By Ann Newman and Robert Wenslow
The solid form of a compound can encompass a variety of materials, including crystalline (polymorphs, hydrates, solvates, salts, and co-crystals) and amorphous (amorphous materials and amorphous solid dispersions), as shown in the figure. It is important to realize that the solid form present in a formulation will determine a number of important properties including dissolution rate, solubility, and bioavailability, all of which are key to producing a successful formulation in early- or late-stage development. This is especially the case for solid oral dosage formulations. Therefore, it is often recommended to monitor and control the API solid form in both drug substance and drug product in order to ensure consistent biopharmaceutical properties throughout a drug development program.
What happens when the solid form changes during development? The most famous case is ritonavir, where a new crystalline form with significantly lower solubility was found in a marketed soft gel formulation that had been on the market for two years. This resulted in the product being removed from the market while it could be reformulated with the new crystalline material. It is estimated that hundreds of millions of dollars were spent to fix the problem with a loss in revenue of at least $250 million. It is also likely that every large pharmaceutical company has a story like this. But form changes can happen at any point during the development process.
How do you prevent situations like this from happening? By understanding the solid form options and selecting the best form. This involves screening, property determination, and understanding any process related transformations that may occur during development. While changing the solid form in early development is relatively easy, a change in late development or after marketing can be time and cost intensive.
We collected some “good, bad, and ugly” scenarios with respect to API solid form changes in the pharmaceutical industry, to help scientists understand the importance of solid-state throughout the development process. Specific case studies were chosen to outline the impact of API solid form changes brought about by: (1) choosing a non-ideal salt form for early preclinical development; (2) relaxed due-diligence for a “fast-tracked” compound; (3) a serendipitous late stage form change; (4) lack of attention to solid form for an in-licensed compound; and (5) a less than bullet-proof intellectual property (IP) landscape surrounding an innovator molecule.
It is important to understand that adequate attention to API solid form during development will aid in managing risk for a program. Whether you are an innovator company looking to out-license your gold molecule as a platinum package, an innovator company looking to bring a drug to market with a strong patent landscape, or a generic company looking to enter the market with your own IP for the molecule, it should be clear from the case studies presented, that API solid form is an important aspect of any development program.