Softgels are a Shell Game

A softgel is a capsule oral dosage form for medicine. It consists of a gelatin-based shell enrobing a liquid fill. Softgel shells comprise of a mixture of gelatin, a plasticizer (such as glycerin), water and color (if used).

Gelatin is derived from the Latin verb gelare meaning to congeal. Gelatin is a protein obtained fromanimal-based sources. The animal sources used for making softgels are: bovine, porcine and piscine. Gelatin is a GRAS (generally recognized as safe) food ingredient and is listed in the National Formulary (CAS 9000-70-8). Gelatin is considered to be a non-allergenic protein, unlike other proteins such as soy, egg or milk. Gelatin is a hydrocolloid (water loving) material, and together with water will form a semi-solid colloidal gel.

All gelatins are derived from collagen, which is a key intercellular protein found in animal connective tissue. It does not come from horns or hoofsthat is keratin. Gelatin is the chemical denatured product of collagen. Collagen is derived from the Greek word kola, which means to produce glue. It is an extracellular matrix (ECM) protein found in skin, ligaments, tendons, bone, cartilage and other dense connective tissue, and makes up approximately 25 percent of the protein in mammals. At least 27 different types of collagen have been identified, each of which is linked to a particular type of tissue. The types used for gelatin making are type I (skin, bone and tendons) and III (skin).

Gelatin is obtained from collagen by controlled chemical hydrolysis (disintegration) and thermal denaturation. The two basic manufacturing processes  are used to obtain gelatin from its raw material. Type A is an acid process, primarily from skins and connective tissue, with the raw material soaked in dilute acid. Type B is an alkaline process, primarily from bones or hides, with the raw material soaked in successive steps of lime solutions. Both types of gelatin are used in softgel manufacturing.

Official testing methods have been developed by the Gelatin Manufacturers Institute of America Inc. (GMIA). The procedures used are variations of those outlined in the Association of Official Agricultural Chemist (AOAC) Methods of Analysis and the U.S. Pharmacopoeia (USP). Gelatin is usually tested for gel strength, viscosity, pH and moisture.

Other Shell Ingredients

Softgels use gelatin along with other modifying ingredients to create a polymeric film (a thermally reversible aqueous hydrocolloid gel), which becomes the softgel gelatin shell. Solid gelatin cannot be used by itself because of its brittleness, which would cause failure. An additional compound is needed to enable elasticity, decrease transition temperatures, and to modify its physical and chemical characteristics.

The compounds used are called plasticizers. A plasticizer is a substance that weakens the intermolecular attractions between the gelatin polymer chains. They are used to alter the physical properties of a polymer, such as gelatin, in order to be able to create a flexible film. One cannot make a softgel without a plasticizer. The plasticizers used for gelatin are polyhydric alcohols, which are also called polyalcohols, sugar alcohols or polyols. These substances refer to chemical compounds containing multiple hydroxyl groups. When mixed with gelatin, a plasticizer can:

The primary plasticizer compounds used for softgels are glycerin and sorbitol/sorbitan mixtures. Other materials can include invert sugar, organic esters, polyethylene glycols, propylene glycol, sorbitol, castor oil, mannitol, maltitol, sucrose, xylitol and more.

In addition, the shell can be either transparent or opaque. Both types can be colored. The general rule for the use of colorants in softgel shells is the capsule shell should not be lighter than the fill material. Normally, an opaque color is used for suspensions or paste products to conceal the fill material or used to protect the fill material from light.

Before a color is chosen, it is generally a good idea to check the fill mixture against a gel swatch to ensure there is no issue between the two. Occasionally, water-soluble fill ingredients can migrate into the shell or a chemical reaction, causing discoloration of the shell.

Shell colors can be customized using a variety of colorants, which are water soluble dyes or insoluble pigments. The range of natural coloring agents is somewhat limited to what materials are available. Examples include (but are not limited to):

Natural colorants:

Pharmaceutical colorants (pigments):

Pharmaceutical colorants (water soluble dyes):

Shell Formulation

Gelatin formulations can be made or adjusted to handle various fill material requirements (i.e., acidity, water content, etc.) and environmental needs (i.e., specific regions, such as high humidity or cold temperatures).

The ratios between gelatin, plasticizer and water can be changed, which will determine the ultimate softness or hardness of the shell. The type of plasticizer and the ratio of plasticizer to gelatin can make a significant difference in gelatin hardness and physical stability of the softgel. Generally, the less plasticizer used, the harder the shell becomes. Hardness is also a function of the bloom strength of the gelatin being used. Generally, producers prefer the shell be hard to withstand the rigors of shipping, packaging and storage.

A final consideration is the issue of export. Shell formulation considerations for exporting softgels may need to be well thought out. If the softgel is going to a hot, humid climate, it requires a harder shell. There may be registration issues, such as

bovine spongiform encephalopathy (BSE) related to bovine source or porcine and cultural considerations. Further,  there are kosher and Halal gelatins.

The cool thing about softgels is they deliver compounds in a solution form, while offering the convenience of a solid dosage form. The making or manufacturing of softgels is still considered an art Few books or resources are available on how to make or formulate softgels as compared to making tablet or two-piece capsules. So, experience is essential in making good softgels.

Robin Koon, executive vice president at Best Formulations, has more than 25 years of pharmaceutical experience in clinical pharmacy, as a retail drug chain executive overseeing operations, and in managed-care. He also has more than 15 years of pharmaceutical/nutritional manufacturing experience.

Learn more about formulating with softgels and other delivery forms in INSIDER's Contract Manufacturing Content Library.