Tablets, capsules & soft gels: there are several issues to consider when delivering nutraceuticals in any of these formats.
Making a tablet--simple isn't it? Buy the ingredients, mix them all together and punch out the tablets. Piece of cake--or so some people believe. Like many seemingly simple functions tableting is not as easy as it appears. The supplement industry has undergone, and is continuing to see, major changes in the way it does business. Smarter consumers, quality conscious and knowledgeable buyers and ever-increasing scrutiny of analytical factors associated with the products has forced manufactures to better control the factors that collectively determine characteristics of the final product, and ultimately whether it passes or fails today's vigorous quality checks.
Moving Toward Higher Standards
The industry is moving toward pharmaceutical standards. In fact, tests performed on many supplements today were designed to test drugs and have been borrowed from that industry and tailored to the supplement industry. As a result, many supplements now require dissolution testing, accelerated stability testing and United States Pharmacopoeia (USP) monograph testing on weight, thickness, hardness, friability and disintegration. A finished tablet compliant with all USP and Dietary Supplement Health and Education Act (DSHEA) testing for dissolution, assay and accelerated stability is something to be proud of hut in order to achieve such results several important and interrelated factors have to be considered and controlled by the formulator. Depending upon the specific product and client specification, the following four factors are in the order of importance and should be taken into consideration. These include raw materials, processing steps and equipment, analytical objectives and pricing.
In most cases the nature of the active ingredient will dictate the role of the other factors. If the active ingredient makes up the bulk of the tablet vs. a small amount of active such as B12, biotin or folic acid, or is difficult to tablet, the formulator must construct the excipient base appropriately. Not only the amount of active but type of material is an important consideration.
Herbs, vitamins and minerals, fibrous materials and oil-based products all behave differently under compression depending upon the physical characteristics of the material. In addition to the inherent nature of the material, consideration must also be given to the form in which the material is available. Many raw materials are available in powder form, granular form and a combination of both, all of which could provide different results on the same tablet machine.
The expertise and knowledge of the formulator in deciding which materials to specify cannot be underestimated. The objective is always to end up with a free-flowing uniform mixture that gives consistent weights throughout the run and meets the targeted physical specifications and analytical requirements. Fortunately, the improved processing of raw materials has given formulators greater choices from which to choose and more materials are now available as granular instead of powder.
Furthermore, several traditionally difficult materials are now available as coated or spray dried, or put on a substrate to help in the tableting process. Whether it is the result of competitive environment or improved processing with greater flexibility, raw material vendors are more anxious to work with you on obtaining specific forms of the material needed. The variety of raw material forms are helpful in minimizing internal processing requirements and obtaining desired product tableting performance. Also, disintegration agents, lubricants and flow agents are being refined and more directly address specific functions in the tableting process.
Coating materials and systems have also shown improvement over the "old way" of doing things. What used to be the norm--the use of solvents such as methylne chloride, methanol and IPA--has given way to less offensive water- based systems using cellulose. In addition, Zein--a corn based protein and shellac or food glaze--was and still is used by some manufacturers. Materials like Zein worked well for appearance and sealing tablets but they extended disintegration times and interfered with other analytical procedures. In addition, consumers became more conscious of the origins and uses of some of these coatings and began to exclude these products from use.
Another area of importance, is the excipient category. More customers require that no animal or petroleum-based material be used in products, while others object to the use of acids or solvents. More creative forms of cellulose or other botanical-sourced materials are becoming available, which is helping to increase satisfaction levels. That said, raw materials have come a long way in helping manufacturers meet increasing analytical expectations.
To granulate or not to granulate, mill or oscillate, chilsonate or slug, what sequence to blend and how long to blend--these are all important processing decisions that can affect the physical characteristics of the final mix. As previously mentioned, the technical expertise of the formulator is extremely important. If the wrong choice is made, the material will not compress satisfactorily and will have to be reworked to achieve the proper characteristics.
The granulation process involves wetting the raw material and mixing it to introduce granules that, when dried, will facilitate a uniform flow of the material. It is also used to coat certain materials that are sticky or unstable or tend to leak or bleed into the tablet. However, as more directly compressible (granular) and coated materials become available this step is required less and less.
The blending or mixing process creates a uniform and homogenous mixture. Using the wrong equipment on the wrong material or using the correct equipment but over blending, can change particle sizes or over lubricate the material, creating tableting problems. Correct instructions for production should specify mixing times, equipment, and in some cases, loading sequences of material.
