INFORM March 2025

inform March 2025 Volume 36 (3)

The Destiny of DETERGENTS

ALSO INSIDE: Microemulsions for drug delivery Contaminant mitigation strategies Updates to the Safe Choice Standard

EDIBLE OILS REFINING: BASIC PRINCIPLES & MODERN PRACTICES

This course takes a stepwise approach to explain the informed decision-making used by edible oil manufacturers to produce a purified, palatable vegetable oil. It includes practical applications for optimizing plant operations and features modules on cold-pressed vegetable oils and biodiesel fuel pretreatments.

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8 FEATURES

Highly concentrated laundry detergents get the job done on Earth and beyond Laundry detergent producers have delivered their product in many forms, from the powders and solutions of the past to today’s pods and tiles. This article describes the science needed to formulate detergents for a more environmentally friendly, sustainable world—including formulations for doing laundry in outer space.

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Improving the solubility of lipophilic compounds Polyethylene glycol is commonly used in drug delivery nanoparticles, but adverse reactions are becoming more common and new compounds are needed to introduce lipophilic drugs into the blood stream. Surfactant chemists are using their knowledge of micelle formation to create self-microemulsifying drug delivery systems. Read about their successful applications that resulted in getting lipophilic compounds into solution. Improving psoriasis treatment with micro-emulgels This story comes from an AOCS journal and provides another example of the research efforts currently being dedicated toward using surfactant science to expand treatment options. In this case, the authors of a Journal of Surfactants and Detergents paper described solubilizing botanicals in an ointment to relieve psoriasis symptoms. A strategy for navigating MOH risks A researcher describes the sources of potential mineral oil hydrocarbon contamination in the palm oil supply chain and how implementing a comprehensive mitigation strategy can secure a supply chain that aligns with global food safety standards.

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CONTENTS

4 Index to Advertisers 13 AOCS Events

5 Editor’s Letter 6 Division Update

28 Regulatory Review 30 Extracts & Distillates

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ADVERTISING INSTRUCTIONS AND DEADLINES Closing dates are published on the AOCS website (www.aocs.org). Insertion orders received after closing will be subject to acceptance at advertisers’ risk. No cancellations accepted after closing date. Ad materials must be prepared per published print ad specifications (posted on www.aocs.org) and re ceived by the published material closing dates. Ma terials received after deadline or materials requir ing changes will be published at advertisers’ risk. Send insertion orders and materials to the email address below. NOTE: AOCS reserves the right to reject adver tising copy which in its opinion is unethical, mislead ing, unfair, or otherwise inappropriate or incompat ible with the character of INFORM . Advertisers and advertising agencies assume liability for all content (including text, representation, and illustrations) of advertisements printed and also assume responsi bility for any claims arising therefrom made against the publisher. AOCS Advertising: Travis Skodack, Director Membership Phone: 1-217-693-4897 Email: travis.skodack@aocs.org Formerly published as Chemists’ Section , Cotton Oil Press , 1917–1924; Journal of the Oil and Fat Indus tries , 1924–1931; Oil & Soap , 1932–1947; news por tion of JAOCS , 1948–1989. The American Oil Chem ists’ Society assumes no responsibility for statements or opinions of contributors. INFORM (ISSN: 1528-9303) is published 10 times per year in January, February, March, April, May, June, July/August, September, October, November/ December by AOCS Press, 3356 Big Pine Trail, Ste C&D, Champaign, IL 61822 USA. Phone: +1 217-359 2344. Periodicals Postage paid at Champaign, IL, and additional mailing offices. POSTMASTER: Send ad dress changes to INFORM , PO Box 7230, Champaign, IL 61826 Subscriptions to INFORM for members of the American Oil Chemists’ Society are included in the annual dues. An individual subscription to INFORM is $195. Outside the U.S., add $35 for surface mail, or add $125 for air mail. Institutional subscriptions to the Journal of the American Oil Chemists’ Society and INFORM combined are now being handled by Wiley. Price list information is available at http://olabout. wiley.com/WileyCDA/Section/id-406108.html. Claims for copies lost in the mail must be received within 30 days (90 days outside the U.S.) of the date of issue. Notice of change of address must be received two weeks before the date of issue. For subscription inquiries, please contact Julie May at AOCS, julie.may@aocs.org. AOCS membership information and applications can be obtained from: AOCS, PO Box 7230, Champaign, IL 61826 USA or membership@ aocs.org. NOTICE TO COPIERS: Authorization to photo copy items for internal or personal use, or the inter nal or personal use of specific clients, is granted by the American Oil Chemists’ Society for libraries and other users registered with the Copyright Clearance Center (www.copyright.com) Transactional Report ing Service, provided that the base fee of $15.00 and a page charge of $0.50 per copy are paid directly to CCC, 21 Congress St., Salem, MA 01970 USA.

