Physical Isolation Strategy in Multi-Layer Self-Nanoemulsifying Pellets: Improving Dissolution and Drug Loading Efficiency of Ramipril

Abstract

Background and Purpose

Liquid self-nanoemulsifying drug delivery systems (SNEDDS) face challenges related to stability, handling, and storage. In particular, lipophilic and unstable drugs, such as ramipril (RMP) and thymoquinone (THQ), face challenges in oral administration due to poor aqueous solubility and chemical instability. This study aimed to develop and optimize multi-layer self-nanoemulsifying pellets (ML-SNEP) to enhance the stability and dissolution of ramipril (RMP) and thymoquinone (THQ).

Highlights

Innovative Approach: The study successfully developed multi-layer self-nanoemulsifying pellets (ML-SNEP) to address stability, handling, and storage challenges in liquid SNEDDS, particularly for lipophilic and unstable drugs like ramipril (RMP) and thymoquinone (THQ).

Enhanced Stability and Dissolution: ML-SNEP demonstrated significant improvements in the stability and dissolution of RMP and THQ, with over 86% release within 60 minutes in in vitro studies.

Optimized Manufacturing Process: The fluid bed coating process was meticulously optimized, achieving high coating recovery (>80%) and excellent mono-pellet percentages (≥97%).

Superior Drug Loading Efficiency: The physical isolation strategy in ML-SNEP led to a substantial increase in RMP loading efficiency, reaching 109%, compared to 55% in single-layer SNEP.

Comprehensive Characterization: The pellets were thoroughly characterized using SEM, DSC, XRD, and in vitro dissolution studies, confirming well-defined layers, RMP amorphization, and high dissolution efficiency.

No Negative Impact from Functional Layers: The addition of moisture sealing and anti-adherent layers did not negatively affect drug release, with SNEP-5L showing enhanced dissolution efficiency for both RMP and THQ.

Methods

Liquid SNEDDS containing RMP and black seed oil (as a natural source of THQ) were prepared and characterized. The fluid-bed coating process was optimized by evaluating critical parameters such as inlet temperature, product temperature, air flow rate, atomizing air pressure, spray rate, and column height. Single-layer (SL-SNEP) and multi-layer (ML-SNEP) self-nanoemulsifying pellets were developed by applying various functional layers onto nonpareil sugar spheres. The pellets were characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and in vitro dissolution studies.

Results

Optimized fluid-bed coating parameters resulted in high coating recovery (>80%) and excellent mono-pellet percentages (≥97%). SEM analysis revealed well-defined, completely solidified layers in ML-SNEP. DSC and XRD studies suggested RMP amorphization. In vitro dissolution studies showed >86% RMP and THQ release within 60 minutes for both SL-SNEP and ML-SNEP. The physical isolation strategy significantly improved drug loading efficiency, with ML-SNEP showing 109% RMP loading efficiency compared to 55% in SL-SNEP. The addition of moisture sealing and anti-adherent layers had no negative impact on drug release, with SNEP-5L (including the anti-adherent layer) showing higher dissolution efficiency for both RMP and THQ.

Conclusion

This study successfully developed and optimized ML-SNEP as a novel approach for enhancing the stability and release of RMP and THQ. The physical isolation strategy was a key approach in enhancing drug loading efficiency while preserving the advantageous dissolution properties of liquid SNEDDS. This approach offers valuable insights for developing advanced oral drug delivery systems for poorly water-soluble and labile drugs

Materials

The materials utilized in this study encompassed a diverse range of compounds sourced from reputable suppliers worldwide. Bioactive Oil (BSO) was extracted through the cold press method, as outlined in our prior work23, from raw seeds. Ramipril (RMP), serving as the model drug, was procured from Jai Radhe Sales (Ahmedabad, India), while thymoquinone (THQ) was obtained from Sigma-Aldrich (St. Louis, MO, USA). Emulsifiers and surfactants, including Imwitor 988 (I988), Imwitor 308 (I308)

Ahmad Abdul-Wahhab Shahba, Abdelrahman Y. Sherif, Ehab M. Elzayat, Shaukat Ali, Mohsin Kazi, Physical Isolation Strategy in Multi-Layer Self-Nanoemulsifying Pellets: Improving Dissolution and Drug Loading Efficiency of Ramipril, Journal of Pharmaceutical Sciences, 2025, ISSN 0022-3549, https://doi.org/10.1016/j.xphs.2025.01.017.