Mills, grinders and oscillators are used to control particle sizes by putting the material through several different types of screens. Speed, screen size and charging rate all play a role in determining the end product. This too is another internal processing step that has become less necessary as more choices become available among raw materials.
Dwell time, precompression and tonnage exerted are processing variables that can also affect the material being tableted. As a result, these variables can yield different results from tableting the same material in the same punch shape on three different tablet machines.
Much of the decision making process in determining raw materials and their forms for a specific product is knowing what is expected during the testing process. A timed release or enteric coated product will require different materials and processing steps than will a 30 minute disintegration product. Several countries have their own standards, which differ from the USP monographs and those differences must also be accounted for in the formulation process.
As the industry evolves and moves forward more test requirements and requests for information will come from both consumers and customers. The ability to meet these standards is dependent upon the formulator's expertise and experience, as well as the material choices available in the marketplace. The increased pressure on manufacturers to comply has, again, motivated raw material suppliers to make available both new and improved materials, which provide the formulator with greater control over a tablet's behavior.
Of course, full analytical support to a customer can be expensive. Not only are FT-NIR's (Fourier Transform--Near Infrared), HPLC's (high pressure liquid chromatograph's), dissolution apparatus' and micro facilities expensive to purchase and maintain, they also require precious room. Since procedures such as dissolution are expensive to do, batch size of the product must be taken into consideration in terms of pricing. Obviously a charge for additional work is less of an impact if spread over two million tablets rather than half a million. Also keep in mind that although many routine tests are included in a normal pricing structure, several customers routinely request either a unique methodology, available only from a specific lab, or a test using specialized equipment.
Another factor in analytical work that may surprise newcomers in the industry is that results can vary. Without going into all of the variables, suffice it to say that any veteran of the industry, at one time or another, has been embroiled in a spitting contest between labs over who had the correct results. For this reason, it is always smart to have an agreement with customers designating an acceptable third party lab to resolve discrepancies.
In today's competitive environment price is always a factor. Several key components of cost include raw materials, processing requirements and analytical requirements. Since the raw materials comprise the bulk of the cost it is important to review pricing on a regular basis.
The key is to get the best price without sacrificing quality or service from your suppliers.. If it is hard to choose, it is best to choose the quality material from established vendors using contracts, volume discounts or other mechanisms to get the best price possible. It is also important, however, for R&D departments to keep an open mind to new vendors in the marketplace and innovative materials that contribute to the bottom line. A new material that is more costly per kilogram than a proven "old reliable" could lower costs overall if it reduces one or more processing steps or solves a marginal dissolution situation. Prudent R&D and quality control (QC) decisions dictate documentation and piloting, prior to making wholesale changes. Costs can be looked at on a one time, short term or long term basis but for client and manufacturer, the long term solution will work best.
About the author: Greg Williford is vice president, sales and client services for Vita Tech International, Tustin, GA. He can be reached at 714-832-9700 or firstname.lastname@example.org.
By Tammy Mathis
Marketing Specialist-Dietary Supplements
The history of the capsule dates back to 1730 when it was first mentioned in a pharmacist's travel journal. Since then the evolvement of the dosage form has continued over the centuries facing several issues and overcoming many challenges. In 1931 Arthur Colton made a major breakthrough when he successfully designed a machine that would form and fit together a two-piece capsule on behalf of Park, Davis and Co. Even today's machinery holds the same basic design of Mr. Colton's original model.
The capsule as a dosage form has strong roots and continues to thrive as it provides a natural choice for dosage form decision makers.
The evolution of the capsule continues as the years have spawned a plethora of options. Sizes, colors and print designs offer a way in which companies can differentiate their products. Additionally, capsules are being developed with a variety of materials, which meet specific dietary requirements.
The are several capsule sizes to choose from including 000, 00, and 0, which are popular dietary supplement choices. Beyond these sizes, however, even smaller capsule options exist and include 1,2,3, and 4 (smallest).
A trend that is emerging in the nutraceuticals market is the use of color and print design to differentiate brands. There is an array of acceptable color choices available, including natural colorants. Print design really enables a product to have a visual impact on consumer recall of brands. Additionally, brand names, Internet addresses, logos or special designs are also used by manufacturers to further distinguish product lines.