AOCS MISSION STATEMENT AOCS advances the science and technology of oils, fats, proteins, surfactants, and related materials, enriching the lives of people everywhere.

inform International News on Fats, Oils, and Related Materials ISSN: 1528-9303 IFRMEC 36 (3) Copyright © 2013 AOCS Press

EDITORIAL ADVISORY COMMITTEE

Julian Barnes Etienne Guillocheau Jerry King

Gary List Thais L. T. da Silva Warren Schmidt Raj Shah

Ryan Stoklosa Ignacio Vieitez Bryan Yeh

AOCS OFFICERS PRESIDENT: Tony O’Lenick, SurfaTech, Lawrenceville, Georgia, USA VICE PRESIDENT: Gerard Baillely, Procter & Gamble, Mason, Ohio, USA TREASURER: Greg Hatfield, Bunge Limited, Oakville, Ontario, Canada SECRETARY: Fabiola Dionisi, Societe’ Des Produits Nestlé - Nestlé Research, Lausanne, Vaud, Switzerland PAST PRESIDENT: Grant Mitchell, Salas O’Brien, Cincinnati, Ohio, USA CHIEF EXECUTIVE OFFICER: Patrick Donnelly

AOCS STAFF EDITOR-IN-CHIEF: Rebecca Guenard MEMBERSHIP DIRECTOR: Travis Skodack

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The views expressed in contributed and reprinted articles are those of the expert authors and are not official positions of AOCS.

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EDITOR’S LETTER

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Surfactants for better consumer products and healthcare treatments

A growing number of consumers are making a conscious choice when it comes to laundry. They wash fuller loads at a lower temperature to save energy and extend the clothes’ lifetime. Sustainable laundry detergents are made with fewer ingredients, biodegradable materials, natural fragrances, and they are more highly concentrated. In our cover story this month, multiple industry experts describe the complex science behind making a concentrated laundry detergent. Read about the many challenges that must be considered and how developing a detergent for space might help formulators overcome them. Next, microemulsions have emerged as promising advanced drug delivery systems due to their unique proper ties and versatile applications. This distinct class of disper sions, containing oil, water, and amphiphile, are characterized by their transparency or translucency and thermodynamic stability. They offer several advantages, like prolonged shelf life, improved drug solubilization, and ease of preparation and administration, that make them attractive for drug delivery. Microemulsions maintain constant droplet sizes with min imal oil/water interfacial tension. This stability and uniformity contribute to their effectiveness as drug carriers, allowing for controlled or sustained release across a range of administra tion routes. From ocular to percutaneous, topical, transdermal, and parenteral applications, microemulsions offer versatile delivery platforms that can accommodate various therapeu tic needs. And by reducing the volume of the drug delivery vehicle, they help minimize toxic side effects associated with conventional formulations. In the case of lipophilic drug admin istration, microemulsions facilitate absorption by aiding in the solubilization of the compounds in the human body. In this issue, we have two stories about drug delivery with microemulsions. The first is the story of researchers who use their knowledge of the HLD-NAC model to tune microemulsion formulates for optimal containment of lipophilic compounds. The second feature article summarizes a recent research paper

on the development of a new, microemulsion psoriasis treat ment that is made more effective with fewer side effects than what is currently available. Our last feature article is by a researcher who describes how her company instituted a mineral oil hydrocarbon risk assessment on their palm oil processing supply chain and the mitigation steps they implemented to ensure the highest pos sible food safety. Their lessons learned are translatable to any edible oil manufacturer. I look forward to seeing everyone next month in Portland!

Yours in science,

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Surfactants and Detergents Division Spotlight

PHIL VINSON, 2025 SAMUEL ROSEN AWARD WINNER

the Fabric and Home Care organization. While this has been a period of tremendous technical achievement in our surfactant platform, I feel my role in mentoring younger scientists and researchers and developing the next generation for P&G R&D has been the most important accomplishment. INFORM: What is your most significant contribution to the surfactant industry? Vinson: With over 100 patented innovations, I have worked both with internal partners across many functions and with outstanding external partners across the industry to bring many transformational innovations to life. As the largest com mercial user of surfactants in the world, P&G has used these innovations to help create and manufacture new and better detergents to improve billions of consumers’ lives worldwide. INFORM: What difference has AOCS made in your career? Vinson: Early on, AOCS conferences and the Journal of Surfactants and Detergents helped me learn more about the industrial side of surfactants and build my network across the industry. The conferences and journal have also provided me with an avenue for presenting my technical work, chairing ses

The Surfactants and Detergents (S&D) Division is one of AOCS’s largest interest areas. The Division encompasses the sciences and technologies associated with the development and pro duction of surfactants, detergents, and soaps. For this month’s spotlight, INFORM interviewed Phil Vinson, the recipient of the 2025 Samuel Rosen Memorial Award, which recognizes an indi vidual who has made a significant advancement, cumulative advancements, or application of surfactant chemistry princi ples. This award commemorates more than 40 years of Samuel Rosen’s work as an industrial chemist on the formulation of printing inks, initiated and sponsored by Milton J. Rosen. Phil Vinson has a doctorate in chemical engineering from the University of Minnesota. He is currently the Senior Director for Procter & Gamble’s (P&G) Fabric & Home Care Surfactant Innovation Strategy with over 100 patent families on new materials and formulations used in consumer product brands. INFORM: What is your greatest career accomplishment? Vinson: My greatest career achievement has been to lead P&G’s upstream surfactant innovation program, since 2010, for

Phil Vinson

YOUR AOCS COMMUNITY

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Years of experience

Surfactants and Detergents Surfactants : Surfactants are compounds that lower the surface tension between two substances, such as a liquid and a solid or between two liquids. Detergents : Detergents are a type of surfactant specifically designed for cleaning purposes. They are complex formulations that often include multiple ingredients to enhance their cleaning performance. Key Points Surfactants: Lower surface tension, interact with water and oils, used in cleaning, emulsifying, and foaming. Detergents: A type of surfactant for cleaning, complex formulations, break down and remove dirt and stains. Manufacturing Process: Involves formulation, preparing surfactant solution, mixing and blending, neutralization (for liquids), drying (for powders), and packaging.

