Analytics and quantitative approaches are shedding more light on these complex formulations, promising to improve process control and product design.
Ointments and creams may be as old as humanity itself, but their formulation is extremely complex. In a category of their own, these semisolids involve many more ingredients than other dosage forms, and materials in different phases, increasing the potential for variability and interactions. As a result, achieving process understanding and control is more difficult with these materials than it might be for simpler solid dosage form.
As more companies within the pharmaceutical industry, including generic-drug manufacturers, start to embrace the principles of quality by design (QbD), and regulators push for increased process and product understanding, research is under way to gain insights into how these formulations and their components work. The FDA is sponsoring research, funded by the Generic Drug User Fee Amendments of 2012 (GDUFA), into various aspects of semisolid behavior at the University of Mississippi in the United States and the University of Queensland in Australia.
Pharmaceutical and some excipient manufacturers are also working to optimize conditions to allow for improved and consistent quality. At the American Association of Pharmaceutical Scientists (AAPS) annual meeting in October 2015, three days of technical sessions and one full-day workshop focused on this topic (1, 2). An all-day workshop at Rutgers in May 2016, sponsored by the Center for Dermal Research and the excipients manufacturer, BASF, explored these topics in greater depth. This article will report on some highlights from the May workshop (3).
“Semisolids may contain over 20 ingredients, compared with the five or six typically found in injectables. They also contain a wider variety of excipients including oils, waxy solids, emulsifiers, polymers, solvents, and liquid humectants,” explained Bozena Michniak-Kohn, professor of pharmaceutics at Rutgers University, at the May workshop (4). Professor Michniak-Kohn founded and currently directs the Center for Dermal Research at the University. The center, affiliated not only with Rutgers, but also with the Robert Wood Johnson Medical School’s dermatology department, offers testing and research facilities and services for optimizing topical formulations, and for designing, characterizing, optimizing, and evaluating transdermal delivery, featuring microscopy, analytics, and imaging tools.
Potentially, there can be interactions between all components in the formulation, Michniak-Kohn explained, while additional complexity stems from the ingredients’ source (i.e., whether from synthetic, plants or animals), as well as how they are processed. And that doesn’t even begin to address the complexity of interactions with the human skin, where the materials contend with sweat or dryness, and may undergo additional changes. “The kinetics of transport through skin layers is complex, and microstructure may also influence degree of active retention in the skin,” said Michniak-Kohn.
At the workshop, Sameersingh (Sam) Raney, scientific lead for topical and transdermal drug products at FDA’s Office of Generic Drugs, and former professor of pharmaceutics at the North Dakota State University, noted the need to characterize semisolid formulations, and to link potential failure modes to quality attributes and degree of complexity (5). In a typical cream, he notes, “numerous quality attributes may be critical, and numerous failure modes may exist, due to the complex composition of matter.”
As formulation complexity increases, so does the potential number of failure modes, Raney says, but it can also be extremely difficult to distinguish the role that each ingredient plays when determining the root cause. One example that Raney points to is penetration enhancers or modifiers. “An increase in solubility in a formulation can alter the amount of drug available for partitioning into the skin’s stratum corneum (i.e., outermost layer of the epidermis), and increase bioavailability of the drug from a formulation. This [effect] may be interpreted as occurring because of the solubility enhancer, yet the same ingredient won’t give the same results in a formulation in another drug with a different API,” he said.
Reprising his presentation at the AAPS meeting, FDA’s Raney presented a frame for the day’s discussions by posing questions to industry. Noting that his comments represented his personal opinion rather than FDA’s official position, Ramey listed the traditional specifications for semisolids, including appearance, viscosity, particle size pH, homogeneity, content uniformity, microbial tests, and residual solvents. “Are these traditional measures a complete characterization of the dosage form and everything that matters? For example, for pH, how well are the specification ranges justified?” he asked.
Raney went on to ask about quality risk management. “How do we attain product and process understanding where complexity is adequately characterized, potential failure modes are adequately understood, the critical range of each quality attribute is adequately well established in a relevant design space, and quality attributes that might matter are adequately controlled?”
As he noted, the complexity of semisolid formulations has made it difficult to implement a QbD approach at all, or consistently, during topical semisolids development.
Raney reiterated the potential for inactives to affect the physicochemistry, microstructure, functioning, and robustness of the drug product, and the fact that some ingredients might penetrate through the skin and alter its structure and chemistry. “Can they alter the solubility of the active ingredient in the intracellular lipids in the stratus corneum? Can they alter the ordered structure of the stratus corneum’s intracellular lipids? Can they impact the diffusion of actives and inactives into the stratus corneum, and influence the partitioning diffusion and other factors related to bioavailability?” he asked.