Manufacturers are also becoming more sensitive to consumer needs by providing a wider selection of capsule choices that meet specific dietary requirements. Due to the global nature of the marketplace it has become increasingly important to understand the special needs of consumers. For example, the Halal two-piece capsules made by Capsugel meet the specific dietary needs of its Muslim customers and the capsules are certified as Halal by the Islamic Food and Nutrition Council of America (IFANCA). Further, capsules meeting Kosher needs are also available.
Another upward trend is the vegetarian capsule. As companies become more aware of filling specific dietary requests, many have reevaluated and revamped their product lines. Some companies are addressing the matter by adding line extensions and in some cases, they may choose to replace their gelatin capsule products with capsules made of vegetarian material. Although only a small portion of the population would consider themselves strict vegetarian--the larger population is becoming more in tuned to a vegetarian selection as this is a simple way to make a healthy lifestyle choice.
Capsule Manufacturing Issues
As in any manufacturing operation there are those problematic areas that beg for solutions. For encapsulation certain materials such as fruit and vegetable fibers and vitamin C can present challenges to operators of capsule filling machinery These products are sticky and gummy and don't have the proper "flow characteristics" to provide good filling. Tim Sopko, technical service engineer for Capsugel, suggests adding colloidal silicon dioxide to improve the flow of the such gummy solutions, thereby improving overall production efficiencies,
Vegetarian and gelatin capsules pose another set of challenges. Vegetarian capsules and gelatin capsules look identical when unfilled as they have similar unfilled weight specifications and physical properties. However, when they are run on a filling machine, modifications should be made to accommodate gelatin or vegetarian material in order to Optimize production. For instance, vegetarian capsules have much lower moisture content and are somewhat less resilient. Based on this difference, machine changes must be made to accommodate for moving from one material to the other. Both capsules will run well and give very positive results but it is important to remember that they are different and therefore require a different filling set up.
When there is a choice to be made between a compressed dosage form and a capsule--the capsule is a more natural choice because they require less excipients and binders. Moreover, the risk of over compressing a compound into a non-dissolvable mass is reduced. Whether the choice is a gelatin or non-gelatin, capsules offer the perfect container for pure formulations.
Educational Initiatives: A Case Study
Capsugel has a history of experience with pharmaceutical companies and understands how to translate their learnings. Adopting practices from its pharmaceutical accounts, Capsugel coaches its customers in the practices that will ensure a positive encapsulation experience. As an example, customers are encouraged to regularly inspect for worn out parts, which can often be the root of poor machinability. They are also coached in adopting incoming controls, including the examination of the physical properties of raw materials, proper bulk densities and proper fill weights in finished products.
Capsugel also believes in partnering with its customer base. To support this, the company formed Capsugel University (CU). CU gives companies an opportunity to support quality, improvement and productivity through training and education. Its curriculum ranges from general courses such as capsule filling technology, good manufacturing practices (GMPs) and writing standard operating procedures (SOP's) to quality related courses such as statistical process control, data analysis and sampling. In addition to the overall curriculum offered at CU, courses can also be specially designed to meet the needs of its customer base.
About the author: Tammy Mathis is marketing specialist--dietary supplements for Caps ugel, Greenwood, SC. She can be reached at 864-942-3830; E-mail: email@example.com
By Dr. Roger Gordon
Banner Pharmacaps, Inc.
High Point, NC
Soft gels are not just a pretty package. For a majority of consumers they are the most preferred delivery system of any oral dosage form on the market today. According to Advances in Therapy, September/October 2000, soft gels are preferred over tablets 9 to 1 and 16 to 1 over two-piece hardshell forms. It is obvious that these products are clearly making an impact on the way consumers make their choices in today's marketplace.
Getting Rid of a Reputation
A few years ago companies looked to avoid using soft gels because of the lengthy lead times and poor service that was characteristic of an industry with too much demand, too little capacity and few systems to move the process along. Fortunately the situation has turned around in a way that few could have imagined.
Today, 26-week lead times have been whittled down to eight-week lead times, and significantly less if a manufacturer keeps core items in stock. Furthermore, companies are now able to run smaller quantities for new, custom products, enabling marketers to test marker new products before they commit to large volumes without any successful history.