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sions, and serving as a reviewer, associate editor, and on the JSD advisory board, thereby increasing my exposure outside of P&G. INFORM: What do you see as the biggest challenge the industry faces in the future? Vinson: I think the biggest future challenge will be to balance cost, capital, and performance against new government regu lations and environmental sustainability. Doing this in a holis tic manner that takes the full life cycle, including the consumer use component, into account is complex and will require even greater partnership across industry, academia and government organizations. INFORM: What teacher or mentor has inspired your career the most and why? Vinson: It is hard to pick just one person as there have been many important inspirations along the way. My parents and other ancestors demonstrated how one can accomplish amazing things through hard work, deep thought, and creativity. My family, especially Jane, my spouse of 40 years, have always provided support and encouragement. My doctoral advisors at the University of Minnesota, Ted Davis and Skip Scriven, and associated mentors, Wilmer Miller, Jayesh Bellare, Ishi Talmon and Fennel Evans, introduced me to the world of surfactants and provided me with a deep techni cal foundation in colloid science. On occasion, Robert Laughlin, the first Rosen award recip ient, would visit our department at the University. In vari ous project discussions, he illustrated the important role that

surfactants and phase behavior play in P&G’s R&D and com mercial products. Early in my career at P&G, Steve Caravajal and Scott Cooper instilled in me the importance of thor oughly defining the problem to be solved and for building my network. Magda El-Nokaly “adopted” me (and many others) and introduced me to Communities of Practice, and Jeffrey Scheibel and Dan Connor (both former Rosen award recipients) introduced me to industrial processes and precursors import ant to surfactant design and manufacture. These early influ ences set the stage for much of the rest of my career. Along the way, tremendous inspiration—as well as a whole lot of fun—came from the numerous scientists that entered our team and brought with them new skills and perspec tives. Around 2015, William Scheper became the vice president of our organization. Bill worked with each of us to “raise the bar” and set high expectations for our deliverables, while also taking the necessary steps to enable and empower us. This was highly energizing to the organization and an important contribution to my successes over the past decade. INFORM: If you could offer one piece of advice to the new generation of surfactant chemists and formulators, what would that be? Vinson: Dream big and set a high bar for yourself, but also be pragmatic. Learn the science at a deep enough level that you can make wise decisions and recommendations. Create part nerships in order to maximize the opportunity, reduce risk, and facilitate communications. This will help turn your innovations into solutions that are a win-win for consumers, external part ners, and your company.

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With the typical US family washing about 300 loads of laundry every year, water and energy usage can be significant. Engineering advances mean that most modern, high-efficiency washing machines need much less water than older models. However, the machines are larger and hold more clothes, requiring detergents to do more per load. Still, consumers often puzzle over how much detergent to use per load, and how all of that water and electricity use is impacting the environment? Highly concentrated laundry detergents get the job done on Earth and beyond Katie Cottingham

Highly concentrated detergents on the market today aim to address all of these concerns in one product, whether it be in the form of a small splash of liquid in a bottle cap or as a single-dose pod, sheet, or tile. “A concentrated product is more powerful and not watered down, it is convenient, and because it has a smaller dose, it needs less packaging,” says Wendy Saladyga, senior manager, R&D, at Henkel Consumer Brands North America in Connecticut. They sell all ® , Purex ® , and Persil ® detergents. Smaller packages are generally lighter than the huge jugs of the past, which is particularly helpful for differently abled consumers, and they take up less space. Shipping costs and the greenhouse gases involved in transport go down as the product size shrinks. And products such as laundry sheets and tiles are often sold in degradable paper or cardboard packaging. “About four percent of all of your home electricity goes into heating water for laundry, and so the industry is focusing on using cold water,” says Brian Grady, professor at the University of Oklahoma in Norman, Oklahoma. Rising to the challenge, raw materials companies and formulators are designing new types of surfactants, which are the main cleaning ingredi ents in detergents, as well as new ways of combining ingredients. Newer detergents are now able to clean a wide range of stains in cold conditions and developing a product for astronauts to use in space could provide a wealth of knowledge that will benefit Earth-bound consumers. Here we consider the latest science behind cleaning laundry more sustainably, using less water and energy.

• Highly concentrated detergents typically come in smaller packages and are more eco-friendly than detergents of the past. • Scientists have developed new, extended surfactants that could concentrate products even further. • A detergent formulated for use in space is helping scientists optimize products for use here on Earth.

