Ph

Figure 10 Log D profile of a zwitter ion (base) with pKa = 5.6 and 7.0 for acid and base, respectively.

Log Dmem is then calculated as the log of the ratio of the concentration of the compound in the liposome phase to that of the compound in the aqueous phase.

More recently, computer methods have been devised to calculate these values. The molecule is broken down into fragments of known lipophilicity, and the log P is calculated using various computer routines. Alternatively, there are atom-based methods, and lipophilicity is measured, and calculated log Ps (c log Ps) agreement is reasonably good.

Partitioning Solvent

The choice of the partitioning solvent can have significant effects on the results obtained and also their relevance to biological systems. The most commonly used solvent is octan-1-ol that simulates the phospholipid membrane. To simulate the blood-brain barrier and skin penetration, octanol, chloroform, cyclohexane, and propylene glycol dipelargonate (PGDP) are more suitable. The log P values measured in these solvents show differences principally due to hydrogen bonding effects. Octanol can donate and accept hydrogen bonds making it amphiprotic; cyclohexane is inert; chloroform is a proton donor; and PGDP is an electron acceptor that can only accept them. Despite scores of very good publications and hundreds of studies on the choice of the solvent to be used, the choice remains very fluid. Differences in the log P values between different solvents of solvent mixture systems have often proven useful in QSAR studies. The differences in the partitioning value between PGDP-water and octanol-water or between octanol-water and alkali-water point to differences in hydrogen bonding capacity that affects skin penetration. Compounds with high log P values and low H bonding capacity can readily get past ester/phosphate groups in skin membranes.

Partitioning experiments have been carried out using liposomes, where neutral log P values from liposomes tend to be very similar to those measured in octanol, but the log P values of the ion pair differ. The "surface ion pair" log P is found to be much higher in bases, zwitter ions, and amphophiles. The values for

Log D Profile

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