Raney discussed the importance of using Q3 principles encompassing qualitative and quantitative composition, as well as physicochemical attributes, rheological characteristics, polymorphic form, drug release rate, globule size, and pH. The next step, he said, is to determine which attributes are critical to product quality, and within which range a quality attribute is robust.
He emphasized the need to understand how differences in composition and manufacturing affect states of matter, arrangement of matter, complex dynamic distribution of the drug, and the metamorphosis of semisolid on skin. “Can we study qualitative differences and observe when a quality attribute is critical, when a potential failure mode may be at risk, and how qualities and failures are multifactorial effects?” he asked. As an example, he mentioned pH and how it can influence ionization state, polymorphic state, stability, solubility, ratio of dissolved to undissolved, distribution of drug in microstructure, amount of drug in the phase in contact with skin, rheology of semisolid, dose application, spreading product transfer, and patient perception of quality.
Raney presented these challenges, but in a practical context. “In complex products, consider how failure modes arise from and convolute among multiple quality attributes, consider how risk of failure modes can be mitigated once the associated individual and collective quality attributes are designed into the product and controlled within a well characterized design space,” he said.
“This requires considering which quality attributes to characterize, what measurement techniques to use and how to interpret results,” he said, “as well as such factors as patient impact, storage, dispensing and redispensing issues, dose application maintenance and removal, perceptions of quality, and the robustness of therapeutic effect in the real world.”
Following Mr. Raney, S. Narasimha Murthy, PhD, associate professor of pharmaceuticals and drug delivery at the University of Mississippi, whose group is currently performing some GDUFA-funded research, discussed how his team is evaluating Q3 critical quality attributes of semisolid topical dosage forms, and their impact on bioequivalence (6).
The researchers studied commercial creams containing the antiviral active ingredient, acyclovir, comparing Zovirax, sold in the US and United Kingdom, with Aciclovir and Aciclostad, sold in Austria. There were many significant differences between these formulations of “the same” product.
Researchers used methods that included in-vitro permeation and x-ray diffraction, and evaluated pH and potential failure modes for pH, as well as drug absorption versus dissolution rate, polymorphism, particle size, and particle morphology. They also evaluated undissolved active in cream and in aqueous phase.
Professor Murthy concluded that microstructural differences could have significant influence of the performance of the product. He also noted the need for a powerful nondestructive testing tool that would be able to characterize product without disturbing the original microstructure.
In addition, he says, there is a need to consider potential failure modes during drug development, while attempting to design certain quality attributes into the product. As he noted, his group’s research has also shown the importance of solvent properties within the formulation.
The program then shifted to a focus on analytical methods and excipients within the formulation. Norman Richardson, global technical marketing manager for skin delivery, presented results of work that he, Amy Ethier, and colleagues at BASF’s global skin delivery lab in Tarrytown, NY (7), are doing to analyze excipients and their impact on the microstructure of semisolid formulations, taking a Q3-based approach. “The goal is to improve the quality of analysis and make the overall study more quantitative,” Richardson said. “Performance of semisold formulations is determined by Q3, and Q3 is determined by formulation. Microstructure provides a complementary, and sometimes predictive, component to system analysis.”
Since 2014, research at Tarrytown has been focusing on the impact of excipient selection. These efforts began with polyethylene glycol ointments, results of which were presented at AAPS 2015, but the team’s focus has since moved into creams and emulsions, which are far more complex, Richardson said.
The group has focused on different types of microscopy to study overall structure and morphology. Richardson noted that topical formulations using the same API at the same concentration can look vastly different under the microscope, with differences in structure beyond the API (e.g., in waxes and the phases that are formed). The researchers focused on elucidating the role that excipient selection and processing play in these differences.
The BASF team demonstrated the variability of microstructure in creams by imaging five different products, including an antifungal, skin rash treatment, local analgesic and anti-itch cream. Each cream was distinctively different. The hypothesis is that these differences are driven by excipient selection. “These are themodynamically unstable products that change over time,” Richardson said. “We also wanted to know how that affects Q3.”
One of the team’s first observations was that different products designed for different functions appeared very different under the microscope. For instance, the local anesthetic was seen as comprised of large round bodies, where the antiseptic creme showed small droplets.
The research also examined differences between the products in terms of performance criteria (i.e., viscosity, stability, sensory properties, appearance, API release, and absorption).
Because of advances in microscopy, Richardson noted, it is possible to see in much greater detail. “You can extract a lot of detail with the right microscopy,” he said. The researchers are also looking at what is between the APIs crystals, and oil droplets. In some cases they have seen complex phases that form lamellar structures that extend between oil droplets, noting prior research by others in this area (8).
In an effort to quantify the characterization of emulsion droplets and reduce variability in results, the team prepared slides to ensure that samples were the same size and thickness, by taking 3 mg of product and putting it in the middle of the microscope slide, squeezing it down to exactly 2 cm diameter.
