Understanding Soft Capsule Fill Formulations:
Key Components and Considerations
The fill material in soft capsules consists of active ingredients (APIs or nutrients) and inactive ingredients (excipients or additives), formulated as solutions, dispersions (liquid-in-liquid), or suspensions (solid-in-liquid). These are prepared in reactors using conventional mixing/homogenization equipment. For suspensions, mixing conditions are critical to break down solid agglomerates. Post-preparation, the product is stored in tanks until encapsulation, often under vacuum or inert gas to protect oxygen-sensitive compounds.
Pharmaceutical solutions must be carefully designed to optimize the stability of the active ingredient and the final product (often related to compatibility with the shell), maximize the bioavailability of the active ingredient, and ensure proper manufacturing and filling processes. Lipophilic solutions are the most commonly used formulations, typically using liquid carriers such as soybean or castor oils and/or medium-chain triglycerides (MCTs).
For lipophilic suspensions, thickeners or viscosity enhancers are added, such as hydrogenated oils or waxes, such as hydrogenated castor oil or beeswax. Hydrophilic formulations, primarily based on PEG, are also used. PEG400 and PEG600 are the most common carriers, but compounds with similar structures, such as glycerol, PG, propylene carbonate, and methoxy PEG, can also be used. To adjust the viscosity of hydrophilic formulations, suspending agents such as MW PEG or cellulosic polymers may be added. Surfactants (such as lecithin, Tween), antioxidants, and solid polymer particles are often added for blending or as a coating to improve content uniformity and/or drug stability. Recently, other formulations such as self-emulsifying systems and microemulsions composed of lipophilic solvents and surfactants have also received attention in improving drug bioavailability.
The following ingredients are not recommended for inclusion in drug solution formulations:
- High levels of liquid (more than 10% of the drug solution formulation), such as water or low molecular weight hydrophilic polymers such as glycerol, PG, PEG200 or PEG300; they tend to migrate from the interior to the gelatin outer layer and act as gelatin plasticizers, thereby changing the structure of the gelatin layer;
- Volatile compounds such as ethanol, which can quickly pass through the capsule outer layer and almost completely disappear at the end of the drying process, carrying away other components in the drug solution;
- Aldehydes and other carbonyl groups, as they promote cross-linking reactions and change the dissolution process of the final product; and
- Formulations with extreme pH values, as acidic and alkaline components (such as acid salts, mineral acids or organic acids) promote the hydrolytic degradation of gelatin, resulting in brittle gelatin.
In addition to the final pH value of the liquid formulation (optimally in the range of 2.5-7.5), other physicochemical properties, such as viscosity and flowability, are critical to the manufacturing and filling processes. Liquid or semisolid dosage forms must possess sufficient viscosity and flowability to ensure uniformity of the formulation during production and accurate metering of the product by plunger pumps at temperatures of approximately 35°C or lower. Furthermore, for suspensions, the size of the solid component should be considered; it must be less than 200 microns to ensure a good seal in the capsule. To this end, the raw materials for the active and inactive ingredients should be carefully selected to achieve a suitable formulation.
Thoughtful excipient selection ensures performance, stability, and patient benefit. What challenges have you faced in soft capsule formulation?
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