SURFACTANTS AND DETERGENTS

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A RECIPE FOR CLEAN From the old standby of laundry powder to the now-dominant liquid—and emerging products like pods, sheets, and tiles— the recipe for cleaning clothes has steadily evolved (although some aspects have remained the same). Regardless of the for mat, detergents work with water and agitation to remove soils from fabrics and keep them tucked away in suds so they can go down the drain with the wastewater. The surfactant is the workhorse cleaning agent, but deter gents also can have builders, or chelators, to sop up metal ions in hard water. In addition, the recipe typically includes dispersion agents to help keep dirt separated from fabrics, fragrances for a fresh smell, and stabilizers to keep the ingre dients from separating and to protect enzymes from degrad ing. Enzymes are often added to break down specific types of stains. Although bleach is unstable in liquid detergents, it works well as a component in powders and is found in many powder formulations. Detergents usually include three or four surfactants that remove stains by reducing the interfacial tension between the water and the stains on the fabric. To do this, the hydrophilic head—which can be charged or nonionic—binds water, and the hydrophobic tail binds oils at the other end of the mol ecule. High concentrations of surfactant lead to the forma tion of micelles, small spherical aggregates of surfactant with the headgroups on the outside and tails in the core. Micelles lock away oils so they can be removed from clothing and

Enzymes digest specific stains Proteases: Proteins in blood, egg, grass, sweat Amylases: Starches, such as pasta and chocolate Lipases: Fats in fatty foods and oils Cellulases: Natural cotton fibers to remove pills Mannanases: Sticky gums that are in foods like mayonnaise and cosmetics

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washed down the drain. Using multiple surfactants lowers the critical micelle concentration at which these spheres form, boosting the cleaning power of the detergent. Dirt particles are removed when a negatively charged anionic surfactant adsorbs to the particle and the fabric, weakening the attrac tion between the two. “You typically have a primary surfactant that is doing the majority of the work,” says Larisa Reyes, research scientist at Dow in Freeport, Texas. “It is there because it is very efficient, but you tend to add secondary or co-surfactants to enhance either the cleaning, solubility, or compatibility of that primary surfactant.” Anionic surfactants, such as linear alkylbenzene sulfonates (LAS) and alcohol ether sulfates (AES), have negatively charged heads. These compounds are effective against soil, dirt, clay, and some oils. They foam easily, but are sensitive to hard water, binding calcium and magnesium ions in the water and making it more difficult for them to form micelles. Nonionic surfactants, such as alcohol ethoxylates (AE), do not have a net charge so they are not as sensitive to hard water. They are the least expensive of the surfactants and can remove many types of food stains, oils, and greases.

“Liquid detergents usually contain a combination of LAS, AES, and a nonionic,” says George Smith, technology manager, Sasol Chemicals, in Westlake, Louisiana. “Everybody changes the ratios depending on their formulation, style, and other properties that they want in the detergent.” Powders are gen erally based on LAS. GETTING CONCENTRATED Making a detergent more concentrated is not as simple as removing most of the water. “As you concentrate, it becomes harder to formulate,” says Grady. “The higher the surfactant concentration, the more likely it is going to interact with the other ingredients, particularly enzymes.” To make detergents more concentrated, formulators can use less of some ingredients or optimize others. “For example, if you have an ingredient that is doing two roles instead of just one, then you can make the detergent more compact,” says Reyes. “Or you can have one component that is much more efficient so that you can reduce the amount of a less efficient one.” In the 1980s and 1990s, structured liquids were a pop ular way to concentrate detergents in Europe, says Smith.

PODS, SHEETS, TILES, OH MY! Single-dose formats are a fast-growing segment of the laundry industry, says Saladyga. PODS Almost every major detergent

TILES Still being market-tested, Tide evo ® is a non-woven tile. It has six layers and is P&G’s most concentrated form with no added fillers, according to Sivik.

brand, including Arm & Hammer™, Tide ® , and all ® sells detergent pods, sometimes called paks. Smith says they debuted in the 1960s, but did not really take off until they were re-introduced in 2012 by Procter & Gamble. According to Smith and Grady, they contain highly concen trated surfactant enclosed in a poly vinyl alcohol pouch.

SHEETS Several brands, such as Arm & Hammer™, Tru Earth, and Clean People, sell laundry sheets. They look like a dryer sheet and are casted lay ers of detergent with polyvinyl alco hol and other ingredients. About half of a sheet’s weight is surfactant, says Smith.

