By David Lyon, Ph.D., Senior Fellow, Molly Adam, Lonza R&D Spray Drying Expert, Bioavailability Enhancement, and John Baumann, Director, R&D, Lonza Small Molecules
During drug development, various techniques can be applied to enhance the bioavailability of small molecule drugs, which often face delivery challenges from low solubility. One such approach is using amorphous solid dispersions (ASDs), where the crystalline active pharmaceutical ingredient (API) is converted into an amorphous, high-energy form and combined with a polymer to provide both stability and performance. The process predominantly used for the successful development of ASDs is spray drying. However, this process necessitates the use of large quantities of organic solvent, leading to an increased environmental footprint. Additionally, a substantial number of poorly soluble compounds, also known as "brick-dust" APIs, suffer from poor solubility in organic solvents, further exacerbating the issue through the extra waste and additional utilities required to operate the process for extended periods of time. Low organic solubility of the API results in low overall solids concentration in the spray, presenting additional technical challenges for product collection efficiency or poor flow and compressibility during downstream manufacture of tablets.
One solution commonly employed is the use of harmful solvents that have properties suitable for spray drying, such as dichloromethane (DCM) or tetrahydrofuran (THF) to maximize the API solubility. The toxicity of these types of solvents poses health and environmental concerns. Spray drying with DCM, which is an ozone-depleting gas, has increased in usage over the last several years. In addition to a negative impact on the environment, chlorinated solvents have been observed to participate in a common mechanism(s) of action producing neurotoxicological consequences in humans and animals. The use of uninhibited THF causes additional health and process safety challenges related to peroxide levels during large-scale manufacture.
Download the full article to learn more about how to transition to alternative solvents or leverage process aids that can address the challenges associated with the use of these chemicals, helping create a sustainable, greener footprint for companies focused on a cleaner tomorrow.