Drugs amine ionization

In contrast to tertiary amines, drugs that are quaternary ammonium salts are 100% ionized, not well absorbed from the gut, and, in general, do not have CNS effects. For... 

Drug molecules frequently contain functional groups such as amines and carboxylic acids that are ionized under normal physiological conditions. Typically, these are registered in databases in their neutral forms that are perfectly reasonable when the main objective is efficient retrieval of structures. Representation of tautomers [6, 7], which differ only in bond type and hydrogen atom connectivity, raises similar issues while measurement of the relevant equilibrium constants is significantly more difficult. 

When amino acid ester prodrugs of acetaminophen were prepared (Kovach et al., 1975 Pitman, 1976), the hydrobromide salt of the glycine ester showed enhanced solubility in water, but the hydrochloride salt of th -aspartic acid ester exhibited a solubility lower than that of the parent compound. The enhanced solubility resulted from the formation of a salt, while the parent drug is a weakly acidic phenol and behaves as essentially a neutral molecule in solution. The reduced solubility in the case of th0-aspartic acid ester resulted from ionization of the terminal carboxylic acid, which, with the protonated amine, gives a zwitterionic compound. The zwitterion also behaved as a molecule with an overall neutral character, as is commonly observed with zwitterion behavior in aqueous media, but its larger size resulted in a further reduced solubility. 

Gradients of aqueous and organic mobile phases are typically used for LC-MS/MS analysis of drug compounds and metabolites. The most common aqueous solvents are water with 0.1 % formic acid or 0.1 % acetic acid (v/v) or volatile buffers like 5 mM ammonium-acetate or ammonium-formate. Often adjusted to a certain pH value with the corresponding acid or base (the pH of the eluents will have to be optimized with respect to the polarity of the analytes, since ionic species will have very low or no retention on the reversed pahse LC-columns). Other volatile buffers can be used as well. Phosphate buffers should be avoided, since they will cause suppression of the ionization and thus lead to very bad analytical performance (Venn 2000). Reagents like triethyl-amine should also be avoided as mobile phase or as part of mobile phases. They induce ion suppression as well. In terms of the organic solvents, methanol and acetonitrile are very widely used and they are very well suitable for LC-MS. Other solvents can be used as well, as long as they are compatible with the materials used in the LC-MS system. 

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