When a topical drug product underperforms, the path forward depends on understanding the cause of the problem. A cream that fails stability, an ointment that cannot be dispensed from its tube, a gel with inconsistent viscosity, or a product with poor drug release may all require different reformulation strategies.
For CPL, successful reformulation begins with a disciplined technical evaluation. The goal is not to make random changes until the product improves. The goal is to understand the formulation, reproduce the issue, identify the root cause, and develop a product following a systematic approach that can perform consistently through development, scale-up, regulatory review, and commercial manufacturing.
Starting With the Sponsor’s Observations
The first step is understanding what the sponsor is seeing. Is there phase separation, grittiness, poor release, impurity formation, or a usability concern? Has the viscosity or rheology changed? Is the appearance and microstructure unacceptable? Is the product failing in clinical performance? Is it unstable on long-term stability?
Those early observations help CPL determine where to begin. A stability issue may point toward excipient compatibility, emulsion structure, viscosity, or process conditions. A patient compliance issue may require changes to sensory properties, spreadability, stiffness, or the overall vehicle. A clinical efficacy issue may require a closer look at drug release and skin penetration.
This initial diagnosis is essential because topical products are complex. The same visible defect can sometimes have multiple possible causes. A viscosity drop may be related to raw material variability, process conditions, temperature exposure, polymer behavior, or chemical interaction. A change in drug release may reflect excipient substitution, microstructure differences, or process scale-up effects.
Evaluating Appearance, Texture, and Physical Stability
CPL begins by examining the product’s visible and physical characteristics. Appearance, texture, grittiness, uniformity, spreadability, and phase behavior can provide important early clues.
For creams and emulsions, the physical structure of the formulation is especially important. A product may look acceptable at first glance but reveal deeper problems under microscopic evaluation. CPL uses microscopy to better understand the product’s microstructure, including the distribution and uniformity of oil globules as well as particles, the strength of the emulsion network, and whether the oil and aqueous phases are properly homogenized.
If globules are irregular, poorly distributed, or unstable, the product may be at risk for separation, inconsistent performance, or long-term instability. These findings help guide the next stage of reformulation.
Reproducing the Defect in the Lab
After the initial evaluation, CPL often attempts to reproduce the sponsor’s defect at the lab scale. This is an important step because it helps confirm whether the issue is tied to the formulation itself, the process, the materials, or a combination of factors.
By following the sponsor’s existing formulation and process, CPL can observe whether the same problem appears under controlled conditions. If the defect can be reproduced, the team gains a much clearer understanding of the technical cause. If it cannot be reproduced, that may point toward another source of variability, such as equipment differences, raw material lots, storage conditions, or scale-dependent process behavior.
This step also helps CPL avoid unnecessary reformulation. In some cases, the formulation concept may be sound, but the process needs to be adjusted. In other cases, the process may be reasonable, but the excipient system or material attributes are not robust enough.
Investigating Composition and Excipient Compatibility
Excipient compatibility is one of the most important parts of topical reformulation. Semi-solid and liquid products involve far more interaction than many sponsors realize. APIs and excipients may interact through oxidation, degradation, solubilization effects, pH shifts, viscosity changes, impurity formation, or altered release behavior.
CPL has seen cases where sponsors reached clinical stages without completing sufficient excipient compatibility work. When issues appear late, the team may need to conduct binary compatibility studies, N-minus-one formulation work, texture analysis, rheological testing, and other targeted evaluations to determine which excipient or combination of excipients is creating the problem.
This is especially critical when a formulation contains multiple APIs. In one case discussed by CPL’s team, a product with two APIs showed stability limitations because of interactions between the APIs and certain excipients. CPL developed a reformulation strategy by liposomal application that protected one API while suspending the other, helping increase the product’s stability and extend its viability.
That type of solution requires more than replacing one ingredient with another. It requires a deep understanding of how APIs behave within different vehicles and how excipients influence both stability and performance.
Using Calculations and Formulation Science to Stabilize the System
For emulsion-based products such as creams, CPL also evaluates whether the emulsifier system is appropriate for the formulation. The team may use tools such as HLB/ HLD calculations to determine whether the right surfactant system and excipient levels are being used to stabilize the product.
This scientific DoE based approach helps move reformulation beyond trial and error. If a cream is separating or showing a weak emulsion structure, the issue may be related to the type or level of emulsifier, the oil phase, the aqueous phase, the order of addition, or the energy applied during processing. Understanding these factors helps the team make targeted changes that improve stability without creating unnecessary regulatory or performance issues.
Reformulating Without Creating New Regulatory Problems
Reformulation must also consider regulatory impact. Sponsors that have already completed toxicology studies, held pre-IND discussions, or advanced into clinical planning cannot always make large formulation changes without consequences.
Changing an excipient, changing the level of an excipient, or changing the vehicle may require additional justification or testing. Even when excipients are generally regarded as safe (GRAS) or listed in the IID, there may be limits on acceptable levels for a specific route, dosage form, or intended use. If a reformulation exceeds those levels, additional toxicology work may be required.
CPL works to solve formulation problems while minimizing avoidable regulatory disruption. When possible, the team selects excipients with established use and levels that are supported by regulatory precedent, including excipients listed in regulatory resources such as the Inactive Ingredient Database or STEP database. This allows sponsors to address technical problems while reducing the risk of creating larger regulatory hurdles.
Connecting Reformulation to IVRT, IVPT, and Skin Performance
Topical reformulation cannot be judged only by appearance and stability. The product must also perform in vivo & in vitro. CPL’s internal capabilities include skin lab support for IVRT and IVPT work, allowing the team to evaluate whether a reformulated product releases the drug appropriately and targets the intended skin layer.
This is particularly valuable when selecting the right vehicle. A sponsor may assume that a product should be a cream, gel, or ointment, but the best dosage form depends on the API, indication, dermatopharmacokinetic target, stability requirements, and patient experience. A formulation intended to reach the dermis may need a different strategy than one intended to act at the surface.
By pairing formulation development with IVRT and IVPT capabilities, CPL can evaluate performance earlier and make more informed decisions before the program advances too far.
Designing for Scale-Up From the Beginning
A common reason reformulation becomes necessary is that the original process was never designed for scale-up. A formulation may work in small lab batches but fail when transferred to larger equipment. Key and Critical Processing Paramaters like mixing time, homogenization, cooling rate, temperature control, vacuum, and order of addition can all change how a semi-solid product behaves.
CPL’s formulation scientists work closely with scale-up and manufacturing teams, which allows process considerations to be addressed early. The team can evaluate whether a proposed process is practical, reproducible, and scalable before the program reaches a stage where changes become more costly.
This is a major advantage for sponsors. A topical formulation should not be developed in isolation from manufacturing reality. CPL’s integrated approach helps ensure that the formulation and process are aligned from the start.
Turning Reformulation Into a Controlled Strategy
For sponsors, underperformance can feel like a setback. But with the right technical partner, reformulation can become a strategic process that helps to establish a controlled design space to deliver a robust drug product throughout its life cycle. CPL begins by understanding the problem, evaluating the formulation, reproducing the defect, identifying root causes, and then applying targeted changes that support performance, stability, usability, regulatory expectations, and future scale-up.
The best reformulation strategy is not the fastest change. It is the right change. For topical drug products, that means understanding the full relationship between API, excipients, vehicle, process, patient use, and regulatory pathway.
CPL’s experience in semi-solids and liquids gives sponsors a reliable partner that can move quickly without losing scientific discipline. For underperforming topical products, that combination can be the difference between restarting a program and rescuing one.