10 Physicochemical Drug

Interactions and Incompatibilities

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 such as:

• pH effects
• change of solvent characteristics on dilution
• cation-anion interactions
• salting-out and salting-in
• chelation
• ion-exchange interactions
• adsorption to excipients and containers
• interactions with plastics
• protein binding.

Equations can be written to describe most of these, but these formulae can be applied
in vivo only as a first-line calculation 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
previous 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 on to
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). The excipient may
sometimes, as in the case of infusions, be the solvent.
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. With the decline in traditional forms of extemporaneous dispensing this
aspect of pharmaceutical incompatibility may have appeared to have decreased some-
what 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, particu-
larly 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

A. T. Florence et al., Physicochemical Principles of Pharmacy

© A. T. Florence and D. Attwood 1998
450 Physicochemical Drug Interactions and Incompatibilities

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 and which when infused
have potentially serious consequences. The mechanism of crystallisation from solution
often involves 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 and therefore a
drug may be compatible with one batch of fluid and not another. The proper application
of the equations relating pH and pKa to solubility discussed in section 5.2.4 should allow
additions to be safely made or to be avoided.

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 I 0.1. 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 per se
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 benzylpenicillin sodium or the
soluble form of an acidic drug whose solubility will be reduced at low pH may not be

Table 10.1 Changes in pH of 5 per cent dextrose (1000 em~ foUowing

drug additions*

Drug Quantity LlpH Final pH

Aminophylline 250mg +4.2 8.5

500mg +4.2 8.5
Cephalothin sodium lg +0.1 4.2
2g +0.2 4.3
Oxytetracycline hydrochloride 500mg -1.25 2.9
lg -1.45 2.7

*From M. Edward. Am. J. Hosp. Pharm. 24, 440 (1967)