Atropine Aqueous Cream

Complexation, precipitation or phase separation can occur in these circumstances, the product being affected by changes in ionic strength, temperature and pH. Examples of cation-anion interactions include those between procainamide and phenytoin sodium, procaine and thiopental sodium, and hydroxyzine hydrochloride and benxylpeni-cillin (Scheme 10.1). The nature of many of these interactions has not been studied in detail. In the absence of such work it is necessary to predict possible incompatibilities from a knowledge of the physical properties of the drug and other components in the formulation. Sometimes, however, as when chlor-promazine and morphine injections are mixed, the incompatibility is not due to an interaction between the two drugs but to drug-bactericide interaction, the chlorocresol contained in the morphine injection (prepared by heating with a bactericide) precipitated with the chlorpromazine, possibly by an anion-cation interaction. Nitrofurantoin sodium must be diluted prior to use with 5% dextrose or with sterile water for injection;

alkyl ^-hydroxybenzoates (parabens), phenol or cresol, all of which tend to precipitate the nitrofurantoin, must be absent.

Phase diagrams such as that shown in Fig. 10.6 are useful in determining regions of incompatibility and compatibility in cation-anion mixtures because admixture is not always contraindicated. The example shown here is for mixtures of disodium cromoglicate (DSCG, sodium cromoglicate) - a di-anionic drug - with a cationic surfactant, tetradecyl-dimethylammonium bromide (C14BDAC). As can be seen, the interaction is strongly concentration dependent. In some regions, below the line AB, the two ions coexist. Ion pairs (see below) form in the shaded region below AB. Above this solubility product line, turbidity occurs in the hatched region. On increasing the concentration of surfactant, the complex is solubilised so that the interaction is masked.8

In a study of the incompatibility of organic iodide contrast media and antihistaminic drugs (added to reduce anaphylactic reactions) it was found that the acidity of the antihista-mine solutions used caused the precipitation

Figure 10.6 Phase diagram for mixtures of disodium cromoglicate (DSCG, sodium cromoglicate) and tetradecyldimethy-lammonium bromide (C14BDAC).

Reproduced from reference 8.

Figure 10.6 Phase diagram for mixtures of disodium cromoglicate (DSCG, sodium cromoglicate) and tetradecyldimethy-lammonium bromide (C14BDAC).

Reproduced from reference 8.

of the organic iodide.9 One of the antihistamines, promethazine, reacted strongly with all the contrast media, probably because its solution had the lowest pH of the drugs studied. It is not only with intravenous fluids that such interactions may occur. Examples have been quoted of the inadvisable mixture of syrups; for example, immediate precipitation in a prescribed mixture of a syrup containing cloxacillin sodium (Orbenin) and a syrup (Phensedyl) containing the bases codeine and promethazine. Precipitation was followed by a 20% loss in antibiotic activity in 5 h and 99% loss in 5 days. The double-decomposition reactions involved are likely to be those shown in Fig. 10.7.

Complexes which form are not always fully active. A well-known example is the complex between neomycin sulfate and sodium lauryl sulfate that will form when Aqueous Cream BP is used as a vehicle for neomycin sulfate. Aqueous cream comprises 30% emulsifying ointment, which itself is a mixture of emulsifying wax which contains 10% of sodium lauryl sulfate or a similar anionic surfactant.

Interactions are not always visible. The formation of visible precipitates depends to a large extent on the insolubility of the two combining species in the particular mixture and the size to which the precipitated particles grow. One might assume that in an atropine and phenobarbital mixture, a barbiturate-atropine complex may precipitate. Atropine base is soluble to the extent of 1 part in 460 parts of water. There is only 0.6 mg atropine in a 5 cm3 dose and it is therefore well within its solubility limit. The solubility of phenobarbital is 1 mg cm 3. The 15 mg of phenobarbital sodium (13.5 mg of phenobarbital) which would result if all the sodium salt were to be precipitated would be in excess of its solubility. Only 0.4 mg of phenobarbital is precipitated by 0.6 mg of atropine sulfate, however, and the phenobarbital therefore remains in solution also. There is thus no precipitation.

Interactions between drugs and ionic macro-molecules are another potential source of problems. Heparin sodium and erythromycin lactobionate are contraindicated in admixture, as are heparin sodium and chlorpromazine

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