Salt Selection – Reducing Time to Market

Salt selection is a critical part of the drug development process because selection of an appropriate salt can significantly reduce time to market. Salts are used to alter the physical or chemical properties of a drug substance. If the correct salt is selected, subsequent development will be facilitated. In addition, salts that exhibit advantageous properties are usually patentable as new chemical compounds.

The change in crystal structure that can be accomplished by salt formation can lead to greatly improved properties. In many cases, substances containing free acid or base groups have poor aqueous solubility. Saltification of these groups often improves solubility, thus providing greater bioavailability. It is sometimes the case that a salt provides increased chemical or physical stability compared to the parent drug substance. Salts can also provide a means of purification and/or a way to improve the handleability of a drug substance.

However, not all salts will perform equally well. For example, a crystalline, bioavailable salt with few polymorphs is easier to purify, dry, mill, store, and manufacture into a drug product than a hygroscopic, amorphous salt.

Delays in drug development due to improper salt selection can be costly to the public health by delaying drug availability. Unfortunately, rational salt selection is not always practiced. Often the first salt produced at laboratory scale is used for development without further consideration. In other cases, rather than initiating an orderly, sequenced investigation based on the material properties of the drug substance, drug developers may re-use trial-and-error methods based on past experience.

Even when rational selection processes are used, they can be flawed. For example, it is common to estimate salt solubility by mixing solutions of drug and counterion source until precipitation occurs, then choosing the salt based on a solubility criterion. The true equilibrium solubility of a salt can only be determined in the presence of excess solid salt, and the solubility will differ depending on the form of the excess solid (amorphous, crystalline, polymorphic form).

SSCI uses a decision tree approach to salt selection. An example of this is shown in Figure 1. Steps may be removed, added, or performed in a different order as required by each specific situation. Typically, the entire process can be carried out using between a few hundred milligrams and a few grams of drug substance.

saltselectionfig1

In the first step, salts are generated which contain pharmaceutically-acceptable counterions. Target salts are chosen by considering such factors as:

  • structure of the drug substance
  • pKa of the drug substance
  • chemical stability of the drug substance
  • available literature on structurally-related compounds
  • ease of large-scale preparation of the salt
  • type of drug product
  • anticipated loading of the drug substance in the drug product

Hydrated or solvated salts may be targeted in specific instances. Preparation procedures vary with the chemical and physical properties of the drug substance, but typically involve milligram-scale reactions. Products are analyzed for crystallinity and melting point. Low-melting salts may be relegated to lower priority status at this point. Salts that were originally obtained in an amorphous state may be subjected to additional crystallization procedures (such as slurry ripening, vapor diffusion, or trituration) and reanalyzed.

When crystalline salts are obtained, samples are placed under elevated humidity conditions and monitored as solubility determinations are carried out. Salts that deliquesce or absorb excessive amounts of water are considered of lower priority than those that do not. Analyses of these materials after several days of exposure also provide preliminary data related to hydrate formation.

Concurrent with the hygroscopicity studies, the equilibrium solubility of each salt in the appropriate aqueous media is estimated. The pH values of solutions made in water are usually determined and the information retained for later use. Salts exhibiting appropriate solubilities are taken to the next step.

Physical, and, if necessary, chemical stabilities are determined under accelerated conditions. Samples of each salt kept under appropriate conditions are periodically analyzed to ensure that their crystal forms are sufficiently stable. The observance of new crystal forms at this stage may require additional hygroscopicity and solubility studies.

Salts that pass to the final stage are tested for their propensity to exist in polymorphic forms using an abbreviated screen. Of course, data generated in the hygroscopicity, solubility, and stability determinations are also useful. Salts that appear to exist in one stable, crystalline polymorph are considered “final salt candidates” as shown in Figure 1. As the development process proceeds and additional drug substance becomes available, these salt candidates can be prepared in larger quantities for comparison of other properties such as dissolution rate and excipient compatibility.

In a real-world salt selection effort, experimental results do not always allow straightforward adherence to a decision tree such as shown in Figure 1. At SSCI, we have the synthetic, analytical, and physical characterization expertise to tailor selection efforts to meet specific system requirements. We can work with you to make rational salt selection a part of your drug development process.

For more information on SSCI, please see our contacts page.

2019-03-25T15:28:50+00:00
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