Conh

O CH3 O

Figure 10.7 The interaction of cloxacillin sodium with promethazine hydrochloride, codeine phosphate and ephedrine hydrochloride.

OCH3 O OH

Codeine phosphate

OCH3 O OH

Codeine phosphate

oh chach3 j

Ephedrine hydrochloride

Figure 10.7 The interaction of cloxacillin sodium with promethazine hydrochloride, codeine phosphate and ephedrine hydrochloride.

Figure 10.8 Representation of an organic ion-pair - the anion is shown here interacting with a cationic molecule of complementary shape (purely schematic) thus masking the exposure of the charge to the aqueous environment.

hydrochloride or gentamicin sulfate. Tables of incompatibilities abound with such examples. Interference with the sulfate groups reduces the anticoagulant activity of heparin. The activity of phenoxymethylpenicillin against Staphylococcus aureus is reduced in the presence of various macromolecules such as acacia, gelatin, sodium alginate and tragacanth. 10 The interaction will not, in each case, be electrostatic in origin but may involve binding through hydrophobic interactions.

Ion-pair formation

Ion-pair formation may be responsible for the absorption of highly charged drugs such as the quaternary ammonium salts and sulfonic acid derivatives, the absorption of which is not explained by the pH-partition hypothesis. 11 Ion pairs may be defined as neutral species formed by electrostatic attraction between oppositely charged ions in solution, which are often sufficiently lipophilic to dissolve in non-aqueous solvents. The formation of an ion pair (Fig. 10.8) results in the 'burying' of charges and alteration to the physical properties of the drug. This is discussed more fully at the end of section 9.1.2. Interactions between charged drug species and appropriate lipophilic ions of opposite charge may constitute a drug interaction and may occur in vitro or in vivo.

both weak electrolytes and nonelectrolytes can occur through salting out, a phenomenon discussed in section 5.2.3.

Sodium sulfadiazine and sulfafurazole diolamine in therapeutic doses (1 mg) added to 5% dextrose and 5% dextrose and saline solution have been found to be compatible, yet when added to commercial polyionic solutions (such as Abbott Ionosol B, Baxter electrolyte No.2) both rapidly form heavy precipitates. pH and temperature are two vital parameters, but the pH effect is not simply a solubility-related phenomenon. Polyionic solutions of a lower initial pH (4.4-4.6) cause crystallisation of sulfafurazole at room temperature within 2.5 h, the pH values of the admixtures being 5.65 and 5.75 respectively. Other solutions with slightly higher initial pH levels (6.1-6.6) formed crystals only after preliminary cooling to 20°C at pH values from 4.25 to 4.90. If the temperature remains constant, the intensity of precipitation varies with the composition and initial pH of the solution used as a vehicle.12

Most physicochemically based drug interactions can take place in the body, or outside it, or during concomitant drug administration, so it is probably not profitable to consider them separately. Some interactions, such as complexation, which are probably more important in vivo than in vitro are discussed in detail below.

10.4 Polyions and drug solutions

The extensive clinical use of polyionic solu tions for intravenous therapy means that drugs are frequently added to systems of a complex ionic nature. Reduction in the solubility of

10.5 Chelation and other forms of complexation

The term chelation (derived from the Greek chele meaning lobster's claw) relates to the interaction between a metal atom or ion and another species, known as the ligand, by which a heteroatomic ring is formed. Chelation changes the physical and chemical characteristics of the metal ion and of the ligand. It is simplest to consider the ligand as the electron-pair donor and the metal the electron-pair acceptor, the donation establishing a coordinate bond. Many chelating agents act in the form of anions which coordinate to a metal ion. For chelation to occur there must be at least two donor atoms capable of binding to the same metal ion, and ring formation must be sterically possible. For example ethylenediamine (1,2-diaminoe thane, NH2CH2CH2NH2) has two donor nitrogens and acts as a bidentate (two-toothed) ligand.13,14 When a drug forms a metal chelate, the solubility and absorption of both drug and metal ion may be affected, and drug chelation can lead to either increased or decreased absorption. While the phenomenon can be useful in analytical procedures, in medicine it can lead to problems such as the binding of tetracyclines (which are chelators) to teeth. Deferiprone (I) chelates iron.

Tetracyclines have similar chelating groups in their structure.15 Therapeutic chelators are used in syndromes where there is metal ion overload. EDTA (ethylenediaminetetraacetic

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