Ionisation of weak acids

The addition of an ion-pair reagent into the mobile phase slightly decreases the retention of non-ionised molecules, but increases the retention of ions carrying opposite charges. Hence, aqueous-organic mobile phases with the ion-pair reagent should contain also a buffer with the pH adjusted to enhance the ionisation of weak acids (higher pH) or bases (lower pH) to obtain adequate retention. 

Rgure 3.6 Percentage ionisation of weakly acidic and weakly basic drugs as a function of pH. 

Equation (1.2) applies to the ionisation of weak acids, but a similar expression can be derived for weak bases. The equation for the ionisation of a weak base may be expressed as... 

Determination of pK values for the ionisation of weak acids and weak bases, and for the self ionisation of HaOll)... 

The principle of substituent constants may be illustrated by reference to the ionisation of weak acids, represented by Equation (7)... 

The sparingly soluble sulphates (e.g. those of barium, strontium, and lead) also exhibit increased solubility in acids as a consequence of the weakness of the second-stage ionisation of sulphuric acid (K2 = 1.2 x 10 2 mol L1) ... 

Weakly acidic cation exchangers (e.g. polymethylacrylic acid resins). These resins (Zerolit 226, Amberlite 50, etc.) are usually supplied in the hydrogen form. They are readily changed into the sodium form by treatment with 1M sodium hydroxide an increase in volume of 80-100 per cent may be expected. The swelling is reversible and does not appear to cause any damage to the bead structure. Below a pH of about 3.5, the hydrogen form exists almost entirely in the little ionised carboxylic acid form. Exchange with metal ions will occur in solution only when these are associated in solution with anions of weak acids, i.e. pH values above about 4. 

If a weak acid or weak alkali is used (or both are weak), the standard enthalpy of neutralisation is generally less exothermic. This is because heat energy is required to ionise a weak acid or base. 

When pKa=pH, there will be equal fractions of ionised and unionised drug. This is sometimes used as an alternative definition of pKa, i.e. the pH of a solution in which a substance is 50% ionised and 50% unionised. When pH> pKa the ionised form of weak acids predominates. 

The manner in which the S2 unit is eliminated from thiosulphuric acid remains to be considered. Bassett and Durrant point out that when the known weakness of the second stage ionisation of sulphurous acid is considered in conjunction with the known tendency for sulphur to become co-ordinated with four atoms or groups, it would appear that the direct loss of sulphur by thiosulphuric acid is largely due to a hydrogen atom taking the place of the escaping sulphur atom, thus ... 

The absorption spectrum of 0-1N aqueous solutions of arsenious oxide differs from that of aqueous solutions of alkali arsenites.11 This is characteristic of weak acids, the un-ionised molecules of which appear to be capable of absorbing more light than ionised molecules there is little or no difference in the absorption spectrum of a strong acid and its salts. 

Similar to the log D-pH profile, the distribution of the compounds in a chromatographic partition system is also influenced by the pH. Charged species have much shorter retention times than their uncharged parent compounds. Horvath et al. [105 described first the effect of solute ionisation on the retention of weak acids, bases and ampholytes on octadecyl silica, both theoretically and experimentally. They have found a similar equation to Eqs. (12.11) and (12.12) that describes the pH dependence of the isocratic retention factor (A) for weak acids as shown in Eq. (12.1.3) ... 

Ion suppression. By controlling the ionisation of weakly ionic samples they are retained on reversed phase columns for example, a weak acid is retained using a eluent with a pH below the of the acid. But silica-based materials can only normally be used between pH 1.5-7.5 so increased retention for bases cannot usually be obtained in this way. 

Liquid ammonia has a significant dielectric constant (1.49 D) and is an ionising solvent. Through its lone pair, the molecule is a strong proton acceptor, and the hquid facihtates the extensive dissociation of weak acids (p. 200) thus acetic acid is almost as completely dissociated in liquid ammonia as a mineral acid is in water ... 

A buffer solution is a solution that resists changes in pH. If acid is added then, within reason, the pH does not fall if base is added, the pH does not rise. Buffers are usually composed of a mixture of weak acids or weak bases and their salts and function best at a pH equal to the pKa of the acid or base involved in the buffer. The equation that predicts the behaviour of buffers is known as the Henderson-Hasselbalch equation (named after chemists Lawrence Joseph Henderson and Karl Albert Hasselbalch), and is another vitally important equation worth committing to memory. It is derived as follows, by considering a weak acid that ionises in solution ... 

Acetic acid is a weak acid, so its degree of ionisation is very small and the contribution to the total concentration of acetate anions from ionisation of the acid can be ignored. The total salt concentration is therefore 0.1 m from the fully ionised sodium acetate. 

This may be illustrated by some experiments of Fanjung (Zeitsch physik Chem, 14, 673, 1894), who by means of conductivity measurements determined the dissociation constants (the Ostwald constant) for a series of weak acids in aqueous solutions at various piessures It appears to be a general conclusion that the process of ionisation is accompanied by a contraction, or decrease in volume Hence the Le Chatelier-Braun principle (embodied quantitatively in the above expression) predicts that on increasing the pressure the degree of dissociation should increase also, that is the dissociation constant should increase. Fanjung found this to be the case The term Vl - V2 in this case represents the contraction due to the transfer of 1 gram-mole from the unionised to the ionised state For acetic acid at 180 C Fanjung found that... 

THE EFFECT OF DILUTION ON THE FRACnON IONISED FOR WEAK ACIDS 101... 

The effect of dilution on the fraction ionised for weak acids lying roughly in the range pK = 4.0 to 10.0... 

In aqueous solution, the rates of acid-catalysed dehydrations increase more rapidly than the stoicheiometric acid concentration . The gradual decrease in the concentration of water results in a shortage of solvating molecules and a concomitant increase in the activity of the acidic species (e.g. H(H.,0)j — H(H.,0)3— H(H20)2 etc.). Medium acidity has to be measured from the extent of ionisation of weak bases and the pioneer attempts were based on nitroaniline indicators (189). The difference in pK between two such indicators of similar basicity was found to be independent of the acidity of the medium, suggesting the ratio, —log (aH+yA/yAn+) was a property of the medium and not the indicator, being subsequently termed 7/ (190) and regarded as the tendency of the medium to protonate a neutral indicator molecule. 

Fig. 1.4 An excretion interaction. If the tubular filtrate is acidified, most of the molecules of weakly acid drugs (HX) exist in an un-ionised lipid-soluble form and are able to return through the lipid membranes of the tubule cells by simple diffusion. Thus th are retained. In alkaline urine most of the drug molecules exist in an ionised non-lipid soluble form (X). In this form the molecules are unable to diffuse freely through these membranes and are therefore lost in the urine.

Rejection of weak acids and bases is highly pH dependent when ionised, the rejection is high, and low when non-ionised (e.g., boric acid). 

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