In this article, the theoretical foundation for salts is given with an emphasis on the amount of drug in solution. Consideration is given for the solubility of the non-ionized form, acid dissociation constant and solu...In this article, the theoretical foundation for salts is given with an emphasis on the amount of drug in solution. Consideration is given for the solubility of the non-ionized form, acid dissociation constant and solubility product, which are the limiting constraints. For dissolution of nonionized drugs, the surface pH differs from the bulk pH, giving rise to a lower than expected rate. For salts, theoretical considerations are relatively complex, and an experimental approach to estimating the surface pH is more likely to be of value in predicting the dissolution rate. General guidelines are described for screening, preparing and characterizing drugs as salts, which critically depend on the goal of the product development.Thereafter, our work involving the preparation of salts as a means to generate aerosols from a solution is provided. The solubility of six structurally related compounds was determined in four acids. Thereafter, the amount of the compound in solution was determined as a function of pH, using the acid that provided the highest solubility. Because the pH required to achieve the needed concentration for aerosol generation was low, ammonia vapor was introduced into the air stream to neutralize aerosol droplets. Solvent was then removed from the aerosol by a silica column. The resulting aerosol had a concentration of 96 μg/l and a mass median particle size of 1.8 μm. The reported pharmacokinetic study substantiated the feasibility of evaluating its safety and efficacy of inhalation administration in the rat model.展开更多
文摘In this article, the theoretical foundation for salts is given with an emphasis on the amount of drug in solution. Consideration is given for the solubility of the non-ionized form, acid dissociation constant and solubility product, which are the limiting constraints. For dissolution of nonionized drugs, the surface pH differs from the bulk pH, giving rise to a lower than expected rate. For salts, theoretical considerations are relatively complex, and an experimental approach to estimating the surface pH is more likely to be of value in predicting the dissolution rate. General guidelines are described for screening, preparing and characterizing drugs as salts, which critically depend on the goal of the product development.Thereafter, our work involving the preparation of salts as a means to generate aerosols from a solution is provided. The solubility of six structurally related compounds was determined in four acids. Thereafter, the amount of the compound in solution was determined as a function of pH, using the acid that provided the highest solubility. Because the pH required to achieve the needed concentration for aerosol generation was low, ammonia vapor was introduced into the air stream to neutralize aerosol droplets. Solvent was then removed from the aerosol by a silica column. The resulting aerosol had a concentration of 96 μg/l and a mass median particle size of 1.8 μm. The reported pharmacokinetic study substantiated the feasibility of evaluating its safety and efficacy of inhalation administration in the rat model.
