High loading of lipophilic compounds in mesoporous silica for improved solubility and dissolution performance

• Published in: International journal of pharmaceutics Vol. 654; p. 123946
• Main Authors: Benedikt Brenner, Marvin, Wüst, Matthias, Kuentz, Martin, Wagner, Karl G.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.04.2024
• Subjects: Bioavailability improvement; Dissolution; Drug loading; Extracts; Mesoporous silica; Solubility enhancement; FID; ASX; DAD; CoQ10; LU; TLC; Drug loading; HS; ACN; Dissolution; Bioavailability improvement; DCM; Extracts; ASD; PB; Solubility enhancement; Rf; Mesoporous silica; Bi - FaSSIF - V2
• ISSN: 0378-5173; 1873-3476; 1873-3476
• DOI: 10.1016/j.ijpharm.2024.123946

[Display omitted] •Loading mesoporous silica is an excellent formulation approach for lipophilic APIs.•Drug loads of up to 50% (w/w) could be achieved.•Even at high drug loads all tested APIs remained in a non-crystalline form.•Solubility and dissolution increased decisively with increasing drug load.•In silico calculations explained performance differences between APIs. Loading poorly soluble active pharmaceutical ingredients (API) into mesoporous silica can enable API stabilization in non-crystalline form, which leads to improved dissolution. This is particularly beneficial for highly lipophilic APIs (log D7.4 > 8) as these drugs often exhibit limited solubility in dispersion forming carrier polymers, resulting in low drug load and reduced solid state stability. To overcome this challenge, we loaded the highly lipophilic natural products coenzyme Q10 (CoQ10) and astaxanthin (ASX), as well as the synthetic APIs probucol (PB) and lumefantrine (LU) into the mesoporous silica carriers Syloid® XDP 3050 and Silsol® 6035. All formulations were physically stable in their non-crystalline form and drug loads of up to 50 % were achieved. At increasing drug loads, a marked increase in equilibrium solubility of the active ingredients in biorelevant medium was detected, leading to improved performance during biorelevant biphasic dissolution studies (BiPHa + ). Particularly the natural products CoQ10 and ASX showed substantial benefits from being loaded into mesoporous carrier particles and clearly outperformed currently available commercial formulations. Performance differences between the model compounds could be explained by in silico calculations of the mixing enthalpy for drug and silica in combination with an experimental chromatographic method to estimate molecular interactions.