A Capsule-in-Capsule Platform for Multi-Phase Release of Liquid and Solid Formulations

As consumer demand continues to grow for convenient, high-performance health and wellness products, innovative delivery technologies are becoming increasingly important in supplement formulation. Dual-delivery capsule systems offer a sophisticated approach to nutrient administration by enabling the immediate and targeted release of active ingredients within a single dosage form. By protecting sensitive probiotics,¹ and acid-sensitive digestive enzymes² optimizing ingredient performance, and reducing the need for multiple products, this technology enhances efficacy, improves consumer compliance, and creates new opportunities for differentiated, multi-benefit formulations.

A dual-delivery capsule platform technology was designed and evaluated for next-generation pharmaceutical and nutraceutical products. The platform enables the delivery of multiple APIs within a single dosage unit, reducing pill burden and simplifying dosing regimens to enhance patient convenience, compliance, and overall user experience.

The dual-capsule design provides formulation flexibility by combining liquid and solid fills or immediate-release and sustained-release ingredients within 1 system. This approach allows for the physical separation of sensitive or potentially incompatible actives, helping to preserve stability, efficacy, and product quality throughout the product lifecycle.

Dual-capsule technology offers a significant innovation advantage over traditional capsules by enabling multi-benefit formulations, ingredient protection, targeted release, and premium consumer appeal, making it particularly attractive for advanced nutraceutical products in gut health, women's wellness, sports nutrition, cognitive health, and beauty-from-within categories

Dual-capsule technology provided significantly greater protection of acid-sensitive digestive enzymes and resulted in substantially higher enzyme activity in the upper small intestine compared with standard immediate-release capsules.²

As part of the development program, hypromellose (HPMC) and gelatin capsules were evaluated for their suitability in dual delivery applications. Assessments included compatibility with liquid and solid formulations, manufacturing feasibility, stability, capsule performance, and overall functionality to identify the optimal platform for future combination product development.

Methods

Researchers designed 2 capsule-in-capsule configurations and evaluated the dissolution profile of ginger (Gingeren, Ennature Biopharma) granules independently for use as a sustained-release ingredient with turmeric oil and coenzyme Q10 (COQ10) oils as liquid dosage forms.

The dual capsule configurations were as follows:

• Design 1
  Inner capsule: Size 3 capsule - liquid
  Outer capsule: Size 0 capsule – Solid Ginger granules.
• Design 2
  Inner capsule: Size 3 capsule - Solid Ginger granules.
  Outer capsule: Size 0 capsule – liquid

Capsule filling process. The researchers manufactured an R&D-scale batch of 100 dual delivery capsules was manufactured for each design configuration. Liquid formulations (200 µL) were accurately dispensed into the designated capsules using a calibrated analytical pipette to ensure precise fill volumes and reproducible dosing. Sustained-release ginger granules (100 mg) were individually weighed and filled into the appropriate capsule compartment.

Assembly of the dual capsule system was performed using a capsule filling system (ProFiller 1000, Torpac). The outer capsule was first filled with the designated formulation, followed by insertion of the prefilled inner capsule. The assembled unit was then closed to produce the final capsule configuration.

For designs utilizing an outer capsule containing a liquid formulation, capsule integrity was enhanced through the application of a proprietary HPMC-based banding solution.The solution was applied to the capsule-locking region to provide an effective seal, reduce the risk of leakage in storage and transportation.

Weight variation test: Researchers evaluated10 filled capsules of each design for fill weight uniformity to verify dosing accuracy and process consistency using United States Pharmacopeia (USP) General Chapter <905>³.

Disintegration testing. Disintegration performance of the assembled dual-capsule systems was evaluated using a disintegration tester (Sotax) per USP <701> ⁴ for both designs.

Dissolution testing. Dissolution testing was performed using a USP dissolution test apparatus (Lab India)in accordance with USP guidelines USP <711> ⁵ at designed time points. High-performance liquid chromatography (HPLC) conditions were as follows:

1. Column, C18 (150 X 4.6 mm) 5 µm
2. Flow rate, 0.6 mL /min
3. Injection volume, 20µL
4. Wavelength, 282 nm.
5. Column oven temp: 25 °C
6. Sample temp: 15 °C.

Different retention times were recorded for actives Gingerol and Shogaols.

Results

Visual test. Visual inspection demonstrated that filled capsules from both dual-capsule configurations maintained excellent physical integrity and uniform appearance. Researchers observed no leakage, deformation, or shell defects throughout the study.

The applied banding solution effectively sealed the capsule junction, preventing liquid migration and ensuring containment of the liquid-filled compartment. These results confirm the suitability of the banding process for maintaining product quality, capsule integrity, and formulation stability within the dual-capsule system (see Figure 1).

