Excipient Evolution

by Lisa Schofield | June 3, 2024

The active ingredients may be the star of the show, but excipients are the workhorses behind the scenes.

One would not technically think of excipients when teasing out the concept of a new or improved dietary supplement formula—but they are a critical component. They have not been static, either. Excipients have evolved to adapt to consumer concerns about what they ingest, and about how what they ingest affects the planet in its journey to the bottle.

Cleaning Up

It appears that distillation down to the simplest add-ins with fewer superfluous ingredients is a growing consumer demand.

Chandan Kaiwar, senior product manager, excipients, Kerry, Wisconsin, observed that dietary supplement formulations have been strongly influenced by rising consumer preferences for clean label and natural products, safety concerns and regulatory mandates. “This has had a rippling knock-on effect on the excipient needs and applications of each product maker. Advancements in delivery systems, such as an increase in the use of soft gelatin capsules or non-gelatin capsules, demand excipients with equivalent compatibility and functionality to facilitate delivery of the active ingredients,” he said.

The idea of winnowing a formulation to exclude excipients to claim a clean label is gaining acolytes but it is not easy, according to Alicia Kasch, vice president, RIBUS, Inc. (Sparks, NV) “Formulators are realizing that while they don’t want to use excipients, they need to use them to make their active ingredients more usable from a production standpoint, and overall success. If formulators must use excipients, they’re increasingly more open to clean label excipients versus the traditional synthetic versions,” she explained.

Consumers have been focusing their interests on natural ingredients as they become more skeptical of artificial additives, and this has been a distinctive shift on the excipient portion of dietary supplement formulation, according to Russell Prestipino, global business manager, Colorcon (Pennsylvania).

“The market has been asking for more and more options for clean label excipients—ingredients responding to consumers looking for more natural alternatives, less chemical-sounding names, and fewer ingredients,” he remarked. Additionally, he noted, the number of alternative dosage forms (e.g., gummies, chewable tablets, soft gel capsules) – have significantly increased, representing a growing need of excipient solutions to deliver what consumers are seeking.

Part of what consumers consider clean is free-from materials that may cause allergic reactions, Prestipino added. For example, non-allergenic and hypoallergenic ingredients have been and will continue to be important in the dietary supplement world, as consumers (and parents) pay more attention to ingredients that are free from soy, gluten, dairy, etc.

Kaiwar agreed, noting that most new supplements have “free from” claims on packaging. This usually includes “free from” refined sugar, GMO (genetically modified organism), gluten, dairy, egg, artificial colors, flavors, MSG, among others.

Excipient suppliers are deep in R&D to create viable clean ingredients. According to Kasch, RIBUS has been making clean label excipients for more than 10 years, and clean label food ingredients for more than 30 years. “While we’re the Original Clean Label Ingredient Company, we’ve seen more traditional, synthetic excipient manufacturers launch their own versions of clean label excipients, which shows us that the market demand is not slowing any time soon,” she observed.

Prestipino explained that suppliers are trying to figure out ways to remove the traditional excipients that have been standards in oral solid dose formulations for decades and replacing them with more natural options.

Suppliers are invested in identifying ingredients generally not used for functionality and understanding the properties that these ingredients can offer to better formulate and pair up various properties to make a more optimized and natural solution, he added. “For example, taking functional ingredients such as flow aids and lubricants out of the formulation need to be replaced by less traditional, but equally functional excipients or mixes, that provide the flow and lubricity formulators need to make their processes work efficiently.”

Additionally, Prestipino said, excipient specialists are also making significant efforts to identify materials from sustainable companies and sources. During qualification of raw materials suppliers and their ingredients, work is done to ensure raw materials are responsibly sourced and sustainable, allowing excipient manufacturers to better assess the risk in their supply chains and continually search for more sustainable options.

Kaiwar stated, “Overall, the market is clearly trending toward the use of natural alternative opacifiers to replace established, traditional excipients like the mineral-based titanium dioxide.”

Going, Going, Gone

Indeed, looking to phase out older excipients is becoming more of a priority.

According to Kasch, silicon dioxide is “the biggest one that we’re seeing being replaced, in both conventional and certainly in certified organic products.” In 2013, the USDA (U.S. Department of Agriculture) National Organic Program (NOP) ruled that silicon dioxide cannot be used in organic products as long as organic rice hulls are commercially available, and she is still seeing brands make this change.

Magnesium stearate is another older excipient that Kasch identified as one that many formulators want removed from labels now that there are viable alternatives that meet current demands.

