Ionisation of drugs in solution

With a solution of a dmg, it is not of course possible to alter the dmg concentration in this manner, and an adjusting substance must be added to achieve isotonicity. The quantity of adjusting substance can be calculated as shown in Box 3.7 

Similarly, if w is the weight in grams of adjusting substance to be added to lOOcm of drug solution to achieve isotonicity, then 

Calculate the amount of sodium chloride which should be added to 50 cm of a 0.5% w/v solution of lidocaine hydrochloride to make a solution isotonic with blood semm. 

From reference lists, the values of b for sodium chloride and lidocaine hydrochloride are 0.576°C and 0.130°C, respectively. 

Therefore, the weight of sodium chloride to be added to 50 cm of solution is 0.395 g. 

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Thus the mobility of an ion can be influenced by its pFa value the more it is ionised the greater its mobility and its molecular shape in solution. Since its degree of ionisation may have a bearing on its shape in solution, it can be seen that the behaviour of analytes in solution has the potential to be complex. For many drugs... 

Automated in-tube solid-phase microextraction (SPME) has recently been coupled with liquid chromatography/electrospray ionisation mass spectrometry (LC/ESI-MS), e. g. for the determination of drugs in urine [60, 62]. In-tube SPME is an extraction technique in which analytes are extracted from the sample directly into an open tubular capillary by repeated draw/eject cycles of sample solution. The analyte is then desorbed with methanol and transferred to an analytical HPLC-column. 

It was postulated that the aqueous pores are available to all molecular species, both ionic and non-ionic, while the lipoidal pathway is accessible only to un-ionised species. In addition, Ho and co-workers introduced the concept of the aqueous boundary layer (ABL) [9, 10], The ABL is considered a stagnant water layer adjacent to the apical membrane surface that is created by incomplete mixing of luminal contents near the intestinal cell surface. The influence of drug structure on permeability in these domains will be different for example ABL permeability (Paq) is inversely related to solute size, whereas membrane permeability (Pm) is dependent on both size and charge. Using this model, the apparent permeability coefficient (Papp) through the biomembrane may therefore be expressed as a function of the resistance of the ABL and... 

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 ... 

Alkalinisation of local anaesthetic solution with sodium bicarbonate (NaHC03) increases the pH of the solution to a value near its pKa. This results in an increased proportion of unionised drug available for neural penetration and thereby reduces the onset time. Carbonation is a term used to describe the acidification of a local anaesthetic solution with carbon dioxide. Following injection, the carbon dioxide diffuses into the axoplasm causing a decrease in the pH. This results in a higher proportion of ionised drug within the cell. In theory this should enhance the Na-i- channel block but in practice the results are disappointing. 

We have considered above the effect on the ionisation of a dmg of buffering the solution at given pH values. When these weakly acidic or basic drugs are dissolved in water they will, of course, develop a pH value in their own right. In this section we examine how the pH of dmg solutions of known concentration can be simply calculated from a knowledge of the plC, of the dmg. We will consider the way in which one of these expressions may be derived from the expression for the ionisation in solution the derivation of the other expressions follows a similar route and you may wish to derive these for yourselves. 

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. 

As has been stated before, most of the drugs used in medicine behave in solution as weak acids, weak bases, or sometimes as both weak acids and weak bases. In this chapter we will explore the reasons why drugs behave as acids or bases and what effects ionisation has on the properties of the drug, and develop strategies to separate mixtures of drugs on the basis of changes in their solubility in various solvents. 

Aspirin and other salieylates are acidic compounds that are excreted by the kidney tubules and are ionised in solution. In alkaline solution, much of the drug exists in the ionised form, which is not readily reabsorbed, and therefore is lost in the urine. If the urine is made more acidic (e.g. with ammonium chloride), much more of the drug exists in the un-ionised form, whieh is readily reabsorbed, so that less is lost in the urine and the drug is retained in the body. ... 

When pKa=pH, there will be equal fractions of ionised and unionised drug. This is sometimes used as an alternative definition of pKa, i.e. the pH of a solution in which a substance is 50% ionised and 50% unionised. When pH> pKa the ionised form of weak acids predominates. 

Ambient pH in the extracellular fluid (ECF) is approximately 7.4 but the value varies and this determines the proportions of ionised and unionised local anaesthetic drug. A decrease in ambient pH will increase the amount of ionised drug and reduce the unionised fraction available for transfer across the cell membrane. A common example of this is when infection or inflammation reduces the ambient pH. In the case of lidocaine (lignocaine), a fall in tissue pH from 7.4 to 7.0 will halve the amount of unionised drug. This has obvious implications for efficacy. Similar effects occur following repeated administrations of acidified local anaesthetic solutions. 

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