Advances in tablets and capsules.
Each year, millions of traditional tablets and capsules fill the dietary supplements market. But as these delivery forms face tougher competition from alternatives-think functional foods and beverages-where does this leave tablets and capsules? Thankfully, these delivery forms, too, are taking steps forward to deliver more of what consumers want: convenience, efficacy, lifestyle match, and appeal being just a few.
Bi-layer tablets offer nutraceutical formulators several benefits. “Bi-layer technology can be of great help when nutraceuticals are physically or chemically incompatible,” says Reza Kamarei, PhD, vice president of science and technology, Sabinsa Corp. (East Winsdor, NJ).
“For example,” Kamarei continues, “if one nutraceutical has acidic properties and another has basic properties, or if they are enzyme/substrate pairs, it is best to physically separate them so that they do not react together prior to ingestion and each survives intact during storage.”
Bi-layer tablets can also allow one tablet to contain nutraceutical formulas with different release profiles. “For example,” says Kamarei, “the product could have an immediate-release layer in combination with an extended-release or delayed-release layer.”
Last summer, Sabinsa introduced a bi-layer tablet line under the name Integrated Nutritional Composites (INC). Shaheen Majeed, marketing director, points out that although bi-layer technology is not necessarily new per se (it is more commonly seen in the pharmaceutical sector), this technology is newer to the nutraceuticals side of the market.
Taking this “newness” further, in addition to customizing bi-layer tablets for customers, Sabinsa can also help provide innovative, preconceived condition-specific formulas using the company’s own ingredients. Currently the company offers the following INC Actives designs: Blood Sugar Support INC Actives, Weight Management INC Actives, Heart Health INC Actives, and Heart Health + INC Actives. “Our cardio and cholesterol formula is a modified-release tablet that is designed for cardiovascular and cholesterol support management. This bi-layer tablet has one layer with an immediate-release profile, while the second layer has an extended-release profile,” says Kamarei. In the second formula, “The reason that niacin is formulated in the extended-release layer is to avoid flushing (redness, itching, and tingling) due to sudden release of niacin.”
What does the future hold in store for Sabinsa’s bi-layer innovation? “Sabinsa is also working on condition-specific ingredient combinations which were never really contemplated before, not on paper nor in a single-layer tablet or capsule because we felt people just couldn’t see it,” Majeed says. “For example, a combination of ingredients for digestion and supporting healthy cholesterol levels.”
He says another possible use for bi-layer INC technology would be a case in which it is desirable that probiotic and prebiotic ingredients be consumed at the same time by the consumer-but not necessarily premixed beforehand. Majeed says that bi-layer synbiotic pills may be preferred, 1) to bypass the delicate and time-consuming step of premixing a probiotic and a prebiotic, saving time, energy, and money, and 2) when a company wants to create a visual distinction between the ingredients, in two separate layers in a pill, as part of an effort to teach consumers about the individual and complementary roles of probiotics and prebiotics.
“Looking forward for bi-layer tablets containing numerous natural ingredients with different release profiles, the sky is the limit,” he says.
And if bi-layer tablets are booming, might tri-layer tablets be thrice as nice? At this year’s Vitafoods show, Aenova Group (Pähl, Germany) introduced technology for manufacturing three-layer tablets.
Says Aenova, “Within the last decade, multilayer tablet technology has become increasingly popular due to its suitability for manufacturing high-quality products for the nutraceutical and pharmaceutical markets.”
As with bi-layer tablets, each layer of a tri-layer tablet can feature a different dissolution and release profile. The technology can accommodate the combination of interacting and otherwise incompatible substances in one tablet.
There are user benefits as well. For instance, by combining ingredients, multilayer tablets may make it possible for consumers to reduce the number of pills they need to take in a day. “Most people find it much more convenient to take a solid dosage form once a day in the morning, rather than taking several capsules or tablets at different times during the day,” the company says. “From a marketing perspective, multilayer tablet technology offers many benefits and opportunities to differentiate their brand from competitors’ products.”
An entire brand can be created around the concept of a delayed-release, multilayer tablet. Just ask Gregory Gossett, the managing director of Time Engineered Technologies LLC. The company recently debuted a new supplement called Easy Up Wake Up Formula.
The company describes Easy Up as “a time-delayed coffee bean extract caplet that is engineered to deliver the caffeine equivalent of a cup of coffee seven to eight hours after going to bed. It’s like getting your first cup of coffee when you really need it-right before you wake up! Plus, it delivers a second equivalent cup over the next eight hours.”
Consumers take the supplement before they go to bed. While sleeping, it takes approximately seven to eight hours for the tablet’s coating to dissolve and release the coffee extract, Gossett says. After the first release, the tablet continues to then release more caffeine in the body over the next eight hours. In total, the supplement releases approximately 110 mg of caffeine. (Each supplement contains 200 mg, but the company said not all of that is absorbed or released.)
To achieve the delayed release, the tablet has a double layer of release coating. Plus, Gossett adds, “The inner tablet, or the matrix of the tablet, is made and compressed in a certain way so that it also plays a part in the delayed release.”