“Excipients, such as magnesium stearate, silicon dioxide, stearic acid, talc, etc., are just a few of the various excipients consumers are looking to replace,” said Prestipino. “Some of the many reasons for these requests are potential health concerns, widely covered lawsuits and sustainability awareness.”

Phasing out a critical component of a supplement such as an excipient, isn’t just a swift decision. Kaiwar explained that the process is somewhat arduous. With stringent regulations for and constant scrutiny on the safety of each ingredient and process step in the manufacturing of a finished product, multiple traditional excipients are now being scrutinized. “However, many traditional excipients play crucial roles in an end-use market like pharmaceuticals or dietary supplements and this is challenging the industry,” he related.

In the case of dietary supplements, he added, excipients that can cause an allergic reaction, like gluten-based fillers, lactose (lactose intolerance), or gelatin (halal requirements), are being replaced with less-reactive alternatives designed to cater to consumers with sensitivities or dietary restrictions.

Random Sampling

There are quite a few excipients that help “finish” a formulation. Here are several examples of what your R&D can explore.

According to Kasch, RIBUS manufactures clean label (plant-based, minimally processed) excipients that offer similar functionality to that of their synthetic counterparts. For example, its Nu-FLOW is made from ground rice hulls as an alternative to silicon dioxide. And it is now improved. “With oily or hygroscopic actives, Nu-FLOW wasn’t always effective enough, so we now offer Nu-SORP Oil and Nu-SORP Water for those more difficult formulations,” she described. “These excipients offer the anti-caking that they know in Nu-FLOW with increased adsorption properties of additional plant-based ingredients.”

Prestipino revealed that Colorcon “has been working diligently in this space to design both a clean label lubricant and filler for tablets and capsules that can replace other synthetic options.”

Colorcon’s Nutracore adds processing and formulation functionality that is lost with the removal of ingredients consumers are concerned with, such as magnesium stearate and silicon dioxide, he described. In addition, Nutracore can enhance commercial manufacturing by eliminating sieving and blending steps, resulting in streamlined processes, allowing for manufacturers to increase tablet and capsule output.

“Excipients play very important roles in pharmaceutical and dietary supplement formulations,” said Kaiwar. “Excipients form the backbone of the finished dosage form contributing to robustness, handling and delivery of the active ingredients to the target.”

For supplements, Kerry offers Sheffcoat coatings for supplements available in clear, white or pigmented; Lubritose MCC, a pre-lubricated microcrystalline cellulose that can assist with the poorly compressible natural ingredients or actives; and Disintequik OD oral disintegrating formula for chewable formats.

Roquette Pharma Solutions, France just launched new LYCAGEL Flex hydroxypropyl pea starch premix for nutraceutical and pharmaceutical soft gel capsules. The new plasticizer-free excipient gives manufacturers the ability to select the optimal plasticizer combination and customize formulations for plant-based soft gels.

According to Steve Amoussou-Guenou, technical developer manager Europe at Roquette, gelatin-based soft gel capsules can be challenging to manufacture successfully. Interactions with specific fill types, molecular crosslinking and sensitivity to heat and moisture during storage may compromise the soft gel’s stability, creating deformed, or ineffective supplements. He explained, “These issues are compounded when working with more advanced formulations. Here, manufacturers must precisely balance the ratio of gelatin to plasticizers, such as glycerol or sorbitol, to ensure optimal shell elasticity without increasing the risk of capsule leakage or other defects. What’s more, as a growing number of consumers pursue vegetarian, vegan or flexitarian diets, animal-derived ingredients, like gelatin, are becoming less of a universally accepted standard.”

LYCAGEL Flex features the same hydroxypropyl pea starch and carrageenan foundation as the original LYCAGEL VS 720 Premix, with a new formula that allows producers to select the perfect plasticizer or combination of plasticizers for soft gel formulations.

Upon testing, Amoussou-Guenou reported, capsules produced using LYCAGEL Flex maintained a clear, shiny appearance and optimal hardness with no sticking or seal leakage following six months of storage at 40 degrees celsius and 75 percent relative humidity.

“With no significant increase in disintegration time or water content after months in storage, the capsules did not display crosslinking, demonstrating their ability to maintain the same mechanical strength and capsule integrity at day 180, as they had directly after the production process,” he related.

Excipients overall are morphing to fulfill consumer demands and also provide outstanding performance and flexibility for a growing array of delivery forms and ingredient combinations that create market distinction. NIE