December 10, 2018
“All things are poisons, for there is nothing without poisonous qualities. It is only the dose which makes a thing poison.” ―Paracelsus
"The dose makes the poison" (in Latin: sola dosis facit venenum). This refers to an old adage that shows the basic principal of toxicology—the amount ingested matters. Paracelsus (born in 1493) was a Swiss physician who is known as the father of toxicology.
There are many types of dosage forms to get medicines into the body, including enteral (oral), ophthalmic, inhalation, parenteral, topical and suppository.
For dietary supplements, only the oral (ingested) route is permitted. The law defines dietary supplements as products taken by mouth that contain a "dietary ingredient." Dietary ingredients include vitamins, minerals, amino acids, enzymes, and herbs or botanicals, as well as other substances that can be used to supplement the diet.
Oral Dosage Forms
Powders are solid oral dosage forms—normally a single ingredient or mixtures of various ingredients that are dry, loose, fine particles. They contain active ingredients, sometimes with excipients, coloring and flavoring materials. A bulk powder mixture is also the starting point for making tablets and capsules. Most food powders have low moisture content, thereby reducing the rate of quality degradation. This means food powders can be stored for a longer period of time than other forms of food products.
Typically, the powder is dispersed in a liquid (e.g., water) prior to ingesting or, in the case of effervescent powders, dissolved in water before taking. Oral powders may be sold as divided powders, with each dose packaged individually, or undivided, as a bulk powder.
Mixing of powders (dry blending) is a common operation in the supplements industry. The most important use of mixing is the creation of a homogenous blend of several ingredients that successfully negates the differences in concentration and particle size to create a uniform mixture. Since powders do not mix spontaneously, it can be very difficult to ensure a final homogenous mixture of powders; in some cases, energy must be introduced for the successful mixing of powders. Screening during and after the final blend can help improve uniformity and eliminate lumps.
A powder mixture can either be free-flowing (non-sticking) or cohesive (sticking together forming aggregates). The likelihood of cohesion increases with smaller particle sizes (smaller than 100 µm are normally cohesive). Most powder particles tend to range between 50 and 1,000 µm. Many agglomerate easily when exposed to humid atmosphere or elevated storage temperatures (especially with materials that have hydroscopic or deliquescent tendencies).
Over mixing (agitation) of the powder (especially powders with different bulk densities) may result in particle separation (un-mixing); smaller particles migrate downwards and larger ones move upwards. This is directly related to another problem, particle segregation, which occurs when solids tend to separate due to differences in particle size, density, shape and resilience. Usually this is corrected by using the appropriate high-shear mixing equipment. Sometimes less is more, when it comes to mixing powders.
Another uniformity issue occurs when the proportion of one ingredient is very small, hindering uniformity; the use of titrations (“trits”) preparations can be useful. Trits are used commonly when very small amounts are needed (e.g., micrograms) in a powder formula. Typically, the active material is diluted into a 1 percent or 10 percent potency concentration that gives much more volume to the ingredient being added (more volume means better dispersion and uniformity).
Bulk powders are used in many dietary applications such as various consumer products, premixes, trits, etc.
A tablet is a hard, compressed pellet found in several shapes (round, oval or square) and colors. Typically included in the tablet are excipients (binders, disintegrants, glidants [flow aids], lubricants and flavors/sweeteners), which ensure the tablet is robust and aid in manufacturing.
In general, the processes for tablet manufacture may include granulation and direct compression, and sometimes adding a coating.
Tablets can be either coated or uncoated. For uncoated (e.g., chewable) tablets, sometimes colorants are added to make the uncoated tablets look attractive and more uniform. A coating may be applied to: 1) make the tablet look visually attractive; 2) make the tablet smoother and easier to swallow; 3) hide the taste of the tablet's ingredients; 4) add sweeteners or flavors to mask bad-tasting ingredients; 5) pass through the stomach before dissolving (enteric); 6) make the tablet more resistant to the environment (e.g., humidity) to extend shelf life.
Tablets are designed and made to perform in a variety of ways. They can be made to release normally (under 45 minutes), be fast acting (quick-release), extended-release (slow-release or controlled-release), delay-released (release after passing through the stomach, enteric-coated); be chewable, buccal or sublingual (in the mouth, not swallowed); and be very small (minitabs), multilayered, a tablet-in-tablet, etc.
Capsules are an ingestible dosage form with a shell (a container) that encloses the ingredients. The main advantage is the ability to mask unpleasant taste. The two main types of capsules are hard-shell capsules and soft-shell capsules.
