Solid form development :
From milligram to kilogram scale
Susan M . De Paul and Jürgen Rotzler of Solvias discuss how to discover , select and crystallise the optimal solid form
Early-phase drug discovery involves selecting a molecule with the desired chemistry to treat or cure a target indication . However , the multiple ways in which such molecules can self-assemble in the solid state should not be neglected during the drug development process . Different crystal structures of the same API can have different physicochemical properties , so selecting the best solid form is a crucial step in API development . Doing this can increase the bioavailability and shelf life of the API , safeguard IP and decrease costs by creating a robust , efficient , safe and cost-effective crystallisation process . 1
Trade-offs
Finding the best solid form often involves trade-offs . For instance , selecting the thermodynamically most stable polymorph under typical storage conditions has the advantage that , by definition , this form will not be able to transform into another , more stable form . Thus , the shelf life of the drug product will generally be significantly longer than it would have been if a metastable form had been selected . Due to thermodynamics , the most stable solid form at room temperature will also be the least soluble solid form . If the thermodynamically stable polymorph of the API is not sufficiently bioavailable for the indication , kinetic stabilisation of the amorphous form in an amorphous solid dispersion provides a potential route for improving bioavailability , because the high-energy amorphous form will be more soluble than any crystalline form . While this approach is widely used in the pharmaceutical industry , it forgoes the chemical and thermal stability advantages of a crystalline form , along with the corresponding purification . The advantage of crystallinity can often be combined with high bioavailability by not considering the API on its own but also exploring the properties of multicomponent crystals . Two general options for forming crystalline solid complexes are available :
• Salt formation , which involves the reaction of an acidic or basic functional group on the API with a non-toxic basic or acidic salt coformer
• Co-crystal formation , in which a crystalline complex between the API and a pharmaceutically acceptable coformer is generated without complete proton transfer Hydrogen bonds , Van der Waals interactions and pi stacking are among the common electrostatic interactions that are exploited to engineer co-crystals . While the production of a salt or co-crystal adds an additional synthetic step and increases the bulk of the resulting drug product , these apparent disadvantages will be outweighed when the resulting salt or co-crystal is less hygroscopic , is more soluble and / or has better processability than the original API . Measuring the dissociation constants ( pKa values ) of an API will indicate whether salt formation is an option for a given API or whether co-crystals are the only pathway for forming complexes of two solid components . While salts and co-crystals are scientifically similar in that they consist of two molecular species that crystallise together in a stoichiometric ratio within a single lattice ( indeed , some APIs can form both salts and co-crystals or even combined salt – co-crystals with a single coformer ), they are treated quite differently from a regulatory perspective . The FDA currently classifies a co-crystal as essentially another polymorph of the API , while salts are considered new molecular entities . 2 This distinction has important implications for regulatory filings and IP strategies . Indeed , lengthening the lifetime of intellectual property protection can make a multicomponent system attractive even when the solid API itself has suitable properties for development . The best way for a company to find the ultimate solid form is to perform comprehensive screenings on and analyses of the possible solid forms of its drug substance . Figure 1 shows the approach to solid-form development carried out at Solvias . It starts with
34 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981