Limitation solubility enhancement approach

Caco-2 cells have been valuable in the estimation of drug absorption potential, transport mechanisms, and effect of permeation enhancers on transepithelial transport.35,39,53,67-69,78-81 Owing to the sensitivity of the cells and the limited solubility of new molecular entities, Caco-2 permeability studies are routinely done with relatively low concentration of compounds. One way to increase the solubility of these compounds is to use organic solvents. The low tolerability of Caco-2 cells to organic solvents limits the use of this approach in permeability studies. 

Now consider a solubility isotherm at T, slightly less than the UCEP temperature (figure 3.18d). At this temperature, solid-gas equilibria exist at all pressures, since the SLV line is never intersected. As the UCEP pressure is approached the gas phase becomes highly compressible, due to the influence of the vapor-liquid critical point, and the solubility of the solid in the gas phase begins to increase. As the pressure is increased in the immediate vicinity of the UCEP pressure, the T isotherm exhibits a large solubility enhancement. At pressures much higher than the UCEP pressure, the gas is less compressible, therefore the solubility of the solid quickly reaches a limiting value. This solid solubility behavior is similar to the 50°C naphthalene-ethylene isotherm. 

This approach provides a new sensor design and a greater flexibility in the choice of dyes utilized. Therefore, the applicability of fiber optic sensors for analysis should be enhanced dramatic y. However, the polymer-based energy transfer systems stUl suffer fnom several limitations. First, in order to obtain sufficiently small intramolecular distances between donor and acceptor moieties, the prepolymerized concentrations of the dyes must be high. Oftentimes, high dye concentrations are precluded by limited solubility. Second, in polymers, the distance between dyes is only an... 

The solubility of an ionic dye in water normally increases with temperature, since the enhanced mobility favours electrostatic repulsion between ions rather than closer approach to form aggregates by means of the short-range attractive forces. Addition of a simple inorganic electrolyte, on the other hand, normally lowers the solubility limit at a given temperature. Such additions enhance the ionic character of the aqueous phase and help to stabilise the structure of dye aggregates by forming an electrical double layer within the sheath of clustered water molecules around them. 

Frequently, a simple approach of pH adjustment or cosolvent is not enough to achieve the target concentration. Cosolvents are often used in combination with pH adjustment to further enhance the solubility. Using this approach, Lee et al. (2003) observed that nearly 85% of PLzer, Ann Arbor discovery compounds (> 300) submitted for discovery and preclinical injectable formulation development in the year 2000 could be formulated by pH adjustment, cosolvent addition, or a combination of the two approaches. It was also observed that 11% of compounds were not formulatable using this approach, and another32% ofthe formulation used more than 55% cosolvent. The high solvent content can limit the pertinent safety assessment of lead compounds. Therefore, the synergistic combinations of pH adjustment and cosolvent are not sufLcient to develop commercially... 

While employing this approach for enhancing oral bioavailability of poorly soluble drugs, in which drug absorption is dissolution-rate limited, the following considerations must be taken into account ... 

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