Brand Differentiation for Soft gels
There are more manufacturers than ever to choose from to the point where differentiation has become critical in the industry. Additionally, sales are climbing with the increased popularity of products like CoQ10, fish oil and saw palmetto. Strong science and increased media attention have helped boost sales. While simple oils like vitamin E are obvious products for the soft gel form, complex pastes can also be successfully manufactured and marketed.
These products generally require a solid R&D staff and a project management team in order to successfully manufacture. As an example, Banner Pharmacaps, High Point, NC, has developed a unique applications lab where its scientists work with marketers to test small quantities of product in a soft gel dosage form before going to pilot testing. This allows for significant savings in both time and money in getting a product to market.
Despite overwhelming evidence that consumers prefer the soft gel dosage form, few companies are stepping up to convert their lines and actively market to the consumer. With the aging of the U.S. population, marketers need to pay more attention to the issue of 'swallowability' with respect to the elderly
It is estimated that over 90% of the population over 65--a segment of the population that is very brand loyal--has some difficulty swallowing. Marketers providing products that meet a need for this segment may not only win customers but substantially increase their bottom line.
The Future of Soft gels & Nutraceuticals
Soft gels will continue to play a large role in the marketplace, especially in two areas--first, where the active compound is most effective in a lipid-based system, and secondly, where companies are willing to differentiate their brand by leveraging the consumer's preference for soft gels in their marketing efforts.
Look for companies to be coming out with non-animal based gelatin products, based on market demand. Finding a film-forming compound that is as functional and as robust as gelatin is technically demanding, but solutions are beginning to appear in the market.
In the 21st century, success in the marketplace will be defined by quality products based on sound scientific data that produce visible results in the health and well-being of consumers. In order to do this, however, the industry must regain the confidence of the U.S. consumer and must educate with accurate information. In addition, the U.S. government is headed toward further enforcement of Dietary Supplement Health and Education Act (DSHEA) guidelines, which will only help to increase the credibility of the industry with consumers, the media and health practitioners.
About the author: Dr. Roger Gordon is president--U.S. Operations for Banner Pharmacaps, Inc., High Point, NC, He can be reached at (336) 812-4729.
RELATED ARTICLES: BioProgress Xgel[TM] Film System: Encapsulation Of The Future?
BioProgress, Atlanta, GA, is an emerging biotech company dedicated to commercializing its intellectual property in the field of water soluble and biodegradable films. The company's XGel[TM] Film System is a patented process that eliminates the use of gelatin in manufacturing, among other products, capsules and soft gels. According to the company, gelatin has been the only material suitable for encapsulating non-aqueous products such as vitamin oils (dietary supplements), pharmaceuticals and cosmetic oils since the 1930s. However, BioProgress believes its XGel Film System is revolutionary in that it eliminates animal byproducts from ingestible products used to deliver pharmaceuticals and dietary supplements at lower cost compared with traditional methods.
There are several different options and innovations that have come forth from the company including films that are animal free, non-toxic, non allergenic, biodegradable and comprised of generally recognized as safe (GRAS) ingredients that are commonly used in food and pharmaceutical applications. Capsules can contain liquids, suspensions, pastes or dry powders and capsule dissolution rates can be adjusted to meet specific customer product requirements.
Currently in development, the Septum capsule will be able to combine any combination of two active substances. For example, a combination of oils and powders, with each half specifically modified to dissolve at different times. In terms of enrobing, BioProgress has developed its Nrobe[TM] technology as a high speed process designed to replace traditional two piece hard capsule and tablet coating processes. The enrobing films may be modified to meet specific dissolution and oxygen barrier requirements XGel films are printable or may be pre-printed prior to tablet application and enrobed capsules can be produced in any color or two color combination.
The target for BioProgress is the multibillion dollar expanding global encapsulation market with mass appeal. As the company moves forward it aims to be the leading non-gelatin encapsulation technologists. Furthermore, it will use knowledgebase to develop exclusive product lines. Its revenue streams include licensing intellectual property, selling XGel film systems, selling the XGel film and selling R&D services.
Most recently, the company made its first sale to Peter Black Healthcare Limited (PBHL) based in the U.K. As a part of the deal, BioProgress sold a full license and the first fully functioning XGel Film system. PBHL is a supplier of private label vitamins, minerals and herbal supplements and produces 34% of all capsules made in the U.K. For additional information visit the company's website at www.bioprogress.com.
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|Date:||May 1, 2002|
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