The Role of Coatings and Plasticizers Compatibility in Stability of Advanced Gastro-resistant Self-emulsifying Pellets Designed for the Delivery of Volatile Compounds: A Combined Solid-State NMR and Dissolution Study

The gastro-resistant behaviour of solid self-emulsifying drug delivery systems (S-SEDDS) represents a significant and innovative advancement in delivering poorly soluble drugs. Due to the complexity of these systems and the liquid nature of SEDDS, thorough investigation is essential. This study explored the stability of self-emulsifying (SE) pellets containing the volatile compound thymol coated with gastro-resistant Eudragit® L 30 D-55 water dispersion. The SE pellet cores, composed of Neusilin® US2 with adsorbed SEDDS (thymol, triacylglycerol, Labrasol®, and propylene glycol), microcrystalline cellulose, and chitosan, were prepared using the extrusion/spheronization method and demonstrated optimal technological properties.

Highlights:

Eudragit® L/triethyl citrate coating incompatible with self-emulsifying system

Incompatibility independent of triethyl citrate’s concentration

Solid-state NMR revealed triethyl citrate’s solid-to-liquid transition

Small lipophilic molecules enhance plasticizing effect

Ethylcellulose subcoat delays incompatibility onset

The 6-month stability of three coating compositions, differing in thickness and triethyl citrate (TEC) concentration in the Eudragit® L topcoat, or the application of an ethylcellulose (EC, Surelease®) sub-coat, was investigated using the combined in vitro dissolution testing and solid-state nuclear magnetic resonance (ss-NMR) for detailed structural characterization. The dissolution data of samples with Eudragit® L topcoat data showed an acceleration of thymol release in acidic conditions, preventing the SE pellets from achieving gastro-resistance. The ss-NMR analysis revealed an incompatibility between TEC and SEDDS (specifically propylene glycol), identified as a TEC phase transition to a liquid phase independent of TEC concentration. Additionally, ss-NMR analysis revealed that neat thymol negatively affected coating layer stability by promoting the plasticization of Eudragit® L.

The inclusion of a 10% Surelease® sub-coat yielded positive results, maintaining the gastro-resistant properties of SE pellets stored under 25 °C/60% RH for 6 months. However, ss-NMR analysis confirmed ongoing TEC liquefaction after 3 and 6 months, indicating that the oleic acid and triglycerides in Surelease® as plasticizers contributed to this instability. Therefore, this formulation cannot be deemed stable, and using Surelease® as a sub-layer is only a temporary solution. Overall, while plasticizers are commonly used in pharmaceutical technology, they can introduce significant problems in S-SEDDS development, and their use in sub- or topcoats should be carefully considered or avoided. At the same time, it became evident that in-vitro dissolution testing alone cannot capture the slow processes and interactions occurring within the internal structure of these systems.

Materials

The active substances thymol (a volatile API model for SEDDS) and caffeine (a model non-volatile hydrophilic API; vapour pressure 7.3 × 10⁻⁹ Pa at 25 °C, melting point of 235-237 °C [36], [37]) were purchased from Sigma Aldrich (Taufkirchen, DE). Medium-chain triglycerides – triglyceridi media (TGM; Fagron, CZ), caprylocaproyl polyoxyl-8 glycerides – Labrasol® (LAB; Gattefosse SAS, FR), and propylene glycol (PG; Dr. Kulich Pharma, CZ) were used as starting materials for a liquid SEDDS. Eudragit® L 30 D-55 and Neusilin® US2.

Jan Macku, Jakub Vyslouzil, Jan Muselik, Miroslava Pavelkova, David Vetchy, Daniela Hlavata, Miroslav Slouf, Martina Urbanova, Jiri Brus, Katerina Kubova, The Role of Coatings and Plasticizers Compatibility in Stability of Advanced Gastro-resistant Self-emulsifying Pellets Designed for the Delivery of Volatile Compounds: A Combined Solid-State NMR and Dissolution Study, Journal of Drug Delivery Science and Technology, 2024, 106325, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2024.106325.