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A concentrated detergent with a typical surfactant gels (left), whereas one with an extended surfactant does not (right). Source: Juliana Caixeta Guimarães

“Companies would basically force the surfactant into a lamel lar phase,” he says. “Because it is a dispersion, it has a unique rheology that allows you to suspend things in it, so it was used as a delivery vehicle for sodium tripolyphosphate.” However, phosphates from wastewater cause eutrophication, enriching bodies of water with nutrients that spur algal blooms, which deprive aquatic life of air and sunlight. Thus, phosphate-based materials are no longer used in consumer laundry products. Mark Sivik’s team at Procter & Gamble (P&G) recently developed a highly concentrated tile-shaped product called Tide evo®, which is being test-marketed in Colorado. Sivik is R&D senior director research fellow in Cincinnati, Ohio and his group considered every ingredient, especially surfactants, when creating the material. “We use a portfolio of surfactants, and we use them in a unique way that drives efficiency,” he says. “We look at dif ferent structural features and design them to manage the vis cosity of our product so that when it hits cold water or it is concentrated, it does not get into the gel phase.” He says they have removed many inert ingredients, such as processing and dissolution agents that would be in a typical powder. Another way to make detergents more compact could be by using extended surfactants, which to these experts’ knowledge, are not yet included in products sold today. With such molecules, a linker is inserted where the head and tail of a surfactant meet and it serves as a gradual polarity tran sition zone. The slightly polar linker extends the reach of the hydrophilic head into water and the hydrophobic tail into oil, which improves solubilization, making the detergent more powerful. Typically, polypropylene oxide (PO) groups are placed at the tail and ethylene oxide groups are placed at the head. Extended surfactants can work well, but they have lim itations, according to Smith. “You can get ultralow interfacial tension between oil and water and get really good clean ing, particularly for cold-water washing,” he says. “But once you get more than about four moles of PO on the molecules, it does not pass the biodegradability test, which limits their usefulness.”

Undeterred, Reyes and her team took this approach when developing two new extended surfactants they called advanced prototypes 3 and 10 (AP-3 and AP-10). The new mol ecules are based on PO-modified AE which the researchers tweaked and optimized to meet certain criteria. They found that when concentrating these prototypes into a detergent they averted a potential challenge with gelation that is com mon with nonionic surfactants, like AE.

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“If they have gel issues, they will have some viscosity con trol issues, and that can impact cleaning by not dissolving eas ily,” says Reyes. The results for AP-3 and AP-10 so far are promising. “We have superior viscosity control for the formulations we tested, even if you reduce the solvent in them, and they dissolve quickly in water.” Reyes says that she thinks these properties make the new molecules ideal for concentrated laundry pods. The new compounds clean soils as well as or even better than conventional surfactants in cold water in the formulations tested. Both are readily biodegradable. AP-3 shows lower tox icity to aquatic life and less eye irritation hazard compared to commonly used primary AEs. AP-10 carries no aquatic toxicity classification and is not an eye irritant. The new molecules work well in model formulations in the lab, and they have been tested in commercial detergents. The actual performance may vary with detergent formulations and washing conditions. “The major disclaimer is that formulator and brand owner will have their own proprietary recipe,” she says. SPACE LAUNDRY When trying to innovate a product that has been in the mar ketplace for over a century, considering how to clean in extreme environments can bring new perspectives. And you do not get more extreme than living extraterrestrially.

How do astronauts do laundry in space? The answer is that they do not do laundry at all, and that is a real quali ty-of-life problem for astronauts on long missions. “Astronauts actually have their clothes burned as waste, as no laundry is currently done on the International Space Station (ISS),” says Sivik. Crew members often wear their clothing for as long as two weeks or until they can no longer stand the smell, says William Shearouse, group scientist, who is also at P&G. Not only is the smell and feel of dirty clothes unpleas ant, but with long-term missions planned to the moon and Mars, NASA realized that it would not be cost-effective to peri odically ship clean clothing to astronauts. Thus, the agency teamed up with P&G to develop a space-compatible laundry detergent. To avoid interfering with air handling and water-recycling systems, the detergent could not include volatile organic compounds like fragrances and organic solvents. The final product, called Tide ® Infinity, is concentrated in the sense that it is formulated to only contain ingredients that drive cleaning performance. The surfactants in the product were formulated to be stable using only water as a solvent due in part because water will be part of the mission’s payload for washing clothing in a modified washing machine. As a result, compacting the detergent by removing the relatively small amount of water in the product that would be shipped to the ISS was not needed.

Tide Infinity detergent is formulated for use in space habitats and is seen here in the International Space Station for stability studies. Source: NASA

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“Instead of going super-compact, we thought about how to maximize the cleaning ingredients and the concentration,” says Shearouse. Water was used as a solvent and they lever aged the stabilizing properties of polymers and AEs. The team removed all unnecessary fillers and kept only ingredients required to perform well in zero or micrograv ity. This unique environment impacted the surfactant choice. Without gravity to hold down and manage suds, the research ers opted to use surfactants that would not foam as much as typical detergents, avoiding the use of silicone suds suppres sants and additional water needed for rinsing. This finding is applicable to product development on Earth, too. But the detergent also had to clean clothes, so it under went several tests with cold water in the lab, both on Earth and on the ISS. In addition to the detergent studies, the ISS crew investi gated stain removal with a modified version of the detergent on fabrics with stains from foods and beverages. Curiously, astronauts routinely sport sriracha stains. “In space, crew members go through a bit of sensory deprivation,” says Shearouse. “Because of that, they use a lot of sriracha on their food and it is a common stain.” Further crew member testing is now underway at NASA’s Crew Health and Performance Exploration Analog in Houston, Texas which According to the experts, concentrated laundry detergents are already powerful and do more with less. But there is always room for improvement, and scientists are busy making deter gents more concentrated while also satisfying eco-conscious consumers. “I think the challenge is how do you keep the cleaning effi ciency or effectiveness and incorporate these other targets like sustainability, energy-savings (cold cleaning) and safer materi als,” says Reyes. “The opportunities continue to be vast,” says Sivik. “There will always be a need to develop more efficient ingredients and deliver them in the most effective way possible in the most concentrated form.” He says, just as people became accus tomed to coffee pods that pack a lot of flavor into a small cup or pouch, they are growing used to laundry pods. And Grady and Smith predict there will be even more sin gle-dose products in our future. “I think we are moving toward a pod or sheet future,” says Grady. Reyes emphasizes that regardless of the form or formula tion, companies need to remember the needs of the consumer and put those first. “Ultimately, this research is for them,” she says. Katie Cottingham is a freelance science writer and editor whose work has appeared in publications, such as Science , Scientific America n, and Smithsonian Magazine . She can be contacted at katie.cottingham@yahoo.com. simulates long-duration missions. LIKE A CRISP, CLEAN SHIRT, THE FUTURE IS BRIGHT

