Solubility of Poorly Soluble Drugs in Phosphatidylcholine-Based Drug Delivery Systems: Comparison of the Loading Capacity in the Bulk Formulation and Its Dispersed State.

The aim of this study was to determine the drug loading capacity of phosphatidylcholine-based formulations for four poorly water-soluble drug substances (clofazimine, fenofibrate, artemether, cannabidiol). Two self-dispersing lipid formulations were investigated, which consisted of soybean phospholipids, medium-chain triglycerides and ethanol with a different phospholipid-oil ratio. The direct loading of the bulk formulation was conducted with dual centrifugation, which proved to be a suitable method for screening experiments with the highly viscous formulations. To estimate possible precipitation after dispersion in the gastrointestinal fluids, the solubility of the drugs was investigated in the dispersed formulations. For this purpose, nanodispersions were prepared from the bulk formulations via high pressure homogenization and subsequently subjected to passive loading. A newly developed HPLC method with Charged Aerosol Detection allowed a simultaneous evaluation of the content of soybean lecithin and medium-chain triglycerides in the nanodispersions. When comparing the two phosphatidylcholine-based formulations, a high content of oil was advantageous with regard to a high loading capacity. Drug substances with melting points below 150 °C exhibited a high solubility in the phospholipid-based formulations. A surprisingly high solubility was observed for artemether and cannabidiol with up to 13.0% and 33.3% drug loaded to the formulations, respectively. In the dispersions, a similar solubility as in the bulk formulations was obtained for fenofibrate and cannabidiol. Clofazimine yielded a higher loading result in the nanodispersions than in the bulk formulation.

Suitability of phosphatidylcholine-based formulations for liquid filling in hard capsules.

The current study aimed to evaluate whether phosphatidylcholine-based formulations have suitable properties for liquid filling in hard capsules. Liquid or semisolid formulations were obtained with Miglyol 812 (medium chain triglycerides) or Softisan 378 (semisolid hard fat), respectively, in combination with three different phospholipids (Phospholipon 90 G, Lipoid S 75 or Lipoid S LPC 80) and ethanol. Suitability for the filling process was evaluated by rheological characterization and stringing tests. Liquid and semisolid mixtures with Lipoid S 75 or Phospholipon 90 G (also with addition of Lipoid S LPC 80) exhibited appropriate viscosity at the respective filling temperatures. Liquid mixtures with up to 60% Phospholipon 90 G broke cleanly from the needle during filling simulations. A higher fraction of phospholipid led to stringing which could be reduced by addition of ethanol. The hygroscopicity of the formulations was investigated as was their compatibility with different capsule materials with regard to their impact on capsule brittleness and integrity. Gelatin capsules became brittle due to the hygroscopic properties of phosphatidylcholine-based mixtures whereas hydroxypropyl methylcellulose capsules were compatible with a wide range of formulations. After aeration with nitrogen, the formulations exhibited acceptable stability against oxidation.

Self-dispersing formulations for the delivery of poorly soluble drugs - Miscibility of phosphatidylcholines with oils and fats.

The presented study aimed to develop self-dispersing drug delivery systems based on natural phospholipids. A comprehensive investigation on miscibility was therefore carried out on mixtures containing one or two phosphatidylcholines as emulsifying excipients, ethanol 96% as co-solvent and different oils and fats. The soybean diacyl phosphatidylcholines Phospholipon90G and LipoidS75 as well as the monoacyl phosphatidylcholine LipoidSLPC80 were investigated for their maximum incorporation in the different lipids. Homogeneity and stability of the mixtures were determined according to their macroscopic appearance and by polarized light microscopy. Homogeneous formulations could be prepared with all three phosphatidylcholines in combination with medium chain triglycerides and semisolid hard fat. Phospholipon90G and LipoidS75 further yielded homogeneous formulations with rapeseed oil, soybean oil and diacetylated monoglycerides. Small- and wide-angle x-ray scattering studies indicated the presence of reverse micelles or (liquid) crystalline structures in the mixtures. Formulations with oils and Phospholipon90G or LipoidSLPC80 easily dispersed in Simulated Gastric Fluid making these mixtures suitable as self-dispersing formulations.