Drugs Partitioning Between Aqueous Phases And Lipid Biophases

COO~

Structure XXII Pyrvinium embonate low aqueous solubility. They are virtually unabsorbed from the gut and indeed are used in the treatment of worm infestation of the lower bowel.

plastic containers into formulations. It is, therefore, important that the process can be quantified and understood.

5.8 Partitioning

Here we discuss the topic of partitioning of a drug or solute between two immiscible phases. One phase might be blood or water and the other a biomembrane, or an oil or a plastic. As many processes (not least the absorption process) depend on the movement of molecules from one phase to another, it is vital that this topic is mastered. Here we will learn of the simple concepts of the partitioning of drugs and the calculation of partition coefficient (P) of the nonionised form of the solute (and its logarithm, log P), as well as the use of the log P concept in determining the relative activities or toxicities of drugs from a knowledge of log P between an oil, most commonly octanol, and water. Where P cannot be measured, calculations of log P can be accom-plished.14,15 An outline of the methods available is given here.

Drugs, whether in formulations containing more than one phase or in the body, move from one liquid phase to another in ways that depend on their relative concentrations (or chemical potentials) and their affinities for each phase. So a drug will move from the blood into extravascular tissues if it has the appropriate affinity for the cell membrane and the nonblood phase.

The movement of molecules from one phase to another is called partitioning. Examples of the process include:

• Drugs partitioning between aqueous phases and lipid biophases

• Preservative molecules in emulsions partitioning between the aqueous and oil phases

• Antibiotics partitioning into microorganisms

• Drugs and preservative molecules partitioning into the plastic of containers or giving sets

Plasticisers will sometimes partition from

5.8.1 Theoretical background

If two immiscible phases are placed in contact, one containing a solute soluble to some extent in both phases, the solute will distribute itself so that when equilibrium is attained no further net transfer of solute takes place, as then the chemical potential of the solute in one phase is equal to its chemical potential in the other phase. If we think of an aqueous (w) and an organic (o) phase, we can write, according to equations (3.49) and (3.52),

Rearranging equation (5.27) we obtain

RT an

The term on the left hand side of equation (5.28) is constant at a given temperature and pressure, so it follows that aw/ao = constant and, of course ao/aw = constant. These constants are the partition coefficients or distribution coefficients, P. If the solute forms an ideal solution in both solvents, activities can be replaced by concentration, so that

P is therefore a measure of the relative affinities of the solute for an aqueous and a non-aqueous or lipid phase. Unless otherwise stated, P is calculated according to the convention in equation (5.29), where the concentration in the nonaqueous (oily) phase is divided by the concentration in the aqueous phase. The greater the value of P, the higher the lipid solubility of the solute.

It has been shown for several systems that the partition coefficient can be approximated by the solubility of the agent in the organic phase divided by its solubility in the aqueous phase, a useful starting point for estimating relative affinities.

In many systems the ionisation of the solute in one or both phases or the association of the solute in one of the solvents complicates the calculation of partition coefficient. As early as 1891, Nernst stressed the fact that the partition coefficient as a function of concentration would be constant only if a single molecular species was involved. If the solute forms aggregates or otherwise self-associates, the following equilibrium between the two phases 1 and 2 occurs when dimerisation occurs in phase 2:

phase 1

phase 2 phase 2

phase 1

Hence

0 0

Post a comment