How a CDMO Overcomes Soft Gel Formulation Challenges

The gelatin itself can be one of the obstacles formulators face when manufacturing soft gels. Gelatin is typically an animal-derived material, but is also highly water soluble. While this solubility allows for rapid dissolution when ingested, it also makes the capsules sensitive to heat and humidity, ultimately impacting shelf life. Shell formulation for SGCs typically consists of gelatin, plasticizer(s), water, and other minor additives such as colorants (brand and product identification), flavors, opacifiers (for light-sensitive compounds), sweeteners, and possibly sugar, preservatives, and, in rare cases, active ingredients.

The shell characteristics that a skilled soft gel capsule CDMO will focus on include the following:

Gelatin type. Gelatin can be classified into two types, which is determined by gelatin pretreatment during the gelatin manufacturing process. Type A gelatin is obtained from acid-treated collagen, whereas Type B gelatin is derived from an alkali-treated precursor.³ Type A is more resistant to acidic hydrolysis; Type B more resistant to alkaline hydrolysis. Formulators will choose a gelatin type based on the pH of the fill formulation. Gelatin, plasticizer(s) and water can all be adjusted based on the pH of the fill to ensure compatibility with the shell.

• Gel strength. Gel strength, or bloom value, is the measure of strength and stiffness of the gelatin. Higher bloom value indicates greater gelatin strength; bloom strength in the range of 150-250g is considered suitable for soft gel capsules. Bloom strength will influence the clarity and color of the gelatin capsule.² Gel strength is characterized by a texture analyzer in the R&D lab where compatibility studies are also conducted.
• Viscosity. The grade, bloom strength, and molecular weight of the gelatin will determine its viscosity. Value increases with rising bloom strength. For use in SGCs, the gelatin solution should ideally have a viscosity of 2.8 to 4.5mPas at 60 °C.²
• Elasticity. To achieve elasticity of SGC shells, a plasticizer is required. The plasticizer provides mechanical stability of the shell during and after drying by offsetting induced stresses due to shrinking of the shell. The concentration and type of plasticizers have an impact on the characteristics of the final drug product. Glycerin is the most commonly used plasticizer while sorbitol is selected for hydrophilic formulations and applications requiring lower oxygen permeability. For plasticizer selection, the hydrophilicity and lipophilicity of the fill formulation is characterized by a Hydrophilic Lipophilic Balance (HLB) test.
• Moisture content. A soft gel is very soft when initially produced so controlling moisture content is critical. Final equilibrium water content is determined by the type and quantity of plasticizers.
• Oxygen and light exposure. Both of these need to be controlled; a nitrogen purging system is required to control exposure to oxygen to minimize oxidative reactions while yellow light rooms are needed for light-sensitive products. To obtain protection for light-sensitive ingredients, the shell can be formulated with pigments such as titanium dioxide and iron oxides for an opaque finish. The goal is to protect the stored product and have a a shelf life of at least two years.

In recent years, the fill composition of SGCs has evolved from lipophilic to hydrophilic solutions/suspensions and complex self-emulsifying systems due to requirements from new chemical entities and biopharmaceutical formulations.² Hydrophilic SGC fill formulations are based on polyethylene glycols (PEGs), and this includes low molecular weight PEGs and closely related compounds. Use of PEGs, especially with a low molecular weight such as PEG 200, PEG 300, and water should not exceed more than 10% of fill composition as they act as plasticizers as well for gelatin shell. PEG-based formulations are used to improve solubility, disperse low-dose and high-potency drugs, and improve bioavailability.

Solubility also affects the types of API that can be delivered in the soft gel capsule. The liquid fill must be primarily non-aqueous or oil-based, not water based, to prevent the solubilization of the outer gelatin shell in the fill liquid on storage. API can be either dissolved or suspended in the liquid fill. Suspensions are more complicated fills than solutions due to potential content uniformity issues from API settling. API particle size, suspension viscosity, and agitation speed must be optimized to achieve a uniform suspension. Keep in mind that alkaline or acidic solutions are not good candidates for soft gelatin fill because they can cause crosslinking or hydrolysis and shell leakage.²

When developing an SGC formulation, the possible interaction between the fill material and the gelatin shell must be considered. These interactions may happen during manufacturing, drying, or over the shelf-life of the product. Interactions could include a chemical reaction between fill components and oxidization or degradation products, and the shell or physical interaction such as migration of fill material into or through the shell, and vice versa.2 The extent of these interactions depends on the amount of each component in the shell and fill formulation. One of the most well-known problems of the shell formulation is associated with APIs or excipients containing reactive functional groups such as carbonyl, which can result in gelatin cross-linking.² Cross-linking of gelatin occurs when the gelatin forms new bonds with itself or things in its environment. The reaction is generally irreversible and renders the gelatin insoluble.4 As gelatin is meant to dissolve quickly in water, once cross linking occurs, the gelatin either becomes hard to dissolve in water or will not dissolve at all.

Three of the key challenges in SGC manufacturing are:

1. Chemical stability (reaction between drug and fill/shell excipients, degradation from oxygen and light exposure) – Selection of compatible fill/shell formulation, force degradation studies, and prototype stability studies in preformed air-filled soft gel to identify stability issues. Engineering control such as blanketing nitrogen over the drug solution and purging nitrogen inside the drug solution with a sparger can protect the product.


2. Content uniformity for a suspension fill (API particle size, viscosity, and agitation) – Micronized API should be used and uniformly dispersed by homogenization or sonication. Increased viscosity slows down particle settling. Continuous agitation of the drug suspension in the containers, transfer tubing, and the soft gel machine hopper is critical.


3. Physical stability (leaking, cross-linking, and crystallization of solubilized drug) – Evaluate pH of the formulation and hand fill and seal in preformed air-filled soft gel shell for early prototype stability studies. This is important because during early stages of development API can be extremely limited. But gelatin is relatively inexpensive. This allows scientists to evaluate leaking, cross linking and crystallization, and evaluate stability and understand degradation pathways.