Introduction

The drug development process involves a number of activities which are carried out simultaneously, as shown by the oversimplified depiction in Fig. 1. Once a molecule is discovered that has desirable biological activity, the process of creating a pharmaceutical drug product from this molecule begins. As toxicology and efficacy studies are undertaken, methods for manufacture of the active molecule and for its delivery in therapeutic doses are sought. Critical to the latter effort is finding a form of the active molecule which exhibits appropriate physical properties. The form ultimately selected, called the active pharmaceutical ingredient (API), or drug substance, must be stable and bioavailable enough to be formulated into a drug product, such as a tablet or suspension. This formulation must be effective at delivering the active molecule to the targeted biosystem.

This chapter describes methodology useful in selection of the appropriate solid form of a drug substance for inclusion in a drug product. Form selection is commonly considered among the primary goals of a preformulation study. However, the investigative techniques discussed herein also have application in early drug substance and drug product development activities (shown by the circled area in Fig. 1).

Solid form selection involves the preparation and property evaluation of many derivatives of an active molecule. Drug substance properties of importance in the drug development process may be categorized as shown in Table 1. These properties depend on the nature of the drug substance and the final formulation. Many bioactive organic molecules contain ionizable groups such as carboxylic

Fig. 1 The drug development process.

acid or amino groups. Reaction of these compounds with acids or bases produce salts, which have much different physical properties than the neutral parents. A single molecular entity, be it a salt or a neutral molecule, often exists in multiple solid forms, each of which exhibits unique physical properties. The properties of many such forms need to be evaluated relative to the intended formulation. A lyophilized product that will be dissolved and injected needs to be chemically stable in the dry state and adequately soluble in the carrier. On the other hand, the drug substance in a tablet formulation needs to be processable, chemically stable, and physically stable in the dry state, as well as having adequate solubility for delivery.

Form selection activities should be started as early in the development process as material availability allows. Salt selection, including preparation and eval-

Table 1 Some Important Properties of Drug Substances

Bioavailability Chemical and physical stability Processibility

Dissolution rate

Excipient compatibility

Color

Solubility

Hygroscopicity

Compactibility

Toxicity

Oxidative stability

Density

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