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Improving the

Lipophilic compounds have poor solubility in aqueous environments, including our bodies. This is a problem since many small-molecule drug therapies are lipophilic compounds. There is thus a need for new lipid-based drug delivery systems (LBDDS) to enhance the bioavailability of these com pounds. But the choice of biocompatible ingredients for formulating such LBDDS is limited and for mulating them has proven challenging. solubility of lipophilic compounds Diana Gitig

Traditionally, polyethylene glycols (PEG) have been used to aid in lipophilic drug delivery because of their favorable solvent properties. However, PEG are made from petroleum. Beyond not being environ mentally friendly, they have other associated safety concerns. In some cases, the body recognizes them as foreign material and initiates pro duction of anti-PEG antibodies, triggering the release of proinflam matory cytokines, and leading to accelerated blood clearance of the very active ingredients they are supposed to be delivering. They can inadvertently deliver toxic impurities left over from industrial process ing, like the carcinogen ethylene oxide. And there have been reports of PEG inducing hypersensitivity and anaphylaxis. Finding a replace ment composed of biocompatible compounds is thus of paramount importance. To that end, Mehdi Nouraei worked on self-microemulsifying drug delivery systems, or SMEDDS, when he was a doctoral student in Edgar Acosta’s lab at the University of Toronto in Ontario, Canada. SMEDDS are combinations of linkers, surfactants, and oils that sponta neously form microemulsions, with droplet sizes ranging from 10-100 nm, when they contact an aqueous phase. In contrast to emulsions and nanoemulsions, microemulsions never break. Because they are thermodynamically stable, microemulsions always remain in a single phase. DESIRED DILUTABILITY Acosta is a leading expert in developing delivery systems for lipophilic active ingredients. With over 20 years of experience, his team has created numerous biocompatible lecithin-based formulations that have advanced the field. Nouraei’s research project involved developing a fully dilutable SMEDDS platform which, when diluted, would create single-phase microemulsions and deliver ibuprofen at any water concentration, from zero to nearly 100 percent ( https://doi.org/10.1016/j.ijpharm.2021.121237).

• Many important drug therapies have limited use due to their low aqueous solubility. • Lipid-based drug delivery systems have been used effectively to enhance the solubility and increase the bioavailability of hydrophobic active pharmaceutical ingredients. • For food-grade applications, the polyethylene glycols that are popular encapsulation materials will need to be replaced. • One research group used their HLD-NAC model expertise to create a delivery system that exists as a single-phase liquid upon dilution with water and tested it in a variety of applications from drug therapies to food products.

SURFACTANT APPLICATIONS

inform March 2025, Vol. 36 (3) • 15

Almost all previous formulations were only partially dilu table, forming microemulsions when the water content is high. What is unique about Nouraei’s approach is the complete range of dilutability that is possible. When the SMEDDS preconcen trate is mixed with water, it first turns into reverse micelles and then flips into a bi-continuous system. Finally, at high water con tent, it forms direct micelles. All these phase transitions happen without crossing any phase separation boundaries. This full dilutability is essential, Nouraei said, because when you take a capsule, you do not know how much water is in your stomach and intestine. Nouraei also stressed that this flexibility allows for the design and development of multiple dosage forms. FORMULATION CHALLENGES However, formulating such a successful fully dilutable SMEDDS turned out to be quite a challenging and resource-intensive procedure that involved constructing numerous ternary phase diagrams and testing hundreds (or even thousands) of possi ble formulations to map the dilution profile of each candidate formulation. To accelerate the process, Nouraei turned to the HLD-NAC model: the hydrophilic-lipophilic-difference (HLD) and net-average-curvature (NAC) framework. HLD is a set of equations correlating the hydrophobicity of the oil and the surfactants in the SMEDDS, the salinity of the aqueous solution they are to be dropped into, and the tem perature. NAC then interprets the HLD value as the normalized net curvature of the surfactant-oil-water interface. HLD-NAC can thus be used to determine and predict the required type and characteristics of oils and surfactants to use and the mini

