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Drug Concentration (% w/v)

Figure 5 Effect of drug loading on zero shear viscosity and particle size of lipid solutions.

increase in the mean emulsion droplet diameter (MEDD) due to droplet coalescence and or aggregation.

Optimal Drug: Surfactant Ratio (Phase Diagram Construction)

The stability, maximum drug loading, and self-emulsifying behavior of a binary nonionic surfactant-oil mixture is dependent on both temperature and surfactant. Pseudo-ternary phase diagrams are useful for identifying the optimum concentrations, or concentration ranges, of oil, surfactant and cosurfactant necessary to form an efficient self-emulsifying formulation. In the absence of water, mixtures of oils, surfactants, and cosurfactants can exist as either clear isotropic solutions or as oily dispersions depending on the characteristics of the individual excipients and the formulation oil-to-surfactant ratio. The self-emulsifying properties of any SEDDS formulation will be influenced by the physicochemical properties of the incorporated drug (e.g., polarity and surface activity) and its concentration. Hence, in the search for a formulation with optimal self-emulsifying properties (as determined by the size of the dispersed lipid droplets), the SEDDS phase diagram should be constructed by varying not only the concentrations of the excipients but also that of the drug. In addition to oil droplet size, an acceptable SEDDS will exhibit the following characteristics:

■ Facile formation of a fine emulsion with a lipid droplet size of less than 5 ^m upon dilution with aqueous media and following mild agitation (11,33).

■ Dispersed oil droplets possess sufficient polarity to promote rapid transfer of drug into the aqueous phase.

Ro 15-0773

Ro 15-0773

Peanut oil Labrafac CM-10

Figure 6 Phase diagram for peanut oil/emulsifier, Labrafac CM-10 BM 287/Ro 15-0778 system. (•) region A: good and efficient self-emulsifying system; (■) region B: poor self-emulsifying system; (♦) region C: intermediate self-emulsifying system.

Peanut oil Labrafac CM-10

Figure 6 Phase diagram for peanut oil/emulsifier, Labrafac CM-10 BM 287/Ro 15-0778 system. (•) region A: good and efficient self-emulsifying system; (■) region B: poor self-emulsifying system; (♦) region C: intermediate self-emulsifying system.

For illustrative purposes, a pseudo-ternary phase diagram for a SEDDS formulation prepared from peanut oil, Labrafac CM-10 (surfactant) and a model drug is presented in Figure 6. Regions describing combinations of drug, surfactant, and oil that produce good, intermediate and poor SEDDS formulations, as defined by the above characteristics, are clearly delineated.

Phase diagrams can be constructed with relatively small quantities of drug and excipients. The test formulations, containing varying concentrations of the drug and excipients are sequentially diluted with water and allowed to equilibrate. The resulting dispersions are next examined with optical microscopy under crossed polar filters to determine lipid droplet size, check for drug precipitation, verify the emulsion isotropic behavior and detect liquid crystalline behavior, which will be indicated by birefringence. The information so gathered is used to construct the phase diagram, which allows determination of the optimal ratios of drug, lipid, surfactant, and cosur-factant to use when developing a SEDDS or SMEDDS formulation.

Hygroscopicity of the Lipid

Hygroscopicity of a lipid excipient may dehydrate hard or soft gelatin capsules resulting in brittleness and fracture of the capsule shell. Moisture sorption isotherms of various excipients that are typically used in lipid based formulations are presented in Figure 7. From the opposite perspective, it is critical to ensure that the formulation can withstand influx of water, when soft gelatin encapsulation is employed, a process, which involves exposure to relatively large amounts of

Percent Relative Humidity

Figure 7 Moisture isotherms of typically used lipid excipients. Abbreviations: HS, hydrox-ystearate; MCM, medium chain monoglyceride; PG, propylene glycol; TPGS, tocopherol polyethylene glycol succinate.

Percent Relative Humidity

Figure 7 Moisture isotherms of typically used lipid excipients. Abbreviations: HS, hydrox-ystearate; MCM, medium chain monoglyceride; PG, propylene glycol; TPGS, tocopherol polyethylene glycol succinate.

moisture as compared to hard gelatin encapsulation. These dynamic changes must be thoroughly investigated in the early stages of development.

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