To ensure the tablet works as promised, the company performed rounds of dissolution testing. “We do a 16-hour dissolution test-Electrolab TDT-08L Dissolution Test,” Gossett says. “During the first two hours, testing is done in an acidic medium to simulate the stomach. During the other 14 hours, testing is done in a Phosphate Buffer Solution (alkaline medium) to simulate the intestine environment.”
Gossett says the company has received positive feedback so far. “Most people in the industry say, ‘I can’t believe that someone never thought of this before,’” he says, pointing out that while there are many sleep aids on the market, there are fewer “waking up” aids.
It just goes to show, he says, “The right product concept and the right delivery system are a synergistic combination.”
In the United States, 35% of supplement users say that a vegetarian or non-animal source is important when choosing a supplement. Not only is this figure up from 26% in 2006; this group of consumers seeking a vegetarian source is among the most frequent users of supplements.1 Clearly, delivery systems would do well to cater to this audience.
Capsugel (Greenwood, SC) offers more than a dozen different types of hard-capsule shells. These range from traditional gelatin shells to products that accommodate specific dietary preferences, such as Vcaps vegetarian-based HPMC capsules. The company recently introduced its latest innovation in vegetarian capsules, Plantcaps, made from a pullulan polymer naturally fermented from tapioca.
Plantcaps aren’t your average vegetarian/vegan-friendly capsules, the company says. According to the firm’s Americas region director of sales Mark Vieceli, the capsules can also comply with organic standards. “Certifying agencies have allowed organic labeling for some ingredients delivered in pullulan capsules in the United States due to the capsules’ naturally fermented source.”
Missy Lowery, the company’s marketing manager, adds, “The fact that these capsules are a clean-label product offers companies several marketing advantages, which include the ability to claim the product as vegetable origin, preservative free, gluten free, allergen free, and non-GMO. Moreover, it satisfies consumers’ dietary needs with its GRAS status and kosher and halal certifications. Plus, it has approval by the UK Vegetarian Society.”
Finally, in terms of aesthetics, “The capsules’ elegant crystal-clear transparency and high degree of luster further evoke a natural image important with today’s green-conscious consumer,” concludes Lowery.
In addition to vegetarian offerings, Capsugel’s portfolio spans many different capsule requirements. Innovation is employed to create different physicochemical properties, such as slow disintegration rate or specialized release profile. A wide range of polymer choices is readily available from a variety of gelatin sources: bovine, porcine, or fish. The company’s Licaps capsules contain liquids and semisolids securely and can be used to deliver unique combinations of ingredients. Ingredients that are hygroscopic or moisture-sensitive (e.g., probiotics) and/or have other stability concerns can be formulated in low-moisture vegetarian capsules. Capsugel also recently launched DRcaps capsules, which delay disintegration by as much as 30 minutes in a pH of 1.2. An added benefit is that the capsule coating helps mask any unpleasant ingredient odor or taste.
Compressing dietary supplements and herbal remedies into tablets can be demanding on processing equipment, including tablet presses and compression tooling. In many instances, powders are abrasive, have inconsistent particle-size distributions with variability in the amount of fine and coarse material present, and can also tend to be sticky. However, today there are a variety of solutions to overcome these potential problems.
Obviously, first off, invest in die tooling that will last. “Tablet die wear is a common cause of tablet defects such as lamination and soft edges, which can later be detrimental during the tablet coating process,” says Dale Natoli, president of tablet press specialist Natoli Engineering Company (St. Charles, MO). “Worn dies will also accelerate punch-tip wear and punch-head wear, as particles have the tendency to migrate between the punch tip and die wall, inducing tool binding, tablet discoloration, and black specks, along with many other undesirable issues.”
He suggests using a carbide die over a steel die. “While carbide is more expensive, it is well worth the extra investment, as this type of die will generally last 10 times longer than the traditional steel dies, while reducing tablet deficiencies and increasing tooling lifetime.”
Natoli says his recommendation for solving “sticking” problems during tablet press operation is to try a combination approach. “Simply coating a set of tooling can cost thousands of dollars and still offers no real solution to the problem,” he says. “It is suggested that a manufacturer evaluate tooling [problems] using a combination of different types of composite steels and coatings.”
Start by testing and evaluating different tool coatings to determine which will work best. Typical tooling coatings are composed of either chromium, chromium nitrite, or titanium nitrite. Natoli suggests trying an experimental method to test which coating is best: if a tablet press has 35 stations, divide the tooling into seven separate groups of five tooling sets each. “Have each of the five mini sets prepared with a different combination of tooling coating and type of steel composite,” says Natoli. “This will allow the best scenario to evaluate the different coatings and steel types under the same conditions related to powder characteristics, press speed, ambient conditions, etc. The only variable will be the tooling. By inspecting the tablets and the cup surfaces, it will be easy to determine which coating or type of steel composite is optimal for the powder and operating conditions.”
