one direction or the other. Cost and the volumes required for a solvent-based solution may steer the choice in another direction.
Selecting Surface Active Agents
Many of today’s APIs are hydrophobic to a certain degree. Assuming there’s an aqueous component to the formulation, incorporating APIs can be problematic. To overcome this hurdle, topical formulators have found that adding a surface-active agent is a straightforward and well-precedented solution.
Nonetheless, surface-active agents come with issues – foaming for example. Unless production uses a vacuum vessel, once foam forms it takes a very long time to disperse. Slowing the mixer and extending mixing times can mitigate foaming but that can extend processing times past economically sustainable levels.
Balancing Viscosity & Solvation
In topical formulation, there’s something of a balancing act required between the amount of polymer incorporated and its speed of solvation. It is both a time and materials issue. The time taken for a polymer to solvate depends upon the viscosity of the polymer and the amount in the product.
In application, higher viscosity polymers generally take longer to solvate than lower viscosity polymers. So, to achieve a given viscosity, batch formulators may need less of the high-viscosity version to achieve the same but more economical results.
Potential Impact of Penetration Enhancers
Used primarily for dermal products, penetration enhancers offer limited use in other topical applications (e.g. mucosal, ophthalmic and wound care). Therapeutic potential and effectiveness aside, in addition to their named role, penetration enhancers are often used to speed the solvation of polymers.
For example, HPC disperses and solvates rather slowly in water. However, it disperses quickly in materials such as oleyl alcohol. Consequently, making a slurry of polymer in a non-aqueous co-solvent and then adding that to the bulk product can speed up solvation considerably.
“Processing times at certain steps can be starkly different from lab scale to commercial scale. For example, while stirring times at a 200 g scale require only a couple of minutes in the lab, it will take longer at 200 kg, despite the fact larger equipment is used to complete this processing step.”
LAB-SCALE VERSUS COMMERCIAL-SCALE PRODUCTION
When comparing lab-scale to commercial-scale production, the obvious difference is the volume of the batch produced. However, even though it’s not linear, there is an even larger difference in the amount of time it takes to manufacture batches as production scales increase to commercial levels.
The more time it takes to produce large batches of topical formulations, the more it costs, so the impact of excipient choice on production times is of huge importance. Processing times at certain steps can be starkly different from lab scale to commercial scale. For example, while stirring times at a 200 g scale require only a couple of minutes in the lab, it will take longer at 200 kg, despite the fact larger equipment is used to complete this processing step.
Similarly, heating and cooling small batches in process on a lab bench may be easily controlled over a short time. However, increase the batch size a thousand-fold and homogeneously controlling the heating and cooling of thermally sensitive compounds in a large-capacity vessel can easily take many highly risk-prone and expensive hours to accomplish.
“During the initial formulation studies, consideration needs to be given to the consequences of excipient choice, grade, and quantity on the later stages.”
BETTER EXCIPIENT CHOICES CREATE BETTER PRODUCTS
Given the market and competitive dynamics, optimising formulation to support cost-efficient manufacturing of large batches becomes a truly effective go-to market strategy for today’s topical drugs. For companies looking to increase production volumes and find ways to meet market and patient demand at lower cost, it makes sense to partner with CDMOs having formulators’ experienced in specifying and formulating topicals for industrial-scale batches. Remember, during the initial formulation studies, consideration needs to be given to the consequences of excipient choice, grade, and quantity on the later stages and large scale manufacture of batches in order to avoid costly manufacturing costs or making changes down the road which can cause even costlier delays.
- “Topical Drug Delivery Market Size And Forecast”. Research Report, Verified Market Research, July 2021.