March 22, 2012
Soft gelatin capsules (SGCs) are a solid liquid-filled dosage form, and are widely used in the pharmaceutical, nutritional and cosmetic industries. The term "soft" refers to the addition of plasticizers used in the capsule shell, which make it flexible. These capsules are filled with non-aqueous liquids, suspensions or semi-solids. Often, formulators can add powders to oils, creating what is called a "paste" fill.
SGCs are well-known and accepted by consumers because of certain advantages over tablets and capsules, including elegant appearance in many colors, ease of swallowing, fast disintegration action (dispersion of capsule contents), improved bioavailability, good tolerance to intestinal mucosa, masking of unpleasant flavors or odors, and product differentiation.
In this article, the term equilibrium is being applied to both the physical and chemical properties of water and its interactions regarding softgels. An equilibrium is considered to be stable if the system always returns to it after small disturbances. If the system moves away from the equilibrium after small disturbances, then the equilibrium is considered to be unstable.
Softgels are in many ways alive" and react with the environment. Softgel capsules are sensitive to two environmental conditions: relative humidity and temperature, both which can have negative effects on the equilibrium moisture of the SGC shell. Generally speaking, relative humidity has a more significant effect than does temperature on SGCs. The normal storage conditions for these capsules should be at 20 to 30 degrees Celsius and 30 to 50 percent relative humidity. Good environmental temperature and humidity control is essential when packaging, shipping or storing of SGCs, to minimize the moisture exchange with surrounding environment.
Water is a key factor that can affect the chemical and microbial stability of any SGC product. When dried, the finished softgels have ideally between 8 to 10 percent water left in the shell, which is too low to support microbial growth. The gelatin shell is hygroscopic, meaning moisture will increase in the shell and fill as the relative humidity increases. This can cause the burst strength to decrease, as the capsules absorb moisture in high-humidity conditions. This humid state can cause softgels to become soft, sticky and even possibly fail.
Low humidity environment is equally damaging. The SGC can lose moisture, which will increase the hardness values, meaning the capsule can become over dried, causing cracking and failure.
Fill Material Equilibrium
Diffusion interactions between the fill and the shell during the manufacturing process can also be a problem. The moisture content of the initial shells before drying is around 40 percent, and the equilibrium moisture level (dried softgel) is reached after several days of drying. But during the time period of manufacture and reaching a finished dried softgel, water and any hydrophilic components of the fill material may migrate rapidly into the shell and vice versa. This can potentially cause changes in either or both of the fill and the shell composition.
Oil carriers used in the fill material do not attract water, but many ingredients used in the fill can pull moisture from the shell. When first being made, the gelatin shell contains approximately 40-percent water (8 to 10 percent when dry). During the drying process, water can be carried (absorbed) into the fill material by certain fill ingredients. Specifically, hygroscopic materials (e.g. L-carnitine, choline, betaine, pantothenate, propylene glycol, etc.) can contribute to the fill material having water content increase. This can potentially lead to the material in the capsule being affected or cause eventual shell failure, as this added moisture can or will eventually travel back into the capsule shell.
This transfer of water from the shell can result in a chemical change of the fill material. A compound in the fill may change by undergoing a direct undesirable chemical reaction. This can affect stability, especially with highly water-soluble compounds and compounds susceptible to hydrolysis.
An example of this is when we experienced exploding softgels (seriously!) in the drying chamber. We were making what we thought was a fairly routine multivitamin softgel. The only difference was the use in the formula of multiple mineral sources for each mineral (e.g. for calcium, a blend of: calcium carbonate, calcium citrate, calcium gluconate and calcium aspartate). It looked simple enough initially, since we've made many multivitamin softgels. After post examination, we found mineral aspartates, when exposed to the water in the shell, create aspartic acid. The aspartic acid had combined with the various mineral carbonate salts, creating an acid/base reaction. The result of this was carbon dioxide gas being generated, which exploded the softgels. These issues can be prevented by using a less soluble salt, a coated material, making pH adjustments, use of a different co-solvent, etc.
Note that some compounds (especially those of high water solubility) can migrate from the fill into the shell, resulting in poor dissolution, loss of bioavailability or shell failure.
Softgels are a great dosage form, but a formulator must watch the water and keep the equilibrium stable.
Robin Koon, executive vice president at Best Formulations, has more than 25 years of experience in pharmaceutical, retail drug chain executive and managed care operations.
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