mum amount of surfactant required in a SMEDDS to produce a single-phase microemulsion when it is diluted with water. The model also predicts many other outputs such as drop size, type of microemulsion, viscosity, and surface tension. And when there is a problem, like phase separation due to drug-formula tion interactions, the model can tell you what the problem is and how to tweak the components of your SMEDDS to achieve a smooth dilution path with no phase separation. “We used ibuprofen—a non-steroid anti-inflammatory drug—as a model insoluble compound and noticed that since ibuprofen is a polar oil it plays somewhat of a surfactant role itself. The model guided us to use a super-hydrophilic linker in the SMEDDS to restore the full dilutability of the system,” Nouraei said. The results of an animal study showed a significant increase in the absorption and bioavailability of SMEDDS formulated ibuprofen compared to regular tablets. A NEW APPLICATION Since receiving his doctorate, Nouraei became the Founder, Chief Scientific Officer, and Chairman of the Board at Micellae Delivery Systems, where he used the same approach to discover a delivery system for cannabinoids (https://micellae.com). There is no dearth of companies selling upscale canna bis products to upscale millennials promising to deliver just the right amount of mellow buzz with CBD laced seltzers, teas, juices, and gummies. But behind all of that flashy marketing, some pretty hardcore science is required to figure out how to get lipophilic cannabinoids to dissolve in those yuzu and wild berry tonics.

16 • inform March 2025, Vol. 36 (3)

40 35 30 25 20 15 10

Lecithin + lipophilic linker + hydrophilic linker

D60 SMEDDS (60 vol% surfactant 40 vol% oil)

Ibuprofen in D60 SMEDDS

D60 SMEDDS dilution

2-phase boundary

Ibuprofen suspension

Plasma conc. ug/ml

5 0

HLD-NAC predicted

0 100

200 300 400

500

2 phase region μ E + oil

Time, min

Simulated intestinal fluid

Ethyl caprate + ibuprofen

Demonstrating ibuprofen-loaded SMEDDS are fully dilutable and measuring ibuprofen absorption in vivo. Source: Nouraei, et al. , IJPharm , 610, 121237, 2021.

Cannabinoids are insoluble and have very low bioavail ability (6-12 percent). Using the SMEDDS technology, Micellae has developed a unique absorption-enhancing solution that uses lecithin and other plant-based surfactants in lieu of PEG based surfactants, making theirs the first and only self-dispers ing, fully water-dilutable SMEDDS made entirely of food-grade, plant-based excipients. Their proprietary formulation platform is called O2W, for oil to water. The animal study data on O2W showed promising results on significant reduction of onset time and increase in CBD absorption. “Initially, our focus was on making cannabinoids more sol uble in consumer products like beverages, water-based tinc tures, gummies, and topicals for recreational and wellness uses,” said Nouraei. “However, we have since shifted to lever aging our technology for pharmaceutical applications.” In collaboration with ears, nose and throat specialists at University of Toronto hospitals and the University Health Network, Micellae developed a “fast muco-penetrating” lipid nanoparticle (MP-LNP) intranasal formulation of CBD to treat chronic rhinosinusitis. The promising results from preclinical studies support advancing to a phase 1 clinical trial. O2W is available as a preconcentrate SMEDDS, as a partially diluted SMEDDS, as a diluted microemulsion, as a microencap sulated SMEDDS in solid-state powder form, and as a semi-solid gel. It enhances the speed and extent of CBD absorption, which is essential; a big problem with conventional cannabis edibles is that people do not feel the effects for as long as hours after ingestion, which can lead to overdosing. With Micellae’s O2W formulation, plasma concentration in rats peaks twenty to thirty minutes after ingestion, and people have reported feel ing effects within fifteen minutes or less. This was much quicker than when cannabinoids were delivered via the more standard carriers, olive oil and MCT (medium chain triglyceride) oil. Moreover, about half as much of CBD’s main second ary metabolite, 7-COOH-CBD, was produced in rats fed with

O2W-enhanced CBD compared to rats fed with CBD-MCT. This suggests that CBD delivered via O2W has a higher degree of lymphatic absorption and reduced metabolism in the liver. This can reduce the risk of liver damage sometimes associated with CBD and its metabolites and can also alleviate CBD’s potential drug-drug interactions with the many pharmaceuticals that are metabolized in the liver, especially among chronic users. Because microemulsions, in contrast to nanoemulsions, are thermodynamically stable, O2W-enhanced cannabis-in fused beverages and gummies are shelf stable for over six months to a year at room temperature, as is the undiluted O2W water-free concentrate loaded with CBD. O2W is sta ble in liquids with pHs ranging from 2 (like Coke, Sprite, and 7Up) up to 8 (like alkaline water). It retains its stability through ultra-high-temperature pasteurization, gradual increases of temperature from room temperature to 100 o C, and through multiple cooling and heating cycles. And long-term toxicology studies in rats indicated that it is safe. “We use all plant-based components–oils, polyglycerols, lecithins, and terpenes–but in different ratios,” Nouraei said. “We mix and match ingredients and ratios. The formulation is customized for each application: beverages are different from capsules are different from gummies.” Nouraei stressed that their technology can be used to enhance the delivery and bioavailability of any lipophilic com pound, ranging from pharmaceuticals to nutraceuticals, cos metics, and even agricultural active ingredients, in forms ranging from tablets, capsules, topical, and transdermal creams or patches, to nasal rinses and sprays. Diana Gitig earned her PhD in cell biology and genetics from Weill Cornell Graduate School of Medical Sciences in New York City. She writes about cell and molecular biology, immunology, neuroscience, and agriculture for arstechnica.com. She can be reached dmgitig@gmail.com.

