Opportunities with Softgels

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The pharmaceutical industry is mainly dominated by tablet formulations, but softgels are gaining widespread acceptance as a preferred dosage form. “Softgel capsules are a popular dosage form in the consumer healthcare market because of their unique benefits, such as ease of swallowing and quicker onset of action in relation to tablet formulations,” says Kaspar van den Dries, senior director of formulation sciences, solid dosage forms, and softgels at Patheon, part of Thermo Fisher. “These are important considerations for patients when they are choosing treatment of pain or allergies.” He also notes that a softgel formulation can be used for lifecycle management approaches to prescription, generic, and over-the-counter (OTC) drugs, for cases in which softgel technologies can be used to generate improved versions of existing drugs.

“In the consumer healthcare market, there are plenty of examples of softgel success stories. Compounds such as ibuprofen, naproxen, and diclofenac, when formulated into softgels, have improved performance, which is an important consideration for the patients,” van den Dries highlights. “Another example is chewable ibuprofen, a softgel formulation specifically designed for patients having difficulty swallowing. This product was launched through a lifecycle management approach to existing children’s suspension products and has been well-received in the European market.” 

According to van den Dries, it is increasingly difficult and complex to develop new compounds, especially with the majority of lead compounds in the drug development pipeline presenting with solubility and bioavailability challenges. “In this case, a lipid-based formulation in a softgel capsule can provide significant advances by improving the bioavailability of these compounds and increasing the chance to obtain proof of concept for these molecules,” he explains. 

“Softgel is still the most popular enabling formulation for bioavailability enhancement, compared to other solubilization approaches such as spray drying, hot melt extrusion, or particle size reduction,” van den Dries says, highlighting that most products being approved to date are lipid-based formulations. “Softgels based on lipid formulations make use of the body’s digestive pathways. This approach is, therefore, a well-established route for improving bioavailability, but it is sometimes overlooked or considered as a key risk in development, mainly because of time and cost pressures in early development, as companies don’t want to overspend in early development, when the probability of success is still low. The experienced formulators and senior management responsible for these compounds are aware of these risks and options to reduce them. However, because not all companies have the internal experience or know-how on softgel technologies, you still see programmes with suboptimal formulations, which could have been mitigated by considering softgel formulations early in development.” 

There are also other areas where softgel formulations are being considered, observes van den Dries. “For example, softgels can provide reduced exposure for highly potent compounds (because no powders are involved in the manufacturing process) and improved uniformity for low-dose APIs compared to tablets,” he says. 

Softgel versus liquid-filled hardgel capsules 

In terms of the manufacturing process, softgels provide a number of benefits over liquid-filled hardgel capsules. “Liquid-filled hardgel capsules are produced through a two-step process. The first step is to fill a two-piece hardgel cap with liquid, and the second step is the subsequent banding of these capsules. Small-scale batches are produced using a different type of equipment from that used to make commercial-scale batches,” explains van den Dries. “In contrast, the production of softgel capsules, for both large- and small-scale batches, can be done on the same equipment without the necessity of banding. This flexibility provides significant cost advantages, both on unit price and total development costs. In addition, a softgel formulation is more versatile. By changing the composition of the fill or the gel material, you can obtain a chewable, gummy formulation that makes the medication easy to ingest for children, or people who have difficulty swallowing (e.g., elderly). With softgels, there are also opportunities to create an enteric-release formulation, or even a controlled-release, abuse-deterrent formulation. All of these formulations can be produced on the same equipment. Globally, there is more capacity available in softgel manufacturing than there is available for liquid-filled hardgel capsules, hence, providing more flexibility in the supply chain of products.

The burst strength test

Softgels are dynamic systems where the fill and shell compositions, fill–shell interaction, and process parameters can have a substantial influence on the softgel integrity, highlights Melanie Bayarri, formulation development scientist at Patheon, part of Thermo Fisher Scientific. She observes that with increasing quality requirements, there is a need for pharmaceutical manufacturers to focus on making smart choices early in the development programme. “The burst strength test is an important technique to support formulation and process choices made throughout softgel product development. It is an established method to assess softgels shell robustness,” she says.

“It is performed with a Dr. Schleuniger Pharmatron 400 N model 6D(SG) softgel tester. The apparatus is similar to a tablet tester and compliant with the specifications as laid down in the European Pharmacopoeia-Chapter 2.9.8 (1) and the United States Pharmacopeia-Chapter <1217> (2). It is easy to operate,” Bayarri explains. “A softgel sample is placed individually between two jaws that compresses it at a fixed rate of 2.5 mm/second until the sample bursts or until the maximum force of 400 N. The force (N) required to burst the sample is recorded and in case the softgel does not burst, the result is noted as > 400N,” she says. 

“The evaluation of softgels shell robustness is not only based on the number of bursts and the withstood force before burst, but also on the relative shell flexibility as the apparatus records as well the diameter (mm) of the softgels before compression and at maximum compression,” Bayarri highlights. “Using this test, we can evaluate the influence of critical parameters on the softgels shell robustness related to the formulation design (e.g., fill formulation, gel formulation, fill-gel interaction), process design (e.g., die design, ribbon thickness, hardness, and drying time), and storage temperature.”

“During product development, we assess softgel shell robustness using the burst strength test, and we have been able to establish a good correlation between the burst strength test results and product performance,” Bayarri says. According to her, the generated data are used to support the selection of:

• Adequate shell formulation for a particular product

• The most suitable process parameters, such as the die design, for a specific fill and shell combination

• The optimal target hardness range per product, balancing water activity (related to microbial safety) with hardness and drying time impacting shell robustness.

“The burst strength test is useful to establish formulation and process parameters that not only ensure optimum product performance through shelf life but also guarantee that the product will withstand physical stresses that can occur during packaging and transport activities,” Bayarri sums up.

References

1. EDQM, Ph. Eur., Chapter 2.9.8 “Resistance to Crushing of Tablets” (EDQM, Strasbourg, France, 2016) p. 313.
2. USP, USP General Chapter <1217>, “Tablet Breaking Force,” USP32–NF27 (US Pharmacopeial Convention, Rockville, MD, 2007), p. 726.

Article Details

Pharmaceutical Technology
Vol. 41, No. 12
December 2017
Page: 24–27

Citation

When referring to this article, please cite it as A. Siew, “Opportunities with Softgels,” Pharmaceutical Technology 41 (12) 24–27 (2017).