Hard-shell capsules normally use dry, powdered or granule ingredients, although there is a technology for liquids (oil) that requires sealing or banding the capsule to prevent leaking. Hard-shell capsules come in a variety of sizes, shell types and colors, and can be made from gelatin (bovine, piscine), vegetarian sources (HPMC, tapioca) and enteric.
Soft-shell (softgel) capsules are primarily used for oils and ingredients that are dissolved or suspended in oil. Softgels come in gelatin or vegetarian shells, and can be made in a wide variety of colors.
Liquids are material substances that tend to flow. They occupy the shape of the vessel they are poured into, and cannot retain a shape on their own. They have fewer intermolecular forces of attraction than solids, so they can flow onto a surface due to the loose arrangement of molecules within the matter. There are oftentimes added excipients used for oral liquid formulations such as solvents (e.g., ethanol, glycerin, mineral oil, propylene glycol, etc.), surfactants, flavors, pH adjustments (buffers), preservatives and viscosity enhancers. Types of liquids include:
1. Simple liquid. These can be either a singular liquid (e.g., fish oil, flaxseed oil, etc.) or a mixture of two or more liquids (e.g., similar oils).
2. Solutions. Liquids that have other substances within the intermolecular spaces. For example, mixing sugar or salt into water (the solvent) makes a solution. Solutions may be classified by vehicle as aqueous (i.e., water-based), alcoholic (alcohol-based) or hydroalcoholic (i.e., water- and alcohol-based). Oral solutions include aromatic waters, elixirs, syrups, tinctures, spirits and aerated liquids.
3. Emulsions. Liquids wherein two immiscible liquids are mixed together. A simple, classic example of an emulsion is mayonnaise. Most people know that oil and water are normally immiscible, but with proper mixing and the use of emulsifiers (e.g., surfactants), a permanent mixture (emulsion) can be accomplished. There are two basic types of emulsions: water in oil, where water is suspended into oil, or oil in water, where oil is suspended in water.
4. Suspensions. A liquid mixture where solid particles are dispersed and suspended in a vehicle, remaining undissolved. To be visible to the naked eye, particle size must be larger than 1 micron. The liquid mixture is homogeneous, meaning it has the same proportions of its components throughout the vehicle. Suspensions have the issue of particle settlement. The suspended particles eventually settle down at the bottom of the container. Hence, most have a label that carries instructions to “shake well before use.”
Other Oral Forms
Gummies are a broad category of gelatin, gums (agar, pectin) or starch-based chewable confections. They come in numerous flavors and shapes, and can be fortified with dietary ingredients such as fiber, collagen, probiotics and vitamins.
Lozenges are a solid preparation consisting of sugar and gum designed to dissolve slowly in the mouth. They can contain active ingredients, herbs, spices, honey, etc. They are often flavored with citrus, menthol, peppermint oil and spearmint.
Pastilles are solid, medicated preparations designed to be chewed and slowly dissolve in the mouth. They are softer than lozenges and their bases are either glycerol, gelatin, or acacia and sugar. They can contain active ingredients, herbs, spices, honey, etc.
Teas are an aromatic beverage commonly prepared by pouring hot or boiling water over dried leaves. Traditionally tea refers to Camellia sinensis plant leaves, but herbal teas featuring a variety of botanicals have expanded significantly in recent years.
Food bars, including breakfast bars, energy bars, high-fiber bars, high-carbohydrate bars, meal-replacement bars, protein bars and snack bars, can provide added dietary nutrients and botanicals.
Oral films (strips) are rapidly dissolving films that were initially introduced in the market as breath fresheners. The films are designed to dissolve upon contact with a wet surface, such as the tongue, within a few seconds, meaning the consumer can take the product without need for additional liquid. The disadvantage is high doses cannot be incorporated into the strip.
There are a multitude of oral dosage forms to choose from and a variety of reasons why one dosage form would be chosen over another. Sometimes dosage form is determined by requirements of the ingredients being delivered. Other reasons may include technical improvement (e.g., improved absorption) or cosmetic improvement; product differentiation; stability for selling in certain geographic regions (i.e., hot, humid climates); and cost (powders and tablets are generally the most cost-effective dosage forms).
The final issue is safety. Every oral dose product should be safe to take, as given by the directions on the label.
Robin Koon is executive vice-president at Best Formulations, and has more than 35 years of pharmaceutical experience in clinical pharmacy, as a retail drug chain executive overseeing operations, in managed-care, and manufacturing.
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