Functions of Lipids for Enhancement of Oral Bioavailability of Poorly Water-Soluble Drugs 715 Drug Loading It can affect long-term physical stability of the drug product. As a prerequisite, the saturation concentration of the API in the lipid-based formulation should be carefully established and drug loading has to be optimized in order to avoid potential gelling or drug crystallization under shear stress and/or during storage. Drastic changes in emulsifying properties as indicated by an increasing mean emulsion droplet diameter due coalescence and/or aggregation indicate product instability. Sorption/desorption (hygroscopicity) Isotherm Hygroscopicity of the lipid may induce dehydration of the soft gelatin capsule and hard gelatin capsule shell, resulting in brittleness. Impact of temperature and moisture on the drug solubility characteristics must be investigated. Potential solute migration into the shell must be characterized during the formulation development, particularly when such a drug has good solubility in glycerin and sorbitol, which are commonly used plasticizers in soft gelatin capsules. Shear effect Prolonged shearing was shown to change the rheological behavior of an amorphous drug from Newtonian to pseudoplastic after dissolution in mono- and diglycerides [30]. Changes in the viscous modulus determined by oscillatory measurements indicate formation of structural elements due to presence of hydrogen bonds between drug and the vehicle. These interactions can also be detected by DSC and FT-IR. Moreover, the shear effect was shown to depend on drug concentration. Supersaturated drug solutions are more likely prone to gelation upon shear stress and/or precipitation upon the storage. Lipid Formulations And Oral Bioavailability The simplest approach to evaluate absorption of drugs from lipid-based systems is to prepare a solution or suspension in lipids and do in-vivo assays (see table 4). Tab. 4. Lipid formulations with improved oral bioavailability of API Compound Phenytoin [31] Steroid [32] Lipophilic pro- drugs of phenytoin [33] Antimalarial amine [34] Cinnarizine [35] BA…bioavailability. Study Design BA study in rats after gastric administration Oral BA study in rats BA study in rats after gastric administration Oral BA study in beagle dogs Oral BA study in beagle dogs Formulation Corn oil suspension, corn oil emulsion Solution and suspension in sesame oil Observation and comments BA and Cmax from emulsion> corn oil suspension> aqueous suspension BA from lipid solution 3-fold> aqueous suspension, absorption was a function of solubilised drug Solution in short chain fatty acid, TG BA 4-fold > solution of phenytoin sodium Oleic acid solution Oleic acid solution BA from lipid solution 3-fold > standard capsule BA from lipid solution 4-fold > standard tablet Sci Pharm. 2011; 79: 705–727