Physicochemical drug interactions and incompatibilities

10.1 pH effects in vitro and in vivo 395 10.7 Adsorption of drugs 414

10.2 Dilution of mixed solvent systems 401 10.8 Drug interactions with plastics 417

10.3 Cation-anion interactions 402 10.9 Protein binding 419

10.4 Polyions and drug solutions 405 Summary 425

10.5 Chelation and other forms of Appendix 425 complexation 405 References 429

10.6 Other complexes 410 Further reading 430

This chapter deals with some practical consequences of the physical chemistry of drugs -particularly their interactions with each other, with solvents and with excipients in formulations. Sometimes the interaction is beneficial and sometimes not. In reading this chapter you should appreciate that there are several causes of interactions and incompatibilities which include:

pH effects - changes in pH which may lead to precipitation of the drug Change of solvent characteristics on dilution, which may also cause precipitation Cation-anion interactions in which complexes are formed

Salting-out and salting-in - the influence of salts in decreasing or increasing solubility, respectively

Chelation - in which a chelator molecule binds with a metal ion to form a complex Ion-exchange interactions - in which ionised drugs interact with opposites charged resins Adsorption to excipients and containers - causing loss of drug Interactions with plastics - another source of loss of material

Protein binding - through which the free concentration of drugs in vivo is reduced by binding to plasma proteins

Equations can be written to describe most of these interactions, but these formulae can be applied in vivo only to provide an indication of behaviour because of the complexity of the body. Nevertheless, the equations are important to allow some prediction of the magnitude of effects.

The chapter discusses the topic of drug interactions from a physicochemical rather than a pharmacological or pharmacodynamic viewpoint. Many drug interactions in vitro are, not surprisingly, readily explained by resorting to the physical chemistry discussed in earlier chapters of this book. There is no reason why the same forces and phenomena that operate in vitro cannot explain many of the observed interactions that occur in vivo, although of course the interplay of physicochemical forces and physiological conditions makes simple interpretations a little hazardous. Interactions such as protein binding, whether as a result of hydrophobic or electrostatic interactions, adsorption of drugs onto solids, or chelation and complexation, all occur in physiological conditions and are predictable to a large degree, provided that certain assumptions are made. We can also observe interactions between drugs themselves (drug-drug interactions) or interactions between drugs and excipients (drug-excipient interactions).

Drug-drug or drug-excipient interactions can take place before administration of a drug. These may result in precipitation of the drug from solution, loss of potency, or instability. They can occur even in the solid state under some circumstances. With the decline in traditional forms of extemporaneous dispensing, this aspect of pharmaceutical incompatibility may seem to have decreased somewhat in importance, but other forms of extemporaneous preparation occur today. One example is the addition of drugs to intravenous fluids, a practice which should be carried out with pharmaceutical oversight to avoid incompatibilities and instabilities, particularly with new drugs and formulations and during clinical trials.

An incompatibility occurs when one drug is mixed with other drugs or agents producing a product unsuitable for administration either because of some modification of the effect of the active drug, such as increase in toxicity, or because of some physical change, such as decrease in solubility or stability. Some drugs designed to be administered by the intravenous route cannot safely be mixed with all available intravenous fluids. If, as discussed in Chapter 5, the solubility of a drug in a particular infusion fluid is low, crystallisation may occur (sometimes very slowly) when the drug and fluid are mixed. Microcrystals may be formed which are not immediately visible. When infused, these have potentially serious effects. The mechanism of crystallisation from solution will often involve a change in pH; the problem is a real one because the pH of commercially available infusion fluids can vary within a pH range of perhaps 1-2 units. Therefore, a drug may be compatible with one batch of fluid and not another. The proper application of the equations relating pH and p^a to solubility discussed in section 5.2.4 should allow additions of drugs to be safely made or to be avoided.

We now discuss, in turn, pH effects in vitro and in vivo, cation-anion interactions, electrolyte effects, formation of complexes, ion-exchange interactions, adsorption and protein binding.

10.1 pH effects in vitro and in vivo

The pH of a medium, whether in a formulation or in the body, can be a primary determinant of drug behaviour. For convenience we discuss here pH effects in vitro and in vivo separately.

10.1.1 In vitro pH effects

Chemical, as well as physical, instability may result from changes in pH, buffering capacity, salt formation or complexation. Chemical instability may give rise to the formation of inactive or toxic products. Although infusion times are generally not greater than 2 h, chemical changes following a change in pH may occur rapidly. pH changes often follow from the addition of a drug substance or solution to an infusion fluid, as shown in Table 10.1. This increase or decrease in pH may then produce physical or chemical changes in the system.

The titratable acidity or alkalinity of a system may be more important than pH itself in determining compatibility and stability. 1 For example, an autoclaved solution of dextrose may have a pH as low as 4.0, but the titratable acidity in such an unbuffered solution is low, and thus the addition of a drug such as ben-zylpenicillin sodium, or the soluble form of an acidic drug whose solubility will be reduced at low pH, may not be contraindicated. As seen from Table 10.1, the additive may itself change the pH of the solution or solvent to which it is added. As little as 500 mg of ampicillin sodium can raise the pH of 500 cm3 of some fluids to over 8, and carbenicillin or benzylpenicillin may raise the pH of 5% dextrose or dextrose saline to 5.6 or even higher. Both drugs are, however, stable in these conditions.2

The solubility of calcium and phosphate in total parenteral nutrition (TPN) solutions is dependent on the pH of the solution. TPN solutions are, of course, clinically acceptable only when precipitation can be guaranteed not to occur. Dibasic calcium phosphate, for example, is soluble only to the extent of 0.3 g dm 3 whereas monobasic calcium phosphate has a solubility of 18 g dm 3. At low pH the monobasic form predominates, while at higher pH values the dibasic form becomes available to bind with calcium and precipitates tend to form.3

Calcium solubility curves for TPN solutions containing 1.5% (w/v) amino acid and 10% (w/v) dextrose at pH 5.5 are shown in Fig. 10.1. The broken straight lines show the calcium and phosphate concentrations at 3:1 and 2 : 1 ratios. The dotted curve for Aminosyn solutions shows the concentrations at which precipitation occurs after 18 h at 25°C followed by 30 min in a water bath at 37°C. The full curve is for TrophAmine solutions, and represents calcium or phosphate concentrations at which visual or microscopic precipitation or crystallisation occurs. Compositions to the left of the curves represent physically compatible solutions.

10.1.2 In vivo pH effects

The sensitivity of the properties of most drugs to changes in the pH of their environment

Table 10.1 Changes in pH of 5% dextrose (1000 cm3) following addition of three drugsa




Final pH


250 mg


0 0

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