Solubility ionisation* effect

Smith and Udseth [154] first described SFE-MS in 1983. Direct fluid injection (DFT) mass spectrometry (DFT-MS, DFI-MS/MS) utilises supercritical fluids for solvation and transfer of materials to a mass-spectrometer chemical ionisation (Cl) source. Extraction with scC02 is compatible with a variety of Cl reagents, which allow a sensitive and selective means for ionising the solute classes of interest. If the interfering effects of the sample matrix cannot be overcome by selective ionisation, techniques based on tandem mass spectrometry can be used [7]. In these cases, a cheaper and more attractive alternative is often to perform some form of chromatography between extraction and detection. In SFE-MS, on-line fractionation using pressure can be used to control SCF solubility to a limited extent. The main features of on-line SFE-MS are summarised in Table 7.20. It appears that the direct introduction into a mass spectrometer of analytes dissolved in supercritical fluids without on-line chromatography has not actively been pursued. 

Historically, organic environmental pollutants were hydrophobic, often persistent, neutral compounds. As a consequence, these substances were readily sorbed by particles and soluble in lipids. In modern times, efforts have been made to make xenobiotics more hydrophilic - often by including ionisable substituents. Presumably, these functional groups would render the compound less bioaccumulative. In particular, many pesticides and pharmaceuticals contain acidic or basic functions. However, studies on the fate and effect of organic environmental pollutants focus mainly on the neutral species [1], In the past, uptake into cells and sorption to biological membranes were often assumed to be only dependent on the neutral species. More recent studies that are reviewed in this chapter show that the ionic organic species play a role both for toxic effects and sorption of compounds to membranes. 

The uptake, redistribution and protein binding of methohexitone are somewhat similar to that of thiopentone. Although methohexitone is less lipid soluble than thiopentone, a greater proportion (75%) is non-ionised at body pH and therefore available for pharmacological effect. Hepatic clearance (11 mL-kg-l-min-1) is higher for methohexitone than for thiopentone and the elimination half-life considerably shorter ( 4 hours). While cumulation is less likely to occur with repeated doses, prolongation of anaesthetic effect has been demonstrated when methohexitone was infused for longer than 60 minutes. 

Some local anaesthetics, such as benzocaine, are totally insoluble in water and cannot ionise. Consequently, there is no cation and therefore no Na+ channel block from within the cell. It is suggested that agents, such as benzocaine, which are very lipid-soluble, exert their effect in the phospholipid bilayer of the axon. This is the basis of the membrane expansion theory of local anaesthetic action. It is also possible that they diffuse laterally form the bilayer into the Na+ channel without ever accessing the axoplasm and in effect produce another variety of Na+ channel block. Repetitive depolarisation of a nerve recruits more Na+ channels and maintains them in the open state for a longer period than normal. 

The hydrophilic part of the most effective soluble surfactants (e.g. soaps, synthetic detergents and dyestuffs) is often an ionic group. Ions have a strong affinity for water owing to their electrostatic attraction to the water dipoles and are capable of pulling fairly long hydrocarbon chains into solution with them for example, palmitic acid, which is virtually un-ionised, is insoluble in water, whereas sodium palmitate, which is almost completely ionised, is soluble (especially above its Krafft temperature - see page 93). 

Some of the commonly used techniques for measuring contact angle [215, 216, 217] are the sessile drop method, captive bubble method and Wilhelmy plate method. These techniques have been extensively used and well documented for characterisation of modified PE surfaces [218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230] for various applications. Whitesides et al. [231 ] studied the wetting of flame-treated polyethylene film having ionisable organic acids and bases at the polymer-water interface. The effect of the size of substituted alkyl groups in amide and ester moieties on the surface hydrophilicity was also studied [232]. The biocompatibility of the polyethylene film surface modified with various water-soluble polymers was evaluated using the same technique [233]. The surface properties of hy-perbranched polymers have been very recently reported [234]. 

Consider the effect of pH changes on the disposition of aspirin (acetylsalicylic acid, pKa 3.5). In the stomach aspirin is un-ionised and thus lipid-soluble and diffusible. When aspirin enters the gastric epithelial cells (pH 7.4) it will ionise, become less diffusible and so will localise there. This ion trapping is one mechanism whereby aspirin is concentrated in, and so harms, the gastric mucosa. In the body aspirin is metabolised to salicylic acid (pKa 3.0), which at pH 7.4 is highly ionised and thus remains in the extracellular fluid. Eventually the molecules of salicylic acid in the plasma are filtered by the glomeruli and pass into the tubular... 

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. 

Additives will influence solute-solvent interfacial energies or dissociation of electrolytes through changes in dielectric constant. A reduction in ionisation through a decrease in dielectric constant will favour decreased solubility, but this effect may be counterbalanced by the greater affinity of the undissociated species in the presence of the cosolvent. 

Of the two effects, the solubility effect is usually the stronger. Thus, in the adsorption of hyoscine and atropine on magnesium trisilicate it was noted that hyoscine, although in its completely unionised form, was less strongly adsorbed than atropine, which at the pH of the experiment was 50% ionised. The reason for this apparently anomalous result is clear when the solubilities of the two bases are considered. Hyoscine base is freely soluble (1 in 9.5 parts of water at f5°C) compared with atropine base (f in 400 at 20°C). Even when 50% ionised, atropine is less soluble than hyoscine and consequently is more strongly adsorbed. 

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. 

The internal standard method can compensate for several types of errors that can be caused by sample matrix. Systematic errors due to matrix effects can sometimes be avoided. The internal standard method can also correct for fluctuations in experimental conditions amount of sample analysed, sample introduction, emission source temperature assuming that the signal analyte and internal standard are influenced to the same extent. The main advantage of the internal method over usual calibration methods is that it can provide excellent accuracy and precision and at the same time correct for variable viscosity affects. The method is limited by the availability of a suitable reference element that behaves almost as close to the analyte under test in terms of ionisation energy, solubility, low memory effects, etc. 

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