Correction For The Dmso Effect By The Ashift Method

6.5.1 DMSO Binding to the Uncharged Form of a Compound

It was found that the log S/pH curves were altered in the presence of as little as 0.5% v/v DMSO, in that the apparent pKa values, pKapp, derived from log S versus pH [481], were different from the true pKa values by about one log unit. The pKapp values were generally higher than the true pKa values for weak acids (positive shift), and lower than those for weak bases (negative shift). This has been called the ''A shift'' [Avdeef, unpublished]. It is thought to be caused in some cases by DMSO binding to the drugs. Just as the equilibrium model in Section 6.1.3 was expanded to allow for the salt solubility equilibrium, Eq. (6.4), the same can be done with a binding equation based on DMSO (e.g., in 0.5% v/v);

Such a reaction can cause a shift in the apparent ionization constant. It was discovered that the A shift, when subtracted from the logarithm of the apparent (DMSO-distorted) solubility SAPP, yields the true aqueous solubility constant:

where ± includes — for acids and + for bases. For an amphoteric molecule (which has both acid and base functionality) with two pKa values either sign may be used, depending on which of the two values is selected. DMSO makes the compound appear more soluble, but the true aqueous solubility can be determined from the apparent solubility by subtracting the pKa difference. Figure 6.12 illustrates the apparent solubility-pH curve (solid line) and the true aqueous solubility-pH curve (dashed line), correcting for the effect of DMSO for several of the molecules considered.

6.5.2 Uncharged Forms of Compound-Compound Aggregation

Shifts in pKa can also be expected if water-soluble aggregates form from the uncharged monomers. This may be expected with surface-active molecules or molecules such as piroxicam [500]. Consider the case where no DMSO is present, but aggregates form, of the sort mHA ! (HA)m (6.20)

The working assumption is that the aggregates are water soluble, that they effectively make the compound appear more soluble. If ignored, they will lead to erroneous assessment of intrinsic solubility. It can be shown that Eq. (6.19) also applies to the case of aggregation.

6.5.3 Compound-Compound Aggregation of Charged Weak Bases

Consider the case of a weak base, where the protonated, positively charged form self-associates to form aggregates, but the uncharged form does not. This may be the case with phenazopyridine (Fig. 6.12). Phenazopyridine is a base that consistently shows positive shifts in its apparent pKa, the opposite of what's expected of uncharged compound DMSO or aggregation effects. A rationalization of this effect can be based on the formation of partially protonated aggregates (perhaps micelles). Assume that one of the species is (BH+)n.

It can be shown that for such a case, the observed solubility-pH curve is shifted horizontally, not vertically, as with uncharged-compound DMSO/aggregation effects, and that the apparent intrinsic solubility is not affected by the phenomenon.

6.5.4 Ionizable Compound Binding by Nonionizable Excipients

It can be postulated that a number of phenomena, similar to those of reactions in Eqs. (6.17), (6.19), and (6.20), will shift the apparent pKa in a manner of the discussions above. For example, the additives in drug formulations, such as surfactants, bile salts, phospholipids, ion-pair-forming counterions, cyclodextrins, or polymers may make the drug molecule appear more soluble. As long as such excipients do not undergo a change of charge state in the pH range of interest (i.e., the excipients are effectively non-ionizable), and the drug molecule is ionizable in this range, the difference between the apparent pKa, pKapp, and the true pKa will reveal the true aqueous solubility, as if the excipient were not present. Table 6.2 summarizes some of the relationships developed between solubility, pKa, and pKapp.

6.5.5 Results of Aqueous Solubility Determined from D Shifts

Since the pKa values of the compounds studied are reliably known (Table 6.1), it was possible to calculate the A shifts (Table 6.2). These shifts were used to calculate the corrected aqueous intrinsic solubilities S0, also listed in Table 6.2.

TABLE 6.2 True Aqueous Solubility Determined from pKa Shifts of Monoprotic Compounds

Ionizable True Aqueous

Compound Type A = pKAPP-pKa log S0 Examples

TABLE 6.2 True Aqueous Solubility Determined from pKa Shifts of Monoprotic Compounds

Ionizable True Aqueous

Compound Type A = pKAPP-pKa log S0 Examples


A > 0

log SAPP-A

Diclofenac, furosemide,

0 0

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