BASF’s team used the topical anti-fungal treatment Clotrimazole, as a model, Richardson said, changing one component at a time and observing the results. The product is not meant to dissolve entirely into the skin, but to remain on the surface of the skin.
Using Image J, a free image-analysis software available online from the National Institutes of Health (9), the group identified droplets and mapped them, counting the number of pixels that each oil droplet occupied, then plotting histograms showing the distribution of the areas of these oil droplets as calculated by pixels.
Research showed that different emulsifiers appeared to have an impact on oil phase droplet formulation and stability at 45 °C. The group compared Polyoxyl 20 cetostearyl ether, (BASF tradename: Kolliphor CS20), and sodium lauryl sulfate. Kolliphor CS20 was shown to be more stable, resulting in stability after eight weeks. In contrast, the sodium lauryl sulfate began to separate in less than one week.
BASF’s team also examined the effect of accelerated aging, incubating one sample at ambient conditions and another at 45 °C for six months, then using Image J software to compare images of the two. The average oil droplet size was 50% greater for the sample held at higher temperature and humidity, where it was 5% larger for samples stored at ambient conditions.
Another set of experiments compared the average oil droplet area and minimum stability in weeks, to see if there might be a relationship between oil droplet size and stability. Researchers also evaluated flux versus average oil droplet area. Work provided insights into the properties of components between oil droplets, and such characteristics as swellability, solubilization capacity, and permeability.
Richardson noted previous research on this topic (10) and emphasized the importance of phase behavior and the interaction of fats, oils, and emulsifiers, which create semisolid networks and build stiffness into creams.
The team used x-ray diffraction to study these issues as well as micellar solubilization. Octododecanol was found to have an influence on the solubilization of clotrimazole. “Choosing the right fatty alcohol will influence formulation and sometimes a mix of cetyl and stearyl will result in greater stability,” Richardson noted.
BASF researchers used differential scanning calorimetry (DSC) to examine polymorphic behavior of the waxes. The team also examined the impact of excipient selection and fatty alcohol on rheology, and how oil and emollient affect API crystallinity, using Image J software to image and characterize results.
Following Richardson’s presentation, Padam Bansal, senior vice-president of Amneal Pharmaceuticals, discussed how research is progressing to understand Q3 microstructure in a heterogeneous semisolid matrix, and its impact on drug product quality (11), while Michael Lowenborg, senior manager of formulation and process development at DPT Labs, focused on the impact of process development on microstructure (12).
The forum promoted discussion of important questions, and attempts to find answers in an area that is still relatively new. “At this point, we don’t know what we don’t know,” said Raney in a post-workshop panel discussion, but participants showed an interest in probing this topic, and applying improved analytical methods and procedures, in the future.
1. AAPS 2015, BASF Pharma Ingredients and Services Technical Sessions and Workshops.
2. A. Shanley, “Optimizing Semisold Dosage Forms,” December 2, 2015, PharmTech.com.
3. Center for Dermal Research, “Topical Semi-Solid Microstructure and its Significance in Product Performance and Functionality,” a workshop held on May 24, 2016, at Rutgers University, Center for Dermal Research.
4. B. Michniak-Kohn, “Introduction, The Role of Microstructure in Topical Semi-solid Product Performance and Functionality,” presented at the Center for Dermal Research, Rutgers University, May 24, 2016.
5. S. Raney, “The Matter of Medicine: Does Form Follow Function, or Vice Versa?”, presented at the Center for Dermal Research, Rutgers University, May 24, 2016.
6. S.N. Murthy, “Topical Semisolid Drug Product Critical Quality Attributes (Q3 Characterization) With Relevance to Topical Bioequivalence,” presented at the Center for Dermal Research, Rutgers University, May 24, 2016, Accessed July 28, 2016.
7. N. Richardson, “The Influence of Excipient Choice on Topical Semisolid Microstructure and Performance,” presented at the Center for Dermal Research, Rutgers University, May 24, 2016.
8. B.W. Barry, Topical Drug Bioavailability, Bioequivalence and Penetration, Ed. V. Shah and H. Maibach, pp. 261-176, (Springer, NY, 1986).
9. National Institutes of Health, Image J download page.
10. T. de Vringer, et al., “A Study of the ageing of the gel structure in a nonionic O/W cream by X-Ray Diffraction, Differential Scanning Calorimetry and Spin-Lattice Relaxation Measurements, Colloid and Polymer Science, 1987, 5, pp 448-457.
11. P. Bansal, “Understanding of Q3 Microstructure in the Heterogeneous Semisolid Matrix and its Impact on Drug Quality,” presented at the Center for Dermal Research, Rutgers University, on May 24, 2016.
12. M. Lowenberg, "The Effect of Process Development on Emlsion Microstructures," presented at the Center for Dermal Research, Rutgers University, on May 24, 2016.