The solid form of a drug substance has a huge bearing on its formulation as a drug product. In an ideal world, every API would reliably form beautiful, homogeneous crystals in isolation that would be perfect for creating a dosage form with excellent bioavailability. But in the real world, that is unusual. Rather, a significant amount of work is commonly required to bridge the gap between the bulk API that comes out of synthesis and a solid form with all the attributes required by formulation scientists to make a good drug product.
That bridge is provided by experts in solid form services (SFS), who will look for a solid form that meets all the needs of the formulation team, but, crucially, one that can also be scaled up reliably to a commercial scale. This will include its full characterisation, including an assessment of whether it has the solubility and bioavailability properties that are required.
The first step is likely to be a search for the most stable crystal polymorph of the API. Molecules can exist in multiple different crystal forms (see Figure 1). One of these is likely to be more thermodynamically stable than the others, and therefore this is by far the most advisable choice. Going with a metastable polymorph may cause significant problems down the line if it interconverts into another form, leading to batch failure.
If this crystalline form meets all the solubility and bioavailability criteria, this would be ideal. But if it is insufficiently soluble, the next step would likely be the same as it would be were there no stable polymorph – to look for salt or a cocrystal.
Salt would be the simplest option, and more than half of all marketed medicines are sold in salt form, ranging from NSAID Voltaren (diclofenac sodium) to erectile dysfunction med Viagra (sildenafil citrate). If the API has an ionisable group, then it can be paired with a suitable acidic or basic salt former, and the solubility, bioavailability and stability of the resulting salt crystals assessed to see if they are suitable for formulation.
For APIs with no ionisable groups, cocrystals are a viable option. These tend to be more stable than salts, and therefore might also be a good alternative if the salt form’s stability is poor. The difference between salt and a cocrystal is charge transfer: salts are ionic (proton transfer), whereas cocrystals are a combination of two or more neutral species in a crystalline lattice. A small number of cocrystals are already on the market. Exemestane, a drug used in the treatment of early breast cancer in women, is poorly water-soluble. It has been formulated as a maleic acid cocrystal, with a polymer added to the dissolution medium to vastly improve dissolution compared to the parent drug.
Once the search for a lead crystalline form, either polymorph, salt or cocrystal, has been exhausted, whether because one cannot be found or because they do not have the right performance attributes, it may still be possible to formulate for oral delivery. While a crystalline form of a drug is preferable, if one is not available then alternate technologies such as amorphous spray-dried dispersions can be a viable way to make oral formulations.
Working Through the Workflow
The standard workflow for a solid form screen of a drug would start with the extensive characterisation of the API, including assessing its solubility in various solvents, particularly those that are process-relevant and might be used in later stages of development (see Figure 2). With these data in hand, an extensive screen would be run to look for polymorphs, using different methods such as slurry crystallisation, cooling crystallisation and solvent/ antisolvent techniques. It is also common to look for polymorphs at both ambient and higher temperatures. The latter is useful if a higher temperature downstream processing step is likely to be used, as it will assess whether a new polymorph might form on heating. The idea here is to work out whether another polymorph could appear at some point within the process-relevant space to avoid the potential for batch failure.
Extensive characterisation would be carried out on each of these polymorphs, followed by competitive slurry experiments to define the relationships between the different forms, assessing stability and which other polymorphs they have a tendency to convert into if any. Ideally, one would want to progress to the most thermodynamically stable polymorph rather than one that is metastable, as there is a risk that the latter might revert to the former down the line. This is even the case if the metastable form has the right properties for the formulation, and the thermodynamically stable one does not. In this instance, it might be wise to look to an amorphous form instead, or even look to make a salt or cocrystal that might not have similar polymorphism issues.