Submicron-sized oil-in-water emulsions have been clinically used for decades in parenteral nutrition and also as colloidal drug carrier systems for poorly water soluble substances. Colloidal lipid suspensions can principally be prepared by the same manufacturing techniques as lipid emulsions, such as high pressure homogenization. Lipid emulsions used in parenteral nutrition and drug delivery are composed of vegetable oils which are emulsified in an aqueous phase using fractionated egg or soya lecithins as emulsifying agents. Electron microscopic pictures of freeze fractured replica of tripalmitate dispersions display platelet-like particles independent of the emulsifier composition. The physicochemical processes of melt-emulsified tripalmitate dispersions during the cooling step can be directly monitored by polarized light microscopy of crude lecithin/sodium glycocholate stabilized tripalmitate dispersions. Whereas phospholipid stabilized soy bean oil-in-water emulsions generally display a reasonable long-term stability, the corresponding melt-homogenized tripalmitate suspensions tend to form semisolid gels upon cooling of the hot tripalmitate-in-water emulsions.

Submicron-sized triglyceride emulsions are commonly used as a high-calorie source in parenteral nutrition and may also serve as drug carrier systems for the parenteral, even the intravenous administration of lipophilic drugs. Especially an increased viscosity of the supercooled droplets compared to ordinary triglyceride oils would be favorable with respect to drug release. The development of solid lipid nanoparticles revealed the possibility to prepare submicron-sized particles from crystalline material by the melt-homogenization process. Enteral administration of the lipophilic drugs does often lead to bioavailability problems, particularly upon peroral administration, due to low absorption from the gastrointestinal tract. Ubidecarenone nanoparticles can also serve as an alternative carrier system for lipophilic drugs. Colloidal dispersions of melt-homogenized lipophilic substances can display pronounced supercooling which is much higher than in the bulk and may differ considerably from that of microsized emulsions. The chapter discusses the drawbacks and potential of supercooled emulsions for use in drug delivery.

Colloidal dispersions of the pre-equilibrated cubic phase in the monoolein/poloxamer 407/water system, which are under investigation as potential drug carriers, often contain a considerable fraction of undesired non-cubic particles, particularly when prepared with high concentrations of poloxamer. Recent investigations revealed that the non-cubic particles can be transformed into particles of cubic internal structure by heat treatment. The present study investigates the effect of drug loading on the non-cubic to cubic transformation process during autoclaving of the dispersions. The results indicate that the process can also proceed in dispersions loaded with different concentrations of ubidecarenone, tocopheryl acetate, betamethasone-17-valerate, chloramphenicol or miconazole. At low concentration, none of the drugs had pronounced influence on the autoclaved dispersions whereas with increasing drug concentration different effects were observed. Depending on the type of drug no effects (betamethasone-17-valerate), increasing particle size of the dispersions (chloramphenicol, miconazole) or phase separation upon autoclaving (high load of miconazole) was observed. Except for loading with high amounts of chloramphenicol, which led to the formation of cubic phase particles already without additional heat treatment, the properties of the thermally untreated dispersions were virtually unaffected by drug incorporation.

Clomethiazole (CMZ) was used as a model drug to be incorporated into an emulsion vehicle. The effects of drug concentration and number of homogenisation steps were evaluated using multiple linear regression. The droplet size, measured as a z-average diameter by photon correlation spectroscopy (PCS), was found to be between 60 and 260 nm in the investigated range of CMZ concentrations, highly dependent on the concentration, but more weakly so on the number of homogenisation steps. Slow-scanning high-sensitivity differential scanning calorimetry (DSC) measurements showed that CMZ depresses the phospholipid chain melting temperature in the emulsion system, whereas (13)C nuclear magnetic resonance (NMR) experiments suggested that the CMZ molecules are to a large extent located in the surface region of the emulsion droplets. This interpretation is compatible with results from NMR self-diffusion measurements, which showed that most of the CMZ molecules are rapidly exchanged between emulsion droplets and the aqueous surrounding. It can be concluded that the surface-active drug CMZ has a significant influence on the characteristics of phospholipid-stabilised emulsions through its ability to interact with the phospholipid interface. Thus, the results underline the importance of characterising drug-lipid interactions for the development of lipid-based formulations.

The present study describes a novel pharmaceutical formulation of coenzyme Q10, viz. submicron-sized dispersions of the substance prepared by emulsification of molten coenzyme Q10 in an aqueous phase. Photon correlation spectroscopy reveals mean diameters of 60 to 300 nm depending on process parameters. Coenzyme Q10 nanoparticles remain stable on storage for more than 30 months. Lipophilic drugs can be incorporated into the nanoparticles demonstrating their potential use as a drug carrier system. Transmission electron micrographs of freeze-fractured replica show spherical particles with an amorphous core. Cryo-electron microscopy reveals the coexistence of small unilamellar vesicles in phospholipid stabilized dispersions. Thermoanalysis and X-ray studies indicate that the dispersed and emulsified coenzyme Q10 does not recrystallize even at 4°C over 30 months. These agree with 1H NMR data which demonstrate that coenzyme Q10 molecules have a high mobility when formulated as nanoparticles and that colloidally dispersed coenzyme Q10 remains in the state of a supercooled melt. Despite the high melting point of the bulk material, coenzyme Q10 dispersions represent no suspensions but O/W emulsions according to the IUPAC definition (1).

The recrystallization behaviour, the time course of polymorphic transitions, and the degree of crystallinity of melthomogenized glyceride nanoparticle dispersions were investigated by differential scanning calorimetry (DSC). The results suggest that these properties of the nanoparticles are different from those of the glyceride bulk materials. Crystallization of the molten emulsified glycerides tripalmitate and hard fat in the dispersed state occurs about 20 °C lower than in the bulk. The melting temperature of the colloidal crystalline particles is lowered as much as 12 °C. Unambiguous interpretation of DSC thermograms is only possible using the information about the crystalline modification of the glyceride nanoparticles obtained by X-ray diffraction studies. The lower degree of crystallinity of the dispersed lipids compared to bulk materials is reflected in the reduced heat of fusion of the glyceride nanoparticles. The polymorphic transitions are accelerated in glyceride nanoparticles as compared to their bulk materials and the effect depends on the emulsifier and its concentration. The crystallinity index of hard fat nanoparticles is lower than that of tripalmitate nanoparticles. Incorporation of the model drug ubidecarenone into different lipid matrices resulted in a decreased crystallinity as well as in a delayed transition of residual α-polymorphic material into the stable β-polymorph. The latter effect was also observed for incorporation of glycerol monostearate. The DSC results can be explained in terms of the colloidal nature of the dispersions and the influence of foreign compounds such as emulsifiers, drugs and impurities.