Weight variation test. Fill-weight measurements were performed in accordance with General Chapter <905>³ requirements. All tested dual-capsule units complied with the established ±5% specification, demonstrating acceptable weight variation and uniformity. The results indicate that both capsule designs can be filled reproducibly, with consistent dosage delivery and adequate process control. This level of fill weight consistency supports the manufacturability and scalability of the dual-capsule system (see Figure 2).

Disintegration testing. Researchers performed disintegration testing in accordance with USP requirements for filled capsules. Both dual-capsule configurations exhibited complete disintegration within 30 minutes per USP specifications. The results indicate that the dual-capsule architecture did not hinder capsule shell hydration, rupture, or release of the encapsulated contents. Furthermore, the rapid and consistent disintegration observed across both designs demonstrates the suitability of the system for multi-compartment oral delivery while maintaining compendial performance standards (see Figure 3).

Dissolution testing. Dissolution testing confirmed successful release of Ginger granules at the specified time intervals. Results support the feasibility of incorporating granule formulations within the dual-capsule delivery platform while maintaining the intended release profile (see Figure 4).

Conclusion

The results of this study demonstrate that the dual-capsule delivery system is a robust, scalable, and versatile oral delivery platform capable of successfully incorporating multiple dosage forms within a single unit while maintaining acceptable performance characteristics. Complete disintegration within 30 minutes confirmed the effective release of both capsule compartments, demonstrating that liquid and solid formulations can be combined within a single dosage form without compromising functionality or release performance.

Among the capsule materials evaluated, HPMC capsules provided more consistent disintegration behavior, improved structural integrity, and greater reliability within the dual-capsule configuration compared with gelatin capsules. These attributes support the suitability of HPMC capsules for advanced multi-compartment delivery applications where formulation stability and reproducible performance are critical.

Overall, the study confirms that dual-capsule technology is a practical, manufacturable, and automation-compatible platform for delivering multiple dosage forms within a single unit. The system has potential pharmaceutical and nutraceutical applications by enabling the separation and targeted delivery of incompatible ingredients, acid-sensitive compounds, oxidation-prone actives, poorly soluble APIs, probiotics, enzymes, oils, and botanical extracts. The platform enhances formulation flexibility, product stability, patient convenience, and opportunities for the development of next-generation combination products.

The primary regulatory focus for dual capsule supplements is demonstrating product quality, stability, ingredient compatibility, manufacturing control, and substantiation of any release-profile or bioavailability claims. While dual capsule products are regulated as dietary supplements under the same framework as conventional capsules, their more complex design requires additional scientific and quality documentation to support product performance and shelf-life claims.

Study limitations. Although the dual-capsule system demonstrated successful incorporation of liquid and solid dosage forms with acceptable disintegration performance, further studies are required to assess long-term stability, dissolution characteristics, inter-compartment compatibility, moisture migration, and large-scale manufacturing robustness. In addition, the increased capsule size and manufacturing complexity may present challenges for certain applications and require optimization for commercial implementation.

These limitations do not diminish the platform's value; rather, they identify key development areas necessary to advance dual-capsule technology toward commercial pharmaceutical and nutraceutical products.

References

1. Bron PA, Catalayud, M, Marzorati M, Pane M, Kartal E, Dhir R, Reid G. Delivery of metabolically neuroactive probiotics to the human gut. International Journal of Molecular Sciences. 2021 Aug 24;22(17):9122 doi: 10.3390/ijms22179122. [pmc.ncbi.nlm.nih.gov]
2. Azari E K, Govaert M, Duysburgh C, Glab S, Marzorati M, Saiyed Z. Evaluation of targeted-release capsule formulations for protection of the acid-sensitive enzyme pancreatin under fasted and fed intestinal conditions in vitro. Pharmaceutics 2026, 18(3), 285. doi: 10.3390/pharmaceutics18030285
3. USP.<905> Uniformity of dosage units. USP-NF. 2021.
4. USP. <701> Disintegration. USP-NF. 2025
5. General Chapter <711> Dissolution. USP-NF. 2011.

About the Authors

Erin Burke, PhD, is North America technical director for Solution Centers at Univar Solutions. She leads technical teams responsible for formulation development, innovation, customer collaboration, and application testing across multiple market segments. Dr. Burke works closely with suppliers and customers to accelerate commercialization of new ingredient technologies and develop market-relevant solutions that address evolving industry and consumer needs.

Usha Chowdhury is the pharma technical services manager at Univar Solutions' Houston Solution Center, leading pharmaceutical and nutraceutical formulation innovation in health, wellness, and nutrition. With over 25 years of experience across academia, biotechnology, pharmaceuticals, and nutraceuticals, she has held scientific leadership roles at Thermo Fisher Scientific, Reckitt, and Texas A&M University College of Medicine. Under her leadership, innovation projects from the Houston Solution Center have been presented at leading industry conferences, including AAPS and Excipient World, demonstrating the team's commitment to advancing formulation science and customer-focused innovation.

Jyothi Gautam is senior manager technical sales and works closely with distributors, brand owners and manufacturers and is responsible for providing technical, regulatory and commercial support.