Partition coefficients charged compounds

When both the neutral and the n different charged forms of a compound partition into the organic phase, a minimum of n + 1) titrations with different phase volume ratios is necessary to determine the partition coefficient of each species. For a monoprotic substance, for instance, can be related to pK by an empirical equation [119] ... 

The partition coefficient is needed to determine the moles lost to the membrane, VM CM(t). If ionizable compounds are considered, then one must decide on the types of partition coefficient to use -Kp (true pH-independent partition coefficient) or Kd (pH-dependent apparent partition coefficient). If the permeability assay is based on the measurement of the total concentrations, Cn(t) and CA(t), summed over all charge-state forms of the molecule, and only the uncharged molecules transport across the membrane to an appreciable extent, it is necessary to consider the apparent partition (distribution) coefficient, Kd, in order to explain the pH dependence of permeability. 

Derivation of Membrane-Water Partition Coefficients of a Charged or Neutral Compound or Species. 223... 

Our final task in this chapter is to demonstrate how partition constants/coefficients can be used to calculate the equilibrium distribution of a compound i in a given multiphase system. As already pointed out earlier, for simplicity, we consider only neutral species. As we will see in Chapter 8, the equilibrium partitioning of ionogenic compounds (i.e., compounds that are or may also be present as charged species, as, for example, acids or bases) is somewhat more complicated to describe. However, the general approach discussed here is the same. 

However, more important physicochemical properties in terms of ocular bio-availability are the ones that affect the corneal permeability of the active compound. These include the lipophilicity of the drug as reflected by its n-octanol-water partition coefficient [32], the molecular size and shape [33], the charge [34], and the acid-base properties as determined by its pK [35]. 

Bodor and Huang correlated the octanol/water partition coefficient, Po/w (unitless) at 298 K for a set of 302 compounds with a set of 58 descriptors to obtain Eq. [49]. These parameters include seven QM based descriptors that were calculated with the AMI method. The dipole moment is p(D) Qo and Qn are the square roots of the sum of the squares of charges on the O and N atoms, respectively. The parameter Qon is the sum of absolute values of charges on the O and N atoms, and ABSQ is the sum of the absolute values of the charges on all atoms. In addition to these QM descriptors, the surface area, A (A ), and the ovality, O, were calculated from the QM-optimized geometry. The ovality is defined by actual area/area as a sphere, O = A/[4ti(3V/ 4ti) ]. The molecular mass, M, and two indicator variables, Ngik and Nq, for alkanes and carbon atoms, respectively, were also employed. 

Empirical, semiempirical, and ab initio methods have been used extensively to calculate molecular descriptors. These molecular property descriptors help capture important characteristics of compounds such as bioavailability and receptor affinity. Descriptors such as octanol-water partition coefficient (log P), HOMO/LUMO energies, hammett a, total energy, heats of formation, ionization potential, atomic charges, electron densities, dipole/quadrupole moments, volume, and polar surface area are common examples. For an excellent review of physicochemical descriptors, the reader is directed to the following reference. ... 

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