Drug solubility cosolvency

Similarly to the solubility of active drugs, the solubility of surfactants that were used in CFC systems has significantly changed. Surfactant solubility in HFA 134a ranges from 0.005% to 0.02% w/v, much lower than the concentration required to stabilize suspensions (0.1-2.0% w/v) (24,42). The surfactants can be solubilized with the addition of cosolvents such as ethanol. However, it is most likely that cosolvents will be incompatible with suspension formulations because drug solubility will also be promoted and crystal growth will occur. 

Jouyban, A., M. R. Majidi, H. Jalilzadeh, and K. Asadpour-Zeynali. 2004. Modeling drug solubility in water-cosolvent mixtures using an arti cial neural netwEdfmaco59 505-512. 

S/v is the solubility in water, and f is the fraction of organic solvent in the cosolvent mixture. If the cosolvent mixture contains more than two organic solvents (i.e., a ternary or higher cosolvent mixture), the total drug solubility can be approximated by a summation of solubilization potentials as... 

Figure 3.7 demonstrates that the total drug solubility of flavopiridol increases exponentially as the volume fraction of the cosolvent (i.e., ethanol) increases. As expected from Equation (3.49e), the solubility lines at the different pHs are parallel to one another. 

Due to the complexity of intermolecular interactions in hydrogen-bonded solutions, such as those used in pharmaceutical applications, no single parameter is capable of quantifying all interactions. Several theories have been developed to estimate drug solubility in cosolvent-water mixtures. The relationships that have resulted from these theories range from relatively simple to complex, depending on the desired accuracy of solubility prediction. Some theories and guidelines... 

Numerous methods have been proposed to predict or describe the effect of a particular cosolvent system ° on drug solubility. A practical cosolvent model was developed by Yalkowsky and coworkers " by assuming the mixed solvent system is a linear combination of the pure components. They found that this approach yields the log-linear relationship... 

The use of multiple cosolvents can be a valuable method for solubilizing a poorly water soluble drug when a dosage form necessitates limits on the amount and type of cosolvent that can be utilized. The effects of multiple cosolvents on solubility can be reasonably approximated by simply expanding Eq. (18) to include a liner addition of cosolvents, i.e.. 

The paper is organized as follows first, an equation for the activity coefficient of a solute at infinite dilution in a binary nonideal mixed solvent (Ruckenstein and Shulgin, 2003) is employed to derive an expression for its solubility in terms of the properties of the mixed solvent. Second, various expressions for the activity coefficients of the cosolvents are inserted into the above equation. Finally, the obtained equations are used to correlate the drug solubilities in binary aqueous mixed solvents and the results are compared with experimental data and other models available in the literature. 

Preformulation for special or novel drug-delivery systems is basically similar to that of the conventional dosage forms. However, there are some items that may be characteristic of the drug delivery system, such as the drug solubility of a propellant cosolvent mixture, the excipients compatibility with the specific drug delivery system, and stability requirements that are different from those of conventional products. These items deserve additional consideration. 

Bryostatin I 2 Tumor necrosis factor-a (TNF-a) Bryostatin lyophilized from butanolic solution with povidone to be dissolved in PEG 400, ethanol, and Tween 80 mixture (PET diluent) followed by dilution in normal saline immediately before administration Lyophilized solution with mannitol and the sugar based amorphous protectant dextran, sucrose, or cyclodextrin in citrate buffer Improved drug solubility with reduced requirement of cosolvents for administration and improved shelf-life of the lyophilized formulation StabiUzation of solution from tendency for dimeric and polymeric self-aggregation, leading to the formation of particulates in solution... 

The solubility of a drug candidate may not always be sufficient for its intended pharmacological purpose, and in such cases the solubility may need to be modified (either increased or decreased). These concerns are especially important for parenterals when the active substance does not exhibit the desired level of solubility. The solubility of a given compound can be profoundly altered in a number of ways, such as through the formation of salt species or drug-substrate complexes, or through the use of surfactants or cosolvents [43], In the majority... 

Drug dissociation constants are experimentally determined by manual or automated potentiometric titration or by spectrophotometric methods.40 Current methods allow determination of pXa values with drug concentrations as low as 10 to 100 pM. For highly insoluble compounds (concentration <1 to 10 pM), the Yesuda-Shedlovsky method41 is commonly used where organic cosolvents (i.e., methanol) are employed to improve solubility. The method takes three or more titrations at different cosolvent concentrations, and the result is then extrapolated to pure aqueous system. The dissociation constant can also be determined with less accuracy from the pH-solubility profile using the following modification of Henderson-Hasselbach equation ... 

Although determination of a complete pH-degradation rate profile is desired, it may not always be practical due to limitations of drug supply and time. Also, insufficient solubility in purely aqueous systems may limit determination of pH-degradation rate profiles. Organic cosolvents may be used to increase solubility however, extrapolation to aqueous conditions must be done with caution. Stability of the drug in a suspended form in the desired buffer can be tested in lieu of solution stability. The stress test results must however, be interpreted in relation to the solubility in the suspension medium. The test may provide an empirical indication of pH stability in the presence of excess water. Satisfactory stability in the GI pH range (1 to 7.5) is important for oral absorption. While there are examples of... 

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