Comparison of standard and biorelevant media for the evaluation of enteric capsule performance

Introduction

Capsule-based drug delivery systems have advanced considerably, enabling improved protection of active pharmaceutical ingredients (APIs) and controlled release along the gastrointestinal (GI) tract. Progress in polymer design has been especially important for the oral administration of labile molecules such as peptides, proteins, and RNA-based therapeutics [1]. For RNA-based drugs in particular, enteric protection is essential to withstand gastric conditions and ensure targeted release in specific intestinal regions [2,3]. In this context, dissolution and disintegration behavior are critical parameters for predicting capsule performance and site-specific delivery.

Method

Several bilayer capsule prototypes were developed to evaluate the influence of formulation and curing on capsule performance. Inner layers consisted of HPMC or an HPMC–pullulan blend, while outer layers contained ethylcellulose (EC) with 4% and 6%, sodium alginate. All formulations were cured at 70°C under 5%, 40%, or 75% RH to study polymer organization effects. Capsule performance was assessed in disintegration and dissolution to compare media without and with enzymes using a USP Type II dissolution apparatus for dissolution and a SOTAX DT2 for disintegration . Dissolution was compared between standard media with an acidic phase (HCl 0.1M) then the pH was increased to 6.8 with a phosphate buffer and the last pH tested was 7.4. Then for enzymes adding pepsin was added to HCl 0.1M (gastric),pancreatin to phosphate buffer pH 6.8 (intestinal), and alginate lyase and
pullulanase into media pH 7.4 to evaluate polymer susceptibility to enzymatic activity.

Results

Disintegration behavior

The Figure 2 compares the disintegration times across media formulations and curing conditions.

Figure 2A referred to capsules with an HPMC/pullulan as inner layer and ethyl cellulose and alginate in the outer layer. These capsules exhibited strong dependence on alginate concentration and curing humidity. In standard media, prototypes containing 4% alginate showed longer disintegration times than those with 6% alginate, indicating a more robust barrier. Enzyme-containing media accelerated disintegration, with several formulations opening prematurely (marked by Δ in figures), demonstrating increased enzymatic sensitivity. Figure 2B referred to capsules with HPMC-only inner layers displayed greater structural resistance overall. Multiple conditions preserved capsule integrity for up to 60 minutes in standard media. While enzymatic exposure reduced disintegration times, release remained controlled and dependent on alginate content and curing treatment.

Dissolution performance

Figures 2A and 2B illustrate the effects of inner layer composition, alginate content, and curing conditions on caffeine release. Capsules cured at 75% RH exhibited a markedly slower dissolution profile, with minimal influence of enzymes on caffeine release. In contrast, capsules with a curing at 40% RH showed faster release. Release was further increased in enzyme containing media compared with standard media. In contrast, HPMC-only capsules exhibited slower and more sustained caffeine release, particularly for formulations containing 6% alginate, supporting the formation of an effective diffusion barrier. For both curing conditions (5% RH and 75% RH), the presence of enzymes clearly accelerated capsule opening and increased caffeine release compared with enzyme-free media, highlighting the enzymatic sensitivity of the outer layer.

Conclusion

Alginate concentration and curing humidity emerged as the dominant factors governing bilayer capsule performance. All prototypes exhibited accelerated opening in enzyme-containing biorelevant media compared to EP conditions, demonstrating the added discriminatory power of biorelevant testing. These findings demonstrate the need for biorelevant dissolution assessments to more effectively discriminate among formulations and support the development of enteric systems tailored for intestinal or ileal targeting.

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Source: Capsugel, Elisa Millet, Capsugel, Joseph O’Shea and Brendan Griffin , School of Pharmacy, Vincent Jannin, Capsugel, technical brochure Comparison of standard and biorelevant media

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