The decline in new molecular entity and biologics licensing application approvals by the FDA over the last decade has left drug developers searching for ways of improving their R&D productivity and broadening their development pipelines. Each drug failure represents a significant loss in time and resources spent on candidate development.
Failures in industrialization—the process of developing a laboratory concept into a prototype for IND studies and then a manufacturable product—are a key element in the approval’s decline. There are several challenges in the process of industrializing a candidate molecule, not the least of which is addressing solubility and stability. A molecule’s solid state—the forms it can take when in its solid phase—can have a significant impact on both of these characteristics, and by extension, its bioavailability, toxicity, and efficacy.
High-throughput screens of large chemical libraries, a popular method of identifying candidate molecules, preferentially identify compounds with high molecular weight and poor solubility. Thus, drug developers may end up with dozens of compounds on their laboratory shelves that have promising activity but which are insufficiently soluble and, therefore, insufficiently bioavailable. It is estimated that only 40 percent of the average company’s candidate portfolio has the solubility and bioavailability required to be effective in vivo.
Solubility and stability concerns are exacerbated in part by a failure of the industry to embrace advanced techniques of solid-state chemistry and molecular concepts in product design. Solid-state chemistry, as a discipline, focuses on the synthesis, structure, and properties of solid materials. The information gained through solid-state chemical analyses of candidate molecules can give great insight into their developability and potential for success by allowing researchers and managers to balance each candidate’s physical and chemical characteristics with its pharmacological benefit.
At the same time, investigating alternative solid forms of failed or poorly soluble compounds can provide opportunities to enhance those compounds’ bioavailability and give each a new chance at clinical success.
Different solid forms of the same molecule can vary in solubility by as much as a factor of 106. Knowing this, application of the principles and techniques of solid-state chemistry presents drug developers with a pair of opportunities when launching a development program.