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Solubility problems in formulation

1. Mixtures of acidic and basic compounds Sometimes a combination formulation requires the admixture of acidic and basic drugs. One example (Septrin infusion) is discussed here. Because sulfamethoxazole is a weakly acidic substance and trimethoprim is a weakly basic one, for optimal solubility basic and acidic solutions, respectively, are required. In consequence, in an ordinary aqueous solution sulfamethoxazole and trimethoprim demonstrate a high degree of incompatibility and mutual precipitation occurs on mixing. To optimise mutual dissolution, an aqueous solution which includes 40% propylene glycol is utilised in the formulation of the infusion. This solution, which has a pH between 9.5 and 11.0, allows adequate amounts of both substances to coexist in solution to give the correct ratio of concentration for antibacterial action. On dilution, the infusion becomes less stable and at the recommended 1 in 25 dilution stability is about 7 hours. Owing to incompatibility of the two constituents, their degrees of solubility are sensitive to changes in ionic composition, pH and any drug additives. If there is imbalance in pH or ionic composition, then precipitation of one or other of the components may well occur.

2. Choice of drug salt to optimise solubility The choice of a particular salt of a drug for use in formulations may depend on several factors. The solubility of the drug in aqueous media may be markedly dependent on the salt form. The chemical stability rather than the solubility may be a criterion and in many cases this is dependent on the choice of salt, sometimes through a pH effect. Deliberate choice of an insoluble form for use in suspensions is an obvious ploy; the formation of water-soluble entities from poorly soluble acids or bases by the use of hydrophilic counterions is frequently attempted to produce injectable solutions of a drug. Table 5.13 gives some indication of the range of solubilities that can be obtained through the use of different salt forms, in this case of an experimental antimalarial drug.

The large hydrophobic compound XIX, even as its hydrochloride salt, is poorly soluble and this is presumably the reason for its poor oral bioavailability. Similar conclusions were drawn several years ago for novobiocin. The acid salt administered at 12.5 mg kg-1 to dogs was not absorbed, but the monosodium salt, which is about 300 times as soluble in water, produced plasma levels of 22 g cm-3 after 3 hours. Unfortunately, the sodium salt is unstable in solution. An amorphous form of the acid produced even higher levels of drug than the sodium salt, illustrating the fact that choice of salt and crystalline form of a drug substance may be of critical importance. Some of the solubility differences obviously arise from differences in the pH of the salt solutions, which in the case of compound XIX ranged from 2.4 to 5.8 pH units. This is not atypical. The pH of solutions of salts of a 3-oxyl-1,4-benzodiazepine derivative at 5 mg cm_03 ranged from 2.3 for its dihydrochloride, to 4.3 for the maleate, and to 4.8 for the methanesulfonate. Further examples of the solubility range in drug salts and derivatives are shown in Table 5.14. The increase in the solubility on the formation of the hydrochloride is readily attributable in the case of tetracycline to a lowering of the solution pH by the hydrochloride. The common ion effect can, however, produce an unexpected trend in the solubilities of bases in the presence of high concentrations of hydrochloric acid. Increase in Clconcentrations will cause the equilibrium between solid and solution forms:

to be pushed to the left-hand side, with a resultant decrease in solubility. The solubility of XIX as the hydrochloride decreases from 24 x 10-5 mol dm-3 in 1.3 mmol dm-3 chloride ion, to 3 x10-5 mol dm-3 in 40 mmol dm-3 chloride ion concentration. It should be noted that the stomach contents are rich in chloride ions. The common ion effect will be apparent in many infusion fluids to which drugs may be added, and therefore the effect of pH as well as electrolyte concentrations must be considered.

Consideration of Table 5.14 suggests that the hydrochloride salts of tetracyclines are always more readily dissolved than the base. The situation is more complex than at first appears, however. In dilute HCl at pH 1.2, the free base dissolves more than the hydrochloride, probably owing to the differences in crystallinity. The amount of compound derived from the base in solution decreases with time as the drug is converted to the hydrochloride. At pH 1.6 the rate of solution of the two forms is identical, and at pH 2.1 the

hydrochloride has a higher solubility owing to its effect on local pH around the dissolving particles.

Erythromycin is labile at pH values below pH 4, and hence is unstable in the stomach contents. Erythromycin stearate (the salt of the tertiary aliphatic amine and stearic acid), being less soluble, is not as susceptible to degradation. The salt dissociates in the intestine to yield the free base, which is absorbed. There are differences in the absorption behaviour of the erythromycin salts and differences in toxicity, which may be related to their aqueous solubilities. Erythromycin ethylsuccinate was originally developed for paediatric use because its low water solubility and relative tastelessness were suited to paediatric formulations. The soluble lactobionate is used in intravenous infusions.

3. Drug solubility and biological activity There should be a broad correlation between aqueous solubility and indices of biological activity. On the one hand, as drug solubility in aqueous media is inversely related to the solubility of the agent in biological lipid phases, there will be some relationship between pharmacodynamic activity and drug solubility. On the other, we should expect that drug or drug salt solubility might influence the absorption phase; drugs of very low aqueous solubility will dissolve slowly in the gastro-intestinal tract, and in many cases the rate of dissolution is the rate-controlling step in absorption. With drugs of low aqueous solubility such as digoxin, chlorpropamide, indometacin, griseofulvin, and many steroids, the physical properties of the drug can influence biological properties. At early stages in a drugs development, pharmacological and toxicological tests

are frequently carried out on extemporaneously prepared suspensions whose physical characteristics are not always well defined. This is not good practice as the toxicity of some drugs given by gavage to rats is dependent on the drug species used (Table 5.15). This has been shown to be true with polymorphic forms of the same drug, but in the cases discussed in Table 5.15 different salts of the drugs were used.

There are other examples in which aqueous solubility acts as a rough and ready guide to absorption characteristics. Of the cardiotonic glycosides digitoxin, digoxin and ouabain, the least water soluble, being the most lipid soluble, is best absorbed. But because of the lipophilicity of digitoxin and digoxin, the rate-limiting step is the rate of solution, which is influenced directly by the solubility of the compounds. High molecular weight quaternary salts such as bephenium hydroxynaphthoate and pyrvinium embonate, being quaternary, have low lipid solubility but also have low aqueous solubility. They are virtually unabsorbed from the gut and indeed are used in the treatment of worm infestation of the lower bowel.

Source: Florence, A.T., and Attwood, D., 2006, Physicochemical Principles of Pharmacy