Ionised drugs solubility

Partition coefficient of the un-ionised drug The compound is highly water soluble and cannot be extracted to any great extent into an organic solvent since it is ionised to some extent at all pH values. 

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.

Generally it is only the non-dissociated or unionised drug that is lipid-soluble and a drug s degree of ionisation depends on its dissociation constant (pA) and the pH of the environment in which it finds itself. For an acidic drug this is represented by the Henderson Hasselbalch equation as... 

Partition coefficient Octanol/water ca 70. The drug does not ionise so that the partition coefficient is unaffected by pH. Despite being neutral compound the hydroxyl groups in prednisolone give it a water solubility of ca 0.5 mg/ml. Closely related compounds dexamethasone, betamethasone, triamcinolone, hydrocortisone, betamethasone valerate, betamethasone dipropionate. 

The ability of a drug to penetrate cell membranes is determined by its chemical structure and its physicochemical properties, in particular the degree of ionisation, protein binding and lipid affinity. Lipid-soluble drugs diffuse easily across membranes, whereas water-soluble ones pass through at slower rates. 

Drugs cross biological membranes most readily in the unionised state. The unionised drug is 1000-10000 times more lipid-soluble than the ionised form and thus is able to penetrate the cell membrane more easily. Chemical compounds in solution are acids, bases or neutral. The Bronsted-Lowry definition of an acid is a species that donates protons (H+ ions) while bases are proton acceptors. Strong acids and bases in solution dissociate almost completely into their conjugate base and H+. Weak acids and weak bases do not completely dissociate in solution, and exist in both ionised and unionised states. Most drugs are either weak acids or weak bases. For an acid, dissociation in solution is represented by ... 

Extracellular pH and pKa of the drug Although lipid solubility facilitates diffusion of IV anaesthetics across cellular membranes, only the non-ionised form is able to cross these membranes. The ratio of the non-ionised to ionised fraction depends on the pKa of the drug and the pH of the body fluids (see Chapter 2). 

The coexistence of lipid and water solubility in the same molecule is essential for the action of a local anaesthetic drug. Lipophilicity permits the migration of drug across the phospholipid membrane of the nerve cell hydrophilicity is essential for the ionisation of the drug within the nerve. It follows that lipid and water solubility are the external and internal facilitators of local anaesthetic action in the nerve cell. Both within and without the nerve cell the unionised and ionised forms coexist in dynamic equilibrium. Outside the nerve, the active species is the unionised tertiary amine form. Conversely, inside the cell the ionised form predominates. The lower intracellular pH induces a shift in the equilibrium in favour of ionisation (Figure 5.5). 

Another important physicochemical parameter is the pKa, which describes the ionisation state of a compound at a given pH. The ionisation state of a compound in the different components of the gastro intestinal system (stomach, jejunum, ileum and colon) is crucial for the understanding of drug absorption (Dressman). Ionised compounds generally have better solubility, but passive permeation through the membrane is limited (Comer). 

Many drugs are weak electrolytes, i.e. their structural groups ionise to a greater or lesser extent, according to environmental pH. Most such molecules are present partly in the ionised and partly in the unionised state. The degree of ionisation influences lipid-solubility (and hence diffusibility) and so affects absorption, distribution and elimination. 

These include digoxin and steroid hormones such as prednisolone. Effectively lacking any ionisable groups, they are unaffected by environmental pH, are lipid-soluble and so diffuse readily across tissue boundaries. These drugs are also referred to as nonpolar. 

By manipulation of the pH of the glomerular filtrate, a drug can be made to ionise, become less lipid-soluble, remain in the renal tubular fluid, and so be eliminated in the urine (see p. 97). Maintenance of a good urine flow (e.g. 100 ml/h) helps this process but it is the alteration of tubular fluid pH that is all important. The practice of forcing... 

If we represent the drug as HA and the total samration solubility of the dmg as S, and if Sq is the solubility of the undissociated species HA, it is clear that the total solubility is the sum of the solubility of the unionised and ionised species, that is... 

If, in the first instance, the plasma membrane is considered to be a strip of lipoidal material, homogeneous in nature and with a defined thickness, one must assume that only lipid-soluble agents will pass across this barrier. As most dmgs are weak electrolytes it is to be expected that the unionised form (U) of either acids or bases, the lipid-soluble species, will diffuse across the membrane, while the ionised forms (1) will be rejected. This is the basis of the pH-partition hypothesis in which the pH dependence of drug absorption and solute transport across membranes is considered. The equations of Chapters 3 and 5 are relevant here. 

In case this sounds too much like an advert for the partition coefficient, in reality the simple relationship above only applies if the solute in question does not ionise at the pH of measurement. If the solute is a weak acid or weak base (and a huge number of drugs are), then ionisation to form an anion or a cation will considerably alter the solubility profile of the drug. A fully ionised species will be much more soluble in water than the unionised acid or base, and so the above ratio will vary depending on the pH at which the measurement was carried out. 

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