Formulating solid-dose nutraceutical products, such as tablets, capsules and powders, can cause technical challenges. In order to understand these challenges, it's best to compare pharmaceutical formulation versus nutraceutical formulation. These challenges need to be explored as our industry progresses toward stricter regulations and higher standards, which are, in some ways, identical to those used for the pharmaceutical industry.
The most common multivitamin formulas contain up to 50 active ingredients and two to eight excipients including coating ingredients. Traditional pharmaceutical formulations contain one to four actives and five to six excipients. These higher numbers of active ingredients in nutraceutical formulations bring challenges related to particle size, flow, compressibility, moisture sensitivity, ingredient interaction, content uniformity and quality control (QC) testing. For example, some active ingredients may be available in granular form, while some may be available only in fine powder form; some may be hydrophilic and others hydrophobic. Thus, the ingredient blend may have many different particle sizes and ingredients with a variety of characteristics. Ingredient blends can also have segregation and flow issues. Tablet production from these blends can result in capping, sticking and different patterns on the faces of tablets during compression, as well as basic content uniformity problems.
In the case of pharmaceutical formulation, controlling the properties of ingredients is typically far less complicated due to fewer ingredients per formulation and far less variation in their characteristics. Pharmaceutical ingredients and formulations with their clearly delineated characteristics and specifications lend themselves to the application of mathematical formula or pre-formulation concepts such as angle of repose, excipients compatibility study, compressibility index or Hausner ratio. However, it is difficult to apply these concepts to nutraceutical formulations due to variety and number of ingredients, batch-to-batch ingredient variation and inconsistency in material characteristics. Furthermore, literature addressing the properties of ingredients used in nutraceutical formula is not readily available.
Pharmaceutical products are made from an API (approved pharmaceutical ingredient) and excipients, and pharmaceutical formulations have a published monograph and associated literature. Dietary supplements may be made of foods, old dietary ingredients (ODIs) and new dietary ingredients (NDIs). Most approved ingredients do not have sufficient literature readily available regarding their physiochemical properties. Vendor-supplied certificates of analysis (CoAs) are helpful, but most are basic and incomplete. Most CoAs lack basic information, such as moisture content, density and particle size. Predicting properties of the resulting final blend of these ingredients depends on firsthand experience of a formulator and machine operator rather than just scientific reasoning. For example, formulators and research and development (R&D) personnel would think most herbal formulations require granulation. However, by experience, formulators understand some herbal extracts, such as green tea extract (standardized to contain 98-percent polyphenols and 50-percent epigallocatechin gallate [EGCG]), can be compressed easily without granulation and may even help in the compression of other non-compressible ingredients. Another example is the taste of amino acids, which does not have much research. By experience, formulators understand it is in better to use some amino acids in their salt form instead of pure form in powder formulations because the base form may taste bitter whereas salt form will likely taste sour. For example, L-arginine base has a bitter taste but L-arginine pyroglutamate tastes sour.
Active Ingredient to Excipients Ratio
Nutraceutical formulations are likely to have more actives present in higher weight than pharmaceutical formulas. The constraints of dose size typically result in limited room for excipients. The typical nutraceutical formulation has 70- to 90-percent actives with the balance as excipients, while traditional pharmaceutical formulation has 70- to 90-percent excipients and 10- to 30-percent actives. The fewer excipients and variety of actives in the same formulation make it difficult to achieve certain desired outcomes such as disintegration time, hardness and friability. Moreover, increasingly nutraceutical customers are demanding smaller dosage size and fewer other ingredients" (i.e., excipients), which further narrows options for formulators. In short, as choices for excipients get narrower, it becomes more difficult to formulate and achieve desired outcomes for product.
Many new ingredients enter the market, but information is sparse regarding their physical, chemical and mechanical properties, such as molecular weight, structure, chemical stability, solid-state stability, moisture content, solubility, particle size, flow, compressibility, dissolution and density; all of these factors inform the formulation process. Based on this lack of information, formulation of nutraceutical products often depends on the firsthand experience of the formulator. For example, a small amount of acetyl-L-carnitine HCL in capsule formulation can cause stability problems and may create black specks in capsule formulations as it is ultra sensitive to moisture. Multivitamin ingredients often react with each other, and one or more displacement reactions may take place. However, it is difficult to investigate which ones are reacting due to many minerals and active ingredients in the same formula. While, in the case of traditional pharmaceutical formulation, interaction can be more easily identified due to fewer actives and excipients.
The nutraceutical industry uses a wide variety of botanical and botanical-derived ingredients, so variation in ingredient characteristics is inevitable. Even when a finished dose manufacturer has established accurate specifications for ingredients and has a vendor qualification program in place, natural variations in ingredients can impact finished good integrity. Ingredient materials, such as herbal extracts and dried herb powders, vary based on the region where the crop has grown, season grown in and other factors. For example, the same green tea can have different colors and properties in different seasons with the same vendors. Even if a formulator has run a product 10 times in the past, it can still have issues with tablet integrity or color variations. However, in the case of the pharmaceutical industry, specifications are far more precise and differences in ingredients are minimized. Presently, ingredient variation in the nutraceutical industry drives the need for continuous support from the formulation and R&D teams.
Ingredient and Delivery System Limitations
Some ingredients are suitable neither for tablets nor for capsule formulations; yet, end users still demand these ingredients in a solid-dosage form. This includes ingredients that are sticky, such as sterols, phosphatidylserine, cetyl myristoleate and lecithin; ingredients that are oily, such as powder forms of flaxseed oil, fish oil, evening primrose oil and conjugated linoleic acid (CLA); and ingredients that are moisture sensitive such as acetyl-L-carnitine HCL, L-arginine base, NADH and magnesium chloride. These ingredients are not suitable for compression because they may stick to dies and punches. Nor are they suitable for capsule production because they will not flow unless excessive lubricants are added, which may create secondary problems such as capsule brittleness. The easiest solution for this class of problems is to recommend an appropriate delivery system or use other stable salt forms of the ingredients.
Even though FDA and other certifying agencies are pushing the industry, and brand owners are trying to comply with stricter regulations, it is difficult to achieve certain pharmaceutical standards. The nutrition industry needs to give equal importance to research on physicochemical properties of active ingredients and excipients as it has given on developing scientific evidence for ingredients' ability to work therapeutically. The industry needs to develop databases of physicochemical properties of all approved ingredients for dietary supplements. More research on these properties of ingredients will certainly help us achieve standards as good as pharmaceutical industry.
Ashish Gandhi, M.Pharm., M.H.A., is a research and development (R&D) formulator at Robinson Pharma Inc.
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