Salt formation counterions

The interaction between the adsorbed molecules and a chemical species present in the opposite side of the interface is clearly seen in the effect of the counterion species on the HTMA adsorption. Electrocapillary curves in Fig. 6 show that the interfacial tension at a given potential in the presence of the HTMA ion adsorption depends on the anionic species in the aqueous side of the interface and decreases in the order, F, CP, and Br [40]. By changing the counterions from F to CP or Br, the adsorption free energy of HTMA increase by 1.2 or 4.6 kJmoP. This greater effect of Br ions is in harmony with the results obtained at the air-water interface [43]. We note that this effect of the counterion species from the opposite side of the interface does not necessarily mean the interfacial ion-pair formation, which seems to suppose the presence of salt formation at the boundary layer [44-46]. A thermodynamic criterion of the interfacial ion-pair formation has been discussed in detail [40]. 

In principle, all the curves in Figs. 6.1a, 6.2a, and 6.3a would be expected to have solubility limits imposed by the salt formation. Under conditions of a constant counterion concentration, the effect would be indicated as a point of discontinuity (pA flbbs), followed by a horizontal line of constant solubility. S, -. 

The aqueous solubility of the salt of a drug has also been considered a function of the acid-base strength and aqueous solubility of the counterion employed in the salt formation (Nelson, 1957). As an example, choline itself is considered strongly basic because of the hydroxide counterion,... 

Enzymatic enantioselectivity in organic solvents can be markedly enhanced by temporarily enlarging the substrate via salt formation (Ke, 1999). In addition to its size, the stereochemistry of the counterion can greatly affect the enantioselectivity enhancement (Shin, 2000). In the Pseudomonas cepacia lipase-catalyzed propanolysis of phenylalanine methyl ester (Phe-OMe) in anhydrous acetonitrile, the E value of 5.8 doubled when the Phe-OMe/(S)-mandelate salt was used as a substrate instead of the free ester, and rose sevenfold with (K)-maridelic acid as a Briansted-Lewis acid. Similar effects were observed with other bulky, but not with petite, counterions. The greatest enhancement was afforded by 10-camphorsulfonic acid the E value increased to 18 2 for a salt with its K-enanliomer and jumped to 53 4 for the S. These effects, also observed in other solvents, were explained by means of structure-based molecular modeling of the lipase-bound transition states of the substrate enantiomers and their diastereomeric salts. 

Protonation of the ammonium groups are obtained from the treatment of primary, secondary and tertiary amines with inorganic acids. As the counterion may have a critical role on the stability and biocompatibility of the reagent [85], the selection of the inorganic acid or alkylating reagent used in the salt formation... 

A typical demonstration of the utility of theoretical calculations in the assignment of uncertain signals is reported by Quin et al.30 31 As already found by Bagno,116 the experimental values reported in the literature for S-methyltetrahydrothiophenium salt 1, 750 ppm (referred to CS2), did not fit well with the scaled values, calculated by the B3LYP DFT approach and the EMPI method, which were 87.4 and 121 ppm respectively. With the aid of AIM calculations, it was verified that this discrepancy cannot be ascribed to intermolecular interactions in solution, neither salt formation nor interaction with counterions. The experimental redetermination of chemical shift values has given a value of 95 ppm (ext. ref. CS2), in agreement with calculated values. For S-methylthianium ion 16, a value of 68 ppm has been calculated, compared to an experimental value reported in the literature of 670 ppm.29... 

Solubility is a key determinant of bioavailability, and alteration of solubility by salt formation may be used to improve biopharmaceutical performance. Typical counterions, cations, and anions, used to prepare salts of acidic drugs and basic drugs, are summarized... 

A wide range of potential counterions exists with potential for drug salt formation. However, the actual choice is restricted because of the known or uninvestigated toxicity of many potential counterions. Therefore, consideration must be given to any likely pharmacological and toxicological actions of the counterion. Examples of counterions in use, which have pharmacological actions and potential for toxicity, are lithium, copper, aluminum, calcium, and ammonia. The bromide ion, which has inherent sedative actions also has a 12-day half-life, may accumulate in the body and cause bromism, while iodide can produce iodism. 

TABLE 11.4. Some Counterion Selections for Salt Formation... 

Much of the beneht in solubihty enhancement from salt formation is attributable to the change in solution pH caused by the presence of the counterion. This occurs because the ionization and solubility of acidic drugs (such as barbiturates and non-steroidal anti-inflammatory drugs) increases in basic conditions but decreases in acidic conditions. This behavior is exemplified by derivations of the Henderson-Hasselbalch equations (37.2) and (37.3). The opposite situation occurs for basic drugs such as chlorpromazine, morphine and codeine, which are more soluble in acidic conditions. 

In salt formation from free acid or base, the free acid/base of the drug substance is combined with the base/acid containing the desired counterion in specific molar ratios in a suitable solvent system. There must be adequate solubility of each reactant in the solvent system chosen. The product can be isolated in different ways, often simply by evaporation of the solvent. 

For salt formation by salt exchange, the salt of the drug substance is combined with a salt containing the desired counterion in specific molar ratios in a suitable solvent system. As described above, there must be adequate solubility of each reactant in the solvent system. If the desired salt of the drug substance is less soluble than the starting materials, it will precipitate out and can be isolated by filtration. If no precipitate is obtained, other isolation methods can be employed. A method that was described for iodide salts (19) involved precipitation of the unwanted counterion first. In this case silver salts were used for the counterions (silver sulfate, silver orf/tophosphate, silver lactate) and a silver iodide precipitate was isolated first by filtration. The desired salt of the drug substance was then precipitated from the filtrate by addition of an antisolvent. 

Much less is known about micellar charge and counterion binding in the case of bile salts. Based on the result of ionic self-diffusion measurements [20,163,173], conductance studies [17,18,187], Na, and Ca activity coefficients [16,19,144,188,189] and NMR studies with Na, Rb and Cs [190], a number of generalities can be made. Below the operational CMC, all bile salts behave as fully dissociated 1 1 electrolytes, yet interionic effects between cations and bile salt anions decrease the equivalent conductance of very dilute solutions [17,18,187]. With the onset of micelle formation, counterions become bound to a small degree values at this concentration are about < 0.07-0.13 and are not greatly influenced by the species of monovalent alkali cations [163,190]. At concentrations above the CMC, values remain relatively constant to 100 mM in the case of C and this... 

The UV spectrum of the tetramethyloxazinium salt (3) (counterion AlCU ) in 0.1 M acetic anhydride-AlCl3 complex in dichloromethane shows a maximum absorption at 270 nm (log e 3.92) <85JA5722>. This has been ascribed to the 7t-7t band and was taken as evidence that the cation is an aromatic ring system. UV spectra were earlier taken as evidence for the formation of aromatic oxazinium cations when 3,5-diphenyl-l,2-oxazinone (12) and related oxazinones are alkylated or protonated (Equation (1)) <73ZORi987, 74ZORi5i3>. For example, the UV spectrum of compound... 

DB, double bond X, counterion for salt formation PG, plasma glucose TG, plasma triglyceride. N.A.,... 

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