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18 • inform March 2025, Vol. 36 (3)

Improving psoriasis treatment with

micro-emulgels Rebecca Guenard

Psoriasis, a chronic autoimmune inflammatory skin condition, affects millions globally, often leading to physical discomfort and psychological distress. Existing treatments, including synthetic drugs and phototherapy, frequently come with numerous side effects, from skin irritations to systemic complications like hypertension and joint pain. A recently published paper in the Journal of Surfactants and Detergents describes a topical treatment made with bioactive compounds infused in micro-emugels that improves the drugs’ absorption and bioavailability, maximizing their therapeutic benefit (https://doi.org/10.1002/jsde.12829).

A team of researchers from Wadhwani College of Pharmacy in Maharashtra, India centered the new treatment around quercetin (QCT) and ferulic acid (FA), two plant-derived bio-actives renowned for their antioxidant and anti-inflammatory properties. These compounds show remarkable potential to mitigate psoriasis by suppressing pro-in flammatory mediators, such as TNF-α and IL-17, and preventing the pro tein binding that leads to inflammation. However, their therapeutic use has been limited by poor solubil ity and bioavailability. Quercetin has a 3-hydroxyflavone backbone. Its solubility in water is minimal to non-existent due to its lipophilic and hydrophobic properties. The combination of microemulsions with a hydrogel, described by these researchers, presents an opportunity to develop an alternative, natural psoriasis treatment with fewer negative effects. THE SCIENCE BEHIND MICRO-EMULGELS The micro-emulgels the team formulated used oleic acid as an oil phase, polysorbate 80 as a surfactant, and propylene glycol as a co-sur factant. Together, they create a thermodynamically stable system with nanometer-sized droplets, enhancing drug solubility and skin penetra tion. This advanced delivery mechanism ensures that bio-actives reach deeper layers of the skin effectively. Unlike traditional creams or ointments, micro-emulgels offer superior spreadability, stability, and patient compliance. The integra tion of bio-actives into a hydrogel base also enhances their controlled release, reducing the frequency of application and increasing therapeu tic efficacy.

• A research team describes formulating a microemulsion with encapsulated bioactive compounds and ensconcing them in a hydrogel. • They analyzed the resulting micro emugels and found the bioavailability of the active ingredients improved compared to direct application. • In addition, the physical properties of the resulting formulas indicate a better patient experience which leads to better compliance with treatment regimen. • Their results could lead to an effective treatment for psoriasis suffers.

AOCS JOURNALS

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TESTING THE FORMULATIONS To evaluate their potential as a natural psoriasis treatment, the researchers prepared and tested separate microemulsions with quercetin and ferulic acid before combining them into a formulation. They characterized each microemulsion formu lation by analyzing pharmaceutical properties, such as per cent transmittance, refractive index, globule size, and so on. The results indicate that there was no phase change of the microemulsions due to drug incorporation. In addition, they found uniform distribution of fine globules that were stable and unlikely to coalesce. These characteristics were tailored to ensure not only maximum drug loading but also stability and ease of application. These optimized batches of bioactive containing micro emulsions were then embedded in a hydrogel base and the test of pharmaceutical properties rerun. The results indicated that the team developed a transparent, neutral pH formulation that would be non-irritating for sensitive skin. A significant concern in psoriasis is the risk of secondary bacterial infections, particularly from Staphylococcus aureus . The micro-emulgel formulations also demonstrated potent antibacterial activity, with the QCT-FA combination showing synergistic effects. This dual-action capability—anti-inflamma tory and antimicrobial—positions the formulation as a compre hensive treatment option.

CONTROLLED DRUG RELEASE Ex-vivo diffusion studies highlighted the formulation’s ability to deliver bio-actives at a controlled rate, maintaining therapeutic levels over extended periods. The team performed Franz diffu sion method studies on the optimized microemulsion formu lation batches and free drugs loaded in a hydrogel base. Then plotted the results as the percent cumulative drug released verses time to obtain zero order release of the bioactives. The diffusion study suggested that compared to free drug in hydrogel base, the drug loaded in micro-emulgel showed controlled release of the drug from formulation. The feru lic acid escaped the free form gel too fast with 100 percent released in just four to five hours. While the quercetin, bearing negligible water solubility, showed insufficient release from the hydrogel matrix. The team conducted release studies of drug loaded micro-emulgel formulations, along with further kinetic model ing. The best fitted kinetic models suggested that the release of drugs from the micro-emulgel formulations was indepen dent of the concentration. They also performed a Korsmeyer Peppas kinetic model and determined the drug transport mechanism through the polymer matrix, suggesting the drug was released by anomalous, non-Fickian transport. This means the drug was released from the micro-emulgel by diffusion, as well as erosion. These are favorable results, because a sus