Excipients serve multiple purpose: improving powder flowability, acting as binders in various granulation processes and as disintegration aids, and improving direct-compression properties. For materials to be good excipients, they must have good flow properties and be capable of being compacted under pressure.
Two ingredients in this arena are pregelatinized cornstarch and maltodextrin. Both are listed in the U.S. Pharmacopeia and the National Formulary (USP–NF). Pregelatinized cornstarch is a free-flowing excipient with a higher bulk density than a maltodextrin. It is multifunctional and can perform as a binder, disintegrant, and lubricant.
On the other hand, Susan Freers, technical manager for Grain Processing Corp. (Muscatine, IA), explains the benefits of a maltodextrin excipient like the company’s Maltrin M150. “The physicochemical properties of maltodextrins can be varied to suit different applications. For instance, Maltrin M150 is a spray-dried powder with a fine particle size. It can be used with active ingredients having a fine particle size, without the concern of separation during blending. Because of M150’s excellent binding properties, it is also used to improve tablet friability problems and prevent capping.”
By contrast, another maltodextrin, Maltrin QD 550, offers other benefits. “It is an agglomerated product with a larger particle size and a lighter bulk density than a typical spray-dried maltodextrin,” Freers says. “The particles of this powder contain interstitial spaces that provide excellent carrying properties for oils and finer-particle-size active ingredients. The lighter bulk density of this product also improves disintegration properties for quick-dissolving tablets.”
Some ingredients, although not listed in the USP-NF, may act as excipients while also providing nutritional benefit. Ingredion (Westchester, IL) offers two such products: NutraFlora prebiotic fibers and Aquamin marine complex.
Prebiotic fibers help beneficial gut microflora proliferate. NutraFlora prebiotic fiber, composed of short-chain fructooligosaccharides, may also support bone health, as it helps to increase the absorption of minerals.
As an excipient, “Tablets manufactured with NutraFlora compress well, and since this excipient is very soluble, it has a clean, slightly sweet taste and works well in chewable applications,” says Cristina Munteanu, scientist, technical service. “In capsule applications, NutraFlora is often used in symbiotic products that contain both pro- and prebiotics.”
“However,” she adds, “NutraFlora is hygroscopic and therefore requires product packaging having a good moisture barrier.”
The company also offers Aquamin, a natural, multimineral marine complex derived from responsibly harvested, mineral-rich red algae (Lithothamnion calcareum). As a rich mineral source, Aquamin provides a unique combination of up to 74 minerals such as calcium, magnesium, phosphorous, manganese, etc., which are recognized as important for optimum bone health. Studies in people with moderate-to-severe osteoarthritis of the knee and subsequently given Aquamin showed improvements with pain, stiffness, activity, mobility, as well as walking distance, the company says.
As an excipient, “Aquamin is available in two forms depending on application need. Aquamin tablet grade (TG) is ideal for tableting applications, as it is processed with non-GMO cornstarch to optimize tableting characteristics. Aquamin F is recommended for capsule applications, as it is a fine, free-flowing powder with a smaller particle size and density profile, ideal for capsule plug formation,” sums up Munteanu.
Ensuring product safety for consumers is not only part of GMPs, but it just makes good business sense. Companies may have to go through detailed laboratory preparation and then wait several days to determine and confirm the presence of various bacteria, yeast, and molds in their products. However, more rapid screening and testing methodologies have evolved that are now able to give manufacturers a much faster assurance that their products are free from any harmful contaminants.
Equipment developed by Biolumix (Ann Arbor, MI) now exists that is fully automated, easy to operate, and can detect a single viable bacterial cell within 8 to 14 hours and a single yeast cell within 20 to 30 hours. This technology can be used with either raw materials, in-process samples, or with finished tablet and capsule products. The proprietary technology is based on monitoring changes in a microbial liquid growth medium in which the target microorganisms grow and are detected by unique dyes (color or fluorescence). The dyes change their color or fluorescence as metabolic processes occur. These changes are then detected by the machine’s optical sensors and monitored ten times per hour.
Samples are first diluted 1:10 in growth media, meaning that 1 part of the sample powder or liquid is diluted in 9 parts of growth media so that bacteria can grow. The solution is then subsequently placed into vials containing two zones separated by a membrane filter. An incubation zone is located at the top of the vial and contains the sample undergoing microbial growth. The reading zone is located at the bottom of the vial, and this is in the path of the optical detector. This two-zone vial eliminates masking of the optical pathway by the product and by microbial turbidity. Because changes in the color or fluorescence are monitored in the reading zone, results are not influenced by the sample or the microorganisms.
“This technology has been extensively studied and validated and found to be just as accurate as the older standard Petri plate methodology for the detection of microorganisms in nutraceutical products,” says Dr. Ruth Eden, president, Biolumix. “Furthermore, a company can rapidly be alerted following detection of poor-quality raw materials, in-process materials, and/or finished products. This technology also offers companies tremendous cost savings as well. For example, while outside testing laboratories charge between $10 to $25 per test, Biolumix vials cost between $2 to $3, offering a significant